STJDDEN NATI]RAL DEATII IN INFANCY & EARLY CHILDHOOD

CHAPTER 4

INFE,CTIOUS CONDITIONS 't

204 ì:r

INTRODUCTION ;T

Sudden death is a well recognized sequel to infect¡ons with a wide variety of agents. The outcome of a particular depends on the age of the ¡nfant or child, the v¡rulence of the organism and the immunological status of the host. For example, certain bacteria, such as

Neisseria meningidítis, are capable of producing a fulminant sept¡caemia in previously healthy children with death within hours, whereas Aspergillus sp. is generally only of concern in children who are immunodeficient.

ln spite of the possibility of a lethal outcome from many 'rare' organisms in immunocompromised hosts, this chapter tends to concentrate on more usual clinical syndromes, with only occasional reference to more obscure entities. The format reflects the sequence followed in other chapters with a discussion of based on part¡cular organ systems or mechanisms rather than on specific classes of infectious agents.

ln a review performed by the author of autopsy cases from the Adelaide Children's

Hospital over the past 30 years the most common causes of rapid death were bacterial , airway infections (including epiglottitis), meningitis, septicaemias, viral myocardilis and gastroenter¡t¡s. Table 4-1 lists possible microbiological causes of sudden death in childhood and Appendix l, Chapter 1 1, summarizes the types of mícrobiological specimens that can be taken in the workup of a septic case at'autopsy. 205

TABLE 4.1: TYPES OF INFECTIOUS ILLNESSES ASSOCIATED WITH SUDDEN PAEDIATR¡C

DEATH

1 Cardiovascular 4. Haematological myocarditis rheumatic 5. Gastrointestinal gastroenteritis aort¡tis botulism arteritis primary peritonitis 2 Respiratory hydatid disease retropharyngeal 6 Genitourinary poster¡or lingual abscess pyelonephritis acute epiglottitis 7 Generalized acute laryngotracheobronchitis septicaem¡a bacterial trache¡t¡s viraemia diphtheria endotoxaemia acute bacterial ¡nterst¡t¡al pneumonitis bronchiolitis

CARDIOVASCULAR CONDITIONS

MYOCARDITIS

Myocarditis is a well known cause of sudden and unexpected death in children of all ages and may be found in infants who present with 5¡p941,12a.

Clinical Features t Although some infants and children may have symptoms and signs of heart failure4o, a significant number of cases will have nonspecific clinical features giving no indication of a primary cardiac problem pr¡or to autopsy lvide infral56. ln children a history of exercise_related collapse may suggest myocardial disease and a clinical diagnosis of acute myocardial may have been considered6o. 206

STUDY #4-1

DEMONSTRATION OF THE ASSOCIATION BETWEEN MYOCARDITIS AND SUDDEN

UNEXPECTED DEATH ¡N INFANCY AND CHILDHOOD

INTRODUCTION

Myocarditis is characterised histologically by an inflammatory infiltrate of the myocardium with and/or degeneration of adjacent myocytes, not typical of the ischaemic changes associated with coronary artery diseases. Clinically there may be great variability in symptomatology. To characterise further the clinicopatholog¡cal features of myocarditis found at autopsy in childhood, the following study was undertaken.

MATERIALS AND METHODS

The autopsy files of the Adelaide Children's Hospital from January 1954 to July 199O were reviewed. Data relating to age, sex, clinical presentation, macroscopic description and virological or bacteriological stud¡es were extracted. Histological slides were reviewed and only those cases which fulfilled accepted criteria were retaineds. Between one and 13 blocks

(mean:3.6) were examined per case. Cases where the histological findings were more in keeping with ischaemic damage were excluded. Such findings included confluent areas of coagulative necrosis with a peripheral neutrophil infiltrate, and lesions where the subendocardial myocytes were preserveds.

RESULTS

Thirty-two cases of myocarditis were found out of a total of 4969 autopsies (0.64%). Eight cases which had been called myocarditis originally were discarded as no convincing myocyte necrosis could be demonstrated. The 32 cases were separated into two groups: Group A,

1161321, where myocarditis was an isolated significant finding, and Group B, .16132t', where myocarditis was incidental to other conditions to which death was ascribed. The sex rat¡o ¡n each group approached unity. No difference in age range was seen, although B/16 of Group A were aged one year or less compared to only 3/16 in Group B (Table 4-2). The duration of symptoms was similar in each group, from 12 hours to three weeks in Group A and from one 207

day to one month in Group B. ln each group there were five cases of sudden death (defined as

death occurring within 24 hours of the onset of symptoms!.

TABLE 4-2: CLINICAL FEATURES OF 32 PATIENTS WITH HIsToLoGIcAL EVIDENCE oF MYOCARDITIS AT AUTOPSY

Group A Group B

Total 16 16

M:F 9:7 7:9

Age Range I days-9 years 11 days-15years

< 12 months 8 3

> 12 months 8 13

Duration of symptoms 12 hours-3 weeks 1 day-1 month

Sudden death 5 5

Symptoms observed in Group B related to the ultimate cause of death which was bronchopneumonia in 1O (three cases with negative cultures, two cases cultures grew coliforms, lwo staphylococc.rs, one Pseudomonas sp, one Aspergittus teffeus, and one streptococcusl, meningitis in two lboth Acanthamoebal, subdural haematoma, encephalitis (culture negativel, (motor trauma vehicle accidentl and asphyxia (due to inhalation of foreign body) in one case each, ln Group A, where myocarditis alone was diagnosed, non specific symptoms such as anorexia, vomiting, tachypnoea and pyrexia were recorded. There were three cases where signs suggestive of heart failure were observed and three where no symptoms were noted prior to death.

ln Group A 3/16 hearts and in Group B 5/16 hearts were grossly unremarkable, or showed only minor changes. Combinations of pallor, dilatation, hypertrophy (wt. >g5th percentile)36, endocardial fibrosis, petechial haemorrhage and pericardial effusion characterised the remainder (Table 4-3). No mural thrombi were present in any case. 208

TABLE 4-3: MACROSCOPIC APPEARANCE OF HEARTS w¡TH HISTOLOGICAL EVIDENCE OF

MYOCARDITIS

Group A Group B

Normal or minor changes 3 5

Dilatation only 2 3

Dilatation & Pallor 6 1

Dilatation & Hypertrophy 5 1

Pallor in any chamber 6 2

Wt > 95 percentile 7 5

Petechial haemorrhages 4 2

Endocardial fibrosis in any chamber, with hypertrophy 4 0

Pericardial effusion with dilatation 2 0

Pericardial effusion 2 2

(Please note that these groups are not mutually exclusivel.

Histologically, neutrophils were present in 8/16 Group B, compared to 4116 Group A hearts (Table 4-41. Conversely, 15/16 Group A and 9/16 Group B infiltrates included . Plasma cells and eosinophils were seen more frequently ¡n Group A. The only statist¡cally significant difference between the two groups was the presence of lymphocytes

(two ta¡led test¡ng, : 0.05, 5% level of significance). 209

TABLE 44: HISTOLOGICAL FEATURES OF ISOI.ATED (GROUP A} AND "INCIDENTAL. (GRoUP

B) MYOCARD¡TIS

GroupA GroupB pValue Test Significance Applied

Myoc¡e necrosis 16 16

Neutrophils 4 I o.27 + NS

Lymphocytes 15 I 0.04 t* +

Plasma cells 7 4 0.46 + NS

Eosinophils 3 2 1.00 +* NS

Key: + Yates corrected Chi-square ++ Fisher exact test (2 tailedl + Signifícant at the 5% level ( : 0.0b, 2 tailed testl NS Not signif¡cant.

Virological studies were conducted in 10/16 Group A and 6/16 Group B cases.

Antibody to coxsackie 84 virus was detected in one case from Group A, and in one case from

Group B (that associated with inhalation of a foreign body). Antibody to varicella was detected in one case from Group A. Coxsackie 85 and 83 were cultured from brain and CSF respeclively in one case each from Group A.

There were five cases in each group where sudden death was the mode of presentation (Table 4-5)' ln Group A, three of these patients were less than one year of age, three of the pat¡ents had macroscopically normal hearts, one heart had dilated chambers and weighed in excess of the 9Sth percentile, and the remaining heart had dilated chambers only. ln Group B sudden death occurred in one infant less than one year old. Only one heart in the five cases of sudden death in Group B was macroscopically unremarkable. Two hearts weighed >gsth percentile, one of which showed chamber dilatation, and the remaining two of which also showed dilated chambers. Microscopic examination showed a predominantly lymphocytíc infiltrate in all cases in both groups excepting one case in Group B where eosinophils predominated: other findings in this case included long standing bronchiectasis and colonizing 210

asperg¡llosis in sections. A second patient in Group B died suddenly from an inhaled foreign body, and in the remaining three significant bronchopneumonia was found.

TABLE 4-5: CASES OF SUDDEN DEATH ASSOCIATED WITH |SO|-ATED (GROUP Al AND

INCIDENTAL (GROUP BI MYOCARDITIS

Group A fì :5 Group B n:5

Heart grossly normal 3 1

Heart dilated 2 3

Heart weight > 95th %ile 1 2

Age < 12 months 3 1

Drscuss¡oN ln the early part of the 20th Century the term "myocarditis" was used to signify any chronic myocardial disease3l. W¡th increased use of virological techniques it became apparent that an association existed between infection with certain viruses and myocarditis. These viruses include Coxsackie A and B, ECHO, polio, cytomegalo, rubella, mumps, Epstein Barr, influenza A and B, herpes, adeno and virusesso.

It is only recently that histologic criteria have been set out which specify that diagnosis requires myocyte necrosis, i.e. the finding of inflammatory cells alone is insufficient for the diagnosis since the presence of a normal myocardial population has been demonstrats6l15,119. For example, studies have demonstrated'myocarditis'(in the form of a lymphocytic infiltrate) of the conduction tracts in apparently well children who suffered sudden accidental death that was unrelated to any form of cardiac diseases4. Applying the most recent definition to archival material led to eight cases in which myocyte necrosis was not observed being excluded from the current series. This suggests that earlier stud¡es may have overestimated the incidence of this disorder. The diagnosis of myocarditis depends, however, upon adequate sampling because of the often focal nature of the histological changes. lt is also possible, therefore, that a number of cases have been missed in the pastsg. 2L1,

ln infants and children, as in adults, the symptoms of myocarditis may be non-specifiçss.

A "flu-like" illness with pyrexia, signs of congestive heart failure and cardiomegaly and an

abnormal electrocardiogram may occurs3. ln infants, tachypnoea and intercostal recess¡on are

found. The disease may be mild and self limiting, rapidly progressive, or may present with

sudden deathso. DeSa noted that 17 of 24 cases of isolated myocarditis presented with sudden

death, 13 of whom suffered no prodromal illnessal. Five of 16 of our cases presented in this

manner, three of whom were less than one year of age. The cause of sudden death in

myocarditis is generally thought to be an errhythmia due to involvement of the conduction system by foci of inflammation4l. ln older children ¡t is thought that strenuous physical exercise may predispose to sudden death by this mechanism where subclinical myocarditis is presents3.

Macroscopic examination of the heart in histologically proven myocarditis may demonstrate ventricular dilatation, pallor, discolouration, hypertrophy, petechial haemorrhage or endocardial fibrosis {Figure 4-11. DeSaal noted one or more of these features in all of his cases of isolated myocarditis. ln contrast, no macroscopic abnormality other than isolated epicardial petechial haemorrhages was observed in three out of 16 hearts in Group A. lt is noteworthy that 15 out of 16 hearts in Group A compared to nine out of 16 in Group B were inf¡ltrated predominantly by lymphocytes, as this is a characteristic of viral myocarditis3T. ln fact, the presence of lymphocytes was the only statistically significant difference between the two groups. Other histologic features in established cases include myocyte necrosis (Figure 4-21, myocyte hypertrophy and interstitial fibrosis with scarrings4. Microscopically the degree of inflammation in affected hearts is variable, with some cases showing widespread myocyte necrosis with a florid interst¡t¡al inflammatory infiltrate composed of lymphocytes, eosinophils or neutrophils. ln other cases the microscopic changes are more focal. Given the variable distribution of inflammation and necrosis, adequate sampling is required59. However, the diagnosis is usually less of a problem with autopsy specimens than with b¡ops¡es due to the greater amount of material that is available for examination.

The extent of myocardial damage may occasionally appear out of proportion to the relatively unimpressive clinical symptoms, and myocardial inflammation with necrosis has also been an incidental finding in other autopsy series, demonstrating that myocarditis may not always be functionally significant34. Scattered giant cells present in some cases arise from Figure 4-1: Opened left ventricle of a four-month-old boy who suddenly collapsed and died revealing mottling of the myocardium due to extens¡ve myocarditis.

Figure 4-2: Established myocarditis showing a diffuse chronic ¡nflammatory cell infiltrate with associated myocyte necrosis (Haematoxylin & Eosin, x 280),

*' , Figure 4-3: Giant cell myocarditis present in a 13-year-old boy who collapsed and died while at

school, showing pallor and mottling of the myocardium w¡th myocyte necrosis, chronic

inflammation and characteristic giant cell formation (inset) (Haematoxylin & Eosin, x 44o),

Figure 4-4: Tiny bead like valvular vegetations on the tricuspid valve in 13-vear-old oirl who died suddenly from acute rheumatic fever.

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t . tÞ¿ æl -r

;r .t \- ¡ + â .V -.,"1 \i \ t \ # a\ * l-- ?-- t j -ù 2L2

degenerating myocytes in so-called giant-cell or Fiedler's myocarditis. Such was the case in a

13-year-old schoolboy who collapsed and died following an apparently mild febrile illness (Figure

4-3).

Myocarditis may be caused by a variety of noninfectious agents, however, it is most commonly due to microbiological agents, in particular to coxsackie B viruses6T. Other viruses such as may also cause death due to cardiac involvemenllol'111, Table 4-6 lists a variety of possible microbiological causes of myocardial infection.

TABLE 4-6: INFECTIOUS CAUSES OF MYOCARDITIS

1. Viruses Coxsackie A & B, ECHO, polio, influenza A & B, cytomegalovirus,

mumps, rubeola, rubella, Epstein-Barr, adenovirus, varicella-

zoster, variola, vaccinia, hepatitis B, yellow fever

2. Chlamydia Chlamydía psittací(psittacosisl, Chlamydia pneumoníaea

3. Rickettsia Ríckettsia typhí ltvphusl, Ríckettsía tsutsugamushi(scrub typhus)

4. Mycoplasma Mycoplasma pneumoniae 5. Bacteria diphtheria, Salmonella, Brucella, strepococci (ß-haemolytic),

staphylococci, Clostrídíum perfríngens, Neissería meníngitidis,

Borrelía burgdorferi

6. Fungi Aspergillus, Candida, Blastomyces, Cryptococcí,

Coccidioídomyces

7. Protozoa Trypanosoma, Toxoplasma

8. Metazoa Tríchinella, Echinococcus

(Adapted from references gz,rozl

ln Group A, evidence of infection w¡th coxsackie 83, 84, 85 viruses and varicella was obtained. The coxsackie viruses are commonly associated with myocarditis in children and in neonates, the latter presumably acquiring the infection in utero25. Only one positive viral culture was obtained from an infant aged 11 days at death, and this was for coxsackie 83. ln Group B, evidence of viral infection was only obtained from the child who inhaled a foreign body, prior to which he had appeared perfectly healthy. 2L3

The data confirm that the presentation of myocardit¡s ¡n the paediatric age group may

vary from an asymptomatic incidental f¡nd¡ng, to a well defined illness of weeks duration, to

sudden and unexpected death. At autopsy, gross examination of the heart may or mey not

suggest a myocardial abnormality and the presence of myocard¡t¡s may be apparent only after

extens¡ve histological samplingss. The significance of foci of myocardial necrosis and

inflammation in asymptomatic infants and children dying of unrelated disorders is difficult to

determine. lt is possible that these may have spontaneously resolved and remained undetected,

or may have manifested subsequently as a "cardiomyopathy", had the children survived.

Due to the possibility of occult myocarditis at any age, myocarditis may be found at

autopsy in infancy and childhood, even in the absence of specific antemortem symptoms and

signs, or in the presence of coincident lethal disease. This is particularly so in cases of sudden

and unexpected death where it is advisable to submit serum and myocardium for microbiological

and DNA hybridization studies, looking part¡cularly for evidence of coxsackie B viruses22.

Detection of coxsackie B virus-specific lgM may also be helpful in arriving at a diagnosis4s.

H¡stologically, samples should at least include portions of both ventricles and the interventricular

septum. lt should be recognised, however, that there will always be a risk of under-diagnosis

because of the focal and somet¡mes mild nature of the inflammatory changes that may occur. SUMMARY

To characterise the clinicopathological presentation of patients with myocarditis coming to autopsy in childhood, 32 cases of histologically-proven myocarditis were obtained from the f¡les of the Adelaide Children's Hospital. ln 16 of the cases (Group A), myocarditis was the only significant finding and death was ascribed to this condition. ln the remaining 16 (Group B) myocarditis was found in association with other severe disease processes. Clinical histories of the two groups showed sudden death to be a feature in five out of 16 cases in Group A, three of whom had no prodromal symptoms. Five patients in Group B also suffered sudden death, but this was associated with a variety of causes, including bronchopneumonia, and asphyxia. These cases demonstrate the variability in clinicopathological presentat¡on of myocarditis in infancy and childhood and suggest that myocarditis should always be considered a possible diagnosis at autopsy in the pediatric age group, even in the presence of coincident lethal disease.

t*+ Figure 4-5: Typical Aschoff body of rheumatic fever composed of aggregated cells with vesicular nuclei containing a central ribbon of condensed chromatin, so-called Anitschkow cells

(Haematoxylin & Eosin, x44Ol.

] I

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Figure 4-6: Emboiizeci fragment of left ventricular mural in the left anterior descending coronary artery of a six-year-old girl with florid acute rheumatic fever (Haematoxylin & Eosin, x

4s).

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t,',¡t'.

I 2L4

RHEUMATIC FEVER

Clinical Features

Rheumatic fever is a recurrent febrile illness of childhood characterized by subcutaneous

nodules, erythema marginatum of the skin, chorea, migratory polyarthralgia and carditis.

Aetiology

Rheumatic fever follows 'a group A streptococcal infection and is believed to be due to

immunological cross reactiv¡ty between t¡ssue and streptococcal ant¡gens. ln recent years the

incidence of rheumatic fever has declined in Western countrieslt4.

Pathological Features

On gross examination, the heart is often enlarged with dilated chambers and typical vegetations

along the margins of the valve leaflets (Figure 4-4). Microscopically the most characteristic

lesions are Aschoff bodies, which consist of round to oval nodules with central fibrinoid

degeneration and a surrounding rim of cardiac histioc¡es73. Anitschkow cells are also

characteristic and are distinguished by oval vesicular nuclei w¡th centrally aggregated ribbons of

chromatin66. They are also known as 'caterpillar' cells (Figure 4-51.

Occurrence of Sudden Death

Although sudden death is a rare of rheumat¡c fever, it has been reported from early

childhood to late adolescence. For example, an 18-year-old youth with acute rheumatic

valvulitis and myocarditis developed an acute myocardial infarct attributed to embolizat¡on of

friable valvular vegetations6G.ss ¿¡¿ a three-year-old boy with rheumat¡c fever died suddenly due

to involvement of his coronary arteriess3. A six-year-old girl with florid myocarditis due to

rheumatic fever (a referral case to the Adelaide Children's Hospital) also died suddenly with an

embolus into the left anterior descending coronary artery (Figure 4-6).

ENDOCARDIT¡S

Endocarditis is caused by infection of the endocardium or heart valves by a variety of

microbiological agents result¡ng in vegetation formation.

Aetiology

Endocarditis in children usually occurs in those who have underlying defects such as tetralogy of

Fallot, ventricular septal defect with aortic incompetence, left ventricular outflow obstructions or

a ductus arteriosus, with or without corrective surgeryg. lt also occurs in children who have 2L5

had rheumatic fever, but may also be found in children with normal hearts. Endocarditis may

be associated with sepsis elsewhere or with indwelling vascular catheters. Most cases (i.e.

>70oÁl are caused bv Staphylococcus auÍeus or Streptococcus ,¡r¡¿"ns38'87.

Clinical Features

While early symptoms and signs tend to be relatively nonspecific, occasional cases may pursue

a fulminant course with fever, heart failure and embolic phenomena3s. This is particularly so

w¡th staphylococcal endocarditis where there may be significant valvular damage, erosion of

conduction tracts precipitating arrhythmias, or embolization resulting in pulmonary, cerebral or

. Embolisation may also occur with other types of infective

endocarditisl o3.

Pathological Features

At autopsy the classical lesions of endocarditis of splinter haemorrhages under the nails,

subcutaneous nodules in the fingers and toes (Osler's nodes) and haemorrhagic lesions on the

palms and soles (Janeway lesionsl are often not visible. With¡n the heart the m¡tral valve is

most often affected. Lesions include vegetations, valve perforation, annular and

rupture of the chordae43.

The gross appearance of vegetations varies depending on the type of endocarditis

presentss, however in bacterial infections they cons¡st of friable masses of variable size adherent

to the valve cusps. Microscopically, vegetations consist of aggregated cellular debris, fibrin,

bacterial colonies and white blood cells.

Occurrence of Sudden Death

Death from embolic myocardial infarction has occasionally been reported in infants and older

children with endocarditis2o making careful examination of the coronary arteries important in

such cases. The precise mechanism of death may, however, be difficult to ascertain.

AORTIT¡S

Bacterial infection may also involve the aorta in areas of flow disturbance such as a coarctation.

Symptoms of infection may be quite non-specific and sudden death can occur unexpectedly due

to rupture of an eroded vessel wall. Death results from hypovolaemic shock, or from cardiac tamponade if the aortic root is involved. Figure 4-7: Yegetations containing bacteria adherent to the thickened cusp of a dysplastic bicuspid eortic valve in an eight-year-old boy. lnvolvement of the right coronary artery ostium resulted in death from an acute myocardial infarct.

Figure 4-8: Rupture of the aortic (arrows) arch with focal acute inflammat¡on in a six-year-old girl with minimal preceding symptorns, No structural abnormalities or migrated foreign bodies were present. The pulmonary outflow tract is adjacent. 2r6

An alternative mechanism of sudden death was demonstrated in an eight-year-old boy at the Adelaide Children's Hospital with a stenot¡c bicuspid aort¡c valve who developed bacterial infection of the aortic valve cusps and died of an acute myocardial infarct following occlusion of the right coronary artery ostium (Figure 4-7).

Occasionally the aet¡ology of the ¡nf¡ammat¡on may be uncertain, as was the case of a six-year-old girl at the Adelaide Children's Hospital who died suddenly from a ruptured ascending aorta fo¡lowing several hours of non-specific malaise and fever (Figure 4-8). At autopsy focal acute ¡nflammation of the aort¡c arch was found with abscess formation and rupture. No organisms were found on microbiological culture or within tissues on Gram and PAS staining.

ARTERITIS

Coronary artery inflammation with , myocardial infarction and death may occur in children with rheumatic fever, syphilis or endocarditis with abscess formations2.

RESPIRATORY CONDITIONS

RETROPHARYNGEAL ABSCESS

Retropharyngeal abscess may result from infection following a penetrating injury to the posterior pharyngeal wall, or in early childhood may be a sequel to pharyngitis or tonsillitis. Obstruction to the airway and even sudden death can occur if infection ¡s ssrs¡g9s'12o.

POSTERIOR LINGUAL ABSCESS

Acute inflammation in the posterior portion of the tongue may also result in occlusion of the upper airway with unexpected death2s (see Chapter 5). These cases emphasize the importance of careful excision and examinat¡on of the upper airway in all cases of sudden infant death.

ACUTE EPIGLOTTITIS

Clinical Features

The clinical course of acute epiglottis is often fulminant with rapid development of fever, respiratory distress, odynophagia and drooling prior to respiratory obstruction and terminal cardiovascular arrest2. Occasionally symptoms may be relatively nonspecific, consisting of low grade fever and sore throat12, or the infant or child may be found dead in bed. Although it is 2L7

cons¡dered to be pr¡mar¡ly e d¡sease of children aged between one and seven years, it does

occur in younger and older individuals and has been reported in late adolesenceTs.

Occurrencc of Sudden Death

sudden death may occur if an attempt has been made to examine the epiglottis with a tongue

depressor as this may precipitate airway obstruction. The mortal¡ty rate for children in whom

obstruction occurs is around 2OoA even with promp¡ 1¡s¿1tng¡1l3,94. Fatal septic shock may

also be a complication.

Aetiology

The causative organism is almost invariably Haemophílus influenzae type B, although some cases are due to pneumococci, staphylococc¡ or streptococcil06.

Pathological Features

At autopsy the epiglottis is characteristically red, swollen and oedematous (see Figure 5-8).

Microscopic examínation will reveal marked submucosal oedema and acute inflammation with surface ulceration (Figure 4-9).

Autopsy lnvestigation

Blood cultures are an important part of the postmortem workup to determine the aet¡ologic agent and have been reported as positive in 50 to TSùA of casesl28.

Other Eoiolottal Lesions

Due to the vulnerability of the airway to obstruction at.the laryngeal inlet, any condition which causes expansion of the submucosa of the epiglottis and surrounding tissues may result in lethal airway obstruction. The case of a one-year-old girl with neuroblastoma and pseudomonas septicaemia at the Adelaide children's Hospital who developed stridor and died suddenly from marked interstitial haemorrhage around the laryngeat inlet underscores this point (see Figure 7-

8).

ACUTE 1ARYNGOTRACHEOBRONCHITIS

Most cases of acute laryngotracheobronchitis occur in the form of epidemic croup due to parainfluenza and influenza viruses. The clinical course of croup is less severe than acute bacterial epiglottitis and it usually has an excellent prognosis. However, occasional cases occur where airway obstruction is severe enough to warrant endotracheal intubationl2s. Respiratory arrest may also result if the child or infant is recumbent with the head tilted forwardllo. Figure 4-9: Submucosal oedema and acute inflammat¡on in acute epiglottitis (Haematoxylin &

Eosin, x 280).

I

ta

Figure 4-10: Ptosis of abdominal organs caused by a tension pneumothorax complicating staphylococcal pneumonia. The diaphragm can be seen beneath the left costal margin. 2L8

Although there has been debate over the likelihood of croup causing sudden death,

Segard and Koneman have concluded that 'laryngotracheo-bronchitis is a common and acceptable anatomic cause of death in children dying suddenly and unexpectedly'los. An additional problem which may result in death due to airway obstruction in children with viral laryngotracheobronchitis is secondary infection with Stapåylococcus aureus producing thick pseudomembranesT5.

BACTERIAL TRACHEITIS

Acute bacterial tracheitis is most often due to staphylococci, is less acute in onset than bacterial epiglottitis and usually has a good outcome. Unfortunately some cases do occur in which acute airway obstruction results from impaction of tenacious mucopurulent membranessT, although no deaths were recorded in this paper.

DIPHTHERIA

Pharyngeal infection with Corynebacterium diphtheriae affects unvaccinated children aged between two and 15 years. The bacteria produces an exotoxin which causes ep¡thelial inflammation and necrosis with the formation of an inflammatory pseudomembrane composed of necrotic mucosal cells and debrisss. Sudden death may occur from acute airway obstruction due to impaction of the dislodged pharyngeal pseudomembrane in the lower airway.

Alternatively sudden death may resultfrom cardiac damage due to an exotox¡n lvide infral.

ACUTE BACTERIAL PNEUMONIA

Clinical Features

Symptoms and signs of acute bacterial pneumonia in older children are similar to adults, with fever, and pleuritic chest pain. ln infants the diagnosis may not be as obvious, with m¡ld fever and non-specific malaise preceding the sudden onset of respiratory distress.

Aetiology ln children the most common serious lower respiratory tract infection is acute lobar pneumonia due to Streptococcus pneumoniae in gOo/o of cases. Fulminant respiratory infections also occur with Haemophilus influenzae and Staphylococcus aureus, the latter being assoc¡ated w¡th abscess formation and tension pneumothoraces (Figure 4-10). 2L9

Pathological Features

The appearance of the depends on whether the underlying process is an acute lobar or

lobular (broncho-) pneumonia. ln ecute lobar pneumonia confluent areas of pneumonic

consolidation are present which appear solid and airless. ln acute bronchopneumonia the lungs

are mottled w¡th scattered areas of patchy consolidation. On cut sect¡on these appear as

discrete, pale and firm areas throughout both lung fields.

Microscopically alveoli are filled with neutrophils, fibrin and necrotic debris. ln lobar

pneumonia the stage of 'red hepatizat¡on' is marked microscopically by extravasat¡on of red

blood cells into confluent alveol¡ filled with pus. This progresses to the stage of grey

hepatization as the inflammatory and red blood cells disintegrate, ln acute bronchopneumonia

the inflammatory infiltrate is bronchocentric.

Autopsy lnvest¡gat¡on

Although tissue and blood cultures may reveal , prior antibiot¡c treatment

may result in sterile cultures.

Diagnostic Problems

Assessing how well establ¡shed a disease has to be to result in a lethal outcome is a problem

which not ¡nfrequently ar¡ses at autopsy. Unfortunately a preceding history of fever is of

minimal use in establish¡ng the diagnosis of lethal acute bronchopneumonia given the number of

febrile illnesses of childhood. lt is important, therefore, not to attribute death to lesions which

are of doubtful significance and which would probably be overlooked except when the

presentation is of sudden, unexpected death of unceftain aetiology. However, it is sometimes

difficult to determ¡ne where the cut-off point lies between an infection that is relatively

innocuous and one which is lethal.

ln cases of sudden and unexpected death involving young children or infants it is

possible to have a very non-specific history, and yet still find a marked interst¡t¡at and intra-

alveolar acute inflammatory infiltrate at autopsy due to bacterial infection. ln cases where there

is either diffuse involvement of the majority of lung fields by the inflammatory process (Figure 4-

1 11, or in which there is abscess formation w¡th microbiological and histological evidence of disseminated sepsis, establ¡shing the cause of death as infective is not difficult. Other less well established cases are not as straightforward. Figure 4-1 1 : Florid acute bacterial bronchopneumonia in an infant with a relatively unremarkable history of mild fever who was found unexpectedly dead one morning (Haematoxylin & Eosin, x

220t.

Figure 4-12: Diff use rash over the forehead in a young girl dying f rom f ulminant meningococcaemia. 220

INTERSTITIAL PNEUMONITIS

lnterstitial pneumonitis is usually caused by viruses which result in a patchy interstitial chronic

inflammatory infiltrate within the alveolar septae. Although often self-limiting, a fulminant

course may occur in infants or in immunocompromised children. A similar histological picture

can result from a number of other organisms, including mycoplasmas, rickettsiae and

chlamYdi3gl27.

Again, the problem arises of what degree of interstitial inflammation can be accepted as

significant. This is even more difficult than in cases of acute bacterial inflammation as there ¡s a

normal population of peribronchial lymphocytes present in the lungs. ln the past, SIDS deaths

were occasionally attributed to interstitial pneumonitis because of the presence of mildly

increased numbers of peribronchial chronic inflammatory cellsss. Microscopic features of

¡nterstitial pneumonitis in cases of sudden death have been described by Yip, Sein and Lungl27.

BRONCHIOLITIS

The major cause of bronchiolit¡s in infants under six months of age is respiratory syncytial virus

(RSV). Other causat¡ve agents are adeno, parainfluenza and influenza viruses, Bordetetta pel'fussrs and Mycoplasma pneumoníae. Microscopically there is a diffuse mononuclear

inflammatory cell infiltrate around bronchi and bronchioles extending into the surrounding

parenchyma. The airway lumena are also infiltrated by mononuclear cells and are filled with

mucus and necrotic debris.

RSV infection may cause apnoeic episodes, plugging of distal bronchioles with mucus

and inflammatory debris, air trapping within the lungs and sudden 6s¿1¡3,24.

CENTRAL NERVOUS SYSTEM CONDITIONS

MENINGITIS

Bacterial infection of the meninges may result in fulminant disease and sudden death in children

before symptoms are obvious or despite antibacterial therapy. Rupture of intracerebral

abscesses into the subarachnoid space or ventricles is another situation which results in

extens¡ve purulent meningitis with rapid deaths2.

Aetiology

Causative organisms vary depending on age, with Streptococcus group B and enterobacter¡a

being more common in neonates. ln children up to 12 years of age the most common bacterial 22L

pathogens causing mening¡t¡s are Haemophílus influenzae type B, Streptococcus pneumoníae or

Neissería meningitidis; after this age Streptococcus pneumoníae and Neissería meningitídís are

more significant. Fulminant bacterial meningitís may also be caused by other agents such as

Lísteria monocytogenesTo,

Clinical Features

Children with bacterial infection of the meninges may have several days history of nausea,

vomiting and photophobia followed by alteration in conscious state and nuchal rigidity. On the

other hand, infants may have minimal or non-specific symptoms and signs.

lnfection with Neisseria meningitidís in children usually causes minimal or no

inflammation at the site of entry within the upper airway. The clinical history is of a febrile

illness followed by skin rash (Figure 4-121 and collapsel4. Death occurs most commonly in

children under the age of two years who present with a rapid course and are in or

shock96.

Pathological Features

At autopsy, inflammation of the meninges and skin rash may not be apparent on visual

inspection due to the rapid clinical course of the infection6, although this is variable (Figure 4-

131. Death may also occur from septicaemia before meningitis developsl23. Bilateral intra- adrenal haemorrhage, so-called 'Waterhouse-Friderichson' syndrome, may be presentTl (Figure

4-14l.. Microscopy will reveal a polymorphonuclear cell infiltrate of the meninges (Figure 4-1S) and cultures of cerebrospinal fluid should yield bacteria unless prior antibiotic therapy has occurred.

Cerebral infarction has been documented in approximately 5o/o of children with

Haemophilus influenzae meningitistl3 possibly due to arter¡tis with spasm. Necrotising cerebral occurs w¡th group B streptococcal, rickettsial, fungal and viral central nervous system infections3o. (Viral infections include congenital rubella and herpes zoster.) Vascular stenosis following meningitis may also occur in the absence of thrombosis due to a reactive fibrointimal reparative processl 26. Figure 4-13: Suppuration of the meninges in established pneumococcal meningitis Figure 4-14: Bilateral adrenal haemorrhages (Waterhouse-Friderichson syndrome) ¡n a two- month-old infant with meningococcal meningitis and septicaemia.

Figure 4-15: lnfiltration of the meninges by acute inflammatory cells ¡n bacterial meningitis

(Haematoxylin & Eosin, x 110). 222

Occurrence of Sudden Death

Lethal effects derive from septicaemia and/or meningitis, both of which may have a very fulminant course. The septicaemic shock found in cases of meningococcaemia is thought to be caused by a circulating endotoxin which also acts on the myocard¡um and adrenal glands2l.

Myocarditis may be found in a significant number of cases of meningococcal sepsis, somet¡mes with involvement of the atrioventricu¡¿¡ ¡s6s58,97. Other lethal mechanisms involve cerebral oedema due to increased capillary permeability with brainstem herniation, vascular inflammation with thrombos¡s and decreased cerebral due to hypotensions'92.

Autopsy lnvestigation

Cerebrospinal fluid aspirates should be obtained asept¡cally prior to opening the skull, e¡ther through the fontanelle or through the posterior atlanto-occipital membrane. Swabs for microbiological assessment should also be taken from areas of meningeal congest¡on or suppuration. Blood cultures are routine in such cases.

As infection may spread from adjacent areas such as the middle ear, these should be carefully examined at autopsy and microbiological swabs taken ¡f necessary. lt may also be appropriate to check for skull fractures and cerebrospinal fluid leakage in cases of recurrent meningitis.

ENCEPHALIT¡S

Certain viruses may infect the substance of the brain resulting in inflammation, necrosis and oedema. For example, Herpes simplex virus may infect predominantly the temporal and frontal lobes in the ch¡ld/adult type of encephal¡tis, or act more diffusely in the neonatal form. Rapid death may occur in children with these types of infections.

POLIOMYELITIS

Poliomyelitis is caused by an enterovirus which produces paralysis through infection of motor neurons. As with a number of other infections, epidemics are rare in Western countries since the introduction of immunization programs. Death in affected children may occur from respiratory paralysis which may be sudden, mimicking the presentat¡on of SIDS. At autopsy the findings are relatively non specific, although destruct¡on of motor neurons particularly of the anterior horns of the spinal cord may be seen on microscopy4s. 223

HAEMATOLOGICAL CONDITIONS

SPLENIC RUPTURE

Almost any infectious cause of increases the risk of rupture from relatively minor trauma. In Western countries infection with Epstein-Barr virus causing is probably the most common microbiological cause of fatal rupturel5, whereas on a global scale malaria would be of greatei significance,

Malaria

Malaria is an acute febrile illness caused by Plasmodium spp. that is transmitted by mosquito vectors. Plasmodium falciparum infection is the most severe form and may result in death from cerebral involvement with vascular thrombos¡s and localized ischaemia or less often from splenic rupture, At autopsy hepatosplenomegaly may be present with plugging of congested cerebral vessels by red blood cells in which malarial parasites can be seen on microscopy4T,

SICKLE CELL DISEASE

The clinicopatholog¡cal features of are dealt with in Chapter 7. One of the complications of sickle cell disease is reduced splenic function which predisposes to fulm¡nant infections particularly by encapsulated bacteria. lnfectious agents include Streptococcus pneumoníae, Haemophilus influenzae, Salmonella sp., Escherichia coti and Staphytococcus aureus. Affected children have a higher rate of generalized sepsis, osteomyelitis and meningitis than do normal children.

GASTROINTESTINAL INFECTIONS

GASTROENTERITIS

Fulminant viral gastroenteritis resulting in fatal dehydration ís a common global problem in infants and children. Details are discussed in the following study. 224

STUDY #4-2

INVESTIGATION OF THE D¡FFERENTIAL DIAGNOS¡S AND CLINICOPATHOLOGICAL FEATURES

OF UNEXPECTED DEATH DUE TO FATAL DEHYDRATION IN INFANCY AND CHILDHOOD

INTRODUCT¡ON

Dehydration is an ¡mportant cause of death in children and is often associated with gastrointestinal disorders. There are, however, other rarer associations which should be considered. Review of dehydration deaths at the Adelaide Children's Hospital was undertaken to examine autopsy findings and to ascertain specific aetiolog¡es and causative factors.

MATERIALS AND METHODS

The autopsy records of the Adelaide Children's Hospital to¡ a 32 year period from March 1961 to February 1993 were examined. Thirty-seven cases were found where dehydration was the primary cause of death.

RESULTS

Cases ranged in age frcm 2 weeks to 6/, years (mean : 1 1.4 months), w¡th a male to female ratio of 1:1. The most common cause of dehydration was gastroenterit¡s (N : 221 with other less common associated factors including high environmental temperatures (N : 61, mental retardation (N : 3), "chronic infections with failure to thrive" (N = 21, neglect (N - 21, congenital adrenal hyperplasia (N : 1), and a single case of fatal dehydration as a first presentat¡on of cystic fibrosis (these results are summarised in Table 4-7). Most of the cases of fatal gastroenteritis occurred in the 1 960's (N = 7) and 1 970's (N = 12) w¡th only 2 cases occurring in the 1980's and 1 in the current decade. The majority of cases occurred during the autumn/winter months corresponding to outbreaks of infectious gastroenteritis. The remainder occurred within the warmer months, and in one case both high environmental temperature and gastroenteritis contributed to the lethal epísode. Twelve of the 24 children with gastroenteritis died at home, eleven died within 48 hours of arrival at hosp¡tal and one died in transit. 225

TABLE 4-7: CLTNICOPATHOLOGICAL FEATURES OF 37 CASES OF FATAL DEHYDRATIoN IN

INFANCY AND CHILDHOOD

CAUSE OR MAJOR NOS. OF CASES AGE RANGE MEAN ASSOCIATED FACTOR

GASTROENTERITIS 22 2 WEEKS*2O MONTHS 7 MONTHS

HIGH ENV]RONMENTAL 6 3 MONTHS-26 MONTHS 8 MONTHS TEMPERATURE

MENTAL RETARDATION/ 3 2 WEEKS'7S MONTHS 27 MONTHS ABNORMAL CHROMOSOMES

NEGLECT 2 6 MONTHS+12 MONTHS

"CHRONIC INFECTION/ 2 1O MONTHS+ 15 MONTHS FAILURE TO THRIVE"

CYSTIC FIBROSIS 1 58 MONTHS

CONGENITAL ADRENAL 1 8 MONTHS HYPERPLASIA

lmmunoassay for rotavirus performed in three of the children thought to have gastroenteritis yielded a positive result in two cases. ln one case Clostridium welchií was cultured from bowel contents sampled at post mortem.

All cases of dehydration secondary to high environmental temperature occurred during the summer months. All six cases involved infants who were found dead at home. ln three cases poor parent¡ng appeared to play a role. lnadequate intake alone (N : 2) was an important factor contributing to dehydration when mental retardation was present.

The gross autopsy findings indicative of dehydration were sunken eyes (32 casesl, sunken anterior fontanelle (N 171, reduced tissue turgor (N : 311, flabby and wrinkled internal organs which inctuded the liver (N : 141, kidneys (N : 12), adrenal glands (N : S) and pancreas (N : 2l (Figures 4-16 to 4-19). ln three cases the peritoneal cavity was noted to be dry, ln the majority of the cases of gastroenterit¡s (N : 14122]|the ¡ntest¡nes were dilated and filled with fluid faeces and in a small number of cases (6) there was an increased mononuclear infiltrate within the lamina propria of the small intestinal mucosa. Figure 4-16: Deeply sunkerr eyes are evidence of marked dehydration in a two-year-old boy

f

Figure 4-17: Sunken fontanelle in a five-month-old girl due to dehydration following

gastroenteritis. This was associated with basal subarachnoid haemorrhage (see Figure 4-21 1. Figure 4-18: Reflecting the scalp demonstrates more clearly the degree of fontanelle depression in significant dehydration. The case illustrated was a three-month-old girl with gastroenteritis.

Figure 4-19: Shrinkage of the liver capsule in a severely dehydrated six-month-old girl with gastroenteritis.

t I

I

þ, lìt t4 (.f

I þ f' l'å Ås -

(¿ 226

Patchy neuronal necrosis was noted in the cerebral cortex and cerebellum in two of the

six cases of dehydration caused by high environmental temperatures. Generalised wasting and thymic atrophy were seen in both cases of neglect. Characterist¡c ¡nsp¡ssated secretions were

seen within the lungs, salivary glands, intestinal mucosa and pancreas in the case of occult

cystic fibrosis (Figure 4-201. Fibrosis of the pancreas and in the portal tracts of the liver was

also noted. Adrenal gland enlargement with increased cortical convolution was noted ¡n the

single case of congenital adrenal hyperplasia. Vitreous humour electrol¡e analysis was available for review in six cases demonstrating an elevated sodium level in all cases examined (range 155

mmol/l to 188 mmolil).

D¡SCUSS¡ON

Dehydration from any cause may result in electrolyte imbalances with the attendant risk of

sudden death. ln infants and children fulminant gastroenteritis is one of the most important

causes of rapid clinical deterioration if fluid balance is not maintained. lnfants are at part¡cular

risk as watery diarrhoea may be mistaken for urine, leading to underestimation of the severity of the condit¡on. Neglected children who develop gastroenter¡tis are also vulnerable to ¡ethal consequences due to parental inattention and the late seeking of medical care. However, poorly

educated parents may genuinely fail to appreciate the severity of a child's illness. The effects of excessive fluid loss may also be exacerbated in areas with a hot climate, especially in the middle of summer.

Evidence of marked dehydration may be obvious at autopsy as noted in the above study,

with sunken eyes, a depressed fontanelle in infants, dry mucous membranes and internal organs, and decreased skin turgor but th¡s is not invariable. Reflection of the scalp will demonstrate a sunken fontanelle more clearly. As the clinical history may be equivocal and microbiological investigat¡ons unhelpful, Huser and Smialek have recommended that postmortem analysis of vitreous humor should be performed in all cases of unexplained infant death as this may reveal elevatíon in sodium and urea nitrogen levels6l. Knight quotes levels of vitreous humour sodium >155 mmol/L, chloride >135 mmol/L and urea >4O mmol/L as reliable markers of antemortem dehydrationT2. This may be of particular significance if the possibility of parental neglect exists. Examination of the bowel is important, as a case of pseudomembranous colitis due to Clostridíum difficile has been reported in a three-month-old boy presenting as 5¡95104. 227

The cause of sudden death in these cases may be hyperkalaemic cardiac arrhythmia, or cerebral

haemorrhage, or infarction from venous thrombosiss2 ¡Figures 4-21 &.4-221.

Occasionally sudden death may occur without dehydration es was the case in a four-

month-old boy who had apparently recovered from gastroenter¡tis but who had Salmonelta

virchow isolated from the gut, middle ear and cerebrospinal fluid, w¡th organisms identified on

immunohistochemical sta¡ning of the liver19.

ln cases of temperature-related dehydration there are no specific autopsy findings

diagnostic of heat , although generalised tissue anoxia may result in necrosis within many

organs42 as was noted in the brain in two of our cases. A high rectal temperature after death

may be found.

Mentally retarded patients are at increased risk of dehydration due to inadequate intake,

although neglect may be a factor in such cases. In two of our children the cause of death was

attributed to "chronic infections with failure to thrive". lt is difficult from the autopsy reports to

be certain, however, it is possible that these cases also represent neglect.

Death with dehydration and electrolyte disturbance on hot days is a known problem in

children with cystic fibrosisl. The mechanism involves inability to control sodium and chloride

loss at t¡mes of profuse sweat¡ng. lt ¡s, therefore, important to always consider cyst¡c fibrosis

when dehydration is found at autopsy, particularly given the genetic ramificatíons of this

diagnosis.

Another rare condition to be considered in cases of fatal dehydration in childhood is congenital adrenal hyperplasial. For example, one infant in our series died due to dehydration and electrolyte d¡sturbance from the salt losing form of this condition. A history of neonatal death in previous siblings, with dehydrat¡on, should alert the pathologist to the possibilíty of this diagnosis.

This review demonstrates that while fatal dehydration is most often due to gastrointestinal infection, it may be a marker of occult metabolic disease. The familial basis of these disorders makes accurate identification at autopsy extremely ¡mportant. Occult child abuse manifesting itself for the first time as fatal dehydration is another possi bility. **+ Figure 4-2O: Fibrosis with oarenclìymal loss and inspissation of secretions within pancreat¡c ducts in the case of cystic fibrosis that was only diagnosed at autopsy after death due to dehydration.

Figure 4-21: Spontaneous subarachnoid haemorrhage causing sudden death in a five-month-old girl with acute gastroenteritis and dehydration. Figure 4-22: Cerebral venous thromboses with in a nine-month-old boy with acute gastroenteritis and dehydration. 228

BOTULISM 'potent lnfantile botulism is a recognized cause of sudden death due to the actions of a neurotoxin which interferes with respirationT8. Further details are discussed in the section later in the chapter on toxigenic bacteria.

PRIMARY PER¡TONITIS lnfants may die suddenly after the development of primary per¡ton¡tis, symptoms of which are vomiting, diarrhoea and acute prostrat¡on. Causative organisms include Pneumococcus,

Streptococcus and Escherichia coli. At autopsy, purulent asc¡tic fluid will be identified with no demonstrable primary focus of infection.

GENITOURINARY CONDITIONS

PYELONEPHRITIS

The majority of cases of acute bacterial pyelonephritis present with fever and loin pain. Cases in which sudden death is purported to have occurred may represent examples of parental inattention or of underestimat¡on of the severity of symptoms by attending physicians.

GENERALIZED CONDITIONS

SEPTICAEMIA

Generalized bacterial sepsis may cause sudden deterioration and death. For example, group B streptococcal infection is a major cause of sudden death within the first two months of life due to pneumonia, meningitis and generalized sepsis. Fever may not have been marked and the presentation may be of S1DS11,17. At autopsy a focus for the infection may be discernable in some cases, although others may have no apparent source of the pathogen¡c agent. The mechanism of death in children who die suddenly from septicaemia is not always clear6.

ln the absence of a clear-cut h¡story of antemortem sepsis the diagnosis of lethal sept¡caem¡a in cases of sudden death requires not only positive blood cultures, but also microscopic evidence of disseminated seps¡s preferably with isolation of the same organism from multiple sitesl l. H¡stolog¡cal evidence of sepsis may include areas of localized acute inflammation such as an acute pneumonia, or haemorrhage and intravascular fibrin thrombi from disseminated intravascular coagulslie¡l17. ln the absence of these findings the possibility of external contamination, agonal sepsis or postmortem overgrowth must be considered44. 229

VIRAEMIA

Disseminated infection with organisms other than bacteria may also result in sudden and

unexpected cardiac arrest. Examples include adenovirus, rhinovirus and Herpes simplex

u¡¡r532'116. lt has been proposed that disseminated cytomegalovirus infection may be

associated with some cases of SIDS based on the finding of viral inclusions within salivary

glands and brainstem microglial nodules118, however, subsequent studies have not confirmed

1¡¡s l 09.

ENDOTOXAEMIA

A variety of locally invasive bacteria may cause systemic effects due to the elaboration of

systemically-acting potent toxins.

Staohvlococcus aureus

Toxin-producing Staphylococcus aureus may cause sudden death in infants and children

following relatively minor skin ínfectionsl2s. A similar syndrome known as the'toxic shock

syndrome' has occurred in menstruat¡ng adolescent and young adult women33, the

staphylococci being present in contaminated tampons8l. Antemortem symptoms of vomiting,

sore throat and skin rash may progress rapidly to shock with renal and cardiac failures6. lt has

been suggested that staphylococcal enterotoxins may also be involved in some cases that have

Presented as SlDSTa.

Corvn eba cterium dio h th eriae

The exotoxin derived from Corynebacteilum diphtheilae not only causes local changes in the form of ep¡the¡¡al necrosis with pseudomembrane formation in the pharynx, but may also result in myocardial damage. The intensity of myocarditis varies, with 1O to over BO% oÍ affected pat¡ents demonstrating clinical evidence of cardiac disease28.8o. lnvolvement of conduction tracts may lead to heart block and sudden death from arrhythmia. At autopsy fatty change within the myocardium, liver end kidneys may be observed.

Escheríchía coli

Escherichia coli may produce an enterotoxin which is considered by some researchers to be associated with SlDSl8, although the significance of this is at present uncerta¡n. 230

Clostridíum so.

Both Clostridium tetani aîd Closttíd¡um botulinum produce potent neurotox¡ns which may result in sudden death. Tetanus is characterized by progressivé stiffness of voluntary muscles with the development of or laryngeal spasm122. Occasionally the clinical course may be fulminant and death can occur rapidly, particularly in children w¡th sickle cell diseasea.

Changes at autopsy are relatively nonspecific with local inflammation at the site of infection and swelling of motor neurons in the brainstem and spinal cord.

Botul¡sm occurs in infants and children when the neurotoxin produced by Clostridium botulínum is ingested in food. Clinical symptoms and signs usually evolve over some time and consist of vomiting and diarrhoea progressing to respiratory paralysis. ln infants botulism may present as sudden and unexpected death due to overgrowth by intestinal Clostrídium botulinum

IMMUNODEFIC!ENCY STATES

A heterogeneous variety of primary and secondary immunodeficiency states g¡¡s127,99,10o, only some of which are associated with the occurrence of fulminant infections and death

PRIMARY IMMUNODEFICIENCY STATES il X'linked agammaglobulinaemia of Bruton is one of the most common types of heritable immunodeficiencies. ln severe forms it is characterized by marked reduction or absence of serum immunoglobulins resulting in recurrent pyogenic infections from an early age. Findings at autopsy include a lack of germinal centres in lymph nodes and the , with rudimentary and an absence of plasma cells on microscopy.

¡¡) Severe combined immunodeficiency is a heterogeneous disorder characterized by defects in both humoral and cell mediated immunity. Death usually occurs in early life from overwhelming

Pseudomonas sp. or vira! infections. At autopsy the is not found within the anter¡or mediastinum, but is higher up in the neck, and on microscopy is found to be devoid of lymphoid cells and Hassel's corpuscles. Affected children often lack erythrocyte and leukocyte adenosine deaminase, an enzyme which can be tested for on fresh samples. iii) Common variable immunodeficiency represents the most frequent form of serious heritable immunodeficiency. This condition is characterized by reduced blood immunoglobulin levels resulting in afflicted children suffering recurrent pyogenic infections. Examination of lymph nodes reveals hyperplastic lymphoid follicles, in contrast to X-linked agammaglobulinaemia, 23L

ivl DiGeorge syndromc results from third and fourth pharyngeal pouch anomalies such as

aplasia, hypoplasia or ectopia of derived tissues, including the thymus and parathyroid glands.

Sudden death in infants and children with this disorder may also occur due to associated

cardiovascular abnormalities which are discussed in greater detai¡ in Chapter 3.

v) Wiskott-Aldrich syndrome is an X-linked recessive condition characterized by eczema,

thrombocytopaenia and variable T and B cell defects that result in recurrent infections. Sudden

death may occur due to the low number of circulating plate¡ets, as occurred in a five-month-old

boy with Wiskott-Aldrich syndrome who died rapidly at the Adelaide Children's Hospital and was

found at autopsy to have an intracranial haemorrhage.

vil Congenital may occur on íts own, or it may be part of a more extensive syndrome

involving cardiovascular anomalies6s. The clinical presentation of cases in which there are other

congenital malformations present (90%l tends to be overshadowed by cardiovascular problems

in early infancy. However, in children who survive early life, there is still the ever present risk of

fulminant sepsisl07,t2l which may result in sudden and unexpesls6 6ss1¡a6,79. Haemophilus

influenzae infection and intra-adrenal haemorrhages were present in five of the six cases in these

reports, all of which pursued a fulminant course with death often within 12 hours of the onset

of symptoms. Familial cases of congenital hyposplenism have been reportedos.

lf a hypoplast¡c or absent spleen is noted on initial examination of the abdominal cavity

at autopsy, not only should complex cardiovascular abnormalities be looked for, but full

microbiological examination should be conducted. This is particularly so if haemorrhagic adrenal

glands are also present.

vii) Other forms of immunodeficiency syndromes include defects in the complement system and

defects in /neutrophil function such as chronic granulomatous disease.

SECONDARY IMMUNODEFICIENCY STATES

latrooenic

lnfants and children who have recieved for are at increased risk of developing fulminant infections due to opportunistic organisms. These may be multiple and result in disseminated intravascular . Sudden death due to fungal thromboembolism may occur in children infected with angio-invasive fungi such as Aspergittus sp. ln these children it may be difficult to identify fungi in t¡ssue sections unless sampling is extensive as 232

ang¡o-¡nvasion with infarction may have caused widespread tissue necrosis. As well, sampling of venous blood may be inadequate as fungal hyphae may not pass through the capillary bed28.

A proposed autopsy sampling protocol for fungi is outlined in Appendix l.

Acquired lmmunodeficiencv Svndrome (AlDSl

It could be suggested that one of the particularly unpleasant features of AIDS is the prolonged clinical course that sufferers are forced to endure. However, while sudden and unexpected death does not stand out as a part¡cularly obvious presentat¡on, it does occur.

ln adults with AIDS, cardiac lesions have included myocarditis, endocarditis, pericardial effusions, left ventricular hypokinesia, mitral incompetence and right ventricular dilatation3s'4s,s8. Clinical studies of children with AIDS have also demonstrated abnormalities in left ventricular function, sometimes caused by dilated cardiomyopathyo3,e+ or by cytomegalovirus inf ection24 .

Vascular lesions found in children w¡th AIDS may also precipitate sudden death. For example, involvement of the coronary arteries with aneurysm formation has been reported as a cause of death from myocardial infarction in a th¡rty-two-month-old girl with AlDS6s.

Microscopically, vessels show intimal and medial fibrosis with disruption of elastin fibres and medial calcification. These fibrocalcific vascular lesions are similar to those found in idiopathic arterial calcification of infancy.

Vasculitis and perivasculitis of the cerebral vessels may be associated with intracerebral haemorrhage and ischaemic lesions in infected individualsTT. Vasculitis may result in cerebral artery aneurysm formation62 and vascular calcification has been found in the basal ganglia of

¡nfants and children w¡th AlDS16.

A case of sudden death following massive gastrointest¡nal tract haemorrhage in an eight- year-old boy with AIDS has been reported, but unfortunately further comment is not possible as permission for autopsy was not grantedl0. Children with AIDS are also at much higher risk for developing a variety of other opportunistic infections, the features of which have been recently reviewed7,S1,91,1 12.

++++ Referwes Châ1

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CHAPTER 5

RESPIRATORY CONDITIONS 233

INTRODUCTION

Respiratory causes of sudden and unexpected ¡nfant and childhood death often involve acute obstruction of the airway by an impacted foreign body or by an intrinsic lesion such as an inflamed epiglottis. Other major causes of sudden respiratory death are and infective conditions such as acute bronchopneumonia. These disorders are listed in Table 5-1.

TABLE 5-1: RESPIRATORY CAUSES OF SUDDEN PAEDIATRIC DEATH

Asthma

Upper airway obstructlon

Bronchopulmonary dysplasia

Acute bronchopneumonia

Cystic fibrosis

Massive pulmonary haemorrhage

Tension pneumothorax

Two studies of sudden death in children and young adults found respiratory disease as a cause of death in 10 of 31 cases {'32%l and in 12 out of 78 cases l15o/ol, respect¡velyse,8l. ln the earlier series Molander found four cases of bronchopneumonia, three cases of asthma and three cases of acute epiglottitisss, while Siboni and Simonsen found a greater number of cases of fulminant tracheobronchitis (five out of the 12 cases of fatal respiratory disease), with four cases of acute epiglott¡t¡s, two of asthma and a final case in which death was attributed to acute tonsillitissl. Thus acute respiratory disease accounts for a significant proportion of cases of sudden natural death in childhood.

ASTHMA

Asthma is characterized by episodes of wheezy breathlessness due to paroxysmal narrowing of smaller airways, tr¡ggered by a variety of specific allergenic materials. These include pollen, dust, chemical fumes, animal products, aspirin and infectious agents such as viruses and

Aspergillus sp.. Physical stimuli such as cold temperatures may also induce an attack. lt is the most common chronic lung disorder of childhood in a number of countries including the United

States, the United Kingdom and Australia. Although asthma is only rarely associated with a fatal outcome2s, the incidence of asthma-related deaths has been reported to be 234

increasingsl'75'98. Death may occur during status asthmaticus in which severe bronchospasm

persists despite medical treatment, or it may be quite sudden and unexpected. ln the paediatric

age range this tends to occur predominantly in older children and adolescents. For example, no

children under four years of age were found in a series of 1 1 fatal cases taken from autopsy

files at the Adelaide Children's Hospital (range : 4 to 15 years; mean : 1O years). However,

the occurrence of sudden death in occasional younger asthmat¡c children does qualify it for

inclusion in this thesis.

Clinical Features

Children with asthma have episodic wheezing, dyspnoea and hyperinflation of the chest.

lndividuals who are most l¡kely to die are those with a long history of asthma who have had

episodes in the past which were life-threatening or which required hospitalizations. However, it

must be emphasized that sudden death may still occur in individuals who have presented with

only apparently mild episodes, or w¡thout particularly severe histor¡es38,74.

Occurrence of Sudden Death

The mechanisms of sudden death in an acute asthmatic attack are not completely understood and involve cardiac arrhythmias, hypokalaemia or asphyxia. Unfortunately it has been difficult to obtain adequate data due to the rapidity of terminal episodes and their occurrence outs¡de hospital.

Bronchodilators have been implicated in the aetiology of sudden death possibly due to cardiac arrhythmias. Alternatively, bronchodilators may provide temporary symptomatic relief result¡ng in a critical delay in presentation of the pat¡ent to hospital. Delay in seeking treatment for whatever reason has been found to be a significant factor in asthma deaths4a. The possibility of pharyngeal irritation from inhalational agents inducing a vasovagal response and cardiac arrest has also been proposed62.

Although ¡t has been suggested that cardiac arrhythmia exacerbated by anti-asthmatic drugs is the most likely terminal svs¡123.1o2, a clinical study of ten adolescent and adult asthmatics who developed respiratory arrests before, or soon after, arrival at hospital failed to demonstrate significant disturbances of cardiac rhythm. lt was concluded, therefore, that severe asphyxia rather than arrhythmia was the more important factoroo. 235

Sudden massive narrowing of the airways may cause collapse, based on observations of hospitalized asthmat¡c patients who were ¡n¡t¡ally stable but who suddenly deteriorated and required markedly inreased vent¡latory pressuresl03. The possibility of an alternative process such as pneumothorax should also be considered in this situation. This was found in two children in a series of 13 fatal cases49. Pneumothorax may also be associated with fatal air embolism in status asthmaticusTg.

The possibility of electrolyte disturbance ¡n fatal cases has been considered3a. ln particular hypokalaemia due to the action of ß2-agonists may potent¡ate the irritat¡ve effects of , acidosis and of the ß2-agonists themselves on the myocardium. lt has also been proposed that hypokalaemia could induce muscle weakness4s, thus interfering with chest wall and respiratory muscle act¡ons.

Occasionally the presence of other lung lesions may adversely affect the outcome of an acute attack. For example, bronchopneumonia and previous pulmonary thromboembolism were found in three of a series of 13 asthmatic children who died unexpectedly4g. Similarly, viral infection of the lungs may precipitate a lethal episode in predisposed childrens2. Along with bacteriat infections, this may account for the seasonal variation in incidence of lethal episodesTo.

Pneumothoraces and drug hypersensitivity may also act as precipitating factors in a small number of caseslo. Children with an acute asthmatic episode often have nausea and vomiting sometimes exacerbated by medications, but gastric aspiration has not usually been considered a significant contr¡butor to death.

A final possibility that may increase the likelihood of sudden death is adrenal insufficiencys2 which has been demonstrated in adolescent asthmatics secondary to prolonged steroid usagel a.

Pathological Features

At autopsy, a history of rapidly progressive respiratory symptoms prior to collapse will enable clinicopathological correlation to be made in a child in whom fatal asthma is suspected.

However the t¡me from no apparent symptoms to death may be only secondsT6, and the present¡ng history may also be atypical in that hypoxia may have induced with incontinence or impaired consciousness28. 236

The three main components in a fatal asthmatic attack are bronchospasm, plugging of

airways by tenacious secretions and oedema of the mucosa. All may contribute to worsening

hypoxia resulting in cardiorespiratory arrest. Evidence of the latter two processes may be found

at autopsy, with the changes in the airways occurring in response to inflammatory mediators

such as histamine, leukotrienes and eosinophil cationic protein that are released by mast cells

and eosinophils. Tension pneumothorax, although rare, should always be considered in these

children and chest X-ray or opening of the chest under a water seal should be performed.

The lungs are usually markedly hyperinflated, often meeting in the midline and retaining

their shape after evisceration {Figure b-1), One of the most striking features on inspection of

the opened airways and cut surface of the lungs is the presence of thick tenacious mucus plugs

filling bronchi and bronchioles {Figure 5-2). There may also be evidence of bronchiectas¡s and

emphysema.

Classically, the microscopic features of asthma include oedema of the bronchial walls

with an increase in inflammatory cells (particularly eosinophils), thickening of the subep¡thelial

basement membrane and hypertrophy of smooth muscle (Figure 5-3). There may also be

hypertrophy of submucosal mucous glands. The increase in submucosal chronic inflammatory cells may result from a viral infection which has triggered the lethal episode. W¡th¡n the bronchial lumena there may be mucous plugs which contain variable numbers of eosinophils and strands of desquamated ciliated respiratory epithelial cells forming Curshmann spirals. Charcot-

Leyden crystals may be associated with eosinophils. Myocardial contract¡on band necrosis has also been reported in children who have died during status asthmaticus23.

Although the histologic findings may be typical of asthma, it should be stressed that there are no pathognomonic features unique to lethal cases and that lung sections may even appear reasonably normal76. Thus there is a need to rely on an appropriate clinical history and on the exclusion of other possibilities. As well, it should be emphasized that features may be variably distributed involving some, but not necessarily all, bronchí. Figure 5-1: Hyperinflated lungs in a case of sudden death of a five-year-old asthmat¡c boy. Air trapping has caused the bulky lungs to almost completely obscure the anter¡or surface of the heart.

d ú .iVrr I ¡ -i íu , ¡ll 'úr I -" ä tt ,t À' ,ö N à I t Aa- tf' ttt,i

'j\

I

Figure 5-2: Tenacious mucous plugs filling the lower trachea and major bronchi may be found in

asthma {A). Cut surface of the lung showing extruded mucus plugs (arrows) (B).

TJry

!l,Ali .Ì Figure 5-3: Thickening of the basement membrane and bronchiolar smooth muscle with an infiltrate of inflammatory cells containing a preponderance of eosinophils in a 1O-year-old asthmatic girl who died suddenly (Haematoxylin & Eosin, x 4401.

¡

)O-- 'Ë-- fa l4"O;' â- 237

UPPER AIRWAY OBSTRUCTION

Obstruction of the airways most often occurs in children as a result of foreign body impaction, however, there are a variety of intrinsic and extrinsic lesions that may also result ¡n acute airway occlusion, by a variety of different mechanismso,ls,ss'61. These can be classified according to their anatomical location and are listed in Table 5-2. Although not all of these have been reported as causes of sudden death, it is reasonable to suppose that any lesion of the upper airway that causes significant dyspnoea and stridor, and that requires urgent endotracheal intubation, is also capable of causing lethal airway occlusion. While a number of congenital abnormalities, such as choanal atresia, present within the neonatal period, occasional cases with incomplete airway occlusion may not be diagnosed until later in life.

TABLE 5.2: CONDITIONS ASSOCIATED WITH UPPER AIRWAY OBSTRUCTION AND SUDDEN DEATH IN CHILDHOOD

1. Choanal atresia

2. Nasopharyngeal tumours

3. Posterior lingual masses e.g. thyroglossal duct cysts

4. Macroglossia

5. Micrognathic syndromes e.g. Pierre-Robin, Goldenhar, Treacher-Collins, Apert, Crouzon

6. Heterotopic tissues

7. Upper airway infections

L Structural airway defects e.g. tracheomalacia, bronchomalacia

9. Tracheal stenosis

10. Vascular rings

11. Miscellaneous 234

STUDY #5-1

A STUDY OF MECHANISMS OF ASPHYX¡AL DEATH IN INFANCY AND EARLY CHILDHOOD

MATERIALS AND METHODS

Records of the Adelaide Children's Hospital Histopathology Department were reviewed for cases of asphyxial deaths in childhood and infancy. Twenty-seven cases were found and were analysed with respect to age, sex and the circumstances of death.

RESULTS

The median age et death was 15 months (Range : 6 weeks to 7 years| and the male to female ratio was approximately 2:1. Deaths occurred from upper and lower airway obstruction, suffocation and hanging. ln 1 5 of 27 cases death resulted from choking. ln four cases the airways were obstructed by food which included peanuts (N : 1 ), a carrot (N : 1) and mincemeat

(N=2). One child vomited and aspirated while travelling restrained in a car. Foreign bodies found included a toy ball, a woodscrew, a plastic chess piece, and in two cases tablets. Two cases involved airway obstruction from without by material in the oesophagus. ln one case an intraoesophageal bolus (sausage) was found and in another, a one cent coin wedged in the oesophagus was associated with tracheal compression. Accidental choking due to fine granular material was found in three young boys - one died in a sand pit, another at a fert¡l¡zer works and another in a field storage bin containing wheat. Of the remaining 1 2 cases, three cases of wedging between the cot and a mattress or another piece of furniture was identified. Plastic bags over a pillow or mattress asphyxiated two children and another infant died when she fell between the back of the couch and the soft pillows of the seat. Five cases of strangulation/hanging were identified in which there was constriction of the neck by clothing, a curtain cord in one case and the seat belt of a baby car seat in another.

CONCLUSION

These cases demonstrate the range of asphyxial deaths that can occur in infancy and early childhoodol. The absence of pathognomic findings at autopsy, part¡cularly in cases involving wedging or plastic bags may lead to a mistaken diagnosis of SIDS in infants if an adequate death scene investigation has not been conducted.

**r 239

CHOANAL ATRESIA

Obstruction to the airway at the level of the choanae may be unilateral and partial, or bilateral

and complete. When it is complete, either due to membranous or bony obstruction, symptoms

of respiratory distress occur immediately after birth and may result in deathls. ln incomplete

cases infants may survive longer with signs of airway obstruction developing only during

feedinggo. The cause of airway obstruct¡on in these infants is similar to infants wíth Pierre-

Robin anomaly and involves posterior displacement of the tongue22.

ln some cases there may be functional nasal obstruction in the absence of definite

choanal atresia, so-called congenital nasal stenosis4T. The symptoms are similar to choanal

atresia, suggesting that choanal atresia and congenital nasal stenosis represent different

manifestations of the same disorder. Variable combinations of stenosis of the ent¡re nasal

cavity, the anterior port¡on of the nose or the choanae characterize the latter entitys3. A point

to remember in congenital nasal stenosis is that functional airway obstruction may still have

occurred even if it is possible to pass a probe from the nostrils into the nasopharynx.

NASOPHARYNGEAL TUMOURS

A variety of tumours and developmental anomalies such as teratomas and encephalocoeles may

impinge on the upper aerodigestive tract and cause obstructionT3. As well, hypertrophy of the

adenoids and tonsils may result in upper airway blockage, respiratory distress and apnoea, with

some infants developing pulmonary hypertension and cor pulmonalel3,56,

LINGUAL THYROGLOSSAL DUCT CYSTS

Characteristic features are described below.

STUDY #5-2

DEMONSTRATION OF THE ASSOCIAT¡ON BETWEEN LINGUAL THYROGLOSSAL DUCT

REMNANTS AND SUDDEN UNEXPECTED DEATH IN INFANCY

INTRODUCTION

Thyroglossal duct lesions usually present in childhood as cystic midline cervical swellings.

Although they are most often found near the hyoid bone, cysts can potentially be found

anywhere along the course of the duct, which runs from the foramen caecum of the tongue to the thyroid isthmus. Occasionally remnants can be found at unusual sites such as the 240

) suprasternal notch, w¡th¡n the tongue or in more lateral locations. Presenting complaints most often relate to recurrent ¡ocal inflammation and infectionTT. Thyroglossat duct remnants located at the base of the tongue may present with more serious problems due to the¡r crit¡cal position in the upper airway35'ss.63; for example, fatal airway obstruction is a complicat¡on that has been recognised for a number of yearsl2. The following cases of sudden and unexpected death due to a¡rway obstruct¡on by lingual thyroglossal duct cysts in two previously well three-month-old infants, with m¡n¡mal antemortem symptoms, are presented to demonstrate the clinicopathologic features of this entity and its association with sudden deathl6.

CASE REPORTS

Case 1: A three-month-old boy who was last fed at O40O hours was found dead in his cot four hours later. His past history included premature delivery with a birth weight of 1,6909.

Postnatally his course was complicated by possible sepsis and a mildly elevated serum bilirubin which was successfully treated with phototherapy. He was discharged from hospital at the end of one month with a weight oÍ 2,4309. Following discharge he remained well with a 1 kilogram weight gain over the following month. The only unusual feature was occasional irregular,

"rasping" respiration. On the day before his death he was noted to have a mild upper respiratory tract infect¡on.

At autopsy the body was that of a well nourished male infant of three months weighing

3,8259 and measuring 53cm (crown-heell. There were no dysmorphic features or signs of trauma. Abdominal and thoracic cavities and organs were unremarkable except for scattered petechial haemorrhages on the surface of the thymus and visceral pleura. The major finding was in the oropharynx where a large midline cyst measuring 13mm in maximum diameter was located at the base of the tongue obstructing the glottis. The airway above and below the obstructive lesion was normal, as were the surrounding soft tissues of the neck. Sectioning showed the cyst to be unilocular and fluid-filled (Figure 5-4). Microscopic examination revealed a mixed lining of ciliated pseudostratified columnar and non-keratinising squamous epithelium surrounded by a dense fibro-connective tissue capsule that was infiltrated by occasional chronic inflammatory cells. No other significant pathological findings were present. Death was attributed to asphyxia from obstruct¡on of the upper airway by a previously unsuspected lingual thyroglossal duct cyst. Figure 5-4: A sagittal sect¡on of the thyroglossal duct cyst and adjacent base of the tongue of demonstrating the downward displacement of the epiglottis (open arrow) with compromise the upper airway (Case 1). (Haematoxylin and eosin, xB)

t

Figure 5-5: A sagittal sect¡on of the tongue and epiglottis showing a cyst in the region of the

foramen caecum. Note that the tongue and cyst have been displaced anteriorly in this

photograph (Case 2). 24L

Case 2: A previously well three-month-old boy, who was last fed at 1930 hours and checked at

0100 hours, was found dead in his cot at 0600 hours. He was found lying on his back with a crocheted quilt across his face. His past history is unremarkable with no record of antenatal or perinatal problems. He had been taken to his local doctor two weeks before death with a mild upper resp¡ratory tract ¡nfection which settled spontaneously. He had been quite well on the day prior to h¡s death.

At autopsy the body was that of a well nourished male infant of three months. There were no dysmorphic features or signs of trauma. The mouth contained fine white froth. The abdominal and thorac¡c cavities were unremarkable except for multiple petechial haemorrhages on the surface of the thymus w¡th occasional petechiae on the visceral pleura. The major finding was in the oropharynx where an 8mm d¡ameter midline cyst was found in the region of the foramen caecum in the posterior longue (Figure 5-5). The airway above and below the lesion was normal as were the surrounding soft tissues of the neck. Sectioning showed a unilocular cyst conta¡n¡ng clear fluid. Microscopic examination demonstrated a flattened squamous epithelial lining wíth several smaller irregutar adjacent tracts lined by a similar type of epithelium. A surrounding layer of loose fibro-connect¡ve tissue was present. No other significant pathological findings were present. Death was attributed to asphyxia from obstruction of the upper airway by a previously unsuspected lingual thyroglossal duct cyst.

Note, in both cases the possibility of SIDS could not be completely excluded due to the age, history and other post mortem findings, although it was felt that the presence of lesions of a size considered sufficient to obstruct the upper airway precluded this diagnosis. DrscusstoN ln the l¡terature materials causing fatal a¡rway compromise have been extremely diverse, although parts of toys and food products feature quite prominently2T. lnfectious causes of airway obstruction such as acute epiglott¡s or tumours such as subglottic haemangiomas are also not uncommon. Less usual causes include choanal atres¡as, tracheo- and laryngomalacia, retropharyngeal abscesses, and vascular rings9o'1o0. Thyroglossal duct remnants very rarely compromise the airway68 and are usually not included in the l¡st of common causes of airway obstruction in infants and children. 242

The thyroglossal duct develops embryologically from canalisation of an epithelial remnant that connects the caudally migrating thyroid gland to the foramen caecum of the tongue. After the thyro¡d gland reaches its final position in the anter¡or neck at around seven weeks of fetal age the duct regresses and has usually disappeared within two to three weeks. lf remnants remain, however, mucus secretion with no drainage results in cyst formation. This usually occurs in midline remnants lying immediately beneath the hyoid bone. Tracts are lined by either respiratory or squamous epithelium and tend to be multiple with branching and arboris¿1¡e¡85'86.

Subsequent infection is a complication that may lead to medical attent¡on.

Thyroglossal duct remnants located at the base of the tongue tend to present quite differently from other sites because of their critical position in the upper aerodigestive tract. As well, this usually occurs at a younger age than the more common anterior neck remnants.

Review of reported cases shows that airway obstruction manifested by positional stridor, neonatal asphyxia, or even sudden death due to complete airway occlusion, are possible modes of presentat¡on. Other problems may include feeding difficulties or merely a mass effect at the base of the tongue3s.ss.63,68,77. The differential d¡agnosis in this case includes ectopic thyroid tissue, haemangioma or dermoid cystg1. The most sign¡ficant side effect, that of sudden death, emphasizes the need for early diagnosis with surgical treatment if this is to be avoided.

An important antemortem clue to the diagnosis is positional improvement in dyspnoea and stridor when the infant is placed in a prone position on his abdomen as th¡s relieves the pressure of the cyst on the glottis. Of note, the second infant was found dead in a supine position, which is the most vulnerable position for airway obstruction in patients with these posterior lingual lesions.

Obstruction of the airway is reasonably obvious in Case 1 due to the larger size of the cyst and closer proximity to the epiglottis (Figure 5-4). lt is also thought to be the most probable cause of death in Case 2, particularly with the supine position of the body which would have maximised the possibility of glottic obstruction from the remnant.

An adequate paediatric postmortem examination requires careful dissection of the upper aerodigestive tract with complete excision of the soft palate, Waldeyer's ring and tongue, so that these lesions will be adequately demonstrated and not overlooked. Failure to f¡nd the Figure 5-6: En ó/oc dissection of the tongue and upper airway in an infant w¡th mandibular

hypoplasia and recurrent cyanot¡c episodes clearly demonstrating the effects on the laryngeal

inlet of backward displacement of the tongue.

Figure 5-7: A three-month-old boy who was found dead in his bed showing the typ¡cal fac¡al profile of Pierre-Robin anomalad 243

thyroglossal remnant may lead to diagnostic confusion with SIDS, part¡cularly given the presence of petechial haemorrhages that occur secondary to the terminal asphyxial event'

SUMMARY

Two infants discovered dead in their cots (one in the supine pos¡t¡on) were found at autopsy to

have died from asphyxia due to obstruction of the¡r upper airways by lingual thyroglossal duct

cysts.

ttt

MACROGLOSSIA

An interesting case at the Adelaide Children's Hospital concerned a six-month-old girl with

st¡gmata of congenital hypothyroidism who choked and died suddenly while being bottle fed.

No evidence of milk inhalation could be found, however the infant's tongue was of considerable

size protruding from her mouth and causing the floor of the mouth to bulge inferiorly. lt was

considered likely that this had contributed to upper airway obstruction and death.

MICROGNATHISM & ASSOCIATED SYNDROMES

lnfants suffering from a variety of syndromes that are characterized by micro/retrognath¡a are at

risk of acute airway obstruction due to posterior displacement of the tongue. The anatomical

effect of this arrangement on the upper airway is well demonstrated in Figure 5-6 which shows

an en-bloc dissection of the mandible and tongue in an infant with Pierre-Robin anomaly in

which there is complete occlusion of the glottis by the tongue. Occasionally there may also be

an intrinsic abnormality of the epiglottis which may exacerbate the tendency to airway

obstruction.

Pierre-Robin anomaly is characterized by micrognathia and glossoptosis, with or without

cleft palate (Figure 5-7). Anomalies of the limbs are also common and congenital cardiac

defects occur. Many infants with the Pierre-Robin complex also have an underlying syndrome

such as Stickler, Mobius, Joubert, Brachman de Lange and Marden-Walker syndrornes80,

features of which should be checked for at autopsy.

Sudden and unexpected death may occur even while the micrognathic infant is in

hospital and, although the cause may initially appeer uncertainloo, upper airway obstruction is

most l¡kely. Typical histories of choking, cyanosis and difficulty swallowing are supportive of 244

this as the lethal mechanism. lnfants with Pierre-Robin anomaly are also known to suffer central

apnoeic episodes during sleep which may contr¡bute to the terminal episode33.

A review of autopsy files at the Adelaide Children's Hospital identified several cases of

Pierre-Robin anomaly with sudden death attributable to upper airway obstruction. Other conditions with fatal outcomes associated with micrognathia were Treacher-Collins and

Goldenhar syndromes. Acute airway obstruction may also occur in infants with other types of facial skeletal abnormalilies such as maxillary hypoplasia in Crouzon and Apert syndromes.

HETEROTOPIC TISSUES

Choristomas are aggregates of histologically-unremarkable tissues found in heterotopic sites. These may be of minimal significance unless there is compromise of function due to crit¡cal location of the tissue such as within the upper airway. Examples include thymus tissue within the trachea, thyroid tissue within the tongue and gastric mucosa within the hYPoPharYnx4s,so, sT.

UPPER AIRWAY INFECTIONS

Examination of the epiglottis is a mandatory part of every paediatric autopsy. ln cases of acute epiglottitis the epiglonis is red and swollen and may completely occlude the laryngeal inlet (Figure 5-8). Microscopic examination shows a florid neutrophil ¡nfiltrate, sometimes with bacterial colonies' Throat and blood cultures are an essent¡al part of the eutopsy and most often reveal Hemophilus influenzae type B. Acute haemorrhage into the soft t¡ssues around the base of the epiglottis from other causes may also occlude the airway (see Fig 7-g). Although much less common than fatal acute epiglottitis, other acute infections of the upper airway may cause sudden death due to airway occlusion. These include tonsillitis, peritonsillar abscess, retropharyngeal abscess, lingual tonsillitis and posterior lingual abscessl8 (vide ínfral' The relatively nonspecific symptoms and signs that may be present in infants with these conditions makes careful examination of the upper airway essential at autopsy. Figure 5-8: Fatal acute epiglottitis demonstrating complete airway occlusion

Figure 5-9: Separation of muscle bundles in the posterior portion of the tongue by an extensive

acute inflammatory infiltrate, (Haematoxylin & Eosin, x 110). 245

STUDY #5-3

DEMONSTRATION OF THE ASSOCIATION BETWEEN POSTERIOR L¡NGUAL ABSCESS AND

SUDDEN UNEXPECTED DEATH IN INFANCY

CASE REPORT

A five-month-old boy was found unresponsive one afternoon in his cot, having been last seen alive approximately two hours before. Resuscitation was attempted, but was unsuccessful and he was declared dead on arrival at hospital, The pregnancy, delivery and postnatal growth had all been normal and the only significant past medical history had been of an upper respiratory infection two days prior to death for which he had been prescribed codeine. There had been no stridor or dyspnoea noted.

At autopsy fluid blood, petechial haemorrhages of the thymus and visceral pleural surfaces, and pulmonary congestion and oedema were consistent with a diagnosis of SIDS.

There was no evidence of trauma. A small focus of acute bronchopneumonia in the lower lobe of the right lung was not considered to have played a significant role in the cause of death and a

postmortem blood culture was sterile. Of note, an area of extensive acute inflammation with

neutrophil aggregation and interstitial expansion was found at the base of the tongue in the

midline adjacent to deeply placed mixed minor salivary glands and ducts and closely apposed to,

but not involving, the epiglottis (Figure 5-9), No cultures were taken from the lesion and Gram

sta¡ning for micro-organisms was uninformative.

Due to the presence of a relatively large inflammatory mass in the uppdr airway that

could have caused or initiated obstruct¡on and asphyxia, death could not be attributed to SIDS,

but was labelled more generally as "sudden unexpected death in an infant with acute posterior

lingual inflammation" .

DISCUSSION

As already noted, the possibility of intrinsic obstructive lesions within the airway must always

be considered in cases of sudden death. This is of particular importance in infancy as it has

been demonstrated that the infant airway is very suscept¡ble to obstruction due to its relative

narrowness93. ln the case described, sudden death occurred in association with an

inflammatory lesion at the base of the tongue that was only detected at autopsy once careful 246

exam¡nat¡on of the upper aerodigestive tract had been performed. Histological examination

confírmed the diagnosis of extensive acute inflammation. The presence of very focal

bronchopneumonia would be in keeping with the clinical h¡story of infection, but was not in

itself sufficient to have caused death. This was supported by the lack of organism growth on

blood cultures.

The underlying cause of the posterior lingual inflammation in the reported case remains

unclear. While it is possible that it represented an infected thyroglossal duct remnant, the

absence of lining epithelium and the relatively diffuse nature of the infiltrate makes this unlikely.

Another possibility that could not be confirmed due to the extensive acute inflammatory infiltrate

was of an infected retention mucocoele with deeply placed minor sativary glands and ducts

providing a basis for this. The more significant feature, however, was that ¡nterst¡tial

inflammation and oedema had occurred at a critical point in the upper airway,

Although ¡t is impossible in this case to definitely exclude the pathophysiologic

mechanisms that are responsible for SIDS, the presence of a lesion that could have contributed

to, or even caused, death precludes this diagno"¡rlo1. lt is ¡nteresting to note that a recent

report has proposed that infants who die of SIDS have significantly larger tongues than age-

matched controlss2. Given other stud¡es which have suggested that the upper airway in infants dying of SIDS may be narrower than normal93, the presence of any space-occupying process within the airway would, therefore, have an even greater potential for obstruction in this population' lf this is the case, then it would seem appropriate to pay particular attention to the assessment of the upper aerodigestive tract in infants who are in the high risk group for SIDS. SUMMARY

A case is described of sudden and unexpected death in a five-month-old boy who was found to have acute inflammation with multifocal abscess formation at the base of his tongue adjacent to the epiglottis. The case demonstrates the vulnerability of the upper aerodigestive tract in infancy to possible anatomic or functional obstruction from intrinsic lesions and draws attention to the potentially lethal effects of critically-placed posterior lingual inflammation. *** 247

TRA C H EO MAI.AC IA/BRO N C H O MALAC ¡A

These ent¡t¡es are grouped together as they represent conditions in which loss of structural

integrity of the upper airway at various levels results in airway collapse and obstruction.

Tracheomalacia may be primary or it may develop secondarily in infants with tracheo-

oesophageal fistulas and vascular rings, congenital chondromalacia, polychondritis, Ehlers-

Danlos and Larsen syndromesll,106, or as a result of prolonged artificial ventilat¡on (for example

in infants with bronchopulmonary dysplasia). lt is character¡zed by a deficiency in tracheal

cartilagenous rings and although ¡t ¡s generally benign and undergoes spontaneous resolution, it

may result in unexpected death in infancy due to airway compromise24,43.

Bronchomalacia may occur spontaneously, or as part of a familial syndrome. lt is

characterized by incomplete development of cartilage resulting in weakening and collapse of the

walls of the lower airways. The presentat¡on may be of respiratory distress soon after birth2, or

rarely as sudden infant deaths.

TRACHEAL STENOSIS

Tracheal stenosis may predispose to sudden airway occlusion due to increased vulnerability to

mucus plugging or to other conditions which may exacerbate lumenal narrowing.

VASCULAR RINGS

Respiratory distress has been described in infants with aberrant vessels compressing the upper

airway43'so and also in acyanotic congenital cardiac disease due to bronchial compression by

hypertensive pulmonary arteries. Occasionally a massively enlarged heart may also compress the

lungs88. Vascular rings are discussed further in Chapter 3.

MISCELI.ANEOUS

As well as external compression from aberrant vessels, the trachea may be compromised by

food or objects within the oesophagus, or from neck and mediastinal masses17,73'92. Tracheal

compression resulting ¡n stridor in a seven and a half-year-old boy due to achalasia has also been

reported20.

Acute upper airway obstruction is a feature of a variety of other ent¡t¡es. Although they

are e¡ther exceedingly rare, manifest ¡n the neonatal period or are not usually associated with

fatal airway compromise, they have been ment¡oned here for completeness3g'46. lt must be 248

remembered that any ¡esion which narrows the airways increases the risk of acute obstruction

when more common coincident inflammatory conditions occur.

Vocal cord paralysis may be unilateral or bilateral, the latter more often associated w¡th

cerebral problems such as Arnold-Chiari malformation. Although sudden death is not a feature

of reports in the literature, airway obstruction may occur necessitating tracheostomyT3.

Rheumato¡d añhriiis involving the cricoarytenoid joint is rarely found in childhood,

although occasional case reports have documented it as a cause of acute airway occlusion3o.

Ligneous conjunctivitis is a rare, possibly familial condition, of uncertain aetiology in

which recurrent pseudomembranes form on the conjunctivae and within the nasopharynx,

larynx, trachea and bronchis. Girls under the age of three years aÍe most often affected and

significant airway obstruction may result. Histologically there is pseudomembrane formation

with chronic inflammat¡on and neovascularízation21.

Congenital subglottic stenosis is characterized by narrowing of the subglottic area

producing stridor and respiratory distress. There is an association with other congenital lesions

and with Down syndrome. Acute airway obstruction may occur with minimal laryngeal

inflammation, causing a significant percentage of affected infants to require tracheostomy in an earlier series4o, although the risk of sudden death remains even if tracheostomy has been performed. Histopathologically the stenosis may be caused by either soft tissue or cartilagenous narrowing of the subglottic spaceg4.

Laryngomalacia is characterized by collapse of the ep¡glottis and adjacent airway.

Although the possibility of laryngomalacia causing infantile apnoea has been the subject of debate, Sivan, Ben-Ari and Schonfelds3 have documented a series of six infants with recurrent apnoea of infancy who were found on fibre-optic endoscopy to have airway obstruction at the laryngeal orifice due to laryngeal collapse.

Laryngeal webs and atresias are lesions which also cause airway obstruction but which usually present at, or soon after birth73.

Subglottic haemangiomas are benign vascular lesions which may result in respiratory compromíse due to the¡r critical posit¡on (Figure 5-10). As with haemangiomas in other parts of the body in early childhood, spontaneous resolution may occurs4. Other lesions such as Figure 5-10: Marked obstruction of the airway can be seen in this transverse section of the trachea due to an intraluminal haemangloma.

hygroma. Figure 5-1 1 : Narrowing of the laryngeal inlet due to an extens¡vely infiltrating cystic 249

extens¡ve cyst¡c hygromas may also compromise the upper airway if the epiglott¡s ¡s involved

(Figure 5-1 1).

Laryngeal cysts which fill with fluid and cause airway blockage occur in neonates and young infantses. Oedema and haemorrhage associated with endoscopy in these cases may precipitate complete airway occlusion and sudden death73.

Marshall-Smith syndrome is another exceedingly rare condition in which there is micrognathia, choanal atresia, laryngomalacia and pulmonary hypertension, all of which may contribute to sudden ds¿1þ1os.

Harpey and Renault36 have postulated that an excessively long uvula may result in sudden infant death, however confirmatory data are lacking.

Certain subtypes of epidermolysis bullosa produce blistering within the upper aerodigestive tract. lt is conceivable that detachment of an inflammatory pseudomembrane could cause acute airway obstruction.

FOREIGN BODY IMPACTION/MIGRATION

Given the possibility of sudden and unexpected infant death being caused by an occult foreign body, it is worthwhile briefly considering the range of clinicopathological features that may occur. ln the literature the peak age range for choking on foreign bodies is two to three years26, with 90% of cases occurring in children under five years37. Round foods (hot dogs, carrots, candy, nuts, and grapesl are the most frequently asp¡rated foreign objects causing death, although a variety of objects may impact in the upper airway. Symptoms, which include choking, gagging, coughing, or wheezing, may subside when the foreign body moves into the bronchi3T. A significant problem may occur in infancy due to eruption of incisor several months before molar teeth97, as th¡s enables portions of firm food to be bitten off, but not chewed. The diagnosis may be delayed in 30% of cases and only 80% will have a positive history for aspiration. The chest X-ray may be normal and foreign material aspirated into the trachea may

cause delayed death4l. lf there has been medical attention, the foreign object may have been

removed and thus the autopsy may not reveal the cause of death. ln such cases, reading the

medical record should provide appropriate documentation. Optimally the foreign body can be

retrieved by the pathologist for examination and photographic documentation. 250

Foreign bodies causing acute upper airway obstruction in children usually lodge in the pharynx or within the tracheobronchial tree. ln addition, foreign material may pass into the

oesophagus and compromise the upper airway, even in very young infants.

ln infants a foreign body may lodge within the upper oesophagus without causing

significant immediate symptoms. over time, compression of the trachea combined with local

inflammation may cause acute airway blockage. Such was the case in a four-month-old infant

who presented as probable SIDS, the deta¡ls of which are described belowl7.

STUDY #54

DEMONSTRATION OF THE ASSOCIATION BETWEEN OCCULT INTRA.OESOPHAGEAL FOREIGN

BODY AND SUDDEN UNEXPECTED DEATH IN INFANCY

INTRODUCT¡ON

A case is presented which illustrates the potentially lethal complication of delayed airway

obstruction by a foreign body that has by-passed the larynx and lodged in the adjacent oesophagus.

CASE REPORT

A previously well four-month-old boy was last fed at midnight and put to bed at OlOO hours on the morning of his death. He was heard snoring at O4OO hours and found dead at Og30 hours lying prone and face down in bed. The deceased's past medical history included a normal pregnancy and vaginal delivery with a birth weight of 3.5kg. ln the ten days preceding death he had been diagnosed as having a mild upper respiratory tract ¡nfect¡on which was treated with a decongestant mixture. He seemed to be improving on this regime. lt was noted that he had always snored intermittently during sleep. The clinical impression was of SIDS.

At autopsy the body was that of a normally formed four-month-old boy. There were no external dysmorphic features. The pleural and peritoneal cavities were unremarkable and the thoracic and abdominal organs were normally situated. Several petechial haemorrhages were present on the thymus' ln the oesophagus a 1 cent piece (diameter approximately 17mml was found lodged 35mm above the level of the carina. At the site of the impaction the mucosa was eroded bilaterally by the edge of the co¡n. A small emount of white exudate wes present (Figure covering the mucosal defects 5-124). There was no evidence of haemorrhage into the Figure 5-12: A one cent coin firmly wedged in the upper oesophagus in a four-month-old boy who was ¡n¡tially considered to have died of SIDS (A). Histologic cross-section after removal of the coin revealed ulceration on either side of the oesophagus with compression of the adjacent trachea which contained mucopurulent debr¡s (B) (Haematoxylin & Eosin, X 6).

t,

B .t 25L

tissues around the oesophagus. There were no diverticulae or fistulae. The trachea contained a plug of pale mucopurulent material within the lumen extending into each of the major bronchi.

The lungs were slightly atelectatic. All other organ systems were normal.

Microscopic examination of the oesophagus at the level of the coin showed two foci of mucosal ulceration where the lateral edges of the coin had eroded into the wall, with prominent underlying necrosis of the muscularis propria and replacement by granulation and fibrous tissue

(Figure 5-128). A marked mixed inflammatory infiltrate extended into the surrounding tissue involving the adjacent trachea, which showed thickening of the submucosa with squamous metaplasia of the mucosa anteriorly and posteriorly. There was a large amount of mucopurulent material w¡th¡n the lumen of the trachea extending to involve the main bronchi. The trachea above the level of the coin showed moderate mucosal congestion with a mixed inflammatory cell infiltrate, associated with moderate amounts of mucopurulent material within the lumen. Other sections of the oesophagus were unremarkable. Special staining for micro-organisms failed to demonstrate bacteria or fungi. Post-mortem viral and bacterial cultures showed no significant growth.

Death in this four-month-old boy was attributed to acute tracheobronchial obstruction due to chronic mucopurulent tracheobronchitis and external compression associated with an adjacent intra-oesophageal foreign body. On specific questioning, no h¡story of ingestion could be obtained from the parents, although they thought that a two-year-old sibling, who often played with the deceased, may have provided him with the coin.

Drscuss¡oN

Serious complications of intra-oesophageal foreign bodies in infancy and childhood are rare, tending to occur in cases with prolonged impaction, and include oesophageal perforation with abscess formation, aorto-oesophageal fistula formation, mediastinitis and para-oesophageal

¿5ssgss4,32,42'71,87. Tracheobronchial occlusion occurring once an ingested foreign body has passed the larynx and entered the oesophagus is an unusual phenomenon that may, however, be responsible for symptoms of respiratory obstruct¡on2s's6. ln addition to coins and sharp objects, button batteries may be particularly hazardous as leakage of contents may hasten perforation. ln a series oÍ 2394 pat¡ents with intra-oesophageal foreign bodies, the youngest 252

was aged seven months64. lnfants under six months of age who aspirate usually have been

given the foreign body by an older sibling26, as was suspected in this case.

The case reported illustrates the potential danger at a very young age of delayed airway

obstruction from a foreign body that has impacted in the oesophagus. The patient is unusual in

that only signs of a minor upper respiratory tract ¡nfection were exhibited, rather than the more usual acute onset of voice'change, increase in salivation, odynophagia, dysphagia, dyspnoea and

wheezingTl'se. Focal ulcerat¡on of the oesophagus due to pressure necrosis was associated

with inflammation which extended through to the underlying trachea, resulting in tracheobronchitis with thickening of the submucosa and formation of a mucopurulent exudate.

Sudden death from tracheobronchial occlusion occurred due to a combination of tenacious mucopurulent material present within the lumen of an inflamed trachea already narrowed by external compression from the coin. The presence of chronic inffammatory cells and fibrosis w¡th¡n the underlying oesophageal wall and an increase in minor salivary glands within the trachea, with squamous metaplasia of the overlying mucosa, indicates that the process had some chronicity. Of note, acquired tracheo-oesophageal fistulae due to impacted intra- oesophageal coins has occurred by a similar process of localised pressure necrosis and inflammatio n71 ,104.

Although most foreign bodies that pass through the oesophagus are not associated with a serious outcome, occasional cases may occur in which there is perforation of a viscus and occasionally there may even be unexpected death due either to associated vessel perforation or to sepsis.

SUMMARY

Acute upper airway obstruction in a four-month-old boy presenting as SIDS is described. At autopsy external tracheal compression and tracheobronchitis with plugging of the trachea and bronchi by an abundant mucopurulent exudate were found. The source of the inflammation was the adjacent oesophagus where previous impaction of a coin had caused pressure necrosis with mucosal erosion and transmural granulation tissue formation. lntra-oesophageal foreign bodies that have not been aspirated into the tracheobronchial tree must therefore be considered in cases of sudden asphyxia due to airway compromise in early ínfancy. *** Figure 5-13 lrregular scarring and uneven expansion of the lungs in bronchopulmonary

dysplasia.

t 'l h t ¡ ta ì ¡l- r' -\ -r- I .'i .'l¿ G I f n --r\ ¿J 'a ' / t .v:'+\" q'Í., t ! .ù; ,l / ,È úîF a T ,!r¡ ú? ..1 €' ,tt'l ¡ f..; t t w t lì rl . :.? \i\'t \'+ \ l' 1.. "i

Figure 5-14: Prominant septal fibrosis due to bronchopulmonary dysplasia in a six-month old boy dying unexpectedly. There was a history of prolonged ventilation following delivery at 26 weeks

(Haematoxylin & Eosin, x 170),

"l a c'ï. râr 253

BRONCHOPULMONARY DYSPLASIA

Bronchopulmonary dysplasia refers to a chronic lung disease that was first reported in 1967 in infants with severe respiratory distress syndrome who had been treated with artificial vent¡lat¡on and oxygen therapy66. Subsequent stud¡es have demonstrated a variety of contributing aet¡olog¡c agents including nutr¡t¡onal deficiencies and pulmonary oedema6s.

Frequency

The frequency of bronchopulmonary dysplasia in ventilated infants varies from a little over 4% to as high as 7Oo/o in infants ventilated for more than two *ss¡s7'31.

Occurrence of Sudden Death

Infants who have pulmonary changes of bronchopulmonary dysplasia are known to be at increased risk of sudden death, and this has led to diagnostic confusion with sudden infant death syndromeTs. The risk of sudden death has been estimated as seven times that of other infants in the populationg9. Sudden and unexpected death has also been reported in hospitalized infants with bronchopulmonary dysplasia in spite of close cardiorespiratory monitoringl.

Pathological Features

Pathologically there are three distinct phases in the development of bronchopulmonary dysplasia: acute, reparative and chronic stages3. On gross examination, the lungs are ¡nit¡ally smooth surfaced, bulky and increased in weight, but progressively develop scarring so that the f¡nal stage is characterized by marked fissuring (Figure 5-13). There may also be evidence of cardiac hypertrophy in the later stages involving both right and left ventriclesss.

Microscopically, damage occurs from the trachea down to the alveoli, with the earliest changes being necrosis of the l¡n¡ng ep¡thelial cells with ulceration. In particularly severe cases, necrosis may involve the tracheal cartilage resulting in subsequent tracheomalacia. As repair occurs, there may be squamous metaplasia, epithelial dysplasia, submucosal fibrosis and muscular hypertrophy of smaller airways. ln healed cases, evidence of damage may be patchy, with relatively normal appearing hyper-expanded alveoli abutting alveoli that show prominent septal fibrosis with fibrous obliteration of distal airspaces. Alveolar septal fibrosis has been cited as the hallmark of healed bronchopulmonary dysplasiass (Figure 5-14). Pulmonary arteries may show changes compatible with grade I to ll hypertension, and within the heart there may be secondary hypertrophy of cardiac myocytes and interstitial fibrosis. 254

Pathophysiology lnfants who survive with moderate to sever€ bronchopulmonary dysplasia manifest a variety of abnormalities including reduced head growth, general growth delay, pulmonary hypertension, increased airway resistance, reduced lung compliance, bronchial hyper-reactivity, marked maldistribution of ventiletion, carbon dioxide retent¡on, hypochloraemia with metabolic alkylosis, hypoxaemia, sleep-related arterial oxygen desaturation and neurodevelopmental 6"1¡ç¡1s29,67,69.

Given the presence of these features, and abnormal lungs on pathological examinationSg, the diagnosis of SIDS in these infants cannot be sustained.

ACUTE BRONCHOPNEUMONIA

Acute bacterial infection of the lungs and distal airways may cause sudden and unexpected death in children with relatively nonspecific symptoms and signs. Diagnostic difficulties are discussed further in Chapter 4. cYsflc FtBRosts

Cystic fibrosis is described in detail in Chapter L While the respiratory manifestations tend to be chronic, sudden death can occur in children due to electrolyte imbalances or to septic or gastrointestinal complications. Although the lungs in advanced cases may show extensive scarring with mucus plugging of bronchiectat¡c airways, this is not always the case in children who die early from the above complications. For example, a four-month-old boy who was brought to the Adelaide Children's Hospital after being discovered dead in his cot was found at autopsy to have undiagnosed cystic fibrosis with marked atrophy and fibrosis of the pancreas which contained residual ducts distended with typical inspissated eosinophilic secretions. The lungs were only mildly inflamed. Figure 5-15: Microscopic 'l sect¡on from the lungs of an 1-day-old girl who died from massive pulmonary haemorrhage demonstrating filling of the alveoli with red blood cells (Haematoxylin & Eosin, x 170).

I ) t t t- , / L 1l' I F '{ /1 ì tr? { t ? 'Írt

:f / r "å

I

Figure 5-16: Bulging of the diaphragm inferiorly due to massive bilateral tension pneumothoraces.

¡I r{ É1N f¿ 255

MASSIVE PULMONARY HAEMORRHAGE

Massive pulmonary haemorrhage of uncertain aetiology may be responsible for sudden and

unexpected death in severely growth retarded infants (Figure 5-151. Risk factors include intra-

uter¡ne growth retardation, prematurity, b¡rth asphyxia, breech or caesarian delivery, multiple

births, the presence of a patent ductus arteriosus and hyaline membrane diseasesa. However, cases may occur in which none of these features are present. ln older children hereditary haemorrhagic telangiectas¡a (Osler-Weber-Rendu disease) may also result in death due to massive intrapulmonary haemorrhageT 2.

TENSION PNEUMOTHORAX

Tension pneumothorax occurs in a number of conditions such as asthma or staphylococcal pneumonia when there is air trapping with forcing of pressurized air ¡nto the pleural cavity.

Sudden death results from compression of the lungs and shifting of the mediastinum. At autopsy the most obvious initial finding may be ptosis of the abdominal organs and bulging of the diaphragmatic domes into the peritoneat cavity (Figure S-16).

**** Refercnce¡ ChS-1

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Otolaryngology, 1 4, 261 -4. 78. Sauve, R.S. & Singhal, N. (1985). Long-term morbidity of infants with bronchopulmonary dysplasia. Pediatrics, 7 6, 7 25-33. 79. Segal, A.J. & Wasso¡man, M. (1971). Arterial ai¡ ombolism: a cause of sudden death in status asthmaticus. Radiology,99, 271-2. 80. Sheffield, L.J., Reiss, J.4., Strohm, K. & Gilding, M. (1987). A genetic follow-up study of 64 patients with tho Pierre Robin complex, American Journal of Medical Genetics,28,25-36. 81. Siboni, A, & Simonsen, J. (1986). Sudden unexpected natural death in young porsons. furensic Science

lnternational, 31, 1 59-66. 82. Siebert, J.R. & Haas, J.E. (1991). Enlargement of the tongue in sudden infant death syndrome, Pediatric Pathology, 1 1. 813-26. 83. Sivan, Y., Ben-Ari, J. & Schonfeld, T.M. (1991). Laryngomalacia: a cause for early near miss for SIDS. lnternational Journal of Pediatric Otorhinolaryngology, 21, 59-64. 84. Sly, P.D. & Drew, J.H. (1981). Massive pulmonary haemorrhage: a causo of sudden unoxpocted deaths in severoly growth rotardod infants. Australian Paediatric Journal, 17, 32-4. 85. Solomon, J.R. & Rangecroft, L. (1984). Thyroglossal-dúct lesions in childhood. Journal of Pediatric Surgery, 19, 555-61. 86. Soucy, P. & Penning. J. (1984). Tho clinical relovance of certain observations on tho histology of the thyroglossal ùacl, Joumal of Pediatric Surgery, 19, 506-9. Rele¡cncc¡ Gh54

87. Spitz, L. (1987)' Disoases of tho oesophagus. ln Paediatric Ototaryngology. Scott-Brown's Otolaryngology. sth Ed. Vol 6. ed. J.N.G. Evans, pp.534-53. London: Butte¡worths. 88. Stanger, P., Lucas Jr, R.V. & Edwards, J.E. (1g69). Anatomic facto.s causing rospiratory distress in acyånotic congonital cardiac disoase. Special roferenco to bronch¡al obstruction pediatrics, 43,760- 9. 89. Stocker, (1986). J.T. Pathologic features of long-etanding'hoaled'bronchopulmonary dysplasia: a study of ¿K)-month-old 28 3- to infanrs. Human pathology, 17, 943_61 . 90. Strife, (1988). J.L. Upper airway and tracheal obstruction in infants and child¡en. ßadiologic Ctinics of North America, 26,309-22. 91. Telander, R.L. (1977). & Deane, S.A. Thyroglossal and branchial cloft cysts and sinuses. Surgical Clinics of North America. 57,779-91 . 92. Todres, 1.D., Reppert, S.M., p.F. Walker, & G¡illo, H.C. (1g76). Managemont of c¡itical airway obstruction in a child with a mediastinal tumot. Anesthesiology,45, 1OO_2. 93. Tonkin, (19881. S' & Beach, D. The vulnerabil¡tv of th6 infant upper airway. ln Sudden lnfant Death Syndrome. Bisk kctors and Basic Mechanisms, eds. R.M. Harper & H.J. Hoffman, pp. 417-22. New York: PMA Publishing Corp. 94. Tucker, G.F., Ossoff, R.H.. Newman, A.N. & Holinger, L.D. (.l979). Histopathology of congonitol sublglottic stenosis. Thd Laryngoscope, Bg, 966-77. 95. Vanhoucke, F. & Minnigerode, B. (1989). Plostsel¡nge dood ten gevolge v6n een onopgemerkte congenitale larynxcyetð. Actd Otoúinolaryngology Belgica, 43, 125_9. 96. Vos, G.D., Heymans, H.S,A. & Urbanus, N.A.M. (1gg7). lnspiratory stridor and dysphagia bocause of prolonged esophageal foreign body. European Journal of pediatrics, l46, g6-7. 97. Warwick R. &Williams P.L. ods. (1973). Gray'sAnatomy3Sth ed., p. 1233. Edinburgh: Longman. 98. Wasserfallen, J.-8., Schaller, M.-D., Feihl, F. & perret, C.H. (1990). Sudden asphyxic asrhma: a d¡srinct entity? American Review of Respiratory Disease, 142, 1Og41 . 99. Werthar¡mer, J., Brown, E.R., Neff, R.K. & Taeusch Jr, H.W. (1982). Sudden infant death syndromo in infants with bronchopulmonary dysplasia . pediatrics, 69, 30 l _4. 1 00. Williams, A.J.. Williams, M.4., Walker, c.A. & Bush. P.G. (1981). The Robin anomalad (piorre Robin syndrome) - a follow up study. Archives of Disease in chitdhood,56, 663-9. 101. Willinger, M., James, L.S. & Catz, C., (1991). Defining tho sudden infant death syndrome (SIDS): Delibe¡ations of an expert panel convened by the National lnstitute of Child Health and Human Dovelopment, Pediatric pathology, 1 1, 677_94. 102. Wilson, J.D., Suth€rland, D.C. & Thomas, A.C. (19g,|). Has the change ro beta-agonists combined with oral theophyllino incroased casos of fatal asthma? The Lancet, 1 , 12gS-7. 1 03. Wood, D'W. & Locks, H.J. (1976). Deaths due to childhood osthma. Are they provenrablo? Clinical Pediatrics, 15, 677-87. 1 04. Yee, K.F., Schild, J.A. & Holinger, P.H. (1975). Extraluminal foroign bodies (coins) in tho food and air passagos. Annals of Otology, Rhinology and Laryngology, 94,61 9_23. 1 05. Yoder, C.C., Wiswell, T., Cornish, J.D., Cunningham, B.E. & Crumbaker, D.H. (19g8). Marshall-Smith syndrome: fu¡ther delinearion. southern Medical Journat, g1 , 1297-13oo. 1 06. Zalzal,G'H' (1989). Stridorândairwaycompromiso, PediatrìcCtinicsof NarthAmerica,36, 13gg-.l401. ST]DDEN NATURAL DEATH IN INFANCY & EARLY CHILDHOOD

CHAPTER 6

NET]ROLOGICAL CONDITIONS 256

INTRODUCTION

This chapter deals w¡th causes of sudden natural death in infancy and early childhood involving the nervous system, a large number of which are due to vascular or infective disorders26. lt should be stressed, however, that trauma should be suspected if intracranial haemorrhage is found at autopsy. Detailed review of the presenting history should then be undertaken with a complete radiological survey of the body. lf a traumatic aet¡ology can be excluded, other conditions such as cerebrovascular disease may then be looked for. Although fatal cerebrovascular disease in the paediatric age group is not common it is possible that any of the causes of occlusive vascular disease that result in childhood stroke can also result in sudden death. Possible causes of sudden death and stroke in infancy and childhood can be found in

Tables 6-1 & 6-2 (n¿apte¿ from reforences 1o,69,129,'lSg,l+ZJ.qql .

TABLE 6-1: CONDIT¡ONS ASSOCIATED wlTH CENTRAL NERVOUS SYSTEM CAUSES OF

SUDDEN PAEDIATRIC DEATH

Haematologic 5. Metabolic Disorders diatheses Haemoglobinopathies 6 lnfections Meningitis 2 Cardiovascular Encephalitis Thromboembolism Poliomyelitis Vascular malformations Aneurysm rupture 7. Structural Abnormalities Connective tissue disorders Moyamoya disease L Friedreich Ataxia Fibromuscular dysplasia Vasculitides L Tuberous Sclerosis Miscellaneous

3. Tumours 10. Von Recklinghausen disease

4. Epilepsy 11. Guillain-Barrésyndrome 257

TABLE 6-2: CONDITIONS ASSOCIATED WITH CEREBROVASCULAR ACCIDENTS IN INFANCY AND CHILDHOOD

Haematologic 5 Microbiologic Thrombocytopaenia A. Local infection Thromboc¡osis ENT pyogenic infections Polyc¡haemia Cavernous sinus thrombophlebitis Leukaemia Mucormycosis Coagulation disorders Meningitis ant¡coagulant Malaria Disseminated intravascular coagulation Herpes ophthalmicum Haemoglobinopathíes B. Generalized infection Marked anaemia Haemol¡ic uraemic syndrome Mycoplasma disease Bacterial disease 2 Cardiac Fungal disease Cyanotic congenital heart disease lnfective endocarditis Syphilis Myocarditis Hydatid disease Rheumatic fever Myxomas 6. Traumatic Prosthetic valves Closed head injury Rhythm disorders Neck or intraoral injury Cardiomyopathy Foreign body embolism Myocardial infarction Mitral valve prolapse 7 Drug Related Arterial spasm 3 Vascular Necrotising vasculitis Vascular malformations Septic emboli Arterial aneurysms Moyamoya disease I Skeletal Fibromuscular dysplasia Klippel-Feil anomaly Collagen vascular diseases Connective tissue disorders I latrogenic Takayasu disease Angiography Hypertension Radiotherapy Acute hypotension Thromboembolism 10. ldiopathic Heredítary haemorrhagic telangiectas¡a Neurocutaneous syndromes Arterial kinking Migraine External compression Superior vena cava syndrome Arterial agenesis or hypoplasia lnflammatory bowel disease 4 Metabol¡c Diabetes mellitus Homocystinuria Hyperlipidaemia Fabry disease Congenital adrenal hyperplasia Scurvy Vitamin K deficiency Liver disease Congenital C2 deficiency 258

HAEMATOLOGIC CONDITIONS

Due to the relative rigidity of the skull and the plasticity of cerebral tissue, areas of significant haemorrhage develop at the expense of the surrounding brain. Death may therefore occur rapidly from resultant cerebral oedema and brainstem herniation through the foramen magnum.

Once occult trauma has been exctuded there are a number of aetiologically unrelated disorders with very different pathophys¡ologies responsible for intracranial haemorrhage in infants and children.

BLEEDING DIATHESES

Bleeding diatheses are dealt with in greater detail in Chapter 7, however many conditions which predispose to spontaneous haemorrhage in other areas of the body may also cause major problems with intracranial bleeding, One of the most common clinical scenarios resulting in sudden death in this situation involves a child who has an acute leukaemia with thrombocytopaenia either due to marrow infiltration by malignant cells or secondary to chemotheraÞy (see Figure 7-6). Spontaneous intracranial haemorrhage may also occur in other disorders where there is reduction in the number of circulating such as in aplastic anaemia or in Wiskott-Aldrich syndrome.

lntracranial haemorrhage may follow relatively minor trauma in children with coagulation

disorders such as Haemophilia A where there is a reduction in the amount of functional

circulating factor Vlllso (see Figure 7-7).

While intracranial haemorrhage may result from disseminated intravascular coagulation,

bleeding tends to be more widespread and not necessarily unexpected, occurring in patients

who are already seriously ill from severe trauma or infection.

HAEMOGLOBINOPATHIES

lschaemic cerebral events are a known complication of sickle cell disease due to vascular

obstruction by sickled red blood cells. This may lead to intracerebral and subarachnoid

haemorrhage67,137 or to ¡nfarclis¡109 with sudden death. Cerebral vascular occlusion occurs in

as many as 17o/o of children wíth sickle cell disease and may be exacerbated by the

hypercoagulable state in these patients secondary to plasminogen deficiencyo2. Stroke in

children with sickle cell disease has also been reported in association w¡th f ibrointimal

proliferation of the carot¡d arteries156,164. The extent of cerebral ischaemia may be significantly 259

worsened by the anaemia that is present, as anaemia on its own has been associated w¡th

symptomatic hypoxic episodes in ch¡ldren184.

CARDIOVASCUI.AR CONDITIONS

THROMBOEMBOLISM

Thrombosis of the cerebral veins or sinuses with stroke may occur in chíldren with polycythaemia and/or thromboc¡osis secondary to cyanotic congenital heart diseasel43. More

rarely venous thrombosis is due to hypercoagulable states which may be familial or result from (Figures sepsis 6-l & 6-2)1s,88. Dehydration and anaemia may be exacerbating factors, the former playing a major role in cases of cerebral venous sinus thrombosis in infants with profound gastroenterit¡s.

Local sepsis involving the middle ear or sinuses can erode the skull and extend into the adjacent cranial cavity resulting in meningitis and venous sinus thrombosisT6. ln addition it may also cause an arteritís with subsequent occlusive thrombosis and strokelss. Atthough viral upper respiratory tract infection has been associated with cerebral arterial thrombosis16,46 ¡1s role in causing vascular occlusion is ill understoodT4. On occasion no apparent cause for spontaneous intracranial vessel thrombosis will be found in spite of careful pathological examinationS6.

lntracranial embolism either derives from a left-sided întracardiac source or from paradoxical embolism. Bacterial endocarditis associated with congenital cardiac defects or prosthet¡c mater¡als may result in cerebral embolism. Other lesions within the left atrium and ventricle which have led to cerebral ischaemic events are those associated with rheumatic fever, myxomaslo, hydatid cysts,23 marantic endocarditis, cardiomyopathys2, and disorders associated with arrhythmias or infarction, including cardiac transplantation2. Although the latter series included children, it is not certain whether any of them suffered cerebral events.

Theoretically any venous source of embolic material can lead to paradoxical embolism if there is a communicatíon w¡th the left side of the heart, such as an atrial or ventricular septal defect' Embolized material may be thrombus, air or even tumour, as was the case in a eight- year-old boy who suffered extensive cerebral infarction due to occlusion of his left internal carotid artery by Wilms tumour fragments that had passed through a ventricular septal defect during surgeryll2 (see Figure 8-19), Pulmonary disorders such as hereditary haemorrhagic Figure 6-1: Basilar artery thrombosis with occipital lobe and cerebellar infarction in a one-year- old boy with viral pneumonia.

Figure 6-2: Cerebral infarction following cerebral venous thrombosis in a one-month-old boy with

cyanotic congenital heart disease. (E o o l ! c) o) o E o E o (o I ' E .rr, | r a -xdJ {¡ r'r¡¡ o(!Ëo t| o-c t' h (oL 1 }¿, It POCc eH { ! lt, t' c! ,., o'Ã *,ù I kc t'¿¡r o! o I be (! ¡ O¡ -.'t (J- tut ,f r- (¡) ä.33E l.e 9o Èo)'È > ots L+> = \ 'rt' .YFt .h -O a 'r# j+ i¡ E'çEà i,t. '/z- i c- \ qì ¡-Þ ð PO \-,*t. f- ÈP?'Ð '¡ EOot l-+ í)E.-(! (oË (l)= r(J éß lJ- >

Figure 6-5: Subarachnoid haemorrhage visible on external examination of the brain (A) of a nine-

year-old girl who was found dead in bed. The subarachnoid haemorrhage was in continuity with

an area of extensive intracerebellar haemorrhage (B), however, the only residual vessels found

were dilated but otherwise normal meningeal vessels (C).

A B { I t'¡

f li "l Jì. a''

lt' jr, 't, '?f: ) ,i'

4. ¡ a I Figure 6-6: Typical dilated and abnormal vessels with interposed cerebral tissue characteristic of an arteriovenous malformation (Haematoxylin & Eosin, x 280)'

\ a I I

1i

t

¡ tas ì ¡ t a

I

a

à 260

telangiectasia and arteriovenous fistulas may lead to paradoxical cerebral embolisml29 ¡gss

Table 6-2).

VASCU LAR MALFORMAT¡ONS

ln a review of ten autopsy cases of sudden death involving non-traumatic intracranial haemorrhage from clinically unsuspected cerebral lesions in children the most common findings were vascular malformat¡ons and tumours24. The youngest case was a two and a half-year-old boy.

Clinical Features

It is generally considered that children bleeding from an intracranial vascular malformation tend not to die suddenly, the usual presentation being with symptoms and signs of raised intracranial pressure, focal neurological deficits or fittinglls. Sudden and unexpected death may, however, be the presenting feature.

Pathological Features

The first indication of a possible vascular malformation may be the presence of cerebral oedema associated with localized subarachnoid haemorrhage around the base of the brain (Figure 6-31.

A point worth emphasizing is that significant subdural haemorrhage can occur in these patients in association with intracranial haemorrhage without any apparent subarachnoid extension.

Figure 6-4 demonstrates such a phenomenon in a three-year-old boy who died following haemorrhage from an intracerebral arteriovenous malformation.

One of the major problems in trying to provide confirmatory histologic evidence at autopsy of a suspected vascular malformation is that the lesions may be destroyed when haemorrhage occurs (Figure 6-5), For example, it has been estimated that diagnostic material will be found in only 70 to 80% of cases41. lt ¡s important, therefore, to carefully sample as much of the loose and adherent blood clot as possible as remnants of abnormal vessels may st¡ll be present within this material.

Vascular malformations can take a number of different histological forms, w¡th the most common being a tangle of disordered arterioles and venules. Histologically, a typical

arteriovenous malformat¡on can be recognized by the presence of abnormally dilated and shaped

vascular channels composed of an intimate admixture of arterioles, venules and capillaries, often

with residual cerebral tissue interspersed between the vesselsl06 (Figure 6-6). Haemosiderin 26L

deposition, calcification, demyelination, neuronal loss and gliosis adjacent to vascular malformations occur when cases have had a more prolonged time coursel67. Osseous metaplasia has also been descr¡6g6107.

Occurrence of Sudden Death

Byard, Bourne and Hanieh found that nearly one half of their cases of probable bleeding cerebral vascular malformations presented acutely, w¡th one pat¡ent surviving the onset of symptoms for less than one and a half hours, and another being found dead in bed having been apparently well the night be1ore24. Other authors have described similar cases of sudden ¿s¿161so. lt has been suggested that lesions that are within the posterior fossa or near the base of the brain are more likely to be associated with sudden deatha2 (Figure 6-7) although this is not necessarily always (Figure the case 6-8). However, children with vascular malformat¡ons of the medulla may die very quickly if haemorrhage occurs. Occasionally sudden death occurs in children from bleeding vascular malformations of the choroid Þlexuslzg.

ANEURYSM RUPTURE

Death due to haemorrhage from a ruptured intracranial aneurysm is usually a condition of adults, however, sudden collapse and death may also rarely occur in children with this anomaly24.l53.

As there is an association between intracranial aneurysms and cyst¡c renal disease, both the kidneys and liver should be carefully examined and sampled at autopsy, although this applies more to adult patientsl74. There is also an increase in the incidence of intracranial aneurysms in children with coarctation of the aorta, collagen vascular disease, Marfan syndrome, Ehlers-

Danlos syndrome, tuberous sclerosis, Moyamoya disease, fibromuscular dysplasia and syphiliss3. Familial cases rarely involving children have been descr¡5s666.108 and occasionally dissecting aneurysms of the cerebral arteries will be found at autopsy with no apparent predisposing disease 1 os.

The so-called aneurysm of the vein of Galen is caused by direct shunting of branches of the internal carotid or posterior cerebral arteries into the vein of Galen. Although the presentation may be of high output cardiac failure or hydrocephalus in early life, older children and adolescents may present with subarachnoid haemorrhage. Figure 6-7: Massive intracerebellar haemorrhage due to a probable vascular malformation resulting in sudden death of an eight-year-old girl.

occipital lobe of a Figure 6-8: Sudden death due to intraparenchymal haemorrhage within the (AVM)' three-year-old boy caused by to an arteriovenous malformation 262

CONNECT¡VE TISSUE DISORDERS

Although rare, disorders of connect¡ve t¡ssue should be considered in the differential diagnosis of cerebral haemorrhage at any age. These can be separated into primary and secondary groups, represented by disorders such as Ehlers-Danlos syndrome and scurvy, respect¡vely.

While patients with Ehlers-Danlos syndrome type lV often show general fragility of connective tissues with easy bruisability73,123, this is not always the case, and fatal intracranial haemorrhage may be the first manifestation of the disorder2s (see Figure 10-3). lt may, therefore, be appropriate to take fresh and frozen tissue (e.9. skin and aorta) to fac¡litate subsequent collagen analysis and cell culture studies in cases of intracranial haemorrhage where the cause of the bleeding is not immediately apparent at autopsy, part¡cularly ¡f there is evidence of haemorrhage within other organs. For example, lack of type lll collagen in analyses from a five-month-old girl enabled the d¡agnosis of type lV Ehlers-Danlos syndrome to be made, thus explaining the subarachnoid and multifocal visceral haemorrhages that had been found at autopsy2s.

MOYAMOYA DISEASE ln Moyamoya disease a proliferative arterial lesion causes occlusion of the intracranial arteries w¡th the development of a web-like net of vessels at the base of the brain. This creates the characteristic angiographic appearance of Moyamoya, 'someth¡ng hazy just like a puff of cigarette smoke drifting in the air'166. Although originally described in Japan, it is now apparent that the condition has a world-wide d¡stribution114,1s1.

Clinical Features

There are two clinical variants, one which affects older children and causes subarachnoid haemorrhage, and the other which affects younger children and causes exercise-related ischaemia. The angiographic appearances are quite characterisliç16s and usually allow the diagnosis to be established prior to death. The incidence of Moyamoya disease as a cause of childhood stroke varies w¡th different series from four to as high as 50%. Massive intracranial haemorrhage from collateral arteriesll9 or multiple dissecting aneurysms may also be found in affected children. The finding of a familial incidence of greater than 12"/"86 increases the importance of confirming the diagnosis at autopsy. 263

Pathological Features

The major arteries that are affected are the internal carotid, anter¡or and middle cerebral, the posterior communicating and the anterior choroidallo, all of which should be sampled at autopsy. Microscopícally, affected vessels show splitting and reduplication of the internal elastic lamina with eccentr¡c ¡ntimal proliferation resulting in luminat narrowingl8l. Vessels with microaneurysm formation show attenuat¡on of the wall with focal fibrin depositionl4s. Rarely there may be an associated intracranial saccular aneurysm, although this is distinctly uncommon and tends to occur in older adolescents and adults3.

Differential Diagnosis

To establish the diagnosis of Moyamoya disease there has to be bilateral involvement of the cerebral vessels. lf there is evidence of only unilateral disease the differential diagnosis would include the possibility of trauma, cerebral tumour, tuberculosis, von Recklinghausen disease, radiation effect or fíbromuscular dysplasia (although these may also have bilateral involvemenl¡148'180. Moyamoya has also been associated with renovascular hypertens¡q¡182.

FIBROMUSCUI-AR DYSPLASIA

Fibromuscular dysplasia is an uncommon condition which may involve the carotid arteries resulting in vascular occlusion and ischaemic cerebral events47,134. Angiographically, single or multiple stenoses as well as aneurysms are seen, giving the artery a beaded appearancel03.

Microscopically there is marked hyperplasia of the arterial media with d¡sruption of the elastic laminae and adventit¡al fibros¡s. Although generally a disorder of older age groups, cases in children have been reportedloo,lss ¡¡us¡r¡ng both the carotid and vertebral artery systems.

Affected children have had cerebral and cerebellar infarctions102,t32.

VASCUL!TIDES

INFECTIOUS lnvolvement of cerebral vessels in bacterial meningitis may result in ischaemic episodes as deta¡led in Chapter 4. Vasculitis and perivasculitis have also been found in children with AIDS in association with cerebral haemorrhage and.lto¡"I10. Other viral infections such as herpes zoster may also be associated with vasculitis and strokelTs. 264

INFLAMMATORY

Although inflammatory vasculopathies of the cerebral circulation are exceedingly rare in the paediatric age range, a number have been described which may have neurological sequelae.

These include systemic lupus erythematosis, lupus anticoagulant syndrome and granulomatous

3¡1s¡¡1¡583,146,183. Kawasaki disease occasionally has been described as a cause of neurological problems but this is most likely due to thromboembolism rather than direct involvement of the cerebral uss5s¡592,96. Takayasu aort¡tis may rarely give rise to stroke in infancysT. The neurological complications of the vasculidites have been described in detail by Moore and

CuPP5l 13.

MISCELI.ANEOUS

ARTERIAL KINKING

One controversial clinicoradiological entity that has been described in association with cerebral infarction in children is arterial kinking. lt has been proposed that coiling of the internal carotid artery in certa¡n children predisposes to temporary lumenal occlusion with resultant cerebral ischaemia/infarctions3,127'147. However, other investigators have either not commented on kinking in their series of children with strokesTl or have found carot¡d artery elongation in a high percentage of children with no evidence of cerebral ischaem¡3131 . Given the difficulties encountered at autopsy in examining portions of the internal carotid artery, it is unlikely that patholog¡cal examination can contribute to this debate except to exclude other aet¡ologies.

MIGRAINE

On very rare occasions migraine has been reported as a cause of cerebral or cerebellar infarction in chi|dren11,31,43,44,75 sometimes resulting in death21, There is also an association between migraine and epilepsyl 2.

STURGE-WEBER SYNDROME

Sturge-Weber syndrome is one of the neurocutaneous disorders characterized by cutaneous and leptomeningeal angiomatosis. Although the vast majority of cases present with epilepsy, subarachnoid haemorrhage has been reported as a presenting complaint in an adult6.

MITRAL VALVE PROLAPSE

A family has been reported in which there was an apparent association between mitral valve prolapse and embolic stroke at a young age. The two youngest members to manifest 265

hemiplegias were aged six months and ten years respectivelyl¿lo. Other reports have also documented the association of thromboembolic stroke in adolescence with mitral valve prolapsel To.

CARDIAC ARRHYTHMIAS

Cardiac arrhythmias may also rarely be responsible for the development of acute hemiplegia in children, most likely on an embolic basisg.

DRUG OVERDOSE

The occurrence of haemorrhagic stroke in an adolescent due to phenylpropanolamine overdose55 suggests that drug screening at autopsy may be appropriate in some cases of childhood stroke of uncertain aetiology.

Other Factors

Other less common causes of haemorrhagic or ischaemic cerebrovascular accidents in childhood include hypertension, acute hypotension and collagen vascular 6¡srrsss10,65. Finaily, it should be noted that no cause wiil be found in a percentage of ischaemic in children in spite of detailed investigation 1 3.

TUMOURS

Generally tumours of the brain and cranial contents produce symptoms and signs of raised intracranial pressure with and alteration of conscious state. Occasionally the presentat¡on is more dramatic due to an acute disturbance in blood or cerebrospinal fluid flowl,

As well, direct pressure on brainstem respiratory centres may cause sudden death in children with located within the medullal lT.

Metastatic tumours may also result in cerebrovascular accidents in children, particularly in the case of neuroblastoma. Other -related complications include intracranial haemorrhage/thrombosis due to disseminated intravascular coagulation or to chemotherapy with

L-asparginasel 24.

Haemorrhaoe

Haemorrhage has in¡tiated the presentation of between three and 1Oo/o of reported brain tumours in different series in the literaturegs'126 and has a documented association with sudden death in both infancy and ç¡¡¡6¡ee67,1s6. Figure 6-9: Marked cerebral oedema ¡n a two and a half-year-old boy with recent haemorrhage into a fourth ventricular ependymoma showing flattening of gyri (A) and herniation of the cerebellar tonsils through the foramen magnum (arrow) (B). Figure 6-10: Cross section of the cerebellum, in a two and a half-year-old boy showing extens¡ve haemorrhage into a clinically undiagnosed ependymorna. 266

Pathophysiology

Haemorrhage ¡nto a may result in rapid expansion in size w¡th compression of the surrounding cerebral parenchyma. This is usually a complication of tumours such as medulloblastoma, malignant astrocytoma, ependymoma or oligodendroglioma126,136, which have infiltrated and eroded a vessel wall, or bled from rupture of delicate tumour neovasculature.

Pathological Features

At autopsy the presence of markedly increased intracranial pressure may be obvious as soon as the calvarium and dura are removed as th¡s will reveal prominent flattening of cerebral gyri.

Other indicators of cerebral oedema such as uncal grooving and herniation of the cerebellar tonsils may also be present (Figure 6-9).

A variety of tumour types may result in massive intracranial haemorrhage, having

variable locations which include both infra- and supratentorial compartments, and minimal or

often non-specific antemortem symptoms. Figure 6-10 illustrates an ependymoma of the fourth

ventricle in a two and a half-year-old boy2a. lt is also apparent that not only high grade

neoplasms are associated with haemorrhage.

Cerebrospinal Fluid Obstruction

Other rare cerebral lesions which may cause sudden death in childhood are tumours which

cause obstruction to cerebrospinal fluid flow such as colloid cyst of the third ventricle24,l04.

Reported cases have not, however, involved infants2T.

Miscellaneous

Peripheral neural tumours may also cause rapid deteriorat¡on due to ¡nterst¡t¡al haemorrhage as

was the case in a previously well three and a half-month-old girl who developed 'colic' one

evening. Her condition rapidly deteriorated and she died within seven hours due to massive

intraperitoneal haemorrhage caused by metastatic neuroblastoma infiltrating the liver. Autopsy

was performed at the Adelaide Children's Hospital.

EPILEPSY

It is now well recognized that infants and children with epilepsy have a higher mortality rate

than unaffected individuals, although th¡s proposal has not always been acceptedsl. Death may

occur due to an accident resulting from a , a. prime example of which would be

drowningl2l ,lo an associated disease process such as tuberous sclerosis, to status epilepticus, 267

or it may occur suddenly and unexpectedly for reasons that are not immediately obviousl69.

The final group is the most enigmatic as the underlying mechanisms responsible for death are far

from clear. For example, no mechanism of death could be determined at autopsy in four to 30%

of reported cases reviewed by Terrence, Wisotzkey and Perperl69. The rarity of unexpected

death during febrile convulsions in otherwise normal children also suggests that other

mechanisms are operating in children with epilepsy who die suddenly. A certain percentage of

children who have febrile convulsions will, however, later develop epilepsyTB.

Unfortunately the problem of sudden death in epileptics has not been extensively

addressed in the literature39, When it has been reviewed the pat¡ent populations studied have

tended to be adult and include a large number of alcohol abusersgg. As well, other authors have

specifícally excluded younger children from their analyses because of the occurrence of a wide

variety of epileptogenic disorders that are associated with neurological deficitsT2. Conclusions

based on th¡s material are not, therefore, completely applicable to paediatric cases.

Frequency

The estimated frequency of sudden and unexpected death in children with epilepsy is unknown,

however in general epileptic populations it has ranged from one in 200 to one in 680 patientsTT,

Reported figures show that sudden and unexpected death accounts for between 10 and 30% of

all epileptic deaths and that sudden epileptic death represents from 1 to 1 .5oÄ of all natural

deaths, and from 8 to 1 296 of all sudden unexpected deathssT. (These latter data are derived

from predominantly adult cases.) The typical case of unexpected death encountered in

paediatric autopsy practice is of an epileptic child, often w¡th mental retardation, who is found

dead in bed with minimal external or internal findings.

Pathophysiology of Sudden Death

The associat¡on of sudden death with sleep is noteworthy and most likely relates to reduction in

seizure threshold that occurs with an increase in epileptic discharges72,155, For example, up to

79% of cases of sudden epileptic death have been found either in bed or in a bedroomlss.

A variety of theories have been proposed to explain the occurrence of sudden death in epilepsy (Table 6-3) including suffocation from bedding, asphyxia, pulmonary oedema and cardiac dysrhythmia. Suffocation and aspiration of food or foreign material are considered unlikely in most cases72. Although supportive evidence for any of the categor¡es is not great, 26A

Leestma has grouped the currently favoured possibilities into: i) sympathet¡c ¡nduced cardiac arrhythmia, ii) parasympathet¡c induced bradycardia/asystole, iiil apnoea/respiratory failure, iv) a combination of arrhythmia and apnoea, and v) neurogenic pulmonary oedema with cardiac failuregT.

TABLE 6-3: POSTUTATED CAUSES OF SUDDEN DEATH lN EPILEPSY

Trauma

2 Suffocation

3 Asphyxia

4 Cardiac arrhythmia (sympathetically mediated)

5 Bradycardia/asystole (parasympathetically mediated)

6 Apnoea/repiratory failure

7 Neurogenic pulmonary oedema

The most popular theory to explain why apparently stable epileptic children are at

increased risk of sudden death involves autonomic nervous system instab¡lity with abnormal

cardiac rhythms during seizure activity. This is supported by experimental data which show

synchronization of vagal and sympathet¡c activity with cortical discharges in epileptic s¿1s94,152.

It is proposed that an increase in predominantly sympathetic activity can result in tachycardias,

ventricular arrhythmias and asystolegs. Of interest, overt muscle contractions were not

necessary for this synchronization to occur. Vagally-induced cardiac asystole or bradycardias

are considered to be much less common than sympathetically-induced arrhythmiasgT. The

effects of this increased neural activity on the cardiac conduction system may also be

exacerbated by coexistent hypoxia, and it is possible that laryngospasm, which has been

documented in temporal lobe eoil'epsyî38, may also increase ¡ctal hypoxia. However, it should

be noted that there are very few cases of sudden death or cardiac arrest due to epilepsy in

which an arrhythmia has actually been recorded4o,lol'120. Most reported clinical and

experimental cases of arrhythmias associated with cerebral events have not 6sg¡ 1¿1¿¡39'85. As

well, Keilson and colleagues in monitoring 338 epileptic patients found no increase in cardiac

arrhythmias compared to the general population, with only 5o/" oÍ patients showing high-risk

patterns8o,81. There may also be a reverse association of cardiac arrhythmias with seizures, as 269

there has been an increased incidence of epilepsy reported in pat¡ents with hereditary prolongation of the OT interval2o. lt ¡s hypothesized that the seizures in this situation result from cerebral hypoxia secondary to ventr¡cular tachycardia.

Determining the role of apnoea in the terminal event is difficult, with some authors suggesting that seizures may be directly reponsible for delayed respiratory arrest4s. This contrasts with the proposal that apnoea plays only a secondary role during the tonic phase of the seizuresT. As in other situations where complex pathophys¡ological processes are act¡ng ¡t may be that the end result is produced by integration of a number of predisposing factors, rather than the effect of one element in isolation.

Autopsy Findings

The absence of death scene and autopsy findings of disturbed bedding, urinary or faecal incontinence, bile marks on the tongue and foam in the mouth or trachea, does not mean that an epileptic episode did not occur, as these features have been absent in fatal episodes that have been witnessedss. As any type of fit may precede sudden death, not just generalized tonic/clonic convulsions3e, this could explain fewer external findings. ln spite of this, bite marks on the tongue should always be looked for.

Autopsy investigation may show pre-existing chronic brain damage, developmental malformations, evidence of previous surgery or neuronal depopulation and gliosis of the hippocampus secondary to past hypoxic episodes, usually with no evidence of an acute lesion.

Relating these findings to autopsy data in the literature is complicated by the older age and previous alcohol intake of reported casess8. For example, residual traumatic lesions, subdural haematomas and Wernicke's disease characterized the neuropathological findings in the series of

Leestma et a|.98. Similarly, the significance of cardiomegally and interst¡tial and intra-arterial fibrosis within the heartsl,ss is difficult to determine given the medical histories and ages of the reported patients. lt has, however, been suggested that prolonged sympathetic stimulation of the heart may result in similar lesions99.

The presence of neurogenic pulmonary oedema likely represents a secondary phenomenon rather than the cause of death and may imply that death is not instantaneous since oedema takes some time to become establishedr6s. 270

It ¡s ¡mportant at autopsy to take serum for anticonvulsant drug levels, as poor compliance with medicat¡on has been noted by several ¿u1¡s¡s99,169. Therapeutic levels of anticonvulsants in 44Y" of Schwender and Troncoso's cases suggests that this does not preclude the occurrence of sudden death, howeverl55.

Associated Features

A feature of paediatric cases of sudden death in epileptics is the number of infants and children who have an associated severe neurological handicap. Whether this takes the form of profound mental retardation or merely motor difficulties, the most significant feature is that there is seizure activity present which may predispose to sudden death with minimal acute pathological findings. Examples of this occur in infants and children with cerebral palsyag. Unfortunately, as there are usually no specific pathological findings in cases of non-accidental asphyxia in young

infants this possibility should also be borne in mind in cases within that age group.

Conclusion

ln summary, there is no doubt that infants and children with epilepsy from any cause are at

increased risk of sudden death. This often occurs during sleep, and the patholog¡st will quite

often find no major, or acute lesions at autopsy. The absence of seizure-related phenomena

such as disturbed bedding, incontinence and tongue biting does not exclude an epileptic attack,

and the most likely terminal event is lethal cardiac arrhythmia, although it must be admitted that

evidence for this in the literature is incomplete and that most studies have involved adults rather

than children. Given the absence of positive findings at autopsy, the diagnosis often becomes

one of exclusion that relies on clinicopathological correlation, supported to a large degree by the

past history of epilepsy.

METABOLIC DISORDERS

A variety of acquired and familial metabol¡c disorders have been associated with strokes in

children including diabetes mellitus, homocystinuria, congenital adrenal hyperplasia, Menkes

kinky hair syndrome, familial hyperlipidaemias and Fabry disease.

Any condition which interferes w¡th the adequate availability of vitamins necessary for

or in the maintainence of normal vascular integrity may also result in fatal

haemorrhage. Examples include intrinsic liver disease resulting in deficient absorption of vitamin

K or dietary deficiency of vitamin C causing scurvy. 27r

SCURVY

Infants with scurvy tend to be irr¡table w¡th multiple mucosal and cutaneous petechial

haemorrhages and pseudoparalysis due to bone pa¡n. Although not seen as often today, scurvy

still occurs in impoverished commun¡ties. Spontaneous intracranial haemorrhage may be a rare

complicatíon which results in sudden death from subdural or intracerebral coilections. The

underlying problem is a deficiency in dietary intake of vitamin C with interference in the normal

process of hydroxylation of collagen, with resultant vessel fragility. Figure 6-1 1 demonstrates

such a case, showing a coronal section of brain from a 1O-month-old scorbutic child who died

due to massive haemorrhage into the right parietal lobe. Other findings at autopsy which may point to vitamin C deficiency are swollen bleeding gums and swollen joints with wídening of the

costochondral joints producing the so-called scorbutic'rosary'.

HOMOCYSTINURIA

Homocystinuria is a heterogeneous metabolic disorder that may be caused by a deficiency in

cystathion¡ne synthetase. Patients with this disorder have variable mental retardation and

cardiovascular disease with a high rate of thromboembolism6s. The basis for the repeated

thromboembolism is believed to be endothelial shedding with exposure of subepithelial collagen,

as well as a reactive fibrointimal proliferation which may also contribute to reduction in blood peripheral flow and organ ischaemia. Abnormalities in blood clotting have also been

fl9çurns¡1s6125 and cerebral thromboses and fatal cerebral infarcts are well recognized

comPlications6s.l s4.

FABRY DISEASE

Fabry disease, also known as angiokeratoma corporis diffusum universale, is an X-linked

recessive inborn error of metabolism caused by a deficiency of lysosomal alpha-galactosidase

A38. While cardiovascular involvement is a major feature of the disorder, death due to acute myocardial infarction appears to occur only in adults. On the other hand, ischaemic events involving the brain have been reported in childhood in this conditionlo.

LEIGH DISEASE

Leigh disease, or subacute necrotising encephalomyelopathy is a heterogeneous, her¡table, and progressive degenerative disorder of the brain characterized by capillary and glial proliferation within the medulla and thalamus with neuronal degenerationl3s. The aetiology involves girl Figure 6-11: lntracerebral haemorrhage in a 1O-month-old with scurvy

the Figure 6-12: Sagittal section of an Arnold-Chiari malformation demonstrating elongation of

medulla and cerebellar tonsils 272

disordered thiamine metabolism. While affected infants and children generally have a steadily downhill course, the presence of an associated hypertrophic cardiomyopathy occasionally results in sudden death.

MISCELI.ANEOUS

Children with diabetes mellitus or with congenital adrenal hyperplasia have been reported with acute cerebrovascular accidents8,34. lschaemic cerebral events may also complicate familial hyperlipidaemias due to premature atherosclerotic vascular occtusion3T'64'

INFECTIONS

A number of infectious agents which may cause sudden and unexpected death in children due to meningitis, encephalitis or spinal cord involvement are dealt with in Chapter 4. One of the most common agents in Western communities causing fulminant meningitis often resulting in death is

Neissería meningítídíg Death in these cases may be due to brainstem herniation due to massive cerebral oedema associated with adrenal apoplexy in the form of Waterhouse-Friderichsen

syndrome.

STRUCTURAL ABNORMALIT¡ES

It is often difficult to determine the mechanism of death in infants and children who die suddenly

and who are found to have structural defects of the brain such as microcephaly, hydrocephalus,

pachygyria or holoprosencephalyl62. Patients with abnormalities, such as the Arnold:Chiari

malformation where there is chronic tonsillar herniation, are known to have an increased

incidence of sleep apnoeal4s and to be at risk of sudden death from brainstem

compressionss,lT2 (Figure 6-"121. Other problems which may be responsible for sudden death in

children with Arnold-Chiari malformation are laryngeal obstruction due to recurent laryngeal

nerve paralysis and acute shunt blockage. ln developmentally retarded children, epilepsy,

aspiration or bacterial pneumonia are not infrequentlls. lt is also quite possible that there has

been defective autonomic control predisposing to cardiorespiratory arrest in such cases'

ln a study of 146 patients with hydrocephalic spina bifida,'12 died suddenly (8%), due to either pulmonary embolism associated with ventriculovascular shunts, or to shunt blockagel63. patency of the shunt on subsequent exam¡nation does not exclude previous

malfunctionl5T. 273

FRIEDREICH ATAXIA

This rare hereditary spinocerebellar degenerat¡ve disorder, which usually manifests itself before adolescence with limb incoordination, dysarthria, scoliosis, pes cavus, and nystagmus, has a strong association with cardiac problemslg and an increased risk of sudden 6s¿1¡tBs. lnheritance is autosomal recessíve and the aet¡ology of the condition is unknown. Rhythym disturbances, subaortic stenosis, and dilated or hypertrophic cardiomyopathiess,lT,s2 are found in children with this disorder. Microscopic changes in the heart are non-specific with fibrointimal proliferation of the coronary arteries, diffuse myocardialfibrosis and fatty changstt6. There is a high incidence of diabetes mellitus in affected individuals with its associated risk of ketoacidosis. Other documented causes of death are intracranial thromboembolism and haemorrhagsTo.

Clinical Features

Tuberous sclerosis, or Bournevílle disease, is an autosomal dominant condition characterized by mental retardation, epilepsy and facial angiofibromas (so called 'adenoma sebaceum,)28,61. lt has quite variable penetrance w¡th differ¡ng clinical manifestations4. convulsions result from the presence of central nervous system lesions such as cort¡cal tubersl4, however, card¡ac rhabdomyomas are a more important finding in cases of sudden and unexpected death in childhood.

Aetiology

The gene locus for tuberous sclerosis has been assigned to 9q34, with linkage to the ABo blood group35, although there is evidence of heterogeneity with another locus reported on chromosome 11161,

Pathological Features

At autopsy a wide variety of lesions may be observed, rangíng from hypopigmented skin patches and facial angiofibromas to periungal and gingival fibromas, renal cysts and angiomyolipomas3o'111' Cerebral findings consist of ventricular dilatation, central demyelination, cortical tubers composed of aggregates of large bizarre cells ínterspersed with more normal appearing neurons and astrocytes, and subependymal nodules, sometimes with giant cell astrocytomas2s'61 (Figures 6-13 & 6-14). { Ø-n Ø -ft o ,Ã' qo' qç * Eç Oa; \ o(D U, I U, ?? t f*.t' ú'o Ë \ TÞ ãP fD ) o 3_, t fl- oì 3 JOJ J(D ?t O f¡, U) o l. , qfo ìo) I LJ (D o)ì x d.o t f< a .L )a='9 oa ) Øq JO I c¡ a rn3 ooJ o 0.) €r (t th -. \ I a rô C) \. I t crO¿õ' ¡ t t xa (Do) o N o)(D col J oç a \: {, 9o) - o ov t T o ôa t I rQ d. Pö I {a t o oj a o g :õ' (Dw- a ü á ¡ C o JC + ì I o oct I ¡ I 3 t/) ;at o¡ I a (¡) t OJ I a l .l ?e-= # :.lit a t (, .-:(D) o- 1 l 'jt ì o ã \ rD l tr = = g C t, I ¡ l ,ti o- rJ) Ë' c I o Ø \ a Þ t o tt o I f o- - Ò J â C ß C a o \ o o o C C an ø 274

Rhabdomyomas are composed of markedly enlarged myocytes that are packed with glycogen2g. Leaching out of the glycogen during processing leaving strands of cytoplasmic material results in the characteristic 'spider' cells (see Figure 2-141.

Occur¡ence of Sudden Death

Cardiac rhabdomyomas may be a 'forme fruste' of tuberous sclerosis when multiplø122, and may either be completely occult representing an incidental finding at autopsy in early childhood2s, or be responsible for sudden 6s¿1¡18,36,141,177-17s. Rhabdomyomas in these cases may cause outflow obstruction, obstruct coronary artery flow, or may involve conduction pathways resulting in arrhythm¡as52,63'160. These lesions may also lead to cerebral embolization with resultant focal ischaemiaT9. Aortic rupture is another unusual cause of sudden death in young children with tuberous sclerosissT'g3 although the exact reason for this association is unclear.

Autopsy lnvestigation

The importance of accurately diagnosing cases at autopsy lies in the inher¡ted nature of some cases. Although as many as 80% of cases have negative family histories and are assumed to represent new mutations, thorough clinical, echocardiographic and radiological examinat¡on may reveal abnormalities compat¡ble with tuberous sclerosis in apparently normal siblings or parents4.

While not all studies have demonstrated this association6o awareness of this possibility enables extra tissues to be taken for further investigation if needed. For example, cultured fibroblasts from affected patients have demonstrated consistent karyotypic variat¡e¡5149. Given this finding and identification of the gene locus, it may be important at autopsy to remove sterile skin for fibroblast culture and to obtain fresh tissue for DNA studies.

VON RECKLINGHAUSEN DISEASE (NEUROFIBROMATOSIS}

This autosomal dominant condition characterized by pigmented skin patches ('cafe-au-lait spots'), neurofibromas and a variety of other malformations has not been associated with sudden death in infancy or early childhood. However, an unusual case of unexpected death due to haemorrhage into the substance of a massive intrathoracic neurofibroma in a 1S-year-old male with neurofibromatosis has been describedsl. Other potent¡ally-lethal abnormalities that have been reported in children with von Recklinghausen disease include fibromuscular dysplasia of the intracranial vessels43, hypertensive strokel3o, hypertrophic cardiomyopathys4, and right 275

ventr¡culer outf¡ow sþs1¡u61¡s¡143. Cases of have been reported in infants and children with neurofibromatosis and fibromuscular dysplasiago. Hypertension may also occur in affected children due to fibromuscular dysplasia of the renal arteriesl76.

GUILLAIN-BARRÉ SYNDROME

Guillain-Barré syndrome is an acute or subacute illness characterized by motor weakness. The aetiology is not clear although there is an association w¡th preceding gastrointestinal or respiratory infection, immunization or surgery171. The clinical course varies from days to weeks, however, sudden death may occur in rare cases. This was the case in a two and a half- year-old boy autopsied at the Adelaide Children's Hospital who suffered an unexpected respiratory arrest following two days of leg weakness. On the day of his death the weakness had progressed to involve his arms and he had experienced difficulty in swallowing.

SUDDEN INFANT DEATH SYNDROME

A much more detailed review of possible mechanisms responsible for causing the sudden infant death syndrome (SIDS) is provided in Chapter 13, A number of investigators believe that SIDS is due to subtle abnormalities of cerebral and neural biochemical and physiological functions4. lt is postulated that there is a defect in the brain and/or autonom¡c receptors and pathways that puts these infants at risk of sudden death during a particularly vulnerable period of their l¡ves

(between two and four months)22. Whether the morphologic finding of increased brainstem gliosis has any relationship to this postulated malfunction awaits clarification.

t+++ Rcfercncc¡ Ch6-1

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137 Powars, D., Wilson, 8., lmbus, pogolow, C., C, & Allon, J. (197g). Tho natural history of st¡oko in sicklo cell diseaso. The American Journal of Medicine, 65, 461_71. 138 Ravindran, M. (1981). Tomporal lobe soizuro presont¡ng as 'laryngospasm". Clinical Electroencephalography, 12, 139-40. 139 Revhn¡¡¡l C Â I irrat Ai -,'ì li/¡^^^ l, o õ:----r ,t,¡ v¡, srvvorrc, ryr. q rrnrëtur tt, I I JarÞr. ñaototogy oI tscnemtc sttok€s in children. Neuroradiology. 27, 567 -7 B. 1 40. Rice, G,P.A., Boughner, D.R., Stillor, C. & Ebere, G.C. figgO). Familial stroke syndromo associsted with mitral valve prolapse. Annals of Neurology, 7, 1gO_4. 141 Rigle, D.4., Dexter, R.D. & McGee, M.B. (19891. Cardiac rhabdomyoma prosonting as sudden infant death syndrome. Journal of furensic Sciences,34. 69+9. 142 Roach, E.S., Garcia, J'C' & Mclean Jr, W.T. (1984). Cerebrovascular disease in childron. American Family Physican, 30, 215-27. 't43 Rosenquist, G.C., Krovotz, L.J., Haller J¡. J.A., Simon, A.L. & Bannayon, G.A. (197O). Acquired right ventricular outflow obstruction in a child with nourofibromatosis. American Høart Journal, 79, 103- 8. 1 44. Ross. C.A., Curnes, J.T. & Greenwood, R.S. (19g7). Recurront vortebrobasilar ombolism in an infant with Klippel-Feil anomaly. pediatric Neurotogy, 3, 181_3. 1 45. Ruff, M.E., Oakes, W.J., Fisher, S.R. & Spock, A. figg7). Sloep apnea and vocal cord paralysis secondary to type I Chiari malformation. pediatrics, gO, 231-4. 146 Sabharwal, U.K., Keogh, L.H., Weisman, M.H. & Zvaifle¡, N.J. (t982). Granulomstous angiitis of the nervous system: case report and review of tho literaturo. Arthritis and Rheumatism, 25, g42-5. 147. Sarkari, N.B.S., Holmes, J.M. & Bickerstaff, E.R. (1g7O). Nourological man¡festat¡ons associated with internal carotid loops and kinks in child¡en. Journal of Neurology, Neurosurgery and psychiatry. 33, 194- 200. 1 48. Sato, K' & Shimoji, T. (1992). Moyamoya disoaso. ln cerebrovaseular Diseases in Chitdren, ed. A.J. ' Raimondi, M. choux & c. Di Rocco, pp. 227-49. Now york: springer-verrag. 149 scappaticci, s', cerimele, D., Tondi, M., Vivareili, R., Fois, A. & Fraccaro, M. (19gg). chromosome abnormalities in tuberous sclorosis. Human Genetics, Tg, 1S1_6. 150 Schejbal, V' & oollig, W.-P. (1979). Sudden death of children by hemorrhage from a cerebral angioma. Klinische Pad¡atrie, 1 91, 498-5OO. 151 Schoonberg, 8.S., Mellinger, J.F. & Schoonberg, D.G. (1978). Moyamoya disoase in children. Southern Medical Journal, 7'l , 237-41 . 1 52. schraoder' P'L. & Lathers. (1983)' c-M. cardiac noural discha¡go and epileptogonic act¡vity in the cat: an animal model for unexplainod death. Life Sciences, 32, 13l 1_g2. 153 Schulz, E', Hermann, G. & Mette¡, D. (1981). suddon doath from natural causes among children of preschool ago and schoor age. Munchener Medizinische wochenschrift, 12g, 1443-6. 1 54. Schwab, F.J., Peyster, R.G. & Brill, C.B. (1997). CT of corebral venous sinus thrombosis in a ch¡ld with homocystinuria. Pediatric ßadiotogy, 17, 244_5. 155 Schwender,L'A'&Troncoso,J.c' (1986). Evaluationof suddendeathinopilopsy. TheAmericanJournalof furensic Medicine and Pathology, T, 293-7. t 56. Seeler, R.4., Royal, J.E., Powe, L. & Goldbarg, H.R. (1978). Moyamoya in children with sickle cell anomia and cerebrovascurar occrusion. The Journar of pediatrics, 93, gog-ro. 't57 Sekhar, L.N., Moossy, J., Guthkelch, A.N. (1992). Malfunctioning ventriculoperitoneal shunts. Clinical and pathological features. Journal of Neurosurgery, 56, 41 l_1 6. 158 Shields, W.D., Ziter, F.4., Osborn, A.G. & Allen, J. 11g77l. Fibromuscular dysplasia 6s a cause of stroko in infancy and childhood. pediatrics, 59, 999_901. 't 59 Shillito (1964)' J¡, J. Carotid artoritis: a cause of homiplegia in childhood. Journal of Neurosurgery,2ç., s4o- 51. 160 Smith, H.C., Watson, G.H., Patel, R.G. & Super, M. (1ggg). Cardiac rhabdomyomata in tuberous sclerosis: thoir course and diagnostic value. Archìves of Ðisease in Chitdhood,64, l96-200. 161 Smith' M' & simpson. (1989). N.E. Report of the committee on tho gonotic constitution of chromosomes 9 and 1O. Cytogenetics and Cell Genetics, 51 , 202_25. 162. Speights J¡, V.O. & Bauserman, S.C. (199,l). Suddon death in an infant with central norvous system abno¡malities. ped¡atric pathotogy, 1 1, 7S1_9, 't 63 Staal, M.J., Meihuizen-de Regt, M.J. & Hess, J. (1987). Sudden death in hydrocephalic spina bifida aperta psti€nts. Pediatric Neurosciønco, 1 3, 1 3-l g. 1 64. Stockman, J.A., Nigro, M.A., Mishkin, M.M. & oski, F.A. 11972l. occlusion of large cerebral vossols in sickle cell . The New England Journal of Medicíne, 2g7 , g46_9. Rcferenccc Ch6-7

165 Suzuki, J. & Kodama, N. (1983). Moyamoya diseaso - a ¡eview. Stroke, 14, 1O4-9. 166 Suzuki,J.&Takaku,A. (1969). Corobrovascular"Moyamoya"disease. Archivesof Neurology,20,288-99. 't67 Takashima, S. & Becker, L.E. (1980). Neuropathology of corebral arteriovenous malformations in children. Journal of Neurology, Neurosurgery and Psychiatry, 43, 380-5. 168 Terrenco, C.F., Rao, G.R. & perpor, J.A. fi981). Neurog€n¡c pulmonary odoma in unoxpectod, unoxplainod death of epileptic pat¡onts. Annals of Neurology,9, 458-64. 169 Terrence Jt, C.F., Wisotzkey, H.M. & Perper, J.A. (1975). Unexpected, unoxplained death in epileptic patiente. Neurology, 25, 59+8. 170 Tharakan, J., Ahula, G.K., Manchanda, S.C. & Khanna. A. (1982). Mitral valve prolapso and cerebrovascular accidonts in the young. Acta Neurolog¡ca Scandinavica, 66, 295-302. 171 Thomas, P.K., Landon. D.N. & King, R.H.M. (1992). Disoases of the peripho¡al nerves. ln Greenfield's Neuropathology,Sth odn, ed. J.H. Adams & L.W. Duchen, pp. 1116-1245. London: Edward Arnold. 172. Tomaszok, D.E., Tyson, G.W., Bouldin, T. & Hanson, A.R. (1984). Sudden doath in a child with an occult hindb¡ain mdlformation. Annals of Ernergency Medicine, 13, 136-8. 173 van Rþroek. J.J. & Moo¡e, S.A. (199O). Suddon doath from choroid plexus vascular malformation homorrhage: case roport and review of the l¡teraturo. Clinical Neuropathology, 9, 39-45. 174. Wakabayashi, T., Fujita, S., Ohbora, Y., Suyama, T., Tamaki, N. & Matsumoto, S. (1983). Polycystic kidnoy disoase and intracranial aneurysms. Early angiographic diagnosis and oarly oporation for the unruptured aneurysm. Journal of Neurosurgery, 58, 488-91. 175. Walker lll, R.J., El Gammal, T. & Allen Jr. M.B. (1973). Cranial arteritis associatod with herpes zoster. Case report and angiographic findings. Radiology,107, 109-1 1O. 1 76. Wallis, K., Deutsch, V. & Azizi, E. (197O). Hypertension in a case of von Recklinghausen's neurofibromatosis. Helvetica Paediatrica Acta, 2, 147-53. 177. Williams, W.G., Trusler, G.A., Fowler, R.S., Scott, M.E. & Mustard, W.T. (19721. Left ventricular myocardial - fibroma: a case report and roview of cardiac tumors in children. Journal of Pediatric Surgery,7,324- 8. 178. Wilske, V.J. (198O). Tuberöse sklerose - ungewöhnlicher fall eines plötzlichen säuglingstodes. Beitrage Zurgeilchtl¡chen Medizin, 38, 451 -6. 1 79. Winstanley, D.P. (1961). Sudden death from multiple rhabdomyomata of tho hea't. Jounal of Pathology and

Bacteriology, 81, 249-51 . 180 Woody, R.C., Perrot, L.J. & Beck, S.A. (1992). Neurofibromatosis cerebral vasculopathy ¡n an infEnt: clinical, neuroradiographic, and neuropathologic studies. Pediatric Pathology,12, 613-19. 181 . Yamashita, M., Oka, K. & Tanaka, K. (1983). Histopathology of tho brain vascular network in Moyamoya disease. Strokd, 14, 5O-8. 1A2 Yamashita, M., Tanaka, K., Kishikawa, T. & Yokota, K. (1984). Moyamoya disease associated with

ronovascular hypert€nsion. Human Pathology, 1 5, 191-13. 1 83. Yancey, C.L., Doughty, R.A. & Athreya, B.H. (1981). Cent¡al nervous system involvement in childhood systomic lupus orythomatosus. Arthritis and Rheumatism, 24, 1389-95. 1 84. Young, R.S.K., Rannels, D.E., Hilmo,4., Gerson, J,M. & Goodrich, D. (1983). Severe anemia in childhood presenting as trsnsiont ischemic attacks. Stroke, 14,622-3. 185 Zimmerman, M., Gabathuler, J., Adamec, R. & Pinget, L. (1986). Unusual manifestations of heart involvement in Friedrich's ataxia. American Heart Journal, 111, 184-7. ST]DDEN NATTJRAL DEATH IN INFANCY & EARLY CHILDHOOD

CHAPTER 7

IIAEMATOI,O GICAL CONDITIONS 276

INTRODUCTION

Haematologic disorders are not often considered in the differential diagnosis of unexpected death in infancy although most physicians would be aware of sudden death as a potent¡al complication of sickle cell anaemia. While the mechanism of sudden death in sickle cell disease relates most often to splenic sequestration crisis, other complications may also result in quite rapid demise. Similarly, the range of lethal mechanisms in other forms of haematological disorders may be more diverse than initial observations would suggest and include massive haemorrhage, thromboses, stroke, overwhelming infection, airway obstruction and cardiac arrhythmia. A listing of haematological conditions that may result in sudden paediatric death is provided in Table 7-1.

TABLE 7-1: HAEMATOLOGIC CONDITIONS ASSOCIATED WITH SUDDEN PAEDIATRIC DEATH

Haemoglobinopathies

Haematologic malignancies

Disorders of coagulation

Platelet disorders

Anaemia

Haemolytic-Uraemic syndrome

Polycythaemia

Splenic disorders

HAEMOGLOBINOPATHIES

SICKLE CELL ANAEMIA

Of all the disorders caused by structural defects in the haemoglobin molecule, sickle cell disease

is the most s¡gnificant in terms of sudden death. Sickle cell anaemia, which results from the

replacement of glutamic acid by valine in the sixth position on the ß chain of the haemoglobin

molecule4l, is characterized by decreased plasticity of red blood cells resulting in elongation and

'sickling'. The sickled cells are no longer able to traverse the normal vascular channels due to

their altered configuration, and as such are more suscept¡ble to damage and more likely to

obstruct blood vessels. 277

Glinical Features

Homozygous pat¡ents develop a severe and chronic haemolytic anaemia which is marked by

episodic clinical deterioration in the form of 'crises', several of which are potentially lethalas.

Sickle cell disease and trait are much more common in black populations than in white, possibly

related to the partial protective effect that has against malaria.

Although heterozygous patients generally have a more benign clinical course than

homozygotes, under certain circumstances they nevertheless appear to have an increased risk of

sudden death compared to the general population3S.¿2. For example, sickle cell trait has been

associated with an estimated 28 to 40 times increased risk of sudden death in black American

military recruits during exercise2s. This phenomenon is of more concern in young adults rather

than infants. lt is considered that exercise predisposes to acidosis and venous hypoxia, and that

these factors in combination with dehydration and hypotension cause sickling2T,at. These

factors may, however, also precipitate sickling in infants with sickle cell traits2 and have been

associated with sudden death in heterozygous children following general anaesthesia34.

Coagulopathy and exercise-induced rhabdomyolysis associated with unexpected death, as well

as sequestration crisis, occur in heterozygous adults12,24's3,60.

Vaso-occlusive crisis

Vaso-occlusive, or painful, crises which occur retatively frequently in homozygous pat¡ents are

often precipitated by infection and may be lethal in children. The underlying problem is of small vessel occlusion by the deformed erythrocytes resulting in peripheral ischaemia and infarction.

The extremit¡es are most often involved (so-called hand-foot syndrome or sickle cell dactyl¡tisl with ínfarction of the small bones of the hands and feet causing very characteristic changes on

X-ray+t. Cerebral involvement is a more sinister potential complication occurring in approximately 7o/" of homozygous children which may result in intracerebral haemorrhage, subarachnoid haemorrhage and infarction with sudden 6"r1¡38'a6,48,s1. eases have also been reported of fatal cranial sinus thromboses in children6l. Figure 7-1: Markedly enlarged spleen in a 21-month-old Jamaican boy who died from a sickle cell acute splenic sequestration crisis while sleeping in his mother's arms.

Figure 7-2: Engorgement of the splenic parenchyma by sickled red blood cells protruding into the lumen of a sinusoid in the boy described in Figure 7-1 (Haematoxylin & Eosin, x44Ol. 274

aplastic Crisis ln aplastic crises there is temporary cessation of red blood cell production resulting in a marked fall in haemoglobin levels which may be idiopathic or precipitated by infection, folic acid deficiency or exposure to certa¡n drugs4l.

Haemolytic Crisis

Haemolytic crises may be induced by infection or may be precipitated by ant¡ox¡dant drugs when there is an additional haematologic abnormality present such as glucose-6-phosphate dehydrogenase deficiency. Haemolytic crisis may acutely exacerbate the effects of an already established haemolytic anaemia.

Splenic Sequestration Crisis

One of the most feared complications of sickle cell disease is splenic sequestration crisis56'66.

When this occurs there ¡s marked pooling of blood within the spleen and a danger that the patient may die very quickly of circulatory collapsel3. Figure 7-1 illustrates the massive splenic enlargement that may occur. Figure 7-2 shows a tangled array of erythrocytes clogging the splenic vascular channels taken from a Jamaican boy who was not known to have sickle cell diseases lvide infral.

STUDY #9-1

DEMONSTRATION OF THE ASSOCIATION BETWEEN UNSUSPECTED SICKLE CELL DISEASE

AND SUDDEN UNEXPECTED DEATH IN INFANCY

CASE REPORT

A previously well 21-month-old black male had a convulsion while sleeping in his mother's lap.

This was followed by abnormal breathing and cardiac arrest which failed to respond to resuscitation. The only past history was of a mild febrile illness on the day before death which responded to antipyretics. His mother was not aware of any sickle cell disease in the family.

At autopsy the conjunctivae were pale, as were all of the internal organs except for the spleen. The spleen was markedly enlarged (Figure 7-11 (wt. 2569, normal for age : 329) with

prominent congest¡on of the red pulp which was almost completely effaced by masses of tightly

packed sickled red blood cells (Figure 7-21. Post-mortem blood examination showed occasional 279

sickled red cells with a haemoglobin of 18g/1. The sickle test was positive and haemoglobin

electrophoresis revealed HbS (86.6%), HbF (tO.g%), and HbA2 l2.So/ol. The heart was

enlarged (wt. 1149, normal for age = 56g) and the was hypercellular with

increased erythropo¡es¡s,

The cause of death was cardiovascular collapse due to splenic sequestration crisis

associated with previously unsuspected s¡ckle cell disease.

CONCLUSION

This case demonstrates the occurrence of sudden death in early childhood in a boy with

clinically-occult sickle cell disease. Of interest, the presence of cardiomegaly with erythroid

hyperplasia of the bone marrow suggested that significant anaemia with a physiological

response had been present for some time, in spite of his apparently normal health status and growth parameters.

*+*

The diagnosis of acute splenic sequestrat¡on should be suspected at autopsy when the

spleen is markedly enlarged and has a purplish congested appearance due to engorgment with

irreversibly sickled red blood cells. The remainder of the organs are unusually pale, giving the

brain in pafticular a'porcelain-like'appearance (Figure 7-3). Although the detection of sickled

erythrocytes on microscopy does not necessarily imply that sickling was an antemortem

phenomenon2s'63, extensive sickling in acute sequestration should be readily demonstrable.

Other autopsy findings in cases of fatal sickle cell disease include purulent meningitis, cerebral

infarction, cardiomegaly, and hyperplasia of bone marrow.

Splenic sequestrat¡on crisis ís a particularly common presenting feature in infants and children under the age of two years, accounting for a third of cases in one series2. ln this report other presentations of sickle cell disease included pneumococcal sepsis and cerebrovascular accídent. Twenty-four percent of their pat¡ents who died did so on first presentation, including

15% who were dead on arrival at hospital. The fact that sudden death may occur due to splenic sequestration with either no known history of sickle cell disease, or with only minimal / a -, t 5 \ -- à t fl r (1 t t 'l '¡l, 't' t, ,/ ..Ga , t) -9Þ I t ,t, .3 0 lì ,l g ¡r t {., I r¡ , - I â .E I r lrq rÈ J: ln t- Ë.¡ ç1 l+-o "l :r, , n* It tl , I.$ ¡"1 .i '1."i .¡L ,ì V ..,- ¡ir t ,) '11 ;r ê 't:..a :.àI .h l I dt a -\rt(Ð ¡.t' a" *. T ) rÞ a:ì ,\ 2 '¡ rr'o ,, t o .. '¡-,-.. \ @ .a , . a ,þ t t1 .l :F tr a J¡ \ t- \?'t )D {r .a .\ o 'ì J' tð () ¿- t. Õ. {t L!1 i,u-o

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peìrey! ie- aln6t1 llac alìcts alnf,e ut a3ueJeadde,utelq ure¡aclod, e ôurcnpo.td ro¡1ed L 280

symptomsT2 as noted above, may make the autopsy examination crucial in the establ¡shment of the diagnosis.

Cardiovascular Complicat¡ons

Proliferative lesions of the walls of the carot¡d arter¡es that are associated with childhood stroke and death in patients with s¡ckle cell disease may be similar to arterial lesions of Moyamoya

6¡5ssss17,65'71. Thus, at autopsy it ¡s appropriate to sample the carotid arteries in cases of childhood stroke in sickle cell disease, as the brain pathology may not be due solely to local sickling and stasis.

' Sudden death from coronary occlusion with acute myocardial infarction is a rare occurrence in childhood sickle cell disease2s, but has been reported in young adults33.

Cardiomegaly is a reasonably common finding in older children with sickle cell disease, associated with chronic anaemia and high output cardiac failure6a. ln cases of sudden death in which cardiomegaly is found at autopsy, it is possible that the underlying mechanism is ischaemic arrhythmia, rather than acute sequestrat¡on. However, the proposal that thrombot¡c occlusion of intramural coronary arteries in patients with sickle cell disease results in ischaemic left ventricular dysfunct¡on and cardiomyopathyl6 has not been supported by later studiesl9.

The latter authors found no evidence of coronary occlusion or of ischaemic myocardial damage in a series of 52 pat¡ents at autopsy. They concluded that there is no evidence for a specific

'sickle cell cardiomyopathy' and that changes observed resulted from the effects of chronic anaemia exacerbated by acute complications of the disease. Sudden death from pulmonary thromboembolism, possibly preceded by manifestations of 'acute chest syndrome', appears to be a phenomenon that occurs predominantly in affected adultssT,ss'79, although pulmonary vascular changes may be found at earlier ages (FigureT-4l'.

¡nfect¡ous Complications

lnfections in infants and children with s¡ckle cell disease may be fulminant and may also result in sudden deathsa. For example there is a significant¡y ¡ncreased risk of pneumococcal septicaemia and meningitis partícularly in early childhss¿3,so. This is thought to be due to a combination of:

reduced splenic function associated w¡th repeated episodes of infarction which ult¡mately result

in functional asplenia, a defect in the alternative pathway of complement activation, altered 2AL

neutrophil act¡v¡ty, reduced serum opsonizing activ¡ty for pneumococcus, and reticuloendothelial dysfunction due to chronic haemolysis26,43-4s,7 6.

Autopsy lnvestigations

Sickle cell disease should be suspected in any infant who suddenly cóllapses and dies, particularly if there is African heritage. lnvestigations at the t¡me of autopsy include a full septic workup with cerebrospinal fluid and blood cultures, haematocr¡t, haemoglobin and haemoglobin electrophoresis (if possible). Given the possibility of sudden and unexpected death from a variety of mechanisms in asymptomatic infants with sickle cell disease, it would not seem appropriate to make the d¡agnosis of sudden infant death syndrome (SlDSl in this group, although it has been claimed that the incidence of SIDS is higher in these infantsT5.

OTHER HAEMOGLOBINOPATHIES

The association of sudden death and the other haemoglobinopathies is not as well recognized in the literature, although sudden death in childhood may occur with haemoglobin CS73, or in sickle cell disease-ß thalassaemia. The presence of the latter combination in populations around the Mediterranean means that the presence of a white skin does not exclude the possibility of acute splenic sequestration at autopsy (Figure 7-5). lntractable cardiac failure with arrhythmias due to iron overload may occur in children with thalassaemia, however the terminal episode usually extends over one to two days3g.

HAEMATOLOGIC MALIGNANCIES

LYMPHOMAS

The clinical course of infants or children with haematologic malignancies that fail to respond to therapy is usually relatively protracted, with death being neither sudden nor unexpected. When unexpected death does occur a common cause ís fungal thromboembolism following immunosuppressive therapy. A clinical history of prolonged fever, antib¡ot¡c and adrninistration and profound neutropaenia may be clues to the presence of fungal sepsis prior to performance of the autopsy. Overwhelming bacterial sepsis and haemorrhage are also potentially lethal complications which may result in rapid demise.

A less common cause of death may, however, be upper airway compromise due to a local mass effect from mediastinal lymphoma. A case such as this occurred in a two-year-old Figure 7-5: Marked enlargement of the spleen due to acute splenic sequestration in an eight- year-old boy with a Southern European background and combined sickle cell disease-ß thalassaemia.

II

J

Figure 7-6: Sudden death in a three-year-old girl due to haemorrhage into the brainstem with

compression of adjacent v¡tal centres, Clinically unsuspected acute myeloid leukaemia was also

found at autopsy.

J 282

mentally retarded girl thought to have asthma, who was found at autopsy at the Adelaide

Children's Hospftal to have a clinically-unsuspected anterior mediastinal large cell lymphoma

compressing her airways. ln this case other medical problems had made accurate clinical

assessment difficult. Airway obstruct¡on in children with mediast¡nal tumours may also occur

following the induction of anaesthes¡a7,3o ¿¡6 children w¡th th¡s problem are also at risk of

sudden death from cardiac compressign, or from compress¡on of the pulmonary artery in the

supine posit¡on22,32,77. Another potent¡al cause of sudden death in lymphoma is marked metabolic

disturbancesS. This may occur following chemotherapy in sensitive tumours result¡ng in rapid

tumour lysis with marked hyperkalaemia and hypocalcaemialo. Rarely, rupture of the spleen

result¡ng in rapid death may be the first presentation of lymphoma. This usually involves older

children, rather than ¡nfants, and was reported in a 1 5-year-old girl who died soon after the

onset of . Hodgkin's disease was discovered at autopsy62.

LEUKAEMIAS

ln the author's experience the usual cause of sudden death in children with leukaemia is

intracranial haemorrhage due to primary or secondary thrombocytopaenia. Children w¡th acute

promyelocytic leukaemia are particularly prone to developing haemorrhagic complications. Other

mechanisms may involve local cerebral leukaemic infiltration, or hyperviscosity and in

acute disease. Fungal disease may also result in occlusive thromboembolig, and certain types of

chemotherapy, such as aspariginase and methotrexate can cause thromboses and

haemorrhage46.

A three-year-old girl who had been treated with ant¡b¡otics for cervical

and an upper respiratory tract ¡nfection, collapsed and died suddenly. At autopsy at the

Adelaide Children's Hospital massive intrapontine haemorrhage was found in association with an

acute myeloid leukaemia (Figure 7-6), Thus death may occur rapidly in young patients with

leukaemia sometimes even before the clinical diagnosis has been establ¡shed.

DISORDERS OF COAGUI.ATION

Disorders of the coagulation pathways may be inherited, such as deficiencies of Factors Vlll and

lX, or acquired, due to liver disease or to inadequate dietary intake of vitamin K resulting in low 283

levels of factors ll, Vll, lX and X. lndependent of the underlying eetiology, patients with any of

these conditions are at r¡sk of significant haemorrhage, either spontaneously or following minimal trauma.

PRIMARY DEFICIENCIES

lnherited disorders of coagulation usually involve Factor Vlll, Factor lX or von Willebrand factor,

although a number of other less common deficiencies have been described, haematological

details of which have been reviewed elsewhere36.

While pat¡ents with either of the first two deficiencies (haemophilia A or Bl tend to bleed spontaneously into the soft tissues and joints, intracranial haemorrhage remains the major cause premature of mortality36 and has been reported in 2.2 to 7.Bot6 of affected individuals accounting Íor 25 to 30% of deaths overalll4. There are also significantly increased risks associated surgical with and dental procedures, and with minor trauma. Damage to the posterior pharynx, as may occur in a child who falls with an object in the mouth, is a feature of older, ambulatory children, which may result in massive retropharyngeal space haemorrhage with life-threatening upper airway obstruction. Although intracranial haemorrhage is much less

common in von Willebrand disease it remains a potent¡ally fatal complicationso, The following case of a 14-year-old boy with known haemophitia A illustrates how insidious the haemorrhage in these children may be. The boy had suffered mild concussion with no loss consciousness of following a fall from his bicycle. skull X-ray revealed no evidence of fractures, however, in view of his underlying coagulopathy he was admitted to the Adelaide Children's Hospital and observed for three days. At the end of that time he appeared quite well and so was sent home, only to appear at the end of the first week with an acute onset of reduced consciousness, hemiparesis, and death within 24 hours. There had been no additional trauma' At autopsy extensive haemorrhage into his left frontal lobe with intraventricular extension was found {Figure 7-71. Other coagulation dísorders such as congenital afibrinogenaemia and factor Vll and Xlll deficiencies may result in intracranial bleeding in childhood, while antithrombin lll and protein C deficiencies predispose to thrombotic events in adolescence46. state Figure 7-7: lntracerebral haemorrhage resulting in the sudden onset of a reduced conscious followed by death within 24 hours in a 14-year-old boy with haemophilia A. This occurred one week after apparently minor head trauma.

I \ \-^

{ r\ ¿-t

resulted in sudden Figure 7-B: Obstruction to the laryngeal inlet due to interstitial haemorrhage girl neuroblastoma' onset of inspiratory stridor, cyanosis and death in a one-year-old with

Pseudomonas sepsis and chemotherapy-induced thrombocytopaenia, 244

SECONDARY DEFICIENCTES

There are a variety of acquired disorders of coagulation, the most common being disseminated intravascular coagulation associated with sepsis, malignancy or trauma. ln most of these conditions, however, the pat¡ent is in a critical state, and thus haemorrhage is often terminal, multifocal and associated with a range of haemodynamic and metabolic disruptions. Death is, therefore, usually not all that sudden or unexpected.

THROMBOTIC CONDITIONS

Familial hypercoagulable syndromes in which there are repeated episodes of spontaneous thrombosis are documented in the literature. These have been associated with a variety of abnormalities including reduced levels of anti- lll and increased amounts of factor Vl8.

Their rarity makes them only potent¡al causes of sudden paediatric death.

PLATELET DISORDERS

Thrombocytopaenia from any cause may result in spontaneous haemorrhage. A list of possible causes of thrombocytopaenia is given in Table 7-2,

TABLE 7-2: CAUSES OF THROMBOCYTOPAENIA

1. Decreased production i) Decreased megakaryopoiesis - e.g. aplastic anaemia, drugs, chemicals, marrow replacement from leukaemia/lymphoma, solid tumours such as neuroblastoma, osteopetrosis and storage disorders. ii) lneffective thrombopoiesis - e.g. megaloblastic anaemia, hereditary thrombocytopaenias

2. Abnormal distribution or dilution i) Pooling in cases of splenomegaly ii) After stored blood transfusion

3. Increased destruction il lmmunological - e.g. idiopathic thrombocytopaenic purpura

¡¡) Non-immunological - e.g. thrombotic thrombocytopaenia, disseminated intravascular coagulation, haemolytic uraemic syndrome, cardiac prostheses. 285

Occurrence of Sudden Death

Sudden death may occur in children with any of these ent¡ties if bleeding occurs in a vital location, such as within the cranial cavity. Rarely, haemorrhage into soft tissues around the laryngeal inlet may also result in death from airway obstruction. Figure 7-8 illustrates such a case in a one-year-old girl with treated neuroblastoma, Pseudomonas sepsis and marrow aplasia who suffered airway compromise from spontaneous pharyngeal haemorrhage.

The usual conditions associated w¡th sudden lethal intracranial haemorrhage in childhood in this collection of disorders are the acute leukaemias. This is because of replacement of marrow haematopoietic cells by malignant cells, or treatment-induced marrow aplasia with reduction in circulating platelet numbers.

ln a number of childhood malignancies there may be several contributing factors to spontaneous haemorrhage as well as thromboc¡opaenia. These include reduced clotting factors from an inadequate diet associated with the underlying malignancy and chemotheraÞv, or disseminated intravascular coagulation due to concurrent sepsis.

INHERITED PLATELET ABNORMALITIES lnherited disorders of platelets involving abnormal function or reduced numbers are less common than acquired disorders but may also result in lethál haemorrhage at an early age. Miller has separated these cond¡tions into five main groups: il defects of the platelet surface membrane, ii) platelet-type von Willebrand disease, iii) granule defects, e.g. Wiskott-Aldrich syndrome (X-linked thrombocytopaenia with eczema), ivl defective arachidonic metabolism, and vl a miscellaneous group which is quite heterogeneous, including platelet abnormalities associated with congenital heart disease, Down syndrome and metabolic disorders3T.

An example of sudden death in one of these conditions occurred in a five-month-old boy with Wiskott-Aldrich syndrome who was in the Adelaide Children's Hospital for a platelet transfusion when he suffered sudden deterioration and death, lntracerebellar anci diffuse basal subarachnoid haemorrhage were found at autopsy.

IDIOPATHIC THROMBOCYTOPENIC PURPURA ldiopathic thrombocytopenic purpura is the most common childhood thrombocytopenic purpura and is characterized by decreased circulating platelets, increased marrow megakaryocytes, and Figure 7-9: Large cavernorJs haemangioma of the upper thigh causing Kasabach-Merritt syndrome with thrombocytopaenia and resultant fatal subarachnoid haemorrhage.

Figure 7-10: Massive cardiomegaly with chamber dilatation in a seven-year-old boy with thalassaemia. Figure 7-11: 'Thrush breast' dappling of the heart due to marked fatty change in an anaemic nine-year-old boy with acute lymphoblastic leukaemia in relapse.

Figure 7-12: Multiple dense hyperchromic microspherocytes typical of hereditary spherocytosis

(Giemsa, x 1100). # I t o ( o g

^iÈ", I ü "ils % !. :ll (l"ß to {Ll: räEì É a o oc o * /;. o a 286

mucocutaneous bleed¡ng. The underly¡ng aetiology is believed to be an autoimmune response to platelets, often triggered by a preceding viral infection. Although mucosal bleeding may be quite profound, intracranial haemorrhage occurs in only one to two percent of cases46.

KASABACH-M ERRITT SYNDROM E

Kasabach-Merritt syndrome is characterized by a consumpt¡on coagulopathy with reduction in platelet numbers due to trapping and destruct¡on of platelets within large vascular neoplasms that are most often haemangiomas6T. While most ¡nfants and children with this condition survive, this is not always the case as demonstrated in Figure 7-9. This shows a large cavernous haemangioma of the leg in a four-day-old infant that was associated with thrombocytopaenia and unexpected death from subarachnoid haemorrhage. Hyperkalaemia secondary to excessive red blood cell destruction in Kasabach-Merritt syndrome has also been reported as a rare cause of potentially fatal cardiac arrhythmias in this age group74.

ANAEMIA

Unless there is postmortem evidence of previous high output cardiac failure with marked cardiomegaly (Figure 7-10) and erythroid hyperplasia of the bone marrow, it may be difficult to determine the significance of an antemortem diagnosis of anaemia. However, ¡f these findings are present it is reasonable to suggest that anaemia of whatever aetiology may have contributed to sudden death, given the known association of cardiac arrhythmias with hypoxia and cardiomegaly. Other cardiac findings in cases of severe anaemia include chamber dilatation, myocardial infarction/ischaemia and fatty infiltration with a 'thrush breast' pattern to the myocardium6.ls 1¡¡gu¡g 7-111. Certainly it would be difficult to support a diagnosis of sudden infant death syndrome in infants who are found to have these changes, no matter how typical a history. The case of a four-month-old boy with hereditary spherocytosis (Figure 7-12) who was initially thought to have succumbed to SIDS ¡llustrates this point. He had required blood transfusions because of ongoing haemolysis and at autopsy was found to have marked cardiomegaly and marrow erythro¡d hyperplasia thus precluding the diagnosis of SIDS. An additional reason for clearly separating infants who die with anaemia from infants who die of

SIDS is the known association of acute life-threatening events (ALTE) with anaemia in infancyss. 247

Other possible mechanisms relating anaemia and sudden death are those of cerebral ischaemiaTS and increased cyanotíc breath-holding episodesaT. As well, while anaemia may not be solely responsible for the lethal event it may serve to exacerbate pre-existing conditions. An example of this was a 13-month-old boy who had a cardiac arrest and was found to have both severe anaemia and a solitary coronary artery2o.

Anaemia may also be associated with reduction in platelet numbers, as in aplastic and megaloblastic anaemias, which may result in death due to spontaneous haemorrhagel. This was the case in a 1O-year-old boy with a past history of intracranial haemorrhage, who was known to have aplastic anaemia. He presented to the Adelaide Children's Hospital dead on arrival following the acute onset of headache which had rapidly progressed to coma. At autopsy, extensive intracerebral haemorrhage was found involving the left parietotemporal lobes with extens¡on into the subarachnoid space (Figure 7-131,

HAEMOLYTIC.URAEMIC SYNDROME

The aetiology of this disorder, which is characterized by the sudden onset of haemolytic anaemia, thrombocytopaenia and uraemia, is not understood, although the major feature is endothelial damage. Clinically, about one th¡rd of patients have neurological complications with coma, seizures and hemiparesis6S resulting from thrombosis of the microvasculature, metabol¡c abnormalities or systemic hypertensionTo. lntracranial haemorrhagel l and status epilepticusao are two manifestations that have a known association with sudden death.

POLYCYTHAEMIA

The most common forms of polycythaemia in children are secondary to cyanotic congenital heart disease and chronic pulmonary disease. Primary polycythaemia occurs much less often. Other disorders such as cystic renal disease, cerebellar haemangioblastomas and the pickwickian syndrome may also result in marked polycythaemias'21, all of which may predispose to lethal thrombotic cerebral events.

SPLENIC DISORDERS

CONGEN¡TAL ASPLENIA

Congenital absence of the spleen may be associated with both cardiovascutar abnormalities and with an increased risk of fulminant sepsis. The most common associated cardiac anomalies are Figure 7-13: Spontaneous fatal intracerebral haemorrhage in a ten-year-old boy with aplastic anaemra.

f: ) ^ I I \ l T ì-4 4q \ ( ,T { j a¿ /

t

¡r, t t

Figure 7-14: Traumatic rupture of the spleen resulting in sudden death in an adolescent girl with splenomegaly due to infectious mononucleosis.

I

1,+ \.;'1 , 2Aa

transposit¡on of the great vessels, pulmonary stenosis or atresia and total anomalous pulmonary venous drainagess. Deta¡ls of vascular and infectious complications are dealt with in Chapters 3 and 4, respectively.

SPLENIC RUPTURE

Although often related 1o haematologic disorders, splenomegaly from any cause may be associated w¡th rupture and sudden death due to exsanguination. While malaria would be a more frequent cause of splenomegaly on a global scale, infectious mononucleosis and leukaemias are more common causes of splenic enlargement in Western countries. Even relatively mild trauma may cause rupture when the spleen is significantly enlarged. This was the case in an adolescent g¡rl w¡th ¡nfectious mononucleosis (Figure 7-14) who died quite suddenly due to massive intraperitoneal haemorrhage with no history of trauma. Trauma resulting in splenic rupture in individuals with infectious mononucleosis may be minimal; for example, straining at stool, vomiting, coughing, exercise and medícal examination have all been cited as causes4,4o,69. Rupture of the spleen as the initial presentation of Hodgkin's disease has also been reported in adolescence62. Haemangiomas, cysts and Ehlers-Danlos syndrome are other extremely rare causes of spontaneous splenic rupture23.

**++ Referenceg Ch7-1

REFERENCES

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Journal of the National Medical Association, 73, 1 9-26. Zimmerman, T.S. & Ruggori, Z.M. (1987). Von Willebrand diseaso. Human Pathology, 18,140-52. ST]DDEI\ NATTJRAL DEATI{ IN INFANCY & EARLY CHILDHOOD

CIIAPTER 8

GASTR.OINTESTINAL AND GEIITTOI]RINARY COI\DITIONS 249

1 . GASTROINTESTINAL CONDITIONS

INTRODUCTION

Gastrointestinal causes of sudden and unexpected death in infancy such as intussusception, volvulus and small intestinal obstruction24 (Table 8-1) are uncommon. As the clinical presentation of these disorders may be relatively non-specific the diagnosis may not have been established prior to autopsy. However, the cause of death usually becomes obvious once the peritoneal cavity has been opened.

TABLE 8-1: GASTROINTESTINAL CAUSES OF SUDDEN PAEDIATRIC DEATH.

Gastroenteritis Gastro-oesophageal reflux/aspiration lntestinal obstruction Late-presenting congenital diaphragmatic hernia lntussusception Gastrointestinal haemorrhage

Volvulus Cystic fibrosis lntestinal perf oration

GASTROENTERITIS

Gastroenteritis resulting in dehydration and electrolyte imbalance may cause sudden death particularly in early life. The causative agents are often viral infections and the effects of fluid depletion may be exacerbated by hot weather or parental inattention. Further discussion on the role of gastroenteritis in sudden death may be found in Chapter 4.

INTESTINAL OBSTRUCTION

Acute intestinal obstruction in infants and young children may be caused by intussusception and volvulus, with rare lethal episodes resulting from electrolyte imbalance or intestinal perforation with sepsis. As obstruction causes a characteristic clinical picture of colicky abdominal pain and vomiting over some t¡me, it is usually not considered a cause of unexpected death. However, occasional cases of bowel obstruction presenting in a fulminant manner have been reportsfl34'36. As well, cases are occasionally encountered in which either delay by parents in seeking treatment, or inadequate medical treatment, have resulted in early death. For example, two cases have been encountered at the Adelaide Children's Hospital in which death occurred during or shortly after transfer from rural centres. ln the first case a 1 7-month-old boy suddenly 290

collapsed and died from peritonitis associated with ischaemic necrosis of the small intestine due to obstruct¡on from a congenital band (Figure B-l ). ln the second, a five_year_old girl died suddenly from dehydrat¡on due to small bowel obstruction caused by postsurgical adhesions. A change in management strategies may have altered the outcome in both cases.

INTUSSUSCEPTION lntussusception refers to telescoping of a proximal segment of bowel into the adjacent distal bowel (Figure 8-2). Males are affected more often than females, with most cases occurring in infancy' lntussusception is a common cause of ¡ntestinal obstruction in childhood, but is rarely fatal. The presenting features are usually abdominal pain, vomiting, rectal bleeding or an abdominal mass3s. Most cases are ileocolic, with ileo-ileal, jejunojejunal and colocolic occurring less oftent. Lesions that may be found at the leading edge of an intussusception include hyperplastic Peyer's patches, Meckel's diverticulum, duplication cysts, or lesions of Henoch- Schönlein purpura2s.

lf the presenting symptoms are relatively non-specific there is a possibility that the intussusception will remain undetected allowing progression to bowel infarction due to vascular compromise. ln these rare cases there may be precipitate clinical deterioration with unexpected death secondary to the development of septicaemia. Two fatal cases of ileocolic and ileo-ileal intussusception are illustrated in Figures 8-3 & 4, in infants aged five and six months respect¡vely, both of whom presented with sudden collapse and death following non-specific symptoms and signs which were incorrectly attributed to minor upper respiratory tract infections.

Agonal intussusception is an unrelated and incidental finding at autopsy in infants that should be clearly distinguished from the above situation. ln these cases there is no evidence of vascular obstruct¡on or of infarction, and the bowel appears quite viable (Figure B-b).

VOLVULUS

Volvulus is a rare event in infancy which may involve any portion of the gastrointestinal tract from the stomach to the sigmoid colon. lnfants and children with gastric or small intestinal volvulus may present with bilious vomiting, however, clinical symptoms may be non-specific with volvulus of the large intestine3 leading to a delay ¡n treatment. ln most cases the Figure 8-1 : lntestinal band that had caused bowel obstruction on several occasions before death in a three-month-old boy.

Figure 8-2: A typical case of intussusception in which the bowel has been opened to reveal

distension and mottling of the distal bowel (the intussuscepiens) that has enveloped the invaginated

portion of proximal bowel (the intussusceptum). Figure 8-3: Opening of the abdomen in this five-month-old girl who suddenly developed respiratory distress revealed a necrotic segment of distal ileum associated w¡th an ileo-ileal intussusception.

Figure 8-4: Marked intestinal dilatation with distal necrosis of the ileum was the first indication of an ileocolic intussusception in this six-month-old girl who died suddenly en route to hospital after blood was noted in her diaper. Figure 8-5: Agonal intussusception in an infant unrelated to the cause of death

Figure 8-6: Colonic dilatation due to a right sided volvulus in a seven-week-old boy who had appeared quite well prior to being put to bed. Blood, CSF and lung cultures all grew Clostridíum perfríngens.

I|E 29L

underly¡ng pred¡spos¡ng factors are unknown although unusually long loops of colon and chronic const¡pat¡on have been reportedlo. Volvulus may also complicate meconium ileus in infants with cystic fibrosis. Death may occur very rapidly in an infant with a volvulus46 due to vascular compromise of the twisted bowel with ischaemic necrosis and resultant septicaemia.

Figure 8-6 demonstrates a dilated and dusky-appearing colon caused by a right sided colonic volvulus in a seven-week-old boy who had appeared quite well several hours before he was found moribund in his cot. His only significant past h¡story was of minimal episodic vomit¡ng after feeding in the preceding two weeks of life. Blood, cerebrospinal fluid and lung cultures all grew Clostridíum perfringens.

INTESTINAL PERFORATION

Non-traumatic perforation of the intestine may result from ischaemic necrosis due to mechanical obstruction or from localized inflammation associated with acute appendicitisa. Alternatively, traumatic perforatiôn may occur from intraluminal objects.

Perforation with fulminant sepsis may also occur in children with distension of the bowel from impacted material. Untreated Hirschprung disease (Figure 8-7) or the trichobezoars found in the Rapunzel syndrome4s are illustrat¡ve of this phenomenon. Trichobezoars (hair balls) may extend from the stomach or proximal small intestine into the colon in older children. Perforation is believed to result from pressure necrosis on the distended bowel wall from the impacted material. Unexpected cardiac arrest and death due to duodenal perforation during medical treatment has been reported in a 14-year-old girl with a trichobezoar that extended from the stomach into the transverse colonl3.

Other causes of intestinal perforation in infancy and childhood include undiagnosed necrotizing enterocolitis, dermatomyositis, Ehlers-Danlos syndrome and congenital absence of small intestinal musculature.

GASTRO-OEOSOPHAGEAL REFLUX/ASP¡RATION

Mechanisms by which gastro-oesophageal reflux might cause sudden death in infancy, such as reflex apnoea, bradycardia and anaphylaxis, have been discussed in Chapter 1.

The contribution of gastric aspiration to sudden death in other cases is often difficult to determine as reflux of stomach contents has been produced experimentally within cadaverslT 292

and may also occur as an agonal event in a variety of disorders2T. Wh¡le large amounts of food

within the major airways extending into the smaller air passages are compatib¡e with a lethal episode of airway obstruction due to gastr¡c aspiration, clinicopathological correlation is required before this can be accepted as a cause of deatha. For example, histories of sudden collapse while vomiting, of swallowing incoordination in cerebral palsy, or of mental retardation, may lend weight to the possibility of genuine aspirationls. Gastric aspiration becomes more plausible if other causes of death have been excluded, although it is often difficult to accept it as the cause of death in previously apparently healthy infants with no known neurological impairment.

Occasionally a bolus of solid food may be found lodged within the airway or oesophagus in cases of sudden childhood death. The large portion of sausage (Figure 8-8) retrieved from the oesophagus of a 19-month-old child who suddenly collapsed while eating his lunch at a child care centre demonstrates th¡s phenomenon.

LATE-PRESENTING CONGENITAL DIAPHRAGMATIC HERNIA lnfants w¡th congenital diaphragmatic hernias usually show symptoms and signs of marked respiratory distress due to lung compression and pulmonary hypoplasia, exacerbated by persistant fetal circulationl2. These infants often have a scaphoid abdomen. However, occasional infants do not present classically, either because a membrane covers the defect preventing intestinal herniation, or because the defect has been plugged by one of the abdominal organs such as the spleen2g.

It is usually considered that infants with diaphragmat¡c herniae presenting after the neonatal period have an excellent prognosis, reponding well to surgical repai122,44. While this is generally true, it should be emphasized that rare infants and children may suffer a precipitate clinical deterioration with sudden ¿s¿1¡6'8,s. Clinical symptoms and signs in the late-present¡ng group tend to be relatively nonspecific often resulting in misdiagnosis. Presenting problems include failure to thr¡ve, recurrent chest infections, episodic dyspnoea, diarrhoea, constipation, vomiting, dysphagia and colicky upper abdominal pain, On occasion thoracentesis has been performed due to a mistaken clinical diagnosis of pneumothoraxs. Figure 8-7: Markedly dilated descending colon with distal perforation in a fatal case of untreated

Hirschprung disease.

Figure 8-B: A large portion of partially-chewed sausage retrieved from the oesophagus of a 1 9-

month-old boy who collapsed and died while eating.

llllrrrtrl lllllllllttttrrrrrrr r | ¡ Figu-r 8-9: Herniation of the abdominal contents through a small left sided diaphragmatic hernia in a

four-month-old boy resulting in sudden death (Case 3 in Table g_2).

-fh^ íisu¡îtEi¡¡'ra o-¡u:çl-1l"ì. ¡¡ru íciaiivelv'^l^+:.,^1.. ^-^il -:-- -r smaii s¡ze oi tfie ciiaphragmatic cjefects ¡n ¡ate-presenting cases can be appreciated when the diaphragms have been removed as in Cases I & 3 in Table g-2 (A & B respectively)

-l I

Ì

t ¿l '.( \ \ üi !1 .fxi-F

: *F 293

Thus, although rare, congenital diaphragmatic hernias which do not present at birth have the potential to cause sudden and unexpected death {Figure 8-9). This under-recognized phenomenon is clearly demonstrated in the following studiess,s.

STUDY #8.1

DEMONSTRATION OF THE ASSOCTATTON BETWEEN I.ATE-PRESENTING CONGENITAL

DIAPHRAGMAT¡C HERNIAS AND SUDDEN UNEXPECTED DEATH IN INFANCY AND

CHILDHOOD

INTRODUCTION

Congenital posterolateral diaphragmatic hernias (foramen of Bochdalek) usually present as a surgical emergency within hours or days of birth4o. Respiratory distress due to pulmonary hypoplasia resulting from incomplete development and expansion of the lung during gestation is worsened as the herniated bowel fills with swallowed air. The treatment of choice is surgical repair once the neonate has been stabilizedl9.

Occasionally, diaphragmatic hernias present in later life with mild gastrointestinal or respiratory problemsa3. The prognosis in this latter group is thought to be generally better than in patients who present earlier with respiratory difficu¡1¡"s19'40. However, the following three cases taken from the files of the Hospital for Sick Children (HSC), Toronto, Canada over a 37- year period from 1952 to 1989 demonstrate that undiagnosed diaphragmatic hernias in infancy and early childhood may have lethal consequences with sudden collapse and death occuring due to massive intestinal herniation.

CASE REPORTS

Case 1: A previously well two-month-old boy had an episode of crying prior to being put to bed.

This settled and two hours later he was noted by his parents to be groaning in his sleep. This was followed by cardiorespiratory arrest that was unresponsive to resuscitation. The clinical diagnosis was SIDS. His only past history was of occasional "colic" for which a sedative medication had been prescribed.

At autopsy, a two cm diameter defect in the posterolateral portion of the left side of the diaphragm was found with herniation of most of the small and large intestine into the left pleural 294

cav¡ty (Figures 8-10 & 8-111' No hernial sac was present. The proximal part of the small

intestine, measuring 180 cm in length, was dusky in colour due to ischaemic necrosis, The

mediastinum was displaced to the right with hypoplasia of the left lung. The lung weighed 24 g

with a volume displacement of 60 mL compared with the right lung, which weighed 43 g and

displaced 130 mL.

Case 2: A previously well two-year-old girl suffered an unexpected cardiorespiratory arrest following one day's history of a "flu-like" illness with vomiting. Brain death was noted after resuscitation at a local hospital. Chest x-ray showed a left-sided diaphragmat¡c hern¡a with a markedly dilated stomach, which was located in the thorax causing a shift of the mediastinum to the right. Death occurred the following day after transfer to HSC. Consent for autopsy was refused.

Case 3: A previously well four-month-old boy suffered a cardiopulmonary arrest after sudden onset of irritability and seizures. The only recent past history had been of an upper respiratory tract infection for several weeks prior to presentat¡on. Minimal neurological function was noted subsequent to resuscitat¡on at a local hospital. On transfer to HSC brain death was confirmed.

Four additional cardiac arrests were followed by death the next day.

At autopsy, the most significant gross finding was a three cm-diameter defect in the posterolateral portion of the left diaphragm. Approximately 15 cm of dusky, congested distal ascending, transverse, and proximal descending colon along with two thirds of the jejunum and ileum were present above the diaphragm occupying the left pleural cavity (Figure g-g). The heart and lungs were displaced to the right side of the chest. There was no evidence of pulmonary hypoplasia or intestinal malrotation, No hernial sac was present. Microscopic examination showed focal transmural infarction of the herniated portions of the small intestine with mural infarction of the involved portions of large intestine. Cerebral oedema ,rJith neuronal "*t"n"ive hypoxic-ischaemic damage secondary to prolonged anoxia following the numerous cardiac arrests was also present.

Death in all cases was due to cardiovascular and respiratory compromise caused by compression of the heart, lungs, and great vessels by abdominal viscera that had herniated into the thoracic cavity through previously unsuspected diaphragmatic hernias. Figure 8-1 1: Marked dilatation of the stomach may be found in cases of late presenting diaphragmatic hernias which exacerbate respiratory difficulties (Case 1 in Table 8-2).

, I I

I \

I T

\ ,:1 295

DISCUSSION

Congenital posterolateral diaphragmatic hernias develop during early fetal life when the pleuroperitoneal folds that grow laterally from the developing central port¡on of the diaphragm fail to close the defect between the pleural and peritoneal cav¡t¡es28,43. lf there has been failure of closure there exists a potential passage for abdominal contents to herniate into the thorax.

When the defect is large, the bulk of the abdominal organs may find their way into the chest, causing pulmonary hypoplasia with the typical picture of respiratory distress at b¡rth. ln cases of smaller defects there may be no respiratory compromise and so the condition initially remains undiagnose6ls'4o,4s, Although in some series in the literature as many as 13% to 28'16 oÍ patients have been diagnosed after the neonatal period32, the usual incidence is around 5%33.

Late presentat¡on of paediatric post-traumatic diaphragmatic hernias has also been reportedl4.

lntermittent intestinal obstruction may be the only clue to the presence of a late- presenting diaphragmatic hernia33, which may remain undetected well into adult life. The small size of the defect with protective "plugging" of the gap by the spleen or liver is believed to delay intestinal herniation23. ln some cases there may also be a confining sac that prevents visceral herniation until rupture occurs.

The cases described demonstrate that not all late-presenting diaphragmatic hernias have a favorable prognosis, as has been previously reporte619,23,40. On the contrary, they can be associated with a rapidly downhill clinical course with a lethal outcome. ln Case 1, death had occurred during sleep, thus causing clinical confusion with sudden infant death syndrome. ln the other two cases brain death followed the initial sudden cardiac arrests. The proximity of local hospitals enabled partial resuscitation of these two patients, although it soon became obvious that survival was unlikely.

Case 1 is unusual in having asymptomatic pulmonary hypoplasia, in that pat¡ents

diagnosed after the first weeks of life, as in Case 3, usually have lungs of normal weight and

volume32. Whether the episodes of "colic" that occurred in the second patient were related to

intermittent bowel obstruction is difficult to determine, particularly in the absence of vomiting at

any stage. Both Cases 2 and 3 had mild respiratory and gastrointestinal symptoms preceding

their unexpected arrests, which may explain the timing of the fatal herniations. Coughing and 296

vom¡ting ra¡se ¡ntra-abdominal pressure, thus increasing local pressure on any defects present ¡n the diaphragm, making visceral herniation more likelya3. A similar process may have occurred in

Case 1 following the episode of crying. On the other hand, it is also possible that the herniations may have initiated these symptoms.

SUMMARY

Three previously well patients (aged 2, 4, and 24 monthsl are described who suffered unexpected cardiorespiratory arrests due to unsuspected congenital diaphragmatic defects with intestinal herniation. Deaths resulted from cardiovascular and respiratory compromise due to visceral herniation that caused mediastinal and pulmonary compression. ***

STUDY #8-2

DEMONSTRATION OF THE OCCURRENCE OF FATAL GASTRIC PERFORATION AS A CAUSE OF

SUDDEN AND UNEXPECTED DEATH IN CHILDHOOD ASSOCIATED WITH LATE-PRESENTING

CONGENITAL DIAPHRAGMATIC HERNIA

CASE REPORT

A previously-well four-year-old boy complained of left upper quadrant pain associated with vomiting of white mucus one evening. The following ciay he was noted to be rather listless and was not interested in eating. He remained lethargic and anorexic and the next day was taken to the local medical officer who diagnosed an ot¡t¡s med¡a and prescribed oral antibiot¡cs and ear drops. His condition worsened later that day and he suffered an unexpected cardiorespiratory arrest' Resuscitation attempts were unsuccessful and he was certif¡ed dead on arrival at the

Adelaide Children's Hospital, approximately 48 hours after the onset of symptoms. His past history included occasional abdominal discomfort with one or two transient episodes of vom¡t¡ng which were not felt to be particularly serious at the time, A chest X-ray, which had been taken Figure Perforation 8-12: of the stomach that had herniated through a small left sided diaphragmatic hernia resulted in fulminant sepsis in a four-year-old boy (case 5 in Table g-2). 297

two years before death during investigations for a functional cardiac murmur, was completely normal.

At autopsy the body was that of a well nourished boy of around four years of age.

There were no external signs of trauma or dysmorphism and both eyes were slightly sunken.

The major findings were in the left pleural cavity which conta¡ned the stomach, spleen, splenic flexure of the transverse colon, tip of the pancreas and the bulk of the greater omentum, whích had plugged a 50 x 40 mm oval defect in the posterior part of the left diaphragm (Figure 8-12l-.

The rest of the diaphragm was unremarkable and there was no evidence of a hernial sac. The anterior surface of the stomach was discoloured and thinned with two 10mm diameter perforations in the mid portion of the greater curvature. The adjacent wall showed numerous smaller ulcers covered only by serosa. Both pleural cavities contained a large amount of greenish-grey gastric fluid. The left lung was collapsed and the mediastinum was shifted to the right. The heart was unremarkable and the remainder of the small and large intestines, except for the splenic flexure of the colon, were normally situated. Microscopy confirmed the presence of widespread ischaemic necrosis of the anterior gastric wall with perforation. Postmortem blood and tissue cultures grew mixed bacterial and fungal organisms.

Death was attr¡buted to gastric perforation due to ischaemia that had resulted from herniation of the stomach into the left pleural cavity through a previously unsuspected congenital diaphragmat¡c defect. This was associated with compression of the left lung and shifting of the mediastinum to the right.

DISCUSSION

ln the case reported, delay in diagnosis due to the non-specific, and apparently relatively-benign, nature of the presenting symptoms resulted in perforation of the stomach which had herniated

into the left pleural cavity. While gastric dilatation has been demonstrated in children with

delayed presentation of their diaphragmatic herniasT'32, Íatal perforation is an exceedingly rare

complication. This may partly be due to the intra-abdominal location of the stomach in 40-51%

of casesT. The patient did not have any of the other congenital conditions that have been

associated with congenital diaphragmat¡c hernias such as Down syndrome, congenital heart

defects or midline fusion defectss, 298

This case demonstrates, therefore, that late-presenting congenital diaphragmat¡c hernias in childhood may have dire consequences if treatment is delayed. The diagnosis should be

entertained in any child who presents with lower chest signs in association with gastrointestinal

symptoms and an unusual chest X-ray, particularly if these occur on the left side. lt should also previous be noted that chest X-rays may be completely normal, as it was in this case, and so this finding does not exclude the d¡agnosis as has been previously suggestedl6. tf herniation is suspected, urgent surgical repair is indicated.

SUMMARY

previously-well A four-year-old boy presented with a two day history of listlessness, anorexia, quadrant left upper pain and vomiting, followed by sudden cardiorespiratory arrest and death.

At autopsy a 50mm diameter congenital defect in the posterolateral part of the left diaphragm was discovered associated with herniation of the stomach, spleen, greater omentum and portions of the transverse colon and pancreas into the chest cavity. perforation of the anterior wall of the stomach had filled the pleural cavity with gastric contents. This case demonstrates a rare lethal mechanism that has not been reported before as a cause of unexpected death in late presenting congenital diaphragmatic hernias in early childhood. Serious, even fatal, consequences may occur with delayed presentation in childhood quite soon after the onset of symptoms.

t*+

Table 8-2 lists the clinicopathological features of six children, three of whom were infants, who suffered unexpected cardiac arrests caused by gut herniation through unsuspected diaphragmatic hernias. These cases (four of whom have been described in greater detail in the above case reports) demonstrate the diversity of presenting symptoms, signs and clinical diagnoses, the latter including croup, otitis media and SIDS. ln four children the d¡agnosis was not suspected until autopsy, a feature that has been noted in other series6. 299

TABLE 8-2: SUMMARY OF CLINICOPATHOLOGICAL FEATURES OF 6 CASES OF LATE- PRESENTING CONGENITAL DIAPHRAGMAT¡C HERN¡AS WITH SUDDEN DEATH

NO. AGE SEX INITlAL IN¡TIAL AUTOPSY

PRESENTATION CLlNICAL FINDINGS

DIAGNOSIS

1 2Mo M 'colic' SIDS 2cm defect in L.

diaphragm

2. 3Mo M vomiting croup 3cm defect in L,

diaphragm

3 4Mo M irritability cardiac 3cm defect in L.

arrest diaphragm

4 2Y F 'flu' with no autopsy, CXR -hernia

vomiting, 1D L. diaphragm

5 4Y M lethargy, ot¡tis 4cm defect in L.

vomiting media diaphragm

abdominal

pain, 2D

6. 13Y F abdominal gastro- postsurgical hernia repair

pain, 1wk enteritis L. diaphragm

vomiting 1D

D = day;wk = week; Mo : month;Y = year; L = left; M = male; F = female 300

Summary of Pathological Features

At autopsy the usua¡ finding is of small and large intestinal herniation into the chest cavity (Figure 8-91 through relatively small diaphragmatic defects (Figure B-10). This causes

considerable mediastinal shift, usually to the right, as can be seen in the chest X-ray from the

13-year-old girl described in Table 8-2 (Figure 8-13). Atelectasis of the ipsilateral lung occurs,

and a complicating factor may be massive gastric dilatation (Figure g-lll.

Pathophysiology

While the usual mechanism of death is similar to that of untreated tension pneumothorax, cases

with a more prolonged course may develop ischaemic necrosis of the herniated segments of intestine with perforation and sepsis (Figure B-12ll.

GASTROINTESTINAL HAEMORRHAGE

Massive haemorrhage from the gastrointestinal tract during childhood may result from systemic disease or from localized lesions. For example, terminal haemorrhage into the bowel is occasionally seen in malignant disease, part¡cularly in leukaemias or lymphomas, but is usually the final manifestation of a generalized decline.

Brisk haemorrhage may result from upper gastrointestinal peptic ulcer disease in children who may require emergency surgery. ln contrast, the bleeding associated w¡th ulcers due to heterotopic gastric mucosa in Meckel's diverticulae tends to be less spectacular. Both haemorrhage from, and perforation of, peptic ulcers may result in death in childhoodal.

Oesophageal varices may cause fatal haemorrhage in children with but are not descr¡bed as a cause of sudden death in infants. Profuse gastrointestinal haemorrhage may also complicate arteriovenous malformations such as those found in Osler-Weber-Rendu syndrome and angiodysplasia. cYsTtc FtBRosts

Cystic fibrosis is an autosomal recessive disorder caused by a defect in the cystic fibrosis transmembrane conductance regulator gene located on the long arm of chromose¡¡s 738,39.

This defect results in increased viscosity of exocrine secretions with particularly severe effects noted in the pancreas, liver, gastro¡ntestinal tract and lungs. The major pulmonary problems are Figure 8-13: Marked mediastinal deviation to the right in a 13-year-old girl who presented with relatively non-specific symptoms prior to terminal collapse frorn a late-presenting diaphragmat¡c hernia (Case 6 in Table 8-21. (Haematoxylin Figure 8-14: lnspissated mucous within duodenal crypts suggestive of cystic fibrosis

& Eosin, x 'l 1O).

Figure 8-15: lnte .rnal infarction following a small intestinal volvulus in an infant w¡th cystic fibrosis and meconit, r ileus. t

r 301

L caused by recurrent and persistent bacterial and fungal infections which result in progressrve ,'ìr bronchiectasis and destruction of lung parenchyma

Occurrence of Sudden Death

Sudden and unexpected death can occur in the neonatal period due to intestinal volvulus,

infarction and perforat¡on from meconium ileus, or later in life due to electrolyte imbalance and dehydration. Affected infants are particularly vulnerable to dehydration during hot weather as they lose excessive amounts of sodium in their sweat3l. Occasional infants may present with

collapse in hot weather before the diagnosis has been established clinically. Thus the presence

of inspissated secretions within the intest¡nal mucosal, pancreatic and salivary glands at autopsy

may be the first indication of the diagnosis (Figure 8-141.

Figure 8-15 shows an 11-day-old infant who died unexpectedly following a short history

of vomiting and drawing up of the knees. The autopsy findings were of small intestinal volvulus

with infarction associated with meconium ileus and inspissation of secretions w¡th¡n the

remainder of the bowel, pancreas and submandibular gland, characteristic of cyst¡c fibrosis.

2. GENITO-URINARY CONDITIONS

Genitourinary causes of sudden death in infants and children are rare. Table 8-3 summarizes

some of the entities that have been reported as causes of unexpected paediatric death.

TABLE 8-3: GENITOURINARY CAUSES OF SUDDEN PEDIATRIC DEATH

Primary renal disease Wilms tumour

pyelonephritis haemorrhage

glomerulonephritis embolism

Urinary tract obstruction Haemolytic uraemic syndrome

Ovarian torsion

PRIMARY RENAL DISEASE

Although diseases of the urinary tract in children have been cited as causes of sudden death,

detailed clinicopathological information on affected children is generally not availablel 1,37.

However, the author has one case, that of a six-year-old girl who presented to the Adelaide

Children's Hospital with a one day history of vomiting, who died of acute renal failure within 302

hours' At autopsy the kidneys were pale, and microscopy revealed hypercellular glomeruli

typical of acute proliferative glomerulonephritis. Rarely sudden death may also result from a

hypertensive crisis in children with chronic renal insufficiency. Sudden death reported in

apparently stable children with nephrotic syndrome is believed to be due to marked

hyponatraemia resulting from a combination of salt-restriction, vomiting and hot weather2l.

Vitreous humour electrolyte levels are mandatory in such cases.

URINARY TRACT OBSTRUCTION

Untreated urinary tract obstruction usually results in progressive loss of renal function with

associated symptoms and signs of chronic renal failure. However, occasional cases may have

the d¡agnosis made at eutopsy following a supposed precipitate clinical deterioration. Male

infants with posterior urethral valves may present in this manner (Figure g-161.

WILMS TUMOUR

Wilms tumour may result in sudden and unexpected death due to secondary haemorrhage or to

tumour embolism. For example, massive haemorrhage from a Wilms tumour may occur into the

parenchyma of the tumour itself or into the adjacent retroperitoneal tissues and abdominal

cavity. Hypovolaemic shock may ensue followed by death if fluid replacement and urgent

surgery are not undertaken. Figure 8-17 illustrates a Wilms tumour with extensive

intraparenchymal haemorrhage in an infant who died of shock. Haemorrhage may result from

erosion of the tumour into vessels, and may be exacerbated by an accompanying consumption

coagulopathy secondary to disseminated intravascular coagulation.

Embolization of tumour fragments is a particular problem in Wilms tumour due to its

angio-invasive qualitiesaT. Figure B-18 shows a sectioned Wilms tumour which had invaded the

adjacent inferior vena cava and embolized to the main pulmonary trunk in a three-year-old girl.

Portions of necrotic tumour may lodge more distally in branches of the pulmonary arteries and

paradoxical embolization may occur if there is communication between the right and left sides of the heart, Figure 8-19 illustrates cerebral infarction in an eight-year-old boy due to a paradoxical tumour embolus that had passed through a ventricular septal defectso. Figure 8-16: Hypertrophied bladder with bilateral hydroureteronephroses due to posterior urethral valves in a four-month-old boy. His final presentat¡on was of fulminant metabol¡c acidosis with death within 12 hours attributed before autopsy to men¡ngit¡s. Figure 8-1 7: Extensive intraparenchymal hemorrhage into a cystic congenital Wilms tumour resulted in sudden death.

r' \t : , Figure 8-18: Wilms tumour extending along the renal vein ¡nto the inferior vena cava (A), with sudden death in a three-year-old girl due to a saddle tumour embr¡lism blocking the pulmonary outflow tract (Bl. Figure 8-1 9: Base of the brain in an eight-year-old boy who died postoperat¡vely following an

attempted resection of a large Wilms tumour. A portion of turnour that paradoxically embolized through a ventricular septal defect can be seen protruding from the left middle cerebral artery

(arrow) (A). Coronal section of the brain revealing recent infarcts in the areas of the left middle

cerebral and right anterior cerebral arteries due to Wilms tumour emboli (B).

B

t t t I '*

a. 303

HAEMOLYTIC URAEMIC SYNDROME

The haemolytic uraemic syndrome is characterized by the acute onset of a microangiopathic haemolytic anaemia, thrombocytopaenia and renal insufficiency. lt often follows an infectious illness such as gastro¡ntestinal infection with vero-toxin producing Escherichia coli and has been linked with immunization, although this association is speculativels. Children under the age of five years are at particular risk. The aetiology remains obscure, although endotoxaemia has been proposed as the initiating event.

Most patients recover, although a small percentage develop chronic renal disease or relapse. Central nervous system manifestations such as respiratory deregulation, seizures and coma may result from vascular thrombosis, systemic hypertension or metabolic derangements such as hypocalcaemia and hyponatraemia42. However, despite the serious hematologic and vascular complications, sudden death is not generally found2o.

OVARIAN TORSION

Torsion and infarction of ovaries has been associated with sudden death in neonates and infants, sometimes associated with massive haernorrhage into cystic ovarian tissue or with intraoperative rupture2. lt has also been suggested that pain in the absense of rupture might precipitate reflex apnoea or bradycardia with lethal consequences25.

++++ Rcfcrcnce¡ Gh8-1

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Alford, B.A. & Mcllhonny, J. (1992). The child with acuto abdominal pain and vomiting. Radiologic Clinics of North America, 30, 441-53. 2. Alrabooah,4., Galliani, C.4., Giacomantonio, M.. Heifetz, S.A. & Lau, H. (1988). Neonatal ovarian torsion: roport of th¡oe cases and roview of tho liloraturø. Pediatr¡c Pathology,8, 1 43-9. 3. Andersen, J,F., Eklöf, O. & Thomasson, B. (1981). Large bowel volwlus in child¡en. Review of case material and tho litoraturo. Pediatric Radiology, 11, 129-38. 4. Aroy, J.B. & Sotos, J. (1956). Unoxpoctod death in early life. Journal of Pediatrics,49, 523-39. 5. Borman, L., Stringer, D.4.. Ein, S. & Shandling. B. (1988). Childhood diaphragmatic hernias presenting aftor the noonatal petiod. Clinical Radiology,39, 237-44. 6. Booker, P.D.. Meerstadt, P.W,D. & Bush. G.H. (1981). Congenital diaphragmatic hernia in tho older child. Archives of Disease in Childhood,56, 253-57. 7. Brill, P.W., Go¡shwind, M.E. & Krasna, l.H. (1977). Massive gastric onlargem€nt w¡th delayed presentetion of congenital diaphragmatic hernia: Report of three cases and ¡eview of tho literaturo. Journal of Pediatric Surgery, 12, 667-71. Byard, R.W., Bohn, D.J., Wilson, G., Smilh, C.R. & Ein, S.H. (199O). Unsuspocted diaphragmatic hernia: a potontisl cause of sudden and unexpected death in infancy and early childhood. Journal of Pediatric

Surgery, 25, 1 1 66-8. 9 Byard, R.W., Bourne, A,J. & Cockington, R.A, (1991). Fatal gastric perforation in a 4-year-old child with a latô-presenting congenital diaphragmatic he¡nia. Pediatric Surgery lnternational, 6, 4+6. 10. Campbell, J.R. & Blank, E. (1974). Sigmoid volvulus in childron. Pediatrics,53,702-5. 11. Canby,J.P.&Jaffurs,W.J. (1963). Suddenandunexpecteddeathinchildhood.AfouryearstudyinaUnited States Army station hospital in Germany. Military Medicine, 128, 613-16. 12. Cullen, M.L.. Klein. M.D. & Philippart, A.l. (1985). Congenital diaphragmatic hornia. Surgrcal Clinics of North America,65, 1115-39. 13. Deslypore, J.P., Praet, M. & Verdonk, G. (1982). An unusual case of trichobozoar: the Rapunzel syndrome. American Journal of Gdstroenterolocy, 77, 467 -7O. 14 Ein, S.H. (19821. Chest and gsstrointestinal tract. ln Children's Fractures, ed. M. Rang, pp 95-123. Philadelphia, PA: Lippincott. 15 Einfeld, S.L., Fairloy, M.J., Green, B.F. & Opitz, J.M. (1987). Sudden death in childhood in a case of the G syndromo. American Journal of Medical Genetics, 28, 293-6. 16 Fromm, S.H. & Lucas, C.E. (1971). An unusual complication of chronic diaphragmatic hernia in an adult patient. Journal of Thoracic and Cardiovascular Surgery, 61, 65+6. 17 Gardner, A.M.N. (1958). Aspiration of food and vomit. Auarterly Journal of Medicine, 27, 227-42. 18 Gianantonio, C.A., Vitacco, M., Mendilaharzu, F., Gallo, G.E. & Sojo, E.T. (1973). Tho hemolyt¡c-uremic syndromo. Nephron, 11 , 17 +92. 19. Graivier, L., Dorman, G.W. & Votteler, T.P. (1971). Congenital diaphragmatic hernia in children. Surgery, Gynecology and Obstetrics, 132, 4O8-10. 20. Hebib, R., Lévy, M., Gagnadoux, M.-F. & Broyor, M. (1982). Progress of the hemol¡ic uremic syndrome in children. Advances in Nephrology, 1 1, 99-128.

21 . Hagge, W.W.. Burke, E.C. & Stickler, G.B. (1967). Sudden death in th€ nophrotic syndrome: salt deplotion as a probable mechanism. Clinical Pediatrics, 6,52+7. 22. Hight, D.W.. Hixon, S.D., Reed, J.O. Watts Jr, F.B. & Hertzler, J.H. (1982). lntermittent diaphragmatic hernis of Bochdalek: roport of a case and literature review. Pediatrics,69, 601-4. 23. Hurdiss, L.W., Taþi, H. & Johnson, L.M. (1976). Delayod appearanco of left-sidod diaphragmatic hernia in infancy. Jornal of Pediatrics, 88, 990-2. 24. Jorgensen, l.M. & Gregersen, M. (1990). Sudden death in childron with gastrointestinal disease. Reports of 24 medico-logal cases. Ugeskrift Laeger, 152, 2233-7. 25. Kasian, G.F., Taylor,8.W., Sugarman, R.G. & Nyssen. J.N. (1986). Ovarian torsion related to sudden infant doath, Canadian Medical Association Journal, 135, 1373. 26. Kluth, D.. Peterson, C., Zimmorman, H.J. & Muhlhaus, K. (1989). The embryology of congonital diaphragmatic ho¡nia. Modern Problems in Paediatrics, 24,7-21 . 27. Knight, B.H. (1975). The significance of tho post mortom discovory of gastr¡c contents in tho air passages. furensic Science, 6, 229-34. 28. Littlo, K.J, & Danzl, D.F. (1991). lntussuscoption associated with Henoch-Schonloin purpura. The Journal of Emergency Medicine, 9, 29-32. Rclcrcncc¡ Ch8-2

29 Lynch, J'M', Adkins, J.C. & Wienor, E.S, (1982). lncarcerated congenital diaphragmatic hornias with bowel obstruct¡on (Bochdalek). Journal of pediatric Surgery, 17, Sg7_&. 30, Moore, L' & Byard, (1992). R'w. Fatal paradoxical embolism to the loft carot¡d artory during partial resecrion of Wilm's tumo¡. pediatric pathology, 12,971-6. 31. Morales, 4.R., Kulesh, M. & Valdes-Dapona, M, (1gg4). Maximising the effoctivoness of the autopsy in casos of sudden dea¡h. Archives of pathology and Laboratory Medicine, log. 460-1. 32. Newman, 8.M.. Afshani. E.. Karp, M.p.. et a/. flg96). presentation of congenital disphragmatic hernia past the nconatal pariod. Archives of Surgury, I 2l , g l 3_6. 33. osebold, w.R. & soper, R.T' (1976). congcnital postorolatoral diaphragmatic hernia past infancy. American Journdl of Surgery, 131 , 749-54. 34. qÍalzgraÍ, R.R., Zumwalt, R.E. & Kenny, M.R. (1988). Mesodiverticular band and sudden death in children. A report of two casos. Archives of pathology and Laboratory Medicind, 112, 1g2-4. 35. Pollack Jr, C.V. & Pende¡, E.S. (199'|). Unusual cases of intussusception. The Journal of Bnergency Medicine,9, 347-55. 36. Powley, J.M. (19651. Unexpoctod deaths f¡om small bowel obstruction. hoceedings of the Royal society of Medicine, 58, 87O-3. 37. Rabson, S.M. (1949). Suddon and unoxpectod natural death. lV. Suddon and unexpected natural death in infants and young childron. The Journal of pediatrics,34, 1 66_73. 38. Riordan, J.R., Rommens, J,M., Kerom, B.-S., Aron, N., Rozmaher, R., G¡zerczak, 2., Ziorenski, J., Lok, s., Plavsic, N., chou, J.-L., Drumm, M.L., rannuzzi, M.c., coilins, F.s. & Tsui, L.-c. fi989). ldentification of the cystic fibrosis geno: cloning and characterization of complementary DNA. Scienca, 245, 1086-73. 39. Rommons, J.M', lannuzz¡, M.c., Kerom, B.-s, Drumm. M.L., Merme¡, G., Dean, M., Rozmaher, R., core, J.L., Kennedy, D., Hidaka, N., Zsiga, M., Buchwald, M., Riordan, J.R., Tsui, L.-c. & collins, F.s. (1989). ldentification of the cystic fibrosis gene: chromosomo walking and jumping. Scienca,24S, l059-65. 40. Ruff, S.J., Campboll, J.R., Harrison, M.tN., et al, (19gO). pediatric diaphragmatic hernias: An l1-year experionce. American Journal of Surgery, 139, 641_5. 41 . Seagram, C.G.F., Stephons, C.A. & Cumming, W.A. (1g73). peptic ulceration at the Hospital for Sick Childrcn, Toronto, during the 2o-year period 1949-1969. Journal of pediatric Surgery, g, 4o7-13. 42. sheth' K'J', swick, H.M' & Haworth. N. (1986). Neurological involvement in hemol¡ic-uremic syndrome. Annals of Neurology, ,l9, gO-9. 43. siegol, M.J', shackelford, G.D. & McAlistor w.H. (1981). Left-sided congenital diaphragmatic hernia: Delayed presontation. American Journal of Roentgenology, 197, 49_6. 44. Storm, W., Gisbonz, K.H. Steiger, (1997). & H. Delayed onsot of loft_s¡ded diaphragmatic hornia in a nowborn. Acta Paediatrica Hungarica, 29, 261_6. 45. Vaughan Jr, E.D., Sawyers, J.L. & Scott Jr, H.W. fl96g). The Rapunzel syndrome: an unusual complication nf intaofinol hau¡-' evtYotrtCtt^^-.' wv,Aa Jrv-lr...õ A. 46. Wong, S'W' and Gardnor, V. (1992). Sudden death in children due to mesentoric defect and mesenteric cyst. The American Journal of Foronsic Medicine and pathology, 19, 21_7. 47. Zekowskí, M.F., Edwards, R.H. & McDonough, E.T. (199O). Wilms,tumor presonting as sudden death due to pathology tumor embolism, Archives of and Laboratory Medicine, 1 14, 6os-g. ST]DDEN NATI]RAL DEATH IN INFANCY & EARLY CHILDHOOD

CHAPTER 9

METABOLIC AND ENDOCRINE CONDITIONS 304

INTRODUCTION

A variety of inborn errors of metabolism listed in Table 9-1 may cause unexpected death in infancy. Clinical presentations include failure to thrive, hypotonia, psychomotor delay, seizures, unusual odours, vomiting or diarrhoea, and there may be a family history of an inherited metabolic disorder. Only the more 'common' conditions are dealt with in detail ¡n the text, which also includes acquired metabolic disorders. As the diagnosis of a metabolic disorder is more likely to be known in older children than in infants the autopsy may assume particular importance in establ¡shing the diagnosis in very early life.

TABLE 9-1: INBORN ERRORS OF METABOLISM THAT HAVE BEEN ASSOCIATED W¡TH

SUDDEN OR UNEXPECTED DEATHS lN INFANCY AND EARLY CHILDHOOD. (raken lrom references 20,36,911

FATTY ACID OXIDATION DISORDERS

Acyl-CoA dehydrogenase deficiencies (MCAD, LCAD) Carnitine palmitoyltransferase deficiency Long chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) Systemic carnitine deficiency

CARBOHYDRATE DISORDERS

Fructose- 1, 6-diphosphatase deficiency Galactosaemia Glycogen storage diseases Hereditary f ructose intolerance Mitochondrial phosphoenolpyruvate carboxykinase deficiency

AMINO ACID DISORDERS

Homocystinuria lsovaleric acidaemia Lysinuric protein intolerance Maple syrup urine disease Non-ketotic hyperglycaemia Tyrosinaemia

UREA CYCLE DISORDERS

Argininosuccinate lyase deficiency Argininosuccinate synthetase deficiency Carbamylphosphate synthetase deficiency Ornithine carbamoyltransferase deficiency 305

ORGANIC ACID DISORDERS

Glutaric aciduria tVpe 2 3-Hydroxy-3-methyl-glutaryl-CoA lyase deficiency Propionic acidaemia Lactate dehydrogenase complex defects 3-Methylcrotonyl-CoA carboxylase deficiency Methylmalonic acidaemia

MISCELLANEOUS

Biotin¡dase deficiency Cytochrome oxidase deficiency Electron transfer flavoprotein deficiency Electron transfer flavoprotein dehydrogenase deficiency Glycerol kinase deficiency GM1 Gangliosidosis Holocarboxylase synthetase deficiency M ucopolysaccharidoses Niemann-Pick disease type C Phosphoenolpyruvate carboxykinase deficiency

Pathological features

The findings at autopsy are quite variable because of the disparate nature of these disorders. However, in infancy certain features should suggest an underlying metabolic defect. These are summarized in Table 9-2 and include cardiomegaly and fatty change in the liver, heart, smooth and skeletal muscle, g-1 and renal tubules36 (Figures & g_2). Unfortunately autopsy findings are

often not specific. For example, cerebral oedema is found in many condit¡ons ranging from trauma to SIDS. Additionally, fatty change within the myocardium has also been found in a wide range of disorders including infections and congenital malformationsls. Hypertrophic or

dilated cardiomyopathies occur but are not specific to any particular metabolic disorder66 (Table 9-3).

TABLE 9-2: AUTOFSY FINDINGS THAT MAY INDICATE AN INBORN ERROR OF METABOLISM

Family history of similar sudden death, part¡curarry in siblings Dysmorphic features Enlargement of liver, spleen, heart Pallor of liver, heart, muscles Cerebral oedema Fatty change in liver, heart, smooth muscle Figure 9-1: Mixed macro- and microvesicular steatosis of the liver indicating the possibility of an underlying metabolic disorder in an infant who died suddenly and unexpectedly (Haematoxylin &

Eosin, x 440).

¡. ^,

Figure 9-2 Oil-red O staining of a frozen section of the heart demonstrat¡ng extensive lipid deposition (x 4401,

) 306

TABLE 9-3: INBORN ERRORS OF METABOLISM ASSOCIATED WITH CARDIOMYOPATHY lN

INFANTS (Mo¿¡tie¿ from ¡eferonco 66)

STORAGE DISORDERS a) Hypertrophic cardiomyopathy Ethanolaminosis Glycogen storage diseases (types ll & lll) Lysosomal glycogenosis without acid maltase deficiency Mucopolysaccharidoses (types I & Vll) b) Dilatedcardiomyopathy Cardiac phosphorylase kinase deficiency Gangliosidoses (GM1 & GM2) c) Uncharacterized Familial steatosis of heart, liver and kidneys

MITOCHONDRIAL D¡SORDERS a) Hypertrophic cardiomyopathy Hereditary hypertrophic cardiomyopathy with mitochondrial myopathy Respiratory chain disorders (cytochrome-c-oxidase deficiency, cytochrome-3- oxidase deficiency, cytochrome-c-reductase coenzyme deficiency) Leigh disease

b) Dilated cardiomyopathy X-linked cardiomyopathy

MISCELLANEOUS a) Dilated/Hypertrophic cardiomyopathy Carnitine deficiency b) Uncharacterized Amino acid disorders Organic acid disorders

Autopsy sampling

The specimens that need to be taken at autopsy in cases of suspected metabolic conditions are listed in Appendix ll, along with appropriate sampling methods. Further details of the laboratory diagnosis of these disorders have been reviewed by Applegarth, Dimmick and Toones.

Frequency

The estimated frequency of metabol¡c disease has been controversial, with some authors claiming that between 5 and 2Oo/" of cases of sudden death in infancy result from metabolic

¿s¡sç1s3s,121. These high figures do not appear to reflect general experiences6.gs. For example, no examples of medium acyl CoA dehydrogenase {MCADI deficiency were identified on fibroblast culture in one study of 70 cases of SIDS, and no abnormal organic acid metabolites 307

were found on exam¡nation of urine, CSF and vitreous humour from 88 SIDS cases in the same

reportso. Similarly, another study of 47 cases of SIDS also failed to ¡denr¡fy any evidence of

organic acidaemias3o. Miller er at. did not find any infants homozygous for the common G-ggs

mutat¡on of medium chain acyl-CoA dehydrogenase (MCADI deficiency in a retrospect¡ve

examination of DNA taken from 67 SIDS infantss4. Thus it seems likely that the number of

cases of sudden infant death caused by metabol¡c disease is closer to 1oÁ or less, although the

possibility of underdiagnosis must be considered in centres that do not test for these cond¡tions.

FATTY ACID OXIDATION DISORDERS

ACYL-CoA DEHYDROcENASE DEF|CtENCtES

Metabolic defects involving fat oxidation have received part¡cular attention due to the possibility

of sudden and unexpected death in infancy producing an identical clinical picture to SIDS. The

enzymes concerned are dehydrogenases involved in the progressive mitochondrial ß-oxidation of

long chain fatty acids mobilized from adipose tissue storesoe. Hypoglycaemia results when

glycogen stores are depleted, as the deficiency of acyl-CoA dehydrogenases hinders

gluconeogenesis from fat stores57.

MEDIUM CHAIN ACYL CoA DEHyDROGENASE (MCAD) DEF|CtENCY

The most common defect is medium chain acyl coA dehydrogenase (MCAD) deficiency which

may cause lethargy, vomiting and seizures. Findings of hepatomegaly, encephalopathy and

marked hepatic steatosis may lead to confusion with Reye syndrome. Alternatively, in some

¡nfants sudden and unexpected death may be the first manifestation, thus leading to confusion w¡th S|DSI03.

Frequency

MCAD deficiency is one of the most common inborn metabolic errors and has an estímated frequency of one per 2O,000 newbornslls.

Aetiology lnheritance of the acyl CoA dehydrogenase deficiencies is autosomal recessive and the gene for

MCAD has been fully characterized on the short arm of chromosome 180, The most common mutation, found in nearly 85% of pat¡ents, involves an A to G nucleotide replacement at position 308

985 resulting in a substitution of glutamate for lysine at pos¡tion 329 of the MCAD precursor

proteinT l .

Pathophysiology

Metabol¡c crises are often precipitated by viral infection or fasting, and result in hypoglycaemia and hypoketonuria, somet¡mes with a metabolic acidosisl l s. This may occur after immunizationso'sl and may be heralded by episodic diarrhoea and vomiting3. The first episode of metabolic decompensat¡on usually occurs in the second year of life31, although it may occur much earlier. For example, a four-day-old infant who presented ¡n a 'Reye-like' manner to the

Blodgett Memorial Medical Center (Michigan, USAI was subsequently proven to have MCAD deficiency on postmortem blood and liver DNA analysis (Dr. S.D. Cohle, personal communication).

Pathological Features

The autopsy findings in the acyl CoA dehydrogenase deficiencies are variable, and although lipid accumulation within hepatocytes and cardiac myocytes is characteristic, it cannot be relied upon. For example, Carter and Variend found fatty change within the heart in only one of three cases with proven MCAD deficiencyls. Similarly, while diffuse hepatic steatosis has been accepted as a marker for ß oxidative defects, it may not be present even in fatal cases74. On the other hand, fatty change in the liver may be found in so many children dying of non- metabolic conditions that Bonnel and Beckwith describe it as'ubiquitous', and consider that ¡t ¡s a nonspecific finding of little use in isolationl 1. Thus diagnosis of the acyl-CoA dehydrogenase deficiencies depends on other investigations.

Diagnosis

Traditionally the diagnosis of acyl-CoA dehydrogenase deficiencies is made by identifying urinary dicarboxylic acids on gas chromatography-mass spectrometry or by measuring enzyme activity in cultured skin fibroblss1sl17. However for most cases of MCAD, molecular analysis of DNA can be performed on DNA extracted from either Í¡ozen blood following polymerase chain react¡on amplifications, from liver extract64, from paraffin embedded formalin-fixed material2e, or from stored Guthrie blood cardsso. 309

LONG AND sHoRT CHAIN ACYL coA DEHYDROGENASE DEFrctENcrES

Long chain acyl CoA dehydrogenase (LCADI deficiency occurs less frequently than MCAD deficiency, but may also result in a'SIDS-like' picture. Other manifestations include neonatal hypoglycaemia, hypotonia, cardiomyopathy and encephalopathy32.ll6 although these may not always be present33. Short chain acyl CoA dehydrogenase (SCADI deficiency is extremely rare and affected infants have not been reported presenting with sudden infant death.

CARNITINE DEFICIENCY

Carnitine deficiency is a disorder of fatty acid metabolism in which there is defective fatty acid transport across mitochondrial membranes. lt may be myopathic or systemicl2.

Clinical Features

The clinical presentation of systemic carnitine deficiency may mimic Reye syndrome with an acute encephalopathyl9 or there may be evidence of cardiac involvement with cardiomegalyss, heart failure and endocardial fibroelastosis. Sudden death may occur following prolonged

¡¡¡¡ssr72,119.

Pathological Features

At autopsy there may be biventricular cardiomegaly with lipid accumulation within myocytes on microscopy4l, although on occasion the myocardium may apparentry be spared63.

CARBOHYDRATE DISORDERS

GLYCOGEN STORAGE DISEASES

Sudden and unexpected death has been reported in both types lc and ll glycogen storage disease, with SIDS being a differential diagnosis in infancyl0'56. Although in one series of 38 infants diagnosed as having died of SIDS, eight were reported to have glucose-o-phosphatase deficiency (type la glycogen storage disease) with two having transport protein T2 deficiency

(type lc glycogen storage disease)1s, doubts have been raised as to the reliability of these resultsg9.

Type ll glycogen storage (Pompe) disease is an autosomal recessive disorder caused by acid maltase deficiency. The clinical expression is varied with both infantile and adolescent/adult types being recognized. ln the classic infantile form (type llal, affected infants are profoundly hypotonic with cardiomegaly and usually die within the first year of life82 (Figure g-3). This Figure 9-3: Cross-sect¡on of the heart in a five-month-old girl with Pompe disease demonstrating massive cardiomegaly.

Figure 9-4: Microscopy of the heart in Pompe disease showing extensive vacuolation of

myocytes due to leaching out of glycogen during processing (Haematoxylin & Eosin, x 280). 310

contrasts w¡th the more benign muscular form which is associated with longer survival. Sudden death is a known complication of type llalo, most likely due to metabol¡c or cardiac sequelael4'tte. A family has been reported in which unexpected death occurred in two siblings with acid maltase deficiency due to rupture of basilar artery aneurysmsT6, although the relationship between the vascular abnormalities and the metabolic disorder is unclear.

Clinical Features

The characteristic finding in this disorder is of failure to thrive with skeletal muscle involvement, hepatomegaly and cardiomegaly, the latter being profound enough to cause outflow obstruction.

Within skeletal and cardiac muscle there is an increase in membrane bound intracytoplasmic glycogen, as well as an increase in free cytoplasmic glycogen within cardiac myocytes (Figure 9-

41.

Diagnosis

As increased cellular glycogen stores are not always present, biochemical testing of tissue for specific enzyme deficiencies is required for diagnosis39.

AMINOACID DISORDERS

HOMOCYSTINURIA

Homocystinuria may be caused by any one of several enzyme defects, including cystathionine synthetase deficiency. This autosomal recessive defect results in increased levels of serum and urine homocystinelT and is characterized by a similar phenotype to Marfan syndrome. Features which separate homocystinuria from Marfan syndrome are the finding of homocystine ¡n plasma and urine, variable mental retardation, generalized osteoporosis, malar flushing and different vascular complicationsl o6.

Occurrence of Sudden Death

Myocardial infarction, cerebrovascular accident and pulmonary thromboembolism are complications of homozygous homocystinuria which may result in premature death in childhood and adolescence, but are not usual in infancy. However, up to 50% of affected pat¡ents have

died before the age of twenty years in some series46,61'106. 311

Pathophysiology

The cause of the thromboembolic phenomenon in homocystinuria is an increase in fragility of

endothelial cellsa with desquamation and exposure of subendothel¡al connect¡ve tissue. Cerebral

arteries, veins and sinuses are all at increased risk of thrombosis. Similar changes have been produced in experimental animals exposed to increased levels of homocysl¡¡s49,s1. Blood coagulation abnormalities have also been reported which may contr¡bute to the thrombotic tendencys3. As well, there ¡s fibromuscular thickening of the intima of vessels w¡th premature atherosclerosis and endocardial fibroelastosis of th€ heartæ. Premature atherosclerosis has been found in heterozygous adults, but does not appear to be a major problem in infants or childrensT.

MAPLE SYRUP URINE DISEASE

While presentat¡on the usual of maple syrup urine disease is with anorexia, vom¡ting and convulsions during the neonatal period, a late onset form is recognized. lt is possible for apparently healthy infants with this condition to present with unexpected cardiorespiratory arrest47.

OTHER INBORN ERRORS OF METABOLISM

BIOTINIDASE DEFIC¡ENCY

Biotinidase deficiency is the major defect in children with late-onset multiple carboxylase deficiency. Features include convulsions, developmental delay, hypotonia, hearing loss, alopecia, ataxia and skin rashes125, however, the clínical presentation may be variable. Metabolíc acidosis may occur in undiagnosed cases resulting in sudden and unexpected death16. GANGLIOSIDOSES

These disorders are characte¡ized by abnormalities in the metabolic handling of complex sugar- conta¡n¡ng cerebrosides. While a chronic clinical course is more typical, with progressive dementia from cerebral storage, sudden death due to cardic arrhythmia may occur in GM1 gangliosidosisss. Figure 9-5: Thickening of the aortic varve in a case of Hurrer syndrome I I ì

Figure 9-6: Typical axial twisting of a hair shaft with pili torti of Menkes syndrome. 31,2

MUCO POLYSACCHARIDOSES

This heterogeneous collect¡on of lysosomal enzyme disorders are characterized by abnormal accumulation of acid mucopolysaccharides within a variety of tissues. Six main types have been identified, the features of which have been well described elsewhere2T. Hurler, Sanfilippo,

Morquio, Scheie and Maratoux-Lamy syndromes are inherited on an autosomal recessive basis, whereas Hunter syndrome is inherited as a sex-linked recessive trait.

As the most severe cardiovascular abnormalities are found in Hurler syndrome, which is due to a deficiency of alpha-L-iduronidase, the following discussion will concentrate predominantly on infants and children with this variant, although similar changes may be found in the other types of mucopolysaccharidoses3T.

Pathological Features

At autopsy, lesions may be found within the coronary arter¡es, elastic arter¡es, endocardium, myocardium and within the heart valves (Figure 9-5), all of which show infiltration by large vacuolated cells with surrounding fibrosis. For example, the coronary arteries, which may be prominent on gross examination, show marked diffuse luminal narrowing due to concentric thickening of the intima which contains numerous clear cells, collagen fibres and increased amounts of acid mucopolysaccharidel3. The media may also be involved and some of the intramural arter¡es may be similarly affected. The absence of cholesterol deposits and the concentric nature of the luminal narrowing help to differentiate the arterial lesions from those seen in premature atherosclerosis2T. The degree of narrowing is marked, with 71o/o of arteries in one study showing 76 to 100% stenosis on cross-sect¡onal study13. Very occasional calcification occurs within coronary arteries and focal intimal changes have also been reported in both the aorta and pulmonary artery68.

Although the heart weight may not necessarily be increased in these disorders there is diffuse thickening of the endocardium resulting in a lack of compliance in the ventricular walls, particularly within the left ventricle. Microscopic examination reveals typical storage cells and collagen deposition within the ventricular myocard¡urn1o1.

Valvular lesions result from the same underlying process and involve particularly the mitral valve43. All of the cardiac valves may be involved and mitral stenosis, aort¡c stenosis and 313

incompetence have all been reported6T'68. Visual inspection of the cardiac valves may reveal

thickened leaflets and shortening of the chordae tendinae.

Occurrence of Sudden Death

Although recognized more for severe mental retardation, hepatosplenomegaly and skeletal

abnormalities, the presence of cardiovascular disease and upper airway narrowing may predispose affected children to sudden death73. For example, ten out of g7 deaths l12o/ol in

children with Hunter-Hurler syndrome were sudden, although the pathophysiology was often not

clea168. The age of the children who died suddenly is not specified in the latter report, and so it

is not certain whether any infants were involved.

Pathophysiology

The cause of sudden death might at first seem relatively straightforeward given the degree of

coronary arterial narrowing that occurs, however, affected infants and children usually do not

show evidence of myocardial ischaemial3,27. This may be Bartly due to somat¡c death occurring prior to the development of histologic changes within the myocardium, although it is felt that other factors such as valve disease, aort¡c narrowing, myocardial infiltration by storage cells, system¡c hypertension, respiratory insufficiency and nutr¡tional anaemia all contribute to

myocardial instability w¡th its attendant risk of sudden ¿g¿16s4,'r01,113. pulmonary hypertension

has also been described in these children34, in one case assoc¡ated with acute postoperative

death 1 os.

Upper airway narrowing is another risk factor which may cause part¡cular difficulties during intubation general for anaesthesia, and which also results in sleep apnoea. Krovetz and Schiebler describe two children out of a total of 87 who died during anaesthetic induction due to this problem68.

HYPERLIPIDAEMIAS

The hyperlipidaemias can be inherited or acquired and are divided into five categories according Frederickson to the classification, each of which is biochemically and aetiologically heterogeneous. sudden death may occur in early childhood in Types I and ll. As well, ischaemic cerebrovascular strokes in infants and children have been associated with low levels of high-density lipoprotein cholesterol, sometimes occuring with high levels of triglyceri6".2s,42. 314

TYPE I

This is the rarest of the inherited hyperlipidaemias and is believed to be due to a defect in extrahepatic lipoprotein lipase or its activator, apoprotein C-ll, resulting in delayed clearance of

chylomicrons from the blood. While patients with this condition do not have accelerated

atherosclerosis, cerebral infarction has been reported in a six-year-old9, and in a two-month-old

infant who died suddenly9s. The cause of death in the latter case was cerebral infarction due to

excessive blood viscosity associated with marked chylomicronaemia. Subsequent investigation

of other family members demonstrated occult lipid abnormalities compat¡ble with lipoprotein

lipase deficiency.

TYPE II

Familial hypercholesterolaemia is characterized by elevated low density lipoproteins and

cholesterol due to a deficiency of low density lipoprotein receptors. lt has an autosomal

dominant inheritance pattern. The homozygous form is clinically the most severe with

manifestations of accelerated atherosclerosis developing in childhood (not infancy) which can

result in death from myocardial infarction at an early age7s,1o9. ln some cases death may be

sudden and unexpectedl24.

At autopsy the ascending aorta shows more severe atherosclerosis than the abdominal

aorta. This may be sufficiently florid to produce an angiographic appearance of supravalvular

stenosis. lnvolvement of the coronary ost¡a2 may precipitate myocardial infarction, even in the

absence of coronary artery disease although the coronary arteries usually show diffuse

involvement with atherosclerotic narrowing. lnvolvement of the aortic and mitral valves with

significant stenosis is also characteristic, along with atherosclerotic deposits in the pulmonary

artery. Microscopically the atherosclerotic plaques are similar to the more usual atheromas that

occur with aging.

Clues to the presence of familial hypercholesterolaemia prior to the commencement of

autopsy include orange-yellow cutaneous xanthomas which may develop in early childhood or

tendon xanthomas and arcus senilis which are more common in older adolescents. 315

TYPES I¡I.V

Type lll and Type lV hyperlipoproteinaemias are characterized by abnormal ß-very low density lipoproteins and elevated very low density lipoproteins, respectively. Although both are

associated with a high incidence of atherosclerosis, sudden death in infancy or childhood does

not appear to be a feature of these 6¡sor6s¡r86.102. Similarly, sudden infant death has not been

found in Type V hyperlipoproteinaemia in which there is elevation of plasma very low density

lipoproteins and chylom¡ç¡6¡s39,1 o2.

MISCELLANEOUS

Premature atherosclerosis is a feature of cockayne, Hutchinson-Gilford (progeria) and werner syndromes2T.

MENKES KINKY HAIR SYNDROME

Menkes Kinky Hair syndrome is an X-linked recessive disorder characterized by mental and growth retardat¡on, abnormal hair growth producing the characteristic 'pili torti' (Figure 9-6), and progressive neurological deterioration with death within one or two years. Other features include hypothermia, convulsions, aneurysms, arterial stenoses and thrombosesgT. Sudden

death may occur, however, and was present in two of six cases reported by Danks et a1,26,

The underlying defect in this syndrome is defective copper absorption w¡th low serum copper and caeruloplasmin levels. Vascular changes are common and superficial vessels may be

aneurysmally dilated and tortuous. Microscopically there is fibromuscular intimal proliferation

with fragmentat¡on of the internal elastic laminaTs and decreased numbers of medial smooth muscle cells in a variety of vessels, including the coronary arteriesl2o, Veins as well as arteries are affectedl22 ry¡11l arterial changes resulting in obliteration of vessel ¡r,ns¡¿26,97.

REYE SYNDROME

Reye syndrome is a metabolic disorder of infancy and early childhood characterized by an acute onset of encephalopathy often associated with hypoglycaemia and/or hyperammonaemia, liver dysfunction and fatty change in the viscera associated with mitochondrial malfunctiontll. The presentation clinical has been confused with a wide range of other metabolic disorders including defects in ketogenesis, amino acid metabolism and the urea cycle, as well as hereditary fructose intolerance, cystic fibrosis and systemic carnitine deficiency. lt has been proposed, therefore, Figure 9-7: Cut surface of the liver in a six year girl who died from Reye syndrome showing diffuse mottl¡ng from lipid accumulation.

Figure 9-8: Marked cerebral oedema with flattening of gyri is a nonspecific finding but may be found in cases of metabol¡c encephalopathy. Figure 9-9: Sectíon from the kidney in the previous case (Fig. 9-B) showing marked lipid accumulation within renal tubular epithelial cells (Haematoxylin & Eosin. x 110). 3 l-6

that the diagnosis of Reye syndrome cannot be made in a child under three years of age unless these disorders have been excludedTo.

Clinical Features

The clinical course of this syndrome may be fulminant, usually occuring in children under ten years of age. lt often follows a viral illness, particularly influenza A and chicken pox, although occasionally sudden death may occur with relatively nonspecific symptoms and signs which were not thought to be significant at the 1¡¡¡s126. Features of vomiting, lethargy, irritability, and coma have raised the possibility of a toxic aetiology. Aspirin is the chief suspect as it is recognized that children who are on salicylate medication for other d¡seases have an increased risk of Reye syndrome48,83,1oo.11o. Additionally, the incidence of the syndrome has declined markedly with declining aspirin use.

ln reviewing the clinical presentat¡on, the diagnosis of Reye syndrome may be less likely in younger children who have had previous episodes of hypoglycaemia or acidosis precipitated by minor illness or fasting, An inherited metabolic disorder is also more probable if there has been a similar sibling death.

Pathological Features

At autopsy the liver may be enlarged and on cut section will show yellowish colouration (Figure

9-71. There may be quite marked cerebral oedema noted when the calvarium is removed (Figure

9-8). Microscopically the pattern of hepatic steatosis may be relatively unhelpful as a number of

conditions may result in microvesicular lipid deposition. However, Reye syndrome can be

differentiated on electron microscopy if tissue preservation is adequate. Unfortunately, evidence

of swelling of mitochondria, w¡th accumulation of flocculent matrix material and loss of

intramitochondrial dense bodiesga may be more discernable in biopsy than autopsy material. ln

contrast, these features are not present in livers of children with MCAD or LCAD

deficienciestlT. Lipid deposits may be found in other organs such as the heart or within the

renal tubules (Figure g-9). 31,7

Occurrence of Sudden Death

Sudden death in fulminant cases may lead to confusion w¡th acyl CoA dehydrogenase

deficiencies or with S|DS79. However, a history of progressive neurological deterioration can usually be elicited.

Autopsy lnvestigation

Meier, Baron and Greenberg, recommended that postmortem levels of serum transaminases,

creatinine kinase, blood ammonia and prothrombin time should be measured in suspected cases

as they are elevateds3, whereas serum alkaline phosphatase, gamma glutamyl transpeptidase

and bilirubin are within the normal range. Further investigative protocols for Reye syndrome and

metabolic disorders w¡th similar presentations have been outlined by Green and Hallas.

MISCELLANEOUS DISORDERS

Mitochondrial encephalomyelopathies are a diverse group of conditions in which there are

structurally abnormal mítochondria with defects in mitochondrial aerobic oxidative metabolism.

While the clinical course is usually chronic with hypotonia, the association with (Table cardiomyopathies 9-3), convulsions and stroke-like episodes raises the possibility of rapid

terminal decl¡ne24,96.

Although cardiomyopathy or cardiac ínvolvement may be present in a range of other

inherited metabolic disorders (Table 9-3) such as Fabry disease (angiokeratoma corporis

diffusum universale), Leigh disease (subacute necrotising encephalomyelopathyl, Refsum disease (phytanic acid alpha-hydroxylase deficiency), Cori-Forbes disease (Type lll glycogen storage disease, amylo-1,6-glycosidase deficiencyl and primary oxalosisl ,22,2s,27, the clinical courses tend to be relatively chronic, the cardiac lesions are of secondary importance, or sudden death usually does not occur in infancy or early childhood.

ENDOCRINE DISORDERS

Endociine disorders are not usually considered in the differential díagnosis of sudden and unexpected deaths in infants as the clinical courses are often prolonged, occurring in children with well established diagnoses. Very occasionally, however, death can occur unexpectedly at the t¡me of the first presentation, or when coincidental stresses result in a fulminant and fatal episode in a child who was felt to be clinically stable. 318

INSULIN DEPENDENT D¡ABETES MELLITUS

The occurrence of sudden death in insulin dependent diabetes mellitus is not a reported problem in infancy. Although children may die on the¡r initial presentat¡on with insulin dependent diabetes mellitusss reports of sudden death in previously undiagnosed individuals due to ketoacidosis have occurred mainly in adultss9. Sudden death has, however, been occasionally reported in undiagnosed children2s. Unexpected death has also been described in diabetic children who were thought to be responding appropriately to treatment for ketoacidosiss3. The mechanisms for this are not well understood but may involve cerebral oedema from excessive rehydration, or hypokalaemia with cardiac arrhythmia. Although blood glucose levels are unreliable at autopsy, analysis of vitreous humour provides a reasonably reliable est¡mate of glucose levels in cases of possible hyperglycaemic ketoacidosis2s. Cerebrospinal fluid glucose levels may be of use if taken within several hours of death and interpreted in conjunction with vitreous humour glucose levels. Vascular complications may infrequently occur in childhood resulting in myocardial or cerebral infarction6'85'107.

ADRENAL HYPOPI.ASIA

Hypoplasia or atrophy of the adrenal glands may result in sudden and unexpected death in infants and children due to Addisonian ç¡¡r¡s7'62,92'104,108. This may mimic SlDS38.

Two types of congenital adrenal hypoplasia have been identified. ln the first the adrenal gland is morphologically similar to the adult adrenal but is considerably reduced in size. This type may be associated with pituitary hypoplasia and anencephaly and may be inherited in an autosomal recessive manner. The second type shows remnants of the fetal coftex in the form

of cytomegaly, is associated with a much longer survival65 and may be inherited in an X-linked

recessive manner. There is, however, considerable variation in clinical expression and there may

be a degree of histological overlap between the two types.

Addison disease in later life may be asymptomatic until exertion precipitates sudden

collapse and deathEs. Careful clinical investigation may reveal a history of weakness, lethargy

and diarrhoea prior to deathloa. An association with Duchenne muscular dystrophy has been

reported in the X-linked v¿¡¡¿¡1112. 31,9

ADRENAL HYPERPI.ASIA

There gfoup are a of enzymatic defects in the cortisol synthet¡c pathway which result in congenital adrenal hyperplasia due to increased stímulation of the adrenal gland by elevated levels of adrenocorticotrophic hormone (ACTHl8s.

Aetiology

These inborn errors of metabolism are autosomal recessively-inherited with the most common defect involving a deficiency in 21-hydroxylase. This results in excessive loss of sodium due to

aldosterone deficiency which may lead to rapidly developing shock and death2t. Clinical Features

Female infants are usually diagnosed at a younger age than males because of virilization with variable clitoral enlargement and fusion of the labioscrotal foldsTT,so (Figure g-10). Males may remain undiagnosed until a fatal episode occurs, although ¡n retrospect there may have been a history of anorexia, failure to thr¡ve or vomiting. Cardiac tachyarrhthymias may have been noted prior to collapse. Hypertension, a feature of 1 1 ß-hydroxylase deficiency, may be associated with stroke at an early age2l.

Pathological Feaiures

At autopsy infants and children may be dehydrated with female infants showing evidence of masculinization, sometimes wíth polycystic ovar¡es. The internal genitalia are normal in appearance' Male infants may have undescended testes and hypospadius, and boys may show signs precocityl23. of sexual The adrenal glands are enlarged with a nodular or diffuse cortical hyperplasia. Histologically the cortex appears homogeneous with loss of distinction between the zona fasciculata and reticularis.

NESIDIOBLASTOSIS

Nesidioblastosis complex, also known as islet cell dysmaturational syndrome, refers to the range of histologic changes that may be found in the pancreas in association with hyperinsulinaemic hypoglycaemia60. Histologic findings in infants with infantile hyperinsulinaemic hypoglycaemia are variable, consisting of apparently normal pancreatic morphology, hyperplasia, adenoma or nesidioblaslssisll4. The latter entity is a proliferation of islet cells from small ducts and acini, with scattering of endocrine cells throughout the pancreatic parenchymaaa (Figure g-111. Figure 9-10: Virulization with clitoral enlargement in an infant with congenital adrenal hyperplasia.

Figure 9-1 1: lmmunoperoxidase sta¡ning of the pancreas for insulin, demonstrating diffuse

dispersion of endocrine cells throughout the pancreatic parenchyma in three-month-old boy with

recurrent hypoglycaemia (x 1101, 320

While nesidioblastosis was once claimed to be a factor in certain infant deaths ascribed to SlDSss it is now apparent that 'disorganization' of islet cells is probably a normal phenomenon related to maturationoo. Certainly a number of infants examined by the author with otherwise typical features of SIDS, have had this finding (see Figure 1-271. lt has been suggested therefore, that this finding is only of significance ¡f hyperinsulinaemia and hypoglycaemia can be demonstrated. Nesidioblastosis has also been associated w¡th the development of hypertrophic cardiomyopathy but this is of uncertain physiological significance in terms of the potential for sudden deaths2.

THYROID DISEASE

Fatal upper airway obstruction may rarely occur in infants with congenital hypothyroidism and macroglossia. lt is possible that hyperthyroidism may induce fatal arrhythmias.

CONCLUSION

Endocrine disorders may, therefore, be responsible for sudden death at all ages, associated with a variety of different mechanisms including marked electrolyte distu¡'bance, cardiac arrhythmia, hypoglycaemia and mechanical airway obstruction.

*+++ Rcfercncec Ch9-1

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79 Mason, J.K. & Bain, A.D. (1982). Roye's syndrome presonting as atypical sudden infant death syndrome? furensic Science lnternational, 20, 39-44, 80 Matsubara, Y., Narisawa, K. & Tada, K. (1992). Medium-chain acyl-CoA dehydrogenase deficiency: molocular pediafzcs, 6spocts. European Journal of 1 51, 1 S+9. 81. McCully, K.S. & Wilson, R.B. (1975). Homocystoino theory of arteriosclerosis. Atherosclerosis,22,2lS-27. 42. McKusick, (199o). v'4. Mendelian inheritance in man. catalogs of autosomal dominant, autosomal recessive ,andxlinkedphønotypes,gthadn. Baltimo¡o:JohnsHopkinsUnivorsitypress. pp121S-g. 83. Meier, F'4" Baron. J.A. & Greenberg, E.R. (19831. Reye's syndrome. A ¡oview f¡om tho foronsic viowpoint. The American Journal of Forensic Medicine end pathotogy, 4, 323_9. 84. Miller, M.E.. Brooks, J.G., Forbes, N., & lnsel, R. (1992). Frequoncy of medium-chain acyl_CoA dohydrogenase deficiency G-985 mutation in suddon infant pediatric death syndrome. Research,3l , 305-7. 85. Molander' N' (1982). sudden natural dosth in lator childhood and adolesconce. Archives of Disease in Childhood, 57, 572-6. 86. Morganroth, J., Lavy, R.l. & Fredrickson, D.S. (19751. The biochemical, clinicel and genetic features of typo lll hyperlipoproteinemia. Annals of lntenal Medicine, g2, 1Sg_74. 87. Mudd, s.H., skovby, pott¡grew, F.. Levy, H.L., K.D., wircken, B., pyerirz, R.E., Andria. G,, Boers, G.H.J.. Bromberg. 1.L., Cerone, R,, Fowler,8., Grobe, H.. Schmidt, H. & Schweitzer, L. (1ggS). The natural history of homocystinuria due to cystathionine &synthase deficiency. American Journal of Human Genetics,37, l-3,l. 88. Neuspiel, D.R. & Kuller, L.H. (1985)' Sudden and unoxpectod natural death in childhood and adolescenco. The Journal of the American Medical Association, 254, 1921_25. 89. New. M.l. & Levine, L.S. (1981). Congonital ad¡enal hyporplasia. Clinical Biochemistry,'l4,2Sg-72. 90. Now, M'l' & Levine, (1984). L'S. Rocont advances in 2l-hydroxylaso deficiency. Annual Review of Medicine, 35, 649-63. 9!. Norman,'M.G', Taylor, G.P. & Clarke, L.A. (199o). Suddon, unexpected, natural dosrh in childhood. pediatric Pathology, lO, 769-84. 92. O'Donohoe, N.V. & Holland, P.D.J. (1968). Familial congonital adrenal hypoplasia. Archives of Disease in Childhood, 43,717-23. 93. Palaroti, G., salardi, s., Piazzi, poggi, s., Legnani, c.. M., Grauso, F., caniato, A.. cocche¡i, s. & caccia¡i, E. (1986). Blood coagulation changes in homocystinuria: effocts of pyridoxine and other specific thorapy. The Journal of pediatrics, lOg, lOOl_6. 94. Partin, J.C., Schubert, W.K. & Partin, J.S. (1971). Mitochondrial ultrastructure in Roye,s syndrome (encephalopathy and fatty dogoneration of tho viscora). The New Engtand Journal of Medicine, 2gS, 1 339-43. 95. Patterson, K., Donnelly, W.H, & Dehner, L.p. (19g2). The ca¡diovascular systom. ln pediatric pathology,vol 1.' ed= J.T' stocker & L.p. Dehner, pp. s75-5s1. phiraderphia: i.B. Lippincott. 96. Pavlakis, S.G., Phillips, P.C., DiMauro, S., Do Vivo, D.C. & Rowland, L.p. (1984). Mitochondrial myopathy, oncephalopathy, lactic acidosis and strokelike opisodos: a distinctive clinical syndromø. Annals of Neurology, 16, 48l-9. 97. Pellogrino, P.4., Zanesco, p.A. L. & Battistella, fi 9g2). Coagulopathies and vasculopathios. ln Cerebrovascular Diseases in Children, ed. A.J. Raimondi, M. Choux & C. Di Rocco, pp 1gg-2o4. New York: Springer-Verlag. 98. Potter, J'M' & Hilton, J.M.N' (l983). Type t hyporlipoprotoinemia prosenring as sudden death in infancy. Australian and New Zealand Journal of Medicine,l3, 3g1_3. 99. Rebuffat, p., E., sottiaux, M., Goyons, Blum, D., Vamos, E., Van Vliet, G., Hasaerts, D., stoonhout, p., Demeirlor, (1991). L' & Kahn, A. Sudden infant death syndromo, as first expression of a metabolic disorder. ln lnborn Errors of Metabolism, Nestlé Nutrition Workshop Series, vol. 24, ed. J. Schaub, F. Van Hoof, & H.L. Vis., pp.7'l-8O. Vovey: Nestoc; Now york: Raven pross. 1 00. Ronnobohm, R.M., Heubi, J.E., Daugherty, C.C. & Daniols, S.R. (19g5). Roye syndromo in childron recoiving salicylato thorapy for connoctive tissue disease. The Journal of pediatrics, 107, g77-gO. 101. Rentoria, V.G., Ferrans. V.J. & Roberts, W,C. (1976). The hoart in tho Hurlor syndrome. Gross, histologic and ultrast¡uctural obsorvations in fivo necropsy cases. The American Journal of Cardiology, 3g, 4g7- 501. 102. Roberts, W.C., Ferrans, V.J., Lovy, R.l. & Fredrickson, D.S. (1973). Cardiovascular pathology in hyperlipoproteinemia. Anotomic observations in 42 necropsy p6tients wlth normal or sbnormal serum lipoprotein pattorns. The American Journal of Cardiology,3l , 5S7-7O. Relerences Ch9-5

103 Roe, C.R., Millington, D.S., Maltby, D.A. & Kinnebrow, P. (1986). Recognition of modium-chain acyl-CoA dehydrogonase deficiency in asymptometic siblings of childron dying of sudden infant death or Roye- liko syndromes. Journal of Pediatrics, 108, 13-l8. 1 04. Russell, M.A., Op¡tz, J.M., Viseskul, C., Gilbert, E.F. & Bargman, G.J. (19771. Suddon infant death due to congonital adrenal hypoplasia. Archives of Pathology and Laboratory Medicine, 1O1, 1 68-9. 105 Schonk, E.A. & Haggorty, J. (1964). Morquio's disease. A radiologic and morphologic study. Pediatrics,34, 839-50. 106 Schimke, R.N., McKusick, V.4., Huang, T. & Pollack, A.D. (1965), Homocystinuria. Studies of 20 families with33affectodmombo¡s, TheJournalof thøAmericanMedicalAssocietion,l93,Tll-19. 107. Shivelhood, E.K. (1947). Myocardial infarction in a twelve-year-old boy w¡th di€betes. American Heart Journal,35, 655-61.

1 08. Sperling, M.4., Wolfsen, A.R. & Fisher. D.A. (1973). Congenital adrenal hypoplasia: an isolated dofoct of organogenosis. The Journal of Ped¡atrics, 82, 444-9. 109 Sprecher, D.L., Schaefer. E.J.. Kent. K.M., Gregg, R.E., Zech, L.4., Hoeg, J.M., McManus, 8., Roberts, W.C. & Brewer Jr. H.B. (1984). Cardiovascular foôtures of homozygous familial hyporcholesterolemia: analysis of 16 patients. The American Journal of Cardiology, 54, 2O-3O. 1 10. Starko, K.M. A Mullick, F.G. (1983). Hepatic and cerebral pathology findings in children with fatal salicylate intoxication: further evidence for a causal relation between salicylate and Roye's syndromo. The Lancet, 1, 326-9. 111. Starko, K.M., Ray, C.G., Dominguez, L.8., Stromberg, W.L. & Woodall, D.F. (1980). Reye's syndrome and salicylate usø. Pediatrics, 66, 859-64. 112 Stuhrmann, M., Heilbronner, H., Reis, 4., Wegner, R.-D., Fischer, P. & Schmidtke, J. (1991). Charactorisation of a Xp21 microdelotion syndrome in a 2-yoer-old boy with muscular dystrophy, glycerol kinaso deficiency and ad¡enal hypoplasia congenita. Human Genetics, 86, 414-1 5. 113 Taylor. D.8., Blaser, S.1., Bu¡¡ows, P.E., Stringer, D.4., Clarke, J.T.R. & Thorner, P. (1991). Arteriopathy and . coarctat¡on of tho abdominal aorta in children with mucopolysaccharidosis: imaging findings. American Journal of Roentgenology, 157 , 819-23. 114. Thomas Jr, C.G., Undorwood, L.E., Carney, C.N., Dolcourt, J.L. & Wh¡tt, J.J. (19771. Neonatal and infantile hypoglycemia duo to insulin €xcoss: n6w aspocts of diagnosis and surgical manag€m€nt. Annals of Surgery, 185, 5O5-17. 115. Touma, E.H. & Charpentier, C. (1992). Modium chain acyl-CoA dehydrogenase deficiency. Archives of Disease in Childhood, 67, 142-5, 1 16. Treem, W.R., Stanley, C,A., Hale, D.E., Leopold, H.B. & Hyams, J.S. (1991). Hypoglycemia, hypotonia. and cardiomyopathy: the evolving clinical picture of long-chain acyl-CoA dehydrogonase deficiency. Pediatrics, 87, 328-33. 117 Treem, W.R., Witzleben, C.A., Piccoli, D.4., Stanley, C.4., Hale, D.E., Coates, P.M. & Watkins, J.B. (19861. Medium-chain and long-chain acyl CoA dehyrdogenas€ deficiency: clinical, patholog¡c and ultrastructu¡al differentiation from Reyo's syndrome. Hepatology, 6, 127O-78. 118 Tripathy, D., Coleman, R.A., Vidaillet Jr, H.J., Steenbergen, C., Hirschhorn, K. & Packor, D.L. (1988). Complete heart block with myocardial membrane-bound glycogen and normal peripheral o-glucosidase activity. Annals of lnternal Medicine, 109, 985-7. 119 Tripp, M.E., Katcher, M.L., Peters, H.4., Gilbert, E.F., Arya, S., Hodach, R.J. & Shug, A.L. ('l 98'l). Systomic carnitine deficiency presenting as familial ondocardial fibroelastosis. A treatable cardiomyopathy. The New England Journal of Medicine. 3O5, 385-9O. '120 Uno, H., Arya, S., Laxova, R. & Gilbert, E.F. (1983). Menkes'syndrome with vascular and andronorgic nerve abnormalitios. Archives of Pathology and Laboratory Medicine, 107, 286-9. 121 Vawter, G.F., McGraw. C.A., Hug, G., Kozakewich, H.P.W., McNaulty, J. & Mandell, F. (1986). An hepatic motabolic profile in suddon intant death (SIDS). furensic Science lnternational,30, 93-8.

122. Whoolor, E.M. & Roberts, P.F. (1976). Menkes's steoly hair syndrome. Archives of Disease in Childhood,Sl , 269-74. 123. White, P.C., New, M.l. & Dupont, B. (1987). Congenital adrenal hyperplasia. (First of two parts). The New

England Journal of Medicine, 31 6, 1 51 9-24. 't24. Williams, M.L. (1989). Death of a child as € result of familial hypercholesterolaomia. The Medical Journal of Australia, 150, 93-4. 125 Wolf,8., Hoard, G.S., Weissbecker. K.A., McVoy, J.R.S., Grier, R.E. & Leshner, R.T. (1985). Biotinidase deficiency: ¡nit¡al clinical features and rapid diagnosis. Annals of Neurology, 18, 614-17. 126. Young, T.W. (1992). Royo's syndromo. A diognosis occasionally first made at medicolegal autopsy. The American Journal of furensic Medicine and Pathology, '13, 21-7. ST]DDEN NATT]RAL DEATH IN INFANCY & EARLY CHILDHOOD

CHAPTER 10

MISCELLANEOUS CONDITIONS 32L

INTRODUCTION

This eclectic chapter summarizes a variety of unrelated conditions that have not been specifically

dealt with elsewhere. For convenience these disorders have been grouped into the following

categories: connective tissue, skeletal, dermatological, muscular, chromosomal and

immunological. An overview of the range of anomalies which should be looked for at the t¡me

of autopsy in infants w¡th these conditions is provided.

CONNECTIVE T¡SSUE DISORDERS

MARFAN SYNDROME

Overview

a) Characteristic Features

The characteristic features of Marfan syndrome that are usually manifested outside infancy

include long arms and legs (dolichostenomelial, long fingers (arachnodactyly), pectus excavatum

or carinatum, kyphoscoliosis, high arched palate, cutaneous striae, ectopia lentis, dilatation of

the ascending aorta and dural ectas¡a. There is microscopic fragmentation of arterial collagen

and elastin with accumulation of acid mucopolysaccharrides

bl Possible Mechanisms of Death

Possible mechanisms of death include arterial dissection, aortic aneurysm rupture and cardiac

arrhythmia

c) Other Potent¡ally Significant Features

Associated features include mitral valve prolapse, aortic incompetence and coronary artery

aneurysms.

Clinical Features

Marfan syndrome is characterized by cardiovascular, ocular and skeletal abnormalities which

have quite variable degrees of clinical expressionl4'87. Patients may have a history of joint

hyperextensibility, recurrent joint dislocations, spontaneous pneumothoraces and ocular

abnormalities such as lens dislocation and retinal detachment. Cardiac arrhythmias may be a

complication of the syndromeT4 and there may be arterial dissection or rupture2'7g. 322

Aetiology

While .l'o/o most cases of Marfan syndrome are inherited in an autosomal dominant manner, ot

cases are sporadic. The genetic defect has been recently mapped to the fibrillin gene on the

long arm of chromosome 1 527,51 ,

Pathological Findings

At autopsy, affected infants may be morphologically unremarkable, although older children are

often readily identifiable due to their increased height and excessive thinness, associated with reduced amounts of subcutaneous fat. The arms and legs may be long due to a

disproportionate increase in the length of the distal long bones and typically the arm span exceeds the height.

The major internal findings involve the cardiovascular system which may show

dissection of the ascending aorta and/or ectasia of the aortic root and valve with saccular

aneurysm formation. There may be aneurysmal dilatation of the sinuses of Valsalva, coronary ertery aneurysms and dilatation of the mitral and tricuspid valve rings12.13,24,eo. There is an increased incidence of mitral valve prolapse due to an increase in size of the vatve leaflets, an

increase in length of the chordae and dilatation of the valve ¿¡¡u¡us81,86. Occasionally

subpleural pulmonary cysts give rise to spontaneous pneumothoracessr.

Microscopically, involved vessels demonstrate cystic medial necrosis with degenerat¡on

of elastin fibres, fragmentation of collagen and accumulation of acid mucopolysacchar¡desl01 (Figure 10-1). Affected cardiac valves also show interstitial mucopolysaccharide aggregationl6.

It has been suggested that the aggregated material results from attempted repair of tissues that contain defectively cross-linked collagen following exposure to the stress of hemodynamic pressuressg. Fibrointimal and medial hyperplasia of intramural coronary arter¡es and of arteries supplying the sinoatrial and atrioventricular nodes have been described4g.

Occurrence of Sudden Death lndividuals with Marfan syndrome are at increased risk of death at all ages due to major arterial dissection, aneurysm rupture23, heart failure or myocardial infarctionoS. While the average age of death in one series was 32 years, a significant number of children have died within the f¡rst decade of life68' Sudden and unexpected death in infancy rnay occur prior to establ¡shment of Figure 1O-1: Typical features of cystic medial necrosis in the aorta characteristic of Marfan syndrome, with fragmentation of elastic lamina and accumulation of interstitial mucopolysaccharide (Movat pentachrome, x 2801.

t ,l

Figure 10-2: Massive intrathoracic haemorrhage from dissection and rupture of a patent ductus

arteriosus as the presenting feature of Marfan syndrome resulted in sudden and unexpected

death in a two-month-old girl.

t 323

the diagnosisl6. For example, fatal rupture of a dissecting aneurysm of a patent ductus arteriosus has been reported as the present¡ng feature in a two-month-old girl3s (vide infrd.

Dissecting aneurysms and arterial rupture have also been reported in the aorta and pulmonary

artery in children74,1o2.

STUDY #1O-1

DEMONSTRATION OF THE ASSOCIATION BETWEEN MARFAN SYNDROME AND SUDDEN

¡NFANT DEATH

CASE REPORT

A two-month-old white girl who was the product of a normal pregnancy and delivery suddenly

collapsed while waiting for a CT scan of her head for suspected hydrocephalus. Cardiac arrest

occurred that was not responsive to resuscitation. Although her developmental milestones had

been normal and there had been no illnesses, multiple minor congenital abnormalities had

prompted investigation. Specifically, she was noted to have an abnormally shaped head, a cleft

palate, arachnodactyly with bilateral metatarsus adductus, finger contractures and a patent

ductus arteriosus. Marfan syndrome was suspected although other family members were

morphologically normal.

At autopsy, external examination revealed a female infant with a long body (crown-heel

= 67 cm, 97th percentile) and long fingers and toes. There was frontal bossing. lnternally, a

false aneurysm of the ductus arteriosus was found. The ductus was patent at both the aortic

and pulmonary ends. The surrounding tissue was friable (Figure 1O-2) and there was a massive

bilateral haemothorax (50mll, haemopericardium (10m1) and haemomediastinum. The aort¡c

arch, pulmonary trunk and heart valves were all significantly dilated. There were several intimal

tears at the junct¡on of the ductus and aorta suggesting dissection as the cause of the false

aneurysm.

Microscopíc examination of the aort¡c arch showed disruption of elastin fibres with an

increased amount of surrounding mucoid ground substance. lncreased mucoid ground

substance with cystic change was also present within the heart valves. The unusually shaped

head had resulted from premature fusion of the lambdoid suture. There was no hydrocephalus. 324

The cause of death was cardiac arrest due to rupture of a dissecting aneurysm of a patent

ductus arteriosus with massive haemothorax and haemopericardium associated with Marfan's syndrome.

SUMMARY

A two-month-old girl with suspected Marfan syndrome, died from a ruptured dissecting

aneurysm of a patent ductus arteriosus. This case represents the youngest reported pat¡ent to

present with lethal Marfan syndrome.

I+t

Associated Features

Rarely, patent ductus arteriosus, pulmonary stenosis, tetralogy of Fallot, and atrial or ventricular septal defects have been reported in patients with Marfan syndromeT4. However, it has been

claimed that the presence of septal defects is coincidental3T. Very occasionally supravalvalvular aort¡c stenosis may be present15,36.

EHLERS-DANLOS SYNDROME TYPE IV

Overview

Ehlers-Danlos syndrome is a heterogeneous group of at least 1 1 subgroups which have different

clinical manifestations, biochemical defects and inheritance patternsgs. While the majority of cases belong to types l, ll and lll, sudden and unexpected death is generally only a feature of type lV, the so-called 'arterial-ecchymotic' variant. The following discussion will deal mainly with this subtype. al Characteristic Features

The characterist¡c features of Ehlers-Danlos type lV include easy bruisability, herniae, colonic diverticula and thin facies. There is variable fragmentation of arterial elastin on microscopy, bl Possible Mechanisms of Death

Possible mechanisms of death include arterial rupture and dissection, left ventricular, uterine, colonic or splenic rupture. 325

c) Other Potentially Significant Features

Associated features include a variety of possibly coincidental congenital cardiac defects, saccular arter¡al aneurysms and pneumothoraces.

Clinical Features lndividuals with Ehlers-Danlos type lV have thin, translucent skin, with premature aging over the hands and feet (acrogeria). ln later childhood the face is characteristically thin due to a lack of subcutaneous fat. Unlike the other subtypes, skin and large joint joint hyperextensibility are not a feature of type lV. Further manifestations of Ehlers-Danlos syndrome in general are rectal prolapse in young children, multiple bruises and dermal scars44'e5. ln children the skin manifestations may be so pronounced that nonaccidental injury has been suspected on more than one occasion71,85. Carotid-cavernous fistulae have been documented3l and very rarely saccular aneurysms of the coronary arteries occur29.

Aetiology

Ehlers-Danlos type lV is dominantly ¡nher¡ted, with approximately half of the cases representing new mutations. The phenotype has been shown by linkage analysis to cosegregate with the

COL3A1 locuses.

Pathological Findings

The most significant complications of Ehlers-Danlos syndrome are spontaneous rupture of large arteries, aort¡c dissection, left ventricular rupture, and splenic and intestinal rupture6'41,10s. T¡s most common cause of death is rupture of branches of the abdominal aorta. Rupture of the gravid uterus and pneumothorax are additional serious complications in later ¡¡1s48,103.

The microscopic findings are variable, and cannot be relied upon to establish the diagnosis as there may be no abnormal features discernable even in the presence of typical morphologic and biochemical featureslT. Some cases may show decreased or absenl, fragmented and disorganized elastin fibres within large arteries2l 's3, thinning of the vessel wall and an increase ¡n ¡nterstitial acid mucopolysaccharide2g. Other cases have not shown marked difference from contr6¡s53'99. Electron microscopy may reveal reduction in collagen fibre diameter34 and prominent dilatat¡on of endoplasmic reticulum, but th¡s also is not invariaþle1s. 326

Occurrence of Sudden Death

Although the average age of death in Ehlers-Danlos type lV is between 35 and 40 yearsss

affected individuals may die suddenly and unexpectedly in infancy from arterial rupture and

dissections, as detailed belowl7. An important point is that fatal arterial rupture may be the

only morphologic feature of Ehlers-Danlos syndrome present.

STUDY #1O-2

DEMONSTRATION OF THE ASSOCIATION OF TYPE IV EHLERS.DANLOS SYNDROME WITH

SUDDEN INFANT DEATH

INTRODUCTION

A unique case of sudden death is described due to spontaneous subarachnoid haemorrhage in a

five-month-old infant girl with previously unsuspected type lV Ehlers-Danlos syndrome (EDS).

CASE REPORT

A female infant was born at term by lower segment caesarean sect¡on to a 2b-year-old

primigravida mother. The pregnancy had been uncomplicated until breech presentation

necessitated surgical intervention. The infant was quite healthy with normal developmental

milestones' She remained well until the day before death at the age of five months, when she

was noted to be transiently febrile and anorexic. This was attributed to teething. On the day of death, she was put to bed by a baby sitter, who subsequently found her unresponsive.

Resuscitation was attempted unsuccessfully by the baby sitter and at the local hospital. Famíly Hístory

Both parents, who were originally from South America, were 25 years of age and were quite healthy. There was no parental consanguinity. The paternal grandparents were in good health, as were three paternal uncles, two aunts, and five cousins. An uncle had died at two days of age of uncertain causes. The maternal grandfather had died at age 54 years of a myocardial infarct; the maternal grandmother and four uncles were all alive and well. Specifically, there was no history of joint laxity, skin hyperextensibility, friable tissues, scarring, bruising, or spontaneous haemorrhages. 327

Autopsy Findings

Postmortem examination revealed an externally normal female infant weighing 6.6k9. On reflection of the scalp, three bruises ranging in size from 1 to 2 cm in maximum diameter were present. There also was diffuse subarachnoid haemorrhage over the frontal, parietal, and occipital lobes (Figure 10-3) with small intraventricular haemorrhages in the anterior horn of the left lateral ventricle and in the fourth ventricle. The remainder of the gross examination was unremarkable. Specifically, there were no arterial aneurysms or arteriovenous malformations present. Features of Menkes' syndrome, which also may present with arterial rupture in childhood, were absent. There were no skin petechiae or adrenal haemorrhages, and microbiological cultures were negative for meningococcus. Despite careful dissection, the precise origin of the haemorrhage could not be localized.

Microscopic examination demonstrated the subarachnoid haemorrhages, as well as focal periarterial haemorrhages in both kidneys, within the submucosa and lamina propria of the small intestine, and within the lung parenchyma. The other organs were normal. No specific abnormalities of connective tissue, such as variable amounts of elastin or increased ground substance, were noted.

Biochemícal Analysis

Pepsin-solubilized collagen was prepared from the patient's skin and aortic tissue according to methods described previously4o. The ratios of alpha 1-to-alpha 2 chains of type I collagen and of type lll-to-type I collagen (alpha 1 chains) were determined by polyacrylamide gel electrophorss¡slo0. Analysis of the skin demonstrated that there was <5% Type lll collagen present, compared to the expected amount of approximately 15-2O%. ln addition, there was a reversal in the usual 2:1 ratio of alpha 1:alpha 2 chains of type lcollagen, with a predominance of alpha 2 chains. Analysis of the aortic tissue also showed a low level of type lll collagen, which constituted approximately 4o/o of the total, rather than the expected value of 2O-3Oo/o.

Again there was a low alpha 1:alpha 2 ratio in type I collagen. Two sets of controls also were analyzed, the first set cons¡sting of aortic and skin tissue from an age-matched control pat¡ent with no evidence of connective tissue disease (P), and the second consisting of standard preparat¡ons of type I collagen from rat tail tendon and type lll collagen from neonatal sheep skin 328

(S). Densitometric scans of the gel separations from the patient and controls are shown in

Figure 10-4. Table 10-1 shows the percentage composition of the collagen subtypes. Fibroblast cultures were not performed.

TABLE 1O-1: COMPOSITION OF COLI.AGEN SUBTYPES IN THE PAT¡ENT, coNTRoL PATIENT (PI AND STANDARD CONTROLS (S}

% Type lll Ratio ø11o2

Sample Collagen Type I Collagen

1 Patient aorta <5 0.48

2 Patient skin <5 0.s3

3 Control {patient} (Pl aorta 22 1.62

4 Control (patienrl (pl skin 21 1.65 (standardl 5 Control (Sl type I 0 1,50

6 Control (standard) (Sl types I

and lll 23 1.68

Cause of Death

Death was attributed to massíve subarachnoid haemorrhage with associated minor renal, gut wall, and intrapulmonary haemorrhages in an infant with type lV Ehlers-Danlos Syndrome.

Further Family Analysís

The parents were reluctant to submit to further investigation; however, later examination of a maternal skin biopsy showed a normal rat¡o of type lll:type I collagen. A second child born one year later was alive and well at a year of age with no stigmata of Ehlers-Danlos syndrome.

DISCUSSION

The reported patient is of interest because of the fatal outcome at an unusually early age associated with the lack of an antemortem diagnosis. ln the literature, complications in females tend to occur at an older age, usually in young adult life after the diagnosis has been established4. ln retrospect, there had been no features of Ehlers-Danlos syndrome noted, presumably because the relative immobility of the S-month-old infant had protected her from much of the trauma that would have led to bruising. most of the brain surface Figure 1O-3: Marked subarachnoid haemorrhage present diffusely ovef girl. in a case of fatal Ehlers-Danlos syndrome in a five-month-old Figure 1o-4: Dens¡tometríc scans of gel separations of pepsin-solubilized collagen from skin and aortic tissue taken from the patient (l and 2), an age-matched p control (3 and 41 , andstandard controls S (5 and d.

PATIENT 0.3 I AORTA 2 SKI N

15

6 coN 3. AORTA 4. SKIN (P) @ ou1 Ð @ .)z Tll (¡ oO. 3

6 5. ó. I EUI (s)

3

50 60 70 50

DISTANCEMIGRATED (mm.) 329

Confirmation of the diagnosis was made by the demonstration of negligible (<5%) amounts of Type lll collagen in the skin and aortic tissue. The reversal of the alpha chain ratio in type I coltagen that was found in this case is an unusual feature in type lV Ehlers-Danlos syndrome. Whether this influenced the clinical presentation is difficult to ascertain, however.

Although no specific light microscope abnormalities of connective tissue were noted, this may have been due to variable expressivity because a wide spectrum of h¡sto¡og¡c features have been reportedse. Finally, the unremarkable family history and normal levels of Type lll collagen in a maternal skin sample suggest either an autosomal recessive mode of inheritance or a spontaneous mutation 1 03.

While there is no doubt that death was caused by intracranial haemorrhage, the exact site of vascular rupture remains uncertain, although arteriovenous malformation and aneurysm were excluded after meticulous gross and microscopic examination. This is not at all unusual in children, however, as up to 2O-3Oo/" of cases of subarachnoid haemorrhage do not have the precise source of bleeding identified2s. The concurrent presence of multifocal interstitial haemorrhages in the lungs, small intestine, and kidneys is consistent with a generalized weakness in blood vessel walls due to the demonstrated lack of Type lll collagen, as spontaneous haemorrhaging f rom blood vessels of varying sizes is a well-recognized complication of type lV Ehlers-Danlos syndrome.

Although the possibility of resuscitation-induced injury was considered, tissues most likely to have been traumat¡zed during the procedure (anterior chest wall, heart and liver) showed no evidence of haemorrhage, so this was not thought to be a significant contributor to the pathological changes present. Most probably, intracranial haemorrhage was the primary event, followed by widespread interstitial haemorrhage from hypoxically damaged structurally defective vessels.

SUMMARY

A previously healthy five-month-old female infant presented with sudden death due to spontaneous subarachnoid haemorrhage associated with minor multifocal visceral haemorrhages.

The clinical diagnosis had been of SIDS. Although the family history was noncontributory and other features of type lV Ehlers-Danlos syndrome were absent, the pattern of haemorrhage was 330

consistent w¡th this type of connective tissue disorder. The diagnosis was confirmed after postmortem analysis of skin and aorta showed <5% type lll collagen (normal>1S%). Extensive

literature review failed to find any other reported cases of sudden death in infancy due to

intracranial haemorrhage in patients with previously unsuspected type lV Ehlers-Danlos

syndrome' Collagen analysis should be performed in cases of unexplained multifocal

spontaneous haemorrhage in infancy so that this rare diagnosis will not be míssed. This case

represents the youngest reported patient to present with lethal Ehlers-Danlos syndrome type lV. ***

Diagnosis

Arterial and visceral rupture are caused by reduced amounts of type lll collage¡19,77. Standard diagnosis depends on analysis of connective tissue for type lll collagen, as above, and on

demonstration of decreased production of type lll procollagen by cultured fibroblastsls. Autopsy lnvestigation

Localized haemorrhage in patients at autopsy, particularly if it is multifocal with no obvious

reason for a bleeding diathesis, should prompt consideratíon of underlying occult Ehlers-Danlos

syndrome type |Vl7. Even in the absence of external morphologic evidence of Ehlers-Danlos

syndromeTS fresh and frozen skin and aorta should be taken from all cases of unexplained

spontaneous haemorrhage so that collagen studies can be perfor.med ¡f ind¡cated. Blood or

t¡ssue for linkage analysis should also be taken.

Associated Features

Mitral valve prolapse occurs in children with type lV Ehlers-Danlos syndrome4s. Congenital cardiovascular anomalies which have been reported in the other subtypes such as bicuspid aortic valve and tetralogy o1 ¡"¡¡6f3.s6,57,'lo7 may be coincidentals. 331

PSEUDOXANTHOMA ELASTICUM

Overview al Characteristic Features

The characteristic features of pseudoxanthoma elasticum include yellow-orange papular skin lesions with calcificat¡on of skin and peripheral arteries. bl Possible Mechanisms of Death

Possible mechanisms of death involve myocardial ischaemia and spontaneous gastrointestinal haemorrhage. cl Other Potentially Significant Features

Associated features include systemic hypertension and mitral valve prolapse

Clinical Features

Skin and ocular changes include drooping skin folds, linear or aggregated yellow cutaneous papules, and angioid streaks of the retina. Vascular manifestations are quite variable and result from ischaemia due to vessel narrowingg,11 which may cause spontaneous haemorrhage, part¡cularly from the gastrointestinal tract.

Aetiology

The underlying problem is believed to be an enzyme defect which results in calcificat¡on of elastic fibres within the walls of muscular arteriess. Similar changes may also be present within the endocardium64. The inheritance pattern is varied with both autosomal recessive (90% of cases) and dominant forms reportedTo'106.

Pathological Features

At autopsy, 'cobblestone' skin lesions, acute myocardial infarction, myocardial scarring, calcified endocardial plaques and gastrointestinal or intracranial haemorrhage may be found.

Elastic fibres in the retina, skin and vasculature are fragmented, disorganized and calcified2a although cutaneous lesions may not always be visibless. Affected arteries show calcification of the intima and media69. Rarely cardiac conduction tracts may be surrounded by fibrous scar tissue result¡ng in sudden unexpected death in adult lifea6. 332

Occurrence of Sudden Death

Sudden death is rare, but may occur in adolescence in association with strenuous exerc¡sel08.

Acute myocardial infarction has been reported in a six-week-old infant with arterial calcification

and a maternal history of pseudoxanthoma elasticum39, and significant vascular disease in other

children has also been documented9o. Affected patients may also have systemic hypertension,

gastrointestinal bleeding and mitral valve prolapse1,61 which may lead to sudden death.

Restrictive cardiomyopathy with pulmonary oedema was reported in one young adult due to

calcified endocardial bands2o. Rarely in adults there may be symptoms and signs from cerebral

ischaemia or haemorrhage from vessel rupture4T.

SKELETAL DISORDERS

ACHONDROPT.ASIA

Overview

a! Characteristic Features

The characteristic features of achondroplasia include rhizomelic dwarfism, enlargement of the

head, trident-shaped hands, an exaggerated lumbar lordosis and thoracic kyphosis. There is

microscopic disorganisation of the growth plate with loss of the normal orderly columns of

chondrocytes and irregular metaphyseal ossificatlon.

b) Possible Mechanisms of Death

Possible mechanisms of death involve brainstem and upper spinal cord compression,

cl Other Potentially Significant Features

Associated features include thoracic cage abnormalities and upper airway obstruction.

Clinical Features

Affected infants are characterized by shortening of the proximal limbs (rhizomelic dwarfism) with

enlargement of the head and a relatively normal thorac¡c cage. The cranial vault has a

characteristic shape due to compensatory overgrowth of the membranous calvarial bones, with

prominent frontal bones, maxillâry hypoplasia and mandibular prognathism. The foramen magnum and spinal canal are reduced in size due to failure of growth of the cartilagenous bones at the base of the skull, and there is hydrocephalus possibly due to obstruction of venous return at the jugular foraminaTs. Radiological features have been described in detail elsewheres4. 333

Aetiology

The genetic defect in this dominantly inherited condition has not been identified.

Occurrence of Sudden Death

Achondroplastic infants are at increased risk of sudden death due to lower brainstem and upper spinal cord comp¡sss¡s¡4s.72. For example, a study of 13 achondroplastic infants who manifested significant apnoeic episodes and sudden death demonstrated compression of the brainstem and upper cervical cord within the narrowed foramen magnum and spinal canalT3

(Figure 10-5). Other authors have also reported sudden death in apparently well achondroplastic i¡fs¡1s1o,62, possibly associated with this type of compression of respiratory control centres32'70'11o. An exacerbat¡ng factor in these children may be arterial hypoxia caused by thoracic cage abnormalities and sleep-related upper airway obstructions6.

It is difficult to estimate the exact ¡ncrease in risk of sudden death of these infants however, the risk of dying suddenly in the first year of life was 7.5% in the study by Hecht er a\.42. These investigators also found that nine of the 13 children dying before five years of age died suddenly, and that compression of the brainstem was found in three of the four children who had autopsies. lt is, therefore, important to examine the cervical cord and brainstem in detail ¡n these cases.

CRANIOSYNOSTOTIC SYNDROMES

Overview

Premature fusion of cranial sutures, craniosynostosis, occurs in a number of inherited conditions and has been associated with sudden death82. Possible mechanisms of death are uncertain but may involve upper airway obstruction due to hypoplasia of the facial skeleton and prolonged central apnoeas during sleep38. Associated features include cerebral compression and possibly coincidental congenital cardiac defects. 334

DERMATOLOGICAL DISORDERS

HYPOHIDROTIC ECTODERMAL DYSPTASIA

Overview

al Characteristic Features

The characteristic features of hypohidrotic ectodermal dysplasia include decreased sweat¡ng,

anomalies of dentition, sparse hair and characteristic facies with frontal bossing and malar

hypoplasia

b) Possible Mechanisms of Death

Death is caused by uncontrolled hypertherm¡a.

Clinical Features

This unusual condition is characterized by hypohidrosis, hypodontia and hypotrichosis. Affected

infants show frontal bossing, low set ears, malar hypoplasia and flattened nasal bridggs8a. One

of the major clinical problems related to the absenee or hypoplasia of eccrine glands is a reducecj

capacity to tolerate heat.

Aetiology

Hypohydrotic ectodermal dysplasia is inherited in an X-linked manner52.

Occurrence of Sudden Death

Although not usually life-threatening, affected infants must be protected from high temperatures, as uncontrolled hyperthermia may result in sudden unexpected death7,8.

EPIDERMOLYSIS BULLOSA

Airway obstruct¡on due to involvement of the upper airway in this condition is described in

Chapter 5.

MUSCULAR DISORDERS

MALIGNANT HYPERTHERMIA

Clinical Features

This rare condition is characterized by a marked increase in muscle metabol¡sm triggered by anaesthesia. Classically th¡s results in tachycardia, hyperthermia and acidosis. Figure 10-5: MRI scan in an achondroplastic boy demonstrating reduction in the size of the foramen magnum with narrowing of the upper cervical spinal cord (arrow).

Figure 10-6: Marked oedema of the upper airway may be the only finding in fatal cases of anaphylaxis (Haematoxylin & Eosin, x 45).

.,.r ¿ :. -

'4"' l'ì: -'.

a 335

Aetiology

It is proposed that the gene for this autosomal dominant condition is localized to the ryanodine receptor locus on chromosomg 19s9,63.

Occurrence of Sudden Death

A number of cases have now been reported with atypical presentat¡ons which include sudden and unexpected death in the absence of anesthetic exposurel09. This has occurred in families who were not known to have this disorders3 and has mimicked the clinical presentation of

SID526.

Pathological Features

Autopsy findings are uninformative and further information may need to be derived from halothane- or caffeine-induced contract¡on tests performed on skeletal muscle biopsy material from other family members.

CHROMOSOMAL ABNORMALITIES

THE TRISOMIC SYNDROMES

Overview lnfants with any one of the three common trisomies, 21 , 18 and 13, may have congenital cardiac defects which may be lead to early death. lt is reasonably clear, however, that death in trisomies 1 I and 13 is usually not particularly sudden, and is certa¡nly not unexpected, as it is assumed that most infants will succumb within the first few months of life. lnfants with Down syndrome are different in that they usually survive into later childhood and adolescence. ln

Down syndrome 'unexpected' death may result from a number of different causes.

Occurrence of Sudden Death

Sudden death in Down syndrome infants can occur from a variety of mechanisms including

those associated with congenital cardiac defects. Structural cardiac defects are found in 40 to

60% of cases and consist predominantly of endocardial cushion defects resulting in hypoxia and

cardiomegaly from left to right shuntingl0+. A full listing of the types of congenital cardiac

defects that may be found in infants with chromosomal abnormal¡t¡es may be found in a review

by Ferrans and Boyce2g. 336

Pulmonary hypertension may be an added problem in these infants, related to cardiac

shunting that occurs through endocardial cushion defects, and also to sleep apnoeasa,g4.

System¡c hypertension due to d¡ffuse fibrointimal hyperplasia has also been reported ¡n Down syndrome30.

Down syndrome infants are at risk of haemorrhagic complications due to an increased

incidence of leukaemia, and of hyperviscosity problems because of neonatal polycythaemia.

Death may also occur because of spinal cord compression from atlanto-occipital instability.

FRAGILE X SYNDROME

Clinical Features

Fragile X syndrome represents the most common heritable type of mental retardat¡on as well as

beíng one of the most frequently encountered genetic syndromes. lt is characterized by variable

mental retardat¡on and a typical morphology which includes prominent jaw and forehead,

dysrnorphic ears, mac¡'o-orchidism, hyperextensible joints and other connective tissue abnormalities such as kyphoscoliosis and pectus excavatum, The fragile site on the X chromosome is in band q27.3 which disrupts the FMRl gene. The clinical and genetic features have been recently summarized by Sutherland and Richardsgs.

Occurrence of Sudden Death

Six out of a total of 68 liveborn children (9%l died suddenly after one year of age in a study of eight families who had retarded members with fragile X syndrome33. ln a follow-up study of the progeny of 86 normal obligate carriers, the mortal¡ty rate before the age of 1B months in males was 171219 (8%), and in females was 6/169 (4%1. Unfortunately, meaningful pathological interpretation of this data is not possible because of the absence of autopsy information in all but one case.

These cases do not, therefore, fulfil the criteria for the diagnosis of SIDS, given the age, lack of autopsy investigation, possibility of hypothalamic-pituitary abnormalities and occurrence of transiently raised intracerebral pressure in affected children33. They do, however, ind¡cate a significantly increased risk of sudden death in infants with this syndrome. 337

TURNER SYNDROME

Clinical Features

Turner syndrome has a characteristic phenotype of short stature, webbing of the neck, broad chest, and delayed sexual maturation.

Aetiology

A 45X0 chromosome complement has been found in 50 to 60% of individuals with the Turner phenotype.

Occurrence of Sudden Death

As well as the above features, infants with Turner syndrome have a variety of cardiovascular anomalies that may result in sudden and unexpected death. These include aortic coarctation, bicuspid aort¡c valve, aortic stenosis and anomalous pulmonary venous drainage6s'66. Rarely rupture of a dissecting aortic aneurysm may occur28.

IMMUNOLOGICAL CONDITIONS

IMMUNOLOGICAL DEFICIENCY

Although immunological under-reactivity has been proposed as a cause of SIDS, research has not supported this contention. lnfants with immunological deficiencies are, however, at increased risk of developing overwhelming sepsis which may result in rapid death (see Chapter

41. Often, but not invariaby, the diagnosis has been established prior to death. As a number of these conditions have a heritable basis the autopsy niay assume a vital role in directing family counselling.

ANAPHYLAXIS

Anaphylaxis refers to a serious, potentially-fatal reaction that is most often due to lgE mediated sensitivity to a foreign substance. lt ¡s less common in children than in adults and is usually associated with drugs such as penicillin or bee or wasp stingsso. ln the latter cases death may also result from asphyxia if there has been a st¡ng involving the upper airways6T. Occasionally angioneurotic oedema may also cause critical epiglottal swellinggT.

Fatal anaphylactic react¡ons to food in infants are poorly characterized in the literature, however, these are well recogn¡zed ent¡ties most often involving the ingestion of nuts, eggs or milk88. Very rarely fatal anaphylaxis may follow rupture of an echinococcal cyst6o. 338

Pathological Features

Autopsy findings are relatively nonspecific and unhelpful, although occasional cases have demonstrated glottal oedema50 (Figure 10-6) or high levels of allergen_specific ISE in postmortem sera9l'92'111. Diagnosis relies on a history of exposure to a particular agent followed by dyspnoea and collapse. The autopsy may exclude other causes of death.

MYASTHENIA GRAVIS

Myasthenia gravis is a disorder of the neuromuscular junction caused by an autoant¡body to acetylcholine receptors. Although uncommon in infancy and childhood, sudden and unexpected death has been reported in young children following respiratory arrest3, with minimal clinical evidence of the disorder preceding the terminal lethal event22. ln older children life-threatening myasthenic crises may follow infections. Some of these cases have a familial distribution.

**+* Refercncee ChlO-1

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50. Jeneen, O.M. (1962). Sudden death due to st¡ngs from bees and wasps. Acta Pathologica et Microbiologice Scandinavica, 54, 9-29. 51 . Kainulainen, K., Pulkkinen, L., Savolainen, A., Kaitila, l. & Peltonen' L. (199o). Location on chromosomo 15 of tho gene defect causing Marfan syndrome. The New England Journal of Medicine, 323, 935-9. 52. Kruse,T.A.,Kolvraa,S.,Bolund,L.,Kaitila, l.,Soderholm,A.L.,dolaChapolle,A.&Macdermot,K.D. (1989). X-linked anhidrotic octodormal dysplasia (EDA), Multipoint linkago analysis. (Abstractl Cytogenetics and Cell Genetics, 51 , 1026. 53. Lach, 8., Nair, S.G., Russell, N.A. & Benoit, B,G. (1987). Spontaneous carotid-cavernous fistula and multiple arterial d¡ss€ct¡ons in type lV Ehlers-Danlos syndrome. Journal of Neurosurgery,68, 462-7. 54. Langer Jr, L.O., Baumann, P.A. & Gorlin, R.J. (19671, Achondroplasia. American Journal of Roentgenology, Radium Therapy and Nuclear Medicine, 1OO, 12-26. 55. Lebwohl, M.. Phelps. R.G., Yannuzzi, L., Chang, S., Schwartz. l. & Fuchs. W. (1987). Diagnosis of pseudoxanthoma elesticum by scar biopsy in pat¡onts without chsracterist¡c skin lesions. The New England Journal of Medicine, 317, 347-50. 56. Lees, M.H., Menashe, V.D., Sunderland, C.O., Morgan, C.L. & Dawson, P.J. (1969). Ehlers-Danlos syndrome associated w¡th mult¡ple pulmonary artory stenoses and tortuous systemic arteries. The Journdl of

Pediatrics, 75, 1 031 -6. 57. Leier, C.V., Call. T.D., Fulkerson, P.K. & Wooley, C.F. (198O!, The spectrum of cardiac defects in the Ehlers- Danlos syndrome, typ€s I and lll. Annals of lnternal Medicine,92, 17'l'8' 58. Loughlin, G.M., Wynne, J.W. & Victorica, B.E. (19811. Sleep apnea as a possible cause of pulmonary hypertension in Down syndromo. The Journel of Pediatrics,93, 435-7. 59. MacLennan, D.H., Duff, C., Zo¡zaÍo, F., Fujii, J., Phillips. M., Korneluk, R.G., Frodis, W., Britt, B.A. & Worton' R.G. (199O1, Ryanodine rocoptor gene is a candidate for predisposit¡on to mal¡gnant hyperthermia. Nature,343, 559-61. 60. Madariaga, 1., de la Fuonte, 4., Lezaun. R., lmizcoz, M.4., Carmona, J.R., Urquia, M. & de los Arcos, E. '(1984). Cardiac echinococcosis and systemic embolism. Report of s case. Thoracic Cardiovascular Surgeon, 32,57-9. 61. Malcolm, A.D. (1985). Mitral valve prolapse associatod w¡th oth€r disorders. Casual coincidônce, common link, or fundamental genetic disturbance? British Heart Journal, 53, 353-62. 62. Marin-Padilla, M. & Marin-Padilla, T.M. (1977). Developmontal abnormalities of the occipital bone in human chondrodystrophies. (Achondroplasia and thanatophoric dwarfisml. Birth Defects, 3,7-23. 63. McCarthy, T.V., Healy, J.M.S., Heffron, J.J.A., Lehane, M., Doufel, T., Lohmann-Horn, F., Fa¡rall. M. & Johnson, K. (199O). Localization of the malignant hyperthermia susceptibility locus to human chromosomo 1 9ql 2-13.2. Nature, 343, 562-4. 64. Mendelsohn, G., Bulkley, B.H. & Hutchins, G.M. (1978). Cardiovascular manifestations of pseudoxanthoma elasticum. Archives of Pathology and Laboratory Mødicine, 1O2, 298-302. 65. Millor, M.J., Geffner, M.E., Lippe, 8.M., ltami, R.M., Kaplan, S.A., DiSessa, T'G', lsabel-Jones, J.B. & Friodman, W.F. (1983). Echocardiography revoals a high incidence of bicuspid aortic valve in Turner syndrom6, The Journal of Pediatrics, 1O2, 47-5O, 66. Moore, J,W., Kirby, W.C., Rogers, W.M. & Poth, M.A. (1990). Partial anomalous pulmonaryvenous drainage associated with 45,X Turner's syndrome. Pediatrics, 86, 273'76. 67. Mosbech, H. (1983). Death caused by wasp and bee stings ¡n Denmark 19ôO-198O. ,38, 195-2OO' 68. Murdoch. J.L., Walker, B.A., Halpern, 8.L., Kuzma, J.W. & McKusick, V.A. 119721. Life expectancy and causos of death in the Marfan syndrome, The New England Journal of Medicine, 286, 804-8. 69. Neldner, K.H. (1993). Pseudoxanthoma elasticum. ln Connective T¡ssue and lts Heritable Disorders. Molecular, Genetic and Medical Aspects, ed. P.M. Royce & B. Steinmann, pp.425-36. New York: Wiley-Liss. 70. Nelson, F.W., Hecht, J.T., Horton, W.4.. Butler, 1.J., Goldie, W.D. & Miner, M. (1988). Neurological basis of rospiratory complications in achondroplasia. Annals of Neurology, 24, 89-93. 71. Owen, S.M. & Durst, R.D. (1984). Ehlers-Danlos syndrome simulating child abuse. Archivøs of DermatologY, 120, 97-101. 72. Pauli, R.M., Conroy, M.M., Langer Jr. L.O., McLone, D.G., Naidich, T., Franciosi, R., Ratner. l.M. & Copps, S.C. (1983), Homozygous achondroplasia with survival beyond infancy. American Journal of Medicdl Genetics, 16, 459-73. 73. Pauli, R.M., Scott, C.1., Wassman Jr, E.R.. Gilbert, E.F., Leavitt, L.4., Ver Hoove, J., Hall, J.G., Partington, M.W., Jones, K.L., Sommer, A.. Feldman, W., Langor, L.O., Rimoin, D.L., Hochl, J'T. & Lobovitz, R. (1984). Apnea and sudden un€xpect€d death in infants with achondroplasia. The Journal of Pediatrics, 1O4. 342-8. Rcfcrcnco¡ Ch104

74. Phornphutkul. C., Rosonthal, A. & Nadas, A.S. (19731. Cardiac manifosrations of Malan syndrome in infancy and childhood. Circulation, 47, Sg7-96. 75. Pierre-Kahn, A.. Hirsch, J.F.. Renier, D., Metzger, J. & Maroteaux, p. fi 9gO). Hydrocephalus and achondroplasia. A study of 25 observations. Chitd's Brein,7,2OS-19, 76. Pope. F.M. (1975). Historical ev¡donce for the gonetic heterogeneity of pseudoxanthoma elasticum. grlf¡:sá Journal of Dermatology, 92. 493-509. 77. Pope, F.M., Martin, G.R. & McKusick, U.O. ('t977). lnheritance of Ehlers-Danlos two lV syndrome. Journal of Medical Genetlcs, 14, 2OO-4. 78. Popo, F.M.' Nicholls, 4.C., Dorrance, D.E., Ch¡ld, A.H. & Narcisi, P. (19S3). Type lll collagon deficiency with normal phenotype. Journal of the Royat Society of Medicine,76, Sl g_2O. 79. Pyeritz, (1981). R.E' Mate¡nal and fetal complications of pregnancy in the Marfan syndrome. The American Journal of Medicine,71, 7g+9O. 80. Pyeritz' R.E. (1993)' Tho Marfan syndrome. ln Connective Tissue end tts Heritable Disorders. Molecular, Genetic and Medical Aspects. ed. P.M. Royce, & B, Steinmann, pp. 437-68. New york: Wiley-Liss, 81. Pyeritz, R.E. & McKusick, V.A. (lg7g). The Marfan syndrome: diagnosis and managemanl, The New England Journal of Medicine, 3eO,772-7. 82. Rabl' V.W., Tributsch, W. & Ambach, E. (1990). Prämature Kraniosynostosis - Ursache plötzlicher todesfälle kindos- jungen im und erwachsonenallør. Beitrage Zur Gerichtlichen Medizin,4g,217-21 . p. 83. Ranklev, E., Flotcher, R. & Krantz, (198S). Malignant hyperploxia and suddon death, TheAmerican Journal of furensic Medicine and Pathology, 6, 149-SO, 84. Reed, W.8., Lopoz, D.A. & Landing, B. (1970). Clinical spectrum of anhid¡otic ectodermal dysplasia. Archives of Dermatology, 1O2, 194-43. 85. Roberts, D.L.L.. Pope, F.M., Nicholls, A.C. & Narcisi, p. (1994). Ehlers-Danlos syndrome rype lV mimicking non-eccidontal injury in a child. British Journal of Dermatology, 3, 341_5, 86. Robe¡ts, W.C. & Honig, H.S. (1982). The spectrum of cardiovascular disease in the - Marfan syndrome: a ciinico-morphologic study of 18 necropsy patients and comparison to 1Sl proviously roported necropsy pst¡€nts. American Heart Journal, 104, 1 lS-35. 87. Salzberg, M.R. & Kramor, R.J. (1984). Dissecting thoracic aortic aneurysm in a 16_year-old. Annals of Emergency Medicine, 13, 191-3. 88. Sampson, H.4., Mendelson, L. & Roson, J.P. (1992). Fatal and near-fatal anaphylactic react¡ons to food in children and adolescents, The New England Journat of Medicine, 327, 3go-4. 89. Saruk, M. & Eisenstein, R. (19771. Aortic lesion in Marfan syndrome. The ultrastructure of cystic modial pathotogy dogeneration. Archives of and Lahoratory Medicine, 1O1 , 7+7. 90. Schachner, L. & Young. D. (1974). Pseudoxanthoma elasticum with severe cardiovascular disease in a child. American Journal of Diseases of Children, 127,571-5. 91. Schwartz, yunginger. H.J., Sutheimer, C., Gauerke, M.B. & J.W. (19gg). Hymenoptera venom-specific lgE antibodiesinpost-mort€mseraf¡omvictimsof sudden,unexpected death. Ctinical Allergy, lg,46l- 8. 92. Schwartz, H.J., Yuninger, J'W., Teigland, J.D., Suthmeimer & Hiss, Y. (1984). Sudden death duo to sting¡ng insect hypersensitivity: postmoiîem demonstration of lgE antivenom antibodies in a fatal case. American Journal of Clinical Pathotogy, Sl, 794-5. 93. Shohet, 1., Rosenbaum, 1., Frand, M.. Duksin, D., Engolberg, S. & Goodman, R.M. (19g7). Cardiovascular complications in the Ehlers-Danlos syndrome with minimal oxternal findings. Clinical Genetics,3l , 14e-s2. 94. Stebbens, V.4., Dennis, J., Samuels, M.p., C¡ofr, C.B. & Southall, D.p. (1991). Sleep related upper airway obstruction in a cohort with Down's syndromo. Archives of Disease in Chitdhood,66, 1333-g. 95. Steinmann, 8., Royco, P.M. & Suporti-Furga, A. (1993). The Ehlers-Danlos syndrome. ln Connective Tissue and lts Heritable Disorders. Molecular, Genatic and MedicatAspecfs, ed. p.M. Royce & B. Steinmann, pp.351-4O7. New Yo¡k: Wiley-Liss. 96. Stokes, D.c., Phillips, J.A., Leonard, c,o., Dorsr, J.p., Kopits, S.E., Trojak, J.E. & Brown, D.L. (1983). Rospiratory complications of achondroplasia. The Journal of Pediatrics, 'lO2, Sg+41 , 97. (19881. Strife. J.L. Upper airway and trachsal obstruct¡on in infants and childron. Radiotogic Ctinics of North America, 26,309-22. 98. Sutherland, G.R. & Richards, R.l. (1992). The fragile X syndrome. ln Baitliàre's Ctinicat paediatrics, od. l. Young. London: Harcourt Brace Jovanovich (in p¡ess). 99. Sulica, V.1., cooper, P.H., Pope, F.M., Hambrlck Jr. G.w., Gerson, B.M. & McKusick, V.A. (,1 979). Cutaneous histologic featuros in Ehlers-Danlos syndrome. Archives of Dermatology, 115, 4O-2. Rcfcrcnccc ChlO-5

100. Sykes, 8., Puddle, 8., F¡encie, M. & Smith, R. (19761. The ostimation of two collagens from human dermie by ¡ntorruptad gel olectropho¡osis. Eiochemicel and Biophysical Rasearch Communications, T2: 1472-AO. 101 Takebayashi. S., Kubota, l. & Takagi. T. (1973). Ultrastructural and histochom¡cal studio8 of vaecular losions in Marfan'e syndromo, w¡th report of 4 autopsy casøs. Acta Pathologica Japonica,23,847-66. 102. Thilenius, O.G., Bharati, S., Arcilla, R.A. & Lev, M. (19801. Cardiac pathology of Morfan's syndrome. Can dissection and rupture of aortic anourysms be prevontod? Cardiology, 65, 1 93-2O4. 103 Thomas, l.T. & F¡ies, J.L. (1987). Thc cardiovascular manifostations of genet¡c dieorders of collagon metabolism. Annals of Clinical and Laboratory Science, 17, 377-82.

1 04. Tubman, T.R.J., Shields, M.D., Craig.8.G., Mulholland, H.C. & Nevin, N.C. (1991). Congenital heartdisesse in Down's syndrome: two yoar prospoctive osrly screoning study. B¡itish Medical Journal, 3O2, 't425-7. 10s. Umlas, J. 119721. Spontaneous rupture of the subclavian artery in the Ehle¡e-Danlos eyndrome. Humen Pathology.3,121-6.

1 06. Viljoen, D.L., Pope, F.M, & Beighton, P. (1987). Heterogeneity of pseudoxanthoma elasticum: delineation of a new fo¡m? Clinical Genetics,32, lOO-5. 107 Wallach, E.A. & Burkhart, E.F. (195O). Ehle¡s-Danlos syndrome assoc¡atod with the tetralogy of Fallot. Archives of Dermatology and Syphilology, 61 ,750-2. 1 08. Wilhelm, K. & Paver, K. 119721. Sudden death in pseudoxanthoma olasticum. The Medical Journal of Australia, 2, 1363-5. 109 Wingard, D,W. (1974). Malignant hyperthermia: a human etress syndromeT (Letter) The Lancet,2, 1450-1 , 110 Yang, S.S., Corbetl, D.P., Brough, A.J., Heidelberger, K,P. & Bornstein. J. (1977). Upper cervical myelopathy in achondroplasia. American Journal of Clinical Pathology, 68, 68-72. 111 Yunginger, J.W., Nelson, D.R., Squillance, D.L., Jones, R.T., Holloy, K.E., Hyma, 8.4., Biedrzycki, L., Sweeny, K.G., Sturner, W.O. & Schwartz, L.B. (1991). Laboratory investigation of deaths due to anaphylaxis. Journal of furensic Sciences, 36, 857-65. STJDDEN NATI]RAL DEATH IN INFANCY & EARLY CHILDHOOD

CHAPTER 11

APPENDX 339

APPENDIX ll: AUTOPS¡ES ¡NVOLVING POSSIBLE SEPSIS

1I SPECIMENS THAT MAY BE TAKEN a) Blood: venous and arterial b) Cerebrospinal fluid c) Trachea swab/tissue d) Lung swab/tissue e) Liver swab/tissue f) Spleen swab/tissue

S) Any other obviously infected/necrotic tissue

h) lndwelling catheters/devices

(Specimens taken for viral, bacterial and fungal cultures)

2l # TABLE: AUTOPSY SAMPLING PROTOCOL FOR SUSPECTED FUNGAL SEPSIS

? DISSEMINATED FUNGAL DISEASE

CENTRE VENOUS

MIDDLE LESION FLUID BLOOD SAMPLE SAMPLE SAMPLE ARTERIAL EDGE

FUNGUS MALIN FROZEN FRESH CULTURE

SPARE WET STAINING TISSUE MOUNT 340

APPENDIX lll: AUTOPS|ES tNVoLvrNG posstBlE METABOLtc DtsoRDERS

Biochemical studies will be directed by histologic and etectron microscopic examinations, however, init¡ally it is appropriate to collect as wide a range of tissues as possible. Many may not be needed, but those that are required must be retrievable in a form that can be used2.

A) SPEC¡MENS TO BE TAKEN a) Urine bl Blood (10 mls)

i) with EDTA

iil with

iii) clorted c) Vitreous humour d) Skin or pericardium e) other tissues - brain, heart, kidney, liver, skeletal muscle, adrenal gland

B) MINIMUM REOUIREMENTS urine, blood, skin and liver

Ci TIME INTERVAL

Although skin fibroblasts may still grow in tissue culture from specimens taken several days after death, accurate t¡ssue enzyme analysis requires specimens to be taken as soon after death as is practicable i.e. within several hours of death. However, both MCAD and LCAD enzymes within liver tissue have been found to be stable for up to 1OO hours if the body ¡s refrigerated, and for at least five years if tissues are maintained at -70o1.

DI METHOD OF TAKING AND STORING SPECIMENS al Urine:

Withdrawn from the bladder by syringe after the abdominal cavity has been opened, lf no urine can be obtained in this manner, the bladder can be opened, the renal pelvis can be 341

aspirated or ur¡ne may be squeezed from the diaper, if this is otherwise clean. Storage is at -

80oC in 1ml aliquots for amino and organic acid analysis. b) Blood:

Blood with EDTA stored as whole blood. Heparinised blood promptly centr¡fuged to enable separate storage of packed cells and plasma in I ml aliquots, Stored at -8O0C if possible, or at -200C if not. c) Vitreous humour:

Withdrawn from the eye by syringe and sent for electrolyte and glucose analysis. d) Skin or pericardium:

Skin cleaned with alcohol and a 3.0 x 3.0 mm piece placed in sterile tissue transport media for fibroblast culture. Storage is possible at -70oC if culture facilities are not immediately available. e) Other Tissues:

i) 1mm cubes placed in 4/" glutaraldehyde for electron microscopy.

ii) 1O x 1cm2 blocks snap frozen in liquid nitrogen and stored at -8OoC for biochemical assay/DNA analysis.

iii) 1mm cubes snap frozen in liquid nitrogen and stored at -8OoC for enzyme histochemistry.

iv) 1cm blocks of heart, liver, brain, muscle, adrenal gland and kidney snap frozen in liquid nitrogen and stored at -8OoC for fat stain¡ng with Oil Red O.

v) Sgms of spleen fresh or stored at -80oC for DNA analysis.

REFERENCES

Bonnet, M.J., Allison, F., Pollitt. R.J. & Va¡iend, S. (199O). Fatty acid oxidation defects as causes of unoxpocl€d death in infancy. Progress in Clínical and Biological Reèearch,32'l ,349-64. 2 Greon, A. & Hall, S.M. (1992). lnvostigation of motabolic disordors resombling Royo's syndromo. Archives of Disease in Childhood,67, 1313-17. 342

APPENDIX lll): AUToPslEs tNVoLVtNc posstBLE NON-AGCTDENTAL tNJURy

SPECIF!C REOUIREMENTS

a) Complete body X-ray

b) Examination of mouth, eyes, palms, soles, genitalia, anus c) Photography of all suspicious lesions dl Shaving of hair and examination of underlying skin el Semen and microbiological swabs f) lncision of livid areas sl Representativesamplingofwounds/bruises/fracturesforhistology h) Excision of some wounds in toto i) X-ray of excised rib cage in infants and children jl Removal of eyes in infants and young children k) Toxicology

APPENDIX lV): AUTOPSIES tNvOLV|NG POSS|BLE PO¡SON|NG

SPECIMENS TO BE TAKEN

Blood: cardiac & peripheral Kidney

Gastric contents Skeletal muscle

Urine Brain

Vitreous humour Liver

Gall bladder contents Hair & nails

APPENDIX VI: AUTOPSY INFORMATION PAMPHLET

Many of the deaths due to disorders in this thesis will be the subject of a medicolegal enquiry due to their sudden and unexpected nature and so parental permission may not be required for the performance of an autopsy. However, where permission is required, the following information pamphlet, which was written by the author and is currently in use at the Adelaide 343

Children's Hospital, may be of use in explaining the process and purpose of an autopsy to parents and guardians.

THE AUTOPSY . AN EXPLANATION

The Hospital staff would like to extend the¡r deepest sympathy to you and your family. The death of a child is one of the most terrible tragedies that can affect a family, and it is often hard to make decisions during this time of grief. A request for an autopsy examination may, therefore, seem intrusive and unnecessary.

Because of this, we have prepared this pamphlet to provide you with information about the autopsy and why doctors feel that ¡t is so important. We hope it will provide answers to some of your questions and help you to make your decision.

Be assured that, with the exception of unexpected deaths from the sudden infant death syndrome and those involving car accidents and drownings etc, which come under the jurisdiction of the State Coroner, the r¡ght to decide what is to happen is entirely yours. The staff will always be guided by this and will be supportive of your decision.

WHAT IS AN AUTOPSY?

An autopsy is a systematic examinat¡on of the body of a person who has died, performed by a doctor who is a specialist in pathology in consultation with the doctors who were looking after the person during life. lt begins with a full external examination followed by an examination of individual organs inside the body. The techniques are similar to those found in the operat¡ng theatre, except that every part of the body is examined. A number of special investigations are also performed which include looking for infections, as well as looking at tissue under a microscope for the presence or absence of particular diseases.

Once the examination is completed, the pathologist prepareò a detailed report of the findings, and a summary of the person's medical history. A copy of this is then sent to their hospital doctor and, if requested, to their local doctor. 344

WHY IS IT NEEDED?

Sometimes parents feel that there was someth¡ng extra that they could have done to prevent their child's death. This is a normal reaction to the loss of a person you love. ln our experience, autopsies may help to alleviate these feelings of guilt by clearly showing the seriousness of the disease and the inability of anyone to prevent the final outcome.

Some people also feel that once a child has died an autopsy can be of little or no help, but this is not true. Doctors are continually learning, not only about rare diseases, but also about more common ones as well. An autopsy enables a full scientific study of all of the different features of a particular illness which then helps doctors to understand better the reasons for the outcome.

Greater understanding may then help children who present with the same or a similar illness in the future. As well, performing an autopsy may be the only way that the cause of a particularly puzzling symptom can be explained. Sometimes even the exact cause of death may not be obvious until after the autopsy.

New treatments and investigations are continually being developed and used in hospitals and a complete autopsy examination may be the only way to fully assess the accuracy of new diagnostic procedures and the response of particular illnesses to new medicines or surgical techniques. By allowing an autopsy to be performed, the family enables direct feedback of this information to doctors, resulting in greater understanding of new technologies, procedures and treatments. lt is only by completely understanding new developments that progress in medicine can be made.

Other advantages of an autopsy include detection of abnormalities that were not obvíous during life, as these may have relevance to other family members,

WHAT IS A 'LIMITED AUTOPSY'?

Sometimes a family may not want a complete autopsy performed. ln this case, although it is less sat¡sfactory, it may be sufficient for the pathologist to examine only one area of the body. For example, a limited autopsy may be restricted to the organs inside the chest in a pat¡ent who has heart or lung disease, or to the head in a patient who has a brain tumour. This is an option that you can discuss further with your doctor if you wish. 345

WILL AN AUTOPSY BE DISFIGUR¡NG?

With modern autopsies there is almost no difference in the appearance of the body at the funeral, and a normal viewing can be held. Although incisions are made, they are placed so that they will not be seen. They are also very carefully closed after the procedure just as in operations. At all times the body ¡s treated with the utmost respect.

WILL TISSUES BE REMOVED?

Often some tissues require very special examinations. This will depend on the disorder causing death and can be discussed with your doctors.

WILL AN AUTOPSY INTERFERE WITH FUNERAL ARRANGEMENTS?

Autopsies are usually completed within a day of death and so there should be no delay in making funeral preparat¡ons. Funeral directors are accustomed to working with pathologists, and can arrange any service that the family may request. Embalming is still possible after an autopsy.

WILL AN AUTOPSY BE AGAINST RELIGIOUS BELIEFS?

Families are sometimes concerned that an autopsy may be against their religious beliefs. Autopsies have been performed on people from a wide range of religions, but if you are concerned it may be best to discuss the matter with someone from your church before deciding. Hospital staff w¡ll be pleased to help you to contact the appropriate person.

We hope that this information has been of use to you in helping to show the value of the autopsy examination, lf you have any further questions your doctor or the patholog¡st will be most w¡ll¡no to answer them for vou.

The following explanatory note to hosp¡tal staff accompanies the autopsy pamphlet:

'lt is hoped that the attached pamphlet may be of assistance. to you in discussing the possibility of an autopsy examination with parents. The pamphlet is intended to supplement discussions with the parents by providing information that they can take some time to read over. lt is not intended in any way to interfere with, or replace, discussions between staff and parents, as these are an essential part of obtaining permission for an autopsy'. 346

APPENDIX Vll: PUBLTCATTONS

Much of the material presented in this thesis has been previously published in peer reviewed journals, is 'in press', or has been submitted for publication. Papers incorporated into the

text are listed below to acknowledge the co-authors contributions. The author of this thesis

has played a major role in the production of the book (12 out of 14 chapters), and in the

papers and proceedings cited, and has therefore been e¡ther first or senior/corresponding

author in all of the material listed.

TEXTBOOK

1 Byard RW, Cohle S. Sudden death in infency, childhood and adolescenco Cambridge University Press, Cambridge, England (ln press).

PAPERSi PROCEEDINGS

Byard RW, Koeley FW, Smith CR. Typo lV Ehlors-Danlos syndromo presenting as sudden infant death. Am J Clin Pathol 199O;93: 579-582. 2. Eyard RW, Moore L, Bourne AJ. Sudden and unexpected doath - a lete effoct of occult intraosophageal

foroign body. Podiatr Pathol 1 99O; 1 0: 837-841 . 3. Byard RW, Cutz E. Sudden and unexpected death in infancy and childhood due to pulmonary thromboombolism - an autopsy study. Arch pathol Lab Med 199o; 114:142-144. 4. Byard RW, Bourne AJ, Silver MM. Tho association of lingual thyroglossal duct remnants with sudden death in infancy. lnt J Pediarr Otolaryngol 1990; 20: 1O7-112. 5. Byard RW, Bourne AJ, Adams PS. Subartorial vontricula¡ septal defoct in an infant with suddon unoxpocted doath: cause or coincidencoT Am J Cardiovasc Pathol 1 990; 3: 333-336. 6. Byard RW' Bohn DJ, Wilson GW, Smith CR, Ein S. Unsuspected diaphragmatic hernia - a potential cause of sudden and unexpected death in infancy and oarly childhood. J Pediatr Surg 1 99O; I l: 1 1 66- 1168. 7 Byord RW, Jimenez CL, Carpentor BF, cutz E, Smith CR. Fou¡ unusual cases of suddon and unexpected

ca¡diovascule¡ death in infancy and childhood. Med sci Law 1 991; 31 : 1 57-l 61 . I Byard RW, Bourne AJ, Cockington RA. Fatal gastric perforation in a four year old ch¡ld with a late present¡ng congenilal diaphragmatic hernia. pediatr Surg lnt ,l 991; 6: 44-46. 9 L¡psett J, Byard RW, Carpenter BF, Jimenez CL, Bourne AJ. Anomalous coronary arteries arising from the aorta associated with sudden death in infancy and oarly childhood - an autopsy series. Arch Pathol Lab Med 1991;115:770-773. 10 Byard RW, Moo¡o L. Total anomalous pulmonary vonous drainage and sudden unexpected death in infancy. Foronsic Sci lnt 1991 ;51:'197-2O2. 11 Byard RW, Bourne AJ, Hanieh A. Sudden and unexpected doath due to hemorrhage from occult contral nervous system lesions: A pediatric autopsy study. Pediatr Neurosurg 1991-92; 17: 88-94. '12 Moore L, Byard RW. Sudden and unexpected death in infancy associated with a singlo coronary artery. Pediatr Pathol 1992; 12:231-236. 13. Smith NM, Tolfer SM, Byard RW. A comparison of the incidenco of c¡omegalovirus inclusion bodies within submandibular and tracheobronchial glands in SIDS and non-SIDS autopsies. p6diatr Pathol 1992; I 2: 185-'l 90. 14. Byard RW, Moore L, Bourne AJ, Lawrenco AJ, Goldwater PN. Clostridium botulinum and suddon infant dealh syndrome: A'lO year prospective study. J Paediatr Child Health 1992;28: l56-157. 347

15. Byard RW, Moore L, Little KET, Bourne AJ. Sudden death in infancy due to delayod cardiac tamponado complicating central venous line insertion and cardiac catheter¡sation. Arch Pathol Lab Med 1992; 1 16: 65¿l-656. 16. Smith NM, Bourne AJ, Clapton WC, Byard RW, The spectium of presentation at autopsy of myocarditis in childhood. Pathology 1992; 24:. 129-131. 17. Byard RW, Moore L. Gastroesophageal reflux and tho sudden infant death syndrome. Pediatr Pathol 1992; 13:53-57. 18. Byard RW, Beal SM. Munchausen syndrome by proxy, infantile apnoea and homicide. J Paediatr Child Health 1993; 29:, 77-79. 19. Byard RW, Foster BK, Byers S. lmmunohistochemical characterisation of tho costochondral junction in

sudden infant death syndrome. J Clin Pathol 1 993; 46: 108-1 1 2. 20. Moore L, Byard RW. Pathological findings in hanging and wodging deaths in infants ond young childron. Am J Forensic Med Pathol 1993; 14: 296-302.

21 . Byard RW, Moore L, Bourne AJ, Lawrence AJ, Goldwater PN. lntestinal Clostridium botulinum and suddon infant doath syndrome. Perinatology Press, lthaca, United States (ln press), 22. Moore L, Byard RW. Hanging and wedging in young children. Procoodings of tho 12th World T¡iennial Meeting of tho lntornational Association of Forensic Scioncos. (ln press). 23. Byard RW, Makrides M. Need M, Neumann M, Gibson RA. Variability in corebral fatty ac¡d composition relatôd to diet in SIDS infants. Proceedings of the 12th World Triennial Meeting of the lntsrnat¡onal Association of Forensic Scioncos. (ln p¡oss). 24. Byard RW, The changing profilo of autopsy diagnosis in cases of sudden and unexpectod infant death in South AustrElia. Procoodings of the 12th World Trionnial Meeting of the lnternational Association of Foronsic Sciences. (ln press). 25. Byard RW, Silver MM. Sudden infant death, airway obstruction and posterior lingual abscess. Oral Surg Oral Med Oral Pathol (ln press). 26. Moore L, Bourne AJ, Beal S, Collett M, Byard RW. Unexpected infant death in association with susponded rocking cradles. Am J Forensic Med Pathol (ln press). 27. Lipsett J, Cohle S, Berry J, Byard RW. Anomalous coronary artorios - a multicontre pediatric autopsy study. Pediatr Pathol (ln press). 28. James CL, Keeling JW, Smith NM, Byard RW. Total anomalous pulmonary venous drainago associatod with fatal outcome in infancy and early childhood. Ped¡atr Pathol (Under consideration).