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Sudden infant death syndrome: A critical review of approaches to research


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This review explores the various research approaches taken attempting to solve the problem of SIDS. It would appear that major clues provided by pathological findings have been largely overlooked and as a consequence much effort, time, and money has been wasted on projects that satisfy only sub-specialty and political needs. Close examination of the pathological clues would provide better insights into the mechanisms underlying this enigmatic and heartbreaking problem.
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Sudden infant death syndrome: a critical review of
approaches to research
P N Goldwater
Arch Dis Child 2003;88:1095–1100
This review explores the various research approaches
taken attempting to solve the problem of SIDS. It would
appear that major clues provided by pathological findings
have been largely overlooked and as a consequence much
effort, time, and money has been wasted on projects that
satisfy only sub-specialty and political needs. Close
examination of the pathological clues would provide better
insights into the mechanisms underlying this enigmatic and
heartbreaking problem.
Correspondence to:
Dr P N Goldwater,
Microbiology & Infectious
Diseases Department, The
Women’s & Children’s
Hospital, North Adelaide,
South Australia 5006;
Accepted 15 March 2003
he enigma of sudden infant death syndrome
(SIDS) has frustrated researchers for too
long. Part of the failure to determine its
aetiology can be attributed to the approach. With
few exceptions, this could be described as having
been ‘‘flawed’’ since ‘‘scientific’’ inquiry began—
around the time when the condition (‘‘cot
death’’) was first defined in 1969 as ‘‘the sudden
death of any infant or young child, which is
unexpected by history, and which a thorough
post mortem examination fails to show an
adequate cause of death’’.
In retrospect, it is
clear that omissions of importance occurred at
the time of the first and second international
conferences on the causes of sudden death in
infants. These omissions included appropriate
consideration of the salient pathological features
observed in the babies who fell under the
accepted definition(s). Many articles which set
out to describe the pathology of SIDS failed to do
so (being incomplete) and drifted off into
unjustified and fanciful supposition as to the
reason for a particular finding.
Why the
pathological evidence was largely overlooked is
hard to understand. This review will explore in
detail the arguments that abounded at the time
and discover why the thinking about SIDS lacked
the logical and considered approach it deserved.
Much of the debate has come from the two main
schools of thought: (1) that SIDS has a single
cause; and (2) that SIDS is an amalgam of
predisposing host and epidemiological risk fac-
tors (see table 1) and is therefore multifactorial.
The ‘‘single cause’’ school, in the main, has
concentrated on single areas of interest (allergy,
nutrition, metabolism, cardiological, pulmonolo-
gical, neurological, endocrinological, toxicologi-
cal, and infection), and with few exceptions,
without much attention given to pathological
clues. These approaches have been driven largely
by sub-specialty and political interest rather than
evidence. Likewise, the multifactorial/multiple
causes school’s attention to pathological infor-
mation has been similarly blinkered. It is too
simplistic to divide the research into these
schools, for the researchers in the ‘‘single cause’’
school who invoke a bacterial toxin (as a likely
single cause) have given due acknowledgment to
the many risk factors that could play a role in
In effect, as will be revealed, a single
bacterial toxin cause acting in concert with the
known risk factors could be labelled as ‘‘multi-
factorial’’. Linking prone sleep position (a major
risk factor) to the many other epidemiological
factors has been difficult. Its relation to SIDS
varies considerably in terms of relative risk. If an
asphyxial mechanism is proposed to underlie an
association with prone (and lateral) sleeping, the
same mechanism almost certainly cannot be
applied to supine sleeping, a position in which
SIDS also occurs. Regrettably, there has been
insufficient research and discussion in regard to
supine SIDS deaths.
Infants classified as dying from SIDS are most
often normally nourished and hydrated. The
nappies are usually wet and contain stool, and
the bladder and rectum are typically empty.
The salient features at post-mortem examination
are the following:
Liquid blood
An early discussion on aspects of pathology that
might have cleared the way to a rational
approach to researching the cause SIDS took
place at the Cambridge Symposium on SIDS in
1970. Liquid, unclotted blood within the cham-
bers of the heart is a common, if not constant
finding in SIDS.
In this regard, Professor Francis
Camps, doyen of forensic pathology, questioned
in passing whether asphyxia could cause lique-
faction of blood. He observed that asphyxiated
animals have normally clotted blood and that an
asphyxial mechanism could not be invoked in
According to Di Maio and Di Maio,
unclotted blood in the context of adult death
does not infer a particular cause of death.
Despite this, these authors claim fluidity of the
blood is one of the ‘‘classical signs’’ of asphyxia
but go on to say these signs are non-specific and
can occur in deaths from other causes. The
contradiction is obvious. However, in the context
of sudden unexpected death in infancy (SUDI)
without apparent cause, with almost every case
exhibiting this finding, it would suggest a very
limited number of potential causes, especially
when normally clotted blood is the usual
postmortem finding in infants dying suddenly
from traumatic injury and non-infective causes. Beckwith
compared rates of completely fluid blood and partly clotted
blood in SIDS and controls and showed that 92% and 7%
respectively, of SIDS babies and 73% and 16%, respectively of
controls had the above mentioned blood states. Despite well
documented information on the high frequency of unclotted
blood in SIDS, some major articles on the pathology of SIDS
ignore the state of the blood.
Confounding these considera-
tions is the observation that many cases of unquestionable
asphyxia have unclotted blood. However, because there are
other conditions in which liquid blood occurs, its finding
does not necessarily infer asphyxia was the basis of the
finding. Nevertheless, the very high frequency of demon-
strable unclotted/liquid blood in SIDS should merit further
On consideration of this clue, the logical approach to
investigation would be to: (1) determine whether or not
perturbation of the clotting cascade underlies this phenom-
enon; and (2) if so, examine the origin of the perturbation,
for example, endothelial cell mediated or other precipitating
factor. A study that investigated disseminated intravascular
coagulation (DIC) in neonatal deaths with the use of
immunohistochemistry to look for fibrin related antigens
(FRA) in tissues in which SIDS babies were used as a
comparison group, showed minimal FRA staining, indicating
DIC is an unlikely underlying mechanism in SIDS.
Since the
pathogenesis of DIC became understood in the 1960s,
paediatric pathologists have been unanimous in excluding
the condition on histopathological grounds. Although DIC is
not part of SIDS, another mechanism must be sought to
explain the phenomenon of liquid blood. Can fibrin
degradation products be formed as a result of a mechanism
other than DIC? It is clear that consistently higher cross
linked fibrin degradation products are found frequently in
SIDS sera compared with other deaths.
This would indicate
that in SIDS, a clotting perturbation has indeed occurred.
Beckwith referred non-specifically to unreferenced experi-
mental findings that ‘‘fibrinolysins are released when the
heart perfuses anoxic tissues, and that they are not released
when the heart stops suddenly’’.
Little, if any, progress has
been made on the pathogenesis of unclotted blood for more
than three decades. Clues may be found in the mechanisms
involved in the development of ‘‘shock lung’’ (acute
respiratory distress syndrome)
(vide infra) in which
activation of both intrapulmonary and circulating cells
Notably, SIDS infants have increased numbers of
mast cells in lung tissue and increased levels of mast cell
especially in those dying prone.
An anaphylactic
reaction (involving degranulation of mast cells), could be
triggered by viral infection (common in SIDS) via interferon
and up-regulation of mast cell MHC II antigens—known
receptors for pyrogenic toxins.
Intrathoracic petechial haemorrhages; size, number,
Much discussion has been devoted to the almost universal
finding in SIDS babies of petechial haemorrhages in their
intra-thoracic organs including the thymus, lungs, visceral
pleura, and epicardium. Indeed, the presence of intrathoracic
petechial haemorrhages is regarded by some pathologists as a
prerequisite for making the diagnosis of SIDS.
most studies have not attempted to delineate differences
between SIDS petechiae and those found in asphyxial deaths.
The few papers that have examined this have shown
differences that would indicate possibly different pathoge-
netic mechanisms. Petechial haemorrhages were encountered
in 87% of SIDS cases, but in non-SIDS cases ‘‘were mostly
absent or less developed in quantitative terms’’.
Others have
commented along similar lines.
30 31
Krouse and Jordan
compared the distribution of petechiae in SIDS and various
other causes of death and with few exceptions, showed
limitation to within the chest cavity in SIDS but extension (to
below the diaphragm) in cases whose terminal course was
complicated by either hypoxaemia, hypercarbia, metabolic
acidosis, coagulopathy, or infection. Table 2 summarises the
incidence of intrathoracic petechial haemorrhages in SIDS
and non-SIDS reported by several investigators and shows
impressive differences between the two groups. Beckwith
has commented on the incidence, distribution and density of
intrathoracic petechiae wherein these differences are appar-
ent. While Prof. Camps had experience with the findings of
experimental asphyxia, he was clearly unaware of the
experimental findings of Handforth,
who killed rats by
tracheal occlusion and observed intrathoracic petechiae at
necropsy. The observation by Beckwith that the petechiae
found on the posterior side of the thymus were more
numerous below than above the innominate vein in SIDS
cases led to the hypothesis that the petechial distribution
could be explained by the dampening effect of the vein on
changes in intrathoracic pressure occurring during breathing
against an occluded upper airway.
The pathological findings
derived by Valde´s-Dapena and colleagues
from the NICHHD
study found petechiae in the pleura less often than most
other studies. Despite this, the finding on gross pathology
(54%) was significantly greater than that in explained (non-
SIDS) deaths (35%). Gross and microscopic results combined
revealed 63% of SIDS cases had pleural petechiae with only
38% of explained deaths. On comparison of frequencies of
intrathoracic petechiae in this analysis, SIDS cases signifi-
cantly more often had these petechiae (82%) compared with
explained deaths (60%). There were discrepancies between
observation of petechiae on gross examination compared
with histopathology, with petechiae of pleura, alveoli, and
septa more often noted on microscopy. Thymic petechiae
were noted in 69% of SIDS cases and 38% of explained deaths
when gross and microscopic findings were combined. Had
quantitative measurements of density of petechiae been
undertaken in this study, further valuable comparative data
Table 1 Predisposing host and epidemiological risk
factors associated with SIDS
Higher parity
Low birth weight, short gestation (intrauterine growth retardation)
Inadequate prenatal care
Maternal smoking
Smoking within the household during pregnancy
Maternal recreational drug use (opiates, cocaine)
Urinary tract infection
Lower socioeconomic status
Race-ethnicity: African-American, indigenous populations: Aboriginal
Australian, Maori, Native Americans
Age at death (peak at 2–4 months)
Male gender
Cold season
IL-10 low producer
IL-1b high producers
5 6 8 10–12
Infections (URTI or gastroenteritis) (recent illness potentiates effectof
prone sleep position and overwrapping)
Passive exposure to cigarette smoke
Lack of breast feeding
Prone sleep position
Bed sharing
Sofa sleeping
Used mattress
Lack of or late immunisation
1096 Goldwater
would have been obtained. However, petechial haemor-
rhages, when present in SIDS, are much denser (in number
per area) than in non-SIDS deaths.
Given that the NICHHD
purported to be broad and encompassing all things
pathological in SIDS, it is disappointing that quantitative and
qualitative analysis of petechiae was not undertaken and
organ weights (see below) were not analysed.
Byard and Krous
relegated petechial haemorrhages to
‘‘minor’’ pathological findings yet they declare these are well
recognised in cases of SIDS and occur in 68–95% of cases and
may be caused by the mechanisms that led to the terminal
Furthermore, the authors contrast the findings seen
in cases of hanging and crush asphyxia in which petechiae of
the conjunctiva and face—findings unusual in infants dying
of other causes (that is, SIDS). They quote Dr John Hilton
that petechiae ‘‘are never present on the conjunctiva, eyelids
or on or in other soft tissues of the head or neck in SIDS’’.
Byard and Krous
support the contention that finding
petechiae on the face, neck, upper chest, or conjunctivae
warrants suspicion and extremely careful investigation. It has
been presumed, but by no means proven, that intrathoracic
petechiae in SIDS are the consequence of breathing against
an occluded upper airway. Just where the alleged obstruction
is thought to occur has never been established. Nor have
other causes of petechial haemorrhage been vigorously
sought. Potential avenues of research that have been largely
overlooked include the clotting cascade, toxic or immunolo-
gical damage to the capillary basement membrane or other
molecular events taking place during toxic or septic shock.
In summary, while intrathoracic petechial haemorrhages
are extremely common in SIDS they are a non-specific
finding; however, the predictive value of finding petechiae
has never been explored (vide infra). Notwithstanding this,
there has been an almost total absence of research into
mechanisms by which petechiae form (other than a
respiratory one).
Fluid-laden, congested organs
The weights of the thymus, lungs, liver, and brain appear to
be significantly greater in SIDS cases than published norms.
The study by Siebert and Haas
analysed data from 500
postmortem examinations performed over 15 years by one
pathologist. It is understandable that so-called ‘‘normal’’
weights tend to be low as a result of underlying disease in
this comparison group. Nevertheless, it is clear that in SIDS
the above mentioned organs are fluid laden and thus heavy.
The underlying pathophysiological processes have not been
the subject of investigation.
To quote Kinney and Filiano,
‘‘Of all neuropathologic
findings, heavy brain weight is perhaps the best established,
because of the simplicity and reproducibility of the method of
measurement, i.e. weighing the unfixed brain at autopsy.’’
The underlying cause of the increased brain weight would
include the following possibilities: cerebral oedema (second-
ary to hypoxia/anoxia or toxic/metabolic factors), agonal
vascular congestion, or megalencephaly. However, no inves-
tigation into mechanisms by which the phenomenon of
heavy brain weight in SIDS occurs has been adequately
studied. One exception is the identification of staphylococcal
toxins in various tissues (including brain) of SIDS babies,
thus suggesting a toxic cause of brain swelling.
To link the pathological finding of heavy brain weight to
prone sleep position and other epidemiological features
requires a special exercise of imagination. One such exercise
has resulted in the ‘‘triple risk’’ model encompassing
vulnerability, a critical development period and exogenous
This is fine when applied to the epidemiological
findings in SIDS but becomes convoluted, complex, and
implausible when a link with prone sleep position is
attempted. It may not be a coincidence that periventricular
leukomalacia, a characteristic finding in babies who develop
cerebral palsy, is also common in SIDS.
45 46
Many of the
epidemiological features of SIDS are shared with those of
cerebral palsy. Not only is the incidence of cerebral palsy
similar to SIDS (2–2.5 cases per 1000 live births), but many
risk factors for the occurrence of cerebral palsy are shared
with SIDS, including maternal age, maternal infection,
multiple births, shorter gestational age, and low birth
The list of neurohistopathological changes
claimed to be associated with SIDS is long, and with the
use of conventional techniques SIDS brains look normal or
have inconsistent minor changes such as mild brain stem
The studies are frequently contradictory.
As mentioned, thymus weights tend to be heavier in SIDS
cases than in ‘‘normal’’ babies. Again the comparison
(normal) group may have had underlying disease that could
have impacted on the health of the thymus and therefore the
organ’s weight. No data exist that correlate the thymus
weights with the density of petechial haemorrhages.
Heavy, fluid laden lungs in SIDS is a frequent, if not
invariable finding. Although asphyxia is described as one of
the conditions in which fluid laden lungs occur, other
Table 2 Incidence of intrathoracic petechial haemorrhages in SIDS and comparison
Reference SIDS cases
Frequency of
petechiae (%) Non-SIDS comparisons
Werne and Garrow
31 80 Absent or sparse in infant
suffocation, CO asphyxia,
12 100 None
Jacobsen and Voight
97 95 Rare in infanticide, accidents
80 79 6 of 43 (14%)
Cooke and Welsh
91 94 10 of 31 (32%) in no case
were they numerous
162 68 12 of 42 (29%)
109 87 16 of 38 (42%)
100 85 None
Valdes-Dapena et al
622 82 39 of 65 (60%)
Risse and Weiler
63 (thymus) 87 13 of 33 (39%) (thymus)
SIDS research: a critique 1097
potential explanations have never been adequately
addressed, especially from the point of view of blood vessel
basement membrane integrity. ‘‘Shock lung’’ is a condition in
which perturbation of the inflammatory pathways leads to
damage of capillary basement membranes and leakage of
fluid into the alveolae and interstitium.
explanations deserve appropriate investigation. Intra-alveolar
haemorrhage would contribute to lung heaviness. The causes
of intra-alveolar haemorrhage are many and varied and have
been widely debated; however, pathologists are wary of the
possibility of mechanical asphyxia when more than 5% of
alveolar area is occupied by red blood cells, but appropriate
studies have not been conducted to provide definitive data.
Others have examined semiquantitative morphological deter-
minants of asphyxia in lung tissue
and showed good
correlation with the types of asphyxia (for example, foreign
body, suffocation, drowning and strangulation) but did not
examine lungs from SIDS cases. Potentially valuable findings
could be forthcoming if similar methodology were to be used
in the context of SIDS.
Fatty change is described in SIDS, but the finding is variable
and therefore cannot adequately explain the increase in
weight of SIDS babies’ livers over comparison babies. Again
the mechanism by which the liver becomes heavy in SIDS
needs addressing.
To my knowledge, no effort has been made to determine the
predictive value of a particular pathological finding in helping
to reach a diagnosis or exclude a diagnosis of SIDS. For
instance, what is the predictive value of thymic petechiae of a
particular density, or pleural or cardiac petechiae at a
particular age? Or, what is the predictive value of an organ
weight at a particular age? Examination of the data from the
NIHCHD study provides some insights. For instance, the
predictive value of finding thymic petechiae (gross and/or
microscopic examination) would be 95.5% predictive of SIDS;
the absence of petechiae would give a predictive value of
14.8%. In the case of intrathoracic petechiae the predictive
value of such a finding is equally high at 94.1% and the
predictive value of their absence would be 16.1%.
Inflammatory infiltrates
Inflammatory changes in the respiratory epithelium is a
common finding in SIDS and probably reflects recent viral
respiratory symptoms noted in up to 44% of cases within the
last two weeks of life.
The degree of inflammation in the
trachea and bronchioles observed in SIDS is considered
inadequate to represent a cause of death.
Nevertheless, a
contributory role of virus infection in SIDS through viral
potentiation of bacterial toxins remains a possibility (vide
Bacterial toxins, viral infection, smoke
Blackwell and colleagues
have given due prominence and
summarised a microbiological perspective of SIDS, but the
focus was mainly on staphylococcal toxins. Independent
studies have shown an increased colonisation rate by
toxigenic bacteria in the gut of babies who have died of
SIDS compared with healthy living babies or babies who died
of other causes.
Other studies have shown nasopharyngeal colonisation by
Escherichia coli
55 56
and Staphylococcus aureus,
with increased
colonisation of the latter in infants who slept prone.
Furthermore, if toxins were involved in SIDS causation,
these should be demonstrable in the sera of SIDS cases.
Indeed the lethal toxicity of serum from SIDS babies
compared to controls has been shown by Alexander and
in infant mice and by Sayers and colleagues
chick embryos. Notably in both studies the sera from control
infants were non-lethal. In addition, E coli strains isolated
from SIDS babies (but not healthy babies) are lethal to
This work failed to show known E coli toxins (for
example, ST, LT, stx) in most SIDS cases and was thus a
stimulus to seek new toxic bacterial proteins; this led to
the discovery of soluble curlin in all SIDS sera of an
Australia series examined.
This finding awaits independent
Generally not appreciated is the fact that bacterial protein
toxins are potentiated (that is, made more lethal) with co-
existent viral infection
54 61 62
and/or exposure to smoke.
63 64
The latter two factors belong in the list of risk factors for
SIDS. It is noteworthy that bacterial toxins potentiate each
indicating a potential role for multiple toxin
(staphylococcal, E coli, clostridial) involvement in SIDS.
The ‘‘reducing the risk’’ and ‘‘back to sleep’’ campaigns were
based on epidemiological findings from several studies in
relation to prone sleep position.
The campaigns perpetuate a
biased approach to this enigmatic and important cause of
post-neonatal death. Although since 1991 the rate of SIDS
seems to have fallen by about 50% in a number of countries,
SIDS remains a major contributor to post-neonatal mortality
and SIDS incidence varies considerably geographically.
Notwithstanding the possible influence of inconsistent
autopsy protocols and criteria for SIDS diagnosis, this
apparent fall may only be a reflection of natural variation.
This idea is supported by Swedish figures, showing that the
rate in the late 1990s has returned to the level observed in the
early 1970s. The decline seen in the early 1990s began before
the introduction of the ‘‘back to sleep’’ campaign.
Australian data are similar to those of Sweden but do not
go back as far. In support of the phenomenon of natural
variation in rates of SIDS is the observed upswing in
Victorian SIDS numbers in 2002 (Victorian Institute of
Forensic Medicine data). This may herald a return to the
disturbing figures observed in the 1980s and 1990s. If the
current practice of avoiding prone sleep position sustains,
reappraisal of sleep position in relation to a rising SIDS
incidence will be necessary.
As mentioned above, mechanisms culminating in
cannot provide the answer to SIDS because the
findings in asphyxial death fly in the face of pathological
evidence; especially in regard to the number and distribution
of petechiae, not to mention organ weight information. Cases
of SIDS captured on 24 hour computerised memory monitors
(tracing pulse, respiratory rate, and blood pressure) also
show asphyxia was an impossibility.
70 71
Invoking an asphyx-
ial mechanism for prone position must logically exclude the
same mechanism for most deaths in supine and lateral
The effect of prone sleep position could hypothetically be
explained on the basis of: (1) greater chance of ingestion of
bacteria contaminating the sleeping surface;
72 73
(2) induction
of temperature dependent bacterial toxins;
and (3) possible
differences in rates of delivery to the systemic circulation of
gut derived lethal toxin.
75 76
A candidate ‘‘toxin’’ is soluble curlin antigen, CsgA (the
subunit of curli fimbriae—a colonisation/adherence factor
common to most Enterobacteriaceae), accompanied (or not)
by other toxins absorbed through the gut reaching the
circulation via the portal system which takes it to the liver.
Fatty change (for which toxaemia is a cause) is found in the
livers of some SIDS babies.
17 77
A second, possibly more
1098 Goldwater
important route of curlin/toxin absorption, would be via the
lymphatic system and the thoracic duct. Curlin protein/toxin
would be delivered via the duct to the innominate vein and
thence to the right side of the heart. The first organ exposed
to curlin would be the lungs followed by the heart and the
thymus. These are the organs in which classical pathological
findings in SIDS are seen (petechiae, and wet/heavy lungs).
Bacterial toxins/products can perturb basement membranes
of small blood vessels leading to the small haemorrhages
(petechiae) and fluid laden organs seen in SIDS. Curlin binds
to fibronectin
and this could precipitate damage to capillary
basement membranes and perturb the clotting system. The
pattern of distribution of petechiae is distinctive and could be
explained by the fact that these would be the first organs
exposed (as explained above) or that these organs are replete
with toxin receptors.
75 76
This hypothesis explains why more
deaths occur in the prone position in which a lethal amount
of toxin is delivered; and in other positions, by inference, a
usually sublethal dose is delivered to the systemic circulation.
Paracelsus’ notion
that ‘‘the dose makes the poison’’
predated our understanding of minimal lethal dose or
LD50. The above mentioned pathological findings in SIDS
Liquid (unclotted) blood within the chambers of the
17 20
and increased cross linked fibrin degradation
(seen in toxaemia/sepsis); in this context, curlin
protein represents contact phase bacterial components
which can activate the proinflammatory pathway,
80 81
involving reactions with fibrinogen and fibronectin
which can lead to depletion of coagulation factors
resulting in a hypocoagulability state.
The finding of an empty bladder in most SIDS cases
17 77
suggests decreased renal perfusion (toxaemic shock)
during the last sleep. Thus this proposed hypotension
could be explained by curlin protein induction of pro-
inflammatory cytokines with release of bradykinin and/or
The link between infection, inflammation, and the risk
factors for SIDS has been expressed similarly by Blackwell
and colleagues.
The role of endotoxin seems in doubt, which
simplifies the search for a more specific toxin candidate. A
number of studies have been unable to ascertain the presence
of endotoxin in amounts different from controls.
Disseminated intravascular coagulation (DIC) would be an
expected finding if endotoxin were involved to any great
extent. The absence of DIC in SIDS supports this.
It is time to address the deficiencies in direction and funding
of SIDS research. Many unresolved issues need clarification:
Clues including susceptibility to infection need to be
addressed by examining several aspects of the innate
immune system which would likely play an important role
through induction of adverse reactions to infection in
infancy. Examination of polymorphisms for mannose-bind-
ing lectin, and pro- and anti-inflammatory cytokines might
provide insights into differences in incidence of SIDS among
different ethnic groups. Energy should go into independent
confirmation of the findings in relation to soluble curlin—a
candidate toxin that seems to fulfil the necessary attributes of
a causal agent. Development of models of infection in the
susceptible host must also be attempted to provide a better
understanding of the mechanism(s) involved in SIDS. There
is a need to reassess the suspected ‘‘red herrings’’ of brain
stem astrocytosis, pulmonary haemosiderin, mycotoxins,
organophosphates, and similar ideas with poor correlations
with SIDS. If SIDS research funding organisations are serious
about finding a solution to SIDS it would be helpful if they
could reassess their directions and philosophical approach.
1 Bergman AB, Beckwith JB, Ray CG, eds. Sudden infant death syndrome—
Proceedings of the Second International Conference on Causes of Sudden
Death in Infants. Seattle: University of Washington Press, 1970.
2 Rognum TO. Definition and pathologic features. In: Byard RW, Krouse HF,
eds. Sudden infant death syndrome: problems, progress and possibilities.
London: Arnold, 2001:4–30.
3 Krous HF. The microscopic distribution of intrathoracic petechiae in sudden
infant death syndrome. Arch Pathol Lab Med 1984;108:77–9.
4 Krous HF. Pathological considerations of sudden infant death syndrome.
Int J Child Adolesc Health 1988;15:231–9.
5 Willinger M. SIDS—a challenge. J Natl Inst Health Res 1989;1:73–80.
6 Valdes-Dapena MA. Sudden infant death syndrome: a review of the medical
literature 1974–1979. Pediatrics 1980;66:597–614.
7 Standfast SJ, Jereb S, Janerich DT. The epidemiology of sudden infant death in
upstate New York: II: Birth characteristics. Am J Public Health
8 Hauk FR. Changing epidemiology. In: Byard RW, Krouse HF, eds. Sudden
infant death syndrome: problems, progress and possibilities. London: Arnold,
9 Gardner A. Urinary tract infections during pregnancy and sudden unexpected
infant death [letter]. Lancet 1985;2:495.
10 Hoffman HJ, Hillman LS. Epidemiology of the sudden infant death syndrome:
maternal, neonatal and postneonatal risk factors [review]. Clin Perinatol
11 Platt MW, Blair PS, Fleming PJ, et al. A clinical comparison of SIDS and
explained sudden deaths: how healthy and how normal? Arch Dis Child
12 Gilbert RE, Wigfield RE, Fleming PJ, et al. Bottle feeding and the sudden infant
death syndrome. BMJ 1995;310:88–90.
13 Blackwell CC, Weir DM, Busuttil A. A microbiological perspective. In:
Byard RW, Krouse HF, eds. Sudden infant death syndrome: problems,
progress and possibilities. London: Arnold, 2001:182–208.
14 Bettelheim KA, Goldwater PN, Dwyer BW, et al. Toxigenic Escherichia coli
associated with sudden infant death syndrome. Scand J Infect Dis
15 Murrell WG, Stewart BJ, O’Neill C, et al. Enterotoxigenic bacteria in the
sudden infant death syndrome. J Med Microbiol 1993;39:114–27.
16 Bettiol SS, Radcliffe FJ, Hunt ALC, et al. Bacterial flora of Tasmanian SIDS
infants with special reference to pathogenic strains of Escherichia coli.
Epidemiol Infect 1994;112:275–84.
17 Williams AL. Sudden infant death syndrome. Aust N Z J Obstet Gynaecol
18 Camps FE. Sudden and unexpected deaths in infancy (cot deaths). In: Report
of the Proceedings of the Sir Samuel Bedson Symposium, Cambridge. April
1970. Bristol: John Wright & Sons, 1972:50.
19 Di Maio DJ, Di Maio VJM, eds. Forensic pathology. New York: Elsevier,
20 Beckwith JB. Observations of the pathological anatomy of the sudden infant
death syndrome. In: Bergman AB, Beckwith JB, Ray CG, eds. Sudden infant
death syndrome. Proceedings of the second International Conference on
Causes of Sudden Death in Infants. Seattle: University of Washington Press,
21 Conover PT, Abramowsky C, Beyer-Patterson P. Immunohistochemical
diagnosis of disseminated intravascular coagulation in newborns. Pediatr
Pathol 1990;10:707–16.
22 Goldwater PN, Williams V, Bourne AJ, et al. Sudden infant death syndrome:
a possible clue to causation. Med J Aust 1990;153:59–60.
23 Kollef MH, Schuster DP. Acute respiratory distress syndrome. N Engl J Med
24 Hamcher J, Lucas R, Lijnen HR, et al. Tumor necrosis factor-a and angiotensin
are mediators of endothelial cytotoxicity in bronchoalveolar lavages of
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med
25 Holdgate ST, Walters C, Walls AF, et al. The anaphylaxis hypothesis of
sudden infant death syndrome (SIDS): mast cell degranulation in cot death
revealed by elevated concentrations of tryptase in serum. Clin Exp Allergy
26 Edston E, Gidlund E, Wickman M, et al. Increased mast cell tryptase in sudden
infant death—anaphylaxis, hypoxia or artefact? Clin Exp Allergy
27 Dimitriadou V, Mecheri S, Koutsilieris M, et al. Expression of functional major
histocompatibility complex class II molecules on HMC-1 human mast cells.
J Leukoc Biol 1998;64:791–9.
28 Haas JE, Taylor JA, Bergman AB, et al. Relationship between epidemiologic
risk factors and clinicopathologic findings in SIDS. Pediatrics
29 Risse M, Weiler G. Differential diagnosis SIDS/non-SIDS on the basis of
histological findings of petechial thymus hemorrhages. Forensic Sci Int
30 Krouse HF, Jordan J. A necropsy study of the distribution of petechiae in non-
sudden infant death syndrome. Arch Pathol Lab Med 1984;108:75–6.
31 Beckwith JB. Intrathoracic petechial hemorrhages: a clue to the mechanism of
death in sudden infant death syndrome. Ann N Y Acad Sci 1988;533:37–47.
32 Handforth PC. Sudden unexpected death in infants. Can Med Assoc J
SIDS research: a critique 1099
33 Valde´s-Dapena M, McFeeley PA, Hoffman HJ, et al. Summary of
histopathologic findings and implications for future SIDS research. In:
Histopathology atlas for sudden infant death syndrome. Washington, DC:
Armed Forces Institute of Pathology, American Registry of Pathology & The
National Institute of Child Health and Human Development, 1993:281–99.
34 Byard RW, Krous HF. Specific pathologic problems and possible solutions. In:
Byard RW, Krouse HF, eds. Sudden infant death syndrome: problems,
progress and possibilities. London: Arnold, 2001:230–1.
35 Beckwith JB. The mechanism of death in sudden infant death syndrome. In:
Culbertson JL, Krouse HF, Bendell RD, eds. Sudden infant death syndrome:
medical and psychological management. London: Edward Arnold,
36 Hilton JMN. The pathology of sudden infant death syndrome. In: Mason JK,
ed. Paediatric forensic medicine and pathology. London: Chapman & Hall
Medical, 1989:156–64.
37 Werne J, Garrow I. Sudden apparently unexplained death during infancy. 1.
Pathologic findings in infants found dead. Am J Pathol 1953;29:633–52.
38 Jacobsen T, Voight J. Sudden and unexpected infant death. II. Result of
medico-legal autopsies of 356 infants aged 0–2 years. Acta Med Leg Soc
(Liege) 1956;9:133–59.
39 Geertinger P. Sudden death in infancy. Springfield, IL: Charles C. Thomas,
40 Cooke RT, Welsh RG. A study in cot death. BMJ 1964;2:1549–54.
41 Marshall TK. The Northern Ireland study: pathology findings. In: Bergman AB,
Beckwith JB, Ray CG, eds. Sudden infant death syndrome. Proceedings of the
Second International Conference on Causes of Sudden Death in Infants.
Seattle: University of Washington Press, 1970:108–17.
42 Siebert JR, Haas JE. Organ weights in sudden infant death syndrome. Pediatr
Pathol 1994;14:973–85.
43 Kinney HC, Filiano JJ. Brain research in sudden infant death syndrome. In:
Byard RW, Krouse HF, eds. Sudden infant death syndrome: problems,
progress and possibilities. London: Arnold, 2001:118–37.
44 Blackwell CC, Gordon AE, James VS, et al. The role of bacterial toxins in
sudden infant death syndrome (SIDS). Int J Med Microbiol 2002;291:561–70.
45 Kinney HC, Brody BA, Finkelstein DM, et al. Delayed central nervous system
demyelination in the sudden infant death syndrome. J Neuropathol Exp
Neurol 1991;50:29–48.
46 Takashima S, Armstrong D, Becker LE, et al. Cerebral white matter lesions in
the sudden infant death syndrome. Pediatrics 1978;62:155–9.
47 Goldenberg R, Nelson K. Cerebral palsy. In: Creasy R, Resnik R, eds.
Maternal-fetal medicine, 4th edn. Toronto: WB Saunders, 1999:1194–214.
48 Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of
normal birth weight. JAMA 1997;278:207–11.
49 Nelson KB, Grether JK. Causes of cerebral palsy. Curr Opin Pediatr
50 Berry PJ. Intra-alveolar haemorrhage in sudden infant death syndrome: a
cause for concern? J Clin Pathol 1999;52:553–4.
51 Delmonte C, Capelozzi VL. Morphologic determinants of asphyxia in lungs: a
semiquantitative study in forensic autopsies. Am J Forensic Med Pathol
52 Hoffman HJ, Damus K, Hillman L, et al. Risk factors for SIDS: results of the
National Institute of Child Health and Human Development SIDS Cooperative
Epideiological Study. Ann N Y Acad Sci 1988;533:13–30.
53 Cutz E, Jackson A. Airway inflammation and peripheral chemoreceptors. In:
Byard RW, Krouse HF, eds. Sudden infant death syndrome: problems,
progress and possibilities. London: Arnold, 2001:156–81.
54 Jakeman KJ, Rushton DI, Smith H, et al. Exacerbation of bacterial toxicity to
infant ferrets by influenza virus: possible role in sudden infant death
syndrome. J Infect Dis 1991;163:35–40.
55 Pearce J, Luke RK, Bettelheim KA. Extraintestinal Escherichia coli isolations
from SIDS cases and other cases of sudden death in Victoria, Australia. FEMS
Immunol Med Microbiol 1999;25:137–44.
56 Harrison LM, Morris JA, Telford DR, et al. The nasopharyngeal flora in
infancy: effects of age, gender, season, viral upper respiratory tract infection
and sleeping position. FEMS Immunol Med Microbiol 1999;25:19–28.
57 Alexander R, Bettelheim KA, Cairney PC, et al. Microbiological investigations
of suspected sudden infant death syndrome (SIDS) cases. Aust Microbiol
1987;8:156, (abstract P4.6).
58 Sayers NM, Drucker DB, Hutchinson IV, et al. Preliminary investigation of
lethally toxic sera of sudden infant death syndrome victims and neutralisation
by commercially available immunoglobulins and adult sera. FEMS Immunol
Med Microbiol 1999;25:193–8.
59 Bettelheim KA, Pearce JL, Evangelidis H, et al. A mouse model for sudden
infant death syndrome. Proceedings of the 2nd SIDS Family International
Conference, Sydney, 1992. Ithaca, NY: Perinatology Press, 1993:121–3.
60 Goldwater PN, Bettelheim KA. Curliated Escherichia coli, soluble curlin and
the sudden infant death syndrome (SIDS). J Med Microbiol
61 Mach AM, Lindsay JA. Activation of Clostridium perfringens cytotoxic
enterotoxin(s) in vivo and in vitro: role of triggers for sudden infant death. Curr
Microbiol 1994;28:261–7.
62 Sarawar SR, Blackman MA, Doherty PC. Superantigen shock in mice with an
inapparent viral infection. J Infect Dis 1994;170:1189–94.
63 Sayers NM, Drucker DB, Telford DR, et al. Effects of nicotine on bacterial
toxins associated with cot death. Arch Dis Child 1995;73:549–51.
64 Sayers NM, Drucker DB. Animal models used to test the interactions between
infectious agents and products of cigarette smoked implicated in sudden infant
death syndrome. FEMS Immunol Med Microbiol 1999;25:115–23.
65 Drucker DB, Aluyi HS, Morris JA, et al. Lethal synergistic action of toxins of
bacteria isolated from sudden infant death syndrome. J Clin Pathol
66 Mitchell EA. SIDS: facts and controversies. Med J Aust 2000;173:175–6.
67 Beal SM, Finch CF. An overview of retrospective case-control studies
investigating the relationship between prone sleeping position and SIDS.
J Paediatr Child Health 1991;27:334–9.
68 Alm B, Norvenius SG, Wennergren G, et al. Changes in the epidemiology of
sudden infant death syndrome in Sweden 1973–1996. Arch Dis Child
69 Galland BC, Taylor BJ, Bolton DPG. Review article. Prone versus supine sleep
position: a review of the physiological studies in SIDS research. J Paediatr
Child Health 2002;38:332–8.
70 Kelly DH, Pathak A, Meny R. Sudden bradycardia in infancy. Pediatr
Pulmonol 1991;10:199–204.
71 Poets CF, Meny RG, Chobanian MR, et al. Gasping and other
cardiorespiratory patterns during sudden infant deaths. Pediatr Res
72 Tappin D, Brooke H, Ecob R, et al. Used infant mattresses and sudden infant
death syndrome in Scotland: case-control study. BMJ 2002;325:1007–12.
73 Blackwell CC, Weir DM, Bussuttil A. Risk factors for cot death increase danger
of infection: association between used mattresses and cot deaths is
multifactorial. BMJ 2003;326:222.
74 Molony N, Blackwell CC, Busuttil A. The effect of prone posture on nasal
temperature in children in relation to induction of staphylococcal toxins
implicated in sudden infant death syndrome. FEMS Immunol Med Microbiol
75 Goldwater PN. Reappraisal of the SIDS enigma: an epidemiological and
clinicopathological approach. J Paediatr Child Health 1992;(suppl 1):S21–5.
76 Goldwater PN. SIDS: more facts and controversies. Med J Aust
77 Valdes-Dapena M. The pathologist and the sudden infant death syndrome.
Am J Pathol 1982;106:118–31.
78 Olsen A, Jonsson A, Normark S. Fibronectin binding mediated by a novel
class of surface organelles on Escherichia coli. Nature 1989;338:652–5.
80 Bian Z, Yan ZQ, Hansson GK, et al. Activation of inducible nitric oxide
synthetase/nitric oxide by curli fibres leads to a fall in blood pressure during
systemic Escherichia coli infection in mice. J Infect Dis 2001;183:612–19.
81 Bian Z, Brauner A, Li Y, et al. Expression of and cytokine activation by
Escherichia coli curli fibers in human sepsis. J Infect Dis 2000;181:602–12.
82 Herwald H,Mo¨rgelin M, Olsen A, et al. Activation of the contact phase system
on bacterial surfaces—a clue to serious complications in infectious diseases.
Nature Medicine 1998;4:298–302.
83 Bian Z, Yan ZQ, Hansson GK, et al. Activation of inducible nitric oxide
synthetase/nitric oxide by curli fibres leads to a fall in blood pressure during
systemic Escherichia coli infection in mice. J Infect Dis 2001;183:612–19.
84 Blackwell CC, Gordon AE, James VS, et al. Making sense of the risk factors for
sudden infant death syndrome (SIDS): infection and inflammation. Rev Med
Microbiol 2001;12:219–29.
85 Crawley BA, Morris JA, Drucker DB, et al. Endotoxin in blood and tissue in the
sudden infant death syndrome. FEMS Immunol Med Microbiol
1100 Goldwater
... Autopsy findings of SIDS cases include increased brain weight, possibly caused by cerebral edema "secondary to hypoxia/anoxia or toxic/metabolic factors" [4]. However, further postmortem examinations suggest that environmental toxins, including lead, mercury, and arsenic, are not a cause of SIDS [5]. ...
... Of relevance, "abnormalities of regulation of the blood brain barrier with disturbances in water homeostasis" could contribute to increased brain weight in SIDS, although possible causes remain controversial [10]. Other organs with increased weight in SIDS include the thymus, liver, and lungs [4]. "It is clear, however, that in SIDS some of these organs are fluid laden and thus Diseases 2022, 10, 59 2 of 10 heavy" [11]. ...
Full-text available
Sudden Infant Death Syndrome (SIDS) occurs unexpectedly in an otherwise healthy infant with no identifiable cause of death following a thorough investigation. A general hypervolemic state has been identified in SIDS, and fluid in the lungs suggests the involvement of pulmonary edema and hypoxia as the cause of death. The present perspective paper reviews pathophysiological, epidemiological, and dietary evidence in SIDS. A grounded theory is presented that proposes an association of SIDS with sodium toxicity from excessive sodium chloride intake, mediated by noncardiogenic pulmonary edema, hypoxia, and alveolar damage. The peak of SIDS cases occurs in infants 2–4 months of age, who are less efficient in excreting excessive dietary sodium load. Evidence implicating sodium toxicity in SIDS includes increased levels of sodium associated with fever and with inflammatory/immune responses in the lungs. Conditions in near-miss SIDS cases are linked to dysregulated sodium, and increased sodium dietary intake suggests that sodium toxicity from a high-salt diet potentially mediates the association of seasonality and socioeconomic status with SIDS incidence. In addition, exposure to sodium toxicity meets three main criteria of the triple risk model of SIDS. The proposed pathophysiological effects of pulmonary edema related to sodium toxicity in SIDS merit further investigations.
... Previous relevant studies have shown increased brain weight and/or cerebral edema in some cases of SIDS [4][5][6][7][8], although the results of some studies are inconsistent with this [9][10][11]. For instance, the study conducted by Aranda et al. demonstrated that the cases diagnosed as SIDS had heavier brain weights compared to age-matched controls [4], and the findings were in line with other related studies [6][7][8]. ...
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Increasing evidence suggests that brain edema might play an important role in the pathogenesis of sudden infant death syndrome (SIDS) and that variants of genes for cerebral water channels might be associated with SIDS. The role of the sulfonylurea receptor 1 (SUR1)–transient receptor potential melastatin 4 (TRPM4) non-selective cation channel in cerebral edema was demonstrated by extensive studies. Therefore, we hypothesized that variants at genes of the SUR1-TRPM4 channel complex might be linked to SIDS. Twenty-four polymorphisms in candidate genes involved in the SUR1-TRPM4 non-selective cation channel were investigated in 185 SIDS cases and 339 controls. One (rs11667393 in TRPM4) of these analyzed SNPs reached nominal significance regarding an association with SIDS in the overall analysis (additive model: p = 0.015, OR = 1.438, 95% CI = 1.074–1.925; dominant model: p = 0.036; OR = 1.468, 95% CI = 1.024–2.106). In the stratified analysis, further 8 variants in ABCC8 (encoding SUR1) or TRPM4 showed pronounced associations. However, none of the results remained significant after correction for multiple testing. This preliminary study has provided the first evidence for a genetic role of the SUR1-TRPM4 complex in the etiology of SIDS, and we suggest that our initial results should be evaluated by further studies.
... SIDS is defined as the sudden and unexpected death of an infant which remains unexplained after a thorough investigation, including performance of an autopsy and review of the clinical history [10]. Although there are no specific symptoms associated with SIDS, an autopsy often reveals congestion and edema of the lungs and inflammatory changes in the respiratory system [8,11]. ...
Full-text available
Although there is considerable evidence that a subset of infants has an increased risk of sudden death after receiving vaccines, health authorities eliminated "prophylactic vaccination" as an official cause of death, so medical examiners are compelled to misclassify and conceal vaccine-related fatalities under alternate cause-ofdeath classifications. In this paper, the Vaccine Adverse Event Reporting System (VAERS) database was analyzed to ascertain the onset interval of infant deaths post-vaccination. Of 2605 infant deaths reported to VAERS from 1990 through 2019, 58 % clustered within 3 days post-vaccination and 78.3 % occurred within 7 days post-vaccination, confirming that infant deaths tend to occur in temporal proximity to vaccine administration. The excess of deaths during these early post-vaccination periods was statistically significant (p < 0.00001). A review of the medical literature substantiates a link between vaccines and sudden unexplained infant deaths. Several theories regarding the pathogenic mechanism behind these fatal events have been proposed, including the role of inflammatory cytokines as neuromodulators in the infant medulla preceding an abnormal response to the accumulation of carbon dioxide; fatal disorganization of respiratory control induced by adjuvants that cross the blood-brain barrier; and biochemical or synergistic toxicity due to multiple vaccines administered concurrently. While the findings in this paper are not proof of an association between infant vaccines and infant deaths, they are highly suggestive of a causal relationship.
... As mentioned above, all subtypes of C. perfringens produce the alpha toxin, which makes it the clear target for assay development for clinical use [188]. Alpha toxin has been linked to human and other animal sudden infant death syndrome and numerous human deaths related to food poisoning by type A [207][208][209]. Since premature diagnosis and harsh treatment are the solution to decreasing morbidity and mortality, development of a rapid sensitive assay for detect and measure C. perfringens alpha toxin is necessary. ...
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div> The genus Clostridium is ubiquitous , because of this they find easily their way into wounds, foods and feeds, being the cause of serious illness on human and domestic animals. Manifestations and pathology can range from mild food poisoning to death . Outstanding to their high toxicity, and the rapid evolution of infection with serious consequences , it is important to detect it rapidly. One approach is to have rapid detection tests to major clostridial toxins in complex matrices (blood, culture media, food and others), that can be implemented in point of care centers. In this review, a survey of recent work is carried out in this line of research and development. </div
... 25 26 Mainstream researchers attribute intrathoracic petechiae to changes in pulmonary pressure; however, this hypothesis does not stand up to scrutiny as argued in previous publications. [27][28][29] Studies by Krous et al 30 31 disproved an association between intrathoracic petechiae and prone position, indicating that hypothetical upper airway obstruction attributable to face-down position is not causally related to development of intrathoracic petechiae. ...
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Despite decades of investigation and millions of dollars spent, the cause of sudden infant death syndrome (SIDS) eludes researchers. It is timely therefore to reconsider the reasons for this failure and to explore how research might go forward with better prospects. This review assesses SIDS research in the context of clinicopathological and epidemiological features and determines that only infection attains congruence. © 2017 BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health.
... My study provides an opportunity to examine the link between all controversial issues particularly SIDS and ALTE. Goldwater stated: This review will explore in detail the arguments that abounded at the time and discover why the thinking about SIDS lacked the logical and considered approach it deserved [21]. ...
Reference charts for body and organ measurements of neonates and infants were derived from data on 900 investigations done by the Office of the Chief Coroner for Ontario. The statistical analyses in this new reference source addressed deficiencies in sources currently available to pathologists.The present study also considered whether organ weights differed based on the classification of infant deaths using the original definition of either sudden infant death syndrome (SIDS) or sudden unexplained death (SUDS) which considers cases occurring in an unsafe sleeping environment or under adverse socioeconomic conditions. Cases of SUDS for both sexes peaked in 5 to 16 weeks of age. The thymus in the SUDS/SIDS age groups less than 25 weeks weighed more than the control group. Adrenal weights in SUDS cases between 9 and 16 weeks weighed less than SIDS cases. This could mean that deaths in unsafe sleep environments are truly sudden in infants who may have a limited adrenal response to acute hypoxia but have been unaffected by preceding chronic stressors.
SIDS (Sudden Infant Death Syndrome) is an entity poorly studied in Brazil although it represents the main cause of death in the first year of life in the industrialized nations. It is probably multifactorial being prone sleeping position the most important risk factor. Other risk factors are male gender, age between two and four months, smoking mothers, low birth weight, and mild upper airway infection, mostly viral. Interaction of predisposing and triggering factors with a particular period of central nervous and immune system development may be necessary for its occurrence. Although well recognized in the industrialized countries it is fairly unknown among us and this situation will only change when health professionals are aware of its importance. Pediatricians and doctors who work in emergency services are the ones who usually are faced with cases of unexpected deaths in children less than one year old whose autopsies should be mandatory. Pathologists who work in services devoted to the identification of the cause of death and Forensic Doctors should be trained in the identification of such cases with a protocol that includes external and internal examination, both macro and microscopic, as well as collection of blood and vitreous humor for serological and electrolyte studies, respectively. The final diagnosis must be based on history, with the exclusion of external causes, macroscopic, microscopic, serological and vitreous humor findings. Only with these results we will be able to determine the real SIDS incidence and its characteristics with which preventive actions can be done.
This chapter discusses a few selected aspects of central nervous system (CNS) development that may be useful in the examination of immature brain and spinal cord tissue. Forensic cases involving CNS malformations frequently include questions of whether some incident during pregnancy or delivery is responsible for the present abnormality. For this reason, neuropathology problems encountered in pregnant women, the fetus and in early childhood, including malformations, are also discussed. The primary forensic interest in this chapter, probably best viewed as a syndrome with varied etiologies, is some preliminary evidence raising the question of whether children with external hydrocephalus may have a greater than average tendency to develop subdural hematomas. A brief introduction to developmental topics is included in several general neuropathology and pediatric autopsy texts, although it should be noted that some sources clearly specify that they extrapolate to humans to some extent from animal experimental material. In the chapter, a few sources representative of the more extensive literature in each category are discussed.
As part of every standard forensic autopsy, the examination of the brain includes assessment with respect to possible edema. The quantification of edema is helpful to make a sound diagnosis in presence of multiple affections and multiple possible causes of death. The water content in certain brain regions is furthermore a promising marker to distinguish between causes of death with no visible evidence, such as suffocation, shaking impact syndrome and sudden infant death syndrome. However, in todays’ forensic medicine, no technique is available for the objective and exact quantification of edema. Therefore, the aim of this work is to develop a fast and easy-to-use measuring system for the accurate determination of the water content in human brain tissue that fits into the procedure of a routine autopsy. For our setups, the dependency between relative permittivity and water content is utilized. In former works, we presented measurements of human brain tissue using a coaxial measuring chamber and an open-ended coaxial probe. However, some drawbacks of the used methods emerged. Thus, a novel probe design using a coplanar transmission line has been developed, addressing the drawbacks of the formerly used methods. This new probe is easy to calibrate and allows fast and accurate sequential scanning for edema in human brain tissue.
We were much interested to see the excellent review article on sudden and unexpected death in infancy in the January issue of Pediatrics (39:123, 1967). We have been working for some years on the condition of congenital deafness with abnormalities of the electrocardiogram, and we feel that this and other genetically determined disorders of cardiac conduction must play a definite though possibly numerically minor role in the causation of sudden and unexpected death in infancy.
As has been already remarked in Chapter 9, Beckwith defined SIDS, now the most common cause of death in the immediate postneonatal period, as follows: ‘The sudden death of any infant or young child which is unexpected by history and in which a thorough post-mortem examination fails to reveal a cause’ [1]. This definition has gained wide, if not universal, acceptance since its introduction in 1969. It implies that the morphological features of the disease must be subtle and not readily identified by the usual techniques; taken literally, it might inhibit any discussion of the pathology of the syndrome. However, if we add ‘other than those manifestations usually observed in such disease’, we may proceed without offending logic [2]. Alternatively, we can use Adelson’s definition — which preceded that of Beckwith — ‘the death of a child who was thought to have been in good health or whose terminal illness appeared to be so mild that the possibility of a fatal outcome was not anticipated’ [3]; the implications of a negative necropsy are thereby avoided.
Editor—Tappin et al found an increased risk of the sudden infant death syndrome in infants who slept on used mattresses, which was further increased if the used mattress was from another home.1 They say that the increased risk might be associated with toxigenic species of bacteria, such as Staphylococcus aureus, which grow well in body fluids that contaminate mattresses. We identified pyrogenic toxins of S aureus in over half of the tissue samples from infants who died of the sudden infant death syndrome in five different countries.2,3 The increased risk for sudden death associated with used mattresses might be due in part to colonisation of infants by toxigenic strains against which the infants have no passive or active immunity. The higher risk associated with mattresses obtained from other homes might be related to introducing strains producing toxins different from those colonising the members of the infant's immediate family. Young infants obtain their normal flora mainly from their mothers, from whom they also obtain passive antibody protection against these micro-organisms and their toxins. We used an enzyme linked immunosorbent assay (ELISA)3 to assess toxin production among staphylococcal isolates obtained from 106 infants dying of the sudden infant death syndrome and 150 healthy infants. Among 116 pairs of S aureus isolates from healthy infants and their mothers, 59 had the same pattern of toxin production. The proportion of toxin producing isolates was not significantly different in the infants who died (55/106, 52%) and the healthy infants (96/150, 64%) (P=0.052). The proportions of specific toxins detected differed significantly between the two populations (χ2=21.62, df=3, P<0.0001) (table).2 The increased risk associated with used cot mattresses might be due in part to increased exposure to toxigenic strains against which the infant lacks antibodies, but these observations must be assessed in relation to other major risk factors such as sleeping prone. Staphylococcal toxins cannot be dismissed as postmortem contamination because they are produced only between 37°C and 40°C, which is above the normal nasopharyngeal temperature of children. Overheating or minor respiratory infection might increase the nasopharyngeal temperature to the range in which toxins are produced. Children lying prone have notable increases in nasal temperatures, and temperatures of 37°C or higher have been recorded in some after 30 minutes in the prone position.4 A large study of sudden infant death syndrome in Scandinavia concluded that the risk factors for the syndrome increase the dangerousness of infection in infancy.5 The findings of Tappin et al are another piece of evidence to support this hypothesis.
Animal test systems are reviewed that have relevance to sudden infant death syndrome (SIDS) are reviewed. These test interactions between infectious agents (or their toxins) and products of cigarette smoke. Infectious agents implicated in SIDS include members of the enterobacteria and clostridia, Staphylococcus aureus and Streptococcus pyogenes. Smoking is thought to be the single most preventable cause of SIDS. Tobacco smoke contains many extremely toxic products including cyanide and nicotine. Many animal test systems are available to examine the potency of bacterial toxins and smoke-derived components. These include mice, hamsters, rats and chick embryos. Such systems reveal synergy between bacterial toxins, especially endotoxin and superantigens. They have also demonstrated potentiation of low levels of bacterial toxin by low levels of both nicotine and its primary metabolite, cotinine. These findings suggest a possible causal explanation for the fact that passive exposure to cigarette smoke is a risk factor in sudden infant death syndrome.
Asphyxia is a name given to different kinds of lesions that can produce similar histologic findings. Thus, because of the varied nature of the different kinds of lesions, as well as the incidence of similar qualitative histologic findings with different causes, the aim of this work was to study special kinds of injuries with particular subsequent impairment. These include some diagnostic problems of sudden death of natural causes, including aspiration, suffocation, drowning, and strangulation. Ranking was made of 167 victims based on the diagnosis as having: aspiration (n = 35), suffocation (n = 88), drowning (n = 27), and strangulation (n = 17). Stepwise discriminant analysis of the resulting data showed that lung necropsies from victims of these four events could be distinguished from one another. Statistical differences among the four groups were observed for eight morphologic parameters. A robust discriminant function permitted an adequate classification of the four groups of disease in 85.03% of the cases. Lung autopsies with congestion, septal hemorrhage, and foreign body showed a specificity of 100% for victims of aspiration, whereas ductal overinsufflation, interstitial edema, and bronchiolar constriction showed a specificity of 81.8% in victims of suffocation. Intraalveolar edema and dilatation of the alveolar spaces with secondary compression of the septal capillaries characterized drowning. Victims of strangulation showed a strong alveolar hemorrhage, with alveolar collapse and overinsufflation, associated with bronchiolar dilatation. It is concluded that semiquantitative analysis of lung autopsies might be a useful supplementary histologic criterion to support the diagnosis of asphyxia.