Petechial haemorrhages, brainstem changes and SIDS
A number of authors have attempted to link brainstem changes with intrathoracic petechial haemorrhages. For example, Waters' group [
63] investigated association of certain aspects of brainstem pathology (for example, apoptosis detection using Terminal Transferase and Biotin-16-dUTP (TUNEL staining) with modifiable risk factors of SIDS (a history of cigarette smoke exposure and the sleep-related parameters of bed sharing and prone sleeping) and included petechiae, and blood in and around the nose [
63]. Waters' group showed positive associations with abnormal brainstem pathology and modifiable SIDS risk factors were only observed for TUNEL staining. These included the presence of petechiae, and blood in or around the nasal area. Not surprisingly the authors found intrathoracic petechiae significantly more frequent in SIDS than controls and noted that 'the presence of petechiae is a common pathological finding amongst SIDS infants but is not conclusive to all SIDS cases, and is observed in infants dying from other causes' [
64].
While the cause of petechiae in SIDS is still unknown, there is some evidence that their distribution and frequency is affected by the age, ethnicity, parity, exposure to cigarette smoke and the sleep position of the infant [
64,
65] the latter leading to the suggestion that the petechiae arise from an obstruction of the airways [
65]. Krous
et al. [
65] claim that 'since upper airway deaths and SIDS cases share a similar distribution of petechiae, it seems reasonable to postulate that airway obstruction might occur in SIDS.' Inconsistencies can be seen in this approach; on the one hand, the number, density and distribution of intrathoracic petechiae between the two conditions have been shown to be reasonably distinctive [
64], whereas on the other hand, respiratory obstruction is frequently accompanied by extrathoracic petechiae. Intrathoracic petechial hemorrhages were encountered by Beckwith in 87% of SIDS cases but in non-SIDS cases 'were mostly absent or less developed in quantitative terms' [
66]. Others have similarly commented [
67,
68].
A comparison of the distribution of petechiae in SIDS and various other causes of death showed, with few exceptions, limitation to within the chest cavity in SIDS but extension to below the diaphragm in infants in whom the terminal course was complicated by hypoxaemia, hypercarbia, metabolic acidosis, coagulopathy, or infection [
68]. Interestingly, and perhaps because the comparison (SUDI) deaths in the study by Goldwater [
61] were selected for having died suddenly, petechiae were rarely encountered in the conjunctiva, peritoneum or on the surface of abdominal organs. In SUDI occurring as a result of asphyxia/strangulation, skin petechiae on the head, neck and upper torso were observed relatively commonly [
68]. Krous
et al. claim their data support the association with an obstructed airway because of the positive association between the presence of petechiae and increased TUNEL staining in the rostral dorsal motor nucleus of vagus (
DMNV), of SIDS infants. This proposition could be seen as illogical and its justification on physiological grounds cannot be sustained. Care in interpretation of positive TUNEL staining is required as it should not be considered as a specific marker of apoptosis but can also indicate necrotic cell death [
69]. Krous
et al. found no association was found between presence or density of intrathoracic petechiae and prone (face down) position or age [
65]. Despite evidence to the contrary, the authors continued to pursue a 'respiratory' pathogenetic explanation.
While no widely accepted animal model for SIDS has been described, intrathoracic petechiae have been observed at necropsy in rats killed by tracheal occlusion [
70] and demonstrated that intrathoracic petechial hemorrhage could be associated with asphyxiation, (pertaining to a rat model). Others have shown similar or even contradictory findings; for example, in newly mature rats that were free of infection, hypoxic asphyxia produced an insignificant number of petechiae, whereas in all littermates infected with an enzootic virus (Sendai) large numbers of petechiae developed with hypoxic asphyxia. Rats similarly infected, but killed with an overdose of pentobarbital sodium, had no petechiae. Most importantly, infected rats with unremitting airway obstruction were free of petechiae. Thus, the experimental conditions necessary for the presence of intrathoracic petechiae were profound hypoxia and infection, with persistent circulation and respiratory effort; persistent airway obstruction
per se appears not to produce petechiae, with or without infection [
71].
Becroft reported the findings on 474 autopsied SIDS cases and found macroscopic petechial hemorrhages in the visceral pleura, capsule of thymus, and epicardium in 458 (96.6%) [
64]. Multivariable analysis of this study showed significant associations among increased frequencies of thymic petechiae and parity, age at death, Maori ethnicity, pacifier (dummy) use, and head covering at death. Also significant were associations between increased frequencies of epicardial petechiae and head covering at death and estimated time of death between 00:00 and 05:59 h; and between increased frequencies of pleural petechiae and maternal smoking and parity. There was a decreased frequency of pleural petechiae in infants placed prone for their final sleep with age acting as a possible confounder for the prone sleep position correlation. The distribution and frequency of petechiae seemed to be affected by SIDS environmental (known) risk factors, but these factors occurred inconsistently for the three organ sites. Regrettably, the findings of Guntheroth
et al. [
71] were ignored as there was a failure to examine associations with viral infection without which knowledge their claim that their findings implied differences in the pathogenesis at each intrathoracic organ site cannot be taken seriously.
The findings of Goldwater [
61] showed the concurrence of petechiae in all three intrathoracic sites was highly predictive of a SIDS diagnosis and indicated that a common causal mechanism almost certainly underlies the specific site petechiae. The occurrence of triple-site petechiae in non-SIDS deaths was shown to be relatively rare. Extrathoracic petechiae occurred almost exclusively in non-SIDS cases. Significant differences were observed between the SIDS and non-SIDS groups: the presence of thymic petechiae in SIDS (89.5%) compared with non-SIDS (47.7%) was highly significant (
P < 0.000001; OR 9.38 (CL 4.5 to 19.9), and their absence was more frequent in non-SIDS (52.3%) compared with SIDS cases (10.4%) (
P < 0.000001). Pleural petechiae were found in 80% SIDS and 47.5% non-SIDS (
P = 0.000002; OR 4.6 (CL 2.3 to 9.1)). Epicardial/cardiac petechiae were found in 79.9% SIDS and 43.6% non-SIDS (
P < 0.000001; OR 5.3 (CL 2.6 to 10.8)). Petechiae in all three sites (thymus, pleura, heart) were found in 62.7% of SIDS and 26.8% of non-SIDS cases (
P < 0.000001; OR 4.6 (CL 2.3 to 9.0)). Of note is the high predictive value of finding petechiae in all three intrathoracic sites (positive predictive value 84.9%) and the predictive value of their absence from all three sites (93.1%) in supporting a diagnosis of SIDS or ruling it out, respectively. The findings, showing such a clear difference between the two groups of SUDI almost certainly indicate different underlying pathogenetic mechanisms.
In a study of 473 SIDS cases by Krous
et al. [
72], face position when found was specifically described for 332 (70%). Of 122 cases found face down, 112 (92%) had intrathoracic petechiae, compared to 85% (179) of 210 infants found with the face up or to the side (
P = 0.06). These data clearly show that hypothetical upper airway obstruction attributable to face-down position is not causally related to development of intrathoracic petechiae. Despite these findings and those of Poets
et al. [
35,
36] Kraus
et al. continue to support an "internal" upper respiratory causation of intrathoracic petechiae.
In conclusion, while anatomical brainstem abnormalities may exist in SIDS brains, the link between these and respiratory function remains tenuous and unproven and the criteria (1. Does the hypothesis take into account the key pathological findings in SIDS? 2. Is the hypothesis congruent with the key epidemiological risk factors? 3. Does the hypothesis link 1 and 2?) remain unsatisfied. Cessation of respiration as a cause of death is often associated with extra-thoracic petechiae which are rarely seen in SIDS. Such a fact tends to undermine the respiratory hypothesis. While many authors claim intrathoracic petechiae are caused by increased intrathoracic pressure associated with respiratory failure, logically we would expect to see accompanying extrathoracic petechiae also. This we do not observe. An alternative mechanism must, therefore, be sought. The answer may lie in the relationship between brainstem anomalies, and a cardiogenic death associated with gasping. These combinations are examined below.
Ambler
et al. [
13] describe the neuropathological findings in 58 infants and children dying suddenly and unexpectedly. Utilizing historical, clinical, laboratory and pathological findings, two subgroups were distinguished: in one, a cause of death was established (CODE); members of the other (more than 50% of the total sample) were SIDS. The importance of historical as well as pathological data in excluding SIDS was stressed. In each subgroup, both focal lesions and diffuse glial reactive hypertrophy were identified in 64% of all children below nine months of age. These changes were not related to age group or maturation and, except for a history of perinatal asphyxia, lesions were not predictably correlated with clinical data. The authors concluded that the brains of children dying of established cause (CODE) are not a suitable control group with which to compare those of SIDS. This begs the question: what is a suitable control group?
Thymomegaly, encephalomegaly, microcardia, light kidneys
Considerable debate simmered for many years of theories such as
status thymico-Lymphaticus [
36]. The essence of the theory was lost after revelation of the unconscionable practice of irradiation of children's thymuses. Underlying disease processes that are associated with the organ weight differences between the SIDS and non-SIDS cases include infection, inborn metabolic disorders, genetic mutations, and immune disorders [
73]. Some investigators speculate that decreased organ growth may contribute to mortality, while others suggest that the differences in organ weight are caused by inadequate reference weight data. An approach that considers organ weights relative to body weight could obviate the need for revised reference data. Allometric regression analysis allows comparisons without the need for reference data, and has been employed in analysis of a wide array of biological data, specifically the relative growth of brain and body weights among the Order Primates [
74], and organ/body weight ratios among SIDS cases [
75,
76].
When organ weights are measured as a function of body weight (not age) some studies show significant differences between cases of SIDS [
77,
78] and non-SIDS while others contradict these [
79]. Reasons for the discrepancies between the studies relate to features of the control groups (presence of infection, gestational age, changes in infant nutritional status with socioeconomic development, and so on). Certainly these may have negated some organ weight differences between SIDS and normal babies but head and brain size (and possibly thymus) are supported by recent data. It is well known that the thymus is relatively large in normal babies. Confusion continues with regard to whether or not this organ is bigger in SIDS than comparison deaths. Where sudden death (for example, through accidental injury is the basis for selection of the comparison group), thymus weights are significantly greater in SIDS babies [
80]. Growth curves derived mathematically from such data indicate a prenatal origin of the larger thymus in SIDS [
80]. Similarly, brain weight (and head circumference) are greater in SIDS cases than comparisons [
81]. This feature is recognised by the National Institute of Child Health & Human Development (NICHD) [
8].
The excessive brain weight might reflect abnormal cerebral development and could be detrimental to vital neural control. In a recent study, Kadhim
et al. [
82] revealed cytokine over-expression in the brains of SIDS victims. Whether increased brain weight is linked to cytokine up-regulation remains, however, moot and merits further exploration.
As alluded to in a previous section, cardiac and renal weights [
53,
54] may also be decreased in SIDS; this possibly reflects the effects of similar prenatal/developmental influences responsible for brain anomalies. Serial examination of the cerebral hemispheres of 20 sudden infant death syndrome victims revealed a high incidence of leukomalacia (40%), leptomeningeal glioneuronal heterotopias (70%) at the base of the cerebrum, and astrogliosis (65%) in the white matter and medulla reticular formation compared with 20 age-matched controls. These results suggest that an antepartum insult may become an important predisposing risk factor in some individuals for sudden infant death syndrome [
83]. Kariks [
84,
85] noted histopathological changes in large proportions of SIDS babies' myocardium. He attributed the changes to shock which would be compatible with general pathological and epidemiological features of SIDS.
Inflammatory cells in airway, lung, and cardiac tissues
The work of Rambaud
et al. [
89] has revealed subtle evidence of acute inflammatory cells within airway, lung and cardiac tissue. Interpretation of these findings remains controversial. However, no consensus is possible regarding the degree of inflammation and evidence of infection.
Krous
et al. [
90] found numbers of lymphocytes, macrophages, and necrotic cardiomyocytes were not statistically different between a small cohort of SIDS and suffocation cases. Based on these findings the authors concluded that very mild myocardial lymphocyte and macrophage infiltration and scattered necrotic cardiomyocytes in SIDS are not pathologic, but may occur after the developing heart is exposed to environmental pathogens, including viruses. This is clearly somewhat questionable given that evidence of viral infection of tissue
per se would be regarded as not normal and, therefore, pathological [
91]. Dettmeyer
et al. challenged Krous
et al. by drawing attention to consensus difficulties of criteria for meeting a diagnosis of myocarditis. Dettmeyer
et al. [
92] subsequently showed that viruses when found in the myocardium are associated with inflammatory change and, therefore, these changes are pathologic. The changes were only found in myocardium from SIDS cases and were not found in unexpected unnatural sudden deaths.
Supportive evidence (such as would be obtained with gene expression of innate immune system genes and in situ hybridization of a wide range of microbial nucleic acids) should provide answers.