While seemingly against mainstream consensus, it would seem improbable that such a regular spectrum of pathologies would be the result of a myriad or even a few possible causes. In the absence of these salient findings, in cases where the history and death scene were not congruent with SIDS, experienced pathologists would consider alternative diagnoses. Other more subtle pathologies, which are less consistent in terms of the proportion of SIDS babies affected, include the brainstem changes alluded to above.
In SIDS categories were developed based on clinical, death scene, and autopsy information [ 57 ]. For the purposes of this paper, while acknowledging this formalization of the redefinition, there is little to be gained by a focus on this.
This being so would, therefore, justifiably be explained by a single pathogenetic process. Unfortunately, there is no study of which I am aware that has reported the pathological findings in such cases. Moreover, there is a general lack of attempt to characterize pathology with the various proposed causes of SIDS.
Petechial haemorrhages in SIDS are small spot haemorrhages of unknown aetiology found on the surfaces and within the tissues of intrathoracic organs. Their presence is regarded by some pathologists as a pre-requisite for making the diagnosis of SIDS [ 58 ], while Hilton is quoted [ 59 ] that petechiae "are never present on the conjunctiva, eyelids or on or in other soft tissues of the head or neck in SIDS.
In non-SIDS, the numbers of petechiae are generally fewer and the distribution less frequently involves all three intrathoracic organs. Until the analysis by Goldwater [ 61 ] and Kleeman et al.
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 BiotindUTP 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 ].
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. 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.
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 ]. 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 autopsied SIDS cases and found macroscopic petechial hemorrhages in the visceral pleura, capsule of thymus, and epicardium in 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 and 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. 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.
Petechiae in all three sites thymus, pleura, heart were found in Of note is the high predictive value of finding petechiae in all three intrathoracic sites positive predictive value The findings, showing such a clear difference between the two groups of SUDI almost certainly indicate different underlying pathogenetic mechanisms. 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. 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 link 1 and 2? 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.
The importance of historical as well as pathological data in excluding SIDS was stressed. 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? 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. 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 ]. The excessive brain weight might reflect abnormal cerebral development and could be detrimental to vital neural control.
In a recent study, Kadhim et al. Whether increased brain weight is linked to cytokine up-regulation remains, however, moot and merits further exploration. 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.
It is surprising that this common pathological finding has not been explored extensively. As far as the author is aware, the study by Goldwater et al. The finding of significantly elevated fibrin degradation products D-dimer in blood from SIDS cases could reflect a perturbation of coagulation pathways brought on by NFkappaB-centered innate immune pathways and a shock-like demise. Infants meeting the currently accepted definition of SIDS are usually normally nourished and hydrated.
The diapers are usually wet and contain stool.
The bladder and rectum are typically empty [ 55 , 56 ]. Interpretation requires care. The finding of vocal cord laryngeal basement membrane thickening by Shatz et al.
The work of Rambaud et al. Interpretation of these findings remains controversial. However, no consensus is possible regarding the degree of inflammation and evidence of infection. 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. 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. SIDS deaths commonly occur during a sleep period. A brain stem abnormality related to neuroregulation of cardiorespiratory or other autonomic functions has been proposed [ 48 ].
The hypothesis is based on autopsy studies indicating possible pre-existing, chronic low-grade hypoxemia attributed to sleep-related hypoventilation. The autopsy evidence for chronic hypoxemia includes 1 : persistence of adrenal brown fat, hepatic erythropoiesis, brain stem gliosis and other structural abnormalities [ 52 ], and 2 : evidence of hypodevelopment of brainstem structures [ 50 ] and multiple neurotransmitter abnormalities in brain stem regions relevant to neural cardiorespiratory regulation [ 93 , 94 ].
These post- mortem studies of neurotransmitters and receptors have identified reduced muscarinic cholinergic binding via 3H-kainate receptors, in the arcuate nucleus, a region of the human brainstem analogous to the ventral medullary surface involved in chemosensitivity to CO 2 in laboratory animals [ 95 , 96 ].
SIDS victims also have been observed to have decreased binding of serotonin in the nucleus raphe obscurus, a brain structure linked to the arcuate nucleus, and in four other brain regions [ 94 ]. These brain regions have their origin in a part of the rhombic lip, which, during embryogenesis gives rise to structures in the brain stem considered important in regulating arousal responsiveness from sleep, as well as breathing, heart rate, and body temperature.
Deficient kainate binding in the arcuate nucleus and deficient serotonergic receptor binding in the brain stem may reflect genetic changes resulting in abnormal prenatal development of the brain stem. It is possible, that these apparent brain stem abnormalities are secondary to "upstream" deficit s for example, genetic mutation s or copy number variation, yet to be defined.
Alternatively, neurotransmitter abnormalities may represent interaction s between environmental risk factors and susceptibility genes associated with autonomic dysregulation.