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 Table of Contents  
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 41-45

Evidence for cerebral microvascular injury in head trauma involving infants and young children

1 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
2 Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
3 Department of Pathology, Wayne County Medical Examiner's Office, Detroit; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

Date of Submission11-Jan-2022
Date of Decision15-Apr-2022
Date of Acceptance27-Apr-2022
Date of Web Publication28-Jun-2022

Correspondence Address:
Rudolph J Castellani
710 N. Fairbanks Court, Olson Pavilion 2-462, Chicago, Illinois 60611
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jfsm.jfsm_41_22

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Background: The pathophysiology of lethal head trauma in infants and young children involves repetitive rotational forces of sufficient magnitude to produce subdural hemorrhage and brain swelling, which leads to considerable morbidity and mortality. The precise mechanism for brain swelling is unclear. Materials and Methods: We examined cerebral tissue from ten pediatric deaths due to blunt force trauma, along with seven control infants who asphyxiated in unsafe sleep environments. To assess the competence of the blood–brain barrier, we performed immunohistochemical stains for albumin and immunoglobulin G (IgG). Results: IgG and albumin were increased in subpial and superficial perivascular tissue in those cases due to blunt force trauma, and in particular, the blunt force trauma associated with subdural hematoma. This included two deaths at the scene without hospital survival time. Conclusions: Our findings suggest disruption of the blood–brain barrier with vasogenic edema as an early event in head trauma involving young children upstream of global ischemic brain injury. We hypothesize that mechanical injury to the cortical vasculature results in vasogenic edema by oncotic (increased plasma proteins in the cortical interstitium) and hydrostatic (increased capillary pressure) mechanisms, with subsequent cortical ischemia. This may explain why ischemic sequelae appear to occur in head trauma involving young children, regardless of whether anoxia, hypotension, or cardiac arrest complicate the disease course and may in part underlie the high morbidity and mortality of head trauma in early childhood.

Keywords: Edema, pediatric head trauma, subdural hematoma, traumatic brain injury

How to cite this article:
Castellani RJ, Scholl AR, Schmidt CJ. Evidence for cerebral microvascular injury in head trauma involving infants and young children. J Forensic Sci Med 2022;8:41-5

How to cite this URL:
Castellani RJ, Scholl AR, Schmidt CJ. Evidence for cerebral microvascular injury in head trauma involving infants and young children. J Forensic Sci Med [serial online] 2022 [cited 2022 Nov 26];8:41-5. Available from: https://www.jfsmonline.com/text.asp?2022/8/2/41/348654

  Introduction Top

Traumatic brain injury in infants and young children may be both severe and heterogeneous and for reasons that are not well understood, may be particularly severe with inflicted trauma. Median mortality is about 20%,[1] compared to about 2% for accidental head trauma.[2] In one prospective study of craniocerebral trauma in children under 24 months of age, inflicted trauma was thought to have occurred in 90% of cases with severe morbidity but represented just 38% of the total.[3] In a review of 837 inflicted head trauma cases, 5% were in a persistent vegetative state, 34% had a severe disability, and 25% had a moderate disability.[2] Neurological problems included hemiparesis, quadriparesis, cranial nerve palsies, intractable epilepsy, microcephaly, blindness, and cognitive and behavioral deficits. Only 11% had a normal outcome.

The severity of traumatic brain injury in this age group is underscored by neuroimaging. Hemispheric hypodensities on neuroimaging occur in up to 50% of inflicted head trauma cases presenting to a hospital.[4] Such hypodensities may involve multiple vascular territories and may be unilateral. Duhaime and Durham coined the term “big black brain” for this phenomenon,[5] the pathogenesis for which is not clear, and which may also be seen in accidental scenarios. It develops rapidly and confers a poor outcome. Importantly, the pathogenesis is not explained on the basis of global ischemia, which is nevertheless common in the aftermath of pediatric head trauma and often obscures the pathology at autopsy examination.

In this study, we explore the structural integrity of the microvasculature by examining tissue expression of immunoglobulin G (IgG) and albumin in young children who suffered blunt force trauma, along with a control group of infants who died of asphyxia in unsafe sleep environments. IgG and albumin have low permeability across the blood–brain barrier,[6] such that increased immunoreactivity in brain tissue is evidence of blood–brain barrier disruption.[7],[8] Given the prominent cerebral swelling that may occur in pediatric head trauma, we were interested in whether blood–brain barrier disruption was an early event or instead occurred with the onset of secondary complications such as global ischemia. Insight into this process may provide avenues for therapeutic intervention.

  Materials and Methods Top

Study design

This was a retrospective case–control study. This study was presented to the West Virginia University Institutional Review Board and exempted from full board review because the study does not involve human subjects (WVU IRB# 1810327242; approval date: October 24, 2018).


Ten decedents, seven females and three males, who suffered blunt force trauma were examined at autopsy at the Wayne County Medical Examiner's Office in Detroit, Michigan. The interpretation of blunt force trauma was made by a board-certified forensic pathologist, and the manner of death was certified as homicide in each case. The mean age of the decedents was 8.30 months (range, 2.5–24 months). Survival time ranged from 0 to 38 h.


Control cases consisted of seven infants (two females and five males) who expired due to asphyxiation in an unsafe sleep environment, also examined at Wayne County Medical Examiner's Office. All decedents were found dead and not resuscitated. The mean age of the control decedents was 2.5 months (range, 0.5–6 months).

Routine gross and microscopic examination

Brains from all decedents were examined at autopsy. Samples of the cerebral cortex from the convexity were taken for light microscopy as representative sections and to further document the gross observations in the blunt force trauma cases. Representative samples of the cerebral cortex were taken for the control cases. All tissues were fixed in 10% neutral-buffered formalin. Samples were then dehydrated in graded ethanol and xylene solutions and embedded in paraffin. Six-micron thick sections were prepared for hematoxylin and eosin staining and immunohistochemistry.


We chose to examine vascular integrity using immunohistochemistry for IgG and albumin, as both proteins remain within the vasculature with an intact blood–brain barrier. IgG and albumin immunohistochemistry has been previously validated in the literature in this context.[9],[10],[11],[12],[13] This was semiquantitated into no specific immunoreactivity (0), mild-to-moderate immunoreactivity (1+), and pronounced reactivity (2+). The score was based on overall intensity in subpial and perivascular regions in the cerebral cortex. One to three paraffin blocks of cerebral cortex from each case were used for immunohistochemistry. Samples were immunostained for IgG and albumin [Table 1]. Procedures and dilutions were validated with appropriate control tissue.
Table 1: Antibody specifications for albumin and IgG immunohistochemical methodology

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[TAG:2]Results [/TAG:2]

Hematoxylin and eosin

Blunt force trauma cases without subdural hematoma showed no specific pathological abnormalities [Table 1]. Among cases with subdural hematoma, pathology of the cerebral parenchymal tissue appeared normal in cases with no survival. Subtle vasogenic edema is difficult to exclude by H and E in such cases. The appearance of other cases with several hours or more of survival varied from that of vasogenic edema without clear evidence of eosinophilic neuronal degeneration (transient global ischemia with cytotoxic edema) to acute ischemic necrosis [Figure 1].
Figure 1: Hematoxylin- and eosin-stained sections of the cerebral cortex showed two general abnormalities in those cases with pathological alterations. Changes in transient global ischemia (a; scale bar = 100 μm) with eosinophilic neurons and diffuse cytotoxic edema were observed in a subset of cases. This change is a secondary event, requiring regional ischemia followed by resuscitation and some period of survival (4–6 h or more). Other cases showed distinct perivascular vacuolation (b; circles indicate cortical blood vessels; scale bar = 200 μm), or vasogenic edema, without features of transient global ischemia

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Immunoglobulin G

A clear pattern emerged from the IgG immunohistochemical preparations in that a subset of cases demonstrated distinct subpial and perivascular immunoreactivity involving penetrating vessels in sections of the cerebral cortex [Figure 2] and [Figure 3]. The diffuse perivascular staining in areas also stained cellular constituents [e.g., [Figure 3]a], which is likely background staining, as IgG in this pathophysiological context is extracellular. Of the ten blunt force trauma cases, four demonstrated 2+ immunoreactivity, three demonstrated 1+ immunoreactivity, and two demonstrated no immunoreactivity. Of the four cases with 2+ immunoreactivity, all had subdural hematomas. Of the three cases with 1+ immunoreactivity, two had subdural hematomas. One 24-month-old child with subdural hematoma showed no specific immunoreactivity for IgG. Two cases with no immunoreactivity had no subdural hematoma or other evidence of traumatic brain injury. None of the seven control cases showed subpial immunoreactivity for IgG.
Figure 2: Immunohistochemical stains for IgG (a, c and e) and albumin (b, d and f) are depicted in three representative cases. (a and b) are cerebral cortex from 2 months, 18-day-old female infant who was found unresponsive from blunt for trauma to the head and not resuscitated. (c and d) are cerebral cortex from a 1 year 3-week-old female toddler, who was also found unresponsive following blunt force trauma to the head and not resuscitated. Both children had accompanying acute subdural hemorrhage. Note at these low magnifications the pronounced subpial immunoreactivity for both IgG and albumin. (e and f) are cerebral cortexes of a 5-month-old infant found dead in an unsafe sleep environment. IgG is negative and albumin shows background staining with no specific pattern. IgG: Immunoglobulin G

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Figure 3: In addition to the cortical subpial IgG, perivascular IgG (a: arrow; scale bar = 500 μm) was noted, which may be related to the subtle perivascular or vasogenic edema (arrow) noted on routine H- and E-stained sections in some cases (b). IgG: Immunoglobulin G

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The albumin immunohistochemical preparations tended to show high background staining. Nevertheless, a distinct subpial enhancement of immunoreactivity similar to IgG [Figure 2] was apparent in six out of ten blunt force trauma cases, all with subdural hematomas. It was prominent in two cases (2+). Some equivocal (0–1+) subpial albumin immunoreactivity was present in two of the three blunt force trauma cases without subdural hematoma. The 24-month-old child with a subdural hematoma and 36-h survival time showed no specific albumin immunoreactivity, similar to its IgG pattern. The seven asphyxiation cases showed no discernible subpial pattern in four cases and equivocal (0–1+) immunoreactivity in three cases.
Table 2: Raw data

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  Discussion Top

The most remarkable finding in this study was the prominence of subpial and perivascular IgG and albumin in cases of lethal blunt force trauma to the head. This finding implies not simply brain swelling as might occur with passive congestion or disturbed cerebrovascular autoregulation, but a disruption in the blood–brain barrier with leakage of plasma proteins and interstitial edema within the superficial cerebrum. The co-occurrence with subdural hematoma further implies mechanical trauma per se as a potential driving factor for the appearance of the subpial and perivascular edema. This raises the possibility of a trauma-induced vicious cycle, in which pathophysiology is set up to drive water across the cerebral vasculature by both oncotic and hydrostatic mechanisms according to the Starling equation, with resulting volume expansion and intracranial hypertension.

The time course of the volume expansion in pediatric traumatic brain injury is not entirely clear and may differ from case to case, but it appears to be rapid in the severely injured young child. A prospective study of pediatric trauma requiring decompressive craniectomy noted a mean time between arrival in the emergency department and surgical intervention of just 93 min for inflicted head trauma patients, with a mean intracranial pressure of 35 mmHg.[14] In an anesthetized sheep model of traumatic brain injury, Byard et al. noted a dynamic response with an abrupt rise in intracranial pressure by 10 min after injury, followed by a decrease to 25 mmHg by 30 min, and then a gradual increase to 30 mmHg by 4 h.[15] In a rat model of traumatic brain injury, Barzò et al. noted increased water and apparent diffusion coefficient by diffusion-weighted imaging during the first 60 min postinjury.[16] In the current study, it is noteworthy that two of the decedents were unresponsive at presentation and were not successfully resuscitated, yet both demonstrated cerebral swelling and prominent subpial IgG and albumin. The absence of resuscitation precludes ischemia reperfusion as a mechanism for this process and again suggests a primary traumatic etiology. Similarly, the perivascular vacuolation on H and E preparations may be observed with pediatric traumatic brain injury and no survival, i.e., decedents found unresponsive and not resuscitated, and may be more primarily related to the trauma sequence.

Ischemic brain injury is common in the pediatric head trauma,[17],[18],[19],[20] most often conceptualized as resulting from intracranial hypertension and consequent decreased cerebral perfusion pressure or from cardiac arrest or sustained hypotension followed by a period of survival (ischemia-reperfusion). Moreover, ischemic stroke per se is increasingly recognized as a complication of pediatric head trauma and abusive head trauma in particular (reviewed in Galardi et al.[21]). Carotid and vertebral artery dissections, seldom described in infants and young children but which may affect older children may also cause catastrophic ischemic injury.[22] Over time, the ischemic injury could add to mass effect through cytotoxic and secondary vasogenic edema, although in pure global ischemic injury, many patients do not develop intracranial hypertension,[23] and it may take several days to develop in those who do.[24] It is therefore unlikely that ischemia plays a significant role in the rapid cerebral edema and increased intracranial pressure seen at presentation in abusive head trauma. Anoxia per se due to apnea has been hypothesized as a mechanism for brain tissue damage from abusive head trauma[18],[19],[20],[25] although anoxia in the absence of ischemia or cardiac arrest does not cause cell death or otherwise contribute to increased intracranial pressure.[26] In short, while global cerebral ischemia often complicates pediatric head trauma, the edema from ischemia reperfusion would be downstream of the acute presentation. The changes noted in this study are more in line with acute volume expansion from craniocerebral trauma. We did note the absence of IgG immunoreactivity in one 24-month-old child with subdural hematoma, although this may have reflected the severity of intracranial hypertension and prolonged nonperfusion (brain death) before withdrawing artificial life support.

In light of the above, it is not surprising that sequelae from pediatric head trauma in severe cases include widespread ischemic atrophy.[27] However, it may not be fully appreciated that hemispheric hypodensities, which represent de facto acute ischemic brain damage, may occur in the absence of cardiac arrest and with patency of arterial supply, as noted above.[4] This tends to suggest nonthrombotic regional ischemia, such as vasospasm[28] or compromise of cortical veins.[29] Such mechanisms may explain why hemispheric hypodensities are more pronounced in cerebral tissue subjacent to subdural hematoma;[5] i.e., a primary ischemic injury induced by mechanical trauma.

This study has clear limitations. The case numbers are small. The analyses are performed on postmortem tissue with variable postmortem intervals, which could affect the extent and specificity of immunolabeling. The average age is also slightly higher in the cases compared to the controls, and there may be differences in the structure and integrity of the blood–brain barrier in young infants compared to toddlers. In the trauma patients, there was variable survival and variable intracranial pathophysiology compared to the controls, who were all found dead with no apparent intracranial pathology but who may have suffered an agonal period before death. As such, this is a descriptive study which we believe may be useful for generating hypotheses or identifying avenues for further research. More studies are needed to determine the specificity of our findings for traumatic brain injury.

  Conclusions Top

Our results raise the possibility of early disruption of physical barriers to plasma proteins in the cerebral tissue of pediatric head trauma victims. Our findings, in conjunction with the literature, suggest trauma-related cortical microvascular injury as a primary driver of permanent brain damage in head trauma involving infants and young children.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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