Diffuse neuronal perikaryal amyloid precursor protein immunoreactivity in an ovine model of non-accidental head injury (the shaken baby syndrome)

doi:10.1016/j.jocn.2009.07.001

Journal of Clinical Neuroscience

Volume 17, Issue 2, February 2010, Pages 237-240

https://doi.org/10.1016/j.jocn.2009.07.001 Get rights and content

Abstract

Non-accidental head injury (“shaken baby syndrome”) is a major cause of death and disability in infants and young children, but it is uncertain whether shaking alone is sufficient to cause brain damage or an additional head impact is required. Accordingly, we used manual shaking in an ovine model in an attempt to answer this question since lambs have a relatively large gyrencephalic brain and weak neck muscles resembling a human infant. Neuronal perikaryal and axonal reactions were quantified 6 hours after shaking using amyloid precursor protein (APP) immunohistochemistry. Neuronal perikaryal APP was widely distributed in the brain and spinal cord, the first time such a diffuse neuronal stress response after shaking has been demonstrated, but axonal immunoreactivity was minimal and largely confined to the rostral cervical spinal cord at the site of maximal loading. No ischaemic-hypoxic damage was found in haematoxylin and eosin-stained sections.

Introduction

In Western industrialised countries, traumatic head injury is the leading cause of death and disability in infancy and childhood¹ and inflicted head injury comprises almost 25% of all head injuries in children less than 2 years of age admitted to hospital.²

Caffey first identified a causal link between shaking and infant subdural and retinal haemorrhages, and long-bone fractures.[3], [4] Subsequently, the neuropathological triad of subdural and retinal haemorrhages and acute encephalopathy was termed the “shaken baby syndrome” (SBS).⁵ It has also frequently been designated “non-accidental head injury” (NAHI)⁶ or, by those who contend that a head impact is a precondition for the development of this lesion complex, the “shaken-impact syndrome”.⁷ However, none of these lesions is pathognomonic of inflicted head trauma.⁸

Death occurs in 10% to 40% of patients with NAHI.⁹ The most severe presentation is that of the collapsed, apnoeic baby or one showing severe respiratory distress, but there may be more subtle and non-specific signs, including lethargy, irritability, seizures, vomiting and inappetence. Survivors frequently experience chronic neurological problems such as cognitive and behavioural disturbances, cerebral palsy, blindness and epilepsy.[10], [11]

One of the dominant controversies in the SBS is whether a head impact is necessary to produce pathology or whether shaking alone is sufficient to injure the brain. Its resolution is frequently impeded by difficulty eliciting the circumstances surrounding these injuries due to denial or obfuscation by the perpetrators.¹² A recent survey of the literature spanning three decades¹³ revealed that abuse was admitted in <20% of cases and that there was evidence of cranial impact in 80%. Other studies[14], [15], [16] have concluded that head impact is not essential. Furthermore, impact of the head with a soft surface may not produce contact injuries, but sufficient angular deceleration may be generated to damage neural tissue due to the sudden deceleration of the head.¹⁷ Biomechanical studies have shown that head impact generates a very much higher loading than shaking.¹⁸ However, while some⁷ argue that shaking is insufficient to injure the brain, others¹⁹ contend that shaking alone cannot be excluded as sufficient cause.

There is currently no satisfactory biomechanical model in which to investigate the pathogenesis of SBS or potential therapeutic intervention strategies.²⁰ Accordingly, since sheep have a relatively large gyrencephalic brain resembling that of humans, we used neonatal lambs to examine neuronal perikaryal and axonal changes in the brain resulting from shaking alone. Neuronal perikaryal reactions and axonal injury in these brains were detected using amyloid precursor protein (APP) immunohistochemistry.

Section snippets

Experimental protocol

Seven anaesthetised and ventilated, 7–10-day-old lambs were manually grasped under the axilla and vigorously shaken with enough force to snap the head back and forth onto the chest, similar to the actions believed to occur in the SBS.[4], [17] This shaking also resulted in considerable lateral and rotational head movement. Each lamb was shaken in this manner regularly (10 times of 30 seconds duration) over a 30-minute period, then placed quietly in the sphinx position for 6 hours under

Results

At necropsy, the only significant macroscopic finding was focal subdural haemorrhage, confined to a 1 × 1 cm area, in two shaken lambs (lambs 1 and 5). Microscopically, neuronal perikaryon APP immunoreactivity (Fig. 1) was widely distributed (Table 1), including cerebral cortical neurons, cerebellar Purkinje cells and brainstem neurons. The neuronal perikaryal APP reaction in the treated group (mean ± standard deviation, 43.3 ± 15.8) was higher than that of the control group (2.3 ± 0.6) (p < 0.01, ANOVA

Discussion

The results of this study showed that vigorous whiplash shaking of lambs produces widespread neuronal perikaryal APP expression. This generalized upregulation of neuronal APP probably represents a non-specific, acute stress response to trauma[21], [22] as it is unlikely that all these APP-immunoreactive neurons were irreversibly damaged. Rapidly developing and widely distributed neuronal perikaryal APP expression was also found in an ovine head impact model²³ due to upregulation of APP

References (37)

S.M. Gentleman et al.
Beta-amyloid precursor protein (beta APP) as a marker of axonal injury after head injury
Neurosci Lett
(1993)
C. Van den Heuvel et al.
Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model
Exp Neurol
(1999)
J.F. Geddes et al.
Inflicted head injury in infants
Forensic Sci Int
(2004)
J.W. Finnie et al.
Effect of impact on different regions of the head of lambs
J Comp Pathol
(2001)
J.D. Ward
Paediatric head injury
A.C. Duhaime et al.
Head injury in very young children: mechanisms, injury types, and ophthalmologic findings in 100 hospitalised patients younger than 2 years of age
Paediatrics
(1992)
J. Caffey
On the theory and practice of shaking infants. Its potential residual effects of permanent brain damage and mental retardation
Am J Dis Child
(1972)
J. Caffey
The whiplash shaken infant syndrome: manual shaking by the extremities with whiplash-induced intracranial and intraocular bleeding, linked with residual permanent brain damage and mental retardation
Paediatrics
(1974)
American Academy of Paediatrics Committee on Child Abuse and Neglect
Shaken baby syndrome: inflicted cerebral trauma
Paediatrics
(1993)
P.C. Blumbergs et al.
Trauma

A.C. Duhaime et al.

The shaken baby syndrome. A clinical, pathological and biomechanical study

J Neurosurg

(1987)

P.G. Richards et al.

Shaken baby syndrome

Arch Dis Child

(2006)

S. Jayawant et al.

Subdural haemorrhages in infants: population based study

B M J

(1998)

A. Ghahreman et al.

Nonaccidental head injuries in children: a Sydney experience

J Neurosurg

(2005)

American Academy of Paediatrics, Hymel KP; Committee on Child Abuse and Neglect; National Association of Medical...

H.F. Krous et al.

Shaken infant syndrome: selected controversies

Paediatr Dev Pathol

(1999)

J.E. Leestma

Case analysis of brain-injured admittedly shaken infants: 54 cases, 1969–2001

Am J Forensic Med Pathol

(2005)

M.G.F. Gilliland et al.

Shaken babies – some have no impact injuries

J Forensic Sci

(1996)

Cited by (25)

Analysis of the pattern of microstructural changes in the brain after mTBI with diffusion tensor imaging and subject-specific FE models
2024, Brain Multiphysics
Traumatic brain injury (TBI) is a major public health challenge. Up to 90 % of TBIs are on the mild spectrum of TBI (mTBI), where diagnosis is a major challenge. Majority of studies in this field have been conducted on human subjects, which inherently suffer from the lack of appropriate control group, selection bias, and individual differences in patients. To overcome these limitations, animal studies have been used as an alternative approach to provide deeper insights into the underlying mechanism related to the injury. Therefore our aim is to investigate various quantitative imaging biomarkers acquired from T1-W and diffusion tensor imaging (DTI) sequences to provide more information about the microstructural changes in the brain after mTBI. We then use this to generate subject-specific finite element models of the brain and examine how the changes in the brain material properties reflected in MR images affects strain distribution patterns on a subsequent head hit. Our study revealed a decrease in FA and an increase in diffusivity indices (MD, AD, RD) in the white matter tracts of the brain. This finding may represent the axonal damage, demyelination and gliosis after mild TBI, which have been shown in other animal and human studies. Moreover, our FE analysis showed that microstructural changes in the brain after mTBI might have weakened the structural integrity of the brain as the subsequent head hit led to wider and more severe brain deformations.
Animal models have been used to investigate biomechanical and pathophysiological aspects of mild traumatic brain injuries in the past. Still, most of them used small animals such as rats and mice. These models provided valuable insight into the pathophysiology of mTBI, but their findings have limitations due to their inherent differences to human brains. We have developed a large animal model of mTBI with sheep brains by combining advanced MRI and finite element analysis as they mimic the human brain better. To the best of our knowledge, this study is the first mTBI neuroimaging study conducted on large animal brains to investigate the diffusional changes in the white matter tracts after mTBI. Our FE analysis revealed that such microstructural changes resulted in tissue softening as the extent of brain deformation increased on a subsequent head hit, indicating increased brain vulnerability after head impacts.
Determining the Tractional Forces on Vitreoretinal Interface Using a Computer Simulation Model in Abusive Head Trauma
2021, American Journal of Ophthalmology
Abusive head trauma (AHT) is the leading cause of infant death and long-term morbidity from injury. The ocular consequences of AHT are controversial, and the pathophysiology of retinal research findings is still not clearly understood. It has been postulated that vitreoretinal traction plays a major role in the retinal findings. A computer simulation model was developed to evaluate the vitreoretinal traction and determine whether the distribution of forces in different layers and locations of the retina can explain the patterns of retinal hemorrhage (RH) seen in AHT.
Computer simulation model study.
A computer simulation model of the pediatric eye was developed to evaluate preretinal, intraretinal, and subretinal stresses during repetitive shaking. This model was also used to examine the forces applied to various segments along blood vessels.
Calculated stress values from the computer simulation ranged from 3-16 kPa at the vitreoretinal interface through a cycle of shaking. Maximal stress was observed at the periphery of the retina, corresponding to areas of multiple vessel bifurcations, followed by the posterior pole of the retina. Stress values were similar throughout all 3 layers of the retina (preretinal, intraretinal, and subretinal layers).
Ocular manifestations from AHT revealed unique retinal characteristics. The model predicted stress patterns consistent with the diffuse retinal hemorrhages (RH) typically found in the posterior pole and around the peripheral retina in AHT. This computer model demonstrated that similar stress forces were produced in different layers of the retina, consistent with the finding that retinal hemorrhages are often found in multiple layers of the retina. These data can help explain the RH patterns commonly found in AHT.
A review on four different paths to respiratory arrest from brain injury in children; implications for child abuse
2020, Journal of Forensic and Legal Medicine
Child abuse was suspected in a case of out-of-hospital arrest with minor brain injuries. Confronted with continued disputes on pathophysiologic correlates even after autopsy, to assist the differentiation of potential causes of sudden cardiopulmonary arrest in children, we tried to identify the mechanism of cardiopulmonary arrest in brain injuries from different causes.
Systematic review was carried out in two stages. First, major external causes of cardiopulmonary arrest among children and infants were identified from Pubmed and Google Scholar search, and then the exact sequence of cardiopulmonary arrest, and their pathophysiologic features were identified based on articles of animal models of brain injury.
From the review, we have identified four major groups of external circumstances for rather sudden cardiopulmonary arrest from brain damage in children, after excluding congenital and other unrelated diseases; 1) impact brain apnea, 2) anoxic insults, 3) drug or other substance induced central nervous system depression, and 4) traumatic brain damage. Each group has different features in the course of cardiac and respiratory arrests. Based on this review of pathophysiologic features of cardio-respiratory responses from external causes, we have presented a suspected, but unlikely, child abuse case of respiratory arrest from brain injury.
The social consequences of both unknowingly missing, and falsely incriminating the abuse can be grave, and the identification of the mechanisms of cardiopulmonary arrest from brain injury can be important for the differentiation of various potential causes.
Response to Edwards GA. Mimics of child abuse: Can choking explain abusive head trauma?
2016, Journal of Forensic and Legal Medicine
A response to Mimics of child abuse: Can choking explain abusive head trauma? [35 (2015) 33-37]
2016, Journal of Forensic and Legal Medicine
In the recently published article in this journal, “Mimics of Child Abuse: Can Choking Explain Abusive Head Trauma?”,¹ the author chose to revisit a discussion prompted by a case report from 5 years ago which was inappropriate in his opinion. He went further to suggest that bringing an unvalidated mechanism of injury into the legal setting “obstructs justice”, is a “further victimization of the child”, and is a “travesty of justice”.¹ Given the “Shaken Baby Syndrome: Rotational Cranial Injuries” has always been only an unvalidated hypothesis lacking experimental confirmation, the exploring of alternative injury mechanisms should be entirely appropriate. In 2010, the post publication discussion ended with a challenge to the American Academy of Pediatrics Committee on Child Abuse and Neglect (AAP COCAN) to either support the pure shaking mechanism with quality EBMS or eliminate any positive support for it from any official policy statement until the exact nature of each injury that pure abusive shaking has the potential to cause is clearly defined and supported with quality experimental research.⁴ Since this is an area of acknowledged controversy by the AAP, it is appropriate to examine the evidence based experimental literature that has emerged over the last five years that is relevant to the abusive shaking hypothesis and the hypothesis of any primary brain-lethal hypoxic event leading to the findings of retinal hemorrhages, extra-axial bleeding, and brain injury when an infant presents to medical attention after an Acute/Apparent Life Threatening Event. In that light, this review was undertaken.
Head kinematics during shaking associated with abusive head trauma
2015, Journal of Biomechanics
Abusive head trauma (AHT) is a potentially fatal result of child abuse but the mechanisms of injury are controversial. To address the hypothesis that shaking alone is sufficient to elicit the injuries observed, effective computational and experimental models are necessary. This paper investigates the use of a coupled rigid-body computational modelling framework to reproduce in vivo shaking kinematics in AHT. A sagittal plane OpenSim computational model of a lamb was developed and used to interpret biomechanical data from in vivo shaking experiments. The acceleration of the head during shaking was used to provide in vivo validation of the associated computational model. Results of this study demonstrated that peak accelerations occurred when the head impacted the torso and produced acceleration magnitudes exceeding 200 m s⁻². The computational model demonstrated good agreement with the experimental measurements and was shown to be able to reproduce the high accelerations that occur during impact. The biomechanical results obtained with the computational model demonstrate the utility of using a coupled rigid-body modelling framework to describe infant head kinematics in AHT.

View all citing articles on Scopus

View full text

Laboratory StudyDiffuse neuronal perikaryal amyloid precursor protein immunoreactivity in an ovine model of non-accidental head injury (the shaken baby syndrome)

Abstract

Introduction

Section snippets

Experimental protocol

Results

Discussion

Neurosci Lett

Exp Neurol

Forensic Sci Int

J Comp Pathol

Paediatric head injury

Head injury in very young children: mechanisms, injury types, and ophthalmologic findings in 100 hospitalised patients younger than 2 years of age

Paediatrics

On the theory and practice of shaking infants. Its potential residual effects of permanent brain damage and mental retardation

Am J Dis Child

The whiplash shaken infant syndrome: manual shaking by the extremities with whiplash-induced intracranial and intraocular bleeding, linked with residual permanent brain damage and mental retardation

Paediatrics

Shaken baby syndrome: inflicted cerebral trauma

Paediatrics

Trauma

The shaken baby syndrome. A clinical, pathological and biomechanical study

J Neurosurg

Shaken baby syndrome

Arch Dis Child

Subdural haemorrhages in infants: population based study

B M J

Nonaccidental head injuries in children: a Sydney experience

J Neurosurg

Shaken infant syndrome: selected controversies

Paediatr Dev Pathol

Case analysis of brain-injured admittedly shaken infants: 54 cases, 1969–2001

Am J Forensic Med Pathol

Shaken babies – some have no impact injuries

J Forensic Sci

Laboratory Study
Diffuse neuronal perikaryal amyloid precursor protein immunoreactivity in an ovine model of non-accidental head injury (the shaken baby syndrome)