ASSIGNING A CENTRAL NERVOUS SYSTEM CAUSE OF DEATH AT AUTOPSY

Assigning cause of death to a central nervous system disease is complicated by the difficulty in inferring function from structure. For example, central nervous system function may be profoundly disturbed to the point of lethality (e.g., tonic-clonic seizures) while no brain lesions are detected. Conversely, central nervous system structure may be substantially altered (e.g., large arachnoid cysts, bifrontal tumors) and yet the child may be clinically asymptomatic. Moreover, children with extensive disruption of the brain (e.g., perinatal ischemic brain injury, survivors of infant head trauma) may live to adulthood despite being at risk for sudden death each day.

Since the brainstem and cervical spinal cord can sustain life despite extensive damage to the cerebral and cerebellar hemispheres, assigning a definitive cause of death based on central nervous system pathology requires evidence of the central nervous system mechanism that links the cause to the death, such as the anatomic disruption of brainstem and/or cervical spinal cord (e.g., mass effect from an expanding hematoma or cerebral edema, acute trauma involving the brainstem or cervical spinal cord). Short of this evidence, a central nervous system cause of death may be inferred, often with reasonable certainty, once a systemic or external etiology has been excluded by thorough investigation and autopsy. For example, presumed seizure-related apnea due to epilepsy with a consistent investigation and negative autopsy. We must recognize the limitations of assigning a definitive cause of death even with extensive neuropathology since such children may be neglected, intentionally asphyxiated, or otherwise subjected to homicidal abuse. In fact, children with long-term disabilities are at increased risk for maltreatment (1).

With respect to sudden deaths in young children that remain unexplained after autopsy, brain examination most often excludes neuropathology sufficient to cause of death (2). Arriving at this conclusion risks misinterpretation on two fronts: 1) oversight of subtle but important lesions either because of incomplete diagnostic work-up or misinterpretation of pathology; 2) misinterpretation of incidental, nonspecific, or genuine pathological lesions as causative. In the first instance, risk of oversight of subtleties may be lessened by a working knowledge of neuroanatomy and neurodevelopment. In the second instance, misinterpretation may be lessened by knowledge of normal variability, artifacts, evidence-based medicine, and the literature. Both sources of error may be reduced by consultation with a neuropathologist. The forensic pathologist must balance diligence within the confines of available resources on the one hand, and mindfulness of the limitations of structure-function correlations on the other.

KNOWN CENTRAL NERVOUS SYSTEM CAUSES OF DEATH

Most central nervous system disorders causing sudden death in infants and children are grossly visible at autopsy. Trauma is the most frequent cause of death from brain failure (3–5). Evidence of blunt force head trauma with subdural hemorrhage and cerebral edema in a child who had acutely collapsed sufficiently implicates brain failure as the primary mechanism. The next most frequent central nervous system causes of death are infection, meningitis and encephalitis. In these instances, the pathology is generally sufficient to conclude a central nervous system mechanism (ischemia, seizure, tissue destruction, etc.) without significant systemic disease. Likewise, hemorrhagic stroke with abrupt mass effect is sufficient to invoke brain failure and a central nervous system cause of death. In children, hemorrhage stroke results from ruptured arteriovenous malformation (36% of cases), aneurysm rupture (13%), undetermined cause (25%) and other lesser common causes (brain tumors, Moya Moya syndrome, venous sinus occlusion, cavernous malformations, and hemorrhagic diatheses) (6–8).

Central nervous system malformations and tumors may cause rapid death but are most often diagnosed during life and a shortened lifespan is expected. However, individuals with such lesions may live for many years and die of other causes. The challenge for death investigation is to identify the acute change and exclude a sufficient intervening cause of death. Congenital malformations can cause death by seizure, acute hydrocephalus or brainstem dysfunction and tumors may hemorrhage or infarct. In the absence of acute pathology or witnessed seizure, the precise mechanism of death remains uncertain, therefore other systemic or external factors must be excluded to determine the definitive cause of death.

BRAINSTEM DYSFUNCTION: MECHANISM, PREDISPOSING VULNERABILITY, OR CAUSE OF DEATH?

While every death ultimately includes central nervous system mechanisms, there is abundant past and present research examining the possibility of brainstem dysfunction as an underlying etiology or predisposing factor in sudden infant deaths; similar robust research in sudden child deaths is lacking. Abnormalities in the brainstem serotonergic system implicated in failed arousal to homeostatic challenges, dysfunctional amygdala-insular connections and changes in cytoarchitecture of the dentate gyrus (9–14) and numerous anatomic and/or functional abnormalities in the arcuate nucleus, nucleus of the tractus solitarius and brainstem neurotransmitter systems (5-HT [10, 11, 14–17], noradrenalin [18], GABA [19] and others) have been described in cases of sudden unexplained death in infancy. To date, no variants of genes in the serotonin pathway are confirmed to increase risk of sudden unexplained death in infancy (20). Many reviews of these findings and their possible interpretations have been published. Given the increasing awareness that unsafe sleep environments are present in many sudden infant deaths, not just as a potential risk factor but as a true cause of asphyxia, brainstem dysfunction may represent a predisposing vulnerability in some infants, rather than a specific cause of death.

Numerous risk factors for sudden unexplained death in infancy may relate to the physiology of CO₂ and brainstem mediated arousal: 1) peak incidence of sudden unexplained death in infancy at 2–4 months of age is after the developmental disappearance of fetal respiratory pacemaker activity which maintains breathing irrespective of CO₂ levels, 2) prone position may contribute to hypercarbia by limiting body wall excursion, 3) overheating may increase metabolic activity and CO₂ production, 4) having the nose and mouth in proximity to objects may increase CO₂ rebreathing, 5) minor inflammation of conducting airways or alveoli may restrict ventilation and promote atelectasis, 6) reduced oxygen transport due to increased carboxyhemoglobin in the setting of smoke exposure may compound the effects of hypercarbia (13). Finally, once the infant falls asleep and brainstem centers responsible for maintaining respiratory rhythm according to CO₂ changes become quiescent, these compounding factors may tip the balance toward death. This multitude of factors acting synergistically is in keeping with the “Triple Risk Model” for sudden unexplained death in infancy, which hypothesizes that death occurs when there is 1) an underlying vulnerability, 2) at a critical developmental period, and 3) an exogenous stressor (21). Whether similar physiologic alterations can be hypothesized to explain some sudden deaths in children over one year of age remains unstudied.

Given the frequent similarities between sudden unexplained death in infancy, sudden unexplained death in childhood, and sudden unexpected death in epilepsy, such as familial or personal history of febrile seizures, death during sleep often occurring in the prone position, and absence of etiologically specific anatomic findings, the question naturally arises whether these deaths share a similar central nervous system mechanism (22, 23). Although the mechanism of death in sudden unexpected death in epilepsy is unclear, post-seizure cortical suppression triggering apnea and immobility and decreased activity in arousal systems and/or autonomic dysfunction producing cardiac asystole or arrhythmias are hypothesized (24–26). Hippocampal abnormalities (malrotation, asymmetry and/or focal granule cell bilamination) described in sudden deaths of infants and toddlers, often with febrile seizures (27–30), are speculated to contribute to death via seizure or impaired modulation of cardiorespiratory centers in the brainstem (31, 32) but have not been proven to be causal. These studies have shown dispersion and bilamination of the dentate gyrus (changes found in lobectomy specimens from persons with intractable epilepsy) in up to 45% of cases of sudden unexplained death in childhood but also in 25% of explained deaths (31, 32). Such overlap between sudden unexplained deaths and controls indicates the diagnostic criteria are too nonspecific to be useful in an individual case. While interesting for further research, these abnormalities have yet to be replicated as a diagnostic entity, and a functional contribution to mechanism or cause of death is unproven (33, 34). While researchers continue to identify and refine predisposing genetic and environmental factors, biomarkers, anatomical/neurochemical abnormalities, the practical impact of the uncertainty of mechanism and cause of sudden death in epilepsy and pediatrics make each a diagnosis of exclusion.

Subtle changes that may border on normal variation (e.g., dispersion or bilamination of the granular layer of the dentate gyrus, gliosis of white matter or medulla) or are identifiable only by specialized research techniques (e.g., putative changes in dendritic arborizations, quantification of tissue volumes or neuronal populations, semi-quantitation of neurotransmitter or receptor expression) are best regarded as provisional or hypothesis-generating data for further research. The literature regarding brainstem abnormalities in sudden unexpected death in infancy is expanding, while studies in sudden unexplained death in childhood are still quite limited. A mechanistic link between brainstem function and sudden death is logical, but a consistent, specific, diagnostic pattern with known functional significance has yet to emerge. Studies plagued with the difficulties of defining and accumulating appropriate control cases, having insufficient and variable medicolegal investigations, and establishing objective, reproducible variables are compounded by our incomplete understanding of neuroanatomic pathways and development of cardiorespiratory control. While it is tempting to factor the findings of recent studies – the newly described anatomic, physiologic, and chemical variants or abnormalities seen in cases of sudden unexpected pediatric deaths – into cause determination in individual cases, more research is needed to define diagnostic criteria, assess reproducibility and interobserver error rate, and to study the functional consequences and/or lethality of the observed abnormalities/variants.

AUTOPSY EXAMINATION OF THE CENTRAL NERVOUS SYSTEM

Gross examination begins with evaluation of the scalp and skull, for trauma, developmental diseases, malformation, assessment of the fontanelles, and cranial bone development. Head circumference should be measured and compared to standard data tables for age of the infant or child. The pathologist should observe removal of the calvarium to immediately appreciate contents of the subdural space before artifact is introduced. The brain is removed with or without calvarial dura attached, depending on the preference of the pathologist, circumstances of the case, and skills of the prosector. Although it is possible to remove the brain with spinal cord attached, this specialized technique is rarely indicated. The brainstem-spinal cord junction should be transected as deep into the foramen magnum as possible, leaving the medulla and posterior vasculature (vertebral arteries and basilar artery) intact and attached to the specimen. The skull base should be examined for appropriate level tentorial insertion, relative sizes of the cranial fossae, and presence of cribriform plates. Prior to stripping from the bone, calvarial and basilar dura is examined for any gross pathology, including subdural fluid collections and patency of skull base dural sinuses (often torn during dura stripping). Grossly (and microscopically) visible hemosiderin staining of dura and thin, semitranslucent, well-organized subdural neomembrane without blood collection are not uncommon incidental findings in early infant dura (35, 36) and are not necessarily evidence of inflicted trauma. However, acute subdural hemorrhages and those with mixed states of organization are rare and should be interpreted in light of age, birth history, and death investigation, as a number of studies have demonstrated a statistically significant association between inflicted abuse and subdural hemorrhage (37–39).

The spinal cord is removed with intact dura by either anterior or posterior approach. Posterior approach, which requires laminectomy through all vertebrae, is preferred because costovertebral joints and neural foramina will remain intact for examination of the rib neck/head region and nerve roots/ganglia in cases of trauma. Furthermore, posterior paravertebral soft tissues can be examined for trauma at this point. Anterior approach is faster because it can be performed through the evisceration incision and the decedent does not need to be turned over. In the absence of trauma, anterior and posterior approaches are equally adequate. Pulling the cord out of the thecal sac through an opening in the lumbar spine prevents observation of subdural accumulations and nerve roots. Orbital plates of infants should be removed and optic nerves visualized to exclude intraorbital pathology and optic nerve sheath hemorrhage. If there is no intracranial hemorrhage or intraorbital pathology, the globes can be left in place and vitreous fluid removed for electrolyte testing. When findings suggest traumatic brain injury, removal and examination of the globes with attached optic nerves and orbital contents (rectus muscles and adipose) is recommended despite varied opinions as to the interpretation of retinal hemorrhages. Middle ear cavities should be evaluated for otitis media, which may be complicated by subdural abscess/empyema, meningitis, or sigmoid sinus thrombosis.

Cerebral vasculature is evaluated for lesions such as malformation, aneurysm, Moya Moya disease, and Vein of Galen aneurysm, which could produce functional derangements (e.g., infarct, thrombus) even in the absence of rupture. Dural sinuses of the convexity and base are incised to examine for thrombus. Leptomeninges are evaluated for any accumulation within the subarachnoid space (e.g., inflammation, hemorrhage, or neoplasm) and cerebral veins are examined for abnormal congestion that may suggest venous thrombosis. Cranial nerves are evaluated for presence/absence, atrophy, or mass. Confirmation of the olfactory bulbs excludes arrhinencephaly and most ventral induction disorders. Given that olfactory bulbs and tracts are commonly avulsed during brain removal, the gyrus recti and cribriform plates are surrogate markers of proper olfactory bulb development when the brain is examined later.

Fixation of the brain and spinal cord with dura (one to two weeks in 10% – 20% formalin solution) prior to sectioning, photography, and histologic sampling is recommended if organ retention is not precluded by statute and the autopsy has not revealed a definitive case of death. Intracranial dura may be examined with or without fixation. Although many pathologists are accustomed to and proficient at examining un-fixed brains, the soft nature of the immature brain and the quality of examination needed to detect even minor developmental anomalies justifies this extra step. The pathologist should minimize handling of young infant brains before fixation to avoid disrupting the anatomy (i.e., weigh infant brains after fixation). Brain weight should be recorded and compared to reference tables (40, 41). Although fixation does change brain weight, the amount of change is not sufficient to impact interpretation since reference tables that include standard deviations show substantial variation in weight for age. Examination of the formalin fixed specimens by a neuropathologist with experience in forensic cases is recommended but at the discretion of the autopsy pathologist if resources are limited or retention of organs is restricted. In one reported series of adult brains evaluated for sudden death, abnormalities were found in 66% of formalin-fixed brains submitted for formal neuropathologic examination, in contrast to only 8.8% of brains examined in the fresh state (42). Recognition and interpretation of central nervous system lesions and distinctions between pathology and normal anatomic variation is challenging.

Numerous developmental malformations and prenatal insults are apparent on external brain examination, including disorders of dorsal induction (e.g., neural tube defects, Chiari type 2 malformations), ventral induction (holoprosencephaly), hindbrain development (e.g., Dandy-Walker and Chiari malformations), migration, and ischemic lesions. These produce a spectrum of lesions that vary from obvious to subtle and may cause seizures or compromise vital functions via herniation or acute hydrocephalus. The size and distribution of sulci and gyri are evaluated for appropriate development, taking age into consideration. The extent of cerebral edema is noted by observation of gyral flattening, sulcal and basilar cistern effacement, and herniation of the uncus (transtentorial herniation) and/or cerebellar tonsils and vermis (transforaminal herniation).

By convention, brains are sectioned in the coronal plain at approximately 1 cm intervals and arranged with the right hemisphere on the right side (opposite neuroimaging) for observation and photographing. Coronal sections are examined for primary malformations of cortex, corpus callosum and deep nuclei, distribution and volume of white matter and extent of myelination, focal lesions, and size and configuration of the ventricular system.

The brainstem is sectioned in the axial plane at 2–3 mm intervals to assess for cerebral aqueduct stenosis or dilatation, distribution, size, shape, and symmetry of white matter tracts and brainstem nuclei, and any focal pathology or signs of ischemia. The cerebellum may be examined in sagittal or horizontal planes, at the discretion of the pathologist, but must include evaluation of the midline to exclude vermal hypoplasia (e.g., Dandy-Walker malformation). Any herniation of the vermis or cerebellar tonsils is noted.

Familiarity with normal neuroanatomy and developmental, spectrum of pediatric neuropathologies, and common artifacts of removal and plane of sectioning, will facilitate identification of potentially significant lesions and reasonably confident exclusion of central nervous system processes as cause of death after examination of the fixed brain. Pryce et al. found that 6% (53/885) of sudden unexpected infant deaths had a neuropathologic cause of death, with 90% of these causes being apparent by clinical history and/or gross examination (2). Those causes were head injury (10%), meningitis (4%), nontraumatic intracranial hemorrhage (two cases) and one each of encephalomyelitis, hydrocephalus, infantile neuroaxonal dystrophy, metabolic encephalopathy, and venous thrombosis.

While microscopic examination of the brain is considered best practice and beneficial to confirm and characterize infection, ischemia, and other lesions, diagnostic yield for cause of death is low, at least in studied infant and adult cases. In the Pryce study of the 663 autopsy-negative unexpected infant deaths, with no significant gross brain findings (cause of death or contributing to cause), 45 (7%) had significant histologic brain findings (2). Only 2% of grossly normal brains had significant histologic findings and in only two cases did histologic brain examination determine the cause of death in the absence of specific macroscopic abnormalities. Folkerth et al. examined 53 unselected, medicolegal, infant and toddler deaths for histologic findings that were critical (Class A), contributory (Class B), or noncontributory (Class C) to the final cause and manner of death; the authors found a frequency of 16.9% Class A, 20.8 % Class B, and 62.3% Class C (34). The high number of critical findings suggests a benefit to microscopic examination, although many Class A and B cases had significant gross findings and clinical presentations that preclude unexplained death prior to histologic sampling. There is no evidence base to indicate a particular schema best balances diagnostic yield with risks of misinterpretation.

A diligent microscopic examination of a pediatric brain for purposes of medicolegal investigation provides a basic survey of cortex, white matter, deep nuclei, brainstem, and cerebellum, with special attention given to macroscopic lesions and areas related to autonomic regulation and epileptogenesis. The most widely referenced postmortem protocols are those of the California Department of Public Health and the Royal College of Pathologists (43, 44). Bajanowski et al. also recommends a thorough sampling (45). Given the investigative and mechanistic similarities between sudden death in epilepsy and in sudden unexplained death in children, recommendations for sampling in epilepsy cases are also relevant (46–49). While some brain regions may be of lower diagnostic yield for cause of death (34), our continued inability to explain the mechanisms and causes of sudden death in the young warrants a balance between resource management and due diligence. Furthermore, low diagnostic yield and resource management are of little concern to a grieving family struggling to find answers. More uniform histologic sampling may benefit research when families subsequently choose to enroll their child’s case for study. Therefore, in pediatric deaths that remain unexplained after gross autopsy examination, microscopic examination of the following brain regions is recommended as minimum: cortex and white matter at frontal watershed (with leptomeninges), hippocampi (bilateral) at level of lateral geniculate nucleus, rostral medulla, cerebellum, grossly apparent lesions that cannot be diagnosed without histology (Table 8.1 and Image 8.1). Microscopic examination of additional regions (e.g., basal ganglia with insula, left posterior thalamus, midbrain, pons, cervical spinal cord) is encouraged as indicated. In anticipation that routine microscopic examination described above or additional case information prompts further examination, representative formalin-fixed sections of cortex from each lobe, both hippocampi, basal ganglia with adjacent insular cortex, thalamus, midbrain, pons, medulla, cerebellum, and cervical cord should be available until the case is complete or office policy for specimen disposal is satisfied, whichever is later. Appropriate tissue blocking is illustrated in Image 8.1. Care should be taken to sample tissues that have limited postmortem handling artifact and are correctly oriented in the cassette to minimize the risk of misinterpretation. Leptomeninges should be sampled in natural juxtaposition to cortex and not as a clump. Sections are stained with hematoxylin and eosin. Additional studies, such as Luxol fast blue stain or immunohistochemistry to assess myelin, special stains or immunohistochemistry to assess axons and neurons, immunohistochemistry for glial fibrillary acidic protein (GFAP) to assess gliosis, or immunohistochemistry for beta-amyloid precursor protein (β-APP) to highlight axonal damage may be needed in some cases. Key considerations in the examination of the central nervous system are highlighted in Table 8.2.

Table 8.1

Histologic Sections for Neuropathologic Examination.

Image 8.1

Sections of formalin-fixed brain with areas to be sampled for microscopic examination (boxes). Asterisk indicates recommended minimum sampling.

Table 8.2

Procedural Guidance and Key Considerations in Evaluation of the Central Nervous System Evaluation.

RESEARCH AND FUTURE DIRECTIONS

The potential role of central nervous system disorders as causes or contributing factors to the sudden unexplained death of infants and children remains a promising avenue for future research. There are two approaches to studying neuropathological contributions to death: focused and broad. Both deserve consideration and have benefits and costs. Focused studies examine hypotheses that posit abnormalities in structures and functional systems related to respiratory, cardiac, and arousal physiology, as well as seizures. Much of this literature is limited by small series and a bias by investigators and journals to publish positive findings more frequently than negative ones (50). Broad studies seek to systematically explore a diverse set of structures and functional systems simultaneously. These “fishing expeditions” suffer from the need to control for multiple comparisons that increase the risk of false positive findings but, benefit from being hypothesis-free, which can reduce bias. Examples include the Allan Brain Atlas, which provides systematic data on cell types, DNA, RNAseq, proteomics, and anatomy. A similar approach to sudden unexplained death in infancy and childhood would greatly enhance our ability to define population-based normative values and to examine multiple hypotheses and generate new ones.

Most neuropathological research on sudden unexplained pediatric deaths has been focused and minimally addressed in children beyond one year of age. Studies on sudden unexplained death in infancy have identified abnormalities in specific brainstem regions (e.g., arcuate nucleus, dorsal motor nucleus of the vagus, nucleus of the solitary tract) and neurotransmitter systems (e.g., catecholamines, neuropeptides, acetylcholine, serotonin), glutamate, brain derived neurotrophic growth factor, cytokines (e.g., Interleukin 6) as well as structural alterations in the hippocampus (11, 15, 32, 51–53). The most promising areas of research include structural abnormalities in brainstem nuclei that control respiration and autonomic functions, functional alterations in serotonergic neurotransmission (e.g., receptors, metabolite levels), and structure and function of the hippocampus.

Translating research findings into causation remains limited by the relatively small numbers of cases and controls that are available for research study. Further, the primary responsibility of the medical examiner is to determine cause and manner of death in his/her particular case, not to engage in research. Indeed, the lack of formal next of kin consent to autopsy and government jurisdiction that accompanies a medicolegal death investigation hinders use of these tissues for research unless families are engaged and proactive. Yet research will ultimately advance the medical examiner’s mission to determine cause and manner of death. Successful research in this field will depend on 1) collaboration between medical examiners and researchers to sensitively approach bereaved families for research consent, 2) development of systematic techniques to process and examine brains and interpret findings, across large populations, while meeting the needs of routine, diagnostic procedures in the individual case, and 3) educating physicians, research organizations (e.g., National Institutes of Health), public health agencies (e.g., Centers for Disease Control and Prevention) and politicians on the need for more research.

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