This minisymposium was originally published in 2017. The information provided in this minisymposium was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this minisymposium.
In this short review, we explore several of the more commonly encountered conditions in forensic neuropathology.
Traumatic Head Injuries
Likely, every individual at some point in his/her life has experienced head trauma. The CNS is protected from injury by bones (calvarium and vertebrae), fibrous meninges, and cerebrospinal fluid (CSF). However, the technologies that allow us to travel at high speeds, that involve high force impacts, and weapons that penetrate these barriers have resulted in tremendous morbidity and mortality throughout the world. Head injury can be roughly categorized as mild, moderate, or severe, with the former leading to minimal or no acute or chronic neurological dysfunction and the latter causing serious dysfunction or death.
Extrinsic forces to the head can cause either “open” or “closed” injury to the brain. Open injuries are those that penetrate skin, underlying connective tissues, and cranial bones, such as gunshot wounds or high-speed vehicular/fall impacts, and can lead to lacerations, hemorrhages, infarctions, and infections. Closed injuries lack penetration, vary from mild to severe, and have equally serious consequences via transmission of force through the protective structures to the brain to effect concussions, contusions, infarctions, and hemorrhages. The American Association of Neurological Surgeons defines a concussion as “a clinical syndrome characterized by immediate and transient alteration in brain function, including alteration of mental status and level of consciousness, resulting from mechanical force or trauma.” At the molecular, cellular, network, and tissue levels, we do not yet have a full understanding of the pathophysiology of concussions. Single concussion and, more so, repeated concussions can have both short- and long-term clinical and pathological sequelae (see the chronic traumatic encephalopathy (CTE) discussion).
Intracranial hemorrhages can occur after head injury and may be life-threatening. Fractures of cranial bones as a result of trauma can lacerate arteries or veins to cause hemorrhages in extra/epidural (synonymous), subdural, subarachnoid, or parenchymal locations. Nonpenetrating trauma can cause similar hemorrhages although epidural bleeds are less common. Deep parenchymal bleeds are also less common and should be distinguished from hypertensive hemorrhages. Traumatic hemorrhages can be chronic or acute, both of which can become space occupying lesions (hematomas) with resultant pressure on the brain and neurosurgical emergencies. Imaging studies are essential in the clinical workup of moderate or severe head injury, and even with mild head injury if the patient experiences symptomatic progression. This is especially true in the elderly, whose diminished brain volume and a higher risk for tearing of bridging veins can lead to slow and subtle chronic subdural hemorrhages. Determination of hemorrhagic onset can be important in some forensic investigations, and is accomplished by evaluating the degree of fibrovascular organization of the clot.
When head/spinal cord traumas are suspected as contributing to death, forensic investigation should include a thorough gross and microscopic examination of the CNS. Remote injuries from trauma often produce surface encephalomalacia and hemosiderin deposition in the tissues at the sites of impact that could be either directly adjacent to the external impact (“coup” lesion) or opposite to this site due to internal impact of the brain against the inner surface of the cranium (“contrecoup” lesion). Acute/subacute brain injury can show impact contusions/hemorrhages and underlying axonal spheroids - swelling of severed axons. Diffuse axonal injury (DAI) is a form of extensive traumatic shearing injury to cerebral white matter tracts as a result of rapid deceleration and rotational forces (eg, severe car accidents, falls, and assaults). While its pathophysiology awaits clarification, DAI occurs hours to days after the initial trauma and is a major cause of posttraumatic unconsciousness and persistent vegetative state. When present, multiple small (1 to 15 mm) abnormalities with or without microbleeds at preferred locations (eg, posterior corpus callosum, dorsolateral brainstem, and parasagittal temporoparietal corticomedullary junction) on imaging studies in an appropriate clinical context are highly suspicious for DAI. Histologically, DAI is characterized by rarefaction of affected white matter with axonal swelling/varicosities and, sometimes, extravasation in the early stage, and with axonal loss, gliosis, siderophages, and atrophy in the late stage. An ancillary immunostain for beta-amyloid precursor protein, which is upregulated within hours of injury, can assist in detecting axonal injury in its early stage regardless of cause.
Pediatric Head/Neck Trauma
Pediatric head/neck trauma is a contentious area of forensic neuropathology, and delineating accidental from inflicted injury can be difficult. Death scene investigation and law enforcement interviews of caretakers are essential components of forensic pathology practice in cases of lethal pediatric head/neck trauma, as is a detailed postmortem neuropathologic examination. Forensic neuropathologic findings often include evidence of blunt head impact (eg, scalp contusions, abrasions, or lacerations) and intracranial hemorrhage with or without skull fractures. Intracranial hemorrhage is most often documented as subdural and subarachnoid. Skull fractures resulting from accidental short-distance falls are typically linear, nondisplaced fractures, most commonly of the parietal bone. Complex and/or displaced fractures, particularly of the occipital bone, are more commonly seen after falls from a height, motor vehicle collisions, or inflicted trauma.
In infancy, a lethal event is sometimes accompanied by a caregiver’s description of shaking the infant. A growing body of evidence supports the concept of acute neck injury causing apnea and subsequent hypoxic brain injury in these cases rather than shaking causing a direct acceleration-deceleration brain injury as previously hypothesized. Neck injuries are evident at autopsy as cervical spinal nerve root/ganglia hemorrhages. These infants typically show evidence of cerebral edema and retinal hemorrhages, and they may demonstrate a thin film of fluid subdural blood and optic nerve sheath hemorrhage at autopsy. In reality, the vast majority of cases involving reported shaking are found at autopsy to have evidence of blunt head impact(s), hence the sometimes used term “shaken impact syndrome.”
A seizure is defined as a single abnormal electrophysiological event in the brain, while epilepsy is defined as a disorder characterized by two or more unprovoked seizures. Seizures are physiologic expressions of lesions involving the cortex. At autopsy, seizure disorders may be linked to structural abnormalities, infection, CNS tumor, or injury, among other etiologies, although approximately 40% of idiopathic childhood epilepsies have no such epileptogenic focus identified by detailed postmortem neuropathologic examination.
Seizures of traumatic origin may result from cortical contusions due to altered neural networks involving the injured gray matter or from scar formation between the cortex/arachnoid layer and an organizing subdural neomembrane. Frontal lobe injuries are particularly associated with generalized seizures and status epilepticus. In elderly patients, approximately one-half of new-onset seizures are rooted in cerebrovascular disease (eg, cerebrovascular event or vascular malformation). Seizures may also be associated with drug and alcohol use/withdrawal.
Epilepsy patients have an approximate 20-fold increased risk of sudden unexpected death when compared with the general population. Sudden unexpected death in epilepsy (SUDEP) is defined as sudden, nontraumatic death in a patient with epilepsy without postmortem evidence of a structural or toxicological cause of death. Most cases occur in sleep, and patients are often discovered unresponsive in a prone position. The mechanism of death is thought to include a terminal seizure with post-ictal cerebral shutdown and subsequent deregulation of cardiopulmonary centers resulting in apnea and cardiac arrhythmias. Hippocampal sclerosis is the most common neuropathological abnormality seen in temporal lobe epilepsy and is generally nontraumatic in nature.
Chronic Traumatic Encephalopathy
A long-term consequence of head injury in some individuals has been the development of clinically variable neurodegenerative diseases collectively termed “chronic traumatic encephalopathy” (CTE). CTE, initially recognized in some boxers nearly 100 years ago as dementia pugilistica, is now actively being investigated in the context of many contact sports. Military exposure to head trauma (eg, blast injury) is also hypothesized to lead to CTE, but only a few neuropathological studies have been reported. The number, intensity, and type of injuries linked with age and potential genetic susceptibility of individuals to developing CTE are largely unknown. Initial symptoms are recognized approximately 10 years after the trauma with memory problems, headaches, dizziness, and social instability; though neuropathologic changes likely precede clinical manifestations. As the disease progresses, dementia, motor disability, tremors, speech difficulty, and increased risk for suicide/homicidal violence can be seen. Currently, no established serum or imaging biomarkers of disease are recognized.
The neuropathological findings at autopsy for CTE have recently been described. The hallmark lesions are accumulation of phosphorylated tau in both neurons and glia with a perivascular distribution in depths of sulci in early stages, and tauopathy with neurofibrillary tangles widely distributed in later stages of disease. Atrophy is seen with variable loss of neurons in the neocortex, hippocampus, midbrain, cerebellum, and brainstem. A cavum septum pellucidum is often observed. Aberrant expression of TAR DNA-binding protein 43 (TDP 43) has also been reported. Unlike in Alzheimer disease, beta-amyloid deposition is not a common feature.
Ingestion/inhalation of a toxic substance can result in distinct neuropathology. Carbon monoxide poisoning, for example, is most often encountered in cases of suicidal inhalation or accidental exposure. Carbon monoxide binds to hemoglobin with approximately 300 times the affinity of oxygen, leading to reversible asphyxia. Survival after insult may be complicated by brain injury, specifically necrosis of the bilateral globi pallidi. Likewise, methanol poisoning can result in distinct brain abnormalities provided there is an interval of survival. Methanol poisoning may be encountered in cases of contaminated moonshine ingestion. These patients may present to urgent care with sudden onset blindness due to the neurotoxicity of methanol. Survival after insult may be complicated by cystic necrosis of the bilateral putamina.
Ethylene glycol poisoning is most often seen in cases of suicide or accidental ingestion. Ethylene glycol is a component of automobile antifreeze, and its ingestion can cause acute kidney injury and death. Oxalate crystals deposit in the tubules of renal parenchyma and in the leptomeninges overlying brain parenchyma, and can be detected histologically by light microscopy and with polarization.
Chronic Ethanol Abuse
Ethanol abuse is associated with over 3 million deaths per year worldwide, the majority of which are related to complications of chronic abuse. Chronic ethanol abuse may be associated with a variety of conditions including Marchiafava-Bignami disease, central pontine myelinolysis (CPM), Wernicke encephalopathy, and alcohol-related brain damage (ARBD). ARBD is characterized by brain atrophy largely due to loss of cerebral hemispheric white matter and frontal lobe cortex. Behavioral disinhibition is related to selective loss of neurons from the superior frontal cortex. Atrophy of the cerebellar vermis due to loss of Purkinje and granule neurons may result in gait ataxia.
Wernicke encephalopathy develops with thiamine deficiency due to malnutrition, and is represented at neuropathologic examination as petechial hemorrhages in the mammillary bodies. Clinical symptoms may include ataxia, confusion, and ophthalmoplegia. Hepatic encephalopathy ensues in patients with severe liver disease, and varies from mild (eg, confusion) to severe (eg, coma) in clinical manifestation. The associated neuropathology includes diffuse brain edema and Alzheimer type II astrogliosis in the basal ganglia, thalamus, and deep cerebral cortex. Alzheimer type II astrogliosis is a nonspecific functional disorder of astrocytes that can be seen with hyperammonemia, uremia, hypercapnia, and hypoglycemia. Alzheimer type II astroglia (or metabolic glia) are characterized by optically clear enlarged nuclei with margination of chromatin and are not related to the neurodegenerative Alzheimer disease.
CPM, also known as osmotic demyelination syndrome, is a neurologic entity classically associated with rapid correction of hyponatremia in markedly malnourished patients; CPM has also been linked to other metabolic imbalances. Clinically, hyponatremic patients demonstrate encephalopathy and seizures; rapid correction of the electrolyte imbalance may result in rapid deterioration several days later that may end in death. Neuropathology is typically centered in the basis pontis which shows loss of myelin with relative preservation of axons. Approximately one-half of cases also demonstrate extrapontine involvement.
Several vascular lesions associated with acute hemorrhages or seizures leading to death are commonly encountered in forensic neuropathology. Hypertensive vasculopathy is characterized by lipohyalinized vessels and Charcot-Bouchard microaneurysms which may result in acute hemorrhage in the basal ganglia, pons, or cerebellar white matter and very rapid death.
Saccular aneurysms occurring in the major arteries of the base of the brain are often clinically asymptomatic until they rupture. Rupture leads to a brisk subarachnoid hemorrhage that can be lethal without therapeutic intervention. Vascular malformations such as arteriovenous malformations and cavernous hemangiomas can occur in any location within the brain and be associated with acute hemorrhage, infarction, or seizures.
Take Home Points
- When there is suspicion of inflicted head/spinal cord trauma contributing to death, forensic neuropathological investigation should include a thorough gross and microscopic examination of the CNS.
- Sudden unexpected death in epilepsy (SUDEP) is defined as sudden, nontraumatic death in a patient with epilepsy without postmortem evidence of a structural or toxicological cause of death. The mechanism of death is thought to involve a terminal seizure with deregulation of cardiopulmonary centers.
- Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy linked to repetitive head trauma.
- Toxic carbon monoxide encephalopathy can be distinguished from toxic methanol encephalopathy by neuropathologic findings, namely necrosis involving the globi pallidi or putamina, respectively.
- Wernicke encephalopathy develops with thiamine deficiency due to malnutrition and is represented at neuropathologic examination as petechial hemorrhages in the mammillary bodies, diffuse brain edema, and Alzheimer type II astrogliosis in the basal ganglia, thalamus, and deep cerebral cortex.
- Vascular malformations such as arteriovenous malformations and cavernous hemangiomas can occur in any location within the brain and be associated with acute hemorrhage, infarction, or seizures.
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