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Non-traumatic neurological conditions in medico-legal work
ARTICLE IN PRESS Current Diagnostic Pathology (2004) 10, 116–127
www.elsevier.com/locate/cdip
MINI-SYMPOSIUM: NEUROPATHOLOGY
Non-traumatic neurological conditions in medico-legal work Colin Smitha,*, Helen Whitwellb a
Neuropathology Unit, Department of Pathology, Western General Hospital, Edinburgh EH4 2XU, UK Department of Forensic Pathology, The Medico-Legal Centre, Watery Street, Sheffield S3 7ES, UK
b
KEYWORDS Forensic neuropathology; Sudden unexpected death; Neurotoxicology
Summary The pathologist who conducts autopsies that are instructed by the Coroner or Procurator Fiscal must be aware of the many potential injurious agents and pathological processes which may involve the nervous system. This review provides an introduction to some of the non-traumatic aspects of forensic neuropathology. Neuropathological disorders may underlie sudden unexpected death in adults and patterns of brain injury may indicate predisposing causes for fatal injuries, such as alcoholic cerebellar degeneration, which is associated with an increased propensity for falls and may be fatal. This review covers some of the common neuropathological disorders encountered at autopsy, such as those related to cerebral blood flow and chronic alcoholism, and includes less common conditions, such as the fatal consequences of recreational drugs and poisons. & 2004 Elsevier Ltd. All rights reserved.
Introduction While much of the forensic neuropathologist’s workload relates to the direct and indirect consequences of traumatic brain injury, a large number of non-traumatic brain insults may be encountered by a pathologist undertaking autopsies on behalf of the Coroner or Procurator Fiscal. This review will cover the causes of sudden unexpected death in adults and the toxicological aspects of forensic neuropathology, but can only be a superficial introduction to a potentially complex field. As such, we recommend prior consultation with a local neuropathologist for cases in which the pathology of the nervous system is suspected to have contributed to the cause of death, or early *Corresponding author. Tel.: þ 44-131-537-1975; fax: þ 44131-537-1013. E-mail address: [email protected] (C. Smith).
discussion with a local neuropathologist in cases where nervous system pathology is unexpectedly identified.
Disorders related to cerebral perfusion Normal function of the brain is dependent on the blood supply delivering adequate levels of both oxygen and glucose. Disruption in the provision of these will result in neuronal injury, which may be further compounded by the accumulation of neurotoxic metabolites such as lactate.1 In this section, the distinction between hypoxia and ischaemia is highlighted and the neuropathological changes are outlined. Hypoxia describes low oxygen levels, either in the blood (hypoxaemia), or in the brain tissue. Hypoxia can be produced in a variety of ways (Table 1),
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ARTICLE IN PRESS Non-traumatic neurological conditions in medico-legal work
Table 1
117
Classification of hypoxia.
Type of hypoxia
Pathophysiology
Clinical example
Structural changes in the brain
Hypoxic
Reduced oxygen tension in pulmonary alveoli results in hypoxaemia and brain hypoxia
Acute: pulmonary oedema
None
Chronic: interstitial lung disease Anaemic
Hypoxaemia caused by low levels of haemoglobin or by competitive binding of oxygen sites on the haemoglobin molecule
Carbon monoxide poisoning
None, if not accompanied by ischaemia
Histotoxic
The neurone is unable to utilize the oxygen due to poisoning of the metabolic pathways within the cell
Cyanide poisoning
None
Stagnant
There is reduced blood flow to the brain, due to either reduced cardiac output or disruption of local perfusion
Reduced cardiac output: cardiac arrest
Neuronal necrosis and if prolonged tissue infarction
Disrupted local perfusion: thrombo-embolic infarct
although the pure forms of hypoxia are rarely seen in forensic practice and produce little pathology.2 More frequently, hypoxia is seen in association with ischaemia (the impairment of the blood supply to the brain), for example, after cardiorespiratory arrest. In ischaemia, blood flow to the brain fails, resulting not only in the failure to deliver oxygen, but also in the accumulation of toxic metabolites. It is the accumulation of metabolites with resulting low tissue pH that accounts for the tissue damage in ischaemia.3 The extent of damage to the brain produced by ischaemia is determined principally by the extent of the ischaemia (whether it is focal or global), and the duration of the ischaemia. Focal ischaemia is characteristically produced by the occlusion of a vessel, while global ischaemia is a consequence of haemodynamic collapse.
Focal ischaemia and cerebral infarction The commonest form of cerebrovascular pathology encountered at autopsy is that of a stroke (Fig. 1). Stroke is a common occurrence, the incidence increasing with age, although cerebro-
Figure 1 Macroscopic image of an acute cerebral infarct involving the middle cerebral artery territory. The infarct is poorly defined but is acting as a mass lesion causing a midline shift and both subfalcine and tentorial herniae. There is some discolouration of the cortex in the area of infarction.
vascular pathology may be seen at any age. In western countries, thrombo-embolic infarcts account for approximately 60–80% of strokes, with
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Table 2
C. Smith, H. Whitwell
Timing of changes in thrombo-embolic infarcts.
Time since infarct
Macroscopic appearance
Microscopic appearance
6–12 h
None
Irreversible ischaemic cell change
12–24 h
Early loss of grey–white matter interface
Neutrophilic infiltrate, although may be relatively inconspicuous
48 h
Cerebral oedema established, with associated mass effect. From about 72 h there may be tissue splitting
Activated macrophages present in damaged tissues
1–3 weeks
Cavitation begins to develop
Gliosis and neovascularization identified
Months
Gliotic scar often golden-brown in colour due to haemosiderin staining
Gliotic scar
intracerebral haemorrhages accounting for most of the remaining cases. Rare causes of stroke include a variety of emboli (see below), vascular dissection, vasculopathies, haematological disorders and genetic disorders. Thrombosis, of either the acute or organizing varieties, may be seen within the major vessels at the base of the brain. More commonly, atherosclerosis is seen in the major branches of the circle of Willis, the carotid arteries (particularly at the bifurcations) and the vertebrobasilar arteries. In rare cases, severe atherosclerosis of the basal vessels may result in severely ectatic vessels. The pathological changes seen at various stages of infarct evolution are detailed in Table 2.4 Rare causes of emboli Fat emboli This is most commonly seen following a traumatic fracture of the long bones or pelvis, usually causing respiratory and neurological dysfunction 24–48 h after the trauma. Macroscopically, the brain is swollen and there are widespread petechial haemorrhages. Frozen sections of brain tissue should be examined to identify the fat emboli.5 Air emboli This may be associated with decompression of deep-sea divers (Caisson’s disease), or with cardiac surgery. Microinfarcts may be seen in the spinal cord6 and cerebrum. Fibrocartilagenous emboli Intervertebral disc material has been described as a cause of cerebral infarction after minor trauma.7 It is also rarely associated with pulmonary emboli.
Global ischaemia Global ischaemia may be absolute in situations where cerebral blood flow ceases for a period of time, such as during cardiac arrest. Alternatively it may be variable in situations where the cerebral blood flow is compromised, such as with systemic hypotension or raised intracranial pressure.
Brain damage after cardiac arrest In this situation, blood flow to the brain ceases for a period of time. The pathological changes associated with cardiac arrest require successful resuscitation with subsequent survival for a period of hours before they can be identified. The period of cessation of cerebral blood flow may only need to last 5–10 min for irreversible brain damage to develop. Macroscopic identification of brain damage, however, requires a survival of approximately 36–48 h. Cortical discolouration may be identified (early laminar necrosis), particularly in the parietal and occipital cortices, or may be accentuated within the depths of gyri. Microscopic diffuse neuronal ischaemic damage can be seen after 5–10 h, initially or predominantly in a pattern reflecting selective neuronal vulnerability. Selective vulnerability refers to the fact that early in global ischaemia, neurones in certain regions will be affected before others.8 The selective vulnerability associated with ischaemia differs from that seen in hypoglycaemia, and these conditions are compared in Table 3. In cases of long-term survival, where the patient will often have been in a vegetative state, the
ARTICLE IN PRESS Non-traumatic neurological conditions in medico-legal work Table 3
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The microscopic distribution of neuronal damage in ischaemia and hypoglycaemia.
Anatomical region
Ischaemia
Hypoglycaemia
Hippocampus
Maximal within sector CA1
Maximal within sector CA1 and within the dentate gyrus
Cerebral cortex
Accentuated within the depths of gyri, particularly at boundary zones, and involving the deeper layers of the cortex
Widespread and most pronounced within the superficial layers
Striatum
Diffuse damage in the striatum, especially of small/medium-sized neurones
Little damage seen in the thalamus
Cerebellum
Purkinje cell ischaemic damage or focal infarction within the boundary zones
The cerebellar cortex, and Purkinje cells in particular, show little evidence of injury
ventricles are enlarged secondary to the loss of grey and white matter.
Brain damage after hypotension In this situation, there is reduced perfusion of the brain. Ischaemic damage is accentuated at boundary zones between arterial territories, with damage to both neurones and surrounding brain parenchyma (watershed infarcts). The entire cerebral cortex may be involved if the hypotension is severe and/or prolonged, therefore the situation can mimic that of post-cardiac arrest. Watershed infarcts may be unilateral due to asymmetry of the circle of Willis (e.g. due to atherosclerosis).
Venous infarction Venous infarction is most commonly associated with cerebral venous thrombosis. This is more common than previously suspected, with a fatal outcome in relatively small numbers of cases. Underlying infection remains an important cause of cerebral venous thrombosis, although the hormonal changes produced by oral contraceptives and pregnancy are probably the most important aetiological factors.9 The superior sagittal sinus is most commonly involved, resulting in parasagittal congestion and parenchymal haemorrhage, involving both cortex and underlying white matter. Microscopically, the appearances are of haemorrhagic infarction. In venous infarction, neutrophils are usually abundant.
Hypoglycaemia Hypoglycaemic brain damage is produced in adults when their blood glucose levels fall below about 1.5 mM. Insulin overdose, resulting in profound hypoglycaemia, may be accidental or intentional (suicide or homicide). The diabetic patient may accidentally administer an incorrect dose of insulin, or may have difficulty in controlling their diabetes, resulting in episodes of hypoglycaemia or hypoglycaemic coma. Rare causes of hypoglycaemia include islet cell tumours of the pancreas (insulinoma). Hypoglycaemia produces a pattern of selective neuronal necrosis which, in its pure form, differs from that seen with ischaemia.10 However, hypoglycaemic coma is often accompanied by seizures or by cardiorespiratory depression, in such a way that ischaemic features may be co-existent with the pathology associated with hypoglycaemia. Macroscopically, the brain shows little abnormality, with only mild swelling. The microscopic distribution of injury is detailed in Table 3.
Non-traumatic cerebral haemorrhages Non-traumatic subarachnoid haemorrhage Bleeding from a saccular or berry aneurysm, accounts for 70–90% of naturally occurring subarachnoid haemorrhage.11 Ruptured vascular malformations, rupture of mycotic aneurysm and subarachnoid haemorrhage, in conjunction with intracerebral haemorrhage account for most other cases. However, in around 20% of cases of
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Figure 2 A ruptured middle cerebral artery aneurysm. Subarachnoid haemorrhage is present. The temporal pole has been removed to access the aneurysm.
subarachnoid haemorrhage with no definite history of trauma, no lesion is identified; these are the socalled aneurysm-negative cases.12 Conditions that are very occasionally associated with aneurysms include: fibromuscular dysplasia;13 various connective tissue disorders;14 polycystic kidneys;12 and vascular abnormalities including arteriovenous malformations.15 Saccular cerebral aneurysms particularly occur at the branch points of the intracranal cerebral arteries. Of these, 85–90% occur in the territory of the terminal internal carotid arteries or the anterior part of the circle of Willis (Fig. 2), and around 5–10% involve the posterior circulation. The majority of aneurysms that rupture are less than 10 mm in size,16 and giant aneurysms are classified as having a diameter greater than 25 mm. At autopsy, identification is best achieved by clearing the fresh haemorrhage, followed by careful dissection of the basal vessels. Following fixation, clearance of the blood can be difficult, impeding the identification of an aneurysm. They may however, be difficult to identify as they can be almost destroyed as they bleed, in particular if they are thin-walled. The site of rupture may be indicated by the location of the haemorrhage: basal cisternsFcircle of Willis aneurysm; haematoma between the frontal lobesFanterior cerebral or anterior communicating artery aneurysm; Sylvian fissureFmiddle cerebral artery aneurysm. Rupture into brain parenchyma can occur and may extend into the ventricular system.
Non-traumatic intracerebral haemorrhage Hypertensive intracerebral haemorrhage This is the commonest cause of intracerebral haemorrhage, accounting for approximately 50%
C. Smith, H. Whitwell
Figure 3 An arteriovenous malformation in the temporal lobe. There is a collection of abnormal vessels which extends into the subarachnoid space.
of all cases.11 The majority occur in the deep cerebral structures, with cortical and subcortical areas less commonly involved. Vascular malformations There are various types of vascular malformation (Fig. 3), which may cause intracerebral haemorrhage and, to a varying degree, subarachnoid haemorrhage. These are outlined in Table 4.
Infection of the central nervous system Infections of the nervous system remain a considerable cause of morbidity and mortality worldwide. With the increasing ease of world travel, particularly to destinations that are ‘off the beaten track’, and an increasing population of immunosuppressed individuals, there is a need for greater awareness of nervous system infections. Nervous system infection may be the cause of sudden unexpected deaths in adults, particularly in the elderly and in immunocompromised individuals. For a more detailed review of this subject the interested reader is referred to recent reviews.17,18
Autopsy techniques Identification of the underlying organisms will require appropriate tissue samples and swabs to be taken at the time of autopsy, often requiring consultation with the microbiology and virology departments. Sterile CSF can be removed from the brain in situ during the autopsy by passing a needle into the lateral ventricles after the dura has been removed, and may be used for PCR identification of viruses.
ARTICLE IN PRESS Non-traumatic neurological conditions in medico-legal work
Table 4
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Classification of vascular malformations. Location
Macroscopic
Microscopic
Arteriovenous malformations
Often found at surface of cerebral hemispheres extending into the subarachnoid space
Collections of abnormal vessels
Arteries and veins of variable diameter and wall thickness separated by gliotic tissue
Cavernous haemangiomas
Anywhere in central nervous system
Resembles a small haematoma
Vessels of variable thickness tightly packed together with no intervening parenchyma
Venous angioma
Subcortical white matter
Usually numerous and can resemble petechial haemorrhages
Thin-walled vessels. Bleeding is uncommon and there is rarely any gliotic reaction
Capillary haemangioma
Often found in the pons
Haemorrhagic nodule
Thin-walled vessels with no gliotic reaction
Fresh brain tissue should be retained and frozen to allow for potential diagnostic molecular investigations, such as viral DNA/RNA identification in cases of encephalitis. At autopsy the air sinuses, the orbit and both the middle and inner ear should be examined for possible foci of infection. Examination of the heart and other viscera may indicate the site of infection. Infections of the nervous system can be considered, based on the underlying organism or their anatomical location.
Classification of infections Bacterial infections Bacteria may enter the nervous system by the haematogenous route (which is most common), or secondary to osteomyelitis and sinusitis/mastoiditis or compound fracture. Bacterial infections are usually suppurative, although notable exceptions include mycobacteria. Fungal infections These tend to be opportunistic infections, often being seen in immunocompromised patients. CNS fungal infection is virtually always associated with systemic infection, although infection in the brain may be most obvious. The spread is usually haematogenous from a focus within the lungs.19 In some cases, infection is the result of a direct spread from either the air sinuses or orbit. Viral infections Viruses generally enter the body via the mucous membranes of the respiratory or gastrointestinal
tract, although in some cases entry may be traumatic, for example after a dog bite. A number of viruses are neurotropic and will move towards the nervous system, usually via peripheral nerves (e.g. rabies). Some viruses show a considerable latent period between primary infection and nervous system disease (e.g. HIV). Protozoal infections These are disseminated haematogenously and can produce a range of pathological appearances depending on the infecting organism. Protozoal infections of the nervous system are common worldwide, but are relatively infrequent in western populations.
Distribution of pathology associated with infections Pachymeningitis This refers to a collection of pus in relation to the dura. Empyemas are collections of pus which are usually subdural and supratentorial, although in the spinal region extradural collections can be seen in association with osteomyelitis. Subdural empyemas are usually associated with open skull fractures or neurosurgical procedures.20 Macroscopically, the appearances are of a collection of pus in the subdural space, often encapsulated by granulation tissue. Leptomeningitis This is more commonly referred to simply as meningitis. The commonest form of meningitis to be encountered in the autopsy room is acute
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Figure 4 Purulent bacterial meningitis. There is a layer of pus overlying the convexity of the cerebral hemisphere.
purulent (bacterial) meningitis (Fig. 4). In adults, bacterial meningitis is usually secondary to bacteraemia, although skull fracture secondary to trauma, or previous neurosurgical procedure may result in recurrent meningitis. The organisms commonly involved in adults are Streptococcus pneumoniae and Neisseria meningitidis.21 Macroscopically, the brain is usually swollen and a purulent membrane is seen overlying it; this tends to be most pronounced over the convexities with S. pneumoniae, and most pronounced basally with other organisms.17 The infection may extend into the ventricles (ventriculitis), and there may be a degree of hydrocephalus that is secondary to CSF obstruction by pus. Microscopically, a florid infiltrate of neutrophils is seen within the subarachnoid space and there is often thrombosis of cortical vessels, with associated superficial cortical infarction. Granulomatous meningitis Macroscopically, tuberculous meningitis has a rather nodular exudate and is most pronounced basally and laterally, particularly overlying the Sylvian fissures. Less commonly, tuberculosis may present as a parenchymal mass (tuberculoma). The differential diagnosis of granulomatous inflammation of the meninges includes the non-infective condition, neurosarcoidosis. Infections of the brain parenchyma Infections of the brain parenchyma may be suppurative or non-suppurative; the suppurative infections will produce an abscess, whereas the nonsuppurative infections tend to produce encephalitis, a non-suppurative diffuse inflammation of the brain parenchyma.
C. Smith, H. Whitwell
Cerebral abscesses Cerebral abscesses can present as space-occupying lesions, resulting in raised intracranial pressure. They can be solitary or multifocal, determined to a degree by the route of entry. Haematogenous dissemination of the organism tends to produce multifocal cerebral abscesses, whereas direct invasion from local infection in the paranasal sinuses, middle ear, or maxillary dental roots tends to produce a solitary lesion.22 For haematogenous dissemination, primary sites include cardiac valves and chronic lung infections (bronchiectasis). Infection may be introduced as a result of intravenous drug abuse. Bacterial organisms are usually responsible for cerebral abscesses in immunocompotent individuals, with S. viridans being the organism most commonly identified. In immunocompromised individuals, fungal organisms such as the Aspergillus species, the Candida species, and protozoa, such as Toxoplasma gondii may be seen. Toxoplasmosis, in particular, is often associated with HIV infection.23 Cerebral abscesses due to haematogenous dissemination are classically said to develop at the cortical grey–white matter interface, although in some cases they are widely distributed throughout the brain. Abscesses associated with paranasal air sinus and maxillary dental root infections are located in the adjacent frontal lobe, while those associated with middle ear infections are usually found in the temporal lobe or (rarely) in the cerebellum.17 Macroscopically, abscesses initially appear as an area of focal swelling and discolouration, often being haemorrhagic. After about 2 weeks, the abscess will have a purulent necrotic centre and a thick capsule. Encephalitis There are some general features of encephalitis which are not dependent on the infecting virus. Macroscopically, the brain is often swollen, with congestion of the parenchymal vessels. There is usually a perivascular lymphocytic infiltrate with both microglial and astrocytic (gliosis) activation. Cell necrosis is variable, ranging from individual neurones in poliomyelitis to extensive tissue infarction (necrotizing encephalitis) in herpes simplex encephalitis. Inclusion bodies may be seen in neurones or glial cells and this may help in identifying the infecting virus.24
Other causes of sudden unexpected death in adults There are a range of potential pathologies that may underlie sudden unexpected death in adults, or
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that may be important in medico-legal practice. These include neoplasia (both primary and metastatic), epilepsy, dementia, demyelination and iatrogenic neuropathology. Of these, two will be considered: sudden unexpected death in epilepsy (SUDEP), and dementia (see also Neuropathological findings in epilepsy, by M. Thom, in this issue).
Epilepsy The clinical condition of epilepsy is best, albeit rather simplistically, defined as a continuing tendency to epileptic seizures. An important point in this definition is that a single seizure does not equate to a diagnosis of epilepsy. Status epilepticus is a clinically defined entity: ‘continuous seizures lasting at least 5 min or two or more discrete seizures between which there is incomplete recovery of consciousness’.25 Certification of death as being due to status epilepticus therefore requires a clear clinical history and should not be applied to a death secondary to a suspected seizure.26 There is an increased risk of premature death associated with epilepsy, and a significant excess of accident-related deaths.27,28 Autopsy examination in known epileptics or in an individual with witnessed seizures may show some of the features associated with seizures, although they are not specific, such as bruising of the tongue and petechial haemorrhages in the mucous membranes. Autopsy examination of deaths in epilepsy should include toxicological examinations of blood and urine for levels of anti-epileptic drugs, ethanol, and recreational drugs. The brain should be retained for detailed neuropathological examination after fixation.29 SUDEP is defined as ‘sudden unexpected witnessed or non-witnessed, non-traumatic and nondrowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus where necropsy does not reveal a toxicological or anatomical cause for death’.30 SUDEP is associated with young age (20–40 years), and poor seizure control. It is more frequently seen in males and in epilepsy secondary to head injury and alcoholism. In approximately 30% of cases there are witnessed seizures prior to death, although in almost 50% of cases the circumstances suggest death during sleep.31 Autopsy examination may show non-specific-seizure-associated pathology and neuropathology secondary to epilepsy.
Disorders associated with dementia Dementia is not a specific disorder, it is more of a generic term for progressive cognitive and beha-
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vioural disturbances produced by a variety of pathological processes. The pathologist may encounter dementia as a cause of abnormal behaviour which may underlie self-harm or a road traffic accident, or they be required to comment on neurodegenerative changes in assault victims who may have been displaying unusually aggressive behaviour. Allegations of maltreatment may also occur, as the victims frequently become cachectic. Dementia is not only caused by neurodegenerative pathology. Other rare causes include neoplasia, infections and metabolic cerebral dysfunction induced by disorders such as chronic renal failure, or endocrine disorders such as hypoparathyroidism. Macroscopic examination should include an assessment of the presence and distribution or the absence of cerebral atrophy, and determination of the brain weight. The adult brain should weigh between 1200 and 1600 g, the weight usually being slightly greater in males. When interpreting brain weight it is important to consider the stature of the individual; a person of small stature will have a small brain that may be outside these guide weights. Beyond the age of about 50 years there is a gradual decrease in brain weight of about 2% per year.32 If atrophy is present the location and severity should be noted (e.g. a frontotemporoparietal distribution is typical of Alzheimer’s disease and a ‘knife-edge’ frontal atrophy is typical of Pick’s disease). In cases of suspected CJD, frozen tissue should be retained to assist with molecular diagnosis. The brain should be sectioned following adequate fixation. Histological sampling is a necessity to achieve a diagnosis. Guidelines for sampling the brain in cases of probable dementia have been published.33 Diagnosis can however, be complex and should be established by an experienced neuropathologist.
Neurotoxicology Alcohol is prevalent in western society, and when abused may result in a range of injuries to the nervous system. Recreational drugs are increasingly used, particularly amongst young adults, and may be associated with fatal neurological consequences. In addition, there is a wide range of toxins which may produce nervous system injury. These toxins may be encountered in the workplace, accidentally, or may be criminally administered. This review will cover the neurotoxic effects of alcohol, recreational drugs and neurotoxins, and the potential implications relating to forensic practice.
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C. Smith, H. Whitwell
Alcohol When considering the effects of alcohol, we are considering the direct effects of ethanol and the secondary effects due to vitamin deficiencies and metabolic dysfunction. Additionally, methanol or ethylene glycol may be consumed as an ethanol substitute. Acute ethanol toxicity Acute alcohol intoxication (inebriation) is rarely fatal in itself, but may predispose the individual to potentially fatal situations. Brain oedema has been observed in some fatal cases.34 Chronic alcoholism Thiamine deficiency The neuropathological features associated with thiamine deficiency are most commonly seen in alcoholics, but may be seen in other rare causes of extreme malnutrition.35 Thiamine deficiency underlies Wernicke–Korsakoff syndrome and cerebellar degeneration. Evidence of both recent and old head injuries are common in chronic alcoholism. In Wernicke’s encephalopathy (Fig. 5) microscopic examination is mandatory as the brain may appear macroscopically normal in up to 25% of cases.36 Acutely, areas of haemorrhagic necrosis are seen in the mamillary bodies and sometimes in the hypothalamic region surrounding the third ventricle. Similar lesions may be seen in the periaqueductal region of the brain stem. In long-standing cases, often with recurrent episodes, the typical pathology is of shrunken brown mamillary bodies. Cerebellar atrophy, predominantly involving the superior part of the vermis, is a frequent finding in chronic alcoholism. Microscopically, there is an obvious loss of Purkinje cells, with associated Bergmann gliosis in the superior vermal region. Similar changes have been described in malnutrition without alcohol involvement.37 Other metabolic disorders related to chronic alcoholism Central pontine myelinolysis This disorder is seen in individuals with a variety of underlying disorders,38 but most commonly in chronic alcoholics. The disorder is thought to be due to electrolyte abnormalities, with profound hyponatraemia being a feature in most cases. Macroscopically, a pale granular region may be visible in the centre of the basis pontis. However, histology that includes the
Figure 5 Shrunken brown mamillary bodies indicative of chronic Wernicke’s. The discolouration is due to previous haemorrhage.
use of specific stains for myelin and axons is usually required to detect the abnormalities. Lesions may be exclusively extrapontine in over 10% of cases.39 Marchiafava-bignami disease This is a very rare condition that was originally described in alcoholics from Mediterranean regions. The lesion is characterized by an area of demyelination in the corpus callosum, particularly in its anterior part. Methanol Methanol is found in a number of common products (e.g. solvents and toiletries), that are sometimes drunk to produce intoxication, and can also be produced by the home brewing of spirits. Toxicity in the acute phase can lead to blindness and cardiorespiratory collapse. At autopsy, the brain is swollen and petechial haemorrhages may be seen. The haemorrhages are pronounced in relation to the third and fourth ventricles and can also be subarachnoid. If the patient has survived for a period of time prior to death, bilateral necrosis of the putamen may be seen, as well as necrosis of the cerebellar cortex.40 In the eyes, there is loss of retinal ganglion cells and loss of optic nerve axons.41 Ethylene glycol Ethylene glycol is considered in this section as it is usually consumed by alcoholics. It has a sweet taste and mimics the inebriation produced by ethanol. At autopsy, there is cerebral oedema and petechial haemorrhages. Non-specific patchy necrosis may be seen in the basal ganglia. Oxalate crystals are seen in the brain and meninges in vessels and in perivascular spaces. These are best demonstrated by use of polarizing filters.
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Recreational drugs Opiates Heroin abuse can result in a wide range of lesions within the nervous system. Some of these may be directly due to heroin, while many others are due to the impurities mixed in with the heroin. Most cases which come to forensic pathologists’ attention involve intravenous administration of heroin. Many impurities are introduced into the blood system and can travel to the brain or spinal cord. Non-sterile injection techniques can introduce infection which, via haematogenous spread, can lead to cerebral abscesses or meningitis. Cerebral infarcts may be seen as a consequence of the emboli of injected materials. The commonest pathology seen in relation to a fatal heroin overdose however, is that of ischaemic damage secondary to hypotension. The brain is swollen and lesions are seen in the parieto-occipital watershed region and often within the globus pallidus.42,43 Cocaine Cocaine abuse in young adults is common and is now recognized as a cause of cerebral infarction. Haemorrhagic and ischaemic infarcts are seen, with haemorrhagic lesions being particularly associated with underlying vascular anomalies such as arteriovenous malformations and cerebral aneurysms.44 Ischaemic infarcts may be the result of vasoconstriction, and increased platelet aggregation and activation.45 Amphetamines Amphetamines are associated with cerebral infarction. In the UK, the commonest amphetamine that is recreationally used is 3,4-methylenedioxymethylamphetamine (MDMA), which goes under the street name of ‘ecstacy’. The neuropathological features identified at autopsy in ‘ecstacy’ users include severe cerebral oedema, possibly secondary to water intoxication, and microscopic perivascular haemorrhages.46 In addition, intracerebral haemorrhages have been described on imaging, and in one case there was a fatal outcome in an individual with an underlying arteriovenous malformation.47
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but a variety of neuropathological features have been described, including axonal neuropathy with giant axonal swellings48 and central nervous system demyelination.49
Neurotoxins Neurotoxins will be discussed under the headings ‘gases’, and ‘heavy metals’. Gases Carbon monoxide (CO) CO poisoning remains a frequent form of suicide and is still, although with decreasing frequency, a cause of death in relation to poorly maintained gas heaters. At autopsy, the brain is swollen and on sectioning has a characteristic pink-red colour due to the accumulation of carboxyhaemoglobin. When the patient has survived for several days, infarcts are seen within the globus pallidus and substantia nigra. Histologically, neuronal loss is common in the hippocampus and Purkinje cell layer of the cerebellar cortex.50 In long-term survivors, a myelinopathy may develop (Grinker’s myelinopathy), the damage being seen throughout the cerebrum, although being most severe posteriorly and deeply.51 Other gases Carbon disulphide (CS2) and methyl bromide have been documented as causing fatal intoxications in industrial settings.52 CS2 has been used in the textile and rubber industries, while methyl bromide was a component of fire extinguishers. Both can result in sudden loss of consciousness and coma. Autopsy studies have demonstrated neuronal loss and gliosis. Methyl bromide intoxication has been associated with petechial haemorrhages and cerebral oedema in the acute stages, in one case with 30-day survival the lesions resembled Wernicke’s encephalopathy.
Volatile substances
Heavy metals Organic arsenic Organic arsenic has been used in the treatment of trypanosomiasis and can be associated with fatal intoxication. Acute haemorrhagic leucoencephalitis has been described, with perivascular demyelination and ‘ball and ring’ type haemorrhages, particularly in the pons and the midbrain.53
Volatile substances include organic solvents such as n-hexane and toluene, which may be inhaled to produce a euphoric effect (e.g. ‘glue-sniffing’). Fatalities are usually due to cardiac arrhythmias,
Mercury Mercury intoxication has been described in two main situations: after industrial pollution of the environment, resulting in the element being
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introduced to the human food chain; and in the use of mercury as a fungicide. Intoxication after industrial pollution was first described at Minamata, Japan, in the mid-1950s,54 and intoxication with fungicide was the cause of many deaths in Iraq in 1971.55 The neuropathological features of mercury intoxication include severe atrophy of the calcarine cortex and cerebellar cortex, with less severe cortical atrophy elsewhere in the cerebrum. Within the cerebellum, the atrophy is most pronounced in the granule cell layer, with preservation of the Purkinje cells. Purkinje cell axonal swellings and spiny dendritic processes have been described.56 Thallium Thallium is used as a pesticide and has been described in accidental, suicidal and homicidal poisoning. The clinical presentation is of unexplained gastrointestinal disturbance followed by a peripheral neuropathy. Motor weakness and cranial neuropathies can develop. The neuropathological features are rather non-specific and include cerebral oedema with petechial haemorrhages. Chromatolysis of motor neurones is seen and sampling of the distal peripheral nervous system may show a loss of myelinated axons.57 Other heavy metals Other heavy metals have been described as causing an encephalopathy in the past, but are now no longer seen. These include aluminium (dialysis encephalopathy) and lead (used in paint and associated with childhood intoxication). Others are seen in only very specific situations (e.g. manganese intoxications have been described in manganese miners). Electrolytes Hypernatraemia Poisoning with excess salt (sodium chloride) can be fatal either acutely or secondarily to chronic administration. This is most often encountered when salt is added to the feed of a baby or an infant. In addition, hypernatraemia may be seen in association with reduced water intake or diabetes insipidus. In the acute situation the brain shrinks and there are subdural and intraparenchymal haemorrhages.58 In chronic situations, when hypernatraemia has developed more slowly, haemorrhages may be absent. Brain swelling may complicate the medical therapy of hypernatraemia. Water intoxication Water intoxication can produce marked hyponatraemia and is associated with cerebral oedema. Forced water intoxication has been described in
C. Smith, H. Whitwell child abuse.59 and excess rehydration can be associated with some recreational drugs, particularly with use of amphetamines.
Conclusion This review has described a range of non-traumatic neurological conditions which may be encountered in forensic practice. Conditions affecting the CNS have been grouped into broad categories and examples have been provided. It is clear that this chapter is not comprehensive and can only serve as an introduction to the many potential causes of non-traumatic injury to the nervous system.
References 1. Miyamoto O, Auer RN. Hypoxia, hyperoxia, ischemia, and brain necrosis. Neurology 2000;54:362–71. 2. Auer RN, Sutherland GR. Hypoxia and related conditions. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology, vol. 1. 7th ed. London: Arnold; 2002. p. 234–80. 3. Siesjo. BK. Pathophysiology and treatment of focal cerebral ischemia. Part II Mechanisms of damage and treatment. J Neurosurg 1992;77:337–54. 4. Kalimo H, Kaste M, Haltia M. Vascular diseases. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology, vol. 1. 7th ed. London: Arnold; 2002. p. 281–355. 5. Kamenar E, Burger PC. Cerebral fat embolism: a neuropathological study of a microembolic state. Stroke 1980;11: 477–84. 6. Palmer AC, Calder IM, Hughes JT. Spinal cord degeneration in divers. Lancet 1987;2:1365–6. 7. Toro-Gonzalez G, Navarro-Roman L, et al. Acute ischemic stroke from fibrocartilaginous embolism to the middle cerebral artery. Stroke 1993;24:738–40. 8. Pulsinelli WA. Selective neuronal vulnerability and infarction in cerebrovascular disease. In: Welch KMA, Caplan LR, Reis DJ, Siesjo. BK, Weir B, editors. Primer on cerebrovascular disease. San Diego: Academic Press; 1997. p. 104–7. 9. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin 1992;10:87–111. 10. Auer RN, Siesjo BK. Biological differences between ischemia, hypoglycemia, and epilepsy. Ann Neurol 1988;24: 699–707. 11. Kalimo H, Kaste M, Haltia M. Vascular diseases. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology. 7th ed. London: Arnold; 2002. p. 281–355. 12. Rinkel GJE, Gijn JV, Wijdicks EFM. Subarachnoid haemorrhage without detectable aneurysm. A review of causes. Stroke 1993;24:1403–9. 13. Cloft HJ, Kalmes DF, Kalmes MH, et al. Prevalence of cerebral aneurysms in patients with fibromuscular dysplasia: a reassessment. J Neurosurg 1998;88:436–40. 14. Stehbens WE. Etiology of intracranial berry aneurysms. J Neurosurg 1989;70:823–31. 15. Weller RO. Subarachnoid haemorrhage and myths about saccular aneurysms. J Clin Pathol 1995;48:1078–81. 16. Forget TR, Benitez R, Veznedaroglu E, et al. A review of size and location of ruptured intracranial aneurysms. Neurosurgery 2001;49:1322–5.
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17. Love S. Autopsy approach to infections of the CNS. In: Love S, editor. Current topics in pathology 95: neuropathology. Berlin: Springer; 2001. p. 1–50. 18. Davis LE, Kennedy PGE, editors. Infectious diseases of the nervous system. Oxford: Butterworth–Heinemann; 2000. 19. Walsh TJ, Hier DB, Caplan LR. Aspergillosis of the central nervous system: clinicopathological analysis of 17 patients. Ann Neurol 1985;18:574–82. 20. Krauss WE, McCormick PC. Infections of the dural spaces. Neurosurg Clin N Am 1992;3:421–33. 21. Gray F, Alonso J-M. Bacterial infections of the nervous system. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology, vol. 2. 7th ed. London: Arnold; 2002. p. 151–94. 22. Wispelwey B, Dacey RGJ, Scheld WM. Brain abscesses. In: Scheld WM, Whitley RJ, Durack DT, editors. Infections of the central nervous system. New York: Raven Press; 1991. p. 457–86. 23. Strittmatter C, Lang W, Wiestler OD, Kleihues P. The changing pattern of human immunodeficiency virus-associated cerebral toxoplasmosis: a study of 46 postmortem cases. Acta Neuropathol 1992;83:475–81. 24. Love S, Wiley CA. Viral diseases In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology, vol. 2. 7th ed. London: Arnold; 2002. p. 1–106. 25. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970–6. 26. Langan Y, Nashef L, Sander JW. Certification of deaths attributable to epilepsy. J Neurol Neurosurg Psychiatry 2002;73:751–2. 27. Hirsch CS, Martin DL. Unexpected death in young epileptics. Neurology 1971;21:682–90. 28. Kenneback G, Ericson M, Tomson T, Bergfeldt L. Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs. Implications for sudden death. Seizure 1997;6:369–75. 29. Black M, Graham DI. Sudden unexplained death in adults. In: Love S, editor. Current topics in pathology 95: neuropathology. Berlin: Springer; 2001. p. 125–48. 30. Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997;38(Suppl 11):S6–8. 31. Black M, Graham DI. Sudden unexplained death in adults caused by intracranial pathology. J Clin Pathol 2002;55:44–50. 32. Esiri M, Hyman BT, Beyreuther K, Masters CL. Ageing and dementia. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology, vol. 1. 7th ed. London: Arnold; 1997. p. 153–233. 33. Lowe JS. Establishing a pathological diagnosis in degenerative dementias. Brain Pathol 1998;8:403–6. 34. Harper CG, Krill JJ. Neuropathology of alcoholism. Alcohol Alcohol 1990;25:207–16. 35. Ihara M, Ito T, Yanagihara C, Nishimura Y. Wernicke’s encephalopathy associated with hemodialysis: report of two cases and review of the literature. Clin Neurol Neurosurg 1999;101:118–21. 36. Harper C. The incidence of Wernicke’s encephalopathy in AustraliaFa neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 1983;46:593–8. 37. Adams RD. Nutritional cerebellar degeneration. Amsterdam: Elsevier; 1976. 38. Lampl C, Yazdi K. Central pontine myelinolysis. Eur Neurol 2002;47:3–10.
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39. Wright DG, Laureno R, Victor M. Pontine and extrapontine myelinolysis. Brain 1979;102:361–85. 40. McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical and pathological study. Ann Neurol 1980;8:161–7. 41. Naeser P. Optic nerve involvement in a case of methanol poisoning. Br J Ophthalmol 1988;72:778–81. . 42. Buttner A, Mall G, Penning R, Weis S. The neuropathology of heroin abuse. Forensic Sci Int 2000;113:435–42. 43. Andersen SN, Skullerud K. Hypoxic/ischaemic brain damage, especially pallidal lesions, in heroin addicts. Forensic Sci Int 1999;102:51–9. . 44. Buttner A, Mall G, Penning R, Sachs H, Weis S. The neuropathology of cocaine abuse. Leg Med 2003;5:S240. 45. Sloan MA. Toxicity/substance abuse. In: Welch KMA, Caplan LR, Reis DJ, Siesj BK, Weir B, editors. Primer on cerebrovascular disease. San Diego: Academic Press; 1997. p. 104–7. 46. Milroy CM, Clark JC, Forrest ARW. Pathology of deaths associated with ‘ecstacy’ and ‘eve’ misuse. J Clin Pathol 1996;49:149–53. 47. Harries DP, De Silva R. ‘Ecstacy’ and intracerebral haemorrhage. Scot Med J 1992;37:150–2. 48. Jones HB, Cavanagh JB. Distortions of the nodes of Ranvier from axonal distension by filamentous masses in hexacarbon intoxication. J Neurocytol 1983;12:439–58. 49. Kornfeld M, Moser AB, Moser HW, Kleinschmidt-DeMasters B, Nolte K, Phelps A. Solvent vapor abuse leukoencephalopathy. Comparison to adrenoleukodystrophy. J Neuropathol Exp Neurol 1994;53:389–98. 50. Auer RN, Sutherland GR. Hypoxia and related conditions. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathology, vol. 1. 7th ed. London: Arnold; 2002. p. 234–80. 51. Neubuerger KT, Clarke ER. Subacute carbon monoxide poisoning with cerebral myelinopathy and multiple myocardial necroses. Rocky Mountain Med J 1945;42:29–34. 52. Osetowska E. Gases. In: Minckler J, editor. Pathology of the nervous system, vol. 2. New York: McGraw-Hill; 1971. p. 1638–44. 53. Adams JH, Haller L, Boa FY, Doua F, Dago A, Konian K. Human African trypanosomiasis (Tb gambiense): a study of 16 fatal cases of sleeping sickness with some observations on acute reactive arsenical encephalopathy. Neuropathol Appl Neurobiol 1986;12:81–94. 54. Shiraki H. Neuropathological aspects of organic mercury intoxication including Minimata disease. In: Vinken PJ, Brutn GW, editors. Handbook of clinical neurology, vol. 36. Amsterdam: North-Holland; 1979. p. 83–145. 55. Bakir F, Damluji S, Amin-Zaki L, Murtadha M, Khalidi A, AlRawi NY. Methylmercury poisoning in Iraq. Science 1973;181:230–41. 56. Jacobs JM, LeQuesne PM. Toxic disorders. In: Adams JH, Duchen LW, editors. Greenfield’s neuropathology. 5th ed. London: Arnold; 1992. p. 234–80. 57. Cavanagh JB, Fuller NH, Johnson HR, Rudge P. The effects of thallium salts, with particular reference to the nervous system changes. A report of three cases. Q J Med 1974;43:293–319. 58. Finberg L. Pathogenesis of lesions in the nervous system in hypernatremic states. I. Clinical observations of infants. Pediatrics 1958;22:40–5. 59. Arieff AI, Kronlund BA. Fatal child abuse by forced water intoxication. Pediatrics 1999;103:1292–5.
www.elsevier.com/locate/cdip
MINI-SYMPOSIUM: NEUROPATHOLOGY
Non-traumatic neurological conditions in medico-legal work Colin Smitha,*, Helen Whitwellb a
Neuropathology Unit, Department of Pathology, Western General Hospital, Edinburgh EH4 2XU, UK Department of Forensic Pathology, The Medico-Legal Centre, Watery Street, Sheffield S3 7ES, UK
b
KEYWORDS Forensic neuropathology; Sudden unexpected death; Neurotoxicology
Summary The pathologist who conducts autopsies that are instructed by the Coroner or Procurator Fiscal must be aware of the many potential injurious agents and pathological processes which may involve the nervous system. This review provides an introduction to some of the non-traumatic aspects of forensic neuropathology. Neuropathological disorders may underlie sudden unexpected death in adults and patterns of brain injury may indicate predisposing causes for fatal injuries, such as alcoholic cerebellar degeneration, which is associated with an increased propensity for falls and may be fatal. This review covers some of the common neuropathological disorders encountered at autopsy, such as those related to cerebral blood flow and chronic alcoholism, and includes less common conditions, such as the fatal consequences of recreational drugs and poisons. & 2004 Elsevier Ltd. All rights reserved.
Introduction While much of the forensic neuropathologist’s workload relates to the direct and indirect consequences of traumatic brain injury, a large number of non-traumatic brain insults may be encountered by a pathologist undertaking autopsies on behalf of the Coroner or Procurator Fiscal. This review will cover the causes of sudden unexpected death in adults and the toxicological aspects of forensic neuropathology, but can only be a superficial introduction to a potentially complex field. As such, we recommend prior consultation with a local neuropathologist for cases in which the pathology of the nervous system is suspected to have contributed to the cause of death, or early *Corresponding author. Tel.: þ 44-131-537-1975; fax: þ 44131-537-1013. E-mail address: [email protected] (C. Smith).
discussion with a local neuropathologist in cases where nervous system pathology is unexpectedly identified.
Disorders related to cerebral perfusion Normal function of the brain is dependent on the blood supply delivering adequate levels of both oxygen and glucose. Disruption in the provision of these will result in neuronal injury, which may be further compounded by the accumulation of neurotoxic metabolites such as lactate.1 In this section, the distinction between hypoxia and ischaemia is highlighted and the neuropathological changes are outlined. Hypoxia describes low oxygen levels, either in the blood (hypoxaemia), or in the brain tissue. Hypoxia can be produced in a variety of ways (Table 1),
0968-6053/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cdip.2004.01.006
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Table 1
117
Classification of hypoxia.
Type of hypoxia
Pathophysiology
Clinical example
Structural changes in the brain
Hypoxic
Reduced oxygen tension in pulmonary alveoli results in hypoxaemia and brain hypoxia
Acute: pulmonary oedema
None
Chronic: interstitial lung disease Anaemic
Hypoxaemia caused by low levels of haemoglobin or by competitive binding of oxygen sites on the haemoglobin molecule
Carbon monoxide poisoning
None, if not accompanied by ischaemia
Histotoxic
The neurone is unable to utilize the oxygen due to poisoning of the metabolic pathways within the cell
Cyanide poisoning
None
Stagnant
There is reduced blood flow to the brain, due to either reduced cardiac output or disruption of local perfusion
Reduced cardiac output: cardiac arrest
Neuronal necrosis and if prolonged tissue infarction
Disrupted local perfusion: thrombo-embolic infarct
although the pure forms of hypoxia are rarely seen in forensic practice and produce little pathology.2 More frequently, hypoxia is seen in association with ischaemia (the impairment of the blood supply to the brain), for example, after cardiorespiratory arrest. In ischaemia, blood flow to the brain fails, resulting not only in the failure to deliver oxygen, but also in the accumulation of toxic metabolites. It is the accumulation of metabolites with resulting low tissue pH that accounts for the tissue damage in ischaemia.3 The extent of damage to the brain produced by ischaemia is determined principally by the extent of the ischaemia (whether it is focal or global), and the duration of the ischaemia. Focal ischaemia is characteristically produced by the occlusion of a vessel, while global ischaemia is a consequence of haemodynamic collapse.
Focal ischaemia and cerebral infarction The commonest form of cerebrovascular pathology encountered at autopsy is that of a stroke (Fig. 1). Stroke is a common occurrence, the incidence increasing with age, although cerebro-
Figure 1 Macroscopic image of an acute cerebral infarct involving the middle cerebral artery territory. The infarct is poorly defined but is acting as a mass lesion causing a midline shift and both subfalcine and tentorial herniae. There is some discolouration of the cortex in the area of infarction.
vascular pathology may be seen at any age. In western countries, thrombo-embolic infarcts account for approximately 60–80% of strokes, with
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Table 2
C. Smith, H. Whitwell
Timing of changes in thrombo-embolic infarcts.
Time since infarct
Macroscopic appearance
Microscopic appearance
6–12 h
None
Irreversible ischaemic cell change
12–24 h
Early loss of grey–white matter interface
Neutrophilic infiltrate, although may be relatively inconspicuous
48 h
Cerebral oedema established, with associated mass effect. From about 72 h there may be tissue splitting
Activated macrophages present in damaged tissues
1–3 weeks
Cavitation begins to develop
Gliosis and neovascularization identified
Months
Gliotic scar often golden-brown in colour due to haemosiderin staining
Gliotic scar
intracerebral haemorrhages accounting for most of the remaining cases. Rare causes of stroke include a variety of emboli (see below), vascular dissection, vasculopathies, haematological disorders and genetic disorders. Thrombosis, of either the acute or organizing varieties, may be seen within the major vessels at the base of the brain. More commonly, atherosclerosis is seen in the major branches of the circle of Willis, the carotid arteries (particularly at the bifurcations) and the vertebrobasilar arteries. In rare cases, severe atherosclerosis of the basal vessels may result in severely ectatic vessels. The pathological changes seen at various stages of infarct evolution are detailed in Table 2.4 Rare causes of emboli Fat emboli This is most commonly seen following a traumatic fracture of the long bones or pelvis, usually causing respiratory and neurological dysfunction 24–48 h after the trauma. Macroscopically, the brain is swollen and there are widespread petechial haemorrhages. Frozen sections of brain tissue should be examined to identify the fat emboli.5 Air emboli This may be associated with decompression of deep-sea divers (Caisson’s disease), or with cardiac surgery. Microinfarcts may be seen in the spinal cord6 and cerebrum. Fibrocartilagenous emboli Intervertebral disc material has been described as a cause of cerebral infarction after minor trauma.7 It is also rarely associated with pulmonary emboli.
Global ischaemia Global ischaemia may be absolute in situations where cerebral blood flow ceases for a period of time, such as during cardiac arrest. Alternatively it may be variable in situations where the cerebral blood flow is compromised, such as with systemic hypotension or raised intracranial pressure.
Brain damage after cardiac arrest In this situation, blood flow to the brain ceases for a period of time. The pathological changes associated with cardiac arrest require successful resuscitation with subsequent survival for a period of hours before they can be identified. The period of cessation of cerebral blood flow may only need to last 5–10 min for irreversible brain damage to develop. Macroscopic identification of brain damage, however, requires a survival of approximately 36–48 h. Cortical discolouration may be identified (early laminar necrosis), particularly in the parietal and occipital cortices, or may be accentuated within the depths of gyri. Microscopic diffuse neuronal ischaemic damage can be seen after 5–10 h, initially or predominantly in a pattern reflecting selective neuronal vulnerability. Selective vulnerability refers to the fact that early in global ischaemia, neurones in certain regions will be affected before others.8 The selective vulnerability associated with ischaemia differs from that seen in hypoglycaemia, and these conditions are compared in Table 3. In cases of long-term survival, where the patient will often have been in a vegetative state, the
ARTICLE IN PRESS Non-traumatic neurological conditions in medico-legal work Table 3
119
The microscopic distribution of neuronal damage in ischaemia and hypoglycaemia.
Anatomical region
Ischaemia
Hypoglycaemia
Hippocampus
Maximal within sector CA1
Maximal within sector CA1 and within the dentate gyrus
Cerebral cortex
Accentuated within the depths of gyri, particularly at boundary zones, and involving the deeper layers of the cortex
Widespread and most pronounced within the superficial layers
Striatum
Diffuse damage in the striatum, especially of small/medium-sized neurones
Little damage seen in the thalamus
Cerebellum
Purkinje cell ischaemic damage or focal infarction within the boundary zones
The cerebellar cortex, and Purkinje cells in particular, show little evidence of injury
ventricles are enlarged secondary to the loss of grey and white matter.
Brain damage after hypotension In this situation, there is reduced perfusion of the brain. Ischaemic damage is accentuated at boundary zones between arterial territories, with damage to both neurones and surrounding brain parenchyma (watershed infarcts). The entire cerebral cortex may be involved if the hypotension is severe and/or prolonged, therefore the situation can mimic that of post-cardiac arrest. Watershed infarcts may be unilateral due to asymmetry of the circle of Willis (e.g. due to atherosclerosis).
Venous infarction Venous infarction is most commonly associated with cerebral venous thrombosis. This is more common than previously suspected, with a fatal outcome in relatively small numbers of cases. Underlying infection remains an important cause of cerebral venous thrombosis, although the hormonal changes produced by oral contraceptives and pregnancy are probably the most important aetiological factors.9 The superior sagittal sinus is most commonly involved, resulting in parasagittal congestion and parenchymal haemorrhage, involving both cortex and underlying white matter. Microscopically, the appearances are of haemorrhagic infarction. In venous infarction, neutrophils are usually abundant.
Hypoglycaemia Hypoglycaemic brain damage is produced in adults when their blood glucose levels fall below about 1.5 mM. Insulin overdose, resulting in profound hypoglycaemia, may be accidental or intentional (suicide or homicide). The diabetic patient may accidentally administer an incorrect dose of insulin, or may have difficulty in controlling their diabetes, resulting in episodes of hypoglycaemia or hypoglycaemic coma. Rare causes of hypoglycaemia include islet cell tumours of the pancreas (insulinoma). Hypoglycaemia produces a pattern of selective neuronal necrosis which, in its pure form, differs from that seen with ischaemia.10 However, hypoglycaemic coma is often accompanied by seizures or by cardiorespiratory depression, in such a way that ischaemic features may be co-existent with the pathology associated with hypoglycaemia. Macroscopically, the brain shows little abnormality, with only mild swelling. The microscopic distribution of injury is detailed in Table 3.
Non-traumatic cerebral haemorrhages Non-traumatic subarachnoid haemorrhage Bleeding from a saccular or berry aneurysm, accounts for 70–90% of naturally occurring subarachnoid haemorrhage.11 Ruptured vascular malformations, rupture of mycotic aneurysm and subarachnoid haemorrhage, in conjunction with intracerebral haemorrhage account for most other cases. However, in around 20% of cases of
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Figure 2 A ruptured middle cerebral artery aneurysm. Subarachnoid haemorrhage is present. The temporal pole has been removed to access the aneurysm.
subarachnoid haemorrhage with no definite history of trauma, no lesion is identified; these are the socalled aneurysm-negative cases.12 Conditions that are very occasionally associated with aneurysms include: fibromuscular dysplasia;13 various connective tissue disorders;14 polycystic kidneys;12 and vascular abnormalities including arteriovenous malformations.15 Saccular cerebral aneurysms particularly occur at the branch points of the intracranal cerebral arteries. Of these, 85–90% occur in the territory of the terminal internal carotid arteries or the anterior part of the circle of Willis (Fig. 2), and around 5–10% involve the posterior circulation. The majority of aneurysms that rupture are less than 10 mm in size,16 and giant aneurysms are classified as having a diameter greater than 25 mm. At autopsy, identification is best achieved by clearing the fresh haemorrhage, followed by careful dissection of the basal vessels. Following fixation, clearance of the blood can be difficult, impeding the identification of an aneurysm. They may however, be difficult to identify as they can be almost destroyed as they bleed, in particular if they are thin-walled. The site of rupture may be indicated by the location of the haemorrhage: basal cisternsFcircle of Willis aneurysm; haematoma between the frontal lobesFanterior cerebral or anterior communicating artery aneurysm; Sylvian fissureFmiddle cerebral artery aneurysm. Rupture into brain parenchyma can occur and may extend into the ventricular system.
Non-traumatic intracerebral haemorrhage Hypertensive intracerebral haemorrhage This is the commonest cause of intracerebral haemorrhage, accounting for approximately 50%
C. Smith, H. Whitwell
Figure 3 An arteriovenous malformation in the temporal lobe. There is a collection of abnormal vessels which extends into the subarachnoid space.
of all cases.11 The majority occur in the deep cerebral structures, with cortical and subcortical areas less commonly involved. Vascular malformations There are various types of vascular malformation (Fig. 3), which may cause intracerebral haemorrhage and, to a varying degree, subarachnoid haemorrhage. These are outlined in Table 4.
Infection of the central nervous system Infections of the nervous system remain a considerable cause of morbidity and mortality worldwide. With the increasing ease of world travel, particularly to destinations that are ‘off the beaten track’, and an increasing population of immunosuppressed individuals, there is a need for greater awareness of nervous system infections. Nervous system infection may be the cause of sudden unexpected deaths in adults, particularly in the elderly and in immunocompromised individuals. For a more detailed review of this subject the interested reader is referred to recent reviews.17,18
Autopsy techniques Identification of the underlying organisms will require appropriate tissue samples and swabs to be taken at the time of autopsy, often requiring consultation with the microbiology and virology departments. Sterile CSF can be removed from the brain in situ during the autopsy by passing a needle into the lateral ventricles after the dura has been removed, and may be used for PCR identification of viruses.
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Table 4
121
Classification of vascular malformations. Location
Macroscopic
Microscopic
Arteriovenous malformations
Often found at surface of cerebral hemispheres extending into the subarachnoid space
Collections of abnormal vessels
Arteries and veins of variable diameter and wall thickness separated by gliotic tissue
Cavernous haemangiomas
Anywhere in central nervous system
Resembles a small haematoma
Vessels of variable thickness tightly packed together with no intervening parenchyma
Venous angioma
Subcortical white matter
Usually numerous and can resemble petechial haemorrhages
Thin-walled vessels. Bleeding is uncommon and there is rarely any gliotic reaction
Capillary haemangioma
Often found in the pons
Haemorrhagic nodule
Thin-walled vessels with no gliotic reaction
Fresh brain tissue should be retained and frozen to allow for potential diagnostic molecular investigations, such as viral DNA/RNA identification in cases of encephalitis. At autopsy the air sinuses, the orbit and both the middle and inner ear should be examined for possible foci of infection. Examination of the heart and other viscera may indicate the site of infection. Infections of the nervous system can be considered, based on the underlying organism or their anatomical location.
Classification of infections Bacterial infections Bacteria may enter the nervous system by the haematogenous route (which is most common), or secondary to osteomyelitis and sinusitis/mastoiditis or compound fracture. Bacterial infections are usually suppurative, although notable exceptions include mycobacteria. Fungal infections These tend to be opportunistic infections, often being seen in immunocompromised patients. CNS fungal infection is virtually always associated with systemic infection, although infection in the brain may be most obvious. The spread is usually haematogenous from a focus within the lungs.19 In some cases, infection is the result of a direct spread from either the air sinuses or orbit. Viral infections Viruses generally enter the body via the mucous membranes of the respiratory or gastrointestinal
tract, although in some cases entry may be traumatic, for example after a dog bite. A number of viruses are neurotropic and will move towards the nervous system, usually via peripheral nerves (e.g. rabies). Some viruses show a considerable latent period between primary infection and nervous system disease (e.g. HIV). Protozoal infections These are disseminated haematogenously and can produce a range of pathological appearances depending on the infecting organism. Protozoal infections of the nervous system are common worldwide, but are relatively infrequent in western populations.
Distribution of pathology associated with infections Pachymeningitis This refers to a collection of pus in relation to the dura. Empyemas are collections of pus which are usually subdural and supratentorial, although in the spinal region extradural collections can be seen in association with osteomyelitis. Subdural empyemas are usually associated with open skull fractures or neurosurgical procedures.20 Macroscopically, the appearances are of a collection of pus in the subdural space, often encapsulated by granulation tissue. Leptomeningitis This is more commonly referred to simply as meningitis. The commonest form of meningitis to be encountered in the autopsy room is acute
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Figure 4 Purulent bacterial meningitis. There is a layer of pus overlying the convexity of the cerebral hemisphere.
purulent (bacterial) meningitis (Fig. 4). In adults, bacterial meningitis is usually secondary to bacteraemia, although skull fracture secondary to trauma, or previous neurosurgical procedure may result in recurrent meningitis. The organisms commonly involved in adults are Streptococcus pneumoniae and Neisseria meningitidis.21 Macroscopically, the brain is usually swollen and a purulent membrane is seen overlying it; this tends to be most pronounced over the convexities with S. pneumoniae, and most pronounced basally with other organisms.17 The infection may extend into the ventricles (ventriculitis), and there may be a degree of hydrocephalus that is secondary to CSF obstruction by pus. Microscopically, a florid infiltrate of neutrophils is seen within the subarachnoid space and there is often thrombosis of cortical vessels, with associated superficial cortical infarction. Granulomatous meningitis Macroscopically, tuberculous meningitis has a rather nodular exudate and is most pronounced basally and laterally, particularly overlying the Sylvian fissures. Less commonly, tuberculosis may present as a parenchymal mass (tuberculoma). The differential diagnosis of granulomatous inflammation of the meninges includes the non-infective condition, neurosarcoidosis. Infections of the brain parenchyma Infections of the brain parenchyma may be suppurative or non-suppurative; the suppurative infections will produce an abscess, whereas the nonsuppurative infections tend to produce encephalitis, a non-suppurative diffuse inflammation of the brain parenchyma.
C. Smith, H. Whitwell
Cerebral abscesses Cerebral abscesses can present as space-occupying lesions, resulting in raised intracranial pressure. They can be solitary or multifocal, determined to a degree by the route of entry. Haematogenous dissemination of the organism tends to produce multifocal cerebral abscesses, whereas direct invasion from local infection in the paranasal sinuses, middle ear, or maxillary dental roots tends to produce a solitary lesion.22 For haematogenous dissemination, primary sites include cardiac valves and chronic lung infections (bronchiectasis). Infection may be introduced as a result of intravenous drug abuse. Bacterial organisms are usually responsible for cerebral abscesses in immunocompotent individuals, with S. viridans being the organism most commonly identified. In immunocompromised individuals, fungal organisms such as the Aspergillus species, the Candida species, and protozoa, such as Toxoplasma gondii may be seen. Toxoplasmosis, in particular, is often associated with HIV infection.23 Cerebral abscesses due to haematogenous dissemination are classically said to develop at the cortical grey–white matter interface, although in some cases they are widely distributed throughout the brain. Abscesses associated with paranasal air sinus and maxillary dental root infections are located in the adjacent frontal lobe, while those associated with middle ear infections are usually found in the temporal lobe or (rarely) in the cerebellum.17 Macroscopically, abscesses initially appear as an area of focal swelling and discolouration, often being haemorrhagic. After about 2 weeks, the abscess will have a purulent necrotic centre and a thick capsule. Encephalitis There are some general features of encephalitis which are not dependent on the infecting virus. Macroscopically, the brain is often swollen, with congestion of the parenchymal vessels. There is usually a perivascular lymphocytic infiltrate with both microglial and astrocytic (gliosis) activation. Cell necrosis is variable, ranging from individual neurones in poliomyelitis to extensive tissue infarction (necrotizing encephalitis) in herpes simplex encephalitis. Inclusion bodies may be seen in neurones or glial cells and this may help in identifying the infecting virus.24
Other causes of sudden unexpected death in adults There are a range of potential pathologies that may underlie sudden unexpected death in adults, or
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that may be important in medico-legal practice. These include neoplasia (both primary and metastatic), epilepsy, dementia, demyelination and iatrogenic neuropathology. Of these, two will be considered: sudden unexpected death in epilepsy (SUDEP), and dementia (see also Neuropathological findings in epilepsy, by M. Thom, in this issue).
Epilepsy The clinical condition of epilepsy is best, albeit rather simplistically, defined as a continuing tendency to epileptic seizures. An important point in this definition is that a single seizure does not equate to a diagnosis of epilepsy. Status epilepticus is a clinically defined entity: ‘continuous seizures lasting at least 5 min or two or more discrete seizures between which there is incomplete recovery of consciousness’.25 Certification of death as being due to status epilepticus therefore requires a clear clinical history and should not be applied to a death secondary to a suspected seizure.26 There is an increased risk of premature death associated with epilepsy, and a significant excess of accident-related deaths.27,28 Autopsy examination in known epileptics or in an individual with witnessed seizures may show some of the features associated with seizures, although they are not specific, such as bruising of the tongue and petechial haemorrhages in the mucous membranes. Autopsy examination of deaths in epilepsy should include toxicological examinations of blood and urine for levels of anti-epileptic drugs, ethanol, and recreational drugs. The brain should be retained for detailed neuropathological examination after fixation.29 SUDEP is defined as ‘sudden unexpected witnessed or non-witnessed, non-traumatic and nondrowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus where necropsy does not reveal a toxicological or anatomical cause for death’.30 SUDEP is associated with young age (20–40 years), and poor seizure control. It is more frequently seen in males and in epilepsy secondary to head injury and alcoholism. In approximately 30% of cases there are witnessed seizures prior to death, although in almost 50% of cases the circumstances suggest death during sleep.31 Autopsy examination may show non-specific-seizure-associated pathology and neuropathology secondary to epilepsy.
Disorders associated with dementia Dementia is not a specific disorder, it is more of a generic term for progressive cognitive and beha-
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vioural disturbances produced by a variety of pathological processes. The pathologist may encounter dementia as a cause of abnormal behaviour which may underlie self-harm or a road traffic accident, or they be required to comment on neurodegenerative changes in assault victims who may have been displaying unusually aggressive behaviour. Allegations of maltreatment may also occur, as the victims frequently become cachectic. Dementia is not only caused by neurodegenerative pathology. Other rare causes include neoplasia, infections and metabolic cerebral dysfunction induced by disorders such as chronic renal failure, or endocrine disorders such as hypoparathyroidism. Macroscopic examination should include an assessment of the presence and distribution or the absence of cerebral atrophy, and determination of the brain weight. The adult brain should weigh between 1200 and 1600 g, the weight usually being slightly greater in males. When interpreting brain weight it is important to consider the stature of the individual; a person of small stature will have a small brain that may be outside these guide weights. Beyond the age of about 50 years there is a gradual decrease in brain weight of about 2% per year.32 If atrophy is present the location and severity should be noted (e.g. a frontotemporoparietal distribution is typical of Alzheimer’s disease and a ‘knife-edge’ frontal atrophy is typical of Pick’s disease). In cases of suspected CJD, frozen tissue should be retained to assist with molecular diagnosis. The brain should be sectioned following adequate fixation. Histological sampling is a necessity to achieve a diagnosis. Guidelines for sampling the brain in cases of probable dementia have been published.33 Diagnosis can however, be complex and should be established by an experienced neuropathologist.
Neurotoxicology Alcohol is prevalent in western society, and when abused may result in a range of injuries to the nervous system. Recreational drugs are increasingly used, particularly amongst young adults, and may be associated with fatal neurological consequences. In addition, there is a wide range of toxins which may produce nervous system injury. These toxins may be encountered in the workplace, accidentally, or may be criminally administered. This review will cover the neurotoxic effects of alcohol, recreational drugs and neurotoxins, and the potential implications relating to forensic practice.
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C. Smith, H. Whitwell
Alcohol When considering the effects of alcohol, we are considering the direct effects of ethanol and the secondary effects due to vitamin deficiencies and metabolic dysfunction. Additionally, methanol or ethylene glycol may be consumed as an ethanol substitute. Acute ethanol toxicity Acute alcohol intoxication (inebriation) is rarely fatal in itself, but may predispose the individual to potentially fatal situations. Brain oedema has been observed in some fatal cases.34 Chronic alcoholism Thiamine deficiency The neuropathological features associated with thiamine deficiency are most commonly seen in alcoholics, but may be seen in other rare causes of extreme malnutrition.35 Thiamine deficiency underlies Wernicke–Korsakoff syndrome and cerebellar degeneration. Evidence of both recent and old head injuries are common in chronic alcoholism. In Wernicke’s encephalopathy (Fig. 5) microscopic examination is mandatory as the brain may appear macroscopically normal in up to 25% of cases.36 Acutely, areas of haemorrhagic necrosis are seen in the mamillary bodies and sometimes in the hypothalamic region surrounding the third ventricle. Similar lesions may be seen in the periaqueductal region of the brain stem. In long-standing cases, often with recurrent episodes, the typical pathology is of shrunken brown mamillary bodies. Cerebellar atrophy, predominantly involving the superior part of the vermis, is a frequent finding in chronic alcoholism. Microscopically, there is an obvious loss of Purkinje cells, with associated Bergmann gliosis in the superior vermal region. Similar changes have been described in malnutrition without alcohol involvement.37 Other metabolic disorders related to chronic alcoholism Central pontine myelinolysis This disorder is seen in individuals with a variety of underlying disorders,38 but most commonly in chronic alcoholics. The disorder is thought to be due to electrolyte abnormalities, with profound hyponatraemia being a feature in most cases. Macroscopically, a pale granular region may be visible in the centre of the basis pontis. However, histology that includes the
Figure 5 Shrunken brown mamillary bodies indicative of chronic Wernicke’s. The discolouration is due to previous haemorrhage.
use of specific stains for myelin and axons is usually required to detect the abnormalities. Lesions may be exclusively extrapontine in over 10% of cases.39 Marchiafava-bignami disease This is a very rare condition that was originally described in alcoholics from Mediterranean regions. The lesion is characterized by an area of demyelination in the corpus callosum, particularly in its anterior part. Methanol Methanol is found in a number of common products (e.g. solvents and toiletries), that are sometimes drunk to produce intoxication, and can also be produced by the home brewing of spirits. Toxicity in the acute phase can lead to blindness and cardiorespiratory collapse. At autopsy, the brain is swollen and petechial haemorrhages may be seen. The haemorrhages are pronounced in relation to the third and fourth ventricles and can also be subarachnoid. If the patient has survived for a period of time prior to death, bilateral necrosis of the putamen may be seen, as well as necrosis of the cerebellar cortex.40 In the eyes, there is loss of retinal ganglion cells and loss of optic nerve axons.41 Ethylene glycol Ethylene glycol is considered in this section as it is usually consumed by alcoholics. It has a sweet taste and mimics the inebriation produced by ethanol. At autopsy, there is cerebral oedema and petechial haemorrhages. Non-specific patchy necrosis may be seen in the basal ganglia. Oxalate crystals are seen in the brain and meninges in vessels and in perivascular spaces. These are best demonstrated by use of polarizing filters.
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Recreational drugs Opiates Heroin abuse can result in a wide range of lesions within the nervous system. Some of these may be directly due to heroin, while many others are due to the impurities mixed in with the heroin. Most cases which come to forensic pathologists’ attention involve intravenous administration of heroin. Many impurities are introduced into the blood system and can travel to the brain or spinal cord. Non-sterile injection techniques can introduce infection which, via haematogenous spread, can lead to cerebral abscesses or meningitis. Cerebral infarcts may be seen as a consequence of the emboli of injected materials. The commonest pathology seen in relation to a fatal heroin overdose however, is that of ischaemic damage secondary to hypotension. The brain is swollen and lesions are seen in the parieto-occipital watershed region and often within the globus pallidus.42,43 Cocaine Cocaine abuse in young adults is common and is now recognized as a cause of cerebral infarction. Haemorrhagic and ischaemic infarcts are seen, with haemorrhagic lesions being particularly associated with underlying vascular anomalies such as arteriovenous malformations and cerebral aneurysms.44 Ischaemic infarcts may be the result of vasoconstriction, and increased platelet aggregation and activation.45 Amphetamines Amphetamines are associated with cerebral infarction. In the UK, the commonest amphetamine that is recreationally used is 3,4-methylenedioxymethylamphetamine (MDMA), which goes under the street name of ‘ecstacy’. The neuropathological features identified at autopsy in ‘ecstacy’ users include severe cerebral oedema, possibly secondary to water intoxication, and microscopic perivascular haemorrhages.46 In addition, intracerebral haemorrhages have been described on imaging, and in one case there was a fatal outcome in an individual with an underlying arteriovenous malformation.47
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but a variety of neuropathological features have been described, including axonal neuropathy with giant axonal swellings48 and central nervous system demyelination.49
Neurotoxins Neurotoxins will be discussed under the headings ‘gases’, and ‘heavy metals’. Gases Carbon monoxide (CO) CO poisoning remains a frequent form of suicide and is still, although with decreasing frequency, a cause of death in relation to poorly maintained gas heaters. At autopsy, the brain is swollen and on sectioning has a characteristic pink-red colour due to the accumulation of carboxyhaemoglobin. When the patient has survived for several days, infarcts are seen within the globus pallidus and substantia nigra. Histologically, neuronal loss is common in the hippocampus and Purkinje cell layer of the cerebellar cortex.50 In long-term survivors, a myelinopathy may develop (Grinker’s myelinopathy), the damage being seen throughout the cerebrum, although being most severe posteriorly and deeply.51 Other gases Carbon disulphide (CS2) and methyl bromide have been documented as causing fatal intoxications in industrial settings.52 CS2 has been used in the textile and rubber industries, while methyl bromide was a component of fire extinguishers. Both can result in sudden loss of consciousness and coma. Autopsy studies have demonstrated neuronal loss and gliosis. Methyl bromide intoxication has been associated with petechial haemorrhages and cerebral oedema in the acute stages, in one case with 30-day survival the lesions resembled Wernicke’s encephalopathy.
Volatile substances
Heavy metals Organic arsenic Organic arsenic has been used in the treatment of trypanosomiasis and can be associated with fatal intoxication. Acute haemorrhagic leucoencephalitis has been described, with perivascular demyelination and ‘ball and ring’ type haemorrhages, particularly in the pons and the midbrain.53
Volatile substances include organic solvents such as n-hexane and toluene, which may be inhaled to produce a euphoric effect (e.g. ‘glue-sniffing’). Fatalities are usually due to cardiac arrhythmias,
Mercury Mercury intoxication has been described in two main situations: after industrial pollution of the environment, resulting in the element being
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introduced to the human food chain; and in the use of mercury as a fungicide. Intoxication after industrial pollution was first described at Minamata, Japan, in the mid-1950s,54 and intoxication with fungicide was the cause of many deaths in Iraq in 1971.55 The neuropathological features of mercury intoxication include severe atrophy of the calcarine cortex and cerebellar cortex, with less severe cortical atrophy elsewhere in the cerebrum. Within the cerebellum, the atrophy is most pronounced in the granule cell layer, with preservation of the Purkinje cells. Purkinje cell axonal swellings and spiny dendritic processes have been described.56 Thallium Thallium is used as a pesticide and has been described in accidental, suicidal and homicidal poisoning. The clinical presentation is of unexplained gastrointestinal disturbance followed by a peripheral neuropathy. Motor weakness and cranial neuropathies can develop. The neuropathological features are rather non-specific and include cerebral oedema with petechial haemorrhages. Chromatolysis of motor neurones is seen and sampling of the distal peripheral nervous system may show a loss of myelinated axons.57 Other heavy metals Other heavy metals have been described as causing an encephalopathy in the past, but are now no longer seen. These include aluminium (dialysis encephalopathy) and lead (used in paint and associated with childhood intoxication). Others are seen in only very specific situations (e.g. manganese intoxications have been described in manganese miners). Electrolytes Hypernatraemia Poisoning with excess salt (sodium chloride) can be fatal either acutely or secondarily to chronic administration. This is most often encountered when salt is added to the feed of a baby or an infant. In addition, hypernatraemia may be seen in association with reduced water intake or diabetes insipidus. In the acute situation the brain shrinks and there are subdural and intraparenchymal haemorrhages.58 In chronic situations, when hypernatraemia has developed more slowly, haemorrhages may be absent. Brain swelling may complicate the medical therapy of hypernatraemia. Water intoxication Water intoxication can produce marked hyponatraemia and is associated with cerebral oedema. Forced water intoxication has been described in
C. Smith, H. Whitwell child abuse.59 and excess rehydration can be associated with some recreational drugs, particularly with use of amphetamines.
Conclusion This review has described a range of non-traumatic neurological conditions which may be encountered in forensic practice. Conditions affecting the CNS have been grouped into broad categories and examples have been provided. It is clear that this chapter is not comprehensive and can only serve as an introduction to the many potential causes of non-traumatic injury to the nervous system.
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