Adult hypoxic and ischemic lesions

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Adult hypoxic and ischemic lesions

TERMINOLOGY

Although ‘hypoxia’ (reduction in oxygen supply or impairment of its utilization) and ‘ischemia’ (reduction in blood supply) are often used interchangeably, and the term ‘hypoxic-ischemic encephalopathy’ is utilized widely in everyday practice, these conditions can have different etiologies, pathophysiologic mechanisms and clinical, as well as morphologic, sequelae in the CNS.

Hypoxia

Blood flow to the CNS may be entirely normal or even somewhat increased. The CNS is relatively resistant to pure hypoxia, but hypoxia

CEREBRAL BLOOD FLOW (CBF)

CBF = cerebral perfusion pressure (CPP)/cerebrovascular resistance (CVR)

CPP = systemic arterial blood pressure − intracranial pressure (ICP)

CBF is approximately 750 mL/min, representing 15% of cardiac output.

As long as mean CPP remains above approximately 5.3 kPa (∼ 40 mmHg), the tone of vascular smooth muscle in intracranial arteries and arterioles (and hence CVR) adjusts in response to changes in CPP to maintain CBF in a constant range of 50–55 mL/100 g/min in adults (the value is higher in children). This is the phenomenon of autoregulation.

Though overall CBF remains constant while CPP remains above the threshold for autoregulation, blood flow varies by anatomic region, according to demand for oxygen and glucose (largely dependent upon neuronal activity), a process described as functional hyperemia or neurovascular coupling. This variability of local blood flow is also used to advantage in functional MRI studies.

The density of capillaries is greater in gray than white matter, reflecting the pronounced difference in their metabolic requirements and resulting in a corresponding difference in blood flow:

• 80–100 mL/100 g/min in gray matter

• 20–25 mL/100 g/min in white matter.

If mean CPP falls below about 5.3 kPa, autoregulation becomes impaired or fails entirely, and CBF falls dramatically.

Threshold CBF for infarction in primate brain is estimated to be 10–12 mL/100 g/min.

exacerbates the damage produced by ischemia. In practice, many causes of stagnant or hypoxemic hypoxia (e.g. cardiac arrest and carbon monoxide poisoning, respectively) also depress cardiac output, resulting in combined hypoxic/global ischemic brain injury.

Global brain ischemia

This occurs with a pronounced decrease in cerebral perfusion pressure (CPP) to a level below the threshold required for optimal vascular autoregulation. Reduced systemic blood pressure or raised intracranial pressure produces such a deleterious reduction in CPP. Cardiac pathologies (producing arrest, dysrhythmia, or tamponade) or traumatic hemorrhage dominate the causes of reduced systemic blood pressure, but these are very varied. Severe head injury is a leading cause of raised intracranial pressure. Resulting brain damage is accentuated in watershed/borderzone regions, the boundaries between vascular territories, especially in the depths of sulci.

CELLULAR MECHANISMS OF ISCHEMIC CELL DEATH

Depolarization of neuronal/axonal membranes within 60–180 seconds of global anoxia leads to changes in extracellular and intracellular electrolyte composition and a decrease in ATP (secondary to impaired glycolysis and oxidative phosphorylation), with associated release of lactate and hydrogen ions and acidosis. ATP may decline to <25% of that in normally perfused tissue.

Ionic fluxes include increased potassium ions (K⁺) in the extracellular space and decreased extracellular calcium ions (Ca⁺⁺), with concomitant rise in intracellular Ca⁺⁺ by up to 25%, a process mediated in part by NMDA receptors.

Increased intracellular Ca⁺⁺ activates calpain and other molecules, with deleterious effects on cytoskeletal and membrane structures.

Mitochondrial injury secondary to Ca⁺⁺ influx causes further decrease in ATP, an increase in free radicals, and a progressive inability to buffer Ca⁺⁺ loads.

Cytoskeletal damage can affect the machinery of protein synthesis, but this may eventually recover.

Lipases, proteases and nucleases are activated, also with deleterious effects.

Free radicals and NO/peroxynitrite, a mediator of NO toxicity, increase.

Excitotoxic activation of glutamate receptors causes induction of heat shock proteins and rapid transcription of IE genes.

Local brain ischemia

This usually results from arterial stenosis and/or mural thrombosis, atheroemboli, or thromboembolic arterial occlusion, any resulting infarct being within the perfusion territory of an affected artery.

ROLE OF ASTROCYTES

Though preservation of neuronal function and circuitry is the goal of resuscitation after cardiac arrest, astrocytes have a major role in mediating either a suboptimal or excellent clinical outcome.

Neurons deplete stores of ATP more rapidly than astrocytes, but astrocytes (like neurons) can release vesicles that contain glutamate or ATP.

Astrocytes are a reservoir of glycogen (by comparison with neurons); during intense activity, astrocytes can convert glycogen to lactate and pass this substrate on to adjacent neurons as an energy source.

Astrocytes play a crucial role in modulating glutamate levels, thus affecting excitotoxicity during ischemic injury.

Astrocytes have a high density of glutamate receptors that may facilitate uptake of extracellular glutamate during hypoxia-ischemia, thus modulating excitotoxic neuronal injury.

REPERFUSION AFTER CIRCULATORY ARREST

After return of spontaneous circulation (following cardiac arrest), a short-lived hyperemia (15 min) is followed by hypoperfusion (‘no-reflow phenomenon’).

Microcirculatory abnormalities include narrowing of capillary lumens due to endothelial swelling (site of the blood–brain barrier/BBB) and perivascular cells; BBB permeability may therefore alter dramatically.

As soon as cerebral circulation is re-established, ‘reperfusion injury’ may occur – with free radical formation, NO toxicity, glutamate release and dramatic calcium shifts.

Edema and microhemorrhages may result.

PATHOPHYSIOLOGIC CONSIDERATIONS

Adult and infant brains react differently to hypoxia and ischemia. In general, infant brains are more resistant than those of adults; hypoxic-ischemic lesions have a different distribution in infants and adults reflecting an age-related differential (selective) vulnerability to such insults (Fig. 8.1). Because of the brain’s immense metabolic demands, after the onset of ischemia levels of brain glycogen, glucose, ATP and phosphocreatine plummet and are often depleted within 10 min of the acute event. After 15 min of cardiac arrest, up to 95% of the brain may be damaged. Primary respiratory arrest (e.g. due to aspiration, anaphylaxis, or airway trauma) may cause transient brain dysfunction, but less severe damage than ischemia. Optimal brain function and respiration are dependent upon the availability of glucose; however, the neuropathology of hypoglycemic brain injury differs from that due to hypoxia-ischemia.

8.1 Regions of selective vulnerability to hypoxic–ischemic damage are different in the adult and infant brain.
Those regions most susceptible to such an insult are colored in the diagram, though individual cases may show much significant variation. Inset (lower left) emphasizes the observation that cerebellar Purkinje cells are especially at risk during hypoxia.

PATHOLOGY

Despite the relatively straightforward clinical stratification of syndromes that result from prolonged brain hypoxia, the macroscopic and microscopic features associated with hypoxic/ischemic insults can be very variable, and matching clinical history to neuropathology can be imprecise.

Lesions may be considered as either acute/subacute or chronic.

HYPOXIC-ISCHEMIC BRAIN INJURY

Hypoxic-ischemic encephalopathy (HIE) has an extremely variable clinical presentation.

Pure hypoxia and ischemia have different sequelae; in experimental models, hypoxia without ischemia does not necessarily cause brain necrosis, but hypoxia exacerbates ischemic necrosis.

Clinical recovery is in general more favorable after hypoxemic hypoxia than after global brain ischemia.

The severity and duration of HIE after transient cerebral hypoxia or ischemia depend upon:

• severity and duration of insult

• blood glucose level – high levels are associated with poor outcome

• CNS (core) temperature – a lower temperature is protective.

Long-term clinical and neurobehavioral sequelae after transient cerebral ischemia may be difficult to predict; diligent patient observation over days or weeks indicates to likely outcome.

In one study of many patients with HIE secondary to cardiac arrest:

• 13% regained independent function during the first (post-arrest) year

• initial presence of pupillary light reflexes, spontaneous eye movements, and extensor/flexor or withdrawal responses to pain were predictors of relatively good clinical outcome.

High resolution MRI and electrophysiologic parameters (somatosensory evoked potentials, SEPs) may be helpful, e.g. preservation of SEPs is associated with greater likelihood of neurologic recovery.

TYPES OF NEURONAL DEATH OF POTENTIAL IMPORTANCE IN HYPOXIC-ISCHEMIC DAMAGE

NECROTIC: Nuclear pyknosis

Brightly eosinophilic cytoplasm (‘red neurons’) plus loss of Nissl substance.

APOPTOTIC: Apoptotic bodies/Nucleosomal segmentation

The relative importance of apoptosis in AIE/HIE is debated; ultrastructural evidence suggests it is of minimal significance, though some apoptotic pathways may be activated in the course of necrotic cell death.

AUTOPHAGIC: Condensed cytoplasm

Large cytoplasmic vacuoles.

MACROSCOPIC APPEARANCES

Acute/subacute lesions include the following:

Precursors of cystic infarcts – especially in watershed territories.

Cortical laminar necrosis (or, in extreme cases and if hypoxia is severe and prolonged, pancortical necrosis). In rare instances with prolonged survival, pancortical necrosis may be associated with calcification.

Patchy gray discoloration of cortex, with blurring of the gray-white matter interface – an appearance almost identical to that of subacute infarction.

Bright pink color and edema – after acute CO poisoning.

Generalized dusky discoloration and softening – the appearance of ‘non-perfused’ brain (Fig. 8.2).

8.2 Coronal section through a nonperfused (‘respirator’) brain.
The brain is edematous with focally accentuated gray-brown discoloration throughout the cortex and extending into the subcortical white matter, most notably in the watershed regions (arrows) between the perfusion territories of the middle and anterior cerebral arteries.

PRINCIPAL CAUSES OF HYPOXIA

Hypoxemic hypoxia (secondary to low O₂ content in blood):

CO poisoning – mechanisms include displacement of O₂ from hemoglobin and direct binding to heme-containing proteins in the CNS.

Near drowning.

Respiratory arrest – drug-induced, status asthmaticus, epiglottitis, airway trauma, aspiration.

Prolonged status epilepticus.

Stagnant hypoxia (inadequate supply of oxygenated blood, e.g. ischemia):

Cardiac arrest with prolonged asystole or hypotension secondary to a myocardial infarct, cardiac tamponade, or major cardiac arrhythmia.

Intraoperative hypotensive episode(s), especially if there is a sustained and/or profound drop in blood pressure or if there is extensive underlying vascular disease (e.g. carotid or vertebrobasilar atherosclerosis) complicated by a superimposed drop in blood pressure

There is evidence that microemboli released into the circulation during such surgery may also contribute to the subsequent encephalopathy.

Severe increases in intracranial pressure (ICP). When ICP reaches mean arterial BP, brain perfusion ceases.

Cessation of brain perfusion after prolonged periods on a respirator.

The term ‘respirator brain’ is sometimes used to describe such brains at autopsy, but a much preferred descriptor is ‘non-perfused brain’ (NPB), i.e. not all individuals who have been on a respirator develop NBP.

Histotoxic hypoxia (inability of brain tissue to utilize available O₂):

Cyanide and sulfide exposure – due to inhibition of mitochondrial enzymes involved in oxidative respiration.

NEURONAL SELECTIVE VULNERABILITY AND EXCITOTOXICITY

Selective vulnerability refers to the differential susceptibility of brain and spinal cord anatomic regions to an hypoxic-ischemic event. The following regions are listed in (approximately) decreasing order of vulnerability to hypoxia (in adults):

Hippocampus – especially CA1 segment of pyramidal cell layer.

Cerebral cortex – especially layers 3 and 5.

Cerebellum – especially Purkinje cells.

Thalamus.

Basal ganglia.

Brainstem.

Hypothalamus and spinal cord.

In both premature and term infants, the pattern of neuronal susceptibility to hypoxic-ischemic injury differs from that in adults (see Chapter 2).

Determinants of selective neuronal vulnerability include:

Variable O₂ and energy requirements of different neuronal populations and of individual neurons within an anatomic region.

Glutamate receptor densities. Glutamate is an excitatory neurotransmitter and neurotoxic when present in excess, as occurs after hypoxic-ischemic injury. Several glutamate transporters are now recognized (EAAT1–5), some (EAAT1/2) predominantly present on astrocytes and others on neurons. All are selectively expressed in different anatomic regions and cell types throughout brain.

Activation of immediate early (IE) genes (e.g. heat shock proteins) by ischemia-induced free radicals and the vasodilatory activity of nitric oxide.

No macroscopic abnormality. The brain may appear normal, but this does not necessarily predict a lack of pathology on microscopic examination.

Chronic lesions that evolve from acute/subacute pathology often become more obvious and include:

Watershed/borderzone infarcts (Fig. 8.3).

8.3 Relatively recent bihemispheric watershed infarcts in anterior cerebral artery/middle cerebral artery border zones.
Note the dusky gray-brown discoloration of the cortex in these regions (arrows), which is accentuated at the junction between the gray and white matter. There is also a region of necrosis in the left thalamus. The patient was a child aged 2 years with double outlet right ventricle who underwent the Fontan procedure. Intraoperative and postoperative complications led to death 15 days later.

Cortical laminar necrosis or variable thinning of the cortex (Figs 8.4, 8.5).

8.4 Coronal brain section from a 73-year-old woman who experienced a cardio-pulmonary arrest with prolonged asystole approximately 1 month prior to death.
Significant neurologic impairment followed the arrest. Coronal sections of the cerebral hemispheres show multiple regions of cortical thinning and discoloration (arrows). Changes are most pronounced in the ACA and MCA vascular territories; by contrast, the inferior aspect of the temporal lobe appears relatively unaffected.

8.5 Cortical laminar necrosis (LN).
(a) Coronal section through the brains of two different patients; a ‘control’ patient, without history of cardiac arrest or neurologic deficit (right), and a patient who survived several days after extended cardiopulmonary arrest (left). Contrasting features between the two include patchy gray discoloration with pronou0nced thinning of the neocortex in a laminar pattern (left). Despite multifocal areas of laminar necrosis (indicated by arrows), many regions are relatively spared (arrowheads). Another slice (b) from brain illustrated in (a, left), highlights the patchy nature of cortical necrosis. (c) Whole mount from a focus of LN showing extensive cortical injury, but with comparative sparing of the superficial cortical layers. Dystrophic calcification had occurred in areas of LN (see Fig. 8.11c). (d) More subtle LN manifests as a thin dark line running through the cortical ribbon (arrowheads).

Cystic necrosis following CO poisoning. This is usually symmetrical, affecting the globus pallidus but sparing other regions of the basal ganglia. Occasionally, this pattern of cavitation is seen without well-documented CO exposure (Fig. 8.6), occurring as the result of cyanide poisoning, heroin overdose, or other causes of global cerebral hypoxia/ischemia.

8.6 Bilateral pallidal cystic necrosis.
(a) Pallidal necrosis in a patient who died after surgery for a malignant glioma in the left temporal lobe. The surgical bed is seen at lower left. He had previously attempted suicide by carbon monoxide poisoning several months before his death. Note the bilateral pallidal cystic necrosis (arrows), which is more extensive on the right than on the left. (b) Comparable coronal section from the brain of a 75-year-old woman with severe toxic epidermal necrolysis syndrome and no history of carbon monoxide poisoning. Recent bihemispheric parieto-occipital infarcts (not shown) and bilateral partial necrosis of globus pallidus (arrows) were noted at necropsy.

Hippocampal atrophy due to hippocampal ‘sclerosis’ (HS). This is the most common microscopic finding in a partial lobectomy for temporal lobe epilepsy, though the role of hypoxic neuronal injury in the pathogenesis of HS is undetermined. (A macroscopic pathology very similar to HS is now recognized as a neuropathologic substrate of unknown etiology in elderly individuals with memory impairment, gross appearances ranging from an atrophic hippocampal formation to a gray band in part of the pyramidal cell layer).

Leukoencephalopathy secondary to anoxia or ischemia (see Fig. 8.15).

8.15 Hypoxic–ischemic leukoencephalopathy.
Note white matter discoloration and necrosis of central part of the corpus callosum (arrows). This patient aged 69 years underwent complicated aortic surgery and developed ‘mental status changes’ and spinal cord paralysis secondary to a cord infarct 1 month before death. There were also widespread necrotic lesions in the cortex and subcortical white matter. Histologic changes included dense collections of macrophages within affected white matter.

In some cases, no macroscopic abnormality is evident. However, most individuals that have been in a PVS due to hypoxic-ischemic brain injury will show some macroscopic lesions.

MICROSCOPIC APPEARANCES

Acute/subacute lesions

Ischemic (irreversibly damaged) neurons have collapsed pyknotic nuclei and brightly eosinophilic cytoplasm (in H&E-stained sections). At later time points, as chromatin is degraded, nuclei become more eosinophilic and appear to blend with surrounding cytoplasm. These changes are first discernible histologically after survival for several hours (most estimates are 4–6 hours minimum), last for up to 2 weeks, and are particularly likely to be seen in neurons that are sensitive to hypoxia, e.g. hippocampal neurons in the CA1 field, pyramidal neurons in the cerebral cortex, cerebellar Purkinje cells, reticular neurons of the thalamus, and medium-sized neurons of basal ganglia (Figs 8.7–8.9). Neuropil may show slight vacuolization or be normal (in contrast to marked neuropil vacuolization in ischemic infarction). Normal neurons may be seen immediately adjacent to affected nerve cell bodies. Hypoxic-ischemic neuronal change is sometimes demonstrated in smear/squash preparations of affected brain regions (Fig. 8.10).

8.7 Acute hypoxic neuronal change.
(a) Normal cortical neurons with basophilic cytoplasm and nuclei with prominent nucleoli. (b) Hypoxic neurons showing pronounced cytoplasmic eosinophilia, collapse of cytoplasm with accentuated (artifactual) pericellular spaces, and pyknotic nuclei with indistinct nucleoli, photographed at magnification comparable to that in panel (b). (c) More subtle and patchy hypoxic–ischemic neuronal change affecting only scattered neurons. (d) Hippocampal pyramidal cell layer (CA1 segment) showing brightly eosinophilic neurons, reflecting severe acute anoxic-ischemic change. (e) Similar region of hippocampus from another patient, with slightly longer interval between anoxia and death. Many eosinophilic neurons are seen, some as ‘ghost’ nerve cell bodies; in addition many reactive cells (probably microglia and some astrocytes) surround dead neurons.

8.8 Hypoxic change in cerebral Purkinje cells.
The cerebellar cortex is especially vulnerable to hypoxic–ischemic lesions. (a) Low-power view of normal cerebellum. (b) High-power view of normal cerebellum. (c) Low-power view of cerebellar cortex from a 74-year-old patient who died shortly after complicated open heart surgery. At low magnification there is little obvious difference between this specimen and that shown in (a). (d) High-power view of (c) showing eosinophilic Purkinje cells with smudged and pyknotic nuclei, which contrast with the normal Purkinje cells that have plump large vesicular nuclei and prominent nucleoli (b).

8.9 Sections of cerebellum from a patient who experienced severe hypoxia prior to death.
In contrast to the preserved cerebellar architecture shown in Fig. 8.8, there is microvacuolization of the molecular layer (post-infarction changes) in addition to profound eosinophilia of Purkinje cells (arrows in panel B).

8.10 Hypoxic neuronal change.
This is clearly demonstrated in smear/squash preparations, as shown here in a preparation of cerebellum.

Ultrastructurally, ischemia (studied almost exclusively in a variety of animal models) produces changes of cellular necrosis (one of many mechanisms of neuronal death), with breaks in nuclear and cell membranes and flocculent densities within mitochondria. Mitochondrial swelling is an early feature, but (in the absence of further alterations) is considered to be a reversible change. ‘Delayed neuronal death’ describes a degeneration of neurons that begins hours to days after a global ischemic insult and is best documented in the hippocampus; there is debate as to the mechanism by which this occurs (necrosis versus apoptosis/role of delayed excitotoxicity).

A non-perfused (‘respirator’) brain shows autolysis and anterior pituitary necrosis, but no inflammatory cell/macrophage infiltration, reflecting the lack of perfusion (that may occur into infarcted brain tissue). Tissue remains soft even after prolonged fixation and stains poorly in histologic sections. If accompanying brain swelling has been severe, fragments of disrupted cerebellum may break away from this structure and be found in the subarachnoid space around the spinal cord at autopsy.

Chronic lesions

Laminar necrosis (LN) usually affects the middle cortical layers, especially laminae 3 and 5. In extreme instances, there may be full-thickness necrosis (Figs 8.5, 8.11). LN may be suspected antemortem on the basis of high-intensity T1-weighted MRI abnormalities that follow a gyral distribution. Necrosis is usually accentuated in watershed zones.

8.11 Hypoxic–ischemic cortical injury.
(a) This patient aged 80 years underwent pituitary surgery 1 month before death. At necropsy there were minimal abnormalities of the brain, but microscopically there was widespread hypoxic neuronal change, vacuolation of the superficial cortex, subtle microvascular proliferation, and gliosis. Hypoxic–ischemic cortical injury. (b) Severe cortical necrosis in a different patient. This is from the brain illustrated in Fig. 8.5b. It shows pancortical necrosis tantamount to infarction. The cellular content of the neuronal layers comprises a mixture of astrocytes and macrophages. (c) High-power view of the cerebral cortex shown in Fig. 8.5c. Note extensive destruction of deep cortical layers, with dystrophic calcification, but relative preservation of superficial cortical layers.

In many brain regions, long-term hypoxic-ischemic damage may appear simply as a focal loss of neurons with variably severe reactive astrocytosis. This is especially dramatic in the pyramidal cell layer of the hippocampus; CA1 is highly vulnerable to hypoxia, whereas CA2 is relatively resistant (Fig. 8.12, 8.13). A distinction is often made between ‘selective neuronal loss and gliosis’, in which neurons disappear with attendant astrocytic gliosis, and ‘infarction’, in which all cellular elements die and macrophages infiltrate to remove cellular debris. In practical terms, the two processes may be difficult to differentiate months or years after the brain injury has occurred, though cystic change and encephalomalacia are certainly more pronounced in an infarct. In infants that experience severe perinatal asphyxia/hypoxia, extensive cystic encephalomalacia (Fig. 8.14) may lead to severe mental retardation and intractable seizures.

8.12 Selective vulnerability to hypoxic–ischemic change in the hippocampal pyramidal cell layer.
(a) Normal hippocampus at low magnification. The figure includes part of the granule cell layer and part of the pyramidal cell layer as far as the prosubiculum/CA1 junction. (b) Segmental loss of neurons and prominent neuropil vacuolation within the CA1 sector of pyramidal cell layer. (c) There is an infarct involving virtually the entire CA1 field or sector and extending into the prosubiculum. Neuron loss and spongy change are seen in the affected neuropil. Note preservation of the granule cell layer (dentate fascia). (d)Normal CA1 zone of hippocampal pyramidal cell layer, contrasted with (e) a region with severe acute anoxic–ischemic change (neuronal eosinophilia, cytoplasmic and nuclear collapse, etc). (f,g) Severe hippocampal sclerosis in a patient with longstanding temporal lobe epilepsy. (f) Arrows indicate junction between sclerotic CA1 zone (at left) and intact prosubiculum (at right). (g) The junction between the two sectors is highlighted; gliotic tissue and neuron depletion in CA1, intact neurons in prosubiculum.

8.13 Sections of hippocampus from a 76-year-old man with history of therapy for gastric carcinoma complicated by seizures and memory impairment. Autopsy showed many small brain infarcts.
(a) The hippocampus shows atrophy and loss of pyramidal cells in CA1 between arrows. (b) The contrast between grossly abnormal CA1 and relatively normal CA2 segments (arrows – border zone) is demonstrated at higher power in (c) and (d), where there is relative preservation of neurons in CA2 (c) but profound neuronal loss and astrocytic gliosis in CA1 (d).

8.14 Multifocal cystic/gliotic encephalopathy. This is a consequence of late intrauterine/perinatal asphyxia in infants.
(a) Representative coronal slice of brain, showing multiple regions of cystic cavitation of the gyral white matter. (b) Low magnification view of a representative gyrus, showing extensive cystic cavitation of its ‘core’, with LN-like change in the adjacent cortical ribbon.

A leukoencephalopathy may coexist with hypoxic-ischemic gray matter damage (Fig. 8.15), and exceptionally may be the predominant finding after prolonged hypoxia in association with hypotension. It has been associated with CO poisoning, but may occur in other settings, such as drug overdose. Histologically, there may be necrosis with abundant macrophages, or loss of myelin in association with relative axonal sparing, reactive astrocytosis, and activation of microglia, as well as overexpression of amyloid precursor protein (APP) within and among adjacent axons. It is important to remember, however, that white matter ‘pallor/degeneration’ in an individual with a past history of severe neocortical HIE may simply represent Wallerian degeneration.

PERSISTENT VEGETATIVE STATE (PVS) AND ‘BRAIN DEATH’

Definition

The vegetative state (VS) is a clinical condition of complete unawareness of self and environment, accompanied by sleep–wake cycles, with either complete or partial preservation of hypothalamic and brainstem autonomic functions.

Persistent VS (PVS) is a VS present 1 month after acute traumatic or non-traumatic brain injury or lasting for at least 1 month in patients with degenerative or metabolic disorders or developmental malformations.

Neuropathologic findings vary according to etiology, but usually include one or more of the following:

Diffuse cortical injury

This is usually hypoxic-ischemic, metabolic (e.g. as a result of hypoglycemic injury or a lysosomal storage disease), or degenerative (e.g. Alzheimer’s disease) in etiology.

Bilateral thalamic injury

This is almost always due to hypoxia-ischemia.

Diffuse white matter injury (leukoencephalopathy)

The commonest cause is diffuse axonal injury secondary to traumatic brain injury (TBI). PVS due to diffuse white matter damage rarely complicates hypoxic-ischemic injury (see Fig. 8.12), and may also result from leukodystrophies associated with lysosomal or peroxisomal defects and other genetic disorders (e.g. Alexander’s disease).

Major developmental CNS malformations

Examples are holoprosencephaly, hydranencephaly, and the sequelae of severe intrauterine/perinatal brain injury resulting from asphyxia (including multi-cystic encephalopathy).

Secondary changes caused for example by seizures, effects of medications, and infections, are often present.

Detailed clinicopathologic investigations suggest that subjects in PVS consistently show profound abnormalities of subcortical white matter and/or thalamic relay nuclei, even when the cerebral cortex, cerebellum and brainstem are relatively normal.

Definitions from the Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. N Engl J Med 1994; 330:1499–1508.