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

image CEREBRAL BLOOD FLOW (CBF)

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

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

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

image 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.

image 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.

image 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:

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

image 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.

image CELLULAR MECHANISMS OF ISCHEMIC CELL DEATH

image 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.

image 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.

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

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

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

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

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

image 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.

image ROLE OF ASTROCYTES

image 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.

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

image 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.

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

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

image REPERFUSION AFTER CIRCULATORY ARREST

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.

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.

image HYPOXIC-ISCHEMIC BRAIN INJURY

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

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

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

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

image 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.

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

image 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.

image 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.

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