Vascular disease and infarcts

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Vascular disease and infarcts

In the setting of rapidly evolving neurologic deficits, stroke is not synonymous with brain infarct, since the types of cerebrovascular disease that usually result in a stroke may involve infarction or intracranial hemorrhage (see Chapter 10). Infarct, a localized area of ischemic brain injury, should also be differentiated from global hypoxic-ischemic brain injury (see Chapter 8). Stroke has been defined by the WHO as ‘rapidly developing clinical signs of a focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death and with no apparent cause other than that of vascular origin’. Stroke ranks as the second most common single cause of death in the developed world.

The definition of brain infarct or infarction (the pathophysiological process that results in an infarct) has undergone numerous refinements over the last 30years as the result of advances in neuroimaging. The goal of neuroimaging is to differentiate permanent/irreversible brain tissue injury from viable tissue at risk for injury, the latter being viewed as tissue that could be salvaged as a stroke evolves over minutes or hours. Increasingly, both clinicians and neuroscientists think of the cerebral vasculature together with its surrounding parenchymal components – the ‘neurovascular unit’. Cellular elements of the neurovascular unit have critical metabolic interrelationships and encompass components of the cerebral capillary and arteriolar walls, as well as surrounding glia and neurons. Function or dysfunction of the neurovascular unit influences the capacity of the CNS to repair itself after stroke.

Transient ischemic attack (TIA) is viewed by clinicians as a warning sign of impending infarction (less commonly cerebral hemorrhage). Therefore, since 2009, TIA has been defined as ‘a brief or transient episode of neurologic dysfunction caused by focal brain, spinal cord or retinal ischemia, with clinical symptoms typically lasting less than one hour and without evidence of acute infarction’.

To place these concepts in a more practical context, brain infarcts can be caused by:

Large vessel (or macrovascular) arterial disease.

Small vessel (or microvascular) arterial disease (arteries <400–500 μm in diameter).

Emboli originating in:

• heart or major artery

• vein in association with a cardiac ‘right–left’ shunt, e.g. patent foramen ovale.

Venous/sinus thrombosis.

STROKE TERMINOLOGY

The term ‘stroke’ includes:

Acute stroke

Infarction describes rapidly developing focal clinical signs of CNS (and/or retinal) dysfunction due to ischemia, and either radiologic evidence of CNS (and/or retinal) ischemia in a defined vascular distribution, or symptoms and signs of CNS dysfunction persisting for at least 24 hours, with exclusion of non-ischemic etiologies.

Intracerebral (parenchymal) hemorrhage describes a focal collection of blood within brain parenchyma (possibly extending to the ventricular system) on neuroimaging or at necropsy, which is not due to trauma, hemorrhagic conversion of an infarct, or cerebral venous (sinus) thrombosis.

Subarachnoid hemorrhage (SAH) describes bleeding into the subarachnoid space (SAS) that is detected on neuroimaging, by lumbar puncture, or at necropsy, and which is not due to trauma or hemorrhagic conversion of an infarct.

Cerebral venous thrombosis (CVT) describes infarction or hemorrhage in the CNS, evident on neuroimaging and due to thrombosis of a cerebral vein or venous sinus.

Silent stroke

Silent brain infarct: radiologic evidence of cerebral infarction (>3 mm in diameter), in the absence of a non-ischemic cause and without a history of acute CNS dysfunction.

Silent cerebral hemorrhage: focal collection of chronic blood products within the brain parenchyma and/or ventricular system on neuroimaging or at necropsy, without a history of acute CNS dysfunction, which is not due to trauma, CVT, or hemorrhagic conversion of a cerebral infarct.

Cerebral infarct subtypes

Carotid (including occlusion) – 15%.

GENETICS OF ISCHEMIC CEREBROVASCULAR DISEASE

Brain infarcts occur as one of many systemic manifestations in various hereditary disorders.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS)

MELAS is due to any of several mutations in mitochondrial DNA.

Muscle biopsy aids diagnosis – mitochondrial cytopathy with ragged red fibers (modified Gomori trichrome stain).

Large or small infarcts may occur, not conforming to major arterial territories. These are sometimes described as infarct-like lesions rather than infarcts, as they are probably caused by defective oxidative metabolism rather than ischemia.

Sickle cell disease (SCD)

SCD is an autosomal recessive hemoglobinopathy characterized by chronic hemolytic anemia and ‘sickle-shaped’ erythrocytes.

SCD results from point mutation in the hemoglobin β-chain.

Number of strokes/100 patient-years increases from 0.13 (<2years of age) to 1.28 (>50years of age).

At least 10% of SCD patients have a stroke during their lifetimes – 75% ischemic, 25% hemorrhagic.

Homocystinuria

Homocystinuria is caused by homozygous defects in genes encoding enzymes of homocysteine metabolism.

Increase in homocysteine causes premature atherosclerosis leading to stroke and infarcts in other end organs.

Vascular pathology includes typical atherosclerotic change.

Fabry disease

X-linked recessive disorder caused by deficiency of the lysosomal enzyme α-galactosidase (1/117 000 live births).

Globotriaosylceramide (GB3) accumulates in many cell types, including endothelium and vascular smooth muscle.

Neuropathy is common.

Stroke is usually ischemic, but may be hemorrhagic.

Large and small blood vessel territories may be involved.

Hereditary hemorrhagic telangiectasia (HHT, Osler–Weber–Rendu syndrome)

HHT is characterized by vascular dysplasia and recurrent hemorrhages.

HHT type 1 is linked to mutations in the endoglin gene, ENG (chromosome 9q).

HHT type 2 is linked to mutations in ACVRL1 (chromosome 12q).

Ehlers–Danlos syndrome type IV

Affected individuals may show arterial dissection and aneurysms.

Ehlers–Danlos syndrome type IV is associated with deficiency of type III collagen, a product of the COL3A1 gene (chromosome 2).

Marfan syndrome

Affected individuals may show aortic dissection, dilatation, or spontaneous rupture, and saccular aneurysms.

Ehlers–Danlos syndrome type IV results from mutations in the gene encoding fibrillin-1 (chromosome 15q21.1); second locus maps to chromosome 3p24.2–25.

Population-based studies of stroke in defined geographic regions (e.g. Iceland) indicate:

Many alleles, each with a small effect, contribute to the pathology of ischemic infarcts.

Most ‘candidate gene’ pathways involve chronic inflammation, lipid metabolism, NO release, coagulation-hemostasis, and renin-angiotensin-aldosterone systems.

Polymorphisms in phosphodiesterase 4D (PDE4D) and lipoxygenase activating protein (ALOX5AP) influence the pathology of ischemic stroke in some populations.

Protein kinase C family single nucleotide polymorphisms may be associated with lacunar infarcts in some populations.

Atrial fibrillation (a common cause of ischemic stroke in those >65years of age) is associated with a sequence variation on chromosome 4q25.

FACTORS IMPORTANT IN ISCHEMIC BRAIN INJURY

Activation of platelets secondary to exposure of vascular subendothelium, fibrin deposition, or ulceration of atheromatous plaque leads to ‘platelet-fibrin thromboemboli’ that may adhere to vessel intima, occlude a vessel lumen, or embolize distally.

Ischemia causes rapid loss of high-energy phosphate compounds, generalized depolarization and release of excitatory amino acids. Subsequent activation of glutamate receptors produces a dramatic influx of Ca^2 +, Na⁺, Cl⁻ ions, with shift of water to intracellular compartments and edema.

Reactive oxygen species cause oxidative stress and subsequent endothelial dysfunction contributes to vasogenic edema.

Induction of new gene products (e.g. heat shock proteins) may be biomarkers of brain damage and severity of stroke and CNS trauma, possibly predicting outcome.

Suppression of protein synthesis upon reperfusion after ischemia involves alterations in eukaryotic translation initiation factors 2 and 4.

Activation primarily by Ca^2 + ions of various enzymes (proteases, lipases, endonucleases), nitric oxide, and free radicals damages membranes, mitochondria and DNA, and in turn induce formation of inflammatory mediators activation of microglia.

ATHEROSCLEROSIS AND STROKE

Atherosclerotic stroke is usually associated with documented risk factors for atherosclerosis and/or a family history of atherosclerosis (often premature). Patients may manifest (simultaneously, before, or after) coronary artery or peripheral vascular disease.

TIA is a common presentation of stroke; a patient experiencing a TIA is at high risk for developing a completed stroke in the near future.

The focal neurologic deficit is referable to the artery involved by unstable atheroma, e.g. a right ICA atheromatous plaque may produce transient or episodic right monocular blindness (amaurosis fugax) and left hemiparesis. Platelet-fibrin emboli or atheroemboli (Hollenhorst plaques) can sometimes be visualized by funduscopic examination.

Atherosclerotic stroke results from inadequate perfusion of a brain territory due either to arterial occlusion or dislodgement and embolization of atheromatous or platelet-fibrin material.

The role of intraplaque hemorrhage or plaque rupture in stroke pathogenesis (e.g. at the carotid bifurcation) is demonstrated in some autopsy studies.

Thrombosis usually originates extracranially, at the carotid artery bifurcation or within the intraosseous portion of the vertebral artery, though thrombus can propagate distally to involve intracranial vessels. Less often, an atherosclerotic intracranial artery is the site of primary thrombosis.

Atherosclerotic plaques examined less than 60 days after an ischemic ‘event’ show more macrophage infiltration after a stroke than after a TIA. Macrophage content declines over time in plaques associated with strokes, but not in plaques associated with TIAs.

EPIDEMIOLOGIC ASPECTS OF STROKE

In each successive decade beyond the age of 55years, the stroke rate doubles in both men and women; incidence for individuals aged 45–54years is ~100/100 000, increasing to >1800/100 000 for those aged over 85years.

In the USA, there are approximately 500 000 new strokes annually.

In 2005, stroke prevalence was 5.8 million among adults aged >20years of age; age-specific prevalence rises from 1–2% to >10% from 45–85years of age.

Stroke causes ~150 000 deaths/year (USA), although this figure has been declining, possibly as the result of stroke risk factor modification.

In the USA, stroke-related death rates vary widely between states: 31–42/100 000 in Arizona, New Mexico, Colorado, New England versus 52–61/100 000 in Oregon, Idaho and the south-eastern states.

Major risk factors for stroke (in addition to those for atherosclerosis) are: oral contraceptive use; some hematologic disorders (e.g. sickle cell disease, polycythemia); some inherited coagulopathies, and various cardiac/vascular diseases.

In most USA studies, brain infarction is approximately 10 times more common than brain hemorrhage. This ratio is lower in some European and virtually all Japanese studies; some series from Asia have found hemorrhage to be almost as common as infarction.

The annual financial burden of stroke in the USA is $65 billion ($219 billion for cancer; $174 billion for diabetes); acute (hospital) care is required by 45–50%, nursing home placement is required by 17–20%, and long-term ambulatory care is required by 35%.

LARGE ARTERIAL DISEASE

ATHEROSCLEROSIS

Atherosclerosis is by far the leading systemic vasculopathy to result in brain infarcts, especially in older patients. Risk factors for and the pathogenesis of atherosclerosis are presumed to be similar, regardless of vascular territory, e.g. coronary, cerebral, mesenteric, and limb arteries. Modifiable risk factors include hypertension, cigarette smoking, hyperlipidemia/hyperlipoproteinemia, and diabetes.

Atherosclerosis can affect both intracranial and extracranial large arteries, and may extend into leptomeningeal arteries. When extracranial (cervical) atherosclerosis (e.g. at the carotid bifurcation) is the proximate cause of cerebral ischemia, a measure of prophylaxis against a large infarct may be achieved through carotid endarterectomy. In recent years, stenting of atherosclerotic arteries has been used as a less invasive procedure than endarterectomy. The benefits of carotid endarterectomy have been clearly established in clinical trials; symptomatic patients with 50–99% stenosis benefit significantly in a comparison with the best medical treatment.

MACROSCOPIC APPEARANCES

The severity of atherosclerosis can vary significantly in different arteries (e.g. severe basilar artery involvement may accompany less prominent MCA involvement). The degree and extent of aortic or coronary atherosclerosis do not predict its severity in the intracranial basal cerebral vasculature, i.e. compartments of the circle of Willis. Atheroma is often most severe at the origins of the vertebral arteries and carotid bifurcation (Figs 9.1, 9.2). Intracranial atherosclerosis is most severe in major branches of the circle of Willis and vertebrobasilar system (Fig. 9.3). Atheroma in distal arterial branches is more common in Asian and African-American subjects. The extent and topography of atherosclerosis in the basal vessels are often best documented by removing the circle of Willis from the fixed brain (Fig. 9.3b). In such a specimen from a subject with severe atherosclerosis, decalcification prior to histologic examination is recommended. Carotid endarterectomy specimens from individuals with TIA or threatened ischemic stroke are often submitted for histologic examination; extent and severity of atheroma within plaques, as well as the presence of plaque ulceration, necrosis and thrombus adherent to intima must be assessed (Fig. 9.2).

9.1 Atheroma of carotid artery.
Sections of common carotid (right) and internal carotid arteries removed at necropsy from a patient with severe atherosclerotic cerebrovascular disease and systemic atherosclerosis. Note severe stenosis of the lumina and eccentric intimal thickening of the internal carotid artery with thrombosis.

9.2 Carotid endarterectomy specimens from two patients.
(a) A specimen cut open to reveal grumous fractured eggshell-like atheromatous material and superimposed mural thrombus. (b) Another specimen cut in cross section showing atheroma at the carotid bifurcation. (Courtesy of Dr Sophia Apple, Department of Pathology and Laboratory Medicine, UCLA Medical Center.)

9.3 Severe atherosclerosis of the circle of Willis and its major branches.
(a) Patchy yellow discoloration of the arterial branches indicating underlying atheroma. (b) Severe atheroma involving the basal arteries of an elderly patient with ischemic-vascular dementia. Arrow indicates basilar artery. Note especially severe atherosclerosis of the basilar, posterior cerebral and middle cerebral arteries. However, patchy atheroma extends even into distal branches. (Courtesy of Dr Ivan Klement.)

MICROSCOPIC APPEARANCES

Histopathologic features of atheroma are best highlighted with stains that differentiate elastica, fibrous tissue, and smooth muscle (e.g. elastica van Gieson). Immunohistochemistry (IHC) using primary antibodies to vascular smooth muscle actin, endothelium (Factor 8, lectins), and macrophages may be helpful. Fibromuscular intimal hyperplasia with an intact endothelium and variable narrowing of the vascular lumen is noted in ‘early’ and asymptomatic vascular lesions, and often discovered incidentally at necropsy (Fig. 9.4). Complicated plaques show cholesterol clefts and prominent lipid-/hemosiderin-laden macrophages and may be heavily calcified. There is usually significant narrowing of the arterial vessel lumen, sometimes in association with ulceration and overlying mural or occlusive thrombus (Fig. 9.5). Immunohistochemistry (IHC) using primary antibodies to smooth muscle actin often demonstrates a thick smooth muscle cell ‘cap’ over a lipid-rich subendothelial plaque. It is quite rare for even severely narrowed segments of the circle of Willis to show plaque ulceration, in contrast to the frequency of this phenomenon in ICA endarterectomy specimens. Severely atherosclerotic arterial segments, especially in the basilar artery may show ectasia or even a fusiform aneurysm.

9.4 Atherosclerosis with fibromuscular intimal hyperplasia.
Eccentric atheroma is prominent in these arteries, but is largely composed of smooth muscle cells and ‘ground substance’ (glycosaminoglycans), though scattered cholesterol clefts are also present. Note the intact endothelium in all instances. The single elastic lamina (as is the case in intracerebral arteries) is also largely intact and best demonstrated in panels b and c. (a) Middle cerebral artery. (b) Meningeal artery, a branch of the posterior cerebral artery. (c) Section of posterior cerebral artery stained with Elastic van Gieson.

9.5 Complicated atherosclerosis.
(a) Prominent eccentric atheroma with smooth muscle cell hyperplasia overlying a region with abundant cholesterol clefts in an intracranial meningeal artery. The atheroma has produced significant stenosis. Note discontinuity in elastica. (b) Low magnification view of cross-section through a major branch of the circle of Willis, with severe stenosis of the lumen. Arrows indicate smooth muscle cell ‘cap’ adjacent to lumen and overlying grumous cholesterol material; no ulceration or mural thrombus is noted adjacent to the lumen. (c) Basal artery showing severe stenosis of the lumen by atheroma on two aspects of the vessel wall. (d) Small meningeal artery almost occluded by atheromatous material; only a small residual lumen remains. (e) Small meningeal artery (branch of ACA) with mild atheroma consisting almost exclusively of fibromuscular intimal hyperplasia; arrows indicate internal elastic lamina.

The distal circulation, both meningeal and parenchymal arteries, may show atherosclerotic changes or deposits of platelet-fibrin material (Fig. 9.6). Rarely, examination of an autopsy brain specimen from an individual with severe atherosclerosis may yield the finding of numerous atheroemboli within infarcted regions (Fig. 9.7).

9.6 Intracerebral atherosclerosis.
Microatheroma almost occluding a tortuous artery in the basal ganglia of a patient with longstanding hypertension.

9.7 Cerebral atherosclerosis and complications of atheroma.
(a) Atherosclerosis in a small artery (external diameter approximately 500 μm) manifesting as fibromuscular intimal hyperplasia. (b) Intraluminal macrophages originating in embolic material from fragmented atheromatous plaques in a 58-year-old hypertensive woman with multiple cerebral and cerebellar infarcts in both watershed and large artery territories. (c) Cholesterol clefts within atheroemboli from fragmented atheromatous plaques occluding lumina of two meningeal arteries (arrows) within brain specimen of a patient with multiple cerebral infarcts. (d) Small intraparenchymal artery occluded by atheromatous material, including foreign body giant cell around cholesterol ‘clefts’. (e) Larger artery in another patient showing occlusive thrombus composed primarily of atheromatous material (‘atheroembolus’) within which prominent residual cholesterol clefts are seen. An ‘embolic’ origin of the atheromatous material is suggested by the relative absence of intrinsic atherosclerosis in the arterial wall.

THE AUTOPSY OF A STROKE PATIENT

Autopsy studies of stroke should not be used to infer epidemiologic data, since patients that come to necropsy are a highly selected group. However, autopsies are crucial in highlighting vascular mechanisms that are of importance in stroke pathogenesis.

The approach to a stroke autopsy varies according to whether the stroke was ischemic or hemorrhagic (or a combination of both).

Clinical history and neuroimaging studies hugely assist postmortem evaluation and allow a clinicopathological timeline to be established.

Especially important for infarction/ischemic stroke

Assess the patency of major neck arteries (carotid/vertebral) by injecting water at their origins and monitoring flow into the cranial cavity after brain removal.

• If any vessel is obstructed, the prosector should attempt to establish:

– site(s) of occlusion/severe stenosis

– cause(s) of occlusion (e.g. atheroma, embolus, dissection, other).

• Vessels (arteries) should be dissected until significant lesions are documented; this sometimes requires painstaking removal of the entire carotid or vertebral artery.

• Dissection of intraosseous portions of the vertebral arteries is facilitated by prior removal of the cervical vertebral bodies. This is achieved from an anterior approach by making a parasagittal saw cut through the medial aspect of the vertebral pedicles (a laterally placed cut will damage the arteries).

Carefully examine the heart, looking particularly for:

• Endocarditis (infective or non-infective/marantic) – culture/histology of any valvular lesion possibly helpful.

• Any cause of a right-to-left shunt (e.g. septal defect, patent foramen ovale).

• Valvular abnormalities, especially in the left heart (e.g. myxomatous degeneration/prolapse of mitral valve, calcific aortic sclerosis with stenosis).

• Evidence of recent myocardial infarction ± mural thrombus or old infarction with ventricular aneurysm ± mural thrombus.

Look for old/recent infarcts in other organs, which may suggest a source of embolism.

If there is minimal evidence of macro/microvascular disease, and cardiac examination is normal, consider hematologic disorders (e.g. antiphospholipid syndrome, platelet abnormalities, coagulopathies). These must be sought in non-neuropathologic components of the autopsy and in antemortem laboratory results or through toxicology specimens to assess a possible role for recreational drugs.

Especially important for hemorrhage:

In the medical history and general autopsy, seek evidence of disease that may be of etiologic significance, even though this may not be discovered in many individuals:

• Hypertension – cardiomegaly with left ventricular hypertrophy, nephrosclerosis.

• Dementia/cognitive impairment – especially in elderly patients this may point to Aβ cerebral amyloid angiopathy (CAA), which is commonly associated with Alzheimer’s disease.

• Neoplasia – hemorrhage in association with metastasis or primary glioma, especially oligodendroglioma.

• History suggesting recreational drug abuse, e.g. amphetamines, heroin.

When a hematoma is documented at the time of brain removal, the prosector must establish:

• In which compartment it is present and (optimally) in which compartment it originated (e.g. subdural, subarachnoid, combined parenchymal/subarachnoid or intraventricular).

• Its approximate volume and effect(s) on surrounding brain (e.g. edema).

• By dissecting (prior to fixation) the circle of Willis and its major branches, whether a ruptured saccular aneurysm has caused any subarachnoid (or intraparenchymal) hematoma.

When a hematoma is first discovered at the time of brain cutting (i.e. it was clinically unsuspected), sample surrounding tissues generously in order to document microvascular disease or remnants of hemangioma/neoplasm. Also evaluate reactive changes in adjacent brain to provide an estimate of its age.

For special studies regarding the evaluation of evacuated intracerebral blood clot, see Chapter 10.

HYPERHOMOCYSTEINEMIA, ATHEROMA, AND BRAIN INFARCTS

Hyperhomocysteinemia occurs in a variety of inherited disorders, including homocystinuria (secondary to cystathione β-synthase deficiency) and several rare disorders of vitamin B12 or folate metabolism.

Elevated blood levels of homocysteine increase the risk of atheroma and of arterial and venous thromboses in several organs, including brain.

Several mechanisms are probably of importance. Homocysteine:

• promotes proliferation of vascular smooth muscle cells

• inhibits proliferation of endothelial cells

• increases release of thrombogenic factors from endothelial cells.

Strong epidemiologic evidence exists that acquired mild hyperhomocysteinemia, in many cases probably due to subclinical folate deficiency, is a risk factor for development of atheroma and subsequent brain infarcts.

FIBROMUSCULAR DYSPLASIA

FMD shows female predominance.

Familial cases make up ~10% of total.

FMD usually becomes symptomatic in the 4th or 5th decade, but occurs over a very broad age range.

Connective tissue disorders and α1-antitrypsin deficiency are associated clinical conditions.

Ischemic (brain) infarcts may occur secondary to vascular stenosis/occlusion.

As many as 20% of patients with carotid dissections show angiographic features of FMD.

FMD is rarely associated with formation of aneurysms on intracranial or extracranial arteries.

ARTERIAL DISSECTION

This is rare and tends to affect young and middle-aged adults. The dissection (Fig. 9.10) is usually spontaneous, but can be initiated by blunt trauma, often quite mild (e.g. neck injury in a motor vehicle accident or chiropractic manipulation of the neck). The dissection may involve extracranial or intracranial parts of the vertebral artery (more common in women) or carotid artery (more common in men). An intimal tear leads to a medial or subendothelial hematoma. The expanding hematoma may occlude the arterial lumen, usually producing infarction of CNS tissue, less commonly hemorrhage. Dissection of intracranial arteries, especially the vertebral artery, may rarely extend through the adventitia, producing subarachnoid hemorrhage. Dissection of intracranial arteries is likely to become more common as aggressive endovascular revascularization procedures (e.g. thromboembolectomy after ischemic stroke) become more widely utilized in clinical neurologic practice (Fig. 9.11).

9.10 Vertebral artery dissection following chiropractic neck manipulation (a–c).
(a) Almost circumferential dissection of blood between internal and external elastic laminae. (b) A thin ‘strip’ of blood (arrows) between internal and external elastic laminae. (c) Breach of internal elastic lamina (possibly related to the entry point for the dissection). (Material studied by kind courtesy of Professor Michael A Farrell, Dublin, Ireland.) (d) Intracranial basilar artery dissection in another patient. A subintimal ‘wedge’ of blood extends into the media.

9.11 Dissection of right MCA following attempted thrombectomy using a fine catheter device.
(a) Fresh autopsy specimen showing severe atheromatous plaque in the intra-Sylvian segment of the right MCA (arrow). Note necrosis of adjacent temporal lobe. (b) A relatively non-atherosclerotic segment of the artery showing extensive sub-intimal dissection (arrowheads indicate the ‘raised’ intima, under which is abundant acute hemorrhage). (c) Magnified view showing the elastica overlying fresh blood. (d) A severely atherosclerotic segment of the MCA showing only a small amount of subintimal blood.

Diagnosis is usually by angiography, which may show a double lumen, focal vessel wall irregularity, and/or a fusiform dilatation. As with most aspects of stroke, neuroimaging shows that many patients with a dissection have minimal brain infarction and can make an excellent recovery; those that have a fatal dissection represent a highly selected population.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Subarachnoid hemorrhage or ischemic infarct with cerebral edema is evident macroscopically. Demonstration of the point of origin of the dissection usually necessitates complete examination of intracranial or extracranial portions of the affected carotid or vertebral artery. A subendothelial or intramural hematoma is found within the vessel wall (Fig. 9.10).

HUMAN IMMUNODEFICIENCY VIRUS (HIV)-ASSOCIATED STROKE

When a stroke occurs in an HIV-infected patient, it may be difficult to ascertain its precise cause. Many of the opportunistic infections and CNS lymphomas seen in such patients may cause, mimic (clinically and by neuroimaging), or contribute to cerebrovascular disease; well known for doing this are cytomegalovirus (CMV), which may infect cells in vessel walls, and varicella-zoster virus (VZV) infections, toxoplasmosis, aspergillosis, and tuberculosis. Frequently, these agents cause extensive, sometimes hemorrhagic, necrosis that can resemble a spontaneous hematoma. One study found evidence of cerebrovascular disease in 5–10% of necropsies carried out on AIDS patients. As many as 20–25% of children with AIDS have evidence of cerebral hemorrhage or infarcts, in roughly equal proportions. Rarely, children with longstanding AIDS develop an aneurysmal arteriopathy of vessels on the circle of Willis.

Pathologies commonly seen in HIV-infected/AIDS patients predispose to embolic infarcts; these are non-bacterial thrombotic/marantic endocarditis, infective endocarditis, or are the result of HIV-associated cardiomyopathy. HIV ‘vasculitis and vasculopathy’ (both conditions are fairly rare, not well characterized pathologically, and lack specific features other than hyalinization and thickening of vessel walls), recreational drug-associated vasculopathy (amphetamines or cocaine), infections or hypercoagulable states (protein S deficiency or antiphospholipid antibody syndrome), or hyperviscosity syndrome may all, individually or in combination, cause ischemic infarcts. Hemorrhagic stroke may result from thrombocytopenia, intracranial CNS lymphoma, or infections, amphetamine or cocaine vasculopathy, or a ruptured infective (mycotic) aneurysm.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

HIV-associated ‘vasculopathy’ has been described as showing non-specific features, including intimal fibromuscular hyperplasia, fragmentation of the internal elastic lamina, and sometimes aneurysmal dilatation of vessel walls, a pathology consistent with ‘healed arteritis’ (Fig. 9.12). HIV-infected individuals (including those responsive to combined retroviral therapy) may be at risk for accelerated atherosclerosis, though factors responsible for this are unclear. Brain parenchymal arteriosclerotic change has also been observed in HIV-infected individuals that develop cerebral microinfarcts. HIV-1 has been demonstrated immunohistochemically in affected vessel walls (possibly within the cytoplasm of macrophages), but its pathogenic role in this location is unclear.