Vascular Diseases

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Vascular Diseases

CHAPTER 28

28

28.1 Physiology of the Cerebral Circulation 542 28.2 Anatomy of Cerebral Vessels 543 28.3 Pathology of Cerebral Arteries 543 28.3.1 Cerebral Atherosclerosis 543 28.3.2 Brain Calcinosis 545

28.3.3 Cerebral Thromboembolism 546 28.3.4 Hypertensive Angiopathy 546 28.3.5 Lacunar Infarcts 548 28.3.6 Amyloid Angiopathy 548 28.3.7 Cystic Medial Necrosis 549 28.3.8 Aneurysms 549

28.3.8.1 Saccular (Fusiform) Aneurysm 550 28.3.8.2 Dissecting Aneurysm 552 28.3.8.3 Infectious (Mycotic) Aneurysm 553 28.3.8.4 Mechanically Induced Aneurysm 553 28.3.9 Inflammatory Vessel Disease (Vasculitis) 553 28.3.9.1 Non-Infectious Primary CNS Vasculitis 553 28.3.9.2 Infectious Vascular Diseases 554 28.4 Pathology of Cerebral Veins 555 28.4.1 Cerebral Venous Thrombosis 555 28.5 Vascular Malformations 557 28.5.1 Cavernous Angioma 557 28.5.2 Capillary Angioma 557 28.5.3 Venous Angioma 557

28.5.4 Arteriovenous Malformation 558

28.5.5 Von Hippel−Lindau Hemangioblastoma 558 28.6 Tumor-Induced Stroke 558

28.6.1 Thrombosis and Embolism 559 28.6.2 Tumor Vessels and Hemorrhage 559 28.7 Extracerebral Causes of Stroke 561 28.7.1 Coagulopathy, Hemostatic Disorder,

Cerebral Thrombosis 561 28.7.2 Cerebral Embolism 561 28.7.3 Circulatory Disturbance 561 28.7.4 Illegal Drugs 564

28.8 Ischemic Stroke: Infarction 564 28.8.1 Classification of Cerebral Ischemia 565 28.8.2 Clinical Features

of Transient and Permanent Focal Ischemia 565

28.8.3 Neuropathology 566

28.9 Spontaneous Intracerebral Hemorrhage 569 28.9.1 Incidence 569

28.9.2 Clinical Features 569 28.9.3 Neuropathology 571 28.9.3.1 Causes of Spontaneous

Intracerebral Hemorrhage 572 28.10 Vascular Diseases of the Spinal Cord 573 28.10.1 Anatomy of the Spinal Vessels 573 28.10.2 Pathology of the Spinal Vessels 573 28.11 Forensic Aspects of Stroke 574

Bibliography 574

References 574

Acute and unexpected death can result from the spontaneous (i.e. not induced by external violence) fatal cerebrovascular disturbances known as

“stroke.” Sacco (1994) defines stroke as an “abrupt onset of focal or global neurologic symptoms caused by ischemia or hemorrhage.” Symptoms that are only transitory or that “resolve within 24 hours” (Kalimo et al. 2002) are characteristic of a “transient ischemic attack” (TIA).

Both stroke and TIA have pathogenetic back- grounds including a variety of diseases affecting global circulation as well as local arteries and veins (for review see Zülch and Hossmann 1988). Their sequelae are attributable to the reduction of cerebral blood flow or rupture of vessels, i.e.,:

▬ Cerebral infarct is a consequence of reduced or stopped cerebral blood flow: according to Futrell (1998) this is referred to as:

− “Embolic” (definite only if a source of embolism was proven, suspected if cerebral infarcts were bilateral).

− “Hemodynamic” (if there was a tight carotid stenosis thought to produce stroke by decreased flow past the stenosis or if there was decreased cardiac output or decreased blood pressure).

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− “Lacunar” (implying “hypertensive small- vessel disease”) if the stroke was small and deep, even though the patient may not have a history of hypertension.

− “Thrombotic” (if none of the other three

“mechanisms” could be demonstrated), which was thought to be the major mechanism for stroke.

▬ Cerebral hemorrhage is usually caused by the rupture of an arterial or venous wall, less often by arterial or venous occlusion.

The effect of stroke is damage of brain tissue (in- farct) or impairment of CNS function secondary to an intracranial space-occupying hemorrhage and/or edema with consequent displacement of brain parenchyma.

The clinical symptoms of stroke are dependent on:

1. The extent of the rupture in the vascular wall and whether an artery or vein is involved

2. The size of the occluded artery 3. The age of the patient

4. The suddenness of the event

5. The site of the affected brain parenchyma 6. How early therapeutic measures are initiated Strokes can be caused by a number of cerebrovascu- lar diseases or by extracerebral disturbances (see be- low), as shown by the epidemiological data. Stroke is the third leading cause of death in the industrialized Western world (Jörgensen and Torvik 1969; Wolf 1990; Sacco 1994). As a major cause of long-term dis- ability, it is the number one cause, representing an economic problem of enormous proportions. The age-adjusted annual incidence of all first-ever strokes varies between 90 and 350 per 100,000 (Terent 1993).

The mortality rate of stroke depends largely on age:

the age-specific death rates by stroke calculated from the 70th year of life double after every 5 years (Mil- likan et al. 1987). The main risk factors for stroke are hypertension, diabetes mellitus, and obesity; additional factors include alcohol abuse, cigarette smoking, oral contraceptives, atrial fibrillation, etc.

The most common result of cerebral vessel dis- ease is cerebral ischemic infarct (60−80%), followed by intracerebral hemorrhages (10%), and subarachnoid hemorrhages (5−10%) (Kalimo et al. 2002). The Framingham Study found that about 400 out of a population of 5,184 persons over 26 years of age suffered stroke, 223 of whom died. Eighty-two percent died after spontaneous intracerebral hemorrhage, 46%

after subarachnoid hemorrhage (SAH), 16% after cerebral embolism, and 15% after infarction (Sacco et al. 1982; see also Bamford et al. 1990). We also have to draw attention to the possibility of transformation of an acute ischemic infarct into a hemorrhagic stroke.

This may be the consequence of thrombolytic ther-

apy, which is suggested to be of benefit to patients with acute ischemic infarct (Larrue et al. 1997). On the other hand a spontaneous hemorrhage may occur that can be explained by a parallel loss of three basal lamina components, which contribute to a loss of microvascular integrity (Hamann et al. 1995).

The vascular diseases associated with stroke are described below. In most cases stroke is followed by a slow disease course, sometimes however by acute, unexpected death. The morphological changes in the brain parenchyma after vessel occlusion or rupture are also described, i.e., the cerebral infarct (pp. 564 ff)and the cerebral hemorrhage (pp. 569 ff).

For information on the non-natural causes of stroke and/or hemorrhage the reader is referred to Parts II and V (for ischemic and hypoxic changes of the brain, see Part III). The following description is based pri- marily on Kalimo et al. (2002).

28.1 Physiology

of the Cerebral Circulation

The physiology of the cerebral circulation is described in greater detail in Part III. Only the data relevant to vascular diseases and their sequelae are discussed here.

Under normal conditions, the adult human brain receives 15−20% of the cardiac output. The average blood flow to the brain as a whole is 750 ml/100 g per min (for review see Powers 1990), the gray matter receiving approximately 80 ml/100 g per min, and the white matter 20 ml/100 g per min. The cerebral venous pressure is usually equal to the intracranial pressure. The force driving blood to the brain is the cerebral perfusion pressure. The pressure can change if an obstruction causes a 70% reduction in the diameter of the major arteries to the brain (carotid and vertebral arteries) distal to the obstruction for which the collateral circulatory pathways are unable to compensate. Carbon dioxide is a known vasodilator of cerebral blood vessels. Reduced hematocrit and he- moglobin are associated with an increase in cerebral blood flow (for further information, see pp. 561 f).

A drop in cerebral perfusion pressure results in an automatic dilation of cerebral arterial vessels, thus reducing resistance and maintaining blood flow. A rise in perfusion pressure to the cranium, in contrast, causes cerebral arteries and arterioles to constrict. An increase in intracranial pressure therefore creates a vasodilation resembling that ensuing upon a decrease in arterial blood pressure.

Autoregulation is effective under normal conditions for intracranial pressures between 60 and 150 mmHg. A reduction in pressure below 60 mmHg exceeds the vasodilatory capacity of vessels, with a

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CHAPTER 28: Vascular Diseases 543

consequent drop in cerebral blood flow. If pressure exceeds 150 mmHg, the vasoconstrictive capacity of vessels is inadequate to prevent a rise in cerebral blood flow that further increases intracranial pressure.

Brain metabolism depends almost entirely for its energy needs on the ability to generate high-energy phosphate compounds via glucose oxidation. Glu- cose consumption is normally about 30 µmol/100 g per min, oxygen consumption about 165 µmol/100 g per min. Approximately 90% of glucose is metabo- lized to carbon dioxide and water.

Cerebral metabolism affects blood flow depend- ing upon cerebral activity. At rest, the brain utilizes only about one-tenth of the glucose and one-third of the oxygen supplied by arterial blood flow. An increase in local neuronal activity (e.g., voluntary hand movement) induces a dramatic rise in local cerebral blood flow. Oxygen metabolism is known to increase much less than cerebral blood flow. The rise in local glucose metabolism is similar to that in cerebral blood flow.

28.2

Anatomy of Cerebral Vessels

The extracranial arteries possess multiple collateral circuits that can guarantee sufficient blood flow to the brain if a single vessel becomes occluded. The most common anastomosis following occlusion of the extracranial portion of the internal carotid artery is the external carotid, external maxillary, ophthalmic, intracranial internal bypass (Dudley 1982).

If the proximal part of the cerebral arteries becomes occluded, blood can be shunted in compensation from the external carotid artery through the thyroid and occipital arteries to the distal vertebral circuit (Fisher 1970). Deficits in collateral circuits can be detrimental to the brain. The salient example is sub- clavian steal syndrome, which is characterized by reduced pressure within the ipsilateral vertebral and distal subclavian arteries secondary to total occlusion of the subclavian artery at its origin.

The large intracranial arteries are connected to one another by the circle of Willis via the basilar artery, creating a special pattern of collateral blood supply. Gradual narrowing of the lumen of the large cerebral arteries, therefore, rarely leads to neurologic deficits, whereas acute and sudden occlusion does. The cerebrum, cerebellum, and brain stem including the medulla oblongata are supplied via this ring of vessels at the base of the brain. Figure 28.1 provides a rough diagram of the blood flow to the individual areas of the brain. For further details the reader is referred to textbooks of anatomy or clinical neuropathology (e.g., Kalimo et al. 2002; Roggendorf

2002). The spinal cord has its own, separate source of blood supply.

Microscopically and functionally, intracranial vessels and extracranial vessels differ only slightly:

intracranial vessels have walls that are thinner per unit diameter. They possess a relatively robust internal elastic lamina but no, or only a rudimentary, external elastic lamina. The brain lends little adven- titial support. Rich anastomoses are localized in the gray matter, end arteries and terminal venules in the white matter.

The intracerebral capillaries differ functionally from extracerebral capillaries in being responsible for maintaining the blood−brain barrier. This task is accomplished mainly by the specialized endothelial cells (see Chap. 4).

Venous drainage is accomplished via the superior sagittal sinus, the inferior sagittal sinus, the straight sinus, the great vein of Galen, the internal jugular vein, and the sigmoid portion of the lateral sinus.

The veins of the cortex enter the subarachnoid space and drain towards the dural sinus, especially in the paramedian and suprasylvian regions. Veins of the parasylvian region drain towards the cavernous and sphenoidal sinuses, while veins on the lateral and inferior surface drain towards the transverse sinuses.

Veins of the superficial system within the brain parenchyma anastomose extensively with the internal cerebral and basal veins of the deep network.

28.3

Pathology of Cerebral Arteries

The following changes are common to the various vessel diseases:

1. Thickening and hardening of vessel walls with narrowing of the lumen (causing a reduction or cessation of blood flow).

2. Thinning of vessel walls due to overload or malformation (weakening the wall and increasing the risk of dilation and/or rupture).

28.3.1

Cerebral Atherosclerosis

Epidemiology and Topography. The most common arterial disease is atherosclerosis, which is associated with − and possibly partly caused by − diabetes mellitus, hypertension, cigarette smoking, dyslipid- emia, etc. Atherosclerosis is the predominant underlying cause of stroke.

Compared to extracerebral systemic atherosclerosis, brain vessels are affected in a relatively small percentage of cases (5%) (Jellinger and Neumayer 1964). About 20% of patients with distinct athero-

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sclerosis of the basal arteries exhibit no atherosclerosis of the intracerebral arteries. Conversely, 50% of patients with intracerebral atherosclerosis show no changes to the vessel walls of the large basal arteries (Baker and Jannone 1959; Reed et al. 1988).

The extracerebral carotid arteries are affected relatively early, especially the carotid siphon. The intracranial portion of the vertebral arteries and both ends of the basilar artery become involved later (Mo- ossy 1966). The frequency of atherosclerosis, especially of the vertebral vessels, increases with age. By age 75 this type of vessel change affects about 95% of cases (Ule and Kolkmann 1972).

Risk Factors. As already mentioned, a variety of risk factors are known, some associated with pathological mechanical overloading, others with pathological biochemical blood constituents capable of inflicting endothelial damage. Atherosclerosis is associated with elevated blood pressure, which can lead in turn to mechanical vessel wall lesions such as recurrent vascular spasms triggered by nicotine consumption or stress. On the other hand, increased cholesterol, low density lipoproteins (LDL), high density lipoproteins (HDL), and the entire group of saturated fats are all closely associated with atherosclerosis.

A combination of several factors increases the inci-

dence of this disease. The extent to which additional genetic factors play a role in this multifactorial disease remains unclear.

Pathogenesis. Initially atherosclerotic disease rep- resents a disruption of the endothelial barrier function secondary to endothelial cell injury (Ross 1993) caused in most cases by hemodynamic stress. Lipo- proteins (LDL, HDL) invade the intima and lamina media, where they are modified in the extravasal compartment. Intravascular blood monocytes leave the blood stream and by migration invade the vessel‘s wall and ingest − like smooth muscle cells − LDL cholesterol. Monocytes transform into foam cells, which appear as fatty streaks in the large vessels. A fibrosis develops, eventually producing fibrous plaques. A variety of additional factors also play a role, including chemokines and free radicals, which participate in a secondary inflammatory process (Koenig 2003).

The formation of fibrous plaques, which are sometimes accompanied by calcium deposition and precipitation of crystalline cholesterol, can take years or decades. Despite narrowing of the lumina, the blood flow remains sufficient in the early stages, in many patients averting the development of functional deficits of the nervous system. Extensive detachment of the intima sometimes does occur, with a consequent

Fig. 28.1. Circle of Willis. Schematic demon- stration of the anatomy of large basilar arteries of the cerebrum including data on the incidence of the topographic distribution of saccular aneurysms

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risk of thrombosis giving rise to acute vascular occlusion, which in turn can lead to neurologic deficits.

Morphology. Atherosclerosis features disruption and splintering of the internal elastic lamina and destruction of the media (Fig. 28.2a). Fibrosis causes scarring of the media and deposition of calcium and crystalline cholesterol. A simultaneous proliferation of foam cells as well as of the medial fibroblasts produces narrowing of the lumen with elevated risk of thrombotic vessel occlusion. The reduction or halt of blood flow in an artery leads to necrosis of the tis- sue that is supplied by this artery, i.e., most often a necrosis of the internal capsule as a consequence of obliteration of the lenticulostriate artery (Fig. 28.2b, c). The thrombosis of the basilar artery as a result of atherosclerosis (Fig. 28.3a) will lead to necrosis in the center of the pons (Fig. 28.3c).

Though there is a direct correlation between the atherosclerosis of brain arteries and stroke, obviously the stroke will not be caused by an atherosclerotic occlusion of intracerebral arteries. In most cases the sclerosis-induced narrowing of the arterial lumen leads to an occlusion by an additional throm-

boembolic event or by a cardiac-induced reduction of blood pressure.

28.3.2

Brain Calcinosis

In cases free of neurologic deficits, calcification of the lamina media of arteries, and of perivascular tissue of arterioles and capillaries is a process that is usually detected as an incidental finding by radiolo- gists and neuropathologists. They occur in the putamen, globus pallidus, caudate nucleus, dentate nucleus, and lateral thalamus (striato−pallido−dentate calcification − see Fig. 28.4a, b) as well as in the cerebral cortex and cerebellar folia. Microscopically they partly appear as extracellular globular, basophilic material of varying diameter, mainly in conjunction with pericytes and astrocytic processes (Kobayashi et al. 1987). They can also be detected as “isolated”

deposits within the media of arteries or of veins and capillaries, and as massive lobulated or spherical concretions (Nakano et al. 1984). Biochemically the deposits contain polysaccharides, proteins and met- als, phosphate and bicarbonate ions (Nakano et al.

1984; Kobayashi et al. 1987).

Fig. 28.2a−d. Arteriosclerosis cerebri. a Narrowing of the lumen of an artery by an atheromatous plaque; b focal cystic necrosis at the internal capsule involving pallidum and thalamic nucleus

as well as c putamen and caudate; d histological demonstration of a cystic scar as the result of an arterial occlusion (c: van Gieson stain; magnification ×100)

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Calcinosis affects 1−2% of the population (Gold- schneider et al. 1980; Forstl et al. 1992; Fenelon et al. 1993). Lowenthal (1986) has reviewed the variety of conditions associated with brain calcinosis; it is however a sporadic process unassociated with neurologic deficits.

28.3.3

Cerebral Thromboembolism

Intracerebral arterial vessels may become occluded by thromboemboli arising in the heart, i.e., from a fibrillating atrial or ventricular wall adjoining an infarct or damaged valve, or they may derive from the aorta, carotid arteries or pulmonary veins. The most common cause of carotid occlusion is atherosclerotic thrombosis. Cardiac surgery entails a high rate (up to 70%) of fat and fibrin platelet embolism. In rare cases, paradoxical emboli may enter the systemic circulation by passing from leg veins through a pat- ent foramen ovale. The consequence beeing single or multiple infarcts in gray and white matter.

Fat emboli mostly lodge in vessels of the white matter, where they cause multifocal perivascular

punctate or ring hemorrhages (Fig. 9.29). In most cases it is not possible to demonstrate embolic material proximal to the infarct. Fisher and Adams (1951) showed that embolism-induced strokes are far more common than is generally assumed, the embolic par- ticles elude detection by drifting to more distant sites or vanishing entirely.

If an embolus vanishes after irreversible infarct, the infarct becomes hemorrhagic when exposed to the full force of arterial blood pressure. The majority of hemorrhagic arterial infarcts can be traced to embolism. Pale infarcts, by contrast, are attributable to atherosclerotic thrombosis.

28.3.4

Hypertensive Angiopathy

Acute hypertensive events must be distinguished from the neuropathological and neurological se- quelae of chronic hypertension. Acute hypertensive encephalopathy is characterized by a sudden and se- vere rise in blood pressure (malignant hypertension) with the clinical signs of elevated intracranial pres- sure, e.g., headache, nausea, vomiting, etc. Chronic

Fig. 28.3a−c. Thrombosis of the basilar artery. a Arteriosclerosis of basilar artery; b thrombus in the lumen of the basilar artery;

c necrosis of the central parts of the pons (arrowheads) as se- quelae of the arterial occlusion

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hypertension (>180 mmHg systolic) gives rise to a specific angiopathy (Fig. 28.5) attributable to forced vessel dilatation secondary to high blood pressure (MacKenzie et al. 1976) or to repeated and prolonged vasoconstriction of arterioles (Toole 1990). Chronic hypertension leads to the development of (non-specific) atherosclerosis of intracerebral vessels com- bined with the (specific) alterations of small vessels termed “small artery disease” or “small vessel disease.” The energy stores for contractile elements are depleted by prolonged vasospasm, resulting in angionecrosis. After many years of hypertension, small arteries (100−200 µm in diameter) and arterioles (100 µm or less) will exhibit fibrinoid necrosis and hyalinosis (Roggendorf et al. 1978). The vessel walls thicken and the lumens narrow, the wall-to-lumen ratio falling progressively from 1:4 to 1:1 or less.

The angionecrosis features an acellular thickening of the intima and media that produces a marked reduction in luminal diameter (Frederiksson et al.

1988). This may result in obscuring of the lumen by arteriolar necrosis, causing microinfarction with

petechial hemorrhage. The basal lamina becomes thickened and the endothelial layer is damaged. The

“fibrinoid” material contains a homogenized mix- ture of various plasma proteins that are eosinophil- ic. Necrosis induces the fibrinoid change. Another phenomenon is hyalinosis, which is a collagenous fi- brosis that replaces the fibrinoid material over time.

Hypertensive angiopathy is also associated with de- velopment of microaneurysms secondary to weaken- ing of blood vessel walls. Should a microaneurysm rupture, the consequence is a globular hemorrhage (Fisher 1972).

Hypertensive hemorrhage in the white matter of the frontal lobe as well as of the parietal and temporal lobes may be the sequelae of chronic hypertension and secondary to small vessel disease (Fig. 28.6).

A sudden unexpected death as a consequence of the chronic hypertension may occur as a result of the acute increase of intracranial pressure and secondary herniation. The neuropathologist must search for markers of vascular disease, i.e., markers of chronic hypertension. He regularly will find pathologic ves-

Fig. 28.4a, b. Brain calcinosis. a Macroscopically, calcification of the basal ganglia is visible and characterizes so-called Fahr‘s dis- ease (circles). b Microscopically, the calcinosis is marked by extra- cellular globular, basophilic material (arrows) as well as calcium

deposits in the lamina media (arrowheads) of arteries, and in the perivascular tissue of arterioles and capillaries (b H&E; magnifica- tion ×100)

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sels in the contralateral hemisphere of the hemorrhages, as it will be impossible to find the ruptured vessel within the hemorrhage. Sometimes he will succeed in getting information on old hemorrhages (relapsing bleeding) which will be characterized by cystic scars and/or hemosiderin-containing macrophages (Fig. 28.5d, 28.23a, b).

Intracerebral hemorrhage is also observed in in- dividuals after prolonged exposure to cold (Caplan et al. 1984) (p. 247), which can trigger increased catecholamine release and a consequent major rise in blood pressure (cf. Ramirez-Lassepas et al. 1980;

Habermann et al. 1981; Schütz 1988). Moreover, otherwise-caused elevated blood pressure can, of course, also lead to vessel wall damage (see also Sect. 28.7.4).

28.3.5

Lacunar Infarcts

The elderly commonly exhibit small perivascular cavities in the basal ganglia (Fig. 28.7a). The exis- tence of multiple small cavities in the gray matter is termed état lacunaire; in the white matter, état criblé (Blackwood 1958). The cavities may be caused by hypertension-induced spiraling elongation of small

intracerebral arteries (Pullicino 1993; Kalimo et al.

2002). Large cavities 5−20 mm in diameter, known as lacunar infarcts, are thought to result from occlusion of perforating arteries 100−200 µm in diameter (Fish- er 1991). The size of the infarct depends on the site of obstruction (Fig. 28.7b, c). An infarct leads ultimately to lacunae, so called due to their appearance in the cavitated state. Multiple lacunae in the thalamus, len- ticular nucleus, and cerebral white matter are often associated with chronic hypertension. Recent stud- ies show that lacunae are probably the result of small artery occlusion secondary to hypertension-induced lipohyalinosis (Fisher 1991) (see also Chap. 31).

28.3.6

Amyloid Angiopathy

Amyloid angiopathies comprise a group of systemic vessel diseases that may also be organ specific, e.g., to the cerebrum. The vessel walls possess extracellular deposition of amyloid, which can be demonstrated histologically by its binding affinity to Congo Red (polarized light: green birefringence), to thioflavine S or T, and to periodic acid Schiff (PAS). Deposition of amorphous material leads to thickening of the vessel walls, which become increasingly more rigid

Fig. 28.5a−d. Hypertensive angiopathy and small vessel dis- ease. a Fibrinoid necrosis and aneurysmal dilatation; b hyalinosis, c aneurysmal dilatation and medial coat splitting. d Hemosiderin-

containing macrophages at the border zone of a hemorrhage give evidence of a relapsing bleeding process (a−c van Gieson stain;

d Prussian blue; magnification a ×100; b, c ×300; d ×500)

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and fragile. The vessels are also conspicuous in H&E stain as being abnormally round and thick-walled, especially in the cortex.

The most common type of amyloid angiopathy is recognizable by deposition of β-amyloid peptide (βA4) affecting medium-sized and small arteries and arterioles (see Fig. 31.4d). Topographically, the sites most often affected are the cerebral cortex and meninges of the parietal and occipital lobes. Bleed- ing due to vessel rupture occurs in the frontal or frontoparietal regions. Amyloid angiopathy is the cause of 5−12% of all primary intracerebral hemorrhages that are not mechanically induced (Gilbert and Vinters 1983).

28.3.7

Cystic Medial Necrosis

This is a systemic disease featuring extensive deposits between elastic laminae, some foci coalescing to form cysts at the expense of surrounding smooth muscle and elastic fibers. The deposits are reactive

with Alcian blue and PAS. Most often affected are larger vessels such as the carotid arteries. The alterations of the lamina media entail an enhanced risk of dissecting aneurysm with consequent arterial occlusion and cerebral infarct. Arterial dissection leads to intramural hematoma due to extravasation of blood into the arterial wall, usually between the intima and media. In intracranial arteries such dissections are very rare events.

28.3.8 Aneurysms

Aneurysms are characterized by focal dilatation of an arterial wall. Four types of intracranial aneurysm can be distinguished morphologically and etiologi- cally. None of the types gives rise to primary symptoms, but each is capable of sudden rupture that leads to possibly lethal subarachnoid hemorrhage (SAH).

Aneurysms are one of the most common causes of sudden unexpected death.

Fig. 28.6a−d. Hypertensive intracerebral hemorrhage. The bleeding commonly occurs within the white matter of the (a) frontal and/or parietal and/or temporal lobes partly involving the cerebral deep gray nuclei (b, d), often bursting through the

ventricular wall and/or (c) the hemispheric surfaces. MR-imaging of hypertensive intracerebral hemorrhage associated with secondary ventricular hemorrhage (kindly provided by Professor Dr.

H.B. Gehl, Lübeck)

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28.3.8.1

Saccular (Fusiform) Aneurysm

Morphology. The sequela of the rupture of an aneurysm of the large basal cerebral arteries is marked by an extensive basal subarachnoid hemorrhage including the cistern of the chiasma, and, rarely, associated with an intracerebral (intraparenchymal) hemorrhage (see p. 573). Saccular aneurysms are spherical, often berry-shaped (Fig. 28.8), but they can also as- sume a variety of other shapes. The diameter ranges

1−25 mm. For pathologists it is important to note that aneurysms tend to shrink post mortem (McCor- mick and Acosta-Rua 1970).

An aneurysm can be extraordinarily difficult to find at autopsy. At autopsy and prior to fixation, the clotted blood should be removed with water before excision of the vessel ring. Despite these measures, the aneurysm cannot always be found. Microscopi- cally (Fig. 28.8d), saccular aneurysms lack both the internal elastic lamina and the muscular tunica media. The wall of the aneurysm is composed of endothelial cells and fibrous connective tissue of varying thickness.

Etiology. Saccular aneurysms are noted for the thin- ness of the vessel wall, the lack of an external elastic lamina, and the absence of perivascular support.

Once it was assumed that aneurysms are congenital, caused by an inborn gap in the muscular layer. To- day it is thought that aneurysms are acquired degen- erative lesions that are aggravated by hemodynamic stress (Stehbens 1989): constant overstretching due to hemodynamic stress at the apical angle of the branching sites of major cerebral arteries cause the elastic and muscular layers to degenerate.

Incidence. Primary non-mechanical SAH account for 5−9% of all strokes, while about 80% of strokes involve mechanically induced SAH, and arteriovenous malformations are responsible for 5−10% of all strokes (Kalimo et al. 2002). The main cause of spontaneous SAH is saccular aneurysm rupture. Such aneurysms are disclosed in approximately 2−5%

of autopsies (Weir 1987), the incidence increasing with age. Sixty percent of ruptured aneurysms occur at the age of 40−60 years. Saccular aneurysms are more common in women than in men (ratio:

3:2). The majority of aneurysms (85−90%) occur in the rostral portion of the circle of Willis (A. cerebri anterior, A. cerebri media), 5−10% in the posterior portion (Fig. 28.1). Aneurysms that rupture are almost always more than 10 mm in diameter (Wiebers et al. 1987). Aneurysms increase in size over time gradually attaining the critical diameter of 10 mm.

Moreover, a large study (n=100 patients) evaluated the relationship between aneurysm size and the volume of SAH (Russell et al. 2003). The authors stated that the smaller cerebral aneurysm size is associated with a large volume of SAH.

Their findings were confirmed by another group (Day et al. 2003) who noted that the incidence of bleeding progressively diminished with larger lesions; patients with stenosis or occluded vessels most often presented with ischemic symptoms, and occasionally with hemorrhage. Giant focal dilatations or serpentine aneurysms are rarely associated with acute bleeding (see also Fig. 28.9); clinical presenta- tion is most often prompted by mass effect or throm-

Fig. 28.7a−c. Lacunar infarcts. Sequelae of chronic hyperten- sion may also include the phenomenon of enlargement of the perivascular spaces in central parts of the cerebral white matter and the basal ganglia (a), which regularly is accompanied by cys- tic necroses of different extent (b, c) as well as by small vessel disease (b H&E; a, c van Gieson stain; magnification a ×300; b, c ×100)

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Fig. 28.8a−d. Rupture of a saccular aneurysm. a Basal subarach- noid hemorrhage; b visible aneurysm in situ; c circle of Willis demonstrating the (unusual localization of the) aneurysm at the

bifurcation of the basilar artery / Aa. cerebri posterior; d histology of the aneurysm; arrows demonstrate the edges of the ruptured vessel‘s wall (H&E, magnification ×50)

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boembolic stroke. In contrast to this statement are the results of a review of the literature given by Horie et al. (2003).

Clinical symptoms arising 1−3 weeks prior to rupture of an aneurysm are often of cerebral na- ture, e.g., headache, nausea, visual defects, etc. The rupture itself is often associated with a rapid rise in blood pressure during physical stress. Clinical diagnosis of saccular aneurysms is made by arteriogra- phy, CT, and/or MRI. The therapeutic intervention

usually involves cross-clamping the aneurysmal sac.

This type of intervention sometimes is accompanied by ischemic stroke of the cortical area supplied by the anterior cerebral artery (Fig. 28.10).

Saccular aneurysms have a high mortality rate:

they comprise 16−24% of all cerebrovascular disease-related deaths. The initial hemorrhage is fatal in about 40% of all patients; 30% of patients die within the first 24 h. The overall fatality of saccular aneurysms is approximately 40−50% (Fogelholm et al. 1993; Broderick et al. 1994). If there is no surgical intervention, one-third of the patients will die within 6 months of recurrent bleeding (Rosenørn et al.

1987), 10−20% will remain severely disabled. Only about 40% of patients recover to full self-sufficiency after SAH (Juvela 2000).

If an unruptured intracranial aneurysm is diag- nosed (Fig. 28.10), the question arises as to whether surgical measures should be taken or not. While Juvela et al. (2000) think such aneurysms require surgical intervention regardless of size, especially in the young and in adults of middle-age, Raabe et al. (2003) put forth criteria incorporating the data of other authors for deciding whether or not surgical treatment is warranted in the individual case (see also: Acta Neurochir Suppl; 2002, 82).

The neuropathology is characterized by the dem- onstration of the ruptured aneurysm and its topographic localization. Moreover, the gross phenomena are a pronounced basal subarachnoid hemorrhage filling out the cisterna interpeducularis and in single cases associated with an intracerebral hemorrhage as a result of a ruptured aneurysm of the middle cerebral artery.

As mentioned previously (Chap. 7, pp. 139 ff), the risk of external violence and aneurysm rupture is discussed. According to the most recent investiga- tions we must accept that there is no association between external violence and rupture of a preexisting aneurysm (Rinkel et al. 1998; Cummings et al. 2000;

Juvela et al. 2000).

28.3.8.2

Dissecting Aneurysm

Intracranial dissecting aneurysms are rare compared to extracranial aneurysms of common carotid and vertebral arteries. In the extracerebral carotid, dissecting aneurysms are also often the result of iatrogenic measures, such as puncture of the common carotid artery or iatrogenic-related trauma. Intra- cranially the supraclinoid segment of the internal carotid artery (Little et al. 1981) and the basilar artery (Steel et al. 1982) are commonly involved. Arte- riosclerosis is the underlying cause in the majority of cases, sometimes in combination with hypertension and diabetes mellitus.

Fig. 28.9a−c. Unruptured giant, fusiform aneurysm of the mid- dle cerebral artery within the white matter of the left temporal lobe (in situ) (a), and after isolation (b) demonstrating the open communication with the artery (c)

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Dissection of intracranial arteries is usually caused by some sort of blunt impact to the head or neck, or by hyperextension of the vertebral arteries. Imaging techniques have shown that such dissections are associated with atherosclerosis, arteritis, hypertension, etc. (O‘Connell et al. 1985; Pozzati et al. 1991; Sasaki et al. 1991). The clinical picture features ischemic stroke (stenosis or occlusion) or rupture-induced SAH.

28.3.8.3

Infectious (Mycotic) Aneurysm

Endocarditis may lead to bacterial aneurysms arising from microbe-bearing emboli. The first manifesta- tion involves a local pyogenic infection of the arterial wall, from which the aneurysm develops (Hart et al.

1987). The vessel wall loses its elasticity and stability and is liable to rupture at the site of infection.

28.3.8.4

Mechanically Induced Aneurysm

Rupture of the wall of large vessels at the base of the brain (circle of Willis) is described elsewhere and is mentioned here only for the sake of completeness (see Chap. 7, p. 143).

28.3.9

Inflammatory Vessel Disease (Vasculitis)

An artery is liable to injury from bacterial toxins, direct bacterial invasion, or from chemical and other toxins. In most cases, however, the underlying cause

of injury remains unknown. A differentiation must be made between infectious and non-infectious vasculitis on the one hand, and systemic vasculitis and primary CNS vasculitis on the other. The diagnosis of systemic vasculitis (polyarteritis nodosa, throm- boangiitis obliterans, systemic lupus erythemato- sus, Wegner‘s granulomatosis) is usually facilitated by the presence of extracranial manifestations (for review see Meister 2003). Clinical diagnosis of the early manifestations of systemic vascular disease of the brain or of primary CNS vasculitis is much more difficult. Definitive diagnosis is often only possible by brain biopsy or by autopsy.

In the following only the primary CNS forms of vasculitis will be discussed.

28.3.9.1

Non-Infectious Primary CNS Vasculitis

The causes of these types of vasculitis are not known, although autoimmune processes are thought to play a role. The clinical picture is generally non-specific.

Polyarteritis (Nodosa). Polyarteritis (or periarteritis or panarteritis) is a disseminated disease of unknown origin. It features focal inflammatory lesions affecting various tissues and organs, usually associated with small and medium-sized arteries and arterioles. All coats of the artery are involved in the inflammatory process, as is the perivascular tissue. The processes include swelling, destruction of the internal elastic membrane, necrosis and fibrillation of the media, infiltration of the adventitia by polymorphonuclear leukocytes and, sometimes, by

Fig. 28.10a, b. The sequelae of a cross-clamping the aneurysmal sac of the anterior cerebral arteries: b ischemic necroses (arrow-

heads) of the territories supplied by the anterior cerebral arteries

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eosinophils. The main pathologic change involves focal necrosis of the medial coat, which may lead to formation of an aneurysm and thrombosis. Small aneurysms occasionally rupture, causing frank hemorrhage or hemorrhagic extravasation.

Giant Cell Arteritis (Temporal Arteritis-Horton). In most cases, extracranial arteries of the head are first affected, the temporal artery in particular, but also the carotid, ophthalmic or vertebral arteries. The salient clinical features are loss of vision and headache.

Macroscopically the morphology is characterized by thickening and hardening of the temporal artery.

Microscopy reveals lymphoplasmacytic infiltrates in the intima and media, with giant cells of both the foreign body and Langhans‘ types (Fig. 28.11). The lumen usually exhibits narrowing or complete occlusion caused by severe proliferation of the intima, a fibrotic process that involves some smooth muscle cells and is often associated with thrombosis at the site of occlusion. The presence of conspicuous but localized periarteritis and mesarteritis lends the appearance of focal granuloma. Most cases also feature focal necrosis of the media and internal elastic membrane. All cell layers undergo secondary fibrosis causing thickening and functional insufficiency.

Takayasu’s Syndrome (Aortic Arch Syndrome). This disease has an etiology similar to that of giant cell arteritis with the difference that it mainly affects the aortic arch and its major branches, especially the left subclavian artery. Thickening of vessel walls can lead to thrombosis, occlusion, and the loss of radial pulse.

Primary Angitis of the CNS (PACNS; Granulomatous Angitis of the CNS). PACNS is a disease not only of arteries, but of veins as well. It affects middle-aged and older persons. Intraparenchymal vessels are mainly involved, as well as various caliber meningeal vessels (Cravioto and Feigin 1959; Aita 1972). The vascular

lesions feature proliferation of connective fibers and mononuclear cells of various types, including large mononuclear cells, plasma cells, lymphocytes, and multinuclear giant cells of foreign body and Lang- hans’ type (Fig. 28.12a, b). Sometimes the brain parenchyma exhibits a distinct microglial reaction.

Granulomatous inflammation occurs in some vessels in the intima, where a thrombus may develop, with consequent infarct. The blood vessels of various vis- cera may also be affected, but CNS symptoms predom- inate. The clinical features are non-specific: multifocal neurological deficits, recurring headaches, and diffuse encephalopathy with memory impairment and confusion (Sigal 1987; Moore 1989; Calabrese et al. 1992). CT or MRI reveal irregularly distributed foci of demyelination which sometimes merge with white matter in cortical regions (Fig. 28.12c, d).

Moya−Moya Disease. This disease affects both chil- dren and adults and is most prevalent in Japan (Coakham et al. 1979). It usually involves the internal carotid arteries. The clinical picture is initially characterized by repeated transient ischemia followed by hemiparesis, often in combination with subdural hemorrhages. The hemorrhages often result from extreme collateralization of vessels with consequent changes in regional cerebral blood supply (Dietrichs et al. 1992).

Microscopically, signs of arteriosclerosis and arteritis are lacking. The arterial lumina are occluded by a loose meshwork of hypocellular connective tissue. The lamina elastica interna is clearly dilated, a phenomenon often associated with recent clot formation in the engorged leptomeningeal veins (Ikeda and Hosoda 1993), which can lead to bleeding (Kono et al. 1990).

Drug-Induced Vasculitis. Vasculitis is relatively common in drug abusers, caused apparently by an aller- gic-hyperergic reaction (Krendel et al. 1990; Freder- icks et al. 1991). Drug-related vasculitis can lead to intracerebral hemorrhage, often seen in association with cocaine and amphetamine use (Sloan 1993) (see pp. 398 ff).

28.3.9.2

Infectious Vascular Diseases

Many types of bacterial infection, especially menin- gitis, also involve the vessels, but usually not primar- ily. A special type of vasculitis is spirochaetal vascu- litis, which is caused by an invasion of arterial walls by Treponema pallidum spirochaetes in patients with syphilis. Among the complications associated with mycotic vasculitis, a clinical feature especially common in patients undergoing immunosuppression after organ transplantation, is a so-called mycotic aneurysm, which is liable to rupture.

Fig. 28.11. Giant cell arteritis (Horton) which is characterized by multinuclear giant cells of the Langhans‘ type (H&E; magnification ×500)

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Lymphocytic granulomatous or necrotizing vessel changes are associated with viral infections (Somer and Finegold 1995), herpes virus infections (chiefly herpes zoster-varicella virus) in particular (MacKenzie et al. 1986). Arteritides are known to be associated with human immunodeficiency virus (HIV) infections (Budka 1991). Lastly, fungal vasculitis affects immunocompromised patients in the form of opportunistic infections.

28.4

Pathology of Cerebral Veins

In addition to the vascular malformations discussed below are diseases of the veins, almost exclusively cerebral venous thromboses. About 70% of all intra-

cranial blood is venous blood, located chiefly in the cerebral sinuses.

28.4.1

Cerebral Venous Thrombosis

The incidence of cerebral venous thrombosis (CVT) is unknown. Since numerous venous anastomoses exist, intracranial vein thromboses often remain bland and without appreciable clinical symptoms.

Even if clinical symptoms do become manifest, diagnosis is complicated by the wide spectrum of clinical features and highly variable mode of onset (Ameri and Bousser 1992). Because impaired drainage of the vein of Galen is often fatal, from the clinical stand- point case reports continue to be warranted (cf.

Funabiki et al. 2002).

Fig. 28.12a−d. Granulomatous angitis (PACNS). Morphological- ly this type of disease is characterized by perivascular and lepto- meningeal infiltration (a) with inflammatory cells (lymphocytes, macrophages) as well as giant cells of the Langhans‘ type (b).

This inflammation is associated with a characteristic multifocal demyelination as demonstrated by myelin stain (c) or by MRI (d) (a, b H&E; c Luxol fast blue stain; magnification a, c ×300;

b ×500)

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Clinical Features. CVT occurs in the perinatal pe- riod (see Chap. 22, pp. 436 ff), in middle age, and in advanced age. Women are affected slightly more often than men (Einhäupl et al. 1990; Ameri and Bousser 1992). The clinical picture is characterized by non-specific symptoms of elevated intracranial pressure: headache, impaired vigilance, meningism, focal deficits, seizures, coma. The diagnosis can only be made by radiology (Thron et al.

1986), three-dimensional MR flow imaging in particular (Dormont et al. 1994). The mortality rate of CVT ranges 5−33% (Thron et al. 1986; Ameri and Bousser 1992). The ability to make early diagnosis and the advent of heparin therapy have lowered the mortality of CVT. A review of the clinical outcome in 55 consecutive CVT patients treated over a 4-year period (Breteau et al. 2003) revealed the following:

48 out of the 55 survived; 29 of the survivors expe- rienced headaches, 7 seizures, 6 motor deficits, and 5 visual field defects. In the absence of cancer and focal deficits, the mortality rates of CVT are low, more than 80% of survivors regaining indepen- dence after 3 years. Nevertheless, the discussion continues regarding whether thrombolysis therapy is indicated, and under which circumstances (Per- kin 2000; Renowden 2000). One therapeutic mea-

sure of proven worth is the prophylactic application of thrombolytic drugs (Hamilton et al. 1994). As re- cently evaluated, a study of 34 cases demonstrated a good neurological and cognitive long-term outcome in patients with cerebral venous sinus thrombosis (Buccino et al. 2003).

Pathogenesis. CVT may occur spontaneously. In women of childbearing age this can result from al- tered hormonal status due to pregnancy, puerperium or oral contraceptives (Vandenbroucke et al. 2001).

Diminished blood flow can be caused by conges- tive heart disease, heat stroke, polycythemias, de- hydration, or by tumor, hematological disorders, or trauma (disseminated intravascular coagulation).

CVT is also associated with infectious disease due to chronic mastoiditis, otitis media, and with sinusitis or sepsis (Ebright et al. 2001) chiefly affecting the cavernous sinus due to local invasion of Staphylococ- cus aureus (for review see Ameri and Bousser 1992;

van Gijn 2000).

Neuropathology. Stagnated blood flow gives rise to ischemic changes and vasogenic edema. The morphological result is a hemorrhagic infarct (Fig. 28.13).

The superior sagittal sinus is most often affected (2/3

Fig. 28.13a−d. Cerebral venous thrombosis. a Thrombosis of the inferior sagittal sinus associated with a periventricular hem- orrhage in a newborn child; b, c, d fibrin precipitation within the

lumen of periventricular vessels (b PAS; c, d Azan stain; magnifi- cation b, c ×100; d ×300)

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of all cases), sometimes in combination with the lateral sinus. The straight sinus is less often affected (Ameri and Bousser 1992). A thrombosis of the deep internal veins and great vein of Galen can trigger an infarct of the basal ganglia and brain stem (Rahman and al Tahan 1993). Whereas the morphological picture in the absence of a demonstrable thrombosis is hard to classify (differential diagnosis: hemorrhagic infarct secondary to arterial thrombosis), the neuro- pathological changes associated with a thrombosis of the superior sagittal sinus are characteristic: sym- metric parasagittal hemorrhagic infarcts of the white and gray matter. Moreover, an obstruction of venous drainage is another cause of non-hemorrhagic in- farct. The consequent elevation of venous pressure diminishes the perfusion pressure, with resulting tissue ischemia.

28.5

Vascular Malformations

Lack of normal maturation of embryonic vascular networks leads to vascular malformations. Although some of the names would suggest otherwise, they are not neoplastic (McCormick 1984), but − obviously

− can exhibit clearly expansive growth (Siddiqui and Jooma 2001). Because the present terminol- ogy is often confusing, a simplified classification is warranted. Roizin (1958) differentiated three types of congenital vascular malformation: aneurysms, hemangioblastomas, and angiomas. But hemangioblastomas are not properly considered under the ru- bric of vascular malformation.

During embryogenesis diverse malformations can arise if the brain’s mesenchymal tissue does not develop properly. Hemangioblastomas, e.g., von Hippel−Lindau disease of the retina and cerebel- lum, appear to originate during vascular plexus formation due to vasoformative cells growing into the neural tube. Facioencephalic malformation of the Sturge−Weber−Dimitri neuroangiomatosis type re- sults from arrested growth during differentiation of the vascular plexus into arteries and veins. Angiomas of the CNS apparently arise during differentiation of the adult pattern of cerebral and spinal arteries and veins. Saccular aneurysms, by contrast, are associ- ated with improper differentiation of vessel wall layers.

Such deformities are sometimes termed “malformation,” sometimes “benign neoplasms” due to the space-occupying masses they produce. Bleeding is a common trait of such malformations and is occasionally accompanied by headache or even coma and death. However, sometimes vascular malformations are accidentally found at autopsy without clinical relevance.

Another criterion for classification is the local- ization of vascular malformations, i.e., whether they are located supratentorially or infratentorially. Mal- formations of the posterior fossa are more prone to hemorrhage and are more often associated with neurologic deficits than their counterparts superior to the tentorium (Gamache and Patterson 1984).

28.5.1

Cavernous Angioma

Cavernous angiomas (Fig. 28.14) feature large, thin- walled, and sinusoidal vascular channels. Their total mass may be small, but they usually exceed 2 cm in diameter and tend to be encapsulated. The vessels are clustered close together, not being separated by normal neural tissue. They often possess hyalinized or calcified vascular walls. Cavernous angiomas usually occur in the cerebral hemispheres, the sub- cortical region in particular, but are also found in the pons, internal capsule region (Challa et al. 1995), and in the ventricular system (Reyns et al. 1999). A recent review (Bertalanffy et al. 2002) showed that out of 72 patients with cavernous angioma, the lesion was located within the brain stem in 24, in the deep white matter of the hemispheres in 18, in the basal ganglia or thalamus in 12, in superficial areas of the hemispheres in 11, and in the cerebellum in 7.

28.5.2

Capillary Angioma

Capillary angiomas are composed of clusters of dilated thin-walled capillaries without elastic lamina or smooth muscle. Neural parenchyma is usually found between and around the capillaries.

28.5.3

Venous Angioma

Venous angiomas feature a network of small med- ullary veins and tend to affect the spinal cord with involvement of the meninges. Although they are a common incidental finding at autopsy, clinically venous angiomas of the brain are thought to represent rare vascular malformations (Handa and Moritake 1984). The vessels of which venous angiomas are composed contain ample elastic tissue and smooth muscle. Thickening of the walls and hyalinization are common features (Wolf et al. 1967).