Vascular and Ischemic Disorders

26  Vascular and Ischemic Disorders David A. Decker, MD, Arie Perry, MD, and Anthony T. Yachnis, MD

Fusiform and Infective (“Mycotic”) Aneurysms  648

hippocampal neuronal necrosis in areas CA1 and CA4, cerebellar Purkinje cell necrosis). This third pattern is seen almost exclusively in the autopsy setting and is therefore not covered in great detail. Instead, this chapter will focus predominantly on the major pathologic changes and characteristic distributions of injury that occur in the clinical syndromes of stroke, brain attack, and cerebrovascular accident, particularly those lesions that may mimic a brain tumor or are biopsied for other reasons (e.g., rule out vasculitis). These clinical terms are often used synonymously and refer to an acute, nonepileptic, nonmigrainous, persistent alteration in neurologic status that results from sudden disruption of blood flow to the central nervous system (CNS). When considering all forms of cerebrovascular disease that result in stroke and stroke syndromes, these disorders are the second most common cause of death and a major cause of disability worldwide.1

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Brief Historical Overview

Arteriovenous Malformations  649

As inaccurate as the term “stroke” may be, it has been utilized in medicine to emphasize the acute onset, as in, the patient was suddenly “struck down” with illness. The first record is credited to Hippocrates, who described sudden paralysis of the right arm with loss of speech,2 although historical descriptions also date back to the ancient Egyptians. Hippocrates depicted sudden onset of numbness or anesthesia as “impending apoplexy,” derived from the Greek word meaning “struck with violence as if by a thunderbolt.” However, further understanding of strokes awaited the invention of the microscope in the 17th century, and another century passed before several investigators described the focal softening of the infarcted brain, the lack of an inflammatory etiology, and the associations with vascular anatomy. It was not until the work of Rudolf Virchow in the 19th century that the mechanisms of various strokes were more thoroughly and clearly elucidated. Arteriosclerosis was first described by Lobstein in 1829, although Virchow revived the term 20 years later and contributed further to its understanding, as well as the etiologic roles of thrombosis and embolism. In 1863, he also published a three-volume treatise on blood vessels, including vascular malformations, forming the basic premises for more current classification schemes. During the late 19th and 20th centuries, anatomists and neurologists described many of the distinct clinical syndromes associated with infarcts of specific regions in the brain and spinal cord and further clarified pathogenetic mechanisms, such as hypoxia, ischemia, and hypertensive hemorrhages.

Introduction 633 Brief Historical Overview  633 Ischemic Cerebral Infarct  634 Hypertensive Cerebrovascular Disease  638 Cerebral Amyloid Angiopathy  641 Vasculitis Involving the Nervous System  644 Giant Cell Arteritis  644 Primary Angiitis of the Central Nervous System  644 Polyarteritis Nodosa  646 Cerebral Aneurysms  646

Cerebral Cavernous Malformations  652 Capillary Telangiectasias  653 Venous Angiomas  654 Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)  654 Moyamoya Syndrome  656

Introduction Reproducible patterns of cerebrovascular injury result from two basic pathologic processes that are occasionally encountered in surgical practice: (1) cerebral infarct resulting from blockage or stenosis of vessels that deprives the brain of oxygen and nutrients and (2) hemorrhage from diseased vessels that may then secondarily cause tissue destruction and hypoxia. A third major pattern results from global hypoxic/ischemic damage, such as occurs with cardiac arrest or hypotension. This type of injury is often referred to as hypoxic/ischemic encephalopathy clinically and is associated with damage to regions of selective vulnerability (e.g., watershed infarcts, laminar necrosis, selective neuronal necrosis,

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Abstract Cerebrovascular diseases including ischemic and hemorrhagic conditions are leading causes of death and disability worldwide. Since ischemic forms of cerebrovascular disease with atherothrombosis represent the most common cause of stroke syndromes, patterns of cerebral infarction are reviewed. Hypertensive vascular disease contributes to the development of atherosclerosis and arteriolosclerosis and is the major cause of acute cerebral hemorrhage and lacunar infarcts, both resulting from damage to deep penetrating arteries. In the aging population, cerebral amyloid angiopathy is an important cause of cerebral hemorrhage that can be focal, multifocal, or massive (lobar hemorrhages). Several

cerebrovascular disease entities encountered in surgical neuropathology include vasculitis and vascular malformations as well as vasculitic forms of cerebral amyloid angiopathy. Saccular and fusiform aneurysms are discussed along with infective aneurysms, which are occasionally encountered in surgical neuropathology. Familial vasculopathies such as “cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy” (CADASIL) and a recessive form (CARASIL) and their genetic associations are covered followed by an overview of moyamoya syndrome.

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Keywords posterior reversible leukoencephalopathy Aβ-related angiitis giant cell arteritis primary angiitis of the CNS arteriovenous malformations cerebral cavernous malformations Notch 3 extracellular domain

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Ischemic Cerebral Infarct Definition and Synonyms

The brain receives about 15% of total cardiac output and accounts for about 20% of the body’s oxygen consumption. Neurons are absolutely dependent on a constant supply of oxygen for survival. Any disease process that reduces oxygen supply to all or some of the brain interferes with function and, when severe enough, can cause the death of brain cells (the most vulnerable being neurons). Anoxia refers to the absence of oxygen, and hypoxia describes reduced concentration of oxygen. The term “hypoxia” tends to be more widely used because it encompasses a range of reduced oxygen concentrations that may be encountered clinically.3 Ischemia is defined as absence of blood flow; oligemia connotes reduced flow. Hypoxia and ischemia almost always coexist, and these terms are often used together. A cerebral infarct is a circumscribed focus or area of brain tissue that dies as a result of localized hypoxia/ischemia due to cessation of blood flow.

Incidence and Demographics The incidence of stroke increases with age from about 1/1000 between the ages of 45 and 55 to about 1/33 for those older than 85 years and is more common in men than women. In the United States, ischemic cerebral infarction accounts for about 80% of all strokes and is eight times more common than spontaneous brain hemorrhage.3 The main causes are atherosclerosis with thrombosis of large vessels or embolic occlusion of distal vessels (or both). Thus, the major risk factors for ischemic stroke are the same as those for atherosclerotic cardiovascular disease. These include diabetes, hypertension, smoking, positive family history, hyperlipidemia, and truncal obesity. Chronic hypertension aggravates atherosclerotic changes in both extracranial and intracranial blood vessels and leads to a more distal arterial distribution of atheromatous changes (arteriolosclerosis or “small-vessel cerebrovascular disease”).4,5

Clinical Manifestations and Localization Clinical characteristics of cerebral hypoxia/ischemia vary widely depending on severity and duration of the insult, the size and location of the lesion, whether brain involvement is widespread or focal, and the availability of collateral circulation. The clinical presentation of an infarct is sudden, and the spectrum of acute neurologic signs and symptoms depends on the amount of brain compromised, location of the lesion, duration of reduced flow, status of collateral circulation, and intrinsic vulnerability of brain cells. Occasionally, the clinical signs of infarction

may present in a stuttering, or stepwise, progression as fractions of the ischemic tissue succumb. Infarcts resulting from embolization or intrinsic cerebrovascular disease occur in circumscribed vascular territories within the distributions of major cerebral arteries.3 Most infarcts are believed to result from the disruption and embolization of platelet thrombi or friable plaque material with subsequent obstruction of intracranial arteries. The thrombus often originates from extracranial locations such as atherosclerotic disease at the bifurcation of the carotid artery or from the heart.3 Occasionally, emboli may arise from calcified, marantic, or infected heart valves. Transient ischemic attacks (TIAs) with brief reversible focal neurologic deficits often precede frank infarcts. Symptoms of a stroke depend on the location and extent of the lesion. The degree of reversibility and magnitude of deficit depend on the ability of the remaining brain tissue to compensate (which is referred to as plasticity). The venous side of the circulation may also undergo thrombosis and cause significant cerebral ischemia. A particularly striking example of this is thrombosis of the superior sagittal sinus, which can occur with some infections and various hypercoagulation states, including pregnancy and systemic malignancies. Here, venous outflow from superficial veins of the superior median aspect of the cerebral hemispheres is obstructed, resulting in marked congestion and hemorrhagic infarction in this region. Seizures are a common presenting complaint with venous infarctions. The lesions under discussion here should be distinguished from so-called “watershed infarcts” that result from diffuse or global hypoxia and occur in arterial border zones representing end-artery regions of supply between the major cerebral blood vessels. Such lesions may result from cardiac arrest, shock, or severe hypotension. Global hypoxia/ischemia resulting in widespread cerebral necrosis may occur in survivors of acute cardiopulmonary arrest in which there was prolonged hypotension or hypoperfusion, drug overdose, birth injury, and profound shock.3 In classic presentations of cerebral infarct (Fig. 26.1), the surgical neuropathologist is not involved, since the diagnosis is made purely on clinical and radiologic criteria. However, atypical presentations, such as young age, a lack of sudden onset, or unusual vascular distributions occasionally overlap with differential diagnostic considerations such as tumor or infection, prompting a biopsy (Fig. 26.2). This occurs most often in the subacute phase when contrast enhancement and mass effects are increased (see next section). Additionally, biopsies are sometimes useful for identifying unusual underlying causes of ischemic damage, such as vasculitis, amyloid angiopathy, cerebral autosomal dominant arteriopathy Fig. 26.1  (A) Computed tomography (CT) 6 to 8 hours after an acute ischemic infarct in the right posterior cerebral artery (PCA) distribution. The infarcted area is hypodense due to focal brain swelling from cytotoxic edema. (B) Magnetic resonance imaging (MRI). Acute right PCA infarct, as visualized by diffusion-weighted imaging.

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Vascular and Ischemic Disorders of swelling, dusky discoloration, and hyperemia in the gray matter of a well-defined vascular territory (Fig. 26.3A). Large acute infarcts may be associated with significant mass effect and herniation. In such cases, a combination of a focal infarct in the specific vascular territory of the initial stroke and border zone lesions caused by compression may be present. If little or no reperfusion occurs in an area of ischemia, the infarct is called “bland” or “anemic.” However, if reperfusion occurs, as is the case for most embolic infarcts, the area of ischemia will appear hemorrhagic (Fig. 26.3B). The incidence of hemorrhagic transformation is strongly correlated to the duration of ischemia and volume of ischemic tissue.7 Hemorrhages may range from small or petechial and clinically symptomatic to lobar and devastating. With organization of the lesion, macrophages enter the tissue to remove necrotic material. This results in softening and disruption of the tissues and a circumscribed pattern of laminar necrosis in which the cortex appears detached from the underlying white matter (Fig. 26.3C). The subpial region of the cortex usually remains intact. With further elimination of the necrotic tissue, the brain tissue undergoes cavitation and the cerebral surface becomes depressed (Fig. 26.3D).

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Histopathology

Fig. 26.2  Magnetic resonance imaging. This subacute infarct in a 6-year-old boy was biopsied due to the atypical clinical presentation and tumor-like qualities, such as contrast enhancement and mass effects (contrast-enhanced T1-weighted MRI).

with subcortical infarcts and leukoencephalopathy (CADASIL), and intravascular lymphoma.

Radiologic Features and Gross Pathology Patients who present with neurologic signs and symptoms of a stroke are typically evaluated by computed tomography (CT) in order to determine the extent of the lesion and the amount of mass effect, as well as to exclude the possibility of some other pathology, such as a hemorrhage. Most CT scans will be unremarkable during the first few hours after an ischemic cerebral infarct. Those with any findings often show only subtle evidence of tissue swelling, such as effacement of sulci or hypodensity with loss of anatomic definition and blurring of gray-white junctions.6 Within 6 to 8 hours of the ictus, the infarcted area will become increasingly hypodense as focal brain swelling ensues due to cytotoxic edema (see Fig. 26.1A). After 1 to 2 days, the lesion becomes easier to detect, often revealing a wedge-shaped region of hypodensity on CT and T1-weighted magnetic resonance imaging (MRI) within a classic vascular territory (e.g., middle cerebral artery). Increasing contrast enhancement (often in a gyral pattern) and mass effects will be observed within a week of the event and may persist as long as 2 months. Over months to years, this pattern gives way to tissue collapse and “encephalomalacia” or cystic degeneration, often with hydrocephalus ex vacuo on the side of the lesion. MRI is far more sensitive in detection of acute ischemic stroke, particularly diffusion-weighted imaging (Fig. 26.1B) in which changes can be seen within minutes of ischemia, but such scans are time consuming and may not be readily available. In atypical presentations, particularly during the subacute phase, infarcts may mimic other mass-forming lesions, such as neoplasms and infections (see Fig. 26.2). Pathologic changes are not detectable on gross examination until 6 to 8 hours after an infarct. The first indication of abnormality is a subtle blurring of the gray-white junction and swelling of affected tissues. Within 1 to 2 days of infarction, there will be congestion with dusky discoloration of the gray matter and slight softening of the tissues. At this time, gross examination will reveal a well-circumscribed area

No apparent histopathologic changes are evident by routine light microscopy within 12 hours of the ischemic event. Low-magnification microscopic changes first emerge between 12 and 24 hours after significant ischemia and consist of circumscribed regions of pallor with variable degrees of vacuolization of the neuropil. At higher magnifications, neurons display cytoplasmic hypereosinophilia and dark shrunken nuclei, consistent with pyknosis (Fig. 26.4A). This neuronal reaction has been variously referred to as ischemic cell change, acute neuronal cell change, eosinophilic cell change, or, simply, “red dead” neurons. The last designation indicates that irreversible damage has occurred. Eosinophilic neurons may persist for several days following the acute event or even longer if blood flow is not reestablished to the region. During the subacute or organizing stage of a cerebral infarct (5 to 30 days), microglia are activated and foamy macrophages infiltrate tissue and begin removing necrotic material (Fig. 26.4B–E). Removal of necrotic debris by macrophages ultimately results in cavitation of cortical layers 2 through 6, with sparing of the subpial layer and persistence of threadlike capillaries. Macrophages may persist in the resulting cavity for years after the original event. Capillary proliferation occurs during the first 2 weeks after infarction (Fig. 26.4C). Unlike demyelinating disorders, which show mostly loss of myelin, a severe axonopathy is also evident in infarcts at this stage, with marked loss of axons in the lesion and axonal spheroids at the edge (Fig. 26.4E). Astrocytic hyperplasia and hypertrophy are also apparent at the edges of the lesion 7 to 10 days after the insult (Fig. 26.4F). In the chronic phase (weeks to years postinfarct), scattered macrophages with or without hemosiderin are found within organized areas of cavitation. Thin strands of residual glial tissue and blood vessels (“glial scar”) often traverse such areas, and scattered reactive astrocytes are seen at the edge. The formation of a cavity in the region of severe hypoxia/ischemia is referred to as “complete liquefactive necrosis,” and necrosis of the most vulnerable population of cells (the neurons) with sparing of astrocytes and other cellular elements of the neuropil is called “incomplete necrosis.” The important concept of “selective vulnerability” maintains that brain cells in different anatomic sites vary considerably in their susceptibility to hypoxia. In general, neurons are most sensitive, followed by oligodendrocytes, astrocytes, and endothelial cells. Also, certain subtypes of neurons display a striking selective vulnerability to hypoxia. For example, the most sensitive neurons in the adult are the pyramidal cells in area CA1 of the hippocampus (“Sommer sector”) and the Purkinje 635

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Fig. 26.3  (A) Wedge-shaped region of hyperemia and softening in an internal carotid artery distribution (combined anterior cerebral artery [ACA] and middle cerebral artery [MCA]). (B) Hemorrhagic infarct. Petechial intracortical hemorrhages are seen as a secondary phenomenon in this hemorrhagic MCA territory infarct. Note the adjacent nonhemorrhagic, but necrotic, white matter. (C) Organizing cerebral infarct. Early cavitation and separation of the cortex from the underlying white matter in ACA infarcts. (D) Remote cerebral infarct. Cavitated (remote) infarct having undergone complete liquefaction necrosis in the right frontal lobe.

cells of the cerebellum. In relatively mild hypoxic injury, only the most vulnerable neurons may be affected. With more severe global hypoxia/ ischemia, laminar necrosis of neurons in layers 3, 5, and 6 of the cerebral cortex occurs, although there is considerable individual variability. For example, thalamic and basal ganglia neurons may be selectively involved in some individuals, rather than the typical patterns of watershed infarcts, laminar necrosis, and neuronal damage in the hippocampus and cerebellum.

Differential Diagnosis Hemorrhagic transformation of an ischemic infarct may be difficult to distinguish from a primary brain hemorrhage. Occasionally, a glioma that diffusely infiltrates the cerebral cortex and subcortical white matter may give the radiographic appearance of an acute to subacute infarct (or vice versa; see Fig. 26.2). In most cases, these are clearly discernable on microscopic examination, although macrophages can display surprising nuclear atypia and mitotic activity. On frozen section in particular, they are notorious for their mimicry of high-grade glioma, whereas they are easily recognized as foamy macrophages on intraoperative smear. In its subacute phase, a macrophage-rich infarct may be difficult to distinguish from active demyelination (see Chapter 24), although the former is much more destructive (i.e., no relative preservation of axons). One must also rule out other destructive processes, such as necrotizing infections (e.g., toxoplasomosis, herpes encephalitis). Lastly, it is important to 636

search carefully for clues to the cause of ischemia in clinically atypical presentations. These include the presence of thromboemboli, vasculitis, amyloid angiopathy, CADASIL, or intravascular lymphoma.

Ancillary Diagnostic Studies Ancillary diagnostic studies are not usually necessary in routine clinical practice since the characteristic histopathology of a cerebral infarct and its various stages of evolution are readily apparent on hematoxylin-eosin (H & E) staining. However, occasionally the surgical pathologist receives a specimen from a patient with an organizing cerebral infarct in whom the clinical or imaging workup suggested a neoplastic or infectious process. In this case, organizing necrosis in the brain can be distinguished from tumor by the identification of CD163 or CD68-immunoreactive macrophages as the prominent component of a cellular-appearing lesion (see Fig. 26.4D). In the differential with active inflammatory demyelinating lesion (“tumefactive” demyelination), Luxol fast blue/ periodic acid–Schiff (LFB-PAS) staining shows loss of myelin and PASpositive macrophages in both processes. However, axonal stains, such as the Bodian or Bielschowsky silver stains, or a neurofilament protein immunostain can be used to detect relative sparing of axons in the case of demyelination versus a loss of axons in organizing necrosis (see Fig. 26.4E). Routine organism stains help to exclude an infectious cause if there are other features to suggest one (e.g., prominent inflammation, granulomas, possible viral inclusions).

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Fig. 26.4  (A) Acute ischemic cell change. Cortical neurons showing hypereosinophilia, shrinkage, and nuclear pyknosis. (B) Organizing subacute infarct. Organizing cerebral infarct with foamy macrophages. (C) Organizing subacute infarct. Same case as Fig. 26.2 showing the edge of a subacute infarct with numerous foamy macrophages and capillary proliferation in the upper right. (D) Organizing subacute infarct. The macrophages are highlighted using a CD68 immunostain. (E) Organizing subacute infarct. An immunostain for neurofilament protein shows marked loss of axons in the lesion (unlike demyelinating disease), and axonal swellings (“spheroids”) at the noninfarcted edge. (F) Reactive astrocytes and hemosiderinladen macrophages at the edge of an organized infarct.

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Treatment and Prognosis Early diagnosis and improved management of complications have led to significant reduction in mortality from acute cerebral infarction. Although available only to a minority of patients, immediate thrombolytic therapy can substantially improve outcomes. Variable degrees of hemorrhagic transformation can occur with administration of thrombolytics, yet these events are often asymptomatic. Hemorrhage can reflect reperfusion, which is associated with improved outcomes. Symptomatic hemorrhage after thrombolytic administration occurs in a small percentage of patients. In addition, treatment with aspirin and other antiplatelet agents plays a significant role in preventive therapy. Treatment of diabetes and hypertension, lowering cholesterol, cessation of smoking, and other measures to control risk factors for stroke are important preventive measures.

Clinical Manifestations and Localization

Hypertensive neuropathology is defined by the typical vascular and parenchymal complications of chronic high blood pressure. Chronicity is important to the definition because patients are often acutely “hypertensive” as part of the normal Cushing reflex response to brain hypoperfusion and this does not constitute true hypertension as a disease process. Thus, hypertensive cerebrovascular disease does not typically follow the many causes of increased intracrianal pressure (e.g., intracerebral hemorrhage) that induce a short-term increase in systemic blood pressure as the body attempts to preserve blood flow to the brain. Lacunar infarct is defined by a greatest dimension of less than 1 cm, usually within deep subcortical structures. By definition, intracerebral hemorrhage originates within the brain parenchyma itself (often deep subcortical structures), rather than external spaces, such as subarachnoid, subdural, and epidural hemorrhages.

Acute hypertensive hemorrhage typically occurs in distributions of the lenticulostriate branches of the middle cerebral artery and in pontine perforators of the basilar artery. Accordingly, hypertensive hemorrhages arise in the deep cerebral nuclei (60%; putamen, thalamus), cerebrum (lobar white matter 20%), cerebellum (13%), and pons (7%). Involvement of the deep nuclei may produce hemiparesis, hemisensory deficits, and visual field defects (putamen), or gaze abnormalities and vomiting (thalamus). Headache, vomiting, and truncal or limb ataxia may occur with cerebellar hemorrhage, and coma with quadriparesis may signal a pontine hemorrhage. Depressed level of consciousness due to acutely increased intracranial pressure is often present and is the most reliable clinical sign for differentiating hemorrhagic from ischemic lesions. Lacunar infarcts often involve the same vessels that give rise to hypertensive hemorrhages, so the focal deficits are often similar, but lacunar infarcts rarely lead to a depressed level of consciousness. Classically, there are five lacunar syndromes: (1) pure motor or (2) pure sensory deficits (affecting face, arm, and leg equally), (3) a combination of these two, (4) ataxic hemiparesis, and (5) the dysarthria/clumsy-hand syndrome. Localization based on the clinical presentation is inexact, as there are multiple locations along the motor or sensory pathways that can produce the same syndrome. Accumulation of appropriately located lacunar infarcts can lead to a stepwise decline in cognition, often referred to as “multi-infarct dementia.” RPLS is an acute neurologic syndrome characterized by diffuse cerebral dysfunction, severe headache, confusion, and visual changes precipitated by a sudden and severe increase in systemic blood pressure. It can occur in patients with kidney disease, eclampsia, disseminated vasculitis, catecholamine-secreting tumors like pheochromocytoma, or following discontinuation of antihypertensive therapy (i.e., “rebound effect”). More recently, cases of RPLS have been associated with antiangiogenic chemotherapeutic agents such as bevacizumab10,11 and cediranib.12 An association with sickle cell disease has also been reported.13 Untreated, the syndrome may progress to coma or fatal hemorrhage.

Incidence and Demographics

Radiology and Gross Pathology

Spontaneous intracranial hemorrhage affects thousands of patients annually in the United States and is believed to account for 10% to 20% of all strokes. Hypertension is the most important underlying cause of acute nontraumatic ICH. The incidence of ICH is around 28 per 100,000 in Caucasians, roughly 56 in African Americans, and even greater in Japanese individuals.3 Around 70% to 90% of patients with ICH have high blood pressure, and cerebral hemorrhage accounts for 15% of deaths in patients with chronic hypertension. The risk of spontaneous ICH increases dramatically after 55 years of age.8 Lacunar infarcts are a common stroke subtype, accounting for 15% to 20% of all strokes, and have a strong relationship to hypertension. Incidence in Caucasians is about 17%, and roughly double that in African Americans and Hispanics, but distribution is nearly equal between the sexes. In Japan, lacunar infarcts account for nearly 40% of all strokes. Like most other stroke subtypes, risk generally increases with age.9 Hypertensive encephalopathy is an older term that overlaps with the more recently introduced terms reversible posterior leukoencephalopathy syndrome (RPLS), reversible posterior leukoencephalopathy (RPLE), and posterior reversible encephalopathy syndrome (PRES). RPLS and PRES are the two most common terms used in the literature currently. Although

Massive hemorrhages involving the deep nuclei manifest as circumscribed areas of fresh and acutely clotted blood, causing tissue disruption, significant mass effect, and herniation (Fig. 26.5A). Blood may dissect medially into the ventricles but only rarely dissects outward through the cortex and into the subarachnoid space. In nonfatal cases, the region of hemorrhage undergoes cavitation and shows yellow-brown hemosiderin staining. Pontine (Fig. 26.5B) and cerebellar hemorrhages are associated with significant brainstem compression. Acute hemorrhages are hyperdense on CT (nearly as bright as bone) and become isodense to brain parenchyma with time. The appearance of hemorrhage on MRI is complex and evolves through stages of hypointensity, isointensity, and hyperintensity with time. A lacunar infarct results from occlusion of a single perforating artery, and therefore they are predominantly located in the deep cerebral nuclei, especially in the putamen (Fig. 26.5C). They may also be found in the periventricular white matter. Careful autopsy studies of the brains of hypertensive individuals have demonstrated that perivascular spaces were frequently widened because of increased tortuosity of parenchymal arteries.14 Lacunar infarcts and enlarged perivascular spaces are usually readily differentiated with MRI or microscopic examination

Hypertensive Cerebrovascular Disease Although the consequences of hypertension are legion, this section focuses on three areas of cerebrovascular disease in which hypertension is most closely causally related: (1) spontaneous intracerebral hemorrhage (ICH), (2) lacunar infarcts, and (3) hypertensive encephalopathy, which now includes the reversible posterior leukoencephalopathy syndrome (RPLS). Diseases included within the spectrum of “vascular dementias,” including Binswanger disease, are also discussed in Chapter 24.

Definition and Synonyms

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RPLS can manifest without elevated blood pressure in certain clinical circumstances, the vast majority of cases occur in the setting of extreme hypertension and another risk factor, such as exposure to certain medications (e.g., FK506), pregnancy (as part of eclampsia), or drug abuse (e.g., cocaine).

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Fig. 26.5  (A) Large acute hypertensive hemorrhage centered on the basal ganglia. (B) Acute hypertensive hemorrhage arising in the pons. (C) Slit-like lacunar infarct of putamen, caudate, and internal capsule. (D) Low-magnification view of a well-circumscribed remote lacunar infarct with liquefactive necrosis, surrounding hyalinized blood vessels.

of surrounding tissue. Using either method, the tissue surrounding a lacunar infarct would show reactive changes and gliosis (bright signal on fluid-attenuated inversion recovery MRI), whereas the tissue surrounding a widened perivascular space would appear normal. Autopsy studies of patients having suffered from RPLS have demonstrated a range of gross pathologic changes. Brain weights are generally within normal limits. As RPLS is a focal disorder that predominantly affects the posterior circulation, pathology may be confined to tissues supplied by branches of the vertebral or basilar arteries. Atypical distributions of RSLS may occur outside of the posterior circulation.15,16 Multiple petechial hemorrhages are occasionally seen. Atherosclerotic changes of the vessels of the circle of Willis are often observed and may be severe.14 Because hypertension is a risk factor shared with many diseases, multiple pathologies may coexist, such as old ischemic or hemorrhagic infarcts. MRI demonstrates increased T2 signal in affected areas, and a variable degree of water restriction may be seen on diffusion-weighted imaging. Signal abnormalities are consistent with modest to moderate edema, below the threshold for gross swelling or herniation.

Histopathology Lacunar infarcts derive their name from the fact that these small ischemic infarcts (see Fig. 26.5D) organize by liquefaction necrosis and undergo

cavitation, leaving behind a fluid-filled defect, or “lake.” Hemosiderinladen macrophages may also be present in such lesions if the initial insult was hemorrhage. Because of the strong association of diabetes and hypertension with accelerated atherosclerosis, atheromatous changes of cerebral blood vessels often extend more distally, involving smaller superficial and parenchymal arteries as well as large vessels at the base. Hyaline atherosclerosis and arteriolosclerosis consist of homogeneous, eosinophilic thickening of the walls of small arteries and arterioles, respectively, obscuring the underlying structural detail and narrowing vascular lumens (Fig. 26.6A). To some extent, this change is a consequence of age, but it is present to a much greater degree in patients with hypertension or diabetes and may occur with concentric mineralization of the media of small arteries, particularly common in the globus pallidus (Fig. 26.6B). Radiation injury (usually iatrogenic) is another less common cause. With acute or malignant hypertension, hyperplastic arteriolosclerosis develops, leading to concentric laminated thickening of the walls of arterioles with progressive narrowing of the lumen. With electron microscopy, these laminations have been shown to consist of smooth muscle cells with thickened, reduplicated basement membranes that lead to an appearance referred to as “onion-skinning” of the vessel wall. 639

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Fig. 26.6  (A) Arteriosclerosis. Fibrointimal sclerosis involving a small parenchymal artery in a patient with hypertension. (B) Vascular calcification. Heavily calcified small arteries of the globus pallidus. This nonspecific change can be seen in patients with hypertension. (C) Hyalinization (“lipohyalinosis”) of a small, white matter artery. (D) Charcot-Bouchard aneurysm. Dilatation of a small hyalinized artery in the basal ganglia, associated with evidence of prior microhemorrhage.

Over time, chronic stress on vessel walls leads to degeneration of the tunica media in the form of fibrinoid necrosis (also called lipohyalinosis). To some extent lesions of this type reflect leakage of plasma proteins across vascular endothelium and excessive extracellular matrix production by smooth muscle cells secondary to chronic hemodynamic or metabolic stress. Vessel walls appear thickened and hyalinized in a segmental distribution (Fig. 26.6C). The development of such a lesion includes the transient appearance of foamy or lipid-laden macrophages and eventually progresses to fibrosis and hyalinization. The traditional view that local weakening of damaged blood vessels in hypertensive patients leads to focal microscopic aneurysmal dilatations at branch points (referred to as cerebral microaneurysms, or Charcot-Bouchard aneurysms) has been debated for over a century. Such aneurysms are only rarely identified in routine autopsy material, and thus most descriptions in the literature are based on single or small numbers of cases17 (Fig. 26.6D). The relationship between these microaneurysms and ICH has not been firmly established. A detailed pathologic study using light microscopy and high-resolution microradiography compared the brains of hypertensive patients (with and without ICH) and normal controls and failed to demonstrate any microaneurysms.17 However, sections though the twists and turns of tortuous blood vessels commonly seen in hypertensive patients 640

often had the appearance of aneurysmal dilation in histologic sections. Although it remains possible that cerebral microaneurysms develop rapidly, immediately preceding fatal hemorrhage, and are obliterated in the process, most evidence suggests these lesions are rare and an unlikely source of ICH. The cause of massive deep nuclear hemorrhages associated with hypertension is most likely multifactorial, with vascular hyalinization and fibrinoid change causing decreased wall compliance and increased fragility. Evidence of microhemorrhage is common surrounding foci of small-vessel disease (see Fig. 26.6D). In the case of RPLS, milder forms do not come to the attention of pathologists, since the changes are typically reversible and likely due to poor autoregulation of the posterior circulation, resulting in cerebral edema. However, rare autopsy studies of acute malignant hypertension have demonstrated foci of fibrinoid vascular necrosis, with miliary microinfarcts and fibrin thrombi occluding the lumina of both necrotic and intact arterioles, most prominently in the brainstem. These vessels were often surrounded by a cuff of mononuclear cells. Extravascular deposits of fibrin were also commonly observed. In all cases, a mixture of segmental hyaline and hyperplastic arteriolosclerosis was demonstrated, with the degree proportional to the severity of hypertension. Chronic lesions showed gliosis with gemistocytic astrocytes and microglial nodules.14

Vascular and Ischemic Disorders

Differential Diagnosis and Ancillary Diagnostic Studies The vasculopathy of hypertension and the associated white matter changes and microinfarcts looks remarkably similar at first glance to the pathology of CADASIL (covered at the end of this chapter). However, hypertensive blood vessels lack the granular PAS-positive, electron-dense medial deposits of CADASIL. Therefore, histochemistry or electron microscopy may be helpful in the rare cases where this distinction is not already apparent based on other clinicopathologic features. Occasionally, it may be difficult to distinguish ICH from a hemorrhagic infarct. In cases of massive ICH, the typical histologic pattern is that of a large hematoma compressing or disrupting otherwise viable tissue. Ischemic changes are common in the tissue immediately surrounding the hematoma, but this differs from hemorrhagic infarcts, where the typical pattern is one of patchy (often petechial) hemorrhage within large zones of necrotic brain.

Genetics The genetics of hypertension are complex and multifactorial. No genetic markers are currently known for predicting which patients are at greatest risk of intracerebral complications.

Treatment and Prognosis The prognosis after ICH varies widely with the size of the hematoma. With small hemorrhages less than 10 mL in volume, patients most often make a good recovery. Massive ICHs with volumes greater than 60 mL have a 90% mortality rate.8 No definitive treatment exists for acute ICH, other than control of blood pressure. Medical control of hypertension and other risk factors are the mainstays of preventive therapy. The prognosis after lacunar infarction is also extremely variable and dependent on the location. The small size of lacunes does not necessarily equate with a proportionally small deficit. Some infarctions, such as in the head of the caudate, may go unnoticed and be only incidentally discovered with imaging studies, whereas others of the same size involving the internal capsule may leave a patient hemiparetic. Preventive therapy is the same as that for hypertension. The deficits caused by RPLS may, as the name implies, often be reversible if treated aggressively and early. Those cases related to acute malignant hypertension often respond to intravenous antihypertensives. Cases related to eclampsia respond only to delivery of the fetus; those related to certain drugs, such as chemotherapeutics, may respond to discontinuing the offending agent (see Chapter 21). In those cases that do not respond to treatment, the effects are often devastating or fatal.

phenotype of the most common variant warrants discussion as if it were a separate entity. The pathologic changes associated with CAA are very common and are found in patients spanning the full spectrum of cognitive decline. In a large retrospective autopsy study of 2060 elderly subjects, CAA of various degrees was detected in 73% of all and in 98% of confirmed cases of typical AD.19,20 This process also predisposes patients to both microscopic and large lobar hemorrhages, generally seen in patients 70 to 80 years of age. It is this clinicopathologic presentation to which the disease label “CAA” usually refers. This disease should be considered in any older adult who presents with spontaneous lobar ICH, especially if the patient is nonhypertensive and multiple microhemorrhages are present. Rarely, CAA may cause symptoms earlier than the fifth and sixth decades.

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Clinical Manifestations and Localization In contrast to the deep cerebral hemorrhages of chronic hypertension, hemorrhages associated with amyloid angiopathy are more peripheral, involving the cerebral cortex and adjacent structures. Clinical symptoms reflect the anatomic extent and location of the hemorrhage. Lobar hemorrhages can occur acutely as a massive acute stroke, or as recurrent hemorrhagic infarctions that take place over a period of years. CAA may involve any lobe of the brain, but has a particular predilection for the occipital lobe. As the disease progresses, patients become increasingly cognitively impaired. A small subset of CAA patients develop an intense inflammatory response (ABRA).21 Presentations overlap between those of typical CAA and those of primary angiitis of the CNS (PACNS; see next section). Patients are slightly younger than classic CAA patients and are more likely to present with mental status changes, seizures, and hallucinations. Occasionally, intralobar masses are difficult to distinguish from hemorrhagic neoplasms, and these are the cases most likely to undergo surgical resection. Others undergo “clot evacuation” in order to alleviate mass effects.

Radiologic Features and Gross Pathology CT is the most useful imaging method in the setting of an acute hemorrhage (Fig. 26.7). Recent advances in neuroimaging have expanded our knowledge of this process. Gradient-echo (GE) MRI is capable of detecting millimeter-sized foci of blood products in brain parenchyma, including hemosiderin, which remains at sites of previous bleeding, allowing hemorrhagic burden to be assessed over time.22 Blood products appear as black spots on GE MRI sequences and must be distinguished from

Cerebral Amyloid Angiopathy Definitions and Synonyms

Cerebral amyloid angiopathy (CAA) is a form of vasculopathy resulting from the deposition of Aβ-amyloid within the walls of meningeal and cortical blood vessels. By definition, it is distinct from the many systemic forms of amyloidosis. An older term is congophilic angiopathy, reflecting its common detection using the Congo red histochemical stain for amyloid, whereas a less common synonym is dysphoric angiopathy, sometimes utilized when the amyloid spills out into the adjacent parenchyma. The term Aβ-related angiitis (ABRA) has been applied to examples of CAA with associated vasculitis, giant cells, or granulomatous inflammation.18 Lobar hemorrhage is a form of ICH that tends to be more superficial than hypertensive hemorrhages and usually involves a single cerebral lobe, the occipital lobe being most common.

Incidence and Demographics Emerging evidence suggests that CAA is not a distinct disease, but a pathologic process that may be the molecular link between Alzheimer disease (AD) and vascular dementia. Nonetheless, the distinctive

Fig. 26.7  Computed tomography showing an acute lobar hemorrhage in a patient with cerebral amyloid angiopathy. 641

Practical Surgical Neuropathology vascular flow voids. One should also note that because of an artifact inherent to GE MRI, called the “blooming effect,” the hemorrhagic lesions appear larger than they really are.23 With specific probes and positron emission tomography (PET), the distribution of β-amyloid can now be directly visualized. Many compounds, most notably Pittsburgh compound B (PiB)24 and the 2,6-disubstituted naphthalene derivative FDDNP,25 reliably predict β-amyloid deposition in human brain parenchyma. As this technology matures, clinical applications for the early detection of AD and evaluation of new antiamyloid therapies may be possible. Gross pathology reveals a large acute lobar hemorrhage that is more peripheral in location than deep hypertensive hemorrhages. Often, multiple subcortical hemorrhages or hemorrhagic infarcts of different ages are also present. Cortical superficial siderosis, a distinct pattern of blood breakdown product deposition in the sulci of the cerebral hemispheres, has been increasingly associated with cerebral amyloid angiopathy26 and has been shown to predict recurrence of intracerebral hemorrhage in this disorder.27

Histopathology On routine H & E staining of lobar hemorrhage/infarct with associated CAA, the majority of the specimen often shows organizing hematoma, with thickened blood vessels in the adjacent brain parenchyma (Fig. 26.8A). The affected vessels of the leptomeninges and superficial cortex show mural thickening and effacement by acellular, homogeneous, eosinophilic

material, which is highlighted with nonspecific histochemical stains for amyloid such as thioflavin S (Fig. 26.8B) and is strongly reactive for Aβ-amyloid peptide using immunohistochemistry (Fig. 26.8C). Capillaries and veins are less often involved, and blood vessels of the deep white matter are typically spared. Arterial and arteriolar amyloid accumulation initially appears in the basement membrane around smooth muscle cells at the peripheral aspect of the media and adventitia. There is progressive destruction of smooth muscle cells, but (generally) sparing of the endothelium until late stages of the disease. Affected vessels become rigid and fragile and in late stages assume a rounded or “double-barrel contour” (Fig. 26.8D). Some vessels ultimately undergo fibrinoid necrosis and rupture with hemorrhage. Vascular amyloid accumulation also likely impairs cerebral autoregulation. More recent studies have suggested that vascular accumulation of Aβ-amyloid may be due to failure of perivascular drainage, which may impair clearance of amyloid in CAA.28,29 In cases of ABRA, the amyloid is associated with vasculitis (Fig. 26.9), the inflammatory component variably consisting of lymphocytes, plasma cells, and epithelioid macrophages, often including multinucleated giant cells or fully formed granulomas, such as those seen in PACNS (see next section).18

Differential Diagnosis Hemorrhages associated with CAA may be accompanied by ischemic lesions that mimic a vasculitis. A high index of suspicion for the diagnosis

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Fig. 26.8  Cerebral amyloid angiopathy (CAA). (A) Surgically evacuated intracerebral hematoma showing numerous thickened and hyalinized vessels in adjacent brain. (B) Leptomeningeal and superficial penetrating vessels with strong fluorescence on thioflavin S stain. (C) Leptomeningeal and superficial penetrating vessels strongly immunoreactive for Aβ-amyloid peptide. (D) Progressive damage to arteries results in a “double-barrel” appearance. 642

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Fig. 26.9  Aβ-amyloid-related angiitis (ABRA). (A) Hyalinized cortical blood vessels are associated with inflammation. (B) Vessel involved by CAA showing associated granulomatous vasculitis (Congo red stain). (C) Aβ-amyloid immunostains highlighting vascular deposits and adjacent diffuse plaques in a case of ABRA. (D) Perivascular T cells are highlighted by a CD3 immunostain.

of ABRA should be maintained for elderly patients with histology suggesting PACNS, especially if amorphous eosinophilic material is seen within vessel walls (see Fig. 26.9A). Occasionally, white matter lesions may occur in a distribution suggesting a Binswanger-like leukoencephalopathy,30 although most cases are limited to the cortex. The small-vessel hyalinization overlaps with hypertensive vasculopathy (or diabetes), although this type of vasculopathy more often extends into deep subcortical structures. The detection of Aβ-amyloid peptide by immunohistochemistry confirms the diagnosis in most cases.

Ancillary Diagnostic Studies Aβ-amyloid deposition can be confirmed by the Congo red stain (see Fig. 26.9B), typically associated with apple-green birefringence seen under polarized illumination; although this stain is tenuous in some laboratories and equivocal results are not uncommon. An unequivocally intense green fluorescence is usually seen with thioflavin S stain (see Fig. 26.8B). However, since most sporadic and some familial cerebral amyloid angiopathies are due to abnormal accumulations of Aβ-amyloid, detection of this peptide by immunohistochemistry has greatly facilitated the histopathologic diagnosis. Immunostaining for Aβ-amyloid often

also reveals neuritic and diffuse plaques in the cortex of individuals with CAA (Figs. 26.8C and 26.9C). In surgical cases, one must be careful not to overdiagnose AD based on this finding alone with a single sample of the cortex (especially in the absence of clinical dementia), although the possibility can be raised in a comment, so that appropriate clinical workup can subsequently be initiated and early therapy instituted if appropriate.

Genetics Amyloid is a pathologic protein in which abnormal folding produces an extensive β-pleated sheet secondary structure. In this conformation, protein polymers form highly insoluble 8- to 10-nm-diameter fibrils. The most common form of CAA is caused by the deposition of degradation products of amyloid precursor protein (APP), which is encoded by a gene located on chromosome 21. Rare inherited forms of CAA result from amyloid composed of cystatin C, transthyretin, gelsolin, and prion protein. APP may be cleaved by α-, β-, or γ-secretase, but under normal physiologic conditions, the action of α-secretase predominates, and the fragments produced are not amyloidogenic. Low levels of Aβ-amyloid, produced by the β- and γ-secretases, do 643

Practical Surgical Neuropathology not form deposits, as Aβ can be cleared from the brain by several mechanisms. Most cases of CAA are apparently sporadic, but mutations in several genes have been implicated in the development of both CAA and AD, which likely accounts in part for the heterogeneity seen in these diseases. Mutations in the APP gene in Flemish and Dutch families have been associated with the most severe forms of CAA. Presenilin 1 and 2 gene mutations have been implicated in early-onset familial AD. All three of these gene mutations predispose cleavage of APP by β-secretase and increase the production of β-amyloid. The ApoE4 allele also plays an important role and may promote the deposition of Aβ-amyloid in vessel walls.31 This allele is also highly associated with vasculitis-associated pathology. A recent study demonstrated ApoE4 homozygosity in 10 of 13 (77%) ABRA versus 2 of 39 (5%) noninflammatory CAA patients.32

Treatment and Prognosis Acute parenchymal brain hemorrhage may cause death due to mass effect and herniation. Excessive bleeding of amyloid-laden blood vessels may complicate surgery for removal of acutely clotted blood. Management of smaller hemorrhages is mainly symptomatic as no specific therapies are available at present. The diagnosis of ABRA is particularly important, since unlike ordinary CAA, immunosuppressive therapies are often part of the regimen, with some patients showing particularly dramatic responses.

Vasculitis Involving the Nervous System

Radiologic and Gross Pathology Although ultrasound of the temporal artery often yields a “halo sign,” radiologic features are not entirely specific in temporal arteritis. Grossly, the resected segment of temporal artery is often unremarkable as well, although in severe cases, a firm, ropy thickening may be noted. It is important to section the segment of artery into relatively thin cross sections in order to maximize the yield, since involvement is often patchy, as it is with nearly all forms of vasculitis. Similarly, cutting multiple levels through the block also increases the detection rate.

Histopathology A definitive diagnosis can be made by temporal artery biopsy. GCA is a panarteritis with transmural infiltration by mononuclear cells, including lymphocytes, monocytes/macrophages, and multinucleated giant cells (Fig. 26.10A and B). Granulomas form in close proximity to a fragmented internal elastic lamina (Fig. 26.10C). The disease appears to represent a disorder of cell-mediated immunity, with CD4+ T lymphocytes playing a key pathogenic role in the activation of monocytes/macrophages and the formation of multinucleated giant cells. The granulomatous reaction results in marked intimal proliferation (Fig. 26.10D) with reduced luminal diameter and resultant ischemic phenomena.

Definitions and Synonyms

Variants

Vasculitis, or inflammation of cerebral blood vessel walls, may occur in the context of a primary systemic disorder, such as giant-cell arteritis and polyarteritis nodosa, or may be localized to cerebral vasculature or to those vessels supplying peripheral nerves. Alternatively, inflammatory changes in nervous system blood vessels may represent secondary involvement by collagen vascular diseases, infections, tumors, and substance abuse (“secondary vasculitis”). Primary vasculitides may preferentially affect large (elastic), medium (muscular), or small (<0.5 mm in diameter) arteries. An idiopathic form of vasculitis limited to the brain and spinal cord is known as primary angiitis of the central nervous system (PACNS).

Takayasu disease is a rare form of vasculitis with pathologic features similar to GCA. It affects the aorta and its major branches and is considered to be the “classic” large-vessel vasculitis. It typically affects young women in the second or third decades of life (female to male ratio about 9 : 1). A systemic phase of the disease marked by nonspecific constitutional symptoms is followed by an occlusive phase characterized by ischemic symptoms.

Giant Cell Arteritis

Incidence and Demographics Giant cell arteritis (GCA) is the most common primary vasculitis affecting the nervous system. It occurs exclusively in adults older than 50, with a peak incidence between age 75 and 85 years. Women are affected twice as often as men. The incidence is 15 to 25/100,000.33

Clinical Manifestations and Localization Extracranial branches of the aorta are typically involved, especially the external and internal carotid arteries (large and midsize arteries) and temporal arteries. Inflammatory changes in these vessels lead to vascular compromise and local end-organ ischemia, which result in the classic symptoms of blindness, headache, scalp tenderness, and jaw claudication when the temporal artery is involved. Involvement of the vertebral arteries is associated with vertigo, dizziness, TIAs, or stroke. Malaise, fever, anorexia, weight loss, and night sweats are nonspecific manifestations of this systemic inflammatory disorder. Acute-phase proteins such as C-reactive protein (CRP) are elevated along with the erythrocyte sedimentation rate (ESR). Normal sedimentation rates, however, may be found in up to 17% of patients with GCA, so that a normal ESR does not exclude GCA.34 The sensitivity of the ESR alone is at least 76%, and that of the CRP alone is 97.5%, but when both tests are abnormal, the sensitivity is 99%.35 About 30% to 40% of patients with GCA also have polymyalgia rheumatica.33 644

More recent studies have identified varicella zoster virus (VZV) in temporal arteries from patients with giant cell arteritis, suggesting that it may play a role in the immunopathogenesis.36,37

Differential Diagnosis and Ancillary Studies GCA is histologically distinctive in its classic form, with little else entering the differential diagnosis. However, in some instances the findings may be subtle, especially in areas of “healed” or “burned out vasculitis,” where there is vascular damage and fibrosis, but minimal inflammation. A Verhoeff-Van Gieson (VVG) stain can therefore be extremely helpful in highlighting the disruption of the internal elastic lamina (Fig. 26.10C).

Treatment and Prognosis Patients with GCA respond well to corticosteroids, and aspirin has some benefit. Therapy for Takayasu disease includes corticosteroids and immunosuppressive agents. The disease is self-limited in some cases, and the 10-year survival is about 90%.

Primary Angiitis of the Central Nervous System Incidence and Clinical Manifestations

Although quite rare, PACNS is the most common vasculitis that, by definition, exclusively involves CNS blood vessels. Patients can present with headaches, stroke-like episodes, or multifocal myelopathies with spinal cord involvement. Males are preferentially affected, and the peak incidence of diagnosis is within the fifth to sixth decades of life. Symptoms are usually multifocal, intermittent, and in most cases progressive.

Radiologic Features and Gross Pathology PACNS is extremely difficult to diagnose clinically, as the disease typically presents with nonspecific features of multiple ischemic microinfarcts resulting from vascular stenosis and obstruction. Unfortunately, the

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Fig. 26.10  Giant-cell arteritis. (A) Cross section of a temporal artery biopsy showing extensive transmural inflammation. (B) High-magnification view showing mononuclear cell infiltrates and multinucleated giant cells. (C) A VVG stain highlights damage and disruption to the internal elastic lamina. (D) Intimal thickening and smooth muscle proliferation are highlighted by a smooth muscle actin immunostain.

“beads on a chain” sign on angiography (representing patchy vascular stenoses) is neither absolutely sensitive nor specific. Therefore, tissue is often required for diagnosis, with a “blind frontal lobe” biopsy being utilized most commonly. The sampled tissue is often grossly unremarkable, unless involved by infarcts. Occasionally, PACNS can even present with a tumor-like appearance with negative vascular imaging.38

Histopathology Midsize and small blood vessels of the leptomeninges and superficial cortex show focal segmental granulomatous changes in classic examples, although less specific forms of inflammation may also be encountered (Fig. 26.11). A transmural infiltrate of mature lymphocytes is typically present, and multinucleated giant cells are often seen within a significantly thickened intima. Fibrinoid necrosis is present in well-developed lesions, but is not necessary for the diagnosis. Given the remarkably patchy nature of this disorder, it is critical to remember that even a negative brain biopsy does not exclude this disorder.

Differential Diagnosis and Ancillary Diagnostic Studies Sarcoidosis, infectious granulomatous meningitis, and intravascular lymphoma have similar presentations. The diagnostic workup often includes imaging studies and cerebral angiography, but these are of

Fig. 26.11  Primary central nervous system angiitis. Small meningeal artery with destructive changes featuring multinucleated giant cells and scanty lymphocytes.

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Practical Surgical Neuropathology limited value as they cannot reliably distinguish PACNS from other conditions.39 Brain biopsy can lead to a definitive diagnosis, but only in a minority of cases.40 Many cases are only diagnosed definitively at autopsy. Thus, PACNS has not been fully characterized, owing mostly to its rarity, but also due to a lack of histologic confirmation in many of the reported cases. Special stains for acid-fast bacilli and fungi should be performed to help exclude infection. Intravascular lymphoma is recognized by the intravascular location and immunohistochemical phenotype (CD20+, B cells) of the atypical lymphoid cells. As discussed previously, rare examples of cerebral amyloid angiopathy (CAA) secondarily develop features of vasculitis that are nearly indistinguishable from PACNS on routine sections. Therefore, amyloid stains such as Congo red, thioflavin S, and the Aβ-amyloid immunostain are recommended to rule out this possibility.

Treatment and Prognosis Although the prognosis was traditionally considered to be poor, with most cases being fatal within a few months, modern immunosuppressive therapy has been effective in some cases.

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Polyarteritis Nodosa This immune complex vasculitis can involve any organ system, except the lungs and spleen. In the nomenclature system developed in 1994 at the Chapel Hill Consensus Conference, polyarteritis nodosa (PAN) was defined by the presence of necrotizing inflammation of midsize or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules.41 The CNS may be affected in 20% to 40% of cases, whereas peripheral nerve damage occurs in over 50% of cases. A PAN-like vasculitis can also be seen in patients infected with hepatitis B or C or human immunodeficiency virus (HIV).42 Peripheral nerve involvement may result in the syndrome of mononeuritis multiplex. Vasculitic changes consist of focal, segmental inflammation with an infiltrate of polymorphonuclear neutrophils and fibrinoid necrosis (Fig. 26.12). Thrombotic occlusion leads to ischemic damage in the affected nerve.

Cerebral Aneurysms

Definitions and Synonyms An aneurysm is defined as an abnormally dilated segment of a blood vessel. Included in this group of CNS vascular diseases are saccular (congenital), fusiform (atherosclerotic), infectious, and traumatic types. Saccular aneurysms, also called berry aneurysms, are the most frequent cause of clinically significant subarachnoid hemorrhage and are the focus of this section. A subarachnoid hemorrhage is one that bleeds into the thin CSF layer between the pial covering of the cortex and the outer layer of the arachnoid mater on the surface of the brain. Unlike subdural hematomas, therefore, the blood tracks along sulci and perivascular Virchow-Robin spaces.

Incidence and Demographics The saccular (berry) aneurysm is by far the most common type of cerebral aneurysm.43 About 2% of the population is believed to have some type of cerebral aneurysm, and they are about twice as common in women.44 Although a congenital etiology is widely accepted, such aneurysms are rare in infancy and childhood, being most common in adults older than 30 years. About 25% of all cerebrovascular deaths are due to ruptured aneurysms. The annual incidence of subarachnoid hemorrhage (SAH) is about 9/100,000 in most of the world; however, it is nearly double that in Japan and Finland. The incidence of SAH increases with age and is highest after the fifth decade.44 Multiple aneurysms are noted in 20% to 30% of individuals with berry aneurysms on autopsy. Risk factors for the development of saccular aneurysms and spontaneous SAH include 646

B Fig. 26.12  Polyarteritis nodosa involving spinal nerve roots. (A) Low-magnification view of acute vasculitis with fibrinoid necrosis. (B) High-magnification view of acute vasculitis with fibrinoid necrosis and neutrophilic infiltration.

chronic hypertension, cigarette smoking, female sex, and African American ethnicity.45

Clinical Manifestations and Localization Most saccular aneurysms remain asymptomatic until rupture or just before rupture. About 50% of patients experience mild symptoms related to an initial small bleed (“sentinel hemorrhage”) days to months before a large SAH.46 The latter is heralded by an acute, severe headache and often loss of consciousness. Stiff neck, nausea/vomiting, muscle weakness, decreased sensation, lethargy, seizures, speech impairment, and impulsivity may also occur. Blood in the subarachnoid space can stimulate vasospasm of the basal arteries, a feared complication of aneurysm rupture that can result in significant cerebral ischemia, infarction, and brain swelling. Occasionally, aneurysms may present with tumor-like symptoms of mass effect by compression of adjacent structures. For example, a posterior communicating artery aneurysm may cause ipsilateral third nerve compression. Symptoms of parenchymal or ventricular hemorrhage may also be observed.

Radiologic Features and Gross Pathology CT or MRI may be used to determine the extent of SAH and the presence of parenchymal or ventricular extension of the bleed. However, the most

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Fig. 26.13  Gross images of saccular aneurysms. (A) Extensive acute subarachnoid hemorrhage following rupture of a saccular aneurysm. (B) Similar case shown in fresh state after gentle rinsing and removal of the bulk of the basal subarachnoid blood. The majority of the circle of Willis is now visible and will be more easily dissected after fixation. (C) Saccular aneurysms. Basal view showing two saccular aneurysms (arrows). (D) Ventricular and parenchymal hemorrhage due to rupture of aneurysm of the anterior cerebral artery with dissection into the parenchyma above. (E) Coiled aneurysm. Cross section of saccular aneurysm showing intraluminal coils and associated thrombus.

sensitive and specific method of identifying the saccular aneurysm itself is cerebral angiography. Variable amounts of basal SAH are found in patients dying acutely (Fig. 26.13A). Identification of the ruptured aneurysm is greatly facilitated by removal of blood in the fresh state under a gentle stream of water (Fig. 26.13B); this improves the ability to dissect the aneurysm by removing the blood before it becomes firm after fixation. The berry aneurysm consists of a thin-walled sac-like structure that is attached to an arterial branch point via a narrow neck. The sac may be spherical, oval, or lobulated, and multiple aneurysms may be present (Fig. 26.13C). Cutting the aneurysm in half along the long axis of the parent artery often reveals its origin. Most saccular aneurysms are 1 to 25 mm in diameter. Those measuring more than 25 mm are called “giant aneurysms.” The rupture site is usually apparent at the apex of the sac. Hemorrhage under arterial pressure may dissect into the brain parenchyma and may extend into the ventricular system (Fig. 26.13D). In patients whose aneurysms were previously treated with endovascular coils (Fig. 26.13E), variable degrees of occlusion may be present. The larger the aneurysmal neck, the less likely that total occlusion will be achieved. The time period between treatment and pathologic assessment

greatly affects the appearance. In specimens obtained less than 1 week after treatment, naked coils may be visible on gross examination of the neck. As time elapses, a thin membrane develops over the neck, which may completely seal the necks of small aneurysms, whereas larger necks are often incompletely sealed (even in those that appear 100% occluded angiographically).47

Histopathology The aneurysm sac often contains thrombotic material in the lumen and fibrocalcific atheromatous plaque in the wall. The junction between an adjacent normal artery and the aneurysm neck shows loss of elastin fibers and smooth muscle,48 with the neck ultimately being composed of hyalinized, collagenous tissue (Fig. 26.14). In survivors of SAH, the subarachnoid space features accumulations of hemosiderin and reactive (fibrotic) meningeal changes. Despite the increasing number of patients with aneurysms treated with endovascular coiling, the histologic response to this treatment is not extensively documented. A number of animal studies and more recent small human series have provided some insight. In specimens 647

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Genetics Although the pathogenesis is not well understood, several genetic loci have been implicated in increased risk for intracranial aneurysm formation, with the strongest evidence existing for anomalies at 1p34, 7q11, 19q13, and Xp22 as they have been replicated in different populations.45 Also there are well-known associations of berry aneurysms with autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome type IV, neurofibromatosis type I, and Marfan syndrome. About 6% to 9% of arteriovenous malformations may occur together with one or more saccular aneurysms.45 The latter also arise in the setting of extracranial vascular disease such as fibromuscular dysplasia and coarctation of the aorta.

Treatment and Prognosis

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About 25% of patients die within the first 24 hours of aneurysm rupture, with another 25% dying within 3 months. Of the survivors, about one-half have some sort of permanent neurologic deficit. Emergent therapeutic measures include stabilization of cardiorespiratory functions and prevention of further bleeding. Once the aneurysm has been located by angiography, depending on its size and the extent of bleeding, endovascular embolization may be attempted, with adequate occlusion occurring in only 50% to 70% of cases. More definitive therapy consists of placing a surgical clip at the aneurysm neck, which controls bleeding and eliminates the risk of rebleeding. Prognosis is a function of the patient’s clinical status on admission. The overall rate of aneurysm rupture is estimated at about 1%.52,53 An increased risk of rupture occurs with aneurysms greater than 5 mm when compared with those 2 to 4 mm52,53; ironically, patients with giant aneurysms may have less risk due to the high frequency of thrombosis and organization within the lumen; such cases more often manifest as masses and are occasionally mistaken for tumors. Aneurysms smaller than 5 mm in size are often managed conservatively. Aneurysms greater than 5 mm are generally treated electively, especially in low-risk patients. Several more recent studies have suggested that endovascular coiling of aneurysms is associated with more favorable outcomes while increased morbidity is seen with clipping.54–56

Fusiform and Infective (“Mycotic”) Aneurysms Fusiform Aneurysms B Fig. 26.14  (A) The origin of this thrombosed aneurysm can be seen in the bottom center. In comparison to the parent artery, the wall of the aneurysm is thin and irregular (trichrome). (B) Disruption of the smooth muscle layer, which all but disappears in the aneurysm wall, as shown by immunohistochemistry for smooth muscle actin.

examined approximately 1 week after treatment, fibrin-coated coils and blood clot are found. Near the aneurysmal wall, the fibrin may show dense neutrophilic infiltrates.47 In older specimens, a thin membrane is generally found covering the coils at the entrance of the aneurysm. The membrane consists of fibrin, hemosiderin-laden macrophages, and invading fibroblasts. Eventually, the blood clot in which the coils are embedded evolves into a mass of mature collagen, fibrocytes, and capillaries. Within larger aneurysms, variable degrees of thrombosis with recanalization may be present.49,50 Electron microscopy has revealed that a three-layered neointima may form over the occluded aneurysmal neck. The most superficial layer consists of endothelial cells with a continuous basal lamina, numerous pinocytotic vesicles, and tight junctions. The deeper layers consist of collagen and smooth muscle cells.51 648

Cerebral fusiform aneurysms are relatively uncommon compared with saccular aneurysms. They may affect either the anterior or posterior circulation and can be divided into two forms—acute and chronic— based on their clinical presentation. The acute form is associated with dissection, and the primary cause is thought to be disruption of the internal elastic lamina leading to rapid formation of an intramural hematoma. Morbidity is primarily related to SAH and the complications that ensue. The chronic form shares some of the same underlying pathology, but morbidity arises primarily from compression of adjacent structures, most commonly cranial nerves, as the aneurysm grows and only rarely from rupture and SAH. Ischemic stroke can also result from thromboembolic occlusion. The histologic characteristics of chronic fusiform aneurysms depend on size and associated symptomatology. Fragmentation of the internal elastic lamina is found in all cases, but the extent is much greater in larger or symptomatic aneurysms. Intimal hyperplasia and degeneration of the media are universally present. As the aneurysm grows, neoangiogenic vessels are frequently observed within the thickened intima and are correlated with the appearance on MRI of contrast enhancement within the aneurysmal wall. The fragile neovasculature is often accompanied by intramural hemorrhage in varying stages. Old, laminated thrombus may constitute a

Vascular and Ischemic Disorders large portion of the thickened vessel wall. Intramural hemorrhage is strongly associated with symptomatic lesions and acceleration of clinical course. Although once believed to be simply the result of atherosclerotic disease, histologic examination of cerebral fusiform aneurysms has revealed degenerative changes that suggest an alternative pathophysiology. In atherosclerotic disease the initial pathologic changes consist of intimal cell proliferation around lipid deposits and thinning of the internal elastic lamina. In contrast, with fusiform aneurysms, disruption of the internal elastic lamina in the absence of lipid deposition appears to be the initial pathologic event, suggesting the possibility of an underlying defect in collagen.57 Prognosis depends heavily on the size and rate of progression of the aneurysm. In long-term follow-up studies approximately half of the aneurysms demonstrated enlargement on serial imaging, which was correlated with a significant increase in morbidity and mortality.58

for pathologic evidence in subtle or equivocal cases. The criteria are based on three categories of information: (1) presence of a predisposing infection, (2) angiographic findings, and (3) other contributing features. The predisposing infections include infective endocarditis, meningitis, orbital cellulitis, and cavernous sinus thrombophlebitis. The angiographic findings include multiplicity, distal location, fusiform shape, and change in size or appearance on subsequent studies. The other contributing features include age younger than 45 years, fever within the last 7 days, recent lumbar puncture, or intraparenchymal hemorrhage visible on brain imaging. If an aneurysm is present with three or more of the supportive criteria from any of the categories described, then a diagnosis of infective aneurysm can be made with a high degree of certainty.60 Treatment consists of antibiotics along with surgical or endovascular intervention.61

Infective Aneurysms

The histopathologic classification of cerebral vascular malformations was developed by McCormick et al. in the 1960s, and this system is still widely accepted and used in clinical diagnostics.62 Vascular malformations are divided into four groups: (1) arteriovenous malformations, (2) cerebral cavernous malformations (cavernous angiomas), (3) capillary telangiectasias, and (4) venous angiomas. The basis for classification takes into account the caliber and configuration of the component blood vessels, the relationship of abnormal vessels to brain parenchyma, and the presence or absence of arteriovenous shunting. A variety of cerebral vascular malformations that do not fit neatly into the following four subtypes may also be encountered.

Vascular invasion by infectious organisms and the associated inflammatory reaction can lead to focal dilations of cerebral blood vessels and symptomatic hemorrhage. Also referred to as “mycotic” aneurysms, such lesions may be caused by bacteria as well as fungi. They account for 5% to 6% of all intracranial aneurysms and most commonly cause focal deficits due to multiple hemorrhagic infarcts, but may also rupture causing SAH. Demonstration of the infectious organism and inflammatory-mediated destruction of the vessel wall is the gold standard (Fig. 26.15), but these criteria are only fulfilled in a minority of published cases of aneurysms excised surgically or at autopsy. Fibrosis of the vessel wall may be the only remaining pathologic change in patients treated with a prolonged course of antibiotics.59 Vasoinvasive fungi such as Aspergillus species that directly invade the vessel wall causing thrombosis and hemorrhage are more readily demonstrable. The clinical course is often rapidly progressive with a high mortality rate (90% for fungal and 30% for bacterial aneurysms), which makes early clinical diagnosis of the utmost importance. A set of diagnostic criteria have been proposed for establishing a clinical diagnosis of infective aneurysm. Awareness of these criteria may guide the search

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Vascular Malformations Definitions and Synonyms

Arteriovenous Malformations Incidence and Demographics

Arteriovenous malformations (AVMs) are a common form of vascular malformations in the brain and are thought to be congenital in origin. AVMs account for 1.5% to 4% of all brain masses, with a peak incidence in young adults between the ages of 20 and 40 years. Hemorrhages from AVMs are responsible for 2% of all strokes.63 In one large study, the mean age at diagnosis was 31.2 years, and incidence was roughly equally distributed between men and women.64

Clinical Manifestations and Localization Most AVMs are supratentorial, occurring within distributions of the major cerebral arteries (middle cerebral artery > anterior > posterior; Fig. 26.16A). Less common sites may include the corpus callosum, choroid plexus, or the optic nerve (the latter associated with Wyburn-Mason syndrome). Among those individuals with an AVM, a small subset (4%) are found to have multiple similar lesions.64 About 50% of patients with AVMs, and especially those who are younger, present with a cerebral hemorrhage. Seizures may occur in 25% of patients with supratentorial AVMs, especially in older individuals. Less than 10% of patients experience subtle onset of headache, focal neurologic deficits, or progressive symptoms that may be encountered as the AVM slowly grows.64 This progressive enlargement probably involves development of collateral arteries and veins. Large AVMs produce ischemia of surrounding brain tissue via a “steal” phenomenon. Up to 58% of AVMs occur with saccular (berry) aneurysms, which form at branch points of arteries feeding the AVM.65

Radiologic Features and Gross Pathology Fig. 26.15  Inflammatory (“mycotic”) aneurysm in a patient with a bacterial CNS infection. Note the marked destruction and acute inflammation surrounding the internal elastic lamina in the upper portion of the figure.

MRI and cerebral angiography are the diagnostic methods of choice. MRI usually shows abnormal collections of large blood vessels (see Fig. 26.16A), and angiography clearly demonstrates the high-flow character of these arteriovenous shunts. 649

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Fig. 26.16  Large right temporal arteriovenous malformation (AVM) treated with preoperative embolization using Onyx copolymer (dark gray-black material). (A) Magnetic resonance imaging of large and tortuous vascular channels on T1-weighted image. (B) External surface of AVM showing dilated draining veins. (C) Tortuous arterterial and venous vessels, as well as intervening gliotic brain parenchyma on cross section, further highlighted microscopically (D, E, next page).

Vascular and Ischemic Disorders

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Fig. 26.16, cont’d  (F) Marked variability in wall thickness is seen on a smooth muscle actin immunostain. (B, courtesy of Dr. Michael Lawton, UCSF Neurosurgery.)

Grossly, the surface of the brain in the region of an AVM contains dilated, thick-walled veins, which represent draining vessels of the lesion (Fig. 26.16B). On cut section, AVMs consist of a tangled mass of blood vessels of varying diameter and wall thickness (Fig. 26.16C), often with entrapped fragments of atrophic brain parenchyma and occasionally with intraluminal embolization material, such as coils or liquid copolymers such as Onyx (Fig. 26.16). There may be evidence of remote or recent hemorrhage (or both). Superficial AVMs tend to have a broad base near the cortical surface were they drain into surface veins, whereas deeper lesions drain into the deep venous system.

Histopathology The variability in size and configuration of the abnormal blood vessels is a striking finding under the microscope (see Fig. 26.16D). In addition, a characteristic feature is the presence of gliotic CNS tissue between the abnormal blood vessels (Fig. 26.16E). Arterial elements may present variable amounts of smooth muscle proliferation (Fig. 26.16F), collagen deposition, and reduplication of the internal elastic lamina, whereas large “arterialized” veins are thick walled and collagenized. Thrombosis with varying stages of recanalization, and sometimes calcification, may be present. If embolization was performed prior to surgery, there may be evidence of endovascular material, which can incite a foreign-body giant cell reaction over time. One popular technique utilizes a nonadhesive liquid known as Onyx; this produces black-pigmented intravascular material (Fig. 26.16) due to the presence of tantalum powder.66

Histologic (and Clinical) Variants The so-called “vein of Galen aneurysm” is really a congenital AVM or arteriovenous fistula that has extensive “feeder arteries” arising from the posterior and occasionally the middle cerebral arteries, which drain

Fig. 26.17  Vein of Galen “aneurysm.” This congenital arteriovenous malformation consists of a prominent residual vein (of Galen) into which several “feeder” arteries drain. The one shown in the image contains a large thrombus.

into an enlarged residual vein (“of Galen”) of the deep venous system (Fig. 26.17). Infants born with this condition usually have cardiomegaly and congestive heart failure due to the excessive degree of arteriovenous shunting. The prognosis was previously poor, but new developments in endovascular techniques have demonstrated favorable outcomes in a majority of treated children.67 One treatment approach involves embolization of the vascular malformation with surgical coils to induce 651

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Fig. 26.18  Spinal cord biopsy in a case of Foix-Alajoinine syndrome in a patient with stepwise neurologic deficits and an associated meningeal arteriovenous fistula (not biopsied). The biopsy shows patchy necrosis and thickened, highly collagenized veins on H & E (A) and trichrome (B) stains.

thrombosis and curtail shunting. Outcome, however, still depends somewhat on the complexity and extent of the lesion and associated “steal” effect of the arteriovenous shunt, which usually result in cerebral ischemia and infarction. Spinal cord AVMs are clinically divided into four categories depending on their location and relationship to the dura. Type 1 refers to a dural arteriovenous fistula, which is not a true AVM. These are usually located on the posterior aspect of the distal spinal cord of older patients. Thrombosis of the abnormal vessels may result in a stepwise, progressive myelopathy that correlates with multifocal spinal cord infarctions (Foix-Alajouanine syndrome; Fig. 26.18). These malformations can also be symptomatic as a result of mass effect by venous congestion, “steal phenomenon,” or hemorrhage. Type 2 spinal cord AVMs, also referred to as glomus malformations, are intramedullary. These lesions usually manifest in younger patients with acute myelopathy. Type 3, juvenile type, have an intramedullary component and may have extensive extramedullary and even extraspinal extension. Type 4 lesions are intradural extramedullary AVMs. They occur in adults and are most commonly located in the distal cord on the anterior aspect. Like type 1 spinal AVMs, type 4 also commonly present with stepwise neurologic deterioration.68

Differential Diagnosis Highly vascular neoplasms may mimic an AVM (e.g., rare pilocytic astrocytomas in which the vasculopathy is more prominent than the tumor). However, the high flows demonstrated by angiography are usually well in excess of those encountered in most tumors. Other types of vascular malformations may also enter the differential diagnosis.

Ancillary Diagnostic Studies Extensive collagen deposition may be demonstrated by the Masson trichrome stain. Abnormalities of the internal elastic laminae of arterial blood vessels can be identified by an elastin stain (VVG).

Genetics AVMs represent a congenital failure of vascular differentiation that results in arteriovenous shunting without an intervening capillary network. Although the pathogenesis is poorly understood, abnormal cerebral arteriovenous shunts developed in mice lacking the gene for 652

the activin receptor-like kinase-1 (a member of the TGF-β family)69; however, the genetic origins in humans have not been identified. AVMs may occur as part of an inherited disease in which a genetic factor has been clearly identified (e.g., hereditary hemorrhagic telangiectasia, autosomal dominant polycystic disease, Marfan syndrome)3 or as part of a developmental neurocutaneous disorder (e.g., NF1, Wyburn-Mason syndrome, Sturge-Weber syndrome). Rare familial AVMs without a known genetic cause have been described.70

Treatment and Prognosis Two-thirds of patients with AVMs suffer clinically significant hemorrhage with an immediate mortality rate of 10% and a 30% to 50% chance of permanent disability. The yearly risk of an acute bleed is between 2% and 4%. This risk is higher in younger individuals (<45 years of age), and options for interventional therapy include surgical resection, endovascular embolization, and radiosurgery. It has been suggested that medical management (i.e., pharmacologic therapy for neurologic symptoms as needed) is superior to interventional therapy in patients with unruptured AVMs.71,72 Sometimes a combination of these options is used. Whether asymptomatic AVMs should be treated continues to be a matter of significant debate.73 In general, more superficially located AVMs in noneloquent locations carry a better prognosis than deep lesions or those that involve the brainstem. Factors associated with an increased risk for hemorrhage include association with an aneurysm, deep location, deep venous drainage, and previous hemorrhage.63

Cerebral Cavernous Malformations

Definitions, Synonyms, Incidence, and Demographics Cerebral cavernous malformations (CCMs, also called cavernous angiomas, cavernous hemangiomas, or cavernomas) are nonarterial vascular abnormalities that arise in all age groups but are most commonly seen in young adults. Postmortem studies have demonstrated CCMs in 0.5% to 0.7% of the population.74 One-third to one-half of patients present with epilepsy or recurrent headaches. The annual risk of a first hemorrhage is estimated to be about 1%. Once the initial hemorrhage has occurred, rates of repeat hemorrhage increase significantly to 2.6% to 13% per patient year (the large range reflects that the number of lesions per patient can vary considerably). In the sporadic form, single or few lesions predominate, whereas in the hereditary form numerous

Vascular and Ischemic Disorders lesions are the norm. The familial form occurs more commonly in those of Latino heritage.75

Clinical Manifestations and Localization CCMs may occur anywhere in the nervous system and leptomeninges, but supratentorial lesions predominate. Seizures occur when the cerebral cortex is involved. Lesions located within the brainstem are often associated with greater morbidity and may have an aggressive course. CCMs are frequently discovered incidentally with brain imaging and may be asymptomatic for many years. Focal neurologic signs and headaches may occur as a result of hemorrhages. Typically, because the blood is not under arterial pressure, hemorrhages are not catastrophic, but repeated episodes can lead to progressive neurologic deficits or intractable epilepsy. Clinical manifestations depend in part on the type of lesion observed as described in later sections.

Radiologic Features and Gross Pathology On T2-weighted MRI, the lesion consists of a compact focus of increased vascularity having a core of variable intensity that is surrounded by a “ring” of hypodensity (Fig. 26.19). This ring corresponds to hemosiderin deposition in the adjacent brain tissue (“ferruginous penumbra”). On gradient-echo MRI, hemosiderin appears conspicuously black and leads to a greater sensitivity of this sequence for detecting smaller lesions. This radiographic appearance is virtually pathognomonic for cavernous angiomas. T1 hyperintense signals may be seen surrounding lesions with recent hemorrhage.76 Lesions may change in number or size on repeat imaging. On gross examination, CCMs are discrete, lobulated, well-circumscribed lesions that vary in diameter from several millimeters to several centimeters. On cut surface, they exhibit a sponge-like appearance and may appear variegated due to regions of hemorrhage, calcification, fibrosis, and xanthomatous degeneration (Fig. 26.20A and B). They are frequently likened in appearance to mulberries.74

Histopathology In contrast to AVMs, cavernous angiomas have no direct arterial contribution. They consist of a compact mass of dilated, generally

thin-walled, variably hyalinized vascular sinusoids (caverns) with little intervening brain tissue (Fig. 26.20C) and a peripheral rim of parenchymal hemosiderin-laden macrophages, spheroids, gliosis, and mineralized capillaries (Fig. 26.20D). Historically, CCMs have been defined as having no intervening brain tissues; however, recent studies have shown that intervening brain tissue does occur, albeit less often than in other forms of cerebral vascular malformations.77 These lesions are composed of a single layer of endothelium without a muscular layer or internal elastic lamina. Ultrastructural studies demonstrate an absence of a blood-brain barrier in the abnormal vessels.78 There is considerable range in degree of fibrosis, thrombosis, and calcification. The surrounding brain tissue is gliotic and contains hemosiderin-laden macrophages. CCMs may occur together with venous angiomas or capillary telangiectasias. Occasionally, patients with cerebral cavernous angiomas may have similar vascular lesions in other organs such as the kidney, liver, lung, or skin.

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Differential Diagnosis The distinctive MRI appearance of cavernous angiomas usually leaves little doubt about the diagnosis. However, a focal remote cerebral hemorrhage or hemorrhagic tumor with perilesional hemosiderin might be possible mimics that can be distinguished histologically.

Genetics The cause is unknown, but some familial forms of CCMs are associated with loss of function mutations79 of the CCM1 gene on chromosome 7q11-21. This gene encodes KRIT1, which interacts with proteins of the RAS family of GTPases. CCM1 mutations may result in altered regulation of angiogenic factors, such as beta-1 integrin via abnormal KRIT1 interaction with an integrin-binding protein ICAP-1. Other genetic disease-related loci have been identified on chromosome 7p15-p13 (CCM2), which codes for MGC4607 (OSM), also known as malcaverin. A third locus has recently been identified at 3q25.2-27 (CCM3), which codes for PDCD10 (TFAR15), a protein associated with apoptosis. The pattern of inheritance is autosomal dominant with variable penetrance, estimated at 60% to 88% in CCM1 families, 100% in CCM2, and 63% in CCM3 families.80 Although disease mechanisms are poorly understood, abnormalities of the endothelial to mesenchymal cell transition81,82 and defective autophagy83 have been suggested.

Treatment and Prognosis Surgery is performed to control seizures and reduce the risk of hemorrhage. The surrounding hemosiderin-laden gliotic tissue may also be excised, as it may be part of the seizure focus, depending on the location of the tissue. The prognosis is usually excellent after surgical resection. Surgical options are more limited for lesions involving the brainstem or other eloquent areas. Cavernous malformations are not typically embolized, and the role of radiosurgery for such lesions is uncertain.

Capillary Telangiectasias

Fig. 26.19  Magnetic resonance image of a small paramedian cavernous angioma (T2-weighted image). The surrounding hypodense ring represents the “ferruginous penumbra.”

These vascular malformations are typically incidental findings of little clinical significance and only rarely become symptomatic.84 They are believed to account for 16% to 20% of all brain vascular malformations, with an estimated prevalence of about 0.4% in the population. Capillary telangiectasias are most commonly found in the ventromedial pons or subcortical white matter and grossly resemble a focal petechial hemorrhage. Microscopically, they consist of dilated capillaries that are separated by normal brain tissue. Hemorrhage from such lesions is rare. On MRI the lesions show hypointense or isointense signal on T1-weighted sequences and may be isointense or slightly hyperintense on T2-weighted sequences. They appear as punctate hypointensities on gradient-echo sequences and are usually not visible on CT.85 653

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Fig. 26.20  Cavernous angioma. (A) On cross section, this large resected cavernous angioma has a “spongy” hypervascular appearance. The variegated appearance is due to regions of fibrosis, xanthomatous degeneration, and calcification. (B) Whole-mount section showing relatively solid aggregate of dilated thin-walled vessels with scattered calcifications. (C) Tight cluster of thin-walled vascular channels with little intervening brain tissue. (D) Brain parenchyma at the edge of a cavernous angioma showing abundant hemosiderin deposition, axonal spheroids, and vascular mineralization representing reactive changes to prior microhemorrhage.

Venous Angiomas Venous angiomas are dilated veins of the superficial or subcortical cerebral vasculature, which are usually asymptomatic. They are similar to varicose veins elsewhere in the body and may be associated with other vascular malformations in the same patient. Surgical pathologists usually do not encounter venous angiomas, except perhaps at autopsy, because they are rarely symptomatic and removal of these functional blood vessels would result in extensive hemorrhagic infarction of the underlying brain.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

654

encephalopathy,” “agnogenic medial arteriopathy,” and “familial Binswanger disease.” However, these terms are more subjective and less accurate, so CADASIL is now the official terminology. Rare autosomal recessive forms of this disorder, referred to as “CARASIL,” are characterized by mutations of the high-temperature requirement A serine peptidase 1 (HTRA1) gene.86

Incidence and Demographics CADASIL occurs worldwide and affects many ethnic groups, although the largest and most thoroughly studied families are from Europe. The exact prevalence of the disease is unknown, but at least 500 affected families are estimated worldwide. A Scottish study estimated the prevalence to be 2 to 4/100,000.87 Both sexes are affected equally.

Definition and Synonyms

Clinical Manifestations and Localization

The term cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) virtually defines itself by including the key features in the diagnosis.86 It is essentially a genetic small-vessel angiopathy caused by Notch 3 mutations and associated with progressive ischemic damage. Previously published synonyms include “hereditary multi-infarct dementia,” “chronic familial vascular

The four major symptoms of CADASIL are (1) migraine with aura, (2) ischemic attacks (transient or strokes), (3) psychiatric findings, and (4) eventual dementia. Migraine headaches may begin in late childhood but most commonly manifest by the third decade. The first ischemic attacks occur with a peak between ages 40 and 50 years. Dementia develops without obvious stroke-like episodes in 10% to 15% of patients. Cognitive

Vascular and Ischemic Disorders decline becomes apparent between the ages of 40 and 70 years, with about 80% of individuals older than 65 years being demented. Depression is the most common psychiatric symptom, and mood disturbances occur in roughly one-third of patients.88 Seizures occur in less than 10% of affected individuals, usually at late stages of the disease. The life expectancy is 15 to 25 years following onset of vascular symptoms. Men tend to develop symptoms and disability faster than women.89

Radiologic Features and Gross Pathology Hyperintense lesions of the subcortical and deep white matter are seen on T2-weighted MRI. Periventricular lesions reminiscent of those seen in multiple sclerosis are also typical, as are lacunar infarcts of the basal ganglia. T2 hyperintensities in bilateral anterior temporal lobes and external capsules are a pathognomonic radiographic appearance in the appropriate clinical setting.90 Lacunar infarcts of the white matter and deep cerebral nuclei may be seen grossly in CADASIL. The leukoencephalopathy ranges from subtle foci of myelin pallor to large, cavitated infarcts (Fig. 26.21A). There may be hydrocephalus ex vacuo resulting from multiple infarcts. The cerebral cortex is typically uninvolved, and there is usually little or no evidence of hemorrhage. Brain atrophy may be significant as the disease progresses.91

Histopathology Affected parenchymal and leptomeningeal arteries are thickened and contain granular, PAS-positive material, which replaces smooth muscle cells of the media and weakens the vessel wall (Fig. 26.21B and C). This granularity corresponds to the pathognomonic accumulation of granular osmiophilic material (GOM) by electron microscopy (see upcoming “Genetics” section). Accumulation of collagen and laminin contributes to arterial wall thickening. Multiple areas of infarction are typically present in various stages of organization. Areas of less severe ischemic damage show myelin pallor with relative preservation of axons. Although CADASIL is primarily a neurologic disease, involvement of systemic arteries has allowed for definitive diagnosis of CADASIL by skin biopsy.92,93 Characteristic GOM is well demonstrated in dermal arterioles, although they are typically less severely involved than cerebral vessels. As such, the light microscopic appearance is usually normal, and the deposits are only found on ultrastructural examination.

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Differential Diagnosis Early in the course of the disease, the radiographic appearance may not be fully developed. MRI may reveal multiple subcortical white matter and deep nuclear infarcts, but these may also be seen in thromboembolic

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Fig. 26.21  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (A) A cross section of the frontal lobes from an autopsy of a CADASIL patient showing variable degrees of white matter ischemia, ranging from subtle discoloration and softening to cavitary infarcts. (B) White matter arteries show marked thickening with granular eosinophilic deposits in vascular walls. (C) Blood vessels in the white matter (blue-green staining is myelin) show violet PAS-positive granular material (Luxol fast blue/periodic acid–Schiff). (D) Electron microscopic view of cerebral arteriole showing characteristic granular osmiophilic material (GOM) associated with smooth muscle cells. 655

Practical Surgical Neuropathology or hypertensive vascular disease. However, in neither condition would GOM be identified. The vascular hyalinization typical of hypertension corresponds to collagenous fibrosis and is not granular in nature. CADASIL differs from CAA by virtue of its relative lack of hemorrhage and deep (rather than superficial) location of the lesions. Vascular immunoreactivity for Aβ-amyloid peptide confirms CAA and rules out CADASIL. Mitochondrial disorders such as mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) can have a similar radiographic appearance to the early stages of CADASIL and should be considered in the differential diagnosis. A rare familial disorder associated with migraine and stroke-like episodes (familial hemiplegic migraine, FHM) is characterized by a mutation of the CACNLA4 gene. Another condition results from mutations in genes coding for collagen, such as COL4A1, producing a syndrome with leukoencephalopathy, lacunar infarcts, and diffuse T2 hyperintensities, but is associated with porencephaly and intracerebral hemorrhages.94 CADASIL has occasionally been misdiagnosed as multiple sclerosis.95

Ancillary Diagnostic Studies The granular vascular deposits in CADASIL are strongly PAS positive (see Fig. 26.21C). They are also immunoreactive for Notch 3 protein (extracellular domain), although this antibody is not available in most labs.92 Degeneration of smooth muscle cells may be demonstrated by smooth muscle actin immunostain. Skin biopsy is 57% sensitive and 100% specific.93 The low sensitivity seems to be due to the fact that skin vessels are involved later in the clinical course than brain. Electron microscopy reveals the presence of diagnostic GOM between degenerating vascular smooth muscle cells or within the thickened basal lamina (Fig. 26.21D). GOM varies in size from 0.2 to 0.8 µm and is composed of nonfilamentous 10- to 15-nm granules.

Genetics

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Moyamoya Syndrome Definition and Synonyms

This disease is defined by progressive stenosis of the arteries of the circle of Willis and formation of abnormal collateral vessels at the base of the brain. The syndrome was first described in Japan using the Japanese term moyamoya to describe the angiographic findings as “something hazy” like a puff of smoke. The primary form is generally referred to as “moyamoya disease,” and the secondary form is “moyamoya syndrome”; however, this distinction in terminology is not always rigorously applied in the literature.

Incidence and Demographics Moyamoya syndrome has now been identified in all major ethnic groups. Primary moyamoya syndrome is an idiopathic disorder that is responsible for approximately 10% of cases. Secondary moyamoya syndrome may occur in the setting of a number of conditions that affect the cerebral vasculature (see Variants and Differential Diagnosis section). Patients may present as early as the first decade of life with cerebral ischemia or hemorrhage. About 50% of patients are children younger than 15 years of age, especially in Asians, with a second peak of incidence during the fourth decade, which is more commonly seen in North America. There is a female predominance in this latter group.100 Some patients remain asymptomatic for extended periods of time. Several reports have shown elevated thyroid antibody levels and increased thyroid function in patients with moyamoya syndrome.101–103

Clinical Manifestations and Localization Neurologic deficits result from either cerebral ischemia or hemorrhage. The specific symptoms depend on the specific brain areas and blood vessels affected. Ischemic events predominate early in the course of vaso-occlusion, whereas hemorrhage is a later finding. One common scenario is a syndrome of alternating hemiparesis that results from bilateral cerebral ischemia.

CADASIL is caused by point mutations or small deletions in the NOTCH 3 gene on chromosome 19p13.86,92 The encoded protein is a transmembrane receptor that plays a critical role in regulating cell differentiation during development. In adults, Notch 3 protein is a cell surface receptor that is expressed almost exclusively in vascular smooth muscle cells (VSMCs) and may promote cell survival. The Notch 3 extracellular domain (N3ECD) accumulates in arterial walls followed by degeneration of VSMCs. The pathogenesis of CADASIL most likely involves a toxic gain of function due to mutation-induced unpaired cysteine in N3EDC, which accumulates in VSMCs and can be detected by immunohistochemistry.86 Other considerations in pathogenesis include excess recruitment of extracellular material by overexpressed N3ECD and decreased vessel integrity induced by excess Notch 3.96,97 CARASIL is a hereditary small-vessel cerebrovascular disease (like CADASIL); however it is transmitted in an autosomal recessive fashion. The affected gene is HTRA1 (high-temperature requirement A serine peptidase 1), which is involved in cell signaling and protein degradation.86 HTRA1 is expressed in blood vessels, skin, and bone. The cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) is a more recently described hereditary small-vessel disorder in which mutations of CTSA (encoding cathepsin A) are related to abnormal degradation of proteins including endothelin-1, resulting in leukoencephalopathy.98

Arterial stenosis is due to fibrointimal proliferation complicated by platelet-fibrin thrombi. In addition, there is reorganization of arterial walls with thinning of the media and disruption of the internal elastic lamina.105 There is a characteristic lack of inflammation or arteriosclerotic changes. These findings predominantly affect the intracranial vessels, but the vascular changes may also involve extracranial vessels such as the renal, coronary, pancreatic, and pulmonary arteries.106

Treatment and Prognosis

Variants and Differential Diagnosis

There is no known effective treatment for the underlying disease. Anticoagulants have been used to prevent thrombotic complications with minimal change in the ultimate outcome. Migraine headaches are treated symptomatically. Donepezil may have some benefit in treating cognitive deficits.99

The diagnostic criteria for definite moyamoya disease described by Fukui require bilateral carotid stenosis of unknown cause, the characteristic angiographic appearance, and exclusion of other diseases that can produce similar appearing findings.107 Primary moyamoya is congenital. Several variants have been described, such as unilateral carotid stenosis or stenosis

Radiologic Features and Gross Pathology The vascular pathology is characterized by stenosis or occlusion of distal branches of the internal carotid arteries combined with an abundance of dilated, thin-walled collateral branches of the posterior circle of Willis. The middle cerebral artery is often thin walled and transparent.104 Cerebral angiography reveals stenosis or occlusion of the distal carotid arteries and a fine network of vessels at the base of the brain with hazy, puffof-smoke appearance. As the middle and anterior cerebral arteries become affected, there is development of leptomeningeal, extracranial, transdural, and transosseous collaterals.

Histopathology

Vascular and Ischemic Disorders of other major cerebral arteries. According to criteria these cases are currently considered “probable moyamoya disease.” Secondary moyamoya may either occur in association with other congenital disorders or result from an acquired disease. Congenital diseases associated with secondary moyamoya include neurofibromatosis type 1, tuberous sclerosis complex, sickle cell anemia, Alpert syndrome, Marfan syndrome, Fanconi anemia, Schimke immuno-osseous dysplasia, and Down syndrome. Acquired diseases that damage the cerebral vasculature may also be associated with secondary moyamoya. They include vasculitis, infection, thrombosis, atherosclerosis, trauma, and postirradiation arteriopathy. Although rare, these factors may initiate or accelerate the progression of moyamoya disease, so they must be excluded before making the diagnosis of congenital moyamoya.

Genetics Primary moyamoya is commonly hereditary. The genes responsible in some cases have been mapped to chromosomes 3p24.2-p26,108 17q25,109 and 8q23.110

Treatment and Prognosis The specific treatment modality depends on the rate of progression and the degree of deficits. Asymptomatic patients or those with indolent disease are often simply observed. Those patients with more aggressive disease are often treated with a surgical bypass. The most commonly performed procedure is the superficial temporal artery to middle cerebral artery (STA-MCA) bypass, which generally reduces, but does not eliminate, complications of the disease. This procedure has a number of technical limitations, most of which are related to the size of blood vessels involved. In affected small children or other patients with suboptimal vessels, an alternative indirect revascularization procedure may be performed. Synangiosis is the general term describing a procedure in which an artery is attached to the surface of the brain instead of being anastomosed directly to another vessel. In the weeks to months that follow the procedure, small branches sprout from the attached vessel and provide blood flow to ischemic brain tissue below. Several variations of this procedure exist, including encephaloduroarteriosynangiosis (EDAS), encephalomyosynangiosis (EMS), or pial synangiosis. Outcomes are reported to be similar to those obtained with STA-MCA bypass. Prognosis is related to the extent of vascular involvement and is poor if anterior and posterior branches of the circle of Willis are affected, whereas unilateral variants often have a benign course. Patients affected earlier in life accumulate more neurologic deficits. Suggested Readings Brisman JL, Song JK, Newell DW. Cerebral aneurysms. Medical progress. N Engl J Med. 2006;355:928–939. Danve A, Grafe M, Deodhar A. Amyloid beta-related angiitis—a case report and comprehensive review of literature of 94 cases. Semin Arthritis Rheum. 2014;44:86–92. Ginsberg MD. Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection. Stroke. 2003;34:214–223. Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain Pathol. 2002;12:358–370. Revesz T, Ghiso J, Lashley T, et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003;62:885–898. Tikka S, Baumann M, Siitonen M, et al. CADASIL and CARASIL. Brain Pathol. 2014;24:525–544.

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