MACROSCOPIC AND MICROSCOPIC APPEARANCES

EDH is easily recognized at necropsy as a biconvex hematoma that is readily seen upon removing the calvarium, but before breaching the dura (Fig. 10.1). Most cases result from rupture of the middle meningeal artery. As patients that have died from EDH are often the victims of a motor vehicle accident or foul play and therefore the subject of a forensic or medicolegal investigation, the size and site of any (causal) skull fracture and the volume of hematoma should be measured and recorded. Skull fractures are best identified after removal of dura from the inner table of the skull. Hematomas of 75–100 mL are usually fatal. The maximum volume that is likely to accumulate is approximately 300 mL. The neuropathologist should also document the effects of any EDH, such as distortion or herniation of brain substance, and the presence of any other traumatic lesions. Such documentation of EDH and its effects on the brain must be carried out at the time of necropsy and brain cutting; microscopic examination of the brain in such cases is often of limited value, except in documenting other evidence of CCT, such as diffuse axonal injury.

Spinal EDH is rare and presents with acute severe pain in the region of bleeding and radiation of the pain to the extremities. In the lumbar spine, it probably results from internal rupture of Batson’s vertebral venous plexus, i.e. a non-arterial source of EDH.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

As with EDH, the location, extent and volume of an acute SDH should be carefully documented at necropsy (preferably with the use of photographic evidence), along with its effects on the underlying brain (Figs 10.2, 10.3). Associated skull fractures (if any) and contusions (especially with acute SDH) should be noted when the brain is removed and subsequently sectioned. If the SDH is subacute or chronic, histologic sections of hematoma will show chronically inflamed vascular and variably fibrotic granulation tissue, with an admixture of blood breakdown products (Fig. 10.4). Portions of organizing or well organized SDH are often submitted as neurosurgical specimens, and described (inappropriately) as a ‘subdural membrane’. The chronicity of such pathology can be estimated from its degree of organization (Fig. 10.4). Eosinophils can be a surprisingly prominent feature of organizing SDH. As dural neoplasms (e.g. metastatic carcinoma from prostate or breast) and hemangiomas are, very rarely, associated with SDH, surgically removed SDH submitted for pathologic evaluation should be carefully examined with these diagnostic possibilities in mind. In childhood non-accidental injury, the volume of subdural blood may be small, often amounting to no more than a thin film over the cerebral hemispheres on either side of the falx cerebri. The posterior fossa may be involved more commonly in children than in adults.

 25% mortality within 25 hours of aSAH

 10–15% mortality prior to reaching hospital

 10% mortality within 24 hours of hospitalization

 1-month mortality of 50–60%.

MACROSCOPIC APPEARANCES

Abundant SAH is obvious at necropsy. However, when the ruptured dome of an aneurysm is embedded within brain parenchyma, a purely intraparenchymal bleed (sometimes with negligible SAH) can result; this may occur particularly with anterior cerebral/anterior communicating artery junction or middle cerebral artery bi/trifurcation aneurysms. This should be borne in mind when someone, especially a young person, experiences or dies from a brain hemorrhage of occult origin (Figs 10.5, 10.6). Massive SAH in a young or middle-aged patient (Figs 10.7, 10.8) from a clinically unproven source of bleeding strongly suggests a berry aneurysm as the etiology. In an autopsy specimen, fresh blood at the base of the brain should be dissected away gently until the aneurysm is discovered (Fig. 10.8). This dissection should not be deferred until the brain has been fixed, because the fixed hematoma is then difficult to dissect, making the source of bleeding much more difficult to locate. The possibility that there is more than one aneurysm, or a combination of vascular abnormalities (berry aneurysm and AVM), should always be considered. Berry aneurysms may occur at branch points of arteries (with high flow) that supply an AVM. A ruptured aneurysm is usually identified by the proximity of abundant hematoma and a tear in the wall of the aneurysm, which can often be seen without the benefit of microscopy. Anterior circulation aneurysms occur at major branch points on the circle of Willis (Fig. 10.9), most commonly:

Posterior circulation aneurysms constitute 10–30% of cases; most arise at the basilar artery bifurcation (‘basilar tip’) (Fig. 10.9); less common sites for aneurysms in the posterior circulation are junctions between the basilar artery and one of its major branches. Massive rupture of a posterior circulation berry aneurysm is one of the few types of ‘stroke’ that can produce sudden unexpected death, sometimes within seconds.

For individuals that survive SAH by days or weeks, then come to necropsy, the pathologist should note:

MICROSCOPIC APPEARANCES

Histologic features of a berry aneurysm, either ruptured or intact, are optimally demonstrated by an elastic stain (e.g. van Gieson or Movat pentachrome). The aneurysm may be unilobular or multilobular. Characteristic histopathologic features include attenuation and focal loss of both elastic tissue and smooth muscle cells of the muscularis, generally most marked close to the site of rupture. There is variable fibrosis of the aneurysm wall and foci of atherosclerosis may be evident (Figs 10.12–10.14). Blood breakdown products in the vicinity may reflect earlier, including asymptomatic or minimally symptomatic, bleeds. When an ‘incidental’ aneurysm is discovered at autopsy (Fig. 10.15), it may be quite large; in elderly patients, there may be superimposed intimal atherosclerotic change within its walls.

Giant berry aneurysms (defined as having a diameter of ≥25 mm) often show mural calcification, and extensive thrombosis with or without recanalization; they are more likely to behave as a mass lesion than to produce massive SAH (Figs 10.16, 10.17).

 brain stem and/or cranial nerve compression (basilar artery aneurysm)

 ischemia secondary to thrombosis, especially brain stem/cerebellar infarcts with a basilar artery aneurysm

 hemorrhage.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Fusiform aneurysms usually affect the basilar artery, especially its middle segment (Fig. 10.20), but may extend inferiorly to involve the upper part of one of the vertebral arteries. Except in children, there may be marked complicated atherosclerosis of the affected arterial wall, including foamy histiocytes, evidence of old intraplaque hemorrhage, calcification, thrombosis (either mural or occlusive), and variable degrees of inflammation.

 a ruptured small berry aneurysm that has become sealed or undergone thrombosis

 rupture of a small vascular malformation, undetectable by angiography or structural imaging; especially one that ‘destroys itself’ as a consequence of the hemorrhage

 an undiscovered bleeding diathesis.

MACROSCOPIC APPEARANCES

Hypertensive BH most commonly originates in the putamen, thalamus, cerebellum, or pons, while smaller hematomas occur in the subcortical white matter/centrum semiovale. Whether large or small, hypertensive hematomas are usually single. Acute hematoma appears as a soft, red (‘red currant jelly’) mass demarcated from brain parenchyma (Figs 10.22–10.26). The hematoma may harden somewhat (though not completely) during formalin fixation and may separate from the brain slice when the (fixed) brain is sectioned. Centrencephalic hypertensive hemorrhage commonly extends directly into the ventricular system (Fig. 10.25), and rarely dissects directly into the subarachnoid space, though it may reach the SAS by passing through exit foramina of the fourth ventricle. Acute (hypertensive) BH usually results in significant brain edema and herniation(s), with prominent subfalcine herniation when (as is usually the case) the hematoma is confined to one cerebral hemisphere. BH in the basis pontis (Fig. 10.24) may result in a ‘locked-in’ clinical state.

If the patient survives the ictus, the hematoma may resorb, leaving a cystic cavity lined by orange-brown altered blood pigment (Figs 10.27, 10.28). Old BH can usually be distinguished from a (hemorrhagic) infarct by:

If a BH in the region of the basal ganglia or thalamus involves the internal capsule, and has been longstanding, wallerian degeneration is usually evident along descending fiber tracts (e.g. corticospinal) in the brain stem and spinal cord (Fig. 10.28C).

MICROSCOPIC APPEARANCES

Sections of an acute hypertensive BH reveal fresh blood where it has dissected through tissue planes and along tracts. Assuming a patient survives the ictus by 2–3 days, inflammatory cells accumulate, initially polymorphonuclear leukocytes, then macrophages. Hemosiderin- and lipid-laden macrophages, hematoidin, and cytoid (granular cytoplasmic) bodies remain visible for years within the wall of the cavity that remains after the hematoma has been resorbed. The cavity wall becomes intensely gliotic (Fig. 10.29).

Pathology in the microvasculature (hypertensive microangiopathy) usually affects arterioles of 50–200 μm in diameter, but larger arteries especially within the basal ganglia may show microatheroma. The onion skin-type thickening of arteriosclerosis/arteriolosclerosis is evident in many vessels, but is particularly prominent in locations where hypertensive BHs are common (Fig. 10.30). Lipohyalinosis describes thickening of the arterial wall by hyaline (non-amyloid) material, within which are embedded variable numbers of lipid-bearing macrophages, resulting in narrowing or obliteration of the vessel lumen (Fig. 10.31). Charcot–Bouchard microaneurysms may be identified as ectatic outpouchings of abnormal vessel walls (Fig. 10.31). Such microaneurysms are now recognized as a relatively non-specific manifestation of cerebral microvascular disease; they are commonly seen in amyloid angiopathy (CAA) and even familial microvasculopathies, such as CADASIL. Charcot–Bouchard microaneurysms are believed to be of pathogenetic importance in hypertensive BH, although they are observed infrequently in histologic sections, in contrast to their relative frequency in CAA. Detailed examination of affected blood vessels in thick slices has shown many of the ’microaneurysms’ from patients with hypertension to be sections through coiled or tortuous vessels rather than true aneurysms. Arterioles adjacent to foci of hemorrhage may also show fibrinoid necrosis (Fig. 10.32).

Though most cases of cerebral arteriosclerosis or lipohyalinosis are sporadic, genetic clues to the pathogenesis of cerebral microvascular disease are beginning to emerge. Mutations in the COL4A1 gene, which encodes the type IV collagen α-1 chain, are associated with both subcortical hemorrhage and lacunar infarcts.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain appears edematous and may contain clusters of petechial hemorrhages, and/or one or more large hematomas. Histologic examination shows perivascular or parenchymal hemorrhages, acute microinfarcts, especially in the pons and basal ganglia, and characteristic alterations in small parenchymal arteries and arterioles. There is fragmentation or loss of nuclei in the walls of affected blood vessels (Fig. 10.33). Some vessels contain intraluminal fibrin thrombi, while others are surrounded by a proteinaceous exudate or admixed fibrin and hemorrhage. Typical histologic changes of MH are evident in other organs, especially the kidneys (Fig. 10.33).

1. Sporadic/age-associated: This is strongly linked to Alzheimer’s disease. Amyloid in affected arterial walls is composed of Aβ. Clinical manifestations include BH and (less commonly) cerebral cortical microinfarcts.

2. Familial (fCAA): There are several varieties of fCAA, some resulting from Aβ accumulation within arterial walls, others caused by one of many different amyloid proteins. They are rare, occur in circumscribed populations and geographic loci, and usually show autosomal dominant inheritance. Not all are associated with BH or even ischemic brain lesions, and CAA may be present as only one of several brain structural abnormalities (Table 10.1).

SPORADIC CAA

The most common form of CAA is associated with Alzheimer’s disease pathology. In CAA, the media of parenchymal microvessels, especially small arteries/arterioles, is replaced by skeins of thin (7–10 nm) filaments. These accumulate initially in the basement membrane that surrounds the smooth muscle cells in the tunica media but as accumulation increases this leads to the degeneration of the cells. Venules and capillaries may also be affected. By light microscopy, the walls of such vessels show the tinctorial properties of amyloid, which is a function of its β-pleated sheet protein structure. These properties are an affinity for Congo red dye and a characteristic yellow-green birefringence when subsequently viewed under polarized light and an affinity for Thioflavin S or T stains (viewed under fluorescent light). CAA involves both cortical and leptomeningeal arteries and arterioles, but rarely affects such vessels in the deep central gray matter, brain stem or cerebellum. At present, CAA can only be diagnosed definitively by brain biopsy or at necropsy.

In the cerebrum, amyloid-laden arteries may be seen passing from the leptomeninges into cortex. Amyloid deposition involving larger meningeal arteries usually manifests as adventitial aggregates of the protein. Recent research on CAA, as well as rare fCAA forms, has provided insights into the molecular pathogenesis of CNS small-vessel disease that may even be relevant to understanding non-CAA forms of cerebral microangiopathy. BH associated with CAA usually occurs because of the development of CAA-associated microangiopathies, especially (Charcot–Bouchard) microaneurysm formation and fibrinoid necrosis of cortical arteries/arterioles. Patients with CAA are also at increased risk for BH when thrombolytic agents are administered.

FAMILIAL CAA (FCAA)

Those variants of fCAA most commonly associated with BH are:

MACROSCOPIC APPEARANCES

Whether the result of sporadic CAA or fCAA, CAA-related BH is usually lobar within the cerebral hemispheres, because CAA is predominantly a meningocortical angiopathy (Figs 10.34–10.37). Posterior fossa structures are rarely the site of bleeds. Smaller CAA-related hematomas are usually superficial, in the cortex or just beneath it, but may extend into the deep subcortical white matter. CAA-related BH often ruptures directly into the subarachnoid space, in contrast to hypertensive BH, which is usually centrencephalic and enters the ventricular cavities. As with hypertensive BH, macroscopic features of CAA-related BH depend upon its duration. Acute BH is evident as fresh cortical or subcortical hematoma in the brain. Old hematomas may resorb, leaving a cavity with surrounding orange-brown discoloration (Fig. 10.38). Because CAA is usually distributed throughout the cortex and meninges, brains with multiple lobar CAA-related BHs are occasionally encountered. A region of brain showing remote hemorrhagic encephalomalacia (Fig. 10.39) needs to be sampled for the presence of possible CAA (or another microangiopathy).

An association between ischemic lesions and severe CAA is now well established. Large regions of encephalomalacia or leukomalacia may be associated with severe CAA in the overlying neocortex. More commonly, abundant cortical microinfarcts are detected (Fig. 10.40).

MICROSCOPIC APPEARANCES

Reactive changes in the brain surrounding a hematoma are as described for hypertensive BH. Rarely, a ruptured amyloid-laden artery may be seen within brain parenchyma adjacent to an acute bleed. CAA is now known to be associated with brain microinfarcts, in addition to BH.

All biochemically distinct types of CAA can be demonstrated by Congo red (with the aid of polarization microscopy) or thioflavin T/S staining (with fluorescence microscopy), though the appearance of affected blood vessels in H&E-stained sections may be strongly suggestive of CAA (Fig. 10.41).

The diagnosis of sporadic CAA or HCHWA-D can be confirmed by anti-Aβ immunohistochemistry, while a diagnosis of HCCAA (HCHWA-I) can be confirmed with anti-cystatin C antibodies (Fig. 10.42).

CAA-associated microangiopathies are characterized by the presence of microaneurysms, hyalinosis/fibrosis of vessel walls, a variable degree of inflammation, fibrinoid necrosis, and (rare) thrombosis (Fig. 10.43). Very rarely, CAA is associated with the development of a severe granulomatous angiitis (Fig. 10.43), which usually presents with rapid cognitive decline and seizures, rather than BH.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

AVM is the malformation that most commonly produces BH and is the second most common cause of SAH (after berry aneurysm). AVMs often extend from brain parenchyma into the subarachnoid space. They contain arteries, veins and abnormal vessels with thin walls and a prominent internal elastic lamina (IEL), or thick walls and no IEL, which are sometimes described as ‘arterialized veins’ (Figs 10.45–10.48). The caliber and mural thickness of vessels vary markedly. Vessel walls show varying degrees of calcification, which may involve the surrounding brain (Fig. 10.49). Very rarely, ossification may be observed in the wall of a blood vessel within a longstanding AVM. Intimal ‘cushions’ caused by fibromuscular hyperplasia and hyalinization are prominent features, but ‘complicated’ atheroma (with foamy histiocytes, cholesterol clefts and plaque ulceration) is extraordinarily rare (Fig. 10.50). The vascular channels of an AVM are usually embedded within brain parenchyma, but involved brain regions always show reactive changes, including astrocytic gliosis, old hemorrhage, cytoid bodies and even Rosenthal fibers (Figs 10.51, 10.52). Signs of old hemorrhage do not always correlate with a history of clinically apparent BH, which suggests that small amounts of blood may leak from an AVM and elicit a tissue response.

Though brain AVMs are usually sporadic, they may be seen as a component of hereditary hemorrhagic telangiectasia, also known as Osler–Weber–Rendu syndrome.

AVMs are commonly treated by therapeutic embolization with various thrombus-inducing substances (Fig. 10.53), which can lead to a pronounced inflammatory and foreign body giant cell reaction in the vascular lumina and walls.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

At the time of brain cutting, which is when it is frequently discovered having been dormant for the life of the affected patient, a cavernous hemangioma appears as a hemorrhagic ‘blush’ or a small hematoma in the brain section (Fig. 10.54). Microscopically, cavernous hemangioma appears as a tightly packed collection of hyalinized vessels (with little or no smooth muscle). It lacks intervening brain parenchyma, but is almost always surrounded by old hemorrhage and reactive astrocytic gliosis (Fig. 10.54). Its vascular channels are often calcified and sometimes thrombosed.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Venous angiomas are found in the subcortical white matter of the cerebral hemispheres (Fig. 10.55), where they resemble (unexpected) petechial hemorrhages. They are composed of thin-walled, moderately dilated vascular channels lying within otherwise normal brain parenchyma, usually without associated altered blood pigment.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Hematomas are often multiple, but may have a distribution similar to those associated with hypertension or CAA. However, microscopic examination of brain tissue adjacent to the hematoma(s) fails to yield any evidence of the type of microangiopathy seen with hypertension or CAA.

 a sudden increase in blood pressure

 an increased likelihood of BH from a pre-existing vascular abnormality, e.g. berry aneurysm or AVM (via an increase in blood pressure)

 an increased risk of endocarditis and subsequent infective aneurysm (among chronic intravenous drug users)

 drug-associated vasculitis.

 Primary CNS neoplasms: oligodendroglioma, glioblastoma, and primary CNS lymphoma (Fig. 10.62).

 Metastatic tumors (especially melanomas, choriocarcinomas, renal cell carcinomas) (Fig. 10.62). A metastatic tumor may present as BH even before the primary neoplasm is evident.

 Disseminated angioinvasive fungal infection (e.g. secondary to Aspergillus) (Fig. 10.63).

 Sickle cell anemia (Fig. 10.64).