The Central Nervous System

Concussion

Concussion is a clinical syndrome of altered consciousness secondary to head injury, typically brought about by a change in the momentum of the head (e.g., following impact with a rigid object). The characteristic clinical picture includes the sudden onset of transient neurologic dysfunction, including loss of consciousness, temporary respiratory arrest, and loss of reflexes. Although neurologic recovery is usually complete, amnesia for the event often persists. The pathogenesis of the disruption of neurologic function is unknown, but likely involves dysregulation of the reticular activating system in the brainstem. Postconcussive neuropsychiatric syndromes, typically associated with repetitive injuries, are well recognized, and there is increasing evidence that significant cognitive impairment can emerge along with distinct pathologic findings termed chronic traumatic encephalopathy (discussed later).

Direct Parenchymal Injury

Contusions and lacerations are brain injuries caused by transmission of kinetic energy to the brain. A contusion is analogous to the familiar bruise caused by blunt trauma, and a laceration is an injury caused by penetration of an object and tearing of tissue. As with any other organ, a blow to the surface of the brain, transmitted through the skull, leads to rapid tissue displacement, disruption of vascular channels, and subsequent hemorrhage, tissue injury, and edema. Hemorrhage can extend into the subarachnoid space from these lesions. The crests of gyri are most susceptible because this is where the direct force is greatest. The most common locations for contusions correspond to the most frequent sites of direct impact and to regions of the brain that overlie a rough and irregular inner skull surface, such as the frontal lobes along the orbital ridges and the temporal lobes. Contusions are less frequent over the occipital lobes, brainstem, and cerebellum, but may be seen when there is an adjacent skull fracture (fracture contusions).

A person who suffers a blow to the head may develop a contusion at the point of contact (a coup injury) or on the brain surface diametrically opposite to it (a contrecoup injury). Their macroscopic and microscopic appearances are indistinguishable, and the distinction between them is based on identification of the point of impact. In general, if the head is immobile at the time of trauma, only a coup injury is found. If the head is mobile, both coup and contrecoup lesions may be found, though the latter predominate and are thought to develop when the brain strikes the opposite inner surface of the skull after sudden deceleration.

Sudden impacts that result in violent posterior or lateral hyperextension of the neck (as occurs when a pedestrian is struck from the rear by a vehicle) may avulse the pons from the medulla or the medulla from the cervical cord, causing instant death.

Morphology

When seen on cross-section, contusions are wedge shaped, with the broad base lying along the surface at the point of impact ( Fig. 28.9A ). The appearance of contusions is similar regardless of the source of the trauma. In the earliest stages, there is edema and hemorrhage, which is often pericapillary. During the next few hours, the extravasation of blood extends throughout the involved tissue, across the width of the cerebral cortex, and into the white matter and subarachnoid space. Morphologic evidence of neuronal injury (pyknosis of the nucleus, eosinophilia of the cytoplasm, and disintegration of the cell) takes 12 to 24 hours to appear, although functional deficits generally occur earlier. Axonal swellings develop along the full length of the damaged neurons. The inflammatory response to the injured tissue follows its usual course, with the appearance of sparse neutrophils followed by abundant macrophages. Old traumatic lesions on the surface of the brain have a characteristic gross appearance. They are depressed, retracted, yellowish brown patches involving the crests of gyri, most commonly those that are located at the sites of contrecoup injuries (inferior frontal cortex, temporal and occipital poles); these lesions, called plaque jaune ( Fig. 28.9B ), can become epileptic foci. More extensive hemorrhagic regions of brain trauma give rise to larger cavitated lesions, which resemble remote infarcts. In old contusions, gliosis and residual hemosiderin-laden macrophages predominate.

Diffuse Axonal Injury

Traumatic brain injuries may also damage the deep white matter regions, cerebral peduncles, superior colliculi, and deep reticular formation in the brainstem. The microscopic findings include axonal swelling, indicative of diffuse axonal injury, and focal hemorrhagic lesions. As many as 50% of individuals who develop coma shortly after trauma, even without cerebral contusions, are believed to have diffuse axonal injury. Axons are injured directly by mechanical forces, with subsequent alterations in axoplasmic flow. Such injuries may occur from marked changes in angular acceleration (e.g., from blast injuries), even in the absence of physical impacts involving the skull.

Morphology

Diffuse axonal injury is characterized by widespread, often asymmetric axonal swellings that appear within hours of the injury and may persist for much longer. The swelling is best demonstrated with silver impregnation techniques or with immunoperoxidase stains for axonally transported proteins, such as amyloid precursor protein and α-synuclein. Later, increased numbers of microglia are seen in damaged areas of the cerebral cortex, and subsequently there is degeneration of the involved fiber tracts.

Epidural Hematoma

The dura is fused with the periosteum and is supplied by a number of dural arteries. These arteries, most notably the middle meningeal artery, are vulnerable to traumatic injury. In adults, this most often occurs with temporal skull fractures in which the fracture crosses the course of the vessel. In children, in whom the skull is deformable, a temporary displacement of the skull bones leading to laceration of a vessel can occur in the absence of a skull fracture.

Once a vessel has been torn, the extravasation of blood under arterial pressure can cause the dura to separate from the periosteum, creating a space ( Fig. 28.11 ). The expanding hematoma compresses the underlying brain. When blood accumulates slowly, patients may experience a lucid period before the onset of neurologic signs. A symptomatic epidural hematoma is a neurosurgical emergency; without prompt diagnosis and drainage, fatal brain herniation may occur within a few hours.

Subdural Hematoma

The dura is composed of two layers—an external collagenous layer and an inner more cellular layer containing fibroblasts. Bridging veins travel from the convexities of the cerebral hemispheres through the subarachnoid space and dura to empty into the dural sinuses. The brain is suspended in CSF, but the venous sinuses are fixed relative to the dura; as a result, traumatic displacement of the brain can tear the veins at the point where they penetrate the dura. The extravasated blood dissects through the two layers of the dura, producing a subdural hematoma. In older individuals with brain atrophy, the bridging veins are stretched, hence the increasing incidence of subdural hematoma with aging. Infants are also very susceptible to subdural hematomas because their bridging veins are thin-walled.

Morphology

Grossly, acute subdural hematomas appear as a collection of freshly clotted blood along the brain surface, without extension into the depths of sulci ( Fig. 28.12 ). The underlying brain is flattened, and the subarachnoid space is often clear. Usually, venous bleeding is self-limited and the resulting hematoma is broken down and organized over time; this most often occurs in the following sequence:

• Lysis of the clot (about 1 week)

• Growth of fibroblasts from the dural surface into the hematoma (2 weeks)

• Early development of hyalinized connective tissue (1 to 3 months)

Typically, the organized hematoma is firmly attached to the inner surface of the dura by ingrowing fibrous tissue and is free of the underlying arachnoid, which does not contribute to healing. The lesion can eventually retract as the granulation tissue matures until only a thin layer of reactive connective tissue remains (“subdural membranes”). In other cases, however, multiple recurrent episodes of bleeding occur (chronic subdural hematoma), presumably from the thin-walled vessels of the granulation tissue.

Focal Cerebral Ischemia

Focal cerebral ischemia follows reduction or cessation of blood flow to a localized area of the brain due to partial or complete arterial obstruction. When the ischemia is sustained, infarction follows in the territory of the compromised vessel. The size, location, and shape of the infarct and the extent of tissue damage that results are influenced by the duration of the ischemia and the adequacy of collateral flow. The major source of collateral flow is the circle of Willis (supplemented by external carotid-ophthalmic artery collaterals). Inconstant collateral leptomeningeal vessels from the surface of the brain may also supply the distal branches of the anterior, middle, and posterior cerebral arteries through cortical-leptomeningeal anastomoses; in contrast, there is little if any collateral flow for the deep penetrating vessels of the thalamus, basal ganglia, and deep white matter.

Occlusive vascular disease of severity sufficient to lead to cerebral infarction may be due to embolization from a distant source, in situ thrombosis, or various vasculitides; the pathology of these conditions is also discussed in Chapters 4 and 11 .

• Embolism to the brain occurs from a variety of sources. Cardiac mural thrombi are among the most common culprits; myocardial infarct, valvular disease, and atrial fibrillation are important predisposing factors. Next in frequency are thromboemboli originating from arteries, most often atheromatous plaques within the carotids. Other sources of emboli include paradoxical thromboemboli, particularly in children with cardiac anomalies; thromboemboli associated with cardiac surgery; and emboli of other types (tumor, fat, or air). The territory supplied by the middle cerebral artery—the direct extension of the internal carotid artery—is most frequently affected by embolic infarction; the incidence is about equal in the two hemispheres. Emboli tend to lodge where blood vessels branch or in areas of preexisting luminal stenosis. “Shower embolization,” as in fat embolism, may occur after fractures; affected individuals manifest generalized cerebral dysfunction with disturbances of higher cortical function and consciousness, often without localizing signs. Widespread hemorrhagic lesions involving the white matter are characteristic of embolization of bone marrow after trauma.

• Thrombotic occlusion of the cerebral arteries is most commonly caused by acute change of vulnerable atherosclerotic plaques, as in coronary artery disease ( Chapter 12 ). The most common sites are the carotid bifurcation, the origin of the middle cerebral artery, and either end of the basilar artery. Thrombi cause progressive narrowing of the lumen, may be accompanied by anterograde extension, and may progress to fragmentation and distal embolization. Atherosclerotic cerebrovascular disease is frequently associated with systemic diseases such as hypertension and diabetes.

• Inflammatory processes that involve blood vessels may also lead to luminal narrowing, occlusion, and, hence, cerebral infarcts. Although infectious vasculitis of small and large vessels occurs with syphilis and tuberculosis, it is now more common in the setting of immunosuppression and opportunistic infection (e.g., aspergillosis). Polyarteritis nodosa and other noninfectious vasculitides may involve cerebral vessels and cause single or multiple infarcts throughout the brain. Primary angiitis of the CNS can also develop in the absence of systemic vasculitis.

• Other conditions that may cause thrombosis (and intracranial hemorrhage) include hypercoagulable states, dissecting aneurysm of extracranial arteries in the neck that supply the brain, and drug abuse (amphetamines, heroin, cocaine).

Brain infarcts are subdivided into two broad groups based on the presence of secondary hemorrhage. Because the brain has end-organ circulation with limited collateral supply, occlusive brain infarcts generally start as nonhemorrhagic (pale/anemic; Fig. 28.13A ); clinically, these nonhemorrhagic infarcts are called ischemic, a confusing term as every infarct, not just this type, is caused by tissue ischemia. Secondary hemorrhage can occur from ischemia-reperfusion injury following spontaneous or therapeutic dissolution or fragmentation of the intravascular occlusive material. This process (termed secondary hemorrhagic transformation and leading to a hemorrhagic infarct) develops if the causative ischemic event lasts long enough to damage small blood vessels in the affected area; the resulting reperfusion hemorrhages are largely petechial in nature, but may be multiple or even confluent (see Fig. 28.13B ). The clinical management of patients with nonhemorrhagic and hemorrhagic infarcts differs greatly, although the underlying causes are the same (for instance, thrombolytic therapy is contraindicated in a patient with brain hemorrhage of any etiology).

Morphology

Both the gross and microscopic appearance of a nonhemorrhagic infarct changes over time. Grossly, there is little change in appearance during the first 6 hours of irreversible injury. By 48 hours, however, the tissue becomes pale, soft, and swollen, and the gray-white matter junction becomes indistinct. From 2 to 10 days, the brain becomes gelatinous and friable, and the previously ill-defined boundary between normal and infarcted tissue becomes more distinct as edema resolves in the viable adjacent tissue. From 10 days to 3 weeks, the tissue liquefies, eventually leaving a fluid-filled cavity that continues to expand until all of the dead tissue has been removed ( Fig. 28.14 ).

Microscopically, the tissue reaction evolves along the following sequence:

• Acute infarct ( Fig. 28.15A ). After the first 6 to 12 hours , neurons in the affected area show eosinophilic neuronal necrosis (increased eosinophilia of the cytoplasm followed by nuclear pyknosis and karyorrhexis; “dead red neurons”); both cytotoxic and vasogenic edema are present. There is loss of the usual tinctorial characteristics of white- and gray-matter structures. Endothelial and glial cells, mainly astrocytes, swell, and myelinated fibers begin to disintegrate. Up to 48 hours , neutrophilic emigration progressively increases and then falls off (but is never as prominent as in myocardial infarction).

  

• Subacute (evolving) infarct ( Fig. 28.15B ). Phagocytic cells, derived from circulating monocytes and activated microglia, are evident at 48 to 72 hours and become the predominant cell type in the ensuing 2 to 3 weeks. The macrophages become stuffed with the products of myelin breakdown or blood and may persist in the lesion for months to years. Reactive astrocytes and newly formed vessels can be seen at the periphery of the lesion as early as 1 week after the insult. As the process of liquefaction and phagocytosis proceeds, astrocytes at the edges of the lesion progressively enlarge, divide, and develop a prominent network of cytoplasmic extensions.

• Healed infarct ( Fig. 28.15C ). After several months , the astrocytic response recedes, leaving behind a dense meshwork of glial fibers admixed with new capillaries and some perivascular connective tissue. In the cerebral cortex, the cavity is separated from the meninges and subarachnoid space by a gliotic layer of tissue, which is derived from the molecular layer of the cortex. The pia and arachnoid are not affected. Infarcts undergo these reactive and reparative stages from the edges inward; thus, different areas of a lesion may appear chronologically divergent, revealing the natural progression of the response.

The features and temporal evolution of hemorrhagic infarctions parallel ischemic infarctions, with the addition of blood extravasation and resorption. In individuals receiving anticoagulant treatment, hemorrhagic infarcts may be associated with extensive intracerebral hematomas. Venous infarcts are often hemorrhagic and may occur after thrombotic occlusion of the superior sagittal sinus or other sinuses, or after occlusion of the deep cerebral veins. Neoplasms, localized infections, and other conditions leading to a hypercoagulable state increase the risk for venous thrombosis.

Lacunar Infarcts

Hypertension affects the deep penetrating arteries and arterioles that supply the basal ganglia and hemispheric white matter as well as the brainstem; these cerebral vessels develop arteriolosclerosis, also known as small vessel disease because it affects arteries 40 to 900 µm in diameter, described in more detail later. If this disease process progresses to thrombosis and complete vessel occlusion, the end-result is development of small cavitary infarcts known as lacunes or lacunar infarcts ( Fig. 28.16 ). These lakelike spaces, arbitrarily defined as less than 15 mm wide, can be single or multiple and involve the putamen, globus pallidus, thalamus, internal capsule, deep white matter, caudate nucleus, and pons, in descending order of frequency. On microscopic examination, there is tissue loss surrounded by gliosis. Depending on their location in the CNS, lacunar infarcts can be clinically silent or cause severe neurologic impairment. Affected vessels may also be associated with widening of the perivascular spaces without tissue infarction ( état criblé ).

Global Cerebral Hypoxia/Ischemia

Global cerebral hypoxia or ischemia occurs when there is a generalized reduction of cerebral perfusion (as in cardiac arrest, shock, and severe hypotension) or decreased oxygen carrying capacity of the blood (e.g., in carbon monoxide poisoning). The clinical outcome varies with the severity and length of the insult. In mild cases, there may only be a transient postischemic confusional state, followed by complete recovery. Nevertheless, irreversible CNS damage may occur in individuals who experience global hypoxic and/or ischemic insults (diffuse hypoxic/ischemic encephalopathy) . Among CNS cells, there is a hierarchy of sensitivity to hypoxia/ischemia: neurons are the most sensitive, although glial cells (oligodendrocytes and astrocytes) are also vulnerable. The most sensitive neurons in the brain are pyramidal neurons in the hippocampus (especially area CA1, also referred to as Sommer sector), cerebellar Purkinje cells, and pyramidal neurons in the cerebral cortex (especially layers III and V); the molecular mechanisms underlying this selective vulnerability are not understood. With severe global cerebral hypoxia/ischemia, widespread neuronal death occurs, irrespective of regional vulnerability; patients who survive this injury often remain in a persistent vegetative state. Other patients meet the current clinical criteria for “brain death,” including evidence of irreversible diffuse cortical injury (isoelectric, or “flat,” electroencephalogram), brainstem damage (such as absent reflexes and respiratory drive), and absent cerebral perfusion. When individuals with this pervasive form of injury are maintained on mechanical ventilation, the brain gradually undergoes widespread liquefaction, producing so-called “respirator brain.”

Border zone (“watershed”) infarcts occur in the regions of the brain or spinal cord that lie at the most distal reaches of the arterial blood supply (i.e., the border zones between arterial territories). In the cerebral hemispheres, the border zone between the anterior and the middle cerebral artery distributions is at greatest risk. Damage to this region, located a few centimeters lateral to the interhemispheric fissure, results in a cortical wedge-shaped infarct that usually shows secondary hemorrhagic transformation ( Fig. 28.17 ) and is often bilateral. Border zone infarcts usually develop after severe hypotensive episodes and are most commonly seen in patients resuscitated after cardiac arrest.

Morphology

In the setting of global ischemia, the brain becomes edematous and swollen, producing widening of the gyri and narrowing of the sulci. The cut surface shows poor demarcation between gray and white matter. The microscopic features of irreversible ischemic injury evolve over time and mimic the changes seen in infarcts; the distinction between global and focal ischemic injury is based not on the nature of cellular pathology but on the overall pattern of brain involvement. Early changes, occurring 6 to 12 hours after the insult, are seen in neurons (dead red neurons described earlier); similar acute changes occur somewhat later in astrocytes and oligodendroglia. Subacute changes, occurring at 24 hours to 2 weeks, include tissue necrosis, influx of macrophages, vascular proliferation, and reactive gliosis. Repair, robust after approximately 2 weeks, is characterized by removal of necrotic tissue, loss of normal CNS architecture, and gliosis. In the cerebral neocortex, the neuronal loss and gliosis are uneven, with preservation of some layers and destruction of others, producing a pattern of injury termed laminar necrosis.

Intraparenchymal Hemorrhage

Rupture of a small intraparenchymal vessel can result in a primary hemorrhage within the brain, often associated with sudden onset of neurologic symptoms (stroke); this should not be confused with the secondary hemorrhagic transformation of an occlusive infarct (described earlier). Spontaneous (nontraumatic) intraparenchymal hemorrhages occur most commonly in middle to late adult life, with a peak incidence at about 60 years of age. Hemorrhages in the basal ganglia and thalamus are commonly designated “ganglionic hemorrhages,” whereas those that occur in the lobes of the cerebral hemispheres are called “lobar hemorrhages”; the two major causes of these patterns of hemorrhage are hypertension and cerebral amyloid angiopathy, respectively. In addition, other local and systemic factors may cause or contribute to nontraumatic hemorrhage, including systemic coagulation disorders, neoplasms, vasculitis, aneurysms, and vascular malformations.

Hypertension is the risk factor most commonly associated with deep brain parenchymal hemorrhages, accounting for more than 50% of clinically significant hemorrhages and for roughly 15% of deaths among individuals with chronic hypertension. Hypertensive intraparenchymal hemorrhage may originate in the putamen (50% to 60% of cases), thalamus, pons, cerebellar hemispheres (rarely), and other regions of the brain ( Fig. 28.18A ). Hypertension leads to a number of vessel wall abnormalities, including accelerated atherosclerosis in larger arteries, hyaline arteriolosclerosis in smaller arteries, and (in severe cases) proliferative changes and frank necrosis of arterioles. Arteriolar walls affected by hyaline change ( Fig. 28.18B ) are thickened but more vulnerable to rupture than normal vessels; these changes are most prominent in the basal ganglia and the subcortical white matter. As described earlier, if small arteries affected by hyaline arteriolosclerosis do not rupture but are occluded, the result is lacunar infarction.

Cerebral amyloid angiopathy (CAA) is the risk factor most commonly associated with lobar hemorrhages ( Fig. 28.18C ). In CAA, amyloidogenic peptides, usually the same ones found in Alzheimer disease (Aβ; see later), are deposited in the walls of medium- and small-caliber meningeal, cortical, and cerebellar vessels; involved vessels are rigid, and as a result fail to collapse during tissue processing and sectioning. Although similar to hyaline arteriolosclerosis on routine hematoxylin and eosin (H&E) stain, the hyaline material in CAA consists of β amyloid rather than collagen ( Fig. 28.18D ) and is primarily seen in the leptomeningeal and cortical (rather than basal ganglia and white matter) vessels. Amyloid deposition can weaken the vessel wall and lead to hemorrhage; as a result, many individuals with CAA have evidence of numerous small hemorrhages within the brain (“microbleeds”) that can be visualized by various imaging methods. As with Alzheimer disease (discussed later), there is a relationship between polymorphisms in the gene that encodes apolipoprotein E (ApoE) and risk of disease; specifically, the presence of either an ε2 or ε4 allele increases the risk of bleeding. Autosomal dominant forms of CAA are associated with certain mutations in the APP gene, which encodes the precursor for the Aβ peptides that are prone to deposit as amyloid.

Other forms of hereditary small-vessel diseases of the CNS have been identified. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder caused by mutations in the NOTCH3 gene that lead to misfolding of the extracellular domain of the NOTCH3 receptor. The disease is characterized clinically by recurrent small vessel strokes (usually infarcts, less often hemorrhages) and dementia. Imaging studies show that the first detectable changes are in white matter, usually presenting around 35 years of age and then progressing further over time. Other forms of the heritable small vessel disease include a disorder associated with mutations in the gene for COL4A1, a component of the vascular basement membrane.

Morphology

Acute primary intraparenchymal hemorrhages are characterized by a central core of clotted blood that compresses the adjacent parenchyma; this compression leads to secondary infarction of the affected brain tissue, with anoxic neuronal and glial changes as well as edema. Eventually the edema resolves, hemosiderin- and lipid-laden macrophages appear, and proliferation of reactive astrocytes is seen at the periphery of the lesion; the cellular events then follow the same time course that is observed after cerebral infarction. Old hemorrhages show areas of parenchymal cavitary destruction with a rim of brownish discoloration.

Subarachnoid Hemorrhage and Ruptured Saccular Aneurysm

The most frequent cause of spontaneous subarachnoid hemorrhage is rupture of a saccular (“berry”) aneurysm in a cerebral artery. (As noted earlier, brain trauma is the most common cause of subarachnoid hemorrhage overall.) Nontraumatic subarachnoid hemorrhage may also result from rupture of a primary intracerebral hemorrhage into the ventricular system, vascular malformation, hematologic disturbances, and tumors.

Saccular aneurysm is the most common type of intracranial aneurysm; other aneurysm types include atherosclerotic (fusiform; mostly of the basilar artery), mycotic, traumatic, and dissecting. These latter three, like saccular aneurysms, are most often found in the anterior circulation, but more often cause cerebral infarction rather than subarachnoid hemorrhage.

Saccular aneurysms are found in about 2% of the population according to recent data from community-based radiologic studies. About 90% of saccular aneurysms are found near major arterial branch points in the anterior circulation ( Fig. 28.19 ); multiple aneurysms exist in 20% to 30% of cases based on autopsy series.

Pathogenesis

Although the etiology of saccular aneurysms remains obscure, the structural abnormality of the involved vessel (absence of smooth muscle and intimal elastic lamina) suggests that they are developmental anomalies. The majority occur sporadically, but genetic factors may be important in their pathogenesis because there is an increased incidence of aneurysms in first-degree relatives of those affected. There is also an increased incidence in individuals with certain Mendelian disorders (e.g., autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome type IV, neurofibromatosis type 1 [NF1], and Marfan syndrome), fibromuscular dysplasia of extracranial arteries, and coarctation of the aorta. Other predisposing factors include cigarette smoking and hypertension (estimated to be present in about half of affected individuals). Although they are sometimes referred to as “congenital,” the aneurysms are not present at birth but develop over time because of an underlying defect in the media of the vessel wall.

Morphology

An unruptured saccular aneurysm is a thin-walled outpouching, usually at an arterial branch point along the circle of Willis or a major vessel just beyond. Saccular aneurysms measure from a few millimeters to 2 or 3 cm in diameter and have a bright red, shiny surface and a thin, translucent wall ( Fig. 28.20 ). Atheromatous plaques, calcification, or thrombi may be found in the wall or lumen of the aneurysm. Sometimes there is evidence of prior hemorrhage, in the form of brownish discoloration of the adjacent brain and meninges. The neck of the aneurysm may be wide or narrow. Rupture usually occurs at the apex of the sac and leads to extravasation of blood into the subarachnoid space, the substance of the brain, or both. The arterial wall adjacent to the neck of the aneurysm often shows some intimal thickening and attenuation of the media. Smooth muscle and intimal elastic lamina do not extend into the neck and are absent from the aneurysm sac itself, which is made up of thickened hyalinized intima and a covering of adventitia.

Vascular Malformations

Vascular malformations of the brain are classified into four principal groups: arteriovenous malformations, cavernous malformations, capillary telangiectasias, and venous angiomas . Of these, the first two are the types associated with risk of hemorrhage and development of neurologic symptoms. Although lacking morphologic features that typify neoplasms, arteriovenous malformations are frequently associated with activating somatic mutations in the KRAS oncogene within the endothelial cells that line the malformed vessels, suggesting that dysregulated RAS signaling has a central role in their pathogenesis.

Morphology

Arteriovenous malformations (tangled networks of wormlike vascular channels with high blood flow due to prominent, pulsatile arteriovenous shunting) may involve vessels in the subarachnoid space, the brain, or both ( Fig. 28.21 ). They are composed of greatly enlarged blood vessels separated by gliotic tissue, often with evidence of prior hemorrhage. Some vessels can be recognized as arteries with duplication and fragmentation of the internal elastic lamina, while others show marked thickening or partial replacement of the media by hyalinized connective tissue.

Cavernous malformations consist of distended, loosely organized vascular channels arranged back to back with collagenized walls of variable thickness; there is usually no brain parenchyma between vessels in this type of malformation. They occur most often in the cerebellum, pons, and subcortical regions, in decreasing order of frequency, and are “low-flow” channels that do not participate in arteriovenous shunting. Foci of old hemorrhage, infarction, and calcification frequently surround the abnormal vessels.

Acute Pyogenic (Bacterial) Meningitis

Distinctive microorganisms cause acute pyogenic meningitis in various age groups: Escherichia coli and the group B streptococci in neonates; Streptococcus pneumoniae and Listeria monocytogenes in the elderly; and Neisseria meningitidis in adolescents and young adults, with clusters of cases raising public health concerns. The introduction of immunization against Haemophilus influenzae has markedly reduced the incidence of this infection in the developed world, particularly among infants (who used to be at high risk).

Affected individuals typically show systemic signs of infection superimposed on symptoms related to meningeal irritation and neurologic impairment, including headache, photophobia, irritability, clouding of consciousness, and neck stiffness. A spinal tap yields cloudy or frankly purulent CSF with as many as 90,000 neutrophils per cubic millimeter, increased CSF pressure and increased protein concentration, and markedly reduced glucose content. Untreated pyogenic meningitis can be fatal, while effective treatment with antibiotics markedly reduces mortality. One feared complication is the Waterhouse-Frederichsen syndrome, which results from meningitis-associated septicemia and hemorrhagic infarction of the adrenal glands ( Chapter 24 ). It occurs most often with meningococcal and pneumococcal meningitis. In the immunosuppressed individual, purulent meningitis may be caused by several other infectious agents, such as Klebsiella or anaerobic organisms, and may have an atypical clinical course and uncharacteristic CSF findings, rendering timely diagnosis more difficult.

Morphology

In acute meningitis, an exudate is evident within the leptomeninges over the surface of the brain ( Fig. 28.22 ). The meningeal vessels are engorged and stand out prominently. The anatomic distribution of the exudate varies; in H. influenzae meningitis, for example, it is usually basal, whereas in pneumococcal meningitis it is often densest over the cerebral convexities near the sagittal sinus. From the areas of greatest accumulation, tracts of pus follow along blood vessels on the surface of the brain. When the meningitis is fulminant, the inflammation may extend to the ventricles, producing ventriculitis. The ventricles may also be the portal for CSF involvement by blood-borne infections because the choroid plexus lacks a blood-brain barrier.

On microscopic examination, neutrophils fill the subarachnoid space in severely affected areas and are found predominantly around the leptomeningeal blood vessels in less severe cases. Particularly in untreated meningitis, Gram stain reveals variable numbers of bacteria. In fulminant meningitis, the inflammatory cells infiltrate the walls of the leptomeningeal veins and may extend focally into the substance of the brain (cerebritis); secondary vasculitis and venous thrombosis may lead to hemorrhagic cerebral infarction.

Leptomeningeal fibrosis may follow pyogenic meningitis and cause hydrocephalus. Particularly in pneumococcal meningitis, large quantities of the capsular polysaccharide of the organism produce a gelatinous exudate that promotes arachnoid fibrosis, a condition referred to as chronic adhesive arachnoiditis .

Acute Aseptic (Viral) Meningitis

Aseptic meningitis is a clinical term used for an absence of organisms by bacterial culture in a patient with manifestations of meningitis, including meningeal irritation, fever, and alterations of consciousness of relatively acute onset. The disease is generally of viral etiology, but may be bacterial, rickettsial, or autoimmune in origin. The clinical course is less fulminant than that of pyogenic meningitis, and the CSF findings also differ; in aseptic meningitis, there is a lymphocytic pleocytosis, the protein elevation is only moderate, and the glucose content is nearly always normal. The viral aseptic meningitides are usually self-limited and are treated symptomatically. Remarkably, the etiologic agent is identified in only a minority of cases; however, this may change through use of more sensitive and specific detection techniques (such as next-generation sequencing), which are under development. When pathogens are identified, enteroviruses are the most common etiology, accounting for 80% of cases. The spectrum of pathogens varies seasonally and geographically. An aseptic meningitis-like picture may also develop subsequent to rupture of an epidermoid cyst into the subarachnoid space or the introduction of a chemical irritant (chemical meningitis). The CSF is sterile in these cases, and there is pleocytosis with neutrophils and an increased protein concentration, but the sugar content is usually normal.

Brain Abscess

A brain abscess is a localized focus of necrosis of brain tissue with accompanying inflammation, usually caused by a bacterial infection. Brain abscesses may arise by direct implantation of organisms, local extension from adjacent foci (mastoiditis, paranasal sinusitis), or hematogenous spread (usually from a primary site in the heart, lungs, or bones of the extremities, or secondary to bacteremia from dental procedures). Predisposing conditions include acute bacterial endocarditis, which may give rise to multiple brain abscesses; congenital heart disease with right-to-left shunting and loss of pulmonary filtration of organisms; chronic pulmonary sepsis, as in bronchiectasis; and systemic disease with immunosuppression. Streptococci and staphylococci are the most common offending organisms identified in nonimmunosuppressed patients.

Morphology

Abscesses are discrete lesions with central liquefactive necrosis surrounded by brain swelling ( Fig. 28.23 ). At the outer margin of the necrotic lesion, there is exuberant granulation tissue with neovascularization. The newly formed vessels are abnormally permeable, accounting for marked vasogenic edema in the adjacent brain tissue. In well-established lesions, a collagenous capsule is produced by fibroblasts derived from the walls of blood vessels. Outside the fibrous capsule is a zone of reactive gliosis containing numerous gemistocytic astrocytes.

Subdural Empyema

Bacterial, and rarely fungal, infections of the skull bones or air sinuses can spread to the subdural space, producing a subdural empyema. Although the underlying arachnoid and subarachnoid spaces are usually not affected, a large subdural empyema with mass effect and/or thrombophlebitis of the bridging veins can cause venous occlusion and infarction of the brain. In addition to symptoms referable to the source of the infection, most patients are febrile and have headache and neck stiffness. The CSF profile is similar to that seen in brain abscesses because both are parameningeal infectious processes. If untreated, focal neurologic signs, lethargy, and coma may develop. With prompt diagnosis and treatment, including surgical drainage, resolution and full recovery is possible, the only residuum being a thickened dura.

Extradural Abscess

Extradural abscess, commonly associated with osteomyelitis, often arises from an adjacent focus of infection, such as sinusitis, or following a surgical procedure. When the process occurs in the spinal epidural space, it may cause spinal cord compression and constitute a neurosurgical emergency.

Tuberculosis

Tuberculosis of the CNS may be part of active disease elsewhere in the body, or appear in isolation following seeding from silent lesions elsewhere, usually the lungs. It may involve the meninges or the brain.

Morphology

The most common pattern of tuberculous involvement is a diffuse meningoencephalitis. The subarachnoid space contains a gelatinous or fibrinous exudate that characteristically involves the base of the brain, effacing the cisterns and encasing cranial nerves. There may be discrete, white areas of inflammation scattered over the leptomeninges. On microscopic examination, involved areas contain a mixed inflammatory infiltrate with lymphocytes, plasma cells, and macrophages. Florid cases show well-formed granulomas with caseous necrosis and giant cells. Arteries running through the subarachnoid space may show obliterative endarteritis and marked intimal thickening. Organisms can often be seen with acid-fast stains. The infectious process may spread to the choroid plexus and ependymal surface, traveling through the CSF. In long-standing cases, a dense, fibrous adhesive arachnoiditis may develop, most conspicuous around the base of the brain. Hydrocephalus may result.

CNS involvement may also take the form of one or more well-circumscribed intraparenchymal masses (tuberculomas), which may be associated with meningitis. A tuberculoma may be as large as several centimeters in diameter, causing significant mass effect. These granulomas usually have central caseous necrosis; calcification may occur in inactive lesions.

Neurosyphilis

Neurosyphilis is a manifestation of the tertiary stage of syphilis and occurs in only about 10% of individuals with untreated infection. The major patterns of CNS involvement are meningovascular neurosyphilis, paretic neurosyphilis, and tabes dorsalis. Affected individuals often show an incomplete or mixed picture, most commonly the combination of tabes dorsalis and paretic disease (taboparesis). Because of impaired cell-mediated immunity, individuals infected with HIV are at increased risk for neurosyphilis, particularly acute syphilitic meningitis or meningovascular disease; the rate of disease progression and severity are also accelerated.

Morphology

Neurosyphilis presents in several distinct forms.

• Meningovascular neurosyphilis is chronic meningitis involving the base of the brain and more variably the cerebral convexities and spinal leptomeninges. In addition, there may be an associated obliterative endarteritis (Heubner arteritis) accompanied by a distinctive perivascular inflammatory reaction rich in plasma cells and lymphocytes. Cerebral gummas (plasma cell-rich mass lesions) may also occur in the meninges and extend into the parenchyma.

• Paretic neurosyphilis is caused by invasion of the brain by T. pallidum and manifests as insidious but progressive cognitive impairment associated with mood alterations (including delusions of grandeur) that terminate in severe dementia (general paresis of the insane). Parenchymal damage of the cerebral cortex is particularly common in the frontal lobe, but also occurs in other areas of the isocortex. The lesions are characterized by loss of neurons, proliferation of microglia, gliosis, and iron deposits; the latter are demonstrable with the Prussian blue stain perivascularly and in the neuropil, and are presumably the sequelae of small bleeds stemming from microvascular damage. The spirochetes can, at times, be demonstrated in tissue sections.

• Tabes dorsalis is the result of damage to the sensory axons in the dorsal roots. This causes impaired joint position sense and ataxia (locomotor ataxia); loss of pain sensation, leading to skin and joint damage (Charcot joints); other sensory disturbances, particularly the characteristic “lightning pains”; and absence of deep tendon reflexes. On microscopic examination, there is loss of both axons and myelin in the dorsal roots, with corresponding pallor and atrophy in the dorsal columns of the spinal cord. Organisms are not demonstrable in the cord lesions.