Pathology_Robbins

Pathology_Robbins. Cerebral arterial occlusion leads first to focal ischemia and then to infarction in the distribution of the compromised vessel. The size, location, and shape of the infarct and the extent of tissue damage that results may be modified by collateral blood flow. Specifically, collateral flow through the circle of Willis or cortical-leptomeningeal anastomoses can limit damage in some regions. By contrast, there is little if any collateral blood flow to structures such as the thalamus, basal ganglia, and deep white matter, which are supplied by deep penetrating vessels.


Pathology_Robbins

Pathology_Robbins. Embolic infarctions are more common than infarctions due to thrombosis. Cardiac mural thrombi are a frequent source of emboli; myocardial dysfunction, valvular disease, and atrial fibrillation are important predisposing factors. Thromboemboli also arise in arteries, most often from atheromatous plaques in the carotid arteries or aortic arch. Emboli of venous origin may cross over to the arterial circulation through a patent foramen ovale and lodge in the brain (paradoxical embolism; see Chapter 4); these include thromboemboli from deep leg veins and fat emboli, usually following bone trauma. The territory of the middle cerebral artery, a direct extension of the internal carotid artery, is most frequently affected by embolic infarction. Emboli tend to lodge where vessels branch or in areas of stenosis, usually caused by atherosclerosis.


Pathology_Robbins

Pathology_Robbins. Thrombotic occlusions causing cerebral infarctions usually are superimposed on atherosclerotic plaques; common sites are the carotid bifurcation, the origin of the middle cerebral artery, and either end of the basilar artery. These occlusions may be accompanied by anterograde extension, as well as thrombus fragmentation and distal embolization. Thrombotic occlusions causing small infarcts of only a few millimeters in diameter, so-called “lacunar infarcts,” occur when small penetrating arteries occlude due to chronic damage, usually from long-standing hypertension (discussed later). Fig. 23.7 ). Nonhemorrhagic infarcts result from acute vascular occlusions and may evolve into hemorrhagic infarcts when there is reperfusion of ischemic tissue, either through collaterals or after dissolution of emboli.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Hemorrhages within the brain are caused by (1) hypertension and other diseases leading to vascular wall injury, (2) structural lesions such as arteriovenous and cavernous malformations, and (3) tumors. Subarachnoid hemorrhages most commonly are the result of ruptured aneurysms but also occur with other vascular malformations. Subdural or epidural hemorrhages usually are associated with trauma.


Pathology_Robbins

Pathology_Robbins. Spontaneous (nontraumatic) intraparenchymal hemorrhages are most common in mid to late adult life, with a peak incidence at about 60 years of age. Most are due to the rupture of a small intraparenchymal vessel. Hypertension is the leading underlying cause, and brain hemorrhage accounts for roughly 15% of deaths among individuals with chronic hypertension. Intracerebral hemorrhage can be clinically devastating when it affects large portions of the brain or extends into the ventricular system; alternatively, it can affect small regions and be clinically silent. Hypertensive intraparenchymal hemorrhages typically occur in the basal ganglia, thalamus, pons, and cerebellum ( Fig. 23.8 ), with the location and the size of the bleed determining its clinical manifestations. If the individual survives the acute event, gradual resolution of the hematoma ensues, sometimes with considerable clinical improvement.


Pathology_Robbins

Pathology_Robbins. Cerebral amyloid angiopathy (CAA) is a disease in which the same amyloidogenic peptides as those found in Alzheimer disease (discussed later) deposit in the walls of medium-and small-caliber meningeal and cortical vessels. The amyloid confers a rigid, pipe-like appearance and stains with Congo red. Amyloid deposition weakens vessel walls and increases the risk for hemorrhages, which differ in distribution from those associated with hypertension. CAA-associated hemorrhages often occur in the lobes of the cerebral cortex (lobar hemorrhages). In addition to these symptomatic hemorrhages, CAA also results in small (<1 mm) cortical hemorrhages (microhemorrhages). The most frequent cause of clinically significant nontraumatic subarachnoid hemorrhage is rupture of a saccular (berry) aneurysm. Hemorrhage into the subarachnoid space also may result from vascular malformation, trauma, rupture of an intracerebral hemorrhage into the ventricular system, coagulopathies, and tumors.


Pathology_Robbins

Pathology_Robbins. In about one-third of cases, rupture of a saccular aneurysm occurs at the time of an acute increase in intra-cranial pressure, such as occurs with straining at stool or sexual orgasm. Blood under arterial pressure is forced into the subarachnoid space, and the patient is stricken with sudden, excruciating headache (known as a thunderclap headache, often described as “the worst headache I’ve ever had”) and rapidly loses consciousness. Between 25% and 50% of affected individuals die from the first bleed, and recurrent bleeds are common in survivors. Not surprisingly, the prognosis worsens with each bleeding episode. About 90% of saccular aneurysms occur in the anterior circulation near major arterial branch points ( Fig.


Pathology_Robbins

Pathology_Robbins. About 90% of saccular aneurysms occur in the anterior circulation near major arterial branch points ( Fig. 23.9 ); multiple aneurysms exist in 20% to 30% of cases. The aneurysms are not present at birth but develop over time because of underlying defects in the vessel media. There is an increased risk for aneurysms in patients with autosomal dominant polycystic kidney disease (Chapter 14) and genetic disorders of extracellular matrix proteins (e.g., Ehler-Danlos syndrome). Overall, roughly 1.3% of aneurysms bleed per year, with the probability of rupture increasing with size. For example, aneurysms larger than 1 cm in diameter have a roughly 50% risk for bleeding per year. In the early period after a subarachnoid hemorrhage, there is an additional risk for ischemic injury from vasospasm of other vessels. Healing and the attendant meningeal fibrosis and scarring sometimes obstruct CSF flow or disrupt CSF resorption, leading to hydrocephalus.


Pathology_Robbins

Pathology_Robbins. Fig.23.10 ).Beyondtheneckoftheaneurysm,themuscularwallandintimalelasticlaminaareabsent,suchthattheaneurysmsacislinedonlybythickenedhyalinizedintima.Theadventitiacoveringthesaciscontinuouswiththatoftheparentartery.Ruptureusuallyoccursattheapexofthesac,releasingbloodintothesubarachnoidspace,thesubstanceofthebrain,orboth. In addition to saccular aneurysms, atherosclerotic, mycotic, traumatic, and dissecting aneurysms also occur intracranially. The last three types (like saccular aneurysms) most often are found in the anterior circulation, whereas atherosclerotic aneurysms frequently are fusiform and most commonly involve the basilar artery. Nonsaccular aneurysms usually manifest as cerebral infarction due to vascular occlusion instead of subarachnoid hemorrhage. Vascular malformations of the brain are classified into four principal types based on the nature of the abnormal vessels: arteriovenous malformations (AVMs), cavernous http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 23.9 Commonsitesofsaccularaneurysms.Anterior cerebral artery Internal carotid artery Posterior cerebral artery Posterior communicating artery Anterior communicating artery Middle cerebral artery Basilar artery 20%34%40%4% malformations, capillary telangiectasias, and venous angiomas. AVMs, the most common of these, affect males twice as frequently as females and most commonly manifest between 10 and 30 years of age with seizures, an intra-cerebral hemorrhage, or a subarachnoid hemorrhage. In the newborn period, large AVMs may lead to high-output congestive heart failure because of blood shunting from arteries to veins. The risk for bleeding makes AVM the most dangerous type of vascular malformation. Multiple AVMs can be seen in the setting of hereditary hemorrhagic telangiectasia, an autosomal dominant condition often associated with mutations affecting the TGFβ pathway.


Pathology_Robbins

Pathology_Robbins. Capillary telangiectasias aremicroscopicfociofdilatedthin-walledvascularchannelsseparatedbyrelativelynormalbrainparenchymathatoccurmostfrequentlyinthepons.Venous angiomas (varices)consistofaggregatesofectaticvenouschannels.Theselattertwotypesofvascularmalformationareunlikelytobleedortocausesymptoms,andmostareincidentalfindings. Hypertension causes hyaline arteriolar sclerosis of the deep penetrating arteries and arterioles that supply the basal ganglia, the hemispheric white matter, and the brain stem. Affected arteriolar walls are weakened and are more vulnerable to rupture. In some instances, minute aneurysms (Charcot-Bouchard microaneurysms) form in vessels less than 300 µm in diameter. In addition to massive intracerebral hemorrhage (discussed earlier), several other pathologic outcomes are related to hypertension.


Pathology_Robbins

Pathology_Robbins. Fig. 23.10 Saccularaneurysms.(A)Viewofthebaseofthebrain,dissectedtoshowthecircleofWilliswithananeurysmoftheanteriorcerebralartery(arrow). (B)ThecircleofWillisisdissectedtoshowalargeaneurysm.(C)Sectionthroughasaccularaneurysmshowingthehyalinizedfibrousvesselwall.Hematoxylin-eosinstain. http://ebooksmedicine.net Fig. 23.11 Arteriovenousmalformation. Lacunes or lacunar infarcts are small cavitary infarcts, just a few millimeters in size, that are found most commonly in the deep gray matter (basal ganglia and thalamus), the internal capsule, the deep white matter, and the pons. They are caused by occlusion of a single penetrating branch of a large cerebral artery. Depending on their location, lacunes can be silent clinically or cause significant neurologic impairment.


Pathology_Robbins

Pathology_Robbins. Rupture of the small-caliber penetrating vessels may occur, leading to the development of small hemorrhages. In time, these hemorrhages resorb, leaving behind a slit-like cavity (slit hemorrhage) surrounded by brownish discoloration. Acute hypertensive encephalopathy most often is associated with sudden sustained increases in diastolic blood pressure to greater than 130 mm Hg. It is characterized by increased intracranial pressure and global cerebral dysfunction, manifesting as headaches, confusion, vomiting, convulsions, and sometimes coma. Rapid therapeutic intervention to reduce the blood pressure is essential. Postmortem examination may show brain edema, with or without transtentorial or tonsillar herniation. Petechiae and fibrinoid necrosis of arterioles in the gray matter and white matter may be seen microscopically.


Pathology_Robbins

Pathology_Robbins. Inflammatory processes involving blood vessels may compromise blood flow and cause cerebral dysfunction or infarction. Infectious arteritis of small and large vessels was previously seen mainly in association with syphilis and tuberculosis, but is now more often caused by opportunistic infections (such as aspergillosis, herpes zoster, or CMV) in the setting of immunosuppression. Some systemic forms of vasculitis, such as polyarteritis nodosa, may involve cerebral vessels and cause single or multiple infarcts. Primary angiitis of the CNS is a form of vasculitis that involves multiple small-to medium-sized parenchymal and subarachnoid vessels and is characterized by chronic inflammation, multinucleate giant cells (with or without granuloma formation), and destruction of vessel walls. Affected individuals present with a diffuse encephalopathy, often with cognitive dysfunction. Treatment consists of immunosuppressive agents.


Pathology_Robbins

Pathology_Robbins. Spontaneoussubarachnoidhemorrhageusuallyiscausedbyastructuralvascularabnormality,suchasananeurysmorarteriovenousmalformation. Trauma to the brain and spinal cord is a significant cause of death and disability. The severity and site of injury affect the outcome: injury of several cubic centimeters of brain parenchyma may be clinically silent (if in the frontal lobe), severely disabling (affecting the spinal cord), or fatal (involving the brain stem).


Pathology_Robbins

Pathology_Robbins. A blow to the head may be penetrating or blunt; it may cause an open or a closed injury. The magnitude and distribution of resulting traumatic brain lesions depend on the shape of the object causing the trauma, the force of impact, and whether the head is in motion at the time of injury. Severe brain damage can occur in the absence of external signs of head injury, and conversely, severe lacerations and even skull fractures do not necessarily indicate damage to the underlying brain. When the brain is damaged, the injuries may involve the parenchyma, the vasculature, or both.


Pathology_Robbins

Pathology_Robbins. When an object impacts the head, brain injury may occur at the site of impact—a coup injury—or opposite the site of impact on the other side of the brain—a contrecoup injury. Both coup and contrecoup lesions are contusions, with comparable gross and microscopic appearances. A contusion is caused by rapid tissue displacement, disruption of vascular channels, and subsequent hemorrhage, tissue injury, and edema. Since they are closest to the skull, the crests of the gyri are the parts of the brain that are most susceptible to traumatic injury. Contusions are common in regions of the brain overlying rough and irregular inner skull surfaces, such as the orbitofrontal regions and the temporal lobe tips. Penetration of the brain by a projectile such as a bullet or a skull fragment from a fracture causes a laceration, with tissue tearing, vascular disruption, and hemorrhage. http://ebooksmedicine.net MORPHOLOGYContusionsarewedge-shaped,withthewidestaspectclosesttothepointofimpact(


Pathology_Robbins

Pathology_Robbins. Concussion describes reversible altered brain function, with or without loss of consciousness, from head injury. The characteristic transient neurologic dysfunction includes loss of consciousness, temporary respiratory arrest, and loss of reflexes. Neurologic recovery is the norm, although amnesia for the event persists. The pathogenesis of the sudden disruption of nervous activity is unknown. Repeated episodes of concussion can result in persistent and profound neurologic deficits including cognitive impairment, parkinsonism, and others, and later development of neurodegenerative processes. Initially described in boxers (dementia pugilistica), it is now recognized to occur in a wider range of settings, such as in athletes participating in contact sports. This syndrome is termed chronic traumatic encephalopathy and is characterized by accumulation of tangles in cerebral cortex and other brain regions (see the “ ” section later in the chapter).


Pathology_Robbins

Pathology_Robbins. CNS trauma often directly disrupts vessel walls, leading to hemorrhage ( Table 23.1 ). Depending on the affected vessel, the hemorrhage may be epidural, subdural, subarachnoid, or intraparenchymal ( Fig. 23.13A ), occurring alone or in combination. Subarachnoid and intraparenchymal hemorrhages most often occur at sites of contusions and lacerations. Fig. 23.12 Cerebraltrauma.(A)Acutecontusionsarepresentinbothtemporallobes,withareasofhemorrhageandtissuedisruption.(B)Remotecontusions,seenasdiscoloredyellowareas,arepresentontheinferiorfrontalsurfaceofthisbrain.


Pathology_Robbins

Pathology_Robbins. Dural vessels—especially the middle meningeal artery— are vulnerable to traumatic injury. In infants, traumatic displacement of the easily deformable skull may tear a vessel, even in the absence of a skull fracture. In children and adults, by contrast, tears involving dural vessels almost always stem from skull fractures. Once a vessel tears, blood accumulates under arterial pressure and dissects the tightly applied dura away from the inner skull surface (see Fig. 23.13B ), producing a hematoma that compresses the brain surface. Clinically, patients can be lucid for several hours after the traumatic event before neurologic signs appear. An epidural hematoma may expand rapidly and constitutes a neurosurgical emergency necessitating prompt drainage and repair to prevent death. Rapid movement of the brain during trauma can tear the bridging veins that extend from the cerebral hemispheres http://ebooksmedicine.net Table 23.1 Patterns of Vascular Injury in the Central Nervous System


Pathology_Robbins

Pathology_Robbins. Table 23.1 Patterns of Vascular Injury in the Central Nervous System SubduralspaceTraumaLeveloftraumamaybemild;slowlyevolvingneurologicsymptoms,oftenwithadelayfromthetimeofinjury Dura (peeled off skull) Dura (still attached to skull) Arterial blood Venous blood Skull fracture B A C Fig. 23.13 Traumaticintracranialhemorrhages.(A)Epiduralhematoma(left) inwhichruptureofameningealartery,usuallyassociatedwithaskullfracture,hasledtoaccumulationofarterialbloodbetweentheduraandtheskull.Inasubduralhematoma(right), damagetobridgingveinsbetweenthebrainandthesuperiorsagittalsinushasledtotheaccumulationofbloodbetweenthethetwolayersofdura.(B)Epiduralhematomacoveringaportionofthedura.


Pathology_Robbins

Pathology_Robbins. (C)Largeorganizingsubduralhematomaattachedtothedura.(B, Courtesy of the late Dr. Raymond D. Adams, Massachusetts General Hospital, Boston, Massachusetts.) http://ebooksmedicine.net through the subarachnoid and subdural space to the dural sinuses. Their disruption produces bleeding into the subdural space. Because the inner cell layer of the dura is quite thin and in very close proximity to the arachnoid layer, the blood appears to be between the dura and arachnoid, but in reality it is between the two layers of the dura. In patients with brain atrophy, the bridging veins are stretched out and the brain has additional space within which to move, accounting for the higher rate of subdural hematomas in older adults. Infants also are susceptible to subdural hematomas because their bridging veins are thin walled.


Pathology_Robbins

Pathology_Robbins. Subdural hematomas typically become manifest within the first 48 hours after injury. They are most common over the lateral aspects of the cerebral hemispheres and may be bilateral. Neurologic signs are attributable to the pressure exerted on the adjacent brain. Symptoms are most often nonlocalizing, taking the form of headache, confusion, and slowly progressive neurologic deterioration. MORPHOLOGYAcutesubduralhematomaappearsasacollectionoffreshlyclottedbloodapposedtothecontourofthebrainsurface,withoutextensionintothedepthsofsulci(see


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYAcutesubduralhematomaappearsasacollectionoffreshlyclottedbloodapposedtothecontourofthebrainsurface,withoutextensionintothedepthsofsulci(see Fig.23.13C ).Theunderlyingbrainisflattened,andthesubarachnoidspaceisoftenclear.Subduralhematomasorganizebylysisoftheclot(about1week),growthofgranulationtissuefromtheduralsurfaceintothehematoma(2weeks),andfibrosis(1–3months).Subduralhematomascommonlyrebleed,presumablyfromthethin-walledvesselsofthegranulationtissue,leadingtomicroscopicfindingsconsistentwithhemorrhagesofvaryingages.Symptomaticsubduralhematomasaretreatedbysurgicalremovalofthebloodandassociatedreactivetissue. CENTRALNERVOUSSYSTEMTRAUMAthrough the subarachnoid and subdural space to the dural sinuses. Their disruption produces bleeding into the subthrough the subarachnoid and subdural space to the dural sinuses. Their disruption produces bleeding into the sub Physicalinjurytothebraincanoccurwhentheinsideoftheskullcomesintoforcefulcontactwiththebrain.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Traumatictearingofbloodvessels,dependingonthelocation,leadstoepidural,subdural,orintraparenchymalhematomaaswellassubarachnoidhemorrhage. The incidence of CNS malformations, giving rise to mental retardation, cerebral palsy, or neural tube defects, is estimated at 1% to 2%. Malformations of the brain are more common in the setting of multiple birth defects. Prenatal or perinatal insults may interfere with normal CNS development or cause tissue damage. During gestation, the timing of an injury determines the pattern of malformation, with earlier events typically leading to more severe phenotypes. Mutations affecting genes that regulate the differentiation, maturation, or intercellular communication of neurons or glial cells can cause CNS malformation or dysfunction. Additionally, various chemicals and infectious agents have teratogenic effects.


Pathology_Robbins

Pathology_Robbins. Some developmental disorders produce profound neuronal dysfunction in the absence of morphologic abnormalities. Genetic underpinnings for various forms of autism have emerged recently; many of the implicated genes contribute to the development or maintenance of synaptic connections. Rett syndrome is an X-linked dominant disorder associated with mutations in the gene encoding a regulator of epigenetic modifications of chromatin. Development in affected girls initially is normal, but neurologic deficits affecting cognition and movement appear by 1 to 2 years of age.


Pathology_Robbins

Pathology_Robbins. One of the earliest steps in brain development is the formation of the neural tube, which gives rise to the ventricular system, brain, and spinal cord. Partial failure or reversal of neural tube closure may lead to several malformations, each characterized by abnormalities involving neural tissue, meninges, and overlying bone or soft tissues. Collectively, neural tube defects are the most frequent type of CNS malformation. Folate deficiency during the first trimester sharply increases risk through uncertain mechanisms and represents an important opportunity for prevention, as administration of folate to women of child-bearing age reduces the incidence of neural tube defects by up to 70%. The combination of imaging studies and maternal screening for elevated αfetoprotein has increased the early detection of neural tube defects. Neural tube defects include the following:


Pathology_Robbins

Pathology_Robbins. Neural tube defects include the following: The most common defects involve the posterior end of the neural tube, from which the spinal cord forms. These can range from asymptomatic bony defects (spina bifida occulta) to spina bifida, a severe malformation consisting of a flat, disorganized segment of spinal cord associated with an overlying meningeal outpouching. Myelomeningocele is an extension of CNS tissue through a defect in the vertebral column that occurs most commonly in the lumbosacral region ( Fig. 23.14 ). Patients have motor and sensory deficits in the lower extremities and problems with bowel and bladder control. The clinical problems derive from the abnormal spinal cord segment and often are compounded by infections extending from the thin or ulcerated overlying skin. Anencephaly is a malformation of the anterior end of the neural tube that leads to the absence of the forebrain and the top of the skull. Varying amounts of posterior fossa structures may be present.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 23.14 Myelomeningocele.Bothmeningesandspinalcordparenchymaareincludedinthecystlikestructurevisiblejustabovethebuttocks. • An encephalocele is a diverticulum of malformed CNS tissue extending through a defect in the cranium. It most often involves the occipital region or the posterior fossa. When it occurs anteriorly, brain tissue may extend into the sinuses.


Pathology_Robbins

Pathology_Robbins. Microencephaly describes the group of malformations in which the volume of brain is too small; usually it is associated with a small head as well (microcephaly). It has a wide range of associations, including chromosome abnormalities, fetal alcohol syndrome, and human immunodeficiency virus (HIV) and Zika virus infection acquired in utero. The unifying feature is decreased generation of neurons destined for the cerebral cortex. During the early stages of brain development, as progenitor cells proliferate in the subependymal ventricular zone, the balance between cells leaving the progenitor population to form the cortex and those remaining in the proliferating pool affects the overall number of neurons and glial cells generated. If too many cells leave the progenitor pool prematurely, there is inadequate generation of mature neurons, leading to a small brain. Megalencephaly, excessive brain volume that is always associated with a large head, is far less common and is mostly associated


Pathology_Robbins

Pathology_Robbins. is inadequate generation of mature neurons, leading to a small brain. Megalencephaly, excessive brain volume that is always associated with a large head, is far less common and is mostly associated with rare genetic disorders.


Pathology_Robbins

Pathology_Robbins. Disruption of neuronal migration and differentiation during development can lead to abnormalities of gyration and neocortical architecture, often taking the form of neurons ending up in the wrong location. Mutations in various genes that control migration result in a variety of malformations. A representative example is holoprosencephaly, characterized by disruption of normal midline patterning. Mild forms show absence of the olfactory bulbs and related structures (arrhinencephaly). In severe forms, the brain is not divided into hemispheres or lobes, and there may be facial midline defects such as cyclopia. The best known genetic causes involve acquired or inherited loss of function mutations in components of the Hedgehog signaling pathway. Other examples include loss of gyri, which may be complete (lissencephaly) or partial, and increased number of irregularly formed gyri (polymicrogyria).


Pathology_Robbins

Pathology_Robbins. Other examples include loss of gyri, which may be complete (lissencephaly) or partial, and increased number of irregularly formed gyri (polymicrogyria). The most common malformations in this region of the brain result in misplacement or absence of portions of the cerebellum. Arnold-Chiari malformation (Chiari type II malformation) combines a small posterior fossa with a misshapen midline cerebellum and downward extension of the vermis through the foramen magnum; hydrocephalus and a lumbar myelomeningocele typically are also present. The far milder Chiari type I malformation has low-lying cerebellar tonsils that extend through the foramen magnum. Excess tissue in the foramen magnum results in partial obstruction of CSF flow and compression of the medulla, with symptoms of headache or cranial nerve deficits often manifesting only in adult life. Surgical intervention can alleviate the symptoms.


Pathology_Robbins

Pathology_Robbins. Dandy-Walker malformation is characterized by an enlarged posterior fossa, absence of the cerebellar vermis, and a large midline cyst. Brain injury occurring in the perinatal period is an important cause of childhood neurologic disability. Cerebral palsy is a term for nonprogressive neurologic motor deficits characterized by spasticity, dystonia, ataxia or athetosis, and paresis attributable to injury occurring during the prenatal and perinatal periods. Signs and symptoms may not be apparent at birth and only declare themselves later, well after the causal event.


Pathology_Robbins

Pathology_Robbins. The two major types of injury that occur in the perinatal period are hemorrhages and infarcts. These differ from the otherwise similar lesions in adults in terms of their locations and the tissue reactions they engender. In premature infants, there is an increased risk for intraparenchymal hemorrhage within the germinal matrix, most often adjacent to the anterior horn of the lateral ventricle. Hemorrhages may extend into the ventricular system and from there to the subarachnoid space, sometimes causing hydrocephalus. Infarcts may occur in the supratentorial periventricular white matter (periventricular leukomalacia), especially in premature infants. The residua of these infarcts are chalky yellow plaques consisting of discrete regions of white matter necrosis and dystrophic calcification ( Fig. 23.15 ). When severe enough to involve the gray matter and white matter, large cystic lesions can develop throughout the hemispheres, a condition termed multicystic encephalopathy.


Pathology_Robbins

Pathology_Robbins. Fig. 23.15 ). When severe enough to involve the gray matter and white matter, large cystic lesions can develop throughout the hemispheres, a condition termed multicystic encephalopathy. Certain infections, which may be acquired transplacentally or during birth, have a propensity to cause destructive brain lesions. Agents in this group (commonly referred to as TORCH) include toxoplasmosis and CMV, which can both result in parenchymal calcifications along with the tissue injury; these are discussed in more detail later. http://ebooksmedicine.net Fig. 23.15 Perinatalbraininjury.Thisspecimenfromapatientwithperiven-tricularleukomalaciacontainsacentralfocusofwhitematternecrosiswithaperipheralrimofmineralizedaxonalprocesses. Malformationsofthebraincanoccurbecauseofgeneticfactorsorexternalinsults. Thedevelopmentaltimingandpositionoftheinjurydetermineitspatternandcharacteristics.


Pathology_Robbins

Pathology_Robbins. Certaininfectionsmayaffectthebrainduringdevelopmentwithsubsequenttissuedestructionandneurologicconsequences. The brain and its coverings can be sites of infection. Some infectious agents have a relative or absolute predilection for the nervous system (e.g., rabies), while others affect many other organs as well as the brain (e.g., Staphylococcus aureus). Damage to nervous tissue may be the consequence of direct injury of neurons or glial cells by the infectious agent or microbial toxins, or may be a consequence of the host immune response. Infectious agents may reach the nervous system through several routes: • Hematogenous spread by way of the arterial blood supply is the most common means of entry. There can also be retrograde venous spread through the anastomoses between the veins of the face and the venous sinuses of the skull.


Pathology_Robbins

Pathology_Robbins. Direct implantation of microorganisms is almost invariably due to open or penetrating trauma; rare cases can be iatrogenic, as when microbes are introduced with a lumbar puncture needle or into a surgical field. Local extension can occur with infections of the skull or spine. Sources include air sinuses, most often the mastoid or frontal; infected teeth; cranial or spinal osteomyelitis; and congenital malformations, such as meningomyelocele. Peripheral nerves also may serve as paths of entry for a few pathogens—in particular, viruses such as rabies and herpes zoster. Basic mechanisms of injury associated with infectious agents are discussed in Chapter 9; in the following sections we discuss infections that are specific to the central nervous system ( Table 23.2


Pathology_Robbins

Pathology_Robbins. The epidural and subdural spaces can be involved by bacterial or fungal infections, usually as a consequence of direct local spread. Epidural abscesses arise from an adjacent focus of infection, such as sinusitis or osteomyelitis. When abscesses occur in the spinal epidural space, they may cause spinal cord compression and constitute a neurosurgical emergency. Infections of the skull or air sinuses may also spread to the subdural space, producing subdural empyema. The underlying arachnoid and subarachnoid spaces usually are unaffected, but a large subdural empyema may produce a mass effect. In addition, thrombophlebitis may develop in the bridging veins that cross the subdural space, resulting in venous occlusion and infarction of the brain. Most patients are febrile, with headache and neck stiffness, and if untreated may develop focal neurologic signs referable to the site of the infection, lethargy, and coma. With treatment, including surgical drainage, resolution of the empyema


Pathology_Robbins

Pathology_Robbins. neck stiffness, and if untreated may develop focal neurologic signs referable to the site of the infection, lethargy, and coma. With treatment, including surgical drainage, resolution of the empyema occurs from the dural side; if resolution is complete, a thickened dura may be the only residual finding. With prompt treatment, complete recovery is usual.


Pathology_Robbins

Pathology_Robbins. Meningitis is an inflammatory process involving the leptomeninges within the subarachnoid space; if the infection spreads into the underlying brain, it is termed meningoencephalitis. These terms are also used in non-infectious settings such as chemical meningitis, a response to a nonbacterial irritant such as debris from a ruptured epidermoid cyst, and carcinomatous meningitis, the spread of metastatic cancer cells to the subarachnoid space. Infectious meningitis can be broadly divided into acute pyogenic (usually bacterial), aseptic (usually viral), and chronic (usually tuberculous, spirochetal, or fungal) subtypes. Examination of the CSF is often useful in distinguishing among the various causes of meningitis. http://ebooksmedicine.net EmpyemaPolymicrobial(staphylococci,anaerobicgram-negative) Rickettsia, Spirochetes, and Fungi


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net EmpyemaPolymicrobial(staphylococci,anaerobicgram-negative) Rickettsia, Spirochetes, and Fungi The most likely causes of bacterial meningitis vary with patient age. In neonates, common organisms are Escherichia coli and group B streptococci. In adolescents and young adults, Neisseria meningitidis is the most common pathogen; in older adults, Streptococcus pneumoniae and Listeria monocytogenes are more common. Across ages, patients typically show systemic signs of infection along with meningeal irritation and neurologic impairment, including headache, photophobia, irritability, clouding of consciousness, and neck stiffness. Lumbar puncture reveals an increased pressure; examination of the CSF shows abundant neutrophils, elevated protein, and reduced glucose. Untreated pyogenic meningitis is often fatal, but with prompt diagnosis and administration of antibiotics, most patients can be saved.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Aseptic meningitis is a clinical term for acute illness with meningeal signs and symptoms that is believed to be of viral origin. The clinical course is less fulminant than in pyogenic meningitis and is typically self-limiting. In contrast to pyogenic meningitis, examination of the CSF often shows lymphocytosis, moderate protein elevation, and a normal glucose level, but bacteria cannot be cultured. While an underlying viral agent is suspected, it is often difficult to identify the responsible virus by culture and serologic methods; application of nucleic acid sequencing has the potential to change our understanding of these cases. There are no distinctive macroscopic findings except for brain swelling, which may be seen in only some instances. On microscopic examination, there is either no recognizable abnormality or a mild to moderate leptomeningeal lymphocytic infiltrate.


Pathology_Robbins

Pathology_Robbins. Several pathogens, including mycobacteria, some spirochetes, and fungi, cause a chronic meningitis; infections with these organisms also may involve the brain parenchyma. Tuberculous meningitis usually manifests with generalized signs and symptoms of headache, malaise, mental confusion, and vomiting. There is only a moderate increase in CSF cellularity, with mononuclear cells or a mixture of polymorphonuclear and mononuclear cells; the protein level is elevated, often strikingly so, and the glucose content typically is moderately reduced or normal. Infection with Mycobacterium tuberculosis also may result in a well-circumscribed intraparenchymal mass (tuberculoma), which may be associated with meningitis. Chronic tuberculous meningitis leads to arachnoid fibrosis and hydrocephalus from interference with resorption of CSF. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 23.16 Bacterialinfections.(A)Pyogenicmeningitis.Athicklayerofsuppurativeexudatecoversthebrainstemandcerebellumandthickenstheleptomeninges.(B)Cerebralabscessesinthefrontallobewhitematter (arrows). (A, From Golden JA, Louis DN: Images in clinical medicine: acute bacterial meningitis. NEnglJMed333:364, 1994. Copyright © 1994 Massachusetts Medical Society. All rights reserved.) Neurosyphilis, a tertiary stage of syphilis, occurs in about 10% of individuals with untreated Treponema pallidum infection. Infection with HIV increases the risk for developing neurosyphilis, and the disease is often more aggressive in this setting. There are several patterns of CNS involvement by syphilis, which may be present alone or in combination. • Meningovascular neurosyphilis is a chronic meningitis, usually involving the base of the brain, often with an obliterative endarteritis rich in plasma cells and lymphocytes.


Pathology_Robbins

Pathology_Robbins. • Meningovascular neurosyphilis is a chronic meningitis, usually involving the base of the brain, often with an obliterative endarteritis rich in plasma cells and lymphocytes. Paretic neurosyphilis stems from parenchymal involvement by spirochetes and is associated with neuronal loss and marked proliferation of microglial cells. Clinically, this form of the disease causes an insidious progressive loss of mental and physical functions, mood alterations (including delusions of grandeur), and eventually severe dementia. Tabes dorsalis results from damage to the sensory nerves in the dorsal roots. Consequences include impaired joint position sense and ataxia; loss of pain sensation, leading to skin and joint damage (Charcot joints); other sensory disturbances, particularly characteristic “lightning pains”; and the absence of deep tendon reflexes.


Pathology_Robbins

Pathology_Robbins. Neuroborreliosis refers to involvement of the nervous system by the spirochete Borrelia burgdorferi, the causative agent of Lyme disease. Neurologic signs and symptoms are highly variable and include aseptic meningitis, facial nerve palsies, mild encephalopathy, and polyneuropathies. Fungal infection of the nervous system can give rise to chronic meningitis and, as with other pathogens, this can be associated at times with parenchymal infection. Immunosuppression increases the risk for these diseases, but it is not a requirement for infection to occur. Several fungal pathogens cause CNS disease:


Pathology_Robbins

Pathology_Robbins. Cryptococcus neoformans can cause both meningitis and meningoencephalitis, often in the setting of immunosuppression. It may be fulminant and fatal in as little as 2 weeks or may be indolent, evolving over months or years. The CSF may have few cells but elevated protein, and the mucoid encapsulated yeasts can be visualized on India ink preparations. Extension into the brain follows vessels in the Virchow-Robin spaces. As organisms proliferate, these spaces expand, giving rise to a “soap bubble”–like appearance ( Fig. 23.17 Histoplasma capsulatum commonly involves the nervous system in the setting of disseminated infection. There is an increased risk for disease in the setting of HIV infection. Histoplasmosis typically causes a basilar meningitis, with elevated CSF protein, mildly decreased glucose, and mild lymphocytic pleocytosis. Parenchymal lesions can occur, mostly from tracking of organisms along Virchow-Robin spaces.


Pathology_Robbins

Pathology_Robbins. Coccidioides immitis, a fungus endemic to desert regions of the American Southwest, most commonly causes meningitis in the setting of disseminated infection. Diagnosis can be made by examining the CSF for specific antibody. Without treatment, coccidioidal meningitis has a high fatality. The entire gamut of infectious pathogens (viruses to parasites) can infect the brain, often in characteristic patterns. In general, viral infections are diffuse, bacterial infections (when not associated with meningitis) are localized, while other organisms produce mixed patterns. In immunosuppressed hosts, more widespread involvement with any agent is typical. http://ebooksmedicine.net Fig. 23.17 Cryptococcalinfection.(A)Whole-brainsectionshowingthenumerousareasoftissuedestructionassociatedwiththespreadoforganismsintheperivascularspaces.(B)Athighermagnification,itispossibletoseethecryptococciinthelesions.


Pathology_Robbins

Pathology_Robbins. Brain abscesses are most often caused by bacterial infections. These can 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 distal bones, or after tooth extraction). Predisposing conditions include acute bacterial endocarditis, from which septic emboli are released that may produce multiple abscesses; cyanotic congenital heart disease, associated with a right-to-left shunt and loss of pulmonary filtration of organisms; and chronic pulmonary infections, as in bronchiectasis, which provide a source of microbes that spread hematogenously. Abscesses are discrete destructive lesions with central liquefactive necrosis surrounded by a rim of vascularized granulation and fibrous tissue (see


Pathology_Robbins

Pathology_Robbins. Fig. 23.16B ). Outside the fibrous capsule is a zone of reactive gliosis. Patients almost invariably present with progressive focal deficits as well as general signs related to increased intracranial pressure. While CSF white blood cell count and protein may be elevated, lumbar puncture has little role in the diagnosis of brain abscess since organisms are more reliably cultured by draining the abscess directly. In addition, if there is significant mass effect from the abscess, the decrease in lumbar CSF pressure following lumbar puncture can result in downward herniation of cerebral contents and neurologic deterioration. A systemic or local source of infection may or may not be apparent. The increased intracranial pressure may cause fatal brain herniation, and abscess rupture can lead to ventriculitis, meningitis, and venous sinus thrombosis. Surgery and antibiotics reduce the otherwise high mortality rate, with earlier intervention leading to better outcomes.


Pathology_Robbins

Pathology_Robbins. Viral encephalitis is a parenchymal infection of the brain that is almost invariably associated with meningeal inflammation (meningoencephalitis). While different viruses show varying patterns of injury, the most characteristic histologic features are perivascular and parenchymal mononuclear cell infiltrates, microglial nodules, and neuronophagia ( Fig. 23.18A–B ). Certain viruses also form characteristic inclusion bodies.


Pathology_Robbins

Pathology_Robbins. Fig. 23.18A–B ). Certain viruses also form characteristic inclusion bodies. The nervous system is particularly susceptible to certain viruses such as rabies virus and poliovirus. Some viruses infect specific CNS cell types, while others preferentially involve particular brain regions (such as the medial temporal lobes, or the limbic system) that lie along the viral route of entry. Intrauterine viral infection following transplacental spread of rubella and CMV may cause destructive lesions, and Zika virus causes developmental abnormalities of the brain. In addition to direct infection of the nervous system, the CNS also can be injured by immune mechanisms after systemic viral infections.


Pathology_Robbins

Pathology_Robbins. Arboviruses (arthropod-borne viruses) are an important cause of epidemic encephalitis, especially in tropical regions of the world, and are capable of causing serious morbidity and high mortality. Among the more commonly encountered types are Eastern and Western equine encephalitis and West Nile virus infection. Patients develop generalized neurologic symptoms, such as seizures, confusion, delirium, and stupor or coma, as well as focal signs, such as reflex asymmetry and ocular palsies. The CSF usually is colorless but with a slightly elevated pressure and an early neutrophilic pleocytosis that rapidly converts to a lymphocytosis; the protein concentration is elevated, but the glucose is normal. Thus, CSF examination helps to distinguish viral from bacterial infections of the CNS. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 23.18 Viralinfections.(AandB)Characteristicfindingsinmanyformsofviralmeningitisincludeperivascularcuffingoflymphocytes(A)andmicroglialnodules(B).(C)Herpesencephalitisshowingextensivedestructionofinferiorfrontalandanteriortemporallobes.(D)Humanimmunodeficiencyvirus(HIV)encephalitis.Notetheaccumulationofmicrogliaformingamicroglialnoduleandmultinucleategiantcell.(C, Courtesy of Dr.T.W. Smith, University of Massachusetts Medical School,Worcester, Massachusetts.) MORPHOLOGYArbovirusencephalitidesproduceasimilarhistopathologicpicture.Characteristically,thereisaperivascularlymphocyticmeningoencephalitis(sometimeswithneutrophils)(see Fig. 23.18A ).Multifocalgraymatterandwhitematternecrosisisseen,oftenassociatedwithneuronophagia,thephagocytosisofneuronaldebris,aswellaslocalizedcollectionsofmicrogliatermedmicroglial nodules (see Fig.23.18B ).Inseverecases,theremaybeanecrotizingvasculitiswithassociatedfocalhemorrhages.


Pathology_Robbins

Pathology_Robbins. Fig.23.18B ).Inseverecases,theremaybeanecrotizingvasculitiswithassociatedfocalhemorrhages. HSV-1 encephalitis may occur in any age group but is most common in children and young adults. It typically manifests with alterations in mood, memory, and behavior, reflecting involvement of the frontal and temporal lobes. Recurrent HSV-1 encephalitis is sometimes associated with inherited mutations that interfere with Toll-like receptor signaling (specifically that of TLR-3), which has an important role in anti-viral defense. Fig.23.18C ).Theinfectionisnecrotizingandoftenhemorrhagicinseverelyaffectedregions.Perivascularinflammatoryinfiltratesusuallyarepresent,andlargeeosinophilicintranuclearviralinclusions(CowdrytypeAbodies)canbefoundinbothneuronsandglialcells. HSV-2 also affects the nervous system, usually in the form of meningitis in adults. Disseminated severe encephalitis occurs in many neonates born by vaginal delivery to women with active primary HSV genital infections.


Pathology_Robbins

Pathology_Robbins. Varicella-zoster virus (VZV) causes chickenpox during primary infection, usually without any evidence of neurologic involvement. The virus establishes latent infection in neurons of dorsal root ganglia. Reactivation in adults manifests as a painful, vesicular skin eruption in the distribution of one or a few dermatomes (shingles). This usually is a self-limited process, but there may be a persistent pain syndrome in the affected region (postherpetic neuralgia). http://ebooksmedicine.net VZV also may cause a granulomatous arteritis that can lead to tissue infarcts. In immunosuppressed patients, acute herpes zoster encephalitis can occur. Inclusion bodies can be found in glial cells and neurons.


Pathology_Robbins

Pathology_Robbins. CMV infects the nervous system in fetuses and immunosuppressed individuals. All cells within the CNS (neurons, glial cells, ependyma, and endothelium) are susceptible to infection. Intrauterine infection causes periventricular necrosis, followed later by microcephaly with periventricular calcification. When adults are infected, CMV produces a subacute encephalitis, which is also often most severe in the periventricular region. Lesions can be hemorrhagic and contain typical viral inclusion–bearing cells.


Pathology_Robbins

Pathology_Robbins. Poliovirus is an enterovirus that most often causes a sub-clinical or mild gastroenteritis; in a small fraction of cases, it secondarily invades the nervous system and damages motor neurons in the spinal cord and brain stem (paralytic poliomyelitis). The loss of motor neurons results in a flaccid paralysis with muscle wasting and hyporeflexia in the corresponding region of the body. In the acute disease, death can occur from paralysis of respiratory muscles. Long after the infection has resolved, typically 25 to 35 years after the initial illness, a poorly understood post-polio syndromeof progressive weakness associated with decreased muscle bulk and pain may appear. The re-emergent weakness has the same distribution as the prior polio infection.


Pathology_Robbins

Pathology_Robbins. Rabies is a fatal encephalitic infection transmitted to humans from rabid animals, usually by a bite. Various mammals are natural reservoirs. Exposure to some bat species, even without evidence of a bite, is also a risk factor. The virus enters the CNS by ascending along the peripheral nerves from the wound site, so the incubation period (usually a few months) depends on the distance between the wound and the brain. The disease manifests initially with nonspecific symptoms of malaise, headache, and fever. As the infection advances, the patient shows extraordinary CNS excitability; the slightest touch is painful, with violent motor responses progressing to convulsions. Contracture of the pharyngeal musculature may create an aversion to swallowing even water (hydrophobia). Periods of mania and stupor progress to coma and eventually death, typically from respiratory failure.


Pathology_Robbins

Pathology_Robbins. In the first 15 years or so after recognition of AIDS, neuropathologic changes were demonstrated at postmortem examination in as many as 80% to 90% of cases, owing to direct effects of the virus on the nervous system (HIV encephalitis), along with opportunistic infections and primary CNS lymphoma. Introduction of highly active antiretroviral therapy (HAART) has decreased the frequency of these secondary effects of HIV infection. However, cognitive dysfunction ranging from mild to full-blown dementia that is lumped under the umbrella term HIV-associated neurocognitive disorder (HAND) continues to be a source of morbidity. This syndrome is believed to stem from HIV infection of microglial cells in the brain and activation of innate immune responses. Neuronal injury likely stems from a combination of cytokine-induced inflammation and toxic effects of HIV-derived proteins.


Pathology_Robbins

Pathology_Robbins. Aseptic meningitis occurs within 1 to 2 weeks of onset of primary HIV infection in about 10% of patients; antibodies to HIV can be demonstrated, and the virus can be isolated from the CSF. The few neuropathologic studies of the early and acute phases of symptomatic or asymptomatic HIV invasion of the nervous system have shown mild lymphocytic meningitis, perivascular inflammation, and some myelin loss in the hemispheres.


Pathology_Robbins

Pathology_Robbins. When effective anti-HIV therapy is begun in the setting of established infection, there is a risk for neurologic involvement associated with the immune reconstitution inflammatory syndrome (IRIS). Neurologic manifestations include rapidly developing cognitive impairment and cerebral edema. The pathogenesis of IRIS is unclear but it is thought to be due to the activation of a previously suppressed inflammatory response brought about by effective treatment of HIV infection. IRIS is often associated with the presence of a mycobacterial, fungal or viral opportunistic CNS infection, although it can also occur in the absence of any other inciting disease. MORPHOLOGYHIVencephalitisisachronicinflammatoryprocesswithwidelydistributedmicroglial nodules, sometimeswithassociatedfocioftissuenecrosisandreactivegliosis(see


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. UnlikeHIVencephalitis,thebrainlesionsofIRISmaybeassociatedwithaCD8+ Tcellinfiltrate,botharoundbloodvesselsanddiffuselyintheparenchyma,intheabsenceofsignificantHIVburdenormultinucleatedcells. Progressive multifocal leukoencephalopathy (PML) is caused by JC virus, a polyomavirus, which preferentially infects oligodendrocytes, resulting in demyelination as these cells are injured and then die. Most people show serologic evidence of exposure to JC virus during childhood, and it is believed that PML results from virus reactivation, as the disease is restricted to immunosuppressed individuals. Patients develop focal and relentlessly progressive neurologic signs and symptoms, and imaging studies show extensive, often multifocal lesions in the hemispheric or cerebellar white matter. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 23.19 Progressivemultifocalleukoencephalopathy.(A)Sectionstainedformyelinshowingirregular,poorlydefinedareasofdemyelination,whichbecomeconfluentinplaces.(B)Enlargedoligodendrocytenucleistainedforviralantigenssurroundanareaofearlymyelinloss. MORPHOLOGYThelesionsarepatchy,irregular,ill-definedareasofwhitematterdestructionthatenlargeasthediseaseprogresses( Fig.23.19 ).Eachlesionisanareaofdemyelination,inthecenterofwhicharescatteredlipid-ladenmacrophagesandareducednumberofaxons.Attheedgesofthelesionaregreatlyenlargedoligodendrocytenucleiwhosechromatinisreplacedbyglassy-appearingamphophilicviralinclusions.Thevirusalsoinfectsastrocytes,leadingtobizarregiantformswithirregular,hyperchromatic,sometimesmultiplenucleithatcanbemistakenforatumor. Fungal infections usually produce parenchymal granulomas or abscesses, often associated with meningitis. The most common fungal infections have the following distinctive patterns:


Pathology_Robbins

Pathology_Robbins. Fungal infections usually produce parenchymal granulomas or abscesses, often associated with meningitis. The most common fungal infections have the following distinctive patterns: Candida albicans usually produces multiple microabscesses, with or without granuloma formation. Mucormycosis, caused by several fungi belonging to the order Mucorales, typically presents as an infection of the nasal cavity or sinuses in a diabetic patient with ketoacidosis. It may spread to the brain through vascular invasion or by direct extension through the cribriform plate. The proclivity of Mucor to invade the brain directly sets it apart from other fungi, which reach the brain by hematogenous dissemination from distant sites. • Aspergillus fumigatus tends to cause a distinctive pattern of widespread septic hemorrhagic infarctions because of its marked predilection for blood vessel wall invasion with subsequent thrombosis.


Pathology_Robbins

Pathology_Robbins. While a wide range of other organisms can infect the nervous system and its covering, only three relatively common entities are considered here. Cerebral infection with the protozoan Toxoplasma gondii can occur in immunosuppressed adults or in newborns who acquire the organism transplacentally from a mother with an active infection. The consequences include the triad of chorioretinitis, hydrocephalus, and intracranial calcifications. In adults, the clinical symptoms are subacute, evolving over weeks, and may be both focal and diffuse. Due to inflammation and breakdown of the blood-brain barrier at sites of infection, imaging studies often show edema associated with ring-enhancing lesions.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYWhentheinfectionisacquiredinimmunosuppressedadults,thebrainshowsabscesses,frequentlymultiple,mostofteninvolvingthecerebralcortex(nearthegray-whitejunction)anddeepgraynuclei.Acutelesionsconsistofcentralfociofnecrosissurroundedbyacuteandchronicinflammation,macrophageinfiltration,andvascularproliferation.Bothfreetachyzoitesandencystedbradyzoitesmaybefoundattheperipheryofthenecroticfoci( Fig.23.20 Cysticercosis is the consequence of an end-stage infection by the tapeworm Tenia solium. If ingested larval organisms leave the lumen of the gastrointestinal tract, where they would otherwise develop into mature tapeworms, they encyst. Cysts can be found throughout the body and are common within the brain and subarachnoid space. Cysticercosis typically manifests as a mass lesion and can cause seizures. Symptoms can intensify when the encysted organism dies, as occurs after therapy.


Pathology_Robbins

Pathology_Robbins. The organism is found within a cyst with a smooth lining. The body wall and hooklets from mouth parts are most commonly recognized. Death of the encysted organism may produce an intense inflammatory reaction in the surrounding brain, often including eosinophils, and marked gliosis. Amebic meningoencephalitis manifests with different clinical syndromes, depending on the responsible pathogen. Naegleria fowleri, associated with swimming in stagnant warm fresh water ponds, causes a rapidly fatal necrotizing encephalitis. By contrast, various species of Acanthamoeba cause a chronic granulomatous meningoencephalitis. http://ebooksmedicine.net Fig. 23.20 Toxoplasmainfection.(A)Abscessesarepresentintheputamenandthalamus.(B)Freetachyzoitesaredemonstratedbyimmunohistochemicalstaining.Inset, Bradyzoitesarepresentasapseudocyst,againhighlightedbyimmunohistochemicalstaining.


Pathology_Robbins

Pathology_Robbins. Prion diseases are a group of infectious diseases in which the causative agent is an abnormal form of a cellular protein. These include sporadic, familial, iatrogenic, and variant forms of Creutzfeldt-Jakob disease (CJD), as well as animal diseases such as scrapie in sheep and bovine spongiform encephalopathy in cattle (“mad cow disease”). The causative protein, termed prion protein (PrP), may undergo a conformational change from its normal shape (PrPc) to an abnormal conformation called PrPsc (sc for scrapie). PrP normally is rich in α-helices, but PrPsc has a high content of β-sheets, a characteristic that makes it resistant to proteolysis (hence an alternative term for the pathogenic form, PrPres—i.e., protease-resistant). More important, when PrPsc physically interacts with PrP molecules, it induces them to adopt the PrPsc conformation (


Pathology_Robbins

Pathology_Robbins. Fig. 23.21 ), a property that accounts for the “infectious” nature of PrPsc. Over time, this self-amplifying process leads to the accumulation of a high burden of pathogenic PrPsc molecules in the brain. Certain mutations in the gene encoding PrPc (PRNP) accelerate the rate of spontaneous conformational change; these variants are associated with early-onset familial forms of prion disease (familial Creutzfeldt-Jakob disease [fCJD]). PrPc also may change its conformation spontaneously (but at an extremely low rate), accounting for sporadic cases of prion disease (sporadic Creutzfeldt-Jakob disease [sCJD]). Accumulation of PrPsc in neural tissue seems to be the cause of cell injury, but the mechanisms underlying the cytopathic changes and eventual neuronal death are still unknown.


Pathology_Robbins

Pathology_Robbins. CJD is a rapidly progressive dementing illness, with a typical duration from first onset of subtle changes in memory and behavior to death in only 7 months. It is sporadic in approximately 85% of cases and has a worldwide annual incidence of about 1 per million. While commonly Fig. 23.21 Pathogenesisofpriondisease.α-HelicalPrPcmayspontaneouslyshifttotheβ-sheetPrPscconformation,aneventthatoccursatamuchhigherrateinfamilialdiseaseassociatedwithgermlinePrPmutations.PrPscmayalsobefromexogenoussources,suchascontaminatedfood,medicalinstrumentation,ormedicines.Oncepresent,PrPscconvertsadditionalmoleculesofPrPcintoPrPscthroughphysicalinteraction,eventuallyleadingtotheformationofpathogenicPrPscaggregates.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net affecting individuals older than 70 years of age, familial forms caused by mutations in PRNP may present in younger individuals. In keeping with the infectious nature of PrPsc, there are well-established cases of iatrogenic transmission by contaminated deep implantation electrodes and human growth hormone preparations. MORPHOLOGYTheprogressiontodeathinCJDusuallyissorapidthatthereislittle,ifany,macroscopicevidenceofbrainatrophy.Onmicroscopicexamination,thepathognomonicfindingisaspongiform transformation of the cerebral cortex and deep gray matter structures (caudate,putamen);thismultifocalprocessresultsintheunevenformationofsmall,apparentlyempty,microscopicvacuolesofvaryingsizeswithintheneuropil(theeosinophilicregionsingreymatterthatcontaindendrites,axons,andsynapses)andsometimesintheperikaryonofneurons( Fig.


Pathology_Robbins

Pathology_Robbins. Starting in 1995, cases of a CJD-like illness appeared in the United Kingdom. The neuropathologic findings and molecular features of these new cases were similar to those of CJD, suggesting a close relationship between the two illnesses, yet this new disorder differed from typical CJD in several important respects: the disease affected young adults; behavioral disorders figured prominently in early disease stages; and the neurologic syndrome progressed somewhat more slowly than typical CJD. Multiple lines of evidence indicate that this new disease, termed variant Creutzfeldt-Jakob disease (vCJD) is a consequence of exposure to the prion disease of cattle, called bovine spongiform encephalopathy. Also, there is now documentation of transmission by blood transfusion. This variant form has a similar pathologic appearance to that in other types of CJD, with spongiform change and absence of inflammation. In vCJD, however, there are abundant cortical amyloid plaques, surrounded by the


Pathology_Robbins

Pathology_Robbins. has a similar pathologic appearance to that in other types of CJD, with spongiform change and absence of inflammation. In vCJD, however, there are abundant cortical amyloid plaques, surrounded by the spongiform change (see


Pathology_Robbins

Pathology_Robbins. Within the CNS, axons are tightly ensheathed by myelin, an electrical insulator that allows rapid propagation of neural impulses. Myelin consists of multiple layers of highly specialized, closely apposed plasma membranes that are assembled by oligodendrocytes. Although myelinated axons are present in all areas of the brain, they are the dominant component in the white matter; therefore, most diseases of myelin are primarily white matter disorders. The myelin in peripheral nerves is similar to the myelin in the CNS, but with several important differences: (1) peripheral myelin is made by Schwann cells, not oligodendrocytes; (2) each Schwann cell in a peripheral nerve provides myelin for only one internode, while in the CNS, many internodes are created by processes coming from a single oligodendrocyte; and (3) the specialized proteins and lipids are also different. Most diseases of CNS myelin do not involve the peripheral nerves to any significant extent, and vice versa.


Pathology_Robbins

Pathology_Robbins. Fig. 23.22 Priondisease.(A)HistologicfeaturesofCreutzfeldt-Jakobdisease(CJD)includespongiformchangeinthecerebralcortex.Inset, Highmagnificationofaneuronwithvacuoles.(B)VariantCJD(vCJD)ischaracterizedbyamyloidplaques(inset) thatsitintheregionsofgreatestspongiformchange. http://ebooksmedicine.net In general, CNS diseases involving myelin are separated into two broad groups. Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to previously normal myelin. The most common diseases in this group result from immune-mediated injury, such as multiple sclerosis (MS) and related disorders. Other processes that can cause this type of disease include viral infection of oligodendrocytes, as in progressive multifocal leukoencephalopathy (see earlier), and injury caused by drugs and other toxic agents.


Pathology_Robbins

Pathology_Robbins. By contrast, in other diseases, myelin is not formed properly or has abnormal turnover kinetics. As would be expected, most of these are caused by mutations that disrupt the function of proteins required for the formation of normal myelin sheaths. These diseases are grouped under leukodystrophy or dysmyelinating diseases. MS is an autoimmune demyelinating disorder characterized by episodes of disease activity, separated in time, that produce white matter lesions that are separated in space. It is the most common demyelinating disorder, having a prevalence of approximately 1 per 1000 individuals in the United States and Europe, and its incidence appears to be increasing. The disease may present at any age, but onset in childhood or after 50 years of age is rare. Women are affected twice as often as men.


Pathology_Robbins

Pathology_Robbins. The lesions of MS are caused by an autoimmune response directed against components of the myelin sheath. As in other autoimmune diseases (Chapter 5), the development of MS is related to genetic susceptibility and largely undefined environmental triggers. The incidence of MS is 15-fold higher when the disease is present in a first-degree relative and roughly 150-fold higher with an affected monozygotic twin. Only a portion of the genetic basis of the disease has been explained, and many of the identified loci are associated with other autoimmune diseases. There is a strong effect of the major histocompatibility complex; each copy of the HLA-DRB1*1501 allele an individual inherits brings with it a roughly 3-fold increase in the risk for MS. Other genetic loci that are associated with MS include the IL-2 and IL-7 receptor genes and other genes encoding proteins involved in immune responses.


Pathology_Robbins

Pathology_Robbins. Immune mechanisms that underlie the destruction of myelin are the focus of much investigation. The available evidence indicates that the disease is initiated by TH1 and TH17 T cells that react against myelin antigens and secrete cytokines. Experimental autoimmune encephalomyelitis, an animal model of MS in which demyelination and inflammation occur after immunization of animals with myelin proteins, can be passively transferred to unimmunized animals with TH1 and TH17 cells that recognize myelin antigens. TH1 cells secrete IFN-γ, which activates macrophages, and TH17 cells promote the recruitment of leukocytes. The demyelination is caused by activated leukocytes and their injurious products. The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages. B lymphocytes and antibodies also play an important, but poorly defined, role in the disease, as indicated by the surprising success of B cell depleting therapies.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. The course of MS is variable, but commonly there are multiple relapses followed by episodes of remission; typically, recovery during remissions is not complete. As a consequence, over time there is usually a gradual, often stepwise, accumulation of neurologic deficits. Imaging studies have demonstrated that there are often more lesions in the brains of patients with MS than might be expected from the clinical examination, and that lesions can come and go much more often than was previously suspected. Changes in cognitive function can be present, but are often much milder than the other deficits. In any individual patient, it is difficult to predict when the next relapse will occur; most current treatments, which are intended to control the immune response, aim at decreasing the rate and severity of relapses rather than recovering lost function.


Pathology_Robbins

Pathology_Robbins. The CSF in patients with MS shows a mildly elevated protein level with an increased proportion of immunoglobulin; in one-third of cases, there is moderate pleocytosis. When the immunoglobulin is examined further, oligoclonal bands usually are identified. These antibodies are directed against a variety of antigenic targets and can be used as markers of disease activity. The contribution of these antibodies to the disease process is unclear. Immune-mediated demyelination can occur after a number of systemic infectious illnesses, including http://ebooksmedicine.net Fig. 23.23 Multiplesclerosis(MS).(A)Sectionoffreshbrainshowingaplaquearoundoccipitalhornofthelateralventricle.(B)Unstainedregionsofdemyelination(MSplaques)aroundthefourthventricle.Luxolfastblue–periodicacid–Schiffstainformyelin.


Pathology_Robbins

Pathology_Robbins. relatively mild viral diseases. These are not thought to be related to direct spread of the infectious agents to the nervous system. Rather, it is believed that immune cells responding to pathogen-associated antigens cross-react against myelin antigens, resulting in myelin damage. There are two general patterns of postinfectious autoimmune reactions to myelin; unlike MS, they both are associated with acute-onset monophasic illnesses. In acute disseminated encephalomyelitis, symptoms typically develop 1 or 2 weeks after an antecedent infection and are nonlocalizing (headache, lethargy, and coma), in contrast with the focal findings of MS. Symptoms progress rapidly, and the illness is fatal in as many as 20% of cases; in the remaining patients, there is complete recovery. Acute necrotizing hemorrhagic encephalomyelitis is a more devastating related disorder, which typically affects young adults and children.


Pathology_Robbins

Pathology_Robbins. Other acquired diseases of myelin include neuromyelitis optica (NMO), an antibody-mediated demyelinating disease centered on the optic nerves and spinal cord, and central pontine myelinolysis, caused by nonimmune damage to oligodendrocytes typically after sudden correction of hyponatremia, that may result in a rapidly evolving quadriplegia. As discussed earlier, progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that occurs after reactivation of the JC virus in immunosuppressed patients.


Pathology_Robbins

Pathology_Robbins. Leukodystrophies are inherited dysmyelinating diseases caused by abnormal myelin synthesis or turnover. They are caused by mutations of genes whose products are involved in the generation, turnover, or maintenance of myelin. Some of these mutations affect lysosomal enzymes, while others involve peroxisomal enzymes; a few are associated with mutations in myelin proteins. Most are of autosomal recessive inheritance, although X-linked diseases also occur. There is typically diffuse involvement of white matter leading to deterioration in motor skills, spasticity, hypotonia, or ataxia. Several clinical features separate leukodystrophies from demyelinating diseases. The leukodystrophies typically present with an insidious and progressive loss of function, often begin at younger ages, and are associated with diffuse and symmetric changes on imaging studies.


Pathology_Robbins

Pathology_Robbins. Other,lesscommonformsofimmune-mediateddemyelinationoftenfollowinfectionsandaremoreacuteillnesses. Leukodystrophiesaregeneticdisordersinwhichmyelinproductionorturnoverisabnormal. http://ebooksmedicine.net Several genetic diseases disrupt metabolic processes in neurons and glia, resulting in progressive disorders that present early in life. These diseases can be grouped by the cells or compartment affected (neurons vs. white matter), the subcellular organelle affected (e.g., lysosome, peroxisome, or mitochondrion), or the metabolic pathway affected (e.g., sphingolipidoses, very long–chain fatty acid metabolism). The mutations underlying these diseases typically affect synthetic or degradation pathways that are specific to the nervous system.


Pathology_Robbins

Pathology_Robbins. Neuronal storage diseases are characterized by the accumulation of storage material within neurons, typically leading to neuronal death. Cortical neuronal involvement leads to loss of cognitive function and may also cause seizures. Most commonly, they are autosomal recessive disorders caused by the deficiency of a specific enzyme involved in the catabolism of sphingolipids (including the gangliosides), mucopolysaccharides, or mucolipids; others appear to be caused by defects in protein or lipid trafficking within neurons. Several examples of these diseases, such as Tay-Sachs and Niemann-Pick diseases and mucopolysaccharidoses, are discussed in Chapter 7.


Pathology_Robbins

Pathology_Robbins. Mitochondrial encephalomyopathies are disorders of oxidative phosphorylation, often affecting multiple tissues including skeletal muscle (Chapter 22). When they involve the brain, gray matter is more severely affected than white matter, as would be expected because of the greater metabolic requirements of neurons. These disorders may be caused by mutations in the mitochondrial or the nuclear genomes. Toxic and acquired metabolic diseases are relatively common causes of neurologic illnesses. Because of its high metabolic demands, the brain is particularly vulnerable to nutritional diseases and alterations in metabolic state. Some of these disorders have uneven pathologic lesions and distinct clinical presentations because of unique features or requirements of different anatomic regions of the brain. A few of the more common types of injury are discussed here.


Pathology_Robbins

Pathology_Robbins. In addition to the systemic effects of thiamine deficiency (beriberi), it also may be associated with the abrupt onset of confusion, abnormalities in eye movement and ataxia, syndrome termed Wernicke encephalopathy. Treatment with thiamine reverses these deficits, but if treatment is delayed the result is a largely irreversible profound memory disturbance called Korsakoff syndrome. Because the two syndromes are closely linked, the term Wernicke-Korsakoff syndrome is often used. The syndrome is particularly common in the setting of chronic alcoholism but also may be encountered in patients with thiamine deficiency resulting from gastric disorders, gastric bypass surgery, or persistent vomiting.


Pathology_Robbins

Pathology_Robbins. In addition to causing anemia, deficiency of vitamin B12 may lead to neurologic deficits associated with changes in the spinal cord, resulting in a syndrome called subacute combined degeneration of the spinal cord. As the name implies, both ascending and descending tracts of the spinal cord are affected. Symptoms develop over weeks. Early clinical signs often include mild ataxia and lower-extremity numbness and tingling, which can progress to spastic weakness of the lower extremities; sometimes, complete paraplegia ensues. Prompt vitamin replacement therapy produces clinical improvement; however, if paraplegia has developed, recovery is poor. Several systemic metabolic derangements may produce CNS dysfunction; only those associated with abnormal glucose levels and liver dysfunction are considered here.


Pathology_Robbins

Pathology_Robbins. Several systemic metabolic derangements may produce CNS dysfunction; only those associated with abnormal glucose levels and liver dysfunction are considered here. Since the brain requires glucose as a substrate for energy production, the cellular effects of diminished glucose generally resemble those of global hypoxia. Hippocampal neurons are particularly susceptible to hypoglycemic injury, while cerebellar Purkinje cells are relatively spared. As with anoxia, if the level and duration of hypoglycemia are sufficiently severe, there may be widespread injury to many areas of the brain. Hyperglycemia is most common in the setting of inadequately controlled diabetes mellitus and can be associated with either ketoacidosis or hyperosmolar coma. Patients develop confusion, stupor, and eventually coma associated with intracellular dehydration caused by the hyperosmolar state. The hyperglycemia must be corrected gradually, because rapid correction can produce severe cerebral edema.


Pathology_Robbins

Pathology_Robbins. Decreased hepatic function may be associated with depressed levels of consciousness and sometimes coma. In the early stages, patients exhibit a characteristic “flapping” tremor (asterixis) when extending the arms with palms facing the observer. Elevated levels of ammonia, which the liver normally clears through the urea cycle, in combination with inflammation and hyponatremia, cause the changes in brain function. Because it is only one contributing factor, ammonia levels in symptomatic patients vary widely. Within the CNS, ammonia metabolism occurs only in astrocytes through the action of glutamine synthetase, and in the setting of hyperammonemia, astrocytes in the cortex and basal ganglia develop swollen, pale nuclei (referred to as Alzheimer type II cells). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The list of toxins with effects on the brain is extremely long. Among the major categories of neurotoxic substances are metals, including lead, arsenic, and mercury; industrial chemicals, including organophosphates (in pesticides) and methanol (causing blindness from retinal damage); and environmental pollutants such as carbon monoxide (combining hypoxia with selective injury to the globus pallidus). Ethanol has a variety of effects on the brain. While acute intoxication is reversible, excessive intake can result in profound metabolic disturbances, including brain swelling and death. Chronic alcohol exposure leads to cerebellar dysfunction in about 1% of cases, with truncal ataxia, unsteady gait, and nystagmus, associated with atrophy in the anterior vermis of the cerebellum.


Pathology_Robbins

Pathology_Robbins. Ionizing radiation, commonly used to treat intracranial tumors, can cause rapidly evolving signs and symptoms including headache, nausea, vomiting, and papilledema, even months to years after irradiation. Affected brain regions show large areas of coagulative necrosis, edema, and blood vessels with thickened walls containing intramural fibrin like material. Neurodegenerative diseases are characterized by the progressive loss of neurons, typically affecting groups of neurons with functional interconnections. Different diseases tend to involve particular neural systems and therefore have relatively stereotypic presenting signs and symptoms ( Table 23.3 Diseases that involve the hippocampus and associated cortices present with cognitive changes, often including disturbances of memory, behavior, and language. With time these progress to dementia, as occurs with Alzheimer disease.


Pathology_Robbins

Pathology_Robbins. Diseases that affect the basal ganglia manifest as movement disorders; these may be hypokinetic, as with Parkinson disease, or hyperkinetic, as with Huntington disease. Diseases that affect the cerebellum or its input and output circuitry result in ataxia, as seen in the spinocerebellar ataxias. When the motor system bears the burden, weakness and difficulty with swallowing and respiration are often seen first, as with amyotrophic lateral sclerosis. A pathologic process shared by most neurodegenerative diseases is the accumulation of protein aggregates, Table 23.3 Features of the Major Neurodegenerative Diseases which serve as histologic hallmarks of specific disorders


Pathology_Robbins

Pathology_Robbins. Table 23.3 Features of the Major Neurodegenerative Diseases which serve as histologic hallmarks of specific disorders Table 23.3 ). Aggregates may arise because of mutations that alter the protein’s conformation or that disrupt pathways involved in processing or clearance of the proteins. In other situations, there may be a subtle imbalance between protein synthesis and clearance (due to genetic, environmental, or stochastic factors) that allows gradual accumulation of proteins. The aggregates often are resistant to degradation by normal cellular proteases, accumulate within cells, elicit an inflammatory response, and may be directly toxic to neurons. As is evident from Table 23.3 , the same proteins may be present as aggregates in multiple diseases. The clinical phenotype of the neurodegenerative disease is determined more by the distribution of the aggregates than by the nature of the aggregating protein. Two other features are common to many neurodegenerative diseases:


Pathology_Robbins

Pathology_Robbins. Two other features are common to many neurodegenerative diseases: There is experimental evidence that many of the protein aggregates that accumulate in neurons affected in these diseases appear to be capable of spreading to healthy neurons. Thus, aggregates can seed the development of more aggregates, and the disease process can spread, like prions. However, there is no evidence for transmission from affected to healthy individuals. Activation of the innate immune system is a common feature of neurodegenerative diseases. The importance of this interaction between the brain and the immune system has been further strengthened by the identification of genes that confer risk for diseases (e.g., TREM2 for Alzheimer disease) that encode components of immune regulatory pathways.


Pathology_Robbins

Pathology_Robbins. Alzheimer disease (AD) is the most common cause of dementia in older adults, with an increasing incidence as http://ebooksmedicine.net a function of age. The incidence is about 3% in individuals 65 to 74 years of age, 19% in those 75 to 84 years of age, and 47% in those older than 84 years of age. Most cases of AD are sporadic, but at least 5% to 10% are familial. Sporadic cases rarely present before 50 years of age, but early onset is seen with some heritable forms. The disease usually manifests with the insidious onset of impaired higher intellectual function, memory impairment, and altered mood and behavior. Over time, disorientation and aphasia, findings indicative of severe cortical dysfunction, often develop; those in the final phases of AD are profoundly disabled, often mute and immobile. Death usually occurs from intercurrent pneumonia or other infections.


Pathology_Robbins

Pathology_Robbins. The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions, in the forms of plaques and tangles, respectively; these changes result in secondary effects including neuronal dysfunction, neuronal death, and inflammatory reactions. Plaques are deposits of aggregated Aβ peptides in the neuropil, while tangles are aggregates of the micro-tubule binding protein tau, which develop intracellularly and then persist extracellularly after neuronal death. Both plaques and tangles appear to contribute to neural dysfunction. The details of the interplay between the processes that lead to the accumulation of these abnormal aggregates are a critical aspect of AD pathogenesis that has yet to be unraveled.


Pathology_Robbins

Pathology_Robbins. Clinical and experimental evidence strongly suggests that Aβ generation is the critical initiating event for the development of AD. Notably, mutations or alterations in copy number of the gene encoding the precursor protein for Aβ are associated with an elevated risk of AD, whereas mutations in the gene for tau do not give rise to AD but rather cause frontotemporal lobar degenerations. Overexpression of Aβ can replicate the disease in animal models. The pathogenesis of AD involves Aβ and Tau deposits, as well as other risk factors and inflammatory reactions. • Role of Aβ. Aβ is created when the transmembrane protein amyloid precursor protein (APP) is sequentially cleaved by the enzymes β-amyloid–converting enzyme (BACE) and γ-secretase (


Pathology_Robbins

Pathology_Robbins. Fig. 23.24 ). APP also can be cleaved by α-secretase and γ-secretase, liberating a different peptide that is nonpathogenic. Mutations in APP or in components of γ-secretase (encoded by the presenilin-1 or presenilin-2 gene) lead to familial AD by increasing the rate at which Aβ, particularly its most aggregation-prone form, is generated. The APP gene is located on chromosome 21, and the risk for AD also is higher in those with an extra copy of the APP gene, such as patients with trisomy 21 (Down syndrome) and individuals with small interstitial duplications of APP, presumably because this too leads to greater Aβ generation. Once generated, Aβ is highly prone to aggregation; it first forms small oligomers, and these eventually propagate into large aggregates and fibrils. It is these aggregates that deposit in the brain and are visible as plaques. There is evidence that these oligomers decrease the number of synapses present and alter the function of those that remain so that the


Pathology_Robbins

Pathology_Robbins. aggregates that deposit in the brain and are visible as plaques. There is evidence that these oligomers decrease the number of synapses present and alter the function of those that remain so that the cellular processes felt to underlie learning and memory are disrupted.


Pathology_Robbins

Pathology_Robbins. Role of tau. Because neurofibrillary tangles contain the tau protein, there has been much interest in the role of this protein in AD. Tau is a microtubule-associated protein present in axons in association with the microtubular network. With the development of tangles in AD, tau shifts to a somatic-dendritic distribution, becomes hyperphosphorylated, and loses the ability to bind to microtubules. The formation of tangles is an important component of AD, but the mechanism of tangle injury to neurons remains poorly understood. Two pathways have been suggested; 1) aggregates of tau protein elicit a stress response, which persists and eventually leads to cell death; and 2), the microtubule stabilizing function of tau protein is lost, leading to neuronal toxicity and death. It has been shown that tau aggregates can be passed across synapses from one neuron to the next; this may underlie some of the spread of lesions across the brain.


Pathology_Robbins

Pathology_Robbins. Other genetic risk factors. The genetic locus on chromosome 19 that encodes apolipoprotein E (ApoE) has a strong influence on the risk for developing AD. Three alleles have been identified (ε2, ε3, and ε4) based on two amino acid polymorphisms. The dosage of the ε4 allele increases the risk for AD. This ApoE isoform promotes Aβ generation and deposition, although the mechanisms have not been established. Overall, this locus has been estimated to convey about one fourth of the risk for development of late-onset AD. Genome-wide association studies have identified multiple other loci that contribute to the risk for AD, but the roles of the encoded proteins in disease pathogenesis are not established.


Pathology_Robbins

Pathology_Robbins. Role of inflammation. Both genetic and histologic studies have indicated that the innate immune system responds to Aβ and tau. Deposits of Aβ elicit an inflammatory response from microglia and astrocytes. This response probably assists in the clearance of the aggregated peptide, but also may stimulate the secretion of mediators that cause neuronal injury over time. Basis for cognitive impairment. Deposits of Aβ and tangles begin to appear in the brain well in advance of cognitive impairment. While there remains disagreement regarding the best correlate of dementia in individuals with AD, the presence of a large burden of plaques and tangles is strongly associated with severe cognitive dysfunction. The number of neurofibrillary tangles correlates better with the degree of dementia than does the number of neuritic plaques. Biochemical markers that have been correlated with the degree of dementia include amyloid burden.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYBrainsinvolvedbyADshowavariabledegreeofcorticalatrophy,resultinginawideningofthecerebralsulcithatismostpronouncedinthefrontal,temporal,andparietallobes.Theatrophyproducesacompensatoryventricularenlargement(hydrocephalusexvacuo).Atthemicroscopiclevel,ADisdiagnosedbythepresenceofneuritic plaques (anextracellularlesion)andneurofibrillary tangles (anintracellularlesion)( Fig.23.25 http://ebooksmedicine.net Fig. 23.25 Alzheimer disease. (A) Plaques (arrow) contain a central core of amyloid and a surrounding region of dystrophic neurites (Bielschowsky stain). (B) Immunohistochemical stain for Aβ. Peptide is present in the core of the plaques as well as in the surrounding region. (C) Neurons containing tangles stained with an antibody specific for tau. Neuritic plaques arefocal,sphericalcollectionsofdilated,tortuous,processesderivedfromdystrophicneurites,oftenaroundacentralamyloidcore(see


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Frontotemporal lobar degeneration (FTLD) encompasses several disorders that preferentially affect the frontal and/ or temporal lobes. As a result, these disorders have certain shared clinical features, such as progressive deterioration of language and changes in personality. The term degeneration is applied to describe the neuropathologic changes; clinically, these syndromes commonly are referred to as frontotemporal dementias. Depending on the disease distribution (frontal or temporal), behavioral changes or language problems may dominate. In general, behavioral and language problems precede memory disturbances, a distinction that assists in the clinical discrimination between FTLD and AD. The onset of symptoms occurs at younger ages for FTLD than for AD.


Pathology_Robbins

Pathology_Robbins. In addition to the clinical classification, two pathologic subgroups exist that are distinguished based on the composition of characteristic neuronal inclusions, which may contain tau or TDP43. One well-recognized subtype of FTLD-tau is Pick disease, which is associated with smooth, round inclusions known as Pick bodies. How tau aggregation may lead to neurodegeneration was discussed earlier, in the context of Alzheimer disease. The other major form of FTLD is characterized by aggregates containing the DNA/RNA-binding protein TDP43 (FTLD-TDP43). It is uncertain how this leads to neurodegeneration; both loss of TDP43 activity and a toxic gain-of-function related to the protein aggregates remain possibilities. TDP43 neuronal inclusions also are found in a large proportion of cases of amyotrophic lateral sclerosis (ALS). This overlap is manifest clinically, as many individuals with ALS also show evidence of FTLD.


Pathology_Robbins

Pathology_Robbins. Fig.23.26C ).InFTLD-TDP,thereislossofnuclearstainingforTDP43associatedwiththeappearanceofTDP43-positiveinclusions(see Fig.23.26D Parkinson disease (PD) is a neurodegenerative disease marked by a hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra. Parkinsonism is a clinical syndrome characterized by tremor, rigidity, bradykinesia, and instability. These types of motor disturbances may be seen in a range of diseases that damage dopaminergic neurons, which project from the substantia nigra to the striatum and are involved in control of motor activity. Parkinson-ism can be induced by drugs such as dopamine antagonists or toxins that selectively injure dopaminergic neurons. Among the neurodegenerative diseases, most cases of parkinsonism are caused by PD, which is associated with characteristic neuronal inclusions containing α-synuclein.


Pathology_Robbins

Pathology_Robbins. PD is associated with protein accumulation and aggregation, mitochondrial abnormalities, and neuronal loss in the substantia nigra and elsewhere in the brain. Based on the genetics of PD, it appears that abnormal protein and organelle clearance due to defects in autophagy and lysosomal degradation have a pathogenic role in the disease. One clue and diagnostic feature of the disease is the Lewy body, a characteristic inclusion containing α-synuclein, a protein involved in synaptic transmission. While PD in most cases is sporadic, point mutations and duplications of the gene encoding α-synuclein cause autosomal dominant PD. Synuclein aggregates are cleared by autophagy (Chapter 2), and several mutations associated with PD are in genes whose products (LRRK2, Parkin, others) all appear to have roles in endosomal trafficking pathways implicated in autophagy. It also has been demonstrated that heterozygosity for the Gaucher disease–causing mutation in glucocerebrosidase is a risk factor for


Pathology_Robbins

Pathology_Robbins. roles in endosomal trafficking pathways implicated in autophagy. It also has been demonstrated that heterozygosity for the Gaucher disease–causing mutation in glucocerebrosidase is a risk factor for PD. Glucocerebrosidase is a lysosomal enzyme, yet another clue suggesting that abnormal turnover of cellular constituents somehow sets the stage for the development of PD.


Pathology_Robbins

Pathology_Robbins. Fig. 23.27 Parkinsondisease.(A)Normalsubstantianigra.(B)DepigmentedsubstantianigrainidiopathicParkinsondisease.(C)Lewybodyinaneuronfromthesubstantianigrastainspink. http://ebooksmedicine.net PD commonly manifests as a movement disorder in the absence of a toxic exposure or other known underlying etiology. The disease usually progresses over 10 to 15 years, eventually producing severe motor slowing to the point of near immobility. Death usually is the result of aspiration pneumonia or trauma from falls caused by postural instability.


Pathology_Robbins

Pathology_Robbins. Movement symptoms of PD initially respond to L-dihydroxyphenylalanine (L-DOPA), but this treatment does not slow disease progression. Over time, L-DOPA becomes less effective and begins to cause problematic fluctuations in motor function. Another treatment for the motor symptoms of PD is deep brain stimulation, in which electrodes are implanted in the globus pallidus or subthalamic nucleus to modulate basal ganglia circuitry, often allowing a significant reduction in L-DOPA dose.


Pathology_Robbins

Pathology_Robbins. While the movement disorder associated with loss of the nigrostriatal dopaminergic pathway is an important feature of PD, it is clear that the disease has more extensive clinical and pathologic manifestations. Lesions in the brain stem (in the dorsal motor nucleus of the vagus and in the reticular formation), in advance of nigral involvement, can give rise to behavioral sleep disorder often before the motor problems. Dementia, typically with a mildly fluctuating course and hallucinations, emerges in many individuals with PD and is attributable to involvement of the cerebral cortex. When dementia arises within 1 year of the onset of motor symptoms, it is referred to Lewy body dementia (LBD).


Pathology_Robbins

Pathology_Robbins. Huntington disease (HD) is an autosomal dominant movement disorder associated with degeneration of the striatum (caudate and putamen). The disorder is characterized by involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical. The disease is relentlessly progressive, resulting in death after an average course of about 15 years. Early cognitive symptoms include forgetfulness and thought and affective disorders, and there may be a progression to severe dementia. As a part of these early behavioral changes, HD carries an increased risk for suicide.


Pathology_Robbins

Pathology_Robbins. HD is caused by CAG trinucleotide repeat expansions in a gene located on 4p16.3 that encodes the protein huntingtin. Normal alleles contain 11 to 34 copies of the repeat; in disease-causing alleles, the number of repeats is increased, sometimes into the hundreds. There is a strong genotype-phenotype correlation, with larger numbers of repeats resulting in earlier-onset disease. Once the symptoms appear, however, the course of the illness is not affected by repeat length. Further expansions of the CAG (glutamine-encoding) repeats occur during spermatogenesis, so paternal transmission may be associated with earlier onset in the next generation, a phenomenon referred to as anticipation (Chapter 7). HD appears to be caused by a toxic gain-of-function related to the expanded polyglutamine tract in huntingtin.


Pathology_Robbins

Pathology_Robbins. HD appears to be caused by a toxic gain-of-function related to the expanded polyglutamine tract in huntingtin. The mutant protein is subject to ubiquitination and proteolysis, yielding fragments that can form large intra-nuclear aggregates. As in other degenerative diseases, smaller aggregates of the abnormal protein fragments are suspected to be toxic. These aggregates have been shown to have a range of potentially injurious actions, including sequestration of transcription factors, disruption of protein degradation pathways, and perturbation of mitochondrial function. It is likely that some combination of these aberrations contributes to HD pathogenesis. MORPHOLOGYOngrossexamination,thebrainissmallandshowsstrikingatrophyofthecaudatenucleusand,sometimeslessdramatically,theputamen( Fig.23.28 ).Theglobuspallidusmaybeatrophiedsecondarily,andthelateralandthirdventriclesaredilated.Atrophyfrequentlyalsoisseeninthefrontallobe,lessoftenintheparietallobe,andoccasionallyintheentirecortex.


Pathology_Robbins

Pathology_Robbins. Microscopicexaminationrevealsseverelossofneuronsfromaffectedregionsofthestriatumalongwithgliosis.Themedium-sized,spinyneuronsthatreleasetheneurotransmittersγ-aminobutyricacid(GABA),enkephalin,dynorphin,andsubstancePareespeciallysensitive,disappearingearlyinthedisease.Thereisastrongcorrelationbetweenthedegreeofdegenerationinthestriatumandtheseverityofmotorsymptoms;thereisalsoanassociationbetweencorticalneuronallossanddementia.Inremainingstriatalneuronsandinthecortex,thereareintranuclearinclusionsthatcontainaggregatesofubiquitinatedhuntingtinprotein(see Fig.23.28 ,inset). Spinocerebellar ataxias (SCAs) are a heterogeneous group of several dozen diseases with clinical findings that include a combination of cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy. They are distinguished from one another based on different


Pathology_Robbins

Pathology_Robbins. Fig. 23.28 Huntingtondisease.Normalhemisphere(left) comparedwithahemispherewithHuntingtondisease(right) showingatrophyofthestriatumandventriculardilation.Inset, Anintranuclearinclusioninacorticalneuronisstronglyimmunoreactiveforubiquitin.(Gross photo courtesy of Dr.Vonsattel, Columbia University, New York, New York.) http://ebooksmedicine.net causative mutations, patterns of inheritance, age at onset, and signs and symptoms. This group of diseases affects, to a variable extent, the cerebellar cortex, spinal cord, other brain regions, and peripheral nerves. Degeneration of neurons, often without other distinctive histopathologic changes, occurs in the affected areas and is associated with mild gliosis. The additional clinical symptoms that accompany the ataxia can help distinguish between well-characterized subtypes. Although many distinct genetic types of SCA have been identified, there remain many cases that do not fall into one of the already characterized forms.


Pathology_Robbins

Pathology_Robbins. As with HD, several forms of SCA are caused by CAG repeat expansions encoding polyglutamine tracts in various genes. In these forms of SCA, as is true for HD, neuronal intranuclear inclusions are present containing the abnormal protein, and there is an inverse correlation between the degree of repeat expansion and age of onset. Other SCAs are caused by repeat expansions in untranslated regions or by other types of mutations.