Nervous System Pathology

Question 1

What is the morphology of the patterns of injury in the nervous system

Answer 1

The cells of the nervous system respond to various forms of injury with distinct morphologic changes.

MORPHOLOGY
Features of Neuronal Injury. In response to injury, a number of changes occur in neurons and their processes (axons and dendrites). Within 12 hours of an irreversible hypoxic-ischemic insult, acute neuronal injury becomes evident on routine hematoxylin and eosin (H&E) staining (Fig. 22–1, A). There is shrinkage of the cell body, pyknosis of the nucleus, disappearance of the nucleolus, and loss of Nissl substance, with intense eosinophilia of the cytoplasm (“red neurons”). Often, the nucleus assumes the angulated shape of the shrunken cell body. Injured axons undergo swelling and show disruption of axonal transport. The swellings (spher- oids) can be recognized on H&E stains (Fig. 22–1, B) and can be highlighted by silver staining or immunohistochemistry. Axonal injury also leads to cell body enlargement and round- ing, peripheral displacement of the nucleus, enlargement of the nucleolus, and peripheral dispersion of Nissl substance (central chromatolysis) (Fig. 22–1, C). In addition, acute injuries typically result in breakdown of the blood-brain barrier and variable degrees of cerebral edema (described later).
Many neurodegenerative diseases are associated with spe- cific intracellular inclusions (e.g., Lewy bodies in Parkinson disease and tangles in Alzheimer disease), also described later. Pathogenic viruses can also form inclusions in neurons, just as they do in other cells of the body. In some neurode- generative diseases, neuronal processes also become thick- ened and tortuous; these are termed dystrophic neurites. With age, neurons also accumulate complex lipids (lipofus- cin) in their cytoplasm and lysosomes.
Astrocytes in Injury and Repair. Astrocytes are the principal cells responsible for repair and scar formation in the brain, a process termed gliosis. In response to injury, astro- cytes undergo both hypertrophy and hyperplasia. The nucleus enlarges and becomes vesicular, and the nucleolus becomes prominent. The previously scant cytoplasm expands and takes on a bright pink hue, and the cell extends multiple stout, ramifying processes (gemistocytic astrocyte). Unlike elsewhere in the body, fibroblasts participate in healing after brain injury to a limited extent except in specific settings (penetrating brain trauma or around abscesses). In long- standing gliosis, the cytoplasm of reactive astrocytes shrinks in size and the cellular processes become more tightly interwoven (fibrillary astrocytes). Rosenthal fibers are thick, elongated, brightly eosinophilic protein aggregates found in astrocytic processes in chronic gliosis and in some low-grade gliomas.
Changes in Other Cell Types. Oligodendrocytes,
which produce myelin, exhibit a limited spectrum of specific morphologic changes in response to various injuries. In pro- gressive multifocal leukoencephalopathy, viral inclusions can be seen in oligodendrocytes, with a smudgy, homogeneous- appearing enlarged nucleus.
Microglial cells are bone-marrow–derived cells that function as the resident phagocytes of the CNS. When acti- vated by tissue injury, infection, or trauma, they proliferate and become more prominent histologically. Microglial cells take on the appearance of activated macrophages in areas of demyelination, organizing infarct, or hemorrhage; in other settings such as neurosyphilis or other infections, they develop elongated nuclei (rod cells). Aggregates of elon- gated microglial cells at sites of tissue injury are termed microglial nodules. Similar collections can be found congregating around and phagocytosing injured neurons (neuronophagia).
Ependymal cells line the ventricular system and the central canal of the spinal cord. Certain pathogens, particu- larly cytomegalovirus (CMV), can produce extensive ependy- mal injury, with typical viral inclusions. Choroid plexus is in continuity with the ependyma, and its specialized epithelial covering is responsible for the secretion of cerebrospinal fluid (CSF).

In summary: Patterns of neuronal injury. A, Acute hypoxic-ischemic injury in cerebral cortex, where the individual cell bodies are shrunken, along with the nuclei. They also are prominently stained by eosin (“red neurons”). B, Axonal spheroids are visible as bulbous swellings at points of disruption, or altered axonal transport. C, With axonal injury there can be swelling of the cell body and peripheral dispersal of the Nissl substance, termed chromatolysis.

Question 2

Where do the nerves and blood vessels of the brown and spinal cord pass through
What is the disadvantage of housing the delicates CNS(brain and spinal cord) in a protective environment? State what the protective environment is
State three disorders that can cause dangerous increase in brain volume within the fixed space of the skull?
What is cerebral edema
What are the types of cerebral edema
When do they often occur together?
When do these types of edema occur
What type of edema can be either localized or generalized and if localized what will cause it
How does hydrocephalus occur
What happens to the edematous brain after cytotoxic edema?
In generalized edema what happens to the gyri,sulci and ventricular cavities
What are gyri and sulci and what is their importance
What produces cerebrospinal fluid?
After it is produced where does it go?
What absorbs it?
What regulates CSF volume
What is hydrocephalus
How does hydrocephalus occur or what is it a consequence of? When is overproduction of CSF seen? If there is localized obstacle to CSC flow what happens to the ventricles?
What is this pattern called? And what commonly causes it?
What happens in communicating hydrocephalus and what causes it
When does hydrocephalus develop in infants? Once sutures fuse in infants what does the hydro cause? What is hydrocephalus ex vacuo

Answer 2

The brain and spinal cord exist within the protective and rigid skull and spinal canal, with nerves and blood vessels passing through specific foramina. The advantage of housing the delicate CNS within such a protective environ- ment is obvious, but this arrangement provides little room for brain parenchymal expansion in disease states. Disor- ders that may cause dangerous increases in brain volume within the fixed space of the skull include generalized cere- bral edema, hydrocephalus, and mass lesions such as tumors.

Cerebral Edema
Cerebral edema is the accumulation of excess fluid within the brain parenchyma. There are two types, which often occur together particularly after generalized injury.
• Vasogenic edema occurs when the integrity of the normal blood-brain barrier is disrupted, allowing fluid to shift from the vascular compartment into the extracellular spaces of the brain. Vasogenic edema can be either local- ized (e.g., increased vascular permeability due to inflam- mation or in tumors) or generalized.
• Cytotoxic edema is an increase in intracellular fluid sec- ondary to neuronal and glial cell membrane injury, as might follow generalized hypoxic-ischemic insult or after exposure to some toxins.
The edematous brain is softer than normal and often appears to “over fill” the cranial vault. In generalized edema the gyri are flattened, the intervening sulci are narrowed, and the ventricular cavities are compressed (Fig. 22–2).

Gyri and sulci are the folds and indentations in the brain that give it its wrinkled appearance. Gyri (singular: gyrus) are the folds or bumps in the brain and sulci (singular: sulcus) are the indentations or grooves. These gyri and sulci form important landmarks that allow us to separate the brain into functional centers

Hydrocephalus
After being produced by the choroid plexus within the ventricles, CSF circulates through the ventricular system and flows through the foramina of Luschka and Magendie into the subarachnoid space, where it is absorbed by arach- noid granulations. The balance between rates of generation and resorption regulates CSF volume.
Hydrocephalus refers to the accumulation of excessive CSF within the ventricular system. This disorder most often is a consequence of impaired flow or resorption; over- production of CSF, typically seen with tumors of the choroid plexus, only rarely causes hydrocephalus. If there is a localized obstacle to CSF flow within the ventricular system, then a portion of the ventricles enlarges while the remainder does not. This pattern is referred to as noncom- municating hydrocephalus and most commonly is caused by masses obstructing the foramen of Monro or compressing the cerebral aqueduct. In communicating hydrocephalus, the entire ventricular system is enlarged; it is usually caused by reduced CSF resorption.
If hydrocephalus develops in infancy before closure of the cranial sutures, the head enlarges. Once the sutures fuse, hydrocephalus causes ventricular expansion and increased intracranial pressure, but no change in head cir- cumference (Fig. 22–3). In contrast with these states, in which increased CSF volume is the primary process, a compensatory increase in CSF volume can also follow the loss of brain parenchyma (hydrocephalus ex vacuo), as after infarcts or with degenerative diseases.

Question 3

Look at picture of types of herniation
What causes intracranial pressure to rise?
The cranial vault is subdivided by what? And what displaces it in relation to the partitions? How does herniation occur?
What four things does it often lead to?
State the three main types of herniation? And state when they occur.
Which type of herniation is associated w compression of the anterior cerebral artery?
Which type of herniation causes blown pupil? And what is a blown pupil?
Which type of herniation causes false localising sign?
What is false localising sign?
What is Kernohan’s notch?
Progression of transtentorial herniation is often accompanied by what? What are Duret hemorrhages and where do these lesions occur? They are the result of what?
Which type of herniation is life threatening and why?
What causes Duret hemorrhage

Answer 3

Herniation
When the volume of tissue and fluid inside the skull increases beyond the limit permitted by compression of veins and displacement of CSF, intracranial pressure rises. The cranial vault is subdivided by rigid dural folds (falx and tentorium), and a focal expansion of the brain dis- places it in relation to these partitions. If the expansion is sufficiently large, herniation occurs. Herniation often leads to “pinching” and vascular compromise of the compressed tissue, producing infarction, additional swelling, and further herniation. There are three main types of herniation :
• Subfalcine (cingulate) herniation occurs when unilateral or asymmetric expansion of a cerebral hemisphere dis- places the cingulate gyrus under the edge of falx. This may be associated with compression of the anterior cere- bral artery.
• Transtentorial (uncinate) herniation occurs when the medial aspect of the temporal lobe is compressed against the free margin of the tentorium. As the temporal lobe is displaced, the third cranial nerve is compromised, resulting in pupillary dilation and impaired ocular movements on the side of the lesion (“blown pupil”). The posterior cerebral artery may also be compressed, resulting in ischemic injury to tissue supplied by that vessel, including the primary visual cortex. If the amount of displaced temporal lobe is large enough, the pressure on the midbrain can compress the contralateral cerebral peduncle against the tentorium, resulting in hemiparesis ipsilateral to the side of the herniation (a so-called false localizing sign). The compression of the peduncle creates a deformation known as Kernohan’s notch. Progression of transtentorial herniation is often accompanied by linear or flame-shaped hemorrhages in the midbrain and pons, termed Duret hemorrhages (Fig. 22–5). These lesions usually occur in the midline and paramedian regions and are believed to be the result of tearing of penetrating veins and arteries supplying the upper brain stem.
• Tonsillar herniation refers to displacement of the cerebellar tonsils through the foramen magnum. This type of herniation is life-threatening, because it causes brain stem compression and compromises vital respiratory and cardiac centers in the medulla.

Duret hemorrhage. As mass effect displaces the brain downward, there is disruption of the vessels that enter the pons along the midline, leading to hemorrhage.

Question 4

In summary what gave you learnt about cerebral edema,hydrocephalus and herniation (what is cerebral edema,hydrocephalus, what four things will cause an increased brain volume? When brain volume increases what does it raise?
Which two ways can Increased pressure damage the brain?)

Answer 4

SUMMARY
Edema, Herniation, and Hydrocephalus
• Cerebral edema is the accumulation of excess fluid within the brain parenchyma. Hydrocephalus is defined as an increase in CSF volume within all or part of the ventricular system.
• Increases in brain volume (as a result of increased CSF volume, edema, hemorrhage, or tumor) raise the pressure inside the fixed capacity of the skull.
• Increases in pressure can damage the brain either by decreasing perfusion or by displacing tissue across dural partitions inside the skull or through openings in the skull (herniations).

Question 5

What are Cerebrovascular diseases
What are the three main pathogenic mechanisms of the disease
What is the clinical designation applied to all these conditions when symptoms begin acutely?
What are the consequences of thrombosis and embolism on the brain?
Similar injury occurs globally when what two things happens?
Hemorrhage accompanies what?
What two things does the brain depend on most?
The brain constitutes how much of body weight,how much resting cardiac output does it receive? How much total body oxygen does the brain consume
Why does cerebral blood flow remain stable over a wide range of blood pressure and intracranial pressure?
By which two mechanisms can the brain be deprived of oxygen and what causes these mechanisms

Answer 5

Cerebrovascular diseases—the broad category of brain disorders caused by pathologic processes involving blood vessels—constitute a major cause of death in the developed world and are the most prevalent cause of neurologic mor- bidity.
The three main pathogenic mechanisms are (1) thrombotic occlusion, (2) embolic occlusion, and (3) vascu- lar rupture.

Stroke is the clinical designation applied to all of these conditions when symptoms begin acutely. Throm- bosis and embolism have similar consequences for the brain: loss of oxygen and metabolic substrates, resulting in infarction or ischemic injury of regions supplied by the affected vessel.
Similar injury occurs globally when there is complete loss of perfusion, severe hypoxemia (e.g., hypo- volemic shock), or profound hypoglycemia.

Hemorrhage accompanies rupture of vessels and leads to direct tissue damage as well as secondary ischemic injury.

Hypoxia, Ischemia, and Infarction
The brain is a highly oxygen-dependent tissue that requires a continual supply of glucose and oxygen from the blood. Although it constitutes no more than 2% of body weight, the brain receives 15% of the resting cardiac output and is responsible for 20% of total body oxygen consumption.
Cerebral blood flow normally remains stable over a wide range of blood pressure and intracranial pressure because of autoregulation of vascular resistance.
The brain may be deprived of oxygen by two general mechanisms:
• Functional hypoxia, caused by a low partial pressure of oxygen (e.g., high altitude), impaired oxygen-carrying capacity (e.g., severe anemia, carbon monoxide poison- ing), or inhibition of oxygen use by tissue (e.g., cyanide poisoning)
• Ischemia, either transient or permanent, due to tissue hypoperfusion, which can be caused by hypotension, vascular obstruction, or both

Question 6

When can widespread ischemic hypoxic injury occur?(state the systolic pressure value)
Clinical outcome of this injury varies with what?
When the injury is mild what can happen?
Which cells are more susceptible to hypoxic injury?
What neurons are the most susceptible to hypoxic injury? Where are they found?

In severe global cerebral ischemia, widespread neuronal death occurs irrespective of regional vulnerability.
True or false
What happens to patients who survive global cerebral ischemia
What is the clinical criteria for brain death
What happens to the brain when brain dead patients are maintained on mechanical ventilation ?
What is respirator brain?

Answer 6

Global Cerebral Ischemia
Widespread ischemic-hypoxic injury can occur in the setting of severe systemic hypotension, usually when sys- tolic pressures fall below 50 mm Hg, as in cardiac arrest, shock, and severe hypotension.
The clinical outcome varies with the severity and duration of the insult. When the insult is mild, there may be only a transient postischemic confusional state, with eventual complete recovery. Neurons are more susceptible to hypoxic injury than are glial cells, and the most susceptible neurons are the pyra- midal cells of the hippocampus and neocortex and Purkinje cells of the cerebellum. In some individuals, even mild or transient global ischemic insults may cause damage to these vulnerable areas. Patients who survive often remain severely impaired neurologically and in a persistent vegetative state. Other patients meet the clinical criteria for so-called brain death, including evidence of diffuse cortical injury (isoelectric, or “flat,” electroencephalogram) and brain stem damage, including absence of reflexes and respiratory drive. When patients with this form of irreversible injury are maintained on mechanical ventilation, the brain gradu- ally undergoes autolysis, resulting in the so-called “respi- rator brain.”

Question 7

What is the morphology of the brain in global ischemia?
What are the three histopathological changes that accompany irreversible ischemic injury?
Explain them (when they occur,what cells or tissues they include)
When are watershed infarcts usually seen?
Which zone is at risk in this infarct?
Damage to this region produces what?

Answer 7

MORPHOLOGY
In the setting of global ischemia, the brain is swollen, with wide gyri and narrowed sulci. The cut surface shows poor demarcation between gray and white matter. The histopath- ologic changes that accompany irreversible ischemic injury (infarction) are grouped into three categories.
Early changes:occurring 12 to 24 hours after the insult, include acute neuronal cell change (red neurons) (Fig. 22–1, A) characterized initially by microvacuolization, followed by cytoplasmic eosinophilia, and later nuclear pyknosis and kary- orrhexis. Similar changes occur somewhat later in astrocytes and oligodendroglia. After this, the reaction to tissue damage begins with infiltration by neutrophils (Fig. 22–6, A).
Sub- acute changes:, occurring at 24 hours to 2 weeks, include necrosis of tissue, influx of macrophages, vascular prolifera- tion, and reactive gliosis (Fig. 22–6, B). Repair, seen after 2 weeks, is characterized by removal of all necrotic tissue, loss of organized CNS structure, and gliosis

Border zone (“watershed”) infarcts :are wedge- shaped areas of infarction that occur in regions of the brain and spinal cord that lie at the most distal portions of arterial territories. They are usually seen after hypotensive episodes. In the cerebral hemispheres, the border zone between the anterior and the middle cerebral artery distributions is at greatest risk. Damage to this region produces a band of necrosis over the cerebral convexity a few centimeters lateral to the interhemispheric fissure.

Question 8

Some infectious agents have a relative or absolute predilection for the nervous system (e.g., rabies), while others can affect many other organs as well as the brain (e.g., Staphylococcus aureus) true or false
Damage to nervous tissue may b the consequence of what? What are the routes through which infectious agents may reach the nervous system?
Why will the epidural and subdural spaces be involved by bac- terial or fungal infections? What causes epidural abscesses? What happens when abscesses occur in the spinal epidural space? What produces subdural empyema? The underlying arachnoid and subarachnoid spaces usually are unaffected, but a large subdural empyema may produce a mass effect. True or false
Where may thrombophlebitis develop? When it develops what does it result in? Most patients w that get the results of thrombophlebitis have what signs and if untreated what signs may be seen? What treatment can be used? Resolution of empyema occurs from where? What happen when resolution is complete

Answer 8

. 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 innate or adaptive immune response.
Infectious agents may reach the nervous system through several routes of entry:
• 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 veins of the face and the venous sinuses of the skull.
• Direct implantation of microorganisms is almost invari- ably due to traumatic introduction of foreign material. In rare cases it can be iatrogenic, as when microbes are introduced with a lumbar puncture needle.
• 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 the rabies and herpes zoster viruses.

Epidural and Subdural Infections
The epidural and subdural spaces can be involved by bac- terial 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 neurosurgi- cal emergency. Infections of the skull or air sinuses may also spread to the subdural space, producing subdural empyema. In addition, throm- bophlebitis 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 head- ache and neck stiffness, and if untreated may develop focal neurologic signs referable to the site of the infection, leth- argy, and coma. With treatment, including surgical drain- age, 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 recov- ery is usual.

Question 9

What is meningitis? And meningoencephalitis? What causes meningitis? Infectious meningitis can be broadly divided into what four subtypes? What exam is often useful in distinguishing between the various causes of meningitis? In neonates what are the common organisms that can cause acute pyogenic meningitis? What about in adolescents and young adults? What about in older individuals? In all age groups patients typically show what signs ? Lumbar puncture reveals what? Exam of the CSF shows what three things? What may be seen on a smear or can be cultured sometimes a few hours before the neu- trophils appear. ?

Untreated pyogenic meningitis is often fatal, but with prompt diagnosis and administration of appropriate antibiotics, many patients can be saved. True or false

In acute meningitis what is evident within the lepto- meninges over the surface of the brain? What’s the appearance of the meningeal vessels? From areas of greatest accumulation ehat is seen? What happens when meningitis is fulminant? On microscopic exam neutrophils fill where or my be found where? In untreated meningitis what does gram stain reveal? Bacterial meningitis may be associ- ated with abscesses in the brain true or false . Phlebitis may lead to what?

Answer 9

Meningitis
Meningitis is an inflammatory process involving the lepto- meninges within the subarachnoid space; if the infection spreads into the underlying brain it is termed meningoen- cephalitis. Meningitis usually is caused by an infection, but chemical meningitis also may occur in response to a nonbac- terial irritant introduced into the subarachnoid space. Infectious meningitis can be broadly divided into acute pyo- genic (usually bacterial), aseptic (usually viral), and chronic (usually tuberculous, spirochetal, or cryptococcal) sub- types. Examination of the CSF is often useful in distin- guishing between various causes of meningitis.

Acute Pyogenic Meningitis (Bacterial Meningitis)
Many bacteria can cause acute pyogenic meningitis, but the most likely organisms vary with patient age. In neonates, common organisms are Escherichia coli and the group B streptococci; in adolescents and in young adults, Neisseria meningitidis is the most common pathogen; and in older individuals, Streptococcus pneumoniae and Listeria monocyto- genes are more common. In all age groups, patients typi- cally 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. Bacteria may be seen on a smear or can be cultured, sometimes a few hours before the neu- trophils appear.

In acute meningitis, an exudate is evident within the lepto- meninges over the surface of the brain
The meningeal vessels are engorged and prominent. From the areas of greatest accumulation, tracts of pus can be followed along blood vessels on the brain surface. When the meningitis is fulminant, the inflammatory cells infiltrate the walls of the leptomeningeal veins and may spread into the substance of the brain (focal cerebritis), or the inflammation may extend to the ventricles, producing ventriculitis. On microscopic examination, neutrophils fill the entire subarachnoid space in severely affected areas or may be found predominantly around the leptomeningeal blood vessels in less severe cases. In untreated meningitis, Gram stain reveals varying numbers of the causative organism. Phlebitis also may lead to venous occlusion and hemor- rhagic infarction of the underlying brain. If it is treated early, there may be little or no morphologic residuum.

Question 10

Aseptic meningitis is a clinical term for what? If this less fulminant or more fulminant than in pyogenic meningitis. ?
Exam of CSF often shows what three things? This disease typically is self limiting true or false? What are the distinctive macroscopic characteristics? On microscopic exam what’s seen?
What pathogens are associated w chronic meningitis? Infections w these organisms also may involve which part of the brain? TB meningitis usually manifested with what signs? What is seen in the CSF fluid? Infection w M tuberculosis may result in what? Chronic TB meningitis is a cause of what and may produce what?

Answer 10

Aseptic Meningitis (Viral Meningitis)
Aseptic meningitis is a clinical term for an illness comprising meningeal irritation, fever, and alterations in conscious- ness of relatively acute onset. The clinical course is less fulminant than in pyogenic meningitis. In contrast to pyo- genic meningitis, examination of the CSF often shows lym- phocytosis, moderate protein elevation, and a normal glucose level. The disease typically is self-limiting. It is believed to be of viral origin in most cases, but it is often difficult to identify the responsible virus. There are no distinctive macroscopic characteristics except for brain swelling, seen in only some instances. On microscopic examination, there is either no recognizable abnormality or a mild to moderate leptomeningeal lymphocytic infiltrate.

Chronic Meningitis
Several pathogens, including mycobacteria and some spirochetes, are associated with chronic meningitis; infec- tions with these organisms also may involve the brain parenchyma.

Tuberculous Meningitis
Tuberculous meningitis usually manifests with general- ized 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 is a cause of arachnoid fibrosis, which may produce hydrocephalus.

Question 11

The subarachnoid space in chronic meningitis contains what? Most often in which part of the brain? There may be what scattered over the leptomeninges? Arteries running through the subarachnoid space may show what? On microscopic exam what’s seen ? Florid cases show what?

Neurosyphilis occurs in which people?
Which patients are at increased risk for this? The Neurosyphilis infections can produce what? Which part of the brain does it usually involve? There can also be paren- chymal involvement by spirochetes (paretic neurosyphilis), leading to what? Clinically this form of disease causes what? What is Tabes dorsalis? Neuroborreliosis represents involvement of the nervous system by what? Neurologic signs and symptoms are highly variable and include ?

Answer 11

The subarachnoid space contains a gelatinous or fibrinous exudate, most often at the base of the brain, obliterating the cisterns and encasing cranial nerves. There may be discrete white granules scattered over the leptomeninges. Arteries running through the subarachnoid space may show oblitera- tive endarteritis with inflammatory infiltrates and marked intimal thickening. On microscopic examination there are mixtures of lymphocytes, plasma cells, and macrophages. Florid cases show well-formed granulomas, often with caseous necrosis and giant cells, similar to the lesions of tuberculosis elsewhere.

Spirochetal Infections
Neurosyphilis, a tertiary stage of syphilis, occurs in about 10% of persons with untreated Treponema pallidum infec- tion. Patients with HIV infection are at increased risk for neurosyphilis, which often is more aggressive and severe in this setting. The infection can produce chronic meningi- tis (meningovascular neurosyphilis), usually involving the base of the brain, often with an obliterative endarteritis rich in plasma cells and lymphocytes. There can also be paren- chymal involvement by spirochetes (paretic neurosyphilis), leading to neuronal loss and marked proliferation of rod- shaped microglial cells. Clinically, this form of the disease causes an insidious progressive loss of mental and physical functions, mood alterations (including delusions of gran- deur), and eventually severe dementia. Tabes dorsalis is another form of neurosyphilis, resulting from damage to the sensory nerves in the dorsal roots that produces impaired joint position sense and ataxia (locomotor 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.

Neuroborreliosis represents involvement of the nervous system by the spirochete Borrelia burgdorferi, the pathogen of Lyme disease. Neurologic signs and symptoms are highly variable and include aseptic meningitis, facial nerve palsies, mild encephalopathy, and polyneuropathies.

Question 12

The entire gamut of infectious pathogens (viruses to para- sites) can potentially infect the brain, often in characteristic patterns true or false
In general viral infections have what characteristics? Brain abscesses are nearly always caused by what? These can arise due to what? Name some predisposing conditions. What do patients w abscesses present with? What markers are high and normal in the CSF? What two things can be fatal and an abscess rupture can lead to what three things?
What is the morphology of abscesses? On microscopic exam what is seen?
Outside the fibrosis capsule what is there? Viral encephalitis is a parenchymal infection of the brain that is almost invariably associated with what? What are the most characteristic histologic features ? The nervous system is particularly susceptible to which viruses? Which places can the viruses affect in the brain? Intrauterine viral infection may cause what? In addition to direct infection of the nervous system, the CNS also can be injured by

Answer 12

Parenchymal Infections
. In general, viral infections are diffuse, bacterial infections (when not associated with meningitis) are local- ized, while other organisms produce mixed patterns. In immunosuppressed hosts, more widespread involvement with any agent is typical.

Brain Abscesses
Brain abscesses are nearly always caused by bacterial infec- tions. 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 extrac- tion).
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 destructive lesions, and patients almost invariably present with progressive focal deficits as well as general signs related to increased intracranial pressure. The CSF white cell count and protein levels are usually high, while the glucose content tends to be normal. A systemic or local source of infection may be apparent or may have ceased to be symptomatic. The increased intracranial pres- sure and progressive herniation can be fatal, and abscess rupture can lead to ventriculitis, meningitis, and venous sinus thrombosis.

MORPHOLOGY
Abscesses are discrete lesions with central liquefactive necrosis and a surrounding fibrous capsule .On microscopic examination, the necrotic center is sur- rounded by edema and granulation tissue, often with exuber- ant vascularization. Outside the fibrous capsule is a zone of reactive gliosis

Viral Encephalitis
Viral encephalitis is a parenchymal infection of the brain that is almost invariably associated with meningeal inflam- mation (and therefore is better termed meningoencephalitis). While different viruses may show varying patterns of injury, the most characteristic histologic features are peri- vascular and parenchymal mononuclear cell infiltrates, microglial nodules, and neuronophagia. 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 tem- poral lobes, or the limbic system) that lie along the viral route of entry. Intrauterine viral infection may cause con- genital malformations, as occurs with rubella. In addition to direct infection of the nervous system, the CNS also can be injured by immune mechanisms after systemic viral infections.

Question 13

Arbovituses are an important cause of epidemic encephalitis , especially where? What signs do patients develop? What’s the appearance of the CSF? What’s the protein level and glucose level? Characteristically what is seen in the morphology?. In severe cases what may be seen? HSV-1 encephalitis may occur in any age group but is most common in which age groups? It typically manifests with what? Recurrent HSV-1 encephalitis is sometimes associated with what? Herpes encephalitis starts in, and most severely involves which parts of the brain? What’s the characteristic of the infections? What infiltrates are usually present? And what inclusions can be found and where? HSV-2 also affects the nervous system in the form of? Disseminated severe encepha- litis occurs in which neonates? Varicella-zoster virus (VZV) causes chickenpox during primary infection, usually without any evidence of neuro- logic involvement. True or false
The virus establishes latent infection where? Reactivating in adults manifests as what? In immunosuppressives patients what may occur

Answer 13

Arboviruses
Arboviruses (arthropod-borne viruses) are an important cause of epidemic encephalitis, especially in tropical regions of the world.Patients develop gen- eralized 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 lympho- cytosis; the protein level is elevated, but the glucose is normal.

MORPHOLOGY
Arbovirus encephalitides produce a similar histopathologic picture. Characteristically, there is a perivascular lymphocytic meningoencephalitis (sometimes with neutrophils) (Fig. 22– 17, A). Multifocal gray and white matter necrosis is seen, often associated with neuronophagia, the phagocytosis of neuronal debris, as well as localized collections of microglia termed microglial nodules (Fig. 22–17, B). In severe cases there may be a necrotizing vasculitis with associated focal hemorrhages

Herpesviruses
HSV-1 encephalitis may occur in any age group but is most common in children and young adults. It typically mani- fests 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 impor- tant role in antiviral defense.

Herpes encephalitis starts in, and most severely involves, the inferior and medial regions of the temporal lobes and the orbital gyri of the frontal lobes (Fig. 22–17, C). The infection is necrotizing and often hemorrhagic in the most severely affected regions. Perivascular inflammatory infiltrates usually are present, and large eosinophilic intranuclear viral inclusions (Cowdry type A bodies) can be found in both neurons and glial cells.
HSV-2 also affects the nervous system, usually in the form of meningitis in adults. Disseminated severe encepha- litis occurs in many neonates born by vaginal delivery to women with active primary HSV genital infections.
The virus establishes latent infection in neurons of dorsal root ganglia. Reactivation in adults mani- fests 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). 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.

Question 14

Cytomegalovirus infects the nervous system in which people? What cells in the CNs are susceptible to infection? Intrauterine infection causes what which is followed by what? What happens when adults are infected? Lesions can be what type and contain what? What is poliovirus? It secondarily invades the nervous system and damages what? With loss of motor neurons it produces what
In acute disease what will cause death?

Long after the infection has resolved, typically 25 to 35 years after the initial illness, a postpolio syndrome of progres- sive weakness associated with decreased muscle bulk and pain can appear. True or false
What is rabies? How does the virus enter the CNs? Incubation period depends on what? How does the disease manifests?(initially and when it advances)

Answer 14

Cytomegalovirus
CMV infects the nervous system in fetuses and immuno- suppressed persons. 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 periventricu- lar calcification. When adults are infected, CMV produces a subacute encephalitis, again often most severe in the peri- ventricular region. Lesions can be hemorrhagic and contain typical viral inclusion–bearing cells.

Poliovirus
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). With loss of motor neurons, it produces 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.

Rabies Virus
Rabies is a severe 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. Virus enters the CNS by ascending along the peripheral nerves from the wound site, so the incubation period depends on the distance between the wound and the brain,
usually taking a few months. The disease manifests ini- tially with nonspecific symptoms of malaise, headache, and fever. As the infection advances, the patient shows extraor- dinary CNS excitability; the slightest touch is painful, with violent motor responses progressing to convulsions. Con- tracture of the pharyngeal musculature may create an aver- sion to swallowing even water (hydrophobia). Periods of mania and stupor progress to coma and eventually death, typically from respiratory failure.

Question 15

Neuropathologic changes in HIV are due to what? What is lumped under the umbrella term HIV-associated neurocognitive disorder (HAND) ? Cognitive symptoms stem from HIV nfections of which part of the brain? This leads to what? The ensuing neuronal injury stems from a combination of what? When does aseptic meningitis occur when there’s onset of primary infection by HIV? What are the early and acute phases of
symptomatic or asymptom- atic HIV invasion of the nervous system
After the acute phase what can commonly be found ?
HIV encephalitis is best characterized
Microscopically as what? Progressive multifocal leukoencephalopathy (PML) is caused by? Which part of the brain does this infect and what does it result in? The disease is restricted to immunosuppressives patients true or false? What signs do patients develop ,often showing what kind of lesions? The lesions are of what nature? What is seen in the center of each lesion and the edges of the lesions? The virus also infects astrocytes leading to what?

Answer 15

to direct effects of virus on the nervous system, opportunistic infections, and primary CNS lymphoma. 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. The cognitive symptoms are believed to stem from HIV infection of microglial cells in the brain. This leads to activation of innate immune responses, both in infected microglial cells and unaffected bystanders. The ensuing neuronal injury likely stems from a combination of cytokine-induced inflammation and toxic effects of HIV-derived proteins.
Aseptic meningitis occurs within 1 to 2 weeks of onset of primary infection by HIV in about 10% of patients; anti- bodies 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 asymptom- atic HIV invasion of the nervous system have shown mild lymphocytic meningitis, perivascular inflammation, and some myelin loss in the hemispheres. After the acute phase, an HIV encephalitis (HIVE) commonly can be found if affected persons come to autopsy.
MORPHOLOGY
HIV encephalitis is best characterized microscopically as a chronic inflammatory reaction with widely distributed infil- trates of microglial nodules, sometimes with associated foci of tissue necrosis and reactive gliosis .The microglial nodules also are found in the vicinity of small blood vessels, which show abnormally prominent endothelial cells and perivascular foamy or pigment-laden macrophages. These changes occur especially in the subcortical white matter, diencephalon, and brain stem. An important compo- nent of the microglial nodule is the macrophage-derived multinucleate giant cell. In some cases, there is also a disorder of white matter characterized by multifocal or diffuse areas of myelin pallor with associated axonal swellings and gliosis. HIV is present in CD4+ mononuclear and multi- nucleate macrophages and microglia.

Polyomavirus and Progressive Multifocal Leukoencephalopathy
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 child- hood, and it is believed that PML results from virus reactivation, as the disease is restricted to immunosup- pressed persons. Patients develop focal and relentlessly progressive neurologic symptoms and signs, and imaging studies show extensive, often multifocal, ring-enhancing lesions in the hemispheric or cerebellar white matter.

MORPHOLOGY
The lesions are patchy, irregular, ill-defined areas of white matter destruction that enlarge as the disease progresses (Fig. 22–18). Each lesion is an area of demyelination, in the center of which are scattered lipid-laden macrophages and a reduced number of axons. At the edges of the lesion are greatly enlarged oligodendrocyte nuclei whose chromatin is replaced by glassy-appearing amphophilic viral inclusions. The virus also infects astrocytes, leading to bizarre giant forms with irregular, hyperchromatic, sometimes multiple nuclei that can be mistaken for tumor.

Question 16

Fungal infections usually produce what? The most common fungal infections have distinctive patterns,what’s the pattern of Candida albicans? What is Mucormycosis? How does it present? How does it spread to the brain? What sets Mucor apart from
Other fungi? Aspergillus fumigatus tends to cause what kind of distinctive pattern and why? Cryptococcus neoformans can cause both meningitis and meningoencephalitis, often in the setting of? The CSF may contain what?
What gives rise to soap bubble like appearance? In endemic areas which three fungi can also infect the CNS especially in the setting of immunosuppression. What are ring enhancing lesions?
In summary,pathogens from viruses through what can infect the brain? What is Prion disease? Different pathogens use distinct routes to reach the brain, and cause different patterns of disease true or false
Bacterial infections may cause what three things? Viral infections can cause what two things? HIV can directly cause meningoencephalitis, or indirectly affect the brain how?

Answer 16

Fungal Encephalitis
Fungal infections usually produce parenchymal granulo- mas or abscesses, often associated with meningitis. The most common fungal infections have distinctive patterns: Candida albicans usually produces multiple microab- scesses, with or without granuloma formation.
• Mucormycosis is the term used to describe rhinocerebral infections caused by several fungi belonging to the order Mucorales. It typically presents as an infection of the nasal cavity or sinuses of a diabetic patient with ketoaci- dosis. It may spread to the brain through vascular inva- sion or by direct extension through the cribriform plate. The proclivity of Mucor to invade the brain directly sets it apart from other fungi, which tend to 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 and subsequent thrombosis.
• Cryptococcus neoformans can cause both meningitis and meningoencephalitis, often in the setting of immuno- suppression. It can be fulminant and fatal in as little as 2 weeks or may exhibit indolent behavior, evolving over months or years. The CSF may have few cells but ele- vated 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. 22–19). The diagnosis is usually established by a positive test for cryptococcal antigens in the CSF or the blood.
In endemic areas, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis also can infect the CNS, especially in the setting of immunosuppression.
Other Meningoencephalitides
Cerebral Toxoplasmosis. Cerebral infection with the pro- tozoan Toxoplasma gondii can occur in immunosuppressed adults or in newborns who acquire the organism trans- placentally from a mother with an active infection. In adults, the clinical symptoms are subacute, evolving during a 1- or 2-week period, and may be both focal and diffuse. Due to inflammation and breakdown of the blood-brain barrier at sites of infection, computed tomography and magnetic resonance imaging studies often show edema around lesions (so-called ring enhancing lesions). In new- borns who are infected in utero, the infection classically produces the triad of chorioretinitis, hydrocephalus, and intracranial calcifications. Understandably, the CNS abnor- malities are most severe when the infection occurs early in gestation during critical stages of brain development. Necrosis of periventricular lesions gives rise to secondary calcifications as well as inflammation and gliosis, which can lead to obstruction of the aqueduct of Sylvius and hydrocephalus.

SUMMARY
Infections of the Nervous System
• Pathogens from viruses through parasites can infect the brain; in addition, prion disease is a protein-induced trans- missible disease unique to the nervous system.
• Different pathogens use distinct routes to reach the brain, and cause different patterns of disease.
• Bacterial infections may cause meningitis, cerebral abscesses, or a chronic meningoencephalitis.
• Viral infections can cause meningitis or meningoen- cephalitis.
• HIV can directly cause meningoencephalitis, or indirectly affect the brain by increasing the risk of opportunistic infections (toxoplasmosis, CMV) or CNS lymphoma.
• Prion diseases are transmitted by an altered form of a normal cellular protein.They can be sporadic, transmitted, or inherited.

Question 17

Why is the brain particularly vulnerable to nutritional diseases and alterations in metabolic state.? Under nutritional diseases,what will thiamine deficiency do to the brain? How does Korsakoff syndrome come about? The syndrome is particularly common in what settings? Wernicke encephalopathy is characterized by what? Early lesions show what? As the lesions resolve what is seen? What lesions seem to best correlate with the memory distur- bance in Korsakoff syndrome.?
Vitamin B12 deficiency may lead to neurologic deficits associated with what? In subacute combined degeneration of the spinal cord which parts of the spinal cord are affected? Name some early clinical signs?

Answer 17

ACQUIRED METABOLIC AND TOXIC DISTURBANCES
Because of its high metabolic demands, the brain is particularly vulnerable to nutritional diseases and alterations in metabolic state.

Nutritional Diseases
Thiamine Deficiency: In addition to the systemic effects of thiamine deficiency (beriberi), there also may be abrupt onset of confusion, abnormalities in eye movement, and ataxia—a syndrome termed Wernicke encephalopathy. Treat- ment with thiamine can reverse these deficits. If the acute stages go untreated, they are followed by largely irrevers- ible profound memory disturbances (Korsakoff syndrome). Because the two syndromes are closely linked, the term Wernicke-Korsakoff syndrome is often applied.
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, including carcinoma and chronic gastritis, or from persis- tent vomiting.

MORPHOLOGY
Wernicke encephalopathy is characterized by foci of hemor- rhage and necrosis, particularly in the mammillary bodies but also adjacent to the ventricles, especially the third and fourth ventricles. Despite the presence of necrosis, there is relative preservation of many of the neurons in these structures. Early lesions show dilated capillaries with prominent endo- thelial cells and progress to hemorrhage. As the lesions resolve, a cystic space appears along with hemosiderin-laden macrophages. Lesions in the medial dorsal nucleus of the thalamus seem to best correlate with the memory distur- bance in Korsakoff syndrome.

Vitamin B12 Deficiency. In addition to pernicious anemia, deficiency of vitamin B12 may lead to neurologic deficits associated with changes in the spinal cord, collectively termed 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 slight ataxia and lower extremity numbness and tingling, which can pro- gress to spastic weakness of the lower extremities; some- times even complete paraplegia ensues. Prompt vitamin replacement therapy produces clinical improvement; however, if paraplegia has developed, recovery is poor.

Question 18

How does hypoglycemia cause brain injury? Which neurons are particularly susceptible to hypo- glycemic injury while which cells are relatively spared?
Hyperglycemia is most common in what setting and may be associated with what? What’s signs do
Patients develop? Research on how hyperglycemia causes brain injury
Rapid correction of hyperglycemia may result in what? In the early stages of hepatic encephalopathy patients exhibit what Characteristic sign? What causes the changes in the brain function? Within the CNS how does ammonia metabolism occur? In the setting of hyerammonemia what happens ? Name five major categories of neurotoxic substances and give an example each. What is the effect of excessive intake of ethanol on the brain? Chronic alcohol exposure leads to what signs? Ionizing radiation can cause rapidly evolving signs and symptoms including? Affected Brian regions show what?

Answer 18

Metabolic Disorders

Hypoglycemia. Since the brain requires glucose as a sub- strate for energy production, the cellular effects of dimin- ished glucose generally resemble those of global hypoxia. Hippocampal neurons are particularly susceptible to hypo- glycemic injury,while cerebellar Purkinje cells are rela- tively spared. As with anoxia, if the level and duration of hypoglycemia are sufficiently severe, there may be wide- spread injury to many areas of the brain.
Hyperglycemia. 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 cor- rected gradually, because rapid correction can produce severe cerebral edema.

Hepatic Encephalopathy. 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 hyponatre- mia, cause the changes in brain function. Because it is only one contributing factor, ammonia levels in symptomatic patients vary widely. Within the CNS, ammonia metabo- lism occurs only in astrocytes through the action of gluta- mine synthetase, and in the setting of hyperammonemia, astrocytes in the cortex and basal ganglia develop swollen, pale nuclei (called Alzheimer type II cells).

Toxic Disorders
Among the major categories of neurotoxic substances are metals, including lead (often causing a diffuse encephalopa- thy), as well as 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 pro- found metabolic disturbances, including brain swelling and death. Chronic alcohol exposure leads to cerebellar dysfunction in about 1% cases, with truncal ataxia, unsteady gait, and nystagmus, associated with atrophy in the ante- rior vermis of the cerebellum.
Ionizing radiation, commonly used to treat intracranial tumors, can cause rapidly evolving signs and symptoms including headaches, nausea, vomiting, and papilledema, even months to years after irradiation. Affected brain regions show large areas of coagulative necrosis, adjacent edema, and blood vessels with thickened walls containing intramural fibrin-like material

Question 19

Degenerative diseases of the CNS are disorders character- ized by what?
Many of these disorders are associated with accumulation of what which serve as a histological hallmark of specific disorders? the clinical manifesta- tions of degenerative diseases are dictated by the pattern of? Patterns that affect the cerebral cortical neurons result in what signs? Those that affect the neurons of the basal ganglia result in what? Those that affect the cerebellum result in ehat? Those that affect the motor neurons result in what? Although many degenerative diseases have primary targets, other brain regions are often affected later in the course of the illness true or false and give an example of this statement.
What is dementia? How does it arise?
What is the most common cause of dementia in the elderly population? How does this disease usually manifest? What does it progress to later? Death usually occurs from what? What is the most important risk factor for this disease?

Answer 19

Degenerative diseases of the CNS are disorders character- ized by the cellular degeneration of subsets of neurons that typically are related by function, rather than by physical location in the brain. Many of these disorders are associ- ated with the accumulation of abnormal proteins, which serve as histologic hallmarks of specific disorders .
the clinical manifesta- tions of degenerative diseases are dictated by the pattern of neuronal dysfunction: those that affect the cerebral corti- cal neurons result in loss of memory, language, insight, and planning, all components of dementia; those that affect the neurons of the basal ganglia result in movement disorders; those that affect the cerebellum result in ataxia; and those that affect motor neurons result in weakness. Although many degenerative diseases have primary targets, other brain regions are often affected later in the course of the illness; thus, while Huntington disease often has move- ment disorders as an early symptom, later cortical involve- ment typically results in the development of cognitive changes as well. Dementia is defined as the development of memory impairment and other cognitive deficits severe enough to decrease the affected person’s capacity to func- tion at the previous level despite a normal level of consciousness. It arises during the course of many neuro- degenerative diseases; it also can accompany numerous other diseases that injure the cerebral cortex .

Alzheimer Disease
Alzheimer disease (AD) is the most common cause of dementia in the elderly population. The disease usually manifests with the insidious onset of impaired higher intel- lectual function and altered mood and behavior. Later, this progresses to disorientation, memory loss, and aphasia, findings indicative of severe cortical dysfunction, and over another 5 to 10 years, the patient becomes profoundly dis- abled, mute, and immobile. Death usually occurs from intercurrent pneumonia or other infections. Age is an important risk factor for AD;

Question 20

State the disease,the protein involved and the location.

Name five major causes of dementia or cognitive impairment and give three examples under each major cause

Answer 20

Disease
 Protein
 Location
 Alzheimer disease 
Aβ -
Extracellular 
Tau- Neurons

Frontotemporal lobar degeneration
Tau
Neurons

Progressive supranuclear palsy
Tau
Neurons and glia

Corticobasal degeneration
Tau
Neurons and glia(location)

 Parkinson disease 
α-Synuclein 
Neurons
 Multiple system atrophy(disease) 
α-Synuclein (protein)
Glia and some neurons(location)

Frontotemporal lobar degenerations(disease)
TDP-43
Neurons

 Amyotrophic lateral sclerosis(disease)
TDP-43 (protein) Neurons (location)
SOD-1 (familial disease) (protein) -Neurons(location)
 Huntington disease 
Huntingtin 
Neurons
 Spinocerebellar ataxias(disease)
Ataxins (various) (protein)
Neurons(location)

Primary Neurodegenerative Disorders
 Alzheimer disease
Frontotemporal lobar degeneration Lewy body dementia
Huntington disease
Spinocerebellar ataxia (certain forms)

 Infections:
 Prion disease
HIV associated neurocognitive disorder Progressive multifocal leukoencephalopathy Viral encephalitis
Neurosyphilis
Chronic meningitis

Vascular and Traumatic Diseases:
Multifocal cerebral infarction
Severe hypertensive cerebrovascular disease
Cerebral autosomal dominant arteriopathy with subcortical infarction
and leukoencephalopathy (CADASIL) Chronic traumatic encephalopathy

 Metabolic and Nutritional Diseases:
 Thiamine deficiency (Wernicke-Korsakoff syndrome) Vitamin B12 deficiency
Niacin deficiency (pellagra)
Endocrine diseases

Miscellaneous:
Neuronal storage diseases
Toxic injury (from mercury, lead, manganese, bromides, others)

Question 21

What causes Alzheimer’s disease ?
How is Aβ created? Mutations in what leads to familial AD how? The protein amyloid precursor protein (APP) is located on which chromosome? Risk of AD is higher in those with what? And give two examples of such people.
What is another major genetic risk factor of AD? How does apolipoprotein E called ε4 (ApoE4) influence Aβ accumulation ? What is a feature of end stage AD? Small aggregates of Aβ may be pathogenic why? Large deposits in the form of plaques also cause what ? presence of Aβ also leads to what which causes what?

Macroscopic exam of the brain shows what which results in what? With significant atrophy what is seen? At the microscopic level how is AD diagnosed? What is the progressive involvement of the different parts of the brain in AD? What methods are helpful in assessing the true lesional burden? Neuritic plaques are of what nature and are often where? Plaques can be found where as well? What contains Aβ? What are diffuse plaques and where are they typically found? What are Neurofibrillary tangles ? Where are they commonly found?

Answer 21

PATHOGENESIS
a peptide called beta amyloid, or Aβ, accumulates in the brain over time, initiating a chain of events that result in AD. 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 (Fig. 22–24). APP also can be cleaved by α-secretase and γ-secretase, which liberates a different peptide that is non- pathogenic. Mutations in APP or in components of γ-secretase (presenilin-1 or presenilin-2) lead to familial AD by increasing the rate at which Aβ is generated. The APP gene is located
on chromosome 21, and the risk of AD also is higher in those with an extra copy of the APP gene, such as patients with trisomy 21 (Down syndrome) and persons with small inter- stitial duplications of APP, presumably because this too leads to greater Aβ generation. The other major genetic risk factor is a variant of apolipoprotein E called ε4 (ApoE4). Each ApoE4 allele that is present increases the risk of AD by approximately 4 fold and also appears to lower the age of onset. How ApoE4 influences Aβ accumulation is unknown; it may increase Aβ aggregation or deposition, or decrease Aβ clearance.
While large deposits of Aβ are a feature of end-stage AD, small aggregates of Aβ may also be pathogenic, as they alter neurotransmission and are toxic to neurons and synaptic endings. Large deposits, in the form of plaques, also lead to neuronal death, elicit a local inflammatory response that can result in further cell injury, and may cause altered region-to- region communication through mechanical effects on axons and dendrites.
The presence of Aβ also leads to hyperphosphorylation of the neuronal microtubule binding protein tau. This increased level of phosphorylation causes tau to redistribute from axons into dendrites and cell bodies, where it aggregates into tangles, which also contribute to neuronal dysfunction and cell death.

MORPHOLOGY
Macroscopic examination of the brain shows a variable degree of cortical atrophy, resulting in a widening of the cerebral sulci that is most pronounced in the frontal, tempo- ral, and parietal lobes. With significant atrophy, there is com- pensatory ventricular enlargement (hydrocephalus ex vacuo). At the microscopic level, AD is diagnosed by the presence of plaques (an extracellular lesion); and neurofibrillary tangles (an intracellular lesion) (Fig. 22–25). Because these may also be present to a lesser extent in the brains of elderly nondemented persons, the current criteria for a diagnosis of AD are based on a combination of clinical and pathologic features. There is a fairly constant progressive involvement of different parts of the brain: pathologic changes (specifically plaques, tangles, and the associated neuronal loss and glial reaction) are evident first in the entorhinal cortex, then in the hippocampal formation and isocortex, and finally in the neo- cortex. Silver staining or immunohistochemistry methods are extremely helpful in assessing the true lesional burden.
Neuritic plaques are focal, spherical collections of dilated, tortuous, silver-staining neuritic processes (dystro- phic neurites), often around a central amyloid core (Fig. 22–25, A). Neuritic plaques range in size from 20 to 200 μm in diameter; microglial cells and reactive astrocytes are present at their periphery. Plaques can be found in the hippocampus and amygdala as well as in the neocortex.The amyloid core contains Aβ .Aβ deposits also can be found that lack the surrounding neuritic reaction, termed diffuse plaques; these typically are found in the superficial cerebral cortex, the basal ganglia, and the cerebel- lar cortex and may represent an early stage of plaque development.
Neurofibrillary tangles are bundles of paired helical filaments visible as basophilic fibrillary structures in the cytoplasm of the neurons that displace or encircle the nucleus; tangles can persist after neurons die, becoming a form of extracellular pathology. They are commonly found in cortical neurons, especially in the entorhinal cortex, as well as in the pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei. A major component of paired helical filaments is abnormally hyperphosphorylated tau (Fig. 22–25, C). Tangles are not specific to AD, being found in other degenerative diseases as well.

Question 22

frontotemporal lobar degeneration (FTLD) dis- orders share clinical features stemming from what? What happens when the frontal lobe bears the greatest burden of disease? And when it begins in the temporal lobe what is often the presenting complaints? These symptoms precede what? On gross inspection of the brain what is seen? Dif- ferent subgroups are characterized by neuronal inclusions involving the affected regions. In some cases the defining inclusions contain tau (FTLD-tau), but the configuration of the tau inclusions differs from the tau-containing tangles of AD. FTLD-tau sometimes is caused by mutations in the gene encoding tau. One well-recognized subtype of FTLD- tau is Pick disease, which is associated with smooth, round inclusions known as Pick bodies. The other major form of FTLD is characterized by aggregates containing the DNA/ RNA-binding protein TDP-43 (FTLD-TDP43). This form of FTLD is associated with predominantly frontal lobe cogni- tive impairment. It is sometimes caused by mutations in the gene encoding TDP-43, which is also mutated in a subset of cases of amyotrophic lateral sclerosis (described later).
True or false
What is Parkinson’s disease? These types of motor disturbances may be seen in. Range of diseases that do what? Parkinsonism can be induced by drugs such as? Among the neurode- generative diseases, most cases of parkinsonism are caused by what which is associated with what? Name some other diseases in which parkinsonismmay be present.

Answer 22

Frontotemporal Lobar Degeneration
Another major category of disease that results in dementia is called frontotemporal lobar degeneration (FTLD). These dis- orders share clinical features (progressive deterioration of language and changes in personality) stemming from the degeneration and atrophy of temporal and frontal lobes; the clinical syndromes commonly are referred to as fronto- temporal dementias. When the frontal lobe bears the greatest burden of disease, behavioral changes often dominate, whereas when the disease begins in the temporal lobe, language problems often are the presenting complaint. These symptoms precede memory disturbances, which can assist in their separation from AD on clinical grounds.
On gross inspection, there is atrophy of the brain that predominantly affects the frontal and temporal lobes.
Parkinson Disease
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. Parkinsonism can be induced by drugs such as dopamine antagonists or toxins that selec- tively injure dopaminergic neurons. Among the neurode- generative diseases, most cases of parkinsonism are caused by Parkinson disease (PD), which is associated with charac- teristic neuronal inclusions containing α-synuclein. Other diseases in which parkinsonism may be present include multiple system atrophy (MSA), in which α-synuclein aggre- gates are found in oligodendrocytes; progressive supranu- clear palsy (PSP) and corticobasal degeneration (CBD), which are both associated with tau-containing inclusions in neurons and glial cells; and postencephalitic parkinsonism, which was associated with the 1918 influenza pandemic.

Question 23

How is Parkinson’s disease caused genetically? What’s the diagnostic feature of the disease?
Name other genetic forms of PD?
Another cause of PD is mutations in what? Histopathological exam of cases associated w this mutations may show what? Some forms of familial PD are associated with mutations in what genes? What’s the function of these genes? What is a typical gross finding at autopsy of a PD patient? Microscopic features include what? What are Lewy bodies? On ultrasound exam Lewy bodies consist of what? What’s the major histologic finding? As implied by the occurrence of a broad array of neuro- logic deficits in PD, immunohistochemical staining for α- synuclein highlights what? These lesions first appear where before involvement w where? As implied by dementia these lesions eventually appear where? PD commonly
Manifests as what disorder? The disease usually progresses over how many years eventually producing what? Death is the result of what? What disorder associated w loss of a certain pathway is an important feature of PD? Lesions can be found where? In line w studies showing what? What things emerges in many persons w PD and is attributable to the involvement of what ? What is Lewy body dementia

Answer 23

Point mutations and duplications of the gene encoding α-synuclein, a protein involved in synaptic transmission, cause autosomal dominant PD. Even in sporadic PD, the diagnostic feature of the disease—the Lewy body—is an inclusion containing α-synuclein. The linkage between α-synuclein and disease pathogenesis is unclear, but other genetic forms of PD provide some clues. Two other causative genetic loci encode the proteins parkin, an E3 ubiquitin ligase, and UCHL-1, an enzyme involved in recycling of ubiquitin from proteins tar- geted to the proteasome, suggesting that defects in protein degradation may have a pathogenic role. Another tantalizing clue comes from the association of PD with mutations in a protein kinase called LRRK2; histopathologic examination of cases associated with LRRK2 mutations may show either Lewy bodies containing α-synuclein or tangles containing tau. Finally, some forms of familial PD are associated with muta- tions in the PARK7 or PINK1 genes, both of which appear to be important for normal mitochondrial function

typical gross finding at autopsy is pallor of the substantia nigra (Fig. 22–26, A and B) and locus ceruleus. Microscopic features include loss of the pigmented, catecholaminergic neurons in these regions associated with gliosis. Lewy bodies may be found in those neurons that remain. These are single or multiple, intracytoplasmic, eosin- ophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo. On ultrastructural examina- tion, Lewy bodies consist of fine filaments, densely packed in the core but loose at the rim, composed of α-synuclein and other proteins, including neurofilaments and ubiquitin. The other major histologic finding is Lewy neurites, dystrophic neurites that also contain abnormally aggregated α-synuclein.
As implied by the occurrence of a broad array of neuro- logic deficits in PD, immunohistochemical staining for α- synuclein highlights more subtle Lewy bodies and Lewy neurites in many brain regions outside of the substantia nigra and in nondopaminergic neurons. These lesions appear first in the medulla and then in the pons, before involvement of the substantia nigra. As implied by the dementia, Lewy bodies and Lewy neurites eventually appear in the cerebral cortex and subcortical areas, including the cholinergic cells of the basal nucleus of Meynert and the amygdala.

Clinical Features
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 intercurrent infection or trauma from frequent falls caused by postural instability.
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 potentially prob- lematic fluctuations in motor function.
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 can be found lower in the brain stem (in the dorsal motor nucleus of the vagus and in the reticular formation) in advance of nigral involve- ment, in line with clinical studies showing that autonomic dysfunction and behavioral disorders often are present in advance of the motor problems. Dementia, typically with a mildly fluctuating course and hallucinations, emerges in many persons 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).

Question 24

What is Huntington disease (HD)
The movement disorder is of what character? Which movements are typical? The disease is progressive true or false? Name some early cognitive symptoms. Does HD carry an increased risk of suicide? What causes HD? What do normal alleles contain? When is the course of the illness not affected by repeat length? What is anticipation and why would it occur? HD appears to be chased by what else? What is the mutant protein subject to? What do smaller aggregates of abnormal protein fragments lead to?
On gross exam what does the brain look like? Pathologic changes develop over the course of illness in ehat way? What happens to the globus pallidus and atrophy is frequently seen where? Microscopic exam reveals what? What things disappear early in the disease? There is a strong correlation between the severity of motor symptoms and what? There’s an association between what and what? In remaining striata neurons and in the vortex what are seen?

Answer 24

Huntington disease (HD) is an autosomal dominant move- ment disorder associated with degeneration of the striatum (caudate and putamen). The movement disorder is chorei- form (dancelike), with increased and involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical. The disease is relentlessly pro- gressive, 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 progres- sion to a severe dementia. As a part of these early behav- ioral changes, HD carries an increased risk of suicide.

PATHOGENESIS
HD is caused by CAG trinucleotide repeat expansions in a gene located on 4p16.3 that encodes the protein hun- tingtin. 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 strong genotype- phenotype correlation, with larger numbers of repeats result- ing in earlier-onset disease. Once the symptoms appear, however, the course of the illness is not affected by repeat length. Further expansions of the pathologic CAG repeats can occur during spermatogenesis, so paternal transmission may be associated with earlier onset in the next generation, a phenomenon referred to as anticipation ?
HD appears to be caused by a toxic gain-of-function muta- tion somehow 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 the critical toxic agent. These aggregates may sequester transcription factors, disrupt protein degradation pathways, perturb mitochondrial function, or alter brain-derived neuro- trophic factor (BDNF) signaling. It is likely that some combination of these aberrations contributes to HD pathogenesis.

MORPHOLOGY
On gross examination, the brain is small and shows striking atrophy of the caudate nucleus and, sometimes less dramati- cally, the putamen (Fig. 22–27). Pathologic changes develop over the course of the illness in a medial to lateral direction in the caudate and from dorsal to ventral in the putamen. The globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated. Atrophy frequently is also seen in the frontal lobe, less often in the parietal lobe, and occasionally in the entire cortex.
Microscopic examination reveals severe loss of neurons from affected regions of the striatum. The medium-sized, spiny neurons that release the neurotransmitters γ- aminobutyric acid (GABA), enkephalin, dynorphin, and sub- stance P are especially sensitive, disappearing early in the disease. Also seen is fibrillary gliosis, which is more extensive than in the usual reaction to neuronal loss. There is a strong correlation between the degree of degeneration in the stria- tum and the severity of motor symptoms; there is also an association between cortical neuronal loss and dementia. In remaining striatal neurons and in the cortex, there are intra- nuclear inclusions that contain aggregates of ubiquitinated huntingtin protein

Question 25

What are Spinocerebellar ataxias (SCAs) ? How are they distinguished from one another? This group of diseases affects what parts of the nervous system? Due to this clinical findings may include what? What usually occurs in affected areas associated w mild gliosis? What can help distinguish between well characterized subtypes? Wha causes SCA? What is friedreich ataxia? Most patients develop ehat? What causes the is disease? Decreased frataxin leads to what? In summary neurodegenerative diseases cause symptoms that depend on what? Cortical diseases manifest as what? Basal ganglia diseases manifests as what? What evolving process can change the phenotype of a disease over time and give an example of such disease. What are the pathology hallmarks of neurodegenerative diseases. Familial forms of these diseases are associated with ehat

Answer 25

Spinocerebellar Ataxias
Spinocerebellar ataxias (SCAs) are a clinically heteroge- neous group of diseases that are frequently caused by trinucleotide repeat expansion mutations. They are distin- guished from one another by differences in causative muta- tions, 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. As a result, clinical findings may include a combination of cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy. Degeneration of neurons, often without distinctive histo- pathologic changes, occurs in the affected areas and is asso- ciated with mild gliosis. The additional clinical symptoms that accompany the ataxia can help distinguish between well-characterized subtypes.

As with Huntington disease, several forms of SCA (SCA types 1, 2, 3, 6, 7, and 17 and dentatorubropallidoluysian atrophy) are caused by CAG repeat expansions encoding polyglutamine tracts in various genes. In these forms of SCA, neuronal intranuclear inclusions are present contain- ing the abnormal protein and there is an inverse correlation between the degree of repeat expansion and age of onset. Other SCAs are caused by trinucleotide repeat expansions in untranslated regions or by other types of mutations.
Friedreich ataxia is an autosomal recessive disorder that generally manifests in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria. Most patients develop pes cavus and kyphoscoliosis, and there is a high incidence of cardiac disease and diabetes. The disease usually is caused by a GAA trinucleotide repeat expansion in the gene encoding frataxin, a protein that regulates cellular iron levels, particularly in the mitochon- dria. Decreased frataxin leads to mito- chondrial dysfunction as well as increased oxidative damage.

SUMMARY
Neurodegenerative Diseases
• Neurodegenerative diseases cause symptoms that depend on the pattern of brain involvement. Cortical disease usually manifests as cognitive change, alterations in per- sonality, and memory disturbances; basal ganglia disorders usually manifest as movement disorders.
• Many neurodegenerative diseases preferentially affect a primary set of brain regions, but other regions can be involved later in the disease course.This evolving process can change the phenotype of the disease over time—as with the appearance of cognitive impairments in people initially affected by the movement disorder of Parkinson disease.
• Many of the neurodegenerative diseases are associated with various protein aggregates, which serve as pathologic hallmarks. It is unclear whether these striking inclusions and deposits are critical mediators of cellular degenera- tion. Familial forms of these diseases are associated with mutations in the genes encoding these proteins or con- trolling their metabolism.

Question 26

Amyotrophic lateral sclerosis (ALS) results from what ? Loss of lower motor neurons results in what signs? Loss of upper motor neurons results in ehat signs? What is usually unaffected? What usually occurs sometimes as a frontotemporal dementia? This disease affects ehich gender more and when and how does it manifest clinically? As the disease progressed to involve more of the motor system what happens? What is the usual cause of death and what leads to this cause? What is bulbar amyotrophic lateral sclerosis? What abnormalities dominate in this ? What is the most frequent genetic cause ? These mutations generate what? What are the next two most common causative genes? What can cause frontotemporal lobar degeneration or a disease w overlapping features of both ALS and FTLD?
Where are the most striking gross changes found? In severe cases what can happen? Microscopic exam demonstrates what? What results in degeneration of the descending corticospinal tracts? Where is it usually seen? When will skeletal muscles show neurogenic atrophy

Answer 26

Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) results from the death of lower motor neurons in the spinal cord and brain stem, and of upper motor neurons (Betz cells) in the motor cortex. The loss of lower motor neurons results in denervation of muscles, muscular atrophy (the “amyotrophy” of the con- dition), weakness, and fasciculations, while the loss of upper motor neurons results in paresis, hyperreflexia, and spasticity, along with a Babinski sign. An additional con- sequence of upper motor neuron loss is degeneration of the corticospinal tracts in the lateral portion of the spinal cord (“lateral sclerosis”). Sensation usually is unaffected, but cognitive impairment does occur, sometimes as a fronto- temporal dementia.
The disease affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later, usually beginning with subtle asymmetric distal extremity weakness. As the disease progresses to involve more of the motor system, muscle strength and bulk dimin- ish and involuntary contractions of individual motor units, termed fasciculations, occur. The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection, which is the usual cause of death. The balance between upper and lower motor neuron involvement can vary, although most patients exhibit involvement of both. In some patients, degeneration of the lower brain stem cranial motor nuclei occurs early and progresses rapidly, a pattern of disease referred to as bulbar amyotrophic lateral sclerosis. With this disease pattern, abnormalities of swallowing and speaking dominate.

PATHOGENESIS
More than a dozen genes have been implicated, but the most frequent genetic cause is mutations in the superoxide dismutase gene, SOD-1, on chromosome 21. These muta- tions are thought to generate abnormal misfolded forms of the SOD-1 protein, which may trigger the unfolded protein response and cause apoptotic death of neurons. The next two most common causative genes both encode DNA/RNA binding proteins, TDP-43 and FUS; how these mutations cause disease is unknown. As already mentioned, mutations in TDP-43 also can cause frontotemporal lobar degeneration (FTLD) or a disease with overlapping features of both ALS and FTLD.
MORPHOLOGY
The most striking gross changes are found in anterior roots of the spinal cord, which are thin and gray (rather than white). In especially severe cases, the precentral gyrus (motor cortex) may be mildly atrophic. Microscopic examination demonstrates a reduction in the number of anterior horn cell neurons throughout the length of the spinal cord associated with reactive gliosis and loss of anterior root myelinated fibers. Similar findings are found with involvement of motor cranial nerve nuclei except those supplying the extraocular muscles, which are spared except in very longstanding survi- vors. Remaining lower motor neurons often harbor cytoplas- mic inclusions that contain TDP-43, except in those cases in which the underlying cause is a mutation in SOD-1.
Death of upper motor neurons—a finding that may be hard to demonstrate microscopically—results in degenera- tion of the descending corticospinal tracts. This is usually easily seen in the spinal cord. With the loss of innervation from the death of anterior horn cells, skeletal muscles show neurogenic atrophy.

Question 27

What are the four unique characteristics of tumors of the nervous system?
What are gliomas? What are the major types of gliomas? The most common types of gliomas are of what characteristics and give some examples. Which type of gliomas tend to form solid masses? What’s re the most common astrocytomas? Where are diffuse astrocytomas usually found? What are the most common presenting signs and symptoms? What are the histological features of diffuse astrocytomas ? Well-differentiated astrocytomas can be static for several years, but at some point they progress; true or false in glioblastoma what mutations have central roles in tumorigenesis? What’s the appearance of well differentiated astrocytomas? The cut surface of the tumor is of what characteristic? What is the characteristic of glioblastoma?some areas of glioblastoma are of what appearance? Well differentiated astrocytomas are characterized by?

The transition between neoplastic and normal tissue is indistinct, and tumor cells can be seen infiltrating normal tissue many centimeters from the main lesion. True or false. Anaplastic astrocytomas show regions of what? Glioblastoma of histological appearance is similar to what? What are pilocytic astrocytomas? Where are they mostly located? There is often what associated w the tumor? Symptomatic recurrence from incompletely respected lesions is often associated w what? Tumors that involve the hypothalamus are especially problematic because they cannot be resected completely true or false. A high proportion of pilocytic astrocytomas have what mutations? What mutations are not found in pilocytic tumors? What is the morphology of policy astrocytoma? The tumor is composed of what? What things are present ? And which are rare?

Answer 27

Tumors of the nervous system have unique characteris- tics that set them apart from neoplastic processes elsewhere in the body.
• Thesetumorsdonothavedetectablepremalignantorin situ stages comparable to those of carcinomas.
• Even low-grade lesions may infiltrate large regions of the brain, leading to serious clinical deficits, nonresect- ability, and poor prognosis.
• Theanatomicsiteoftheneoplasmcaninfluenceoutcome independent of histologic classification due to local effects (e.g., a benign meningioma may cause cardiores- piratory arrest from compression of the medulla) or non- resectability (e.g., brain stem gliomas).
• Even the most highly malignant gliomas rarely spread outside of the CNS; in addition to local infiltration, the subarachnoid space allows for spread to distant sites along the neuroaxis.

Gliomas
Gliomas are tumors of the brain parenchyma that are clas- sified histologically on the basis of their resemblance to different types of glial cells. The major types of glial tumors are astrocytomas, oligodendrogliomas, and ependymomas. The most common types are highly infiltrative or “diffuse gliomas,” including astrocytic, oligodendroglial, and mixed forms. In contrast, ependymomas tend to form solid masses.

Astrocytoma
Several different categories of astrocytic tumors are recog- nized, the most common being diffuse and pilocytic astro- cytomas. Different types of astrocytomas have characteristic histologic features, anatomic distributions, and clinical features.
Diffuse Astrocytoma
Diffuse astrocytomas account for about 80% of adult gliomas. They usually are found in the cerebral hemispheres. The most common presenting signs and
symptoms are seizures, headaches, and focal neurologic deficits related to the anatomic site of involvement. On the basis of histologic features, they are stratified into three groups: well-differentiated astrocytoma (grade II/IV), anaplastic astrocytoma (grade III/IV), and glioblastoma (grade IV/ IV), with increasingly grim prognosis as the grade increases.

In glioblastoma, loss-of-function mutations in the p53 and Rb tumor suppressor pathways and gain-of-function muta- tions in the oncogenic PI3K pathways have central roles in tumorigenesis.

MORPHOLOGY
Well-differentiated astrocytomas are poorly defined, gray, infiltrative tumors that expand and distort the invaded brain without forming a discrete mass. Infiltration beyond the grossly evident margins is always present. The cut surface of the tumor is either firm or soft and gelatinous; cystic degeneration may be seen. In glioblastoma, variation in the gross appearance of the tumor from region to region is characteristic .Some areas are firm and white, others are soft and yellow (the result of tissue necrosis), and still others show regions of cystic degeneration and hemorrhage.
Well-differentiated astrocytomas are characterized by a mild to moderate increase in the number of glial cell nuclei, somewhat variable nuclear pleomorphism, and an intervening feltwork of fine, glial fibrillary acidic protein (GFAP)-positive astrocytic cell processes that give the background a fibrillary appearance. Ana- plastic astrocytomas show regions that are more densely cellular and have greater nuclear pleomorphism; mitotic figures are present. Glioblastoma has a histologic appearance similar to that of anaplastic astrocytoma, as well as either necrosis (often with pseudopalisading nuclei) or vascular pro- liferation .

Pilocytic Astrocytoma
Pilocytic astrocytomas are relatively benign tumors, typi- cally affecting children and young adults. Most commonly located in the cerebellum, they also may involve the third ventricle, the optic pathways, spinal cord, and occasionally the cerebral hemispheres. There is often a cyst associated with the tumor, and symptomatic recurrence from incom- pletely resected lesions is often associated with cyst enlarge- ment, rather than growth of the solid component..
A high proportion of pilocytic astrocytomas have acti- vating mutations in the serine-threonine kinase BRAF— either a specific point mutation (V600E) that is also found in many other cancers ,or more commonly a partial tandem duplication event. Mutations in IDH1 and IDH2 (common in low-grade diffuse astrocytomas) are not found in pilocytic tumors.

. MORPHOLOGY
A pilocytic astrocytoma often is cystic, with a mural nodule in the wall of the cyst; if solid, it is usually well circumscribed. The tumor is composed of bipolar cells with long, thin “hair- like” processes that are GFAP-positive. Rosenthal fibers, eosinophilic granular bodies, and microcysts are often present; necrosis and mitoses are rare.

Question 28

When are oligodendrogliomas under glial tumors or glioblastomas detected(in what decade)? What do these patients typically present w? Where are the lesions mostly found? Such patients enjoy better prognosis than than which patients? What are the most common genetic findings in oligodendroglioma ? Well differentiated oligodendrogliomas are of what characteristic? On microscopic e am what is seen? The tumor typically contains what? Calcification ranges from what to what? Anaplastic oligodendroglioma have what morphology?
Ependymomas most often arise next to what? In the first two decades of life where do they typically occur? In adults where is the most common location of these tumors? Tumors in this site are particu frequent in what setting? The clinical outcome for com- pletely resected supratentorial and spinal ependymomas is better than for which people? In the fourth ventricle these tumors of what appearance? The tumors are composed of what? Tumor cells have what shape? Which are more frequent present? Anaplastic ependymomas show what?

Answer 28

Oligodendroglioma
Oligodendrogliomas account for 5% to 15% of gliomas and most commonly are detected in the fourth and fifth decades of life. Patients may have had several years of antecedent neurologic complaints, often including seizures. The lesions are found mostly in the cerebral hemispheres, mainly in the frontal or temporal lobes.
Patients with oligodendrogliomas enjoy a better prog- nosis than that for patients with astrocytomas of similar grade.. The most common genetic findings are deletions of chromosomes 1p and 19q, alterations that typically occur together.

MORPHOLOGY
Well-differentiated oligodendrogliomas (WHO grade II/IV) are infiltrative tumors that form gelatinous, gray masses and may show cysts, focal hemorrhage, and calcification. On microscopic examination, the tumor is composed of sheets of regular cells with spherical nuclei containing finely granular-appearing chromatin (similar to that in normal oligodendrocytes) surrounded by a clear halo of cytoplasm .The tumor typically contains a delicate network of anastomosing capillaries. Calcification, present in as many as 90% of these tumors, ranges in extent from microscopic foci to massive depositions. Anaplastic oligodendroglioma (WHO grade III/IV) is a more aggressive subtype with higher cell density, nuclear anaplasia and mitotic activity.

Ependymoma
Ependymomas most often arise next to the ependyma- lined ventricular system, including the central canal of the spinal cord. In the first 2 decades of life, they typically occur near the fourth ventricle and constitute 5% to 10% of the primary brain tumors in this age group. In adults, the spinal cord is their most common location; tumors in this site are particularly frequent in the setting of neurofibro- matosis type 2 .The clinical outcome for com- pletely resected supratentorial and spinal ependymomas is better than for those in the posterior fossa.

MORPHOLOGY
In the fourth ventricle, ependymomas typically are solid or papillary masses extending from the ventricular floor. The tumors are composed of cells with regular, round to oval nuclei and abundant granular chromatin. Between the nuclei is a variably dense fibrillary background. Tumor cells may form round or elongated structures (rosettes, canals) that resemble the embryologic ependymal canal, with long, deli- cate processes extending into a lumen .more frequently present are perivascular pseudorosettes in which tumor cells are arranged around vessels with an inter- vening zone containing thin ependymal processes. Anaplastic ependymomas show increased cell density, high mitotic rates, necrosis, and less evident ependymal differentiation.

Question 29

What is central neurocytoma ? What are they characterized by? What are gangliogliomas? Most of these tumors are slow growing but the glial component occasionally becomes what? These lesions often manifest w what? What is Dysembryoplastic neuroepithelial tumor ? How does it often manifest? Where is it typically located? These typically form what?
Some tumors of neuroectodermal origin have what neuroectodermal origin ? What is the most common tumor of neuroectodermal origin ? Where does Medulloblastoma occurs predominantly and in which group of people? Which markers are nearly always expressed? Is it malignant or benign? What are primitive neuroectodermal tumors ? In kids where are medulloblastomas located? What is the appearance of the tumor?
These tumors are extremely cellular with sheets of what cells? What are the characteristics of the individual cells? Focal neuronal differentiation is seen in the form of what? They are characterized by what? In general, tumors with MYC amplifications are associated with poor out- comes, while those linked with mutations in genes of the WNT signaling pathway have a more favorable course. Many tumors also have mutations that activate the sonic hedgehog (shh) pathway, which has a critical role in tumorigenesis but an uncertain relationship to outcome. True or false

Answer 29

Neuronal Tumors
Central neurocytoma is a low-grade neoplasm found within and adjacent to the ventricular system (most commonly the lateral or third ventricles), characterized by evenly spaced, round, uniform nuclei and often islands of neuropil.
Gangliogliomas are tumors with a mixture of glial elements, usually a low-grade astrocytoma, and mature- appearing neurons. Most of these tumors are slow-growing, but the glial component occasionally becomes frankly ana- plastic, and the disease then progresses rapidly. These lesions often manifest with seizures.
Dysembryoplastic neuroepithelial tumor is a distinctive, low-grade childhood tumor that grows slowly and carries a relatively good prognosis after resection; it often mani- fests as a seizure disorder. It typically is located in the superficial temporal lobe and consists of small round neu- ronal cells arranged in columns and around central cores of processes. These typically form multiple discrete intra- cortical nodules that have a myxoid background. Also present are well-differentiated “floating” neurons within pools of mucopolysaccharide-rich myxoid fluid.

Embryonal (Primitive) Neoplasms
Some tumors of neuroectodermal origin have a primitive “small round cell” appearance that is reminiscent of normal progenitor cells encountered in the developing CNS. Dif- ferentiation is often limited, but may progress along mul- tiple lineages. The most common is the medulloblastoma, accounting for 20% of pediatric brain tumors.

Medulloblastoma
Medulloblastoma occurs predominantly in children and exclusively in the cerebellum. Neuronal and glial markers are nearly always expressed, at least to a limited extent. It is highly malignant, and the prognosis for untreated patients is dismal; however, medulloblastoma is exqui- sitely radiosensitive. Tumors of similar histologic type and a poor degree of differentiation can be found elsewhere in the nervous system, where they are called primitive neuroectodermal tumors (PNETs). MORPHOLOGY
In children, medulloblastomas are located in the midline of the cerebellum; lateral tumors occur more often in adults. The tumor often is well circumscribed, gray, and friable and may be seen extending to the surface of the cerebellar folia and involving the leptomeninges . Medul- loblastomas are extremely cellular, with sheets of anaplastic (“small blue”) cells. Individual tumor cells are small, with little cytoplasm and hyperchromatic nuclei; mitoses are abundant. Often, focal neuronal differentiation is seen in the form of the Homer Wright or neuroblastic rosette, which closely resembles the rosettes encountered in neuroblastomas; they are characterized by primitive tumor cells surrounding central neuropil (delicate pink material formed by neuronal processes).

Question 30

Primary CNS lymphoma occur mostly as what? It is most common in which people? Regardless of the clinical context, primary brain lymphoma is an aggressive disease with relatively poor response to chemotherapy as com- pared with peripheral lymphomas. True or false? Patients w primary brain lymphoma are often found where and is an uncommon late complication? Lymphoma originating outside the CBS rarely spreads where and if it does what happens? W the morphology of primary brain lymphoma which structures do the lesions involve ? What kind of spread is common? The tumors are relatively well defined as compared to what? EBV associated tumors show what? Microscopically what may be seen? Primary brain germ cell tumors occur where? Germ cell tumors in what region show strong male predominance? What’s the common primary CNS germ cell tumor? Secondary CNS involve- ment by metastatic gonadal germ cell tumors also occurs. True or false
What are meningiomas? Which people do they usually occur in and are often attached where? Where do these tumors arise from? When do they usually come to attention? What feature is associated w an increased risk of recurrence? Overall prognosis is determined by what? When should a diagnosis of neurofibromatosis type 2 (NF2) be considered? About half of menin- giomas not associated with NF2 have what? Mutations in NF2 are more common in tumors with what growth patterns?

Answer 30

Other Parenchymal Tumors
Primary Central Nervous System Lymphoma
Primary CNS lymphoma, occurring mostly as diffuse large B cell lymphomas, accounts for 2% of extranodal lympho- mas and 1% of intracranial tumors. It is the most common CNS neoplasm in immunosuppressed persons, in whom the tumors are nearly always positive for the oncogenic Epstein-Barr virus.
Patients with primary brain lymphoma often are found to have multiple tumor nodules within the brain paren- chyma, yet involvement outside of the CNS is an uncom- mon late complication. Lymphoma originating outside the CNS rarely spreads to the brain parenchyma; when it happens, tumor usually is also within the CSF or involve- ment of the meninges. MORPHOLOGY
Lesions often involve deep gray structures, as well as the white matter and the cortex. Periventricular spread is common. The tumors are relatively well defined as compared with glial neoplasms but are not as discrete as metastases. EBV-associated tumors often show extensive areas of necro- sis. Microscopically, malignant cells accumu- late around blood vessels and infiltrate the surrounding brain parenchyma.

Germ Cell Tumors
Primary brain germ cell tumors occur along the midline, most commonly in the pineal and the suprasellar region Germ cell tumors in the pineal region show a strong male predominance. The most common primary CNS germ cell tumor is germinoma, a tumor that closely resembles testicular seminoma

Meningiomas
Meningiomas are predominantly benign tumors that arise from arachnoid meningothelial cells. They usually occur in adults and are often attached to the dura. Meningiomas may be found along any of the external surfaces of the brain as well as within the ventricular system, where they arise from the stromal arachnoid cells of the choroid plexus. They usually come to attention because of vague nonlocal- izing symptoms, or with focal findings referable to com- pression of adjacent brain. Although most meningiomas are easily separable from underlying brain, some tumors infiltrate the brain, a feature that is associated with an increased risk of recurrence. The overall prognosis is deter- mined by the lesion size and location, surgical accessibility, and histologic grade.
When a person has multiple meningiomas, especially in association with eighth-nerve schwannomas or glial tumors, the diagnosis of neurofibromatosis type 2 (NF2) should be considered. Acquired loss-of- function mutations in the NF2 tumor suppressor gene on the long arm of chromosome 22 (22q). These mutations are found in all grades of meningioma, suggesting that they are involved with tumor initiation. Mutations in NF2 are more common in tumors with certain growth patterns (fibroblastic, transitional, and psammomatous).

Question 31

Meningiomas grow as what? Extension into what may be present? What are the varied histological patterns in these tumors? Atypical meningiomas are recognized by what? Anaplastic meningiomas are bigot aggressive tumors that may resemble what? In addition to the direct and localized effects produced by metastases, paraneoplastic syndromes may involve what? Many but not all patients with paraneoplastic syn- dromes have antibodies against tumor antigens. What are Some of the more common patterns
What are the most common primary sites of metastatic lesions ? Metastases form what? What boundary is sharp at the microscopic level?

Answer 31

MORPHOLOGY
Meningiomas (WHO grade I/IV) grow as well-defined dura-based masses that may compress the brain but do not invade it .Extension into the overlying bone may be present. Among the varied histologic patterns are syncytial, named for whorled clusters of cells without visible cell membranes that sit in tight groups; fibroblastic, with elongated cells and abundant collagen deposition between them; transitional, which shares features of the syncytial and fibroblastic types; psammomatous, with numerous psammoma bodies and secretory, with gland-like PAS-positive eosinophilic secretions known as pseudopsammoma bodies.

Atypical meningiomas (WHO grade II/IV) are recog- nized by the presence of certain histologic features (promi- nent nucleoli, increased cellularity, pattern-less growth), and often have a higher mitotic rate. 
Anaplastic (malignant) meningiomas (WHO grade III/IV) are highly aggressive tumors that may resemble a high- grade sarcoma or carcinoma, although there usually is some histologic evidence of a meningothelial cell origin.

Metastatic Tumors
Metastatic lesions, mostly carcinomas. The most common primary sites are lung, breast, skin (mela- noma), kidney, and gastrointestinal tract—together these account for about 80% of cases. Metastases form sharply demarcated masses, often at the gray-white junction, and elicit edema . The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with surrounding reactive gliosis.
In addition to the direct and localized effects produced by metastases, paraneoplastic syndromes may involve the peripheral and central nervous systems, sometimes even preceding the clinical recognition of the malignant neo- plasm. Many but not all patients with paraneoplastic syn- dromes have antibodies against tumor antigens. Some of the more common patterns include
• Subacute cerebellar degeneration resulting in ataxia, with destruction of Purkinje cells, gliosis, and a mild inflam- matory infiltrate
• Limbic encephalitis causing a subacute dementia, with perivascular inflammatory cells, microglial nodules, some neuronal loss, and gliosis, all centered in the medial temporal lobe
• Subacutesensoryneuropathyleadingtoalteredpainsensa- tion, with loss of sensory neurons from dorsal root ganglia, in association with inflammation
• Syndrome of rapid-onset psychosis, catatonia, epilepsy, and coma associated with ovarian teratoma and antibodies against the N-methyl-D-aspartate (NMDA) receptor

Question 32

Several inherited syndromes caused by mutations in various tumor suppressor genes are associated with an increased risk of particular types of cancers. True or false? What is Tuberous sclerosis? CNS hamartomas consist of? Why do they often present acutely with obstructive hydrocephalus? What signs are associated with cortical tubers? Extracerebral lesions include what? Which sites may cysts be found at? Cutaneous lesions include which lesions? Tuberous sclerosis results from what? What is the appearance of cortical hamartomas? What are they composed of? These cells may exhibit what features? Similar abnormal cells present where?

Answer 32

Familial Tumor Syndromes

Tuberous Sclerosis
Tuberous sclerosis (TSC) is an autosomal dominant syn- drome characterized by the development of hamartomas and benign neoplasms involving the brain and other tissues. CNS hamartomas variously consist of cortical tubers and subependymal hamartomas, including a larger tumefactive form known as subependymal giant cell astro- cytoma. Because of their proximity to the foramen of Monro, they often present acutely with obstructive hydro- cephalus. Seizures are associated with cortical tubers and can be difficult to control with antiepileptic drugs. Extracerebral lesions include renal angiomyolipomas, retinal glial hamartomas, pulmonary lymphangiomyomatosis, and cardiac rhabdo- myomas. Cysts may be found at various sites, including the liver, kidneys, and pancreas. Cutaneous lesions include angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and subungual fibromas. TSC results from disruption of either TSC1, which encodes hamartin, or TSC2, which encodes tuberin. The two TSC proteins form a dimeric complex that negatively regulates mTOR, a kinase that senses” the cell’s nutrient status and regulates cellular metabolism. Loss of either protein leads to increased mTOR activity, which disrupts nutritional signaling and increases cell growth. MORPHOLOGY
Cortical hamartomas are firmer than normal cortex and have been likened in appearance to potatoes—hence the appella- tion “tubers.” They are composed of haphazardly arranged large neurons that lack the normal cortical laminar architec- ture. These cells may exhibit a mixture of glial and neuronal features, having large vesicular nuclei with nucleoli (like neurons) and abundant eosinophilic cytoplasm (like gemisto- cytic astrocytes). Similar abnormal cells are present in the subependymal nodules, in which large astrocyte-like cells cluster beneath the ventricular surface.

Question 33

In von Hippel–Lindau Disease affected persons develop what where? Patients may have cysts involving which organs?
What happens to the affected gene? Tumors in patients with this disease have generally lost what? What does it result in? What is the principal neurologic manifestation of this disease? On microscopic exam the lesion consists of what?
In summary tumors of CNs may arise from where? Even low-grade or benign tumors can have poor clinical outcomes, depending on what? Distinct types of tumors affect specific brain regions give an example. Distinct types of tumors affect specific age populations . Give an example. Glial tumors are broadly classified into what? Increasing tumor
Malignancy is associated with more what? What tumors are the dominant type of systemic tumors that metastasize to the nervous sys?

Answer 33

von Hippel–Lindau Disease
In this autosomal dominant disorder, affected persons develop hemangioblastomas within the cerebellar hemi- spheres, retina, and, less commonly, the brain stem, spinal cord, and nerve roots. Patients also may have cysts involv- ing the pancreas, liver, and kidneys and have an increased propensity to develop renal cell carcinoma. The affected gene, the tumor suppressor VHL, encodes a protein that is part of a ubiquitin-ligase complex that targets the transcription factor hypoxia-inducible factor (HIF) for deg- radation. Tumors arising in patients with von Hippel– Lindau disease generally have lost all VHL protein function. As a result, these tumors express high levels of HIF, which drives the expression of VEGF, various growth factors, and sometimes erythropoietin, leading to a form of paraneo- plastic polycythemia.

MORPHOLOGY
The cerebellar capillary hemangioblastoma, the principal neurologic manifestation of the disease, is a highly vascular neoplasm that occurs as a mural nodule associated with a large, fluid-filled cyst. On microscopic examination, the lesion consists of numerous capillary-sized or some- what larger thin-walled vessels separated by intervening stromal cells with vacuolated, lightly PAS-positive, lipid-rich cytoplasm.
SUMMARY
Tumors of the Central Nervous System
• Tumors of the CNS may arise from the cells of the cover- ings (meningiomas), the brain (gliomas, neuronal tumors, choroid plexus tumors), or other CNS cell populations (primary CNS lymphoma, germ cell tumors), or they may originate elsewhere in the body (metastases).

• Even low-grade or benign tumors can have poor clinical outcomes, depending on where they occur in the brain.
• Distinct types of tumors affect specific brain regions (e.g., cerebellum for medulloblastoma, an intraventricular loca- tion for central neurocytoma) and specific age populations (medulloblastoma and pilocytic astrocytomas in pediatric age groups, and glioblastoma and lymphoma in older patients).
• Glial tumors are broadly classified into astrocytomas, oli- godendrogliomas, and ependymomas. Increasing tumor malignancy is associated with more cytologic anaplasia, increased cell density, necrosis, and mitotic activity.
• Metastatic spread of brain tumors to other regions of the body is rare, but the brain is not comparably protected against spread of distant tumors. Carcinomas are the dominant type of systemic tumors that metastasize to the nervous system.

Question 34

What does cerebral arterial occlusion leads to? What five factors may be modified by collateral blood flow?
What can limit damage in some regions? There is little collateral flow to which structures? Which infarctions are more common? What thrombi are a frequent source of emboli? What diseases are important predisposing factors? Thromboemboli also arise where? Where do other emboli of venous origin cross over to where? Give some examples of thromboemboli? Which artery is most frequently affected by emboli infarction? Emboli tend to lodge where? Which occlusions are usually superimposed on atherosclerotic plaques? Name come common sites of atherosclerotic plaques. These occlusions may be accompanied by what? Infarcts can be divided in two groups based on what? Name them and what they result from

MORPHOLOGY
The macroscopic appearance of a nonhemorrhagic infarct evolves over time. True or false During the first six hours what’s the appearance of the nonhemorrhagic infarct tissue ? What about by 48 hours? From days 2-10 what happens to the brain? From days 10- week 3 what happens to the brain?
Microscopically the tissue reaction follows a characteristic sequence. What happens after the first 12 hours? What about up to 48hours?
After several months what happens?

The microscopic picture and evolution of hemorrhagic infarction parallel those of ischemic infarction, with the addition of blood extravasation and resorption. True or false
What is seen in the cerebral cortex?
Which parts of the brain are not affected? In persons with coagulopathies, hemorrhagic infarcts may be associated with what?

Answer 34

Focal Cerebral Ischemia
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 flow to structures such as the thalamus, basal ganglia, and deep white matter, which are supplied by deep penetrating vessel

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 ath- eromatous plaques within the carotid arteries or aortic arch. Other emboli of venous origin cross over to the arte- rial circulation through cardiac defects and lodge in the brain (paradoxical embolism) 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.
Thrombotic occlusions causing cerebral infarctions A usually are superimposed on atherosclerotic plaques; common sites are the carotid bifurcation, the origin of the middle cerebral artery, and at either end of the basilar
artery. These occlusions may be accompanied by antero- grade extension, as well as thrombus fragmentation and distal embolization.
Infarcts can be divided into two broad groups based on their macroscopic and corresponding radiologic appear- ance .Nonhemorrhagic infarcts result from acute vascular occlusions and can be treated with thrombolytic therapies, especially if identified shortly after presentation. This approach is contraindicated in hemorrhagic infarcts, which result from reperfusion of ischemic tissue, either through collaterals or after dissolution of emboli, and often produce multiple, sometimes confluent petechial hemor- rhages

During the first 6 hours the tissue is unchanged in appearance, but by 48 hours, the tissue becomes pale, soft, and swollen. From days 2 to 10, the brain turns gelatinous and friable, and the boundary between normal and abnormal tissue becomes more distinct as edema resolves in the adjacent viable tissue. From day 10 to week 3, the tissue liquefies, eventually leaving a fluid-filled cavity lined by dark gray tissue, which gradually expands as dead tissue is resorbed (Fig. 22–7, C).
Microscopically, the tissue reaction follows a characteristic sequence. After the first 12 hours, ischemic neuronal change (red neurons) (Fig. 22–1, A) and cytotoxic and vaso- genic edema predominate. Endothelial and glial cells, mainly astrocytes, swell, and myelinated fibers begin to disintegrate. Up to 48 hours, there is some neutrophilic emigration, which is followed by mononuclear phagocytic cells during the ensuing 2 to 3 weeks. Macrophages containing myelin or red cell breakdown products may persist in the lesion for months to years. As the process of phagocytosis and liquefac- tion proceeds, astrocytes at the edges of the lesion progres- sively enlarge, divide, and develop a prominent network of cytoplasmic extensions.
After several months, the striking astrocytic nuclear and cytoplasmic enlargement regresses. In the wall of the cavity, astrocyte processes form a dense feltwork of glial fibers admixed with new capillaries and a few perivascular connective tissue fibers. In the cerebral cortex, the cavity is delimited from the meninges and subarachnoid space by a gliotic layer of tissue, derived from the molecular layer of the cortex. The pia and arachnoid are not affected and do not contribute to the healing process.
In persons with coagulopathies, hemorrhagic infarcts may be associated with extensive intracerebral hematomas.

Question 35

In intracranial hemorrhage, hemorrhages within the brain are associated with what three things?
Subarachnoid hemorrhages most commonly caused by what ? Subdural or epidural hemorrhages are usually associated with what?
Under primary brain parenchymal hemorrhage spontaneous intraparenchymal hemor- rhages are most common when? Most are due to what? What is the leading cause? Why can Intracerebral hemorrhage be clinically devastating ? Hyper- tensive intraparenchymal hemorrhages typically occur where? What determines its clinical manifestations ? What happens when the person survives ? Acute hemorrhages are characterized by what? With time what happens to the hemorrhages? On microscopic exam early lesions consist of what? Eventually what things appear? What is Cerebral Amyloid Angiopathy(CAA) ? What does the amyloid confer ? What is the effect of amyloid deposition? CAA associated hemorrhages often occur where

Answer 35

Intracranial Hemorrhage
Hemorrhages within the brain are associated with (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 caused by ruptured aneurysms but also occur with other vascular malforma- tions. Subdural or epidural hemorrhages usually are asso- ciated with trauma.

Primary Brain Parenchymal Hemorrhage:
Spontaneous (nontraumatic) intraparenchymal hemor- rhages 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. Hyperten- sion is the leading underlying cause, and brain hemorrhage accounts for roughly 15% of deaths among persons 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. Hyper- tensive intraparenchymal hemorrhages typically occur in the basal ganglia, thalamus, pons, and cerebellum with the location and the size of the bleed determin- ing its clinical manifestations. If the person survives the acute event, gradual resolution of the hematoma ensues, sometimes with considerable clinical improvement.

MORPHOLOGY
Acute hemorrhages are characterized by extravasated blood, which compresses the adjacent parenchyma. With time, hemorrhages are converted to a cavity with a brown, discol- ored rim. On microscopic examination, early lesions consist of clotted blood surrounded by brain tissue showing anoxic neuronal and glial changes as well as edema. Eventually the edema resolves, pigment- and lipid-laden macrophages appear, and proliferation of reactive astrocytes becomes visible at the periphery of the lesion. The cellular events then follow the same time course observed after cerebral infarction.

Cerebral Amyloid Angiopathy
Cerebral amyloid angiopathy (CAA) is a disease in which amyloidogenic peptides, typically the same ones found in Alzheimer disease (discussed later), deposit in the walls of medium- and small-caliber meningeal and cortical vessels. The amyloid confers a rigid, pipelike appearance and stains with Congo red. Amyloid deposition weakens vessel walls and increases the risk of hemorrhages, which differ in distribution from those associated with hypertension. Specifically, CAA-associated hemorrhages often occur in the lobes of the cerebral cortex (lobar hemorrhages).

Question 36

What is the most frequent cause of clinically significant non traumatic subarachnoid hemorrhage? Hemorrhage into the subarachnoid space also may result from what?
Rupture is associated with what? What causes the classical worst headeach I’ve ever had described by patients?
About 90% of saccular aneurysms occur where? There is an increased risk of aneurysms in which patients?
In the early period after subarachnoid hemorrhage, there is an additional risk of what? What sometimes obstruct CSF flow or disrupt CSF resorption, leading to hydrocephalus.
What is an unruptured saccular aneurysm? Beyond the neck of the aneu- rysm, what things are absent? Where does rupture usually occur and what is the effect? Apart from saccular aneurysms what else can occur intracranially? The last three types of the things that can occur intracranially are found where most often whereas atherosclerotic aneurysms frequently are of what characteristic and most commonly involve what artery? Why do
Nonsac- cular aneurysms usually manifest with cerebral infarction ?

Answer 36

Subarachnoid Hemorrhage and Saccular Aneurysms
The most frequent cause of clinically significant non- traumatic subarachnoid hemorrhage is rupture of a saccular (berry) aneurysm. Hemorrhage into the subarachnoid space also may result from vascular malformation, trauma (usually associated with other signs of the injury), rupture of an intracerebral hemorrhage into the ventricular system, hematologic disturbances, and tumors.
Rupture can occur at any time, but in about one third of cases it is associated with acute increases in intracranial pressure, such as with straining at stool or sexual orgasm. Blood under arterial pressure is forced into the sub- arachnoid space, and the patient is stricken with sudden, excruciating headache (classically described as “the worst headache I’ve ever had”) and rapidly loses consciousness.
About 90% of saccular aneurysms occur in the anterior circulation near major arterial branch points ; multiple aneurysms exist in 20% to 30% of cases. Although they are sometimes referred to as congenital, they are not present at birth but develop over time because of underly- ing defects in the vessel media. There is an increased risk of aneurysms in patients with autosomal dominant poly- cystic kidney disease ,as well as those with genetic disorders of extracellular matrix proteins. In the early period after a subarachnoid hemorrhage, there is an additional risk of 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.

MORPHOLOGY
An unruptured saccular aneurysm is a thin-walled outpouch- ing of an artery .Beyond the neck of the aneu- rysm, the muscular wall and intimal elastic lamina are absent, such that the aneurysm sac is lined only by thickened hyalinized intima. The adventitia covering the sac is continu- ous with that of the parent artery. Rupture usually occurs at the apex of the sac, releasing blood into the subarachnoid space or the substance of the brain, or both.I n addition to saccular aneurysms, atherosclerotic, mycotic, traumatic, and dissecting aneurysms also occur intracranially. The last three types (like saccular aneu- rysms) most often are found in the anterior circulation, whereas atherosclerotic aneurysms frequently are fusiform and most commonly involve the basilar artery. Nonsac- cular aneurysms usually manifest with cerebral infarction due to vascular occlusion instead of subarachnoid hemorrhage

Question 37

Vascular malformations of the brain are classified into four principal types based on the nature of the abnormal vessels name them. Which is most common ? Which conditions manifests with this common vascular malformation? Large AVMs occuring in the newborn period can lead to what? What makes AVM the most dangerous type of vascular malformation? Multiple AVMs can be seen in what setting? AVMs may involve which parts of the brain? On gross inspection AVMs resemble what? Microscopic exam shows what? Some vessels can be recognized as what? Cavernous malformations consist of what? Where do they most often occur? What things frequently surround the abnormal vessels? What are Capillary telangiectasias ? Venous angiomas consist of what? Which types of vascular malformations are unlikely to bleed or cause symptoms? inflammatory processes involving blood vessels may cause what? What can arise in the setting of immunosuppression? What systemic forms of vascular is may involve cerebral vessels and cause infarcts? What is primary angiitis of the CNS and is characterized by what? Affected persons present with what?

Answer 37

Vascular Malformations
Vascular malformations of the brain are classified into four principal types based on the nature of the abnormal vessels: arteriovenous malformations (AVMs), cavernous malforma- tions, capillary telangiectasias, and venous angiomas. AVMs, the most common of these, affect males twice as frequently as females and most commonly manifest between the ages of 10 and 30 years with seizures, an intracerebral hemor- rhage, or a subarachnoid hemorrhage. Large AVMs occur- ring in the newborn period can lead to high-output congestive heart failure because of blood shunting from arteries to veins. The risk of bleeding makes AVM the most dangerous type of vascular malformation. Multiple AVMs can be seen in the setting of hereditary hemorrhagic telan- giectasia, an autosomal dominant condition often associ- ated with mutations affecting the TGFβ pathway.
MORPHOLOGY
AVMs may involve subarachnoid vessels extending into brain parenchyma or occur exclusively within the brain. On gross inspection, they resemble a tangled network of wormlike vascular channels (Fig. 22–11). Microscopic examination shows enlarged blood vessels separated by gliotic tissue, often with evidence of previous hemorrhage. Some vessels can be recognized as arteries with duplicated and fragmented internal elastic lamina, while others show marked thickening or partial replacement of the media by hyalinized connective tissue.
Cavernous malformations consist of distended, loosely organized vascular channels with thin collagenized walls without intervening nervous tissue. They occur most often in the cerebellum, pons, and subcortical regions, and have a low blood flow without significant arteriovenous shunting. Foci of old hemorrhage, infarction, and calcification frequently sur- round the abnormal vessels.
Capillary telangiectasias are microscopic foci of dilated thin-walled vascular channels separated by relatively normal brain parenchyma that occur most frequently in the pons. Venous angiomas (varices) consist of aggregates of ectatic venous channels. These latter two types of vascular malfor- mation are unlikely to bleed or to cause symptoms, and most are incidental findings.

Vasculitis
A variety of inflammatory processes involving blood vessels may compromise blood flow and cause cerebral 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 oppor- tunistic infections (such as aspergillosis, herpes zoster, or CMV) arising in the setting of immunosuppression. Some systemic forms of vasculitis, such as polyarteritis nodosa, may involve cerebral vessels and cause single or multiple infarcts throughout the brain. Primary angiitis of the CNS is a form of vasculitis involving multiple small to medium- sized parenchymal and subarachnoid vessels that is char- acterized by chronic inflammation, multinucleate giant cells (with or without granuloma formation), and destruc- tion of vessel walls. Affected persons present with a diffuse encephalopathy, often with cognitive dysfunction. Treat- ment consists of an appropriate regimen of immunosup- pressive agents.

Question 38

What does hypertension cause?
What happens to affected arteriolar walls?

In addition to massive intracerebral hemorrhage (discussed earlier), several other pathologic brain processes are related to hypertension true or false
What are lacunar infarcts? Where are they mostly found? What causes them?
Rupture of the small-caliber penetrating vessels may occur,
leading to what? In time these hemorrhages resorb leaving behind what? Acute hypertensive encephalopathy most often is associated with what? It is characterized by what? And manifests as what? What is the rapid therapeutic intervention? Postmortem exam may show what? What may be seen microscopically? In summary, what is stroke? Cerebral infarction follows what? Which infarcts are most commonly embolic? What will make a non hemorrhagic infarcts become hemorrhagic? Primary intraparenchymal hemorrhages typically are due to what two things?

Spontaneous subarachnoid hemorrhage usually is caused by what?

Answer 38

Other Vascular Diseases
Hypertensive Cerebrovascular Disease
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 vul- nerable to rupture. In some instances, minute aneurysms (Charcot-Bouchard microaneurysms) form in vessels less than 300 μm in diameter..
• Lacunes or lacunar infarcts aresmallcavitaryinfarcts,just a few millimeters in size, 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 signifi-
cant neurologic impairment.
• Rupture of the small-caliber penetrating vessels may occur,
leading to the development of small hemorrhages. In time, these hemorrhages resorb, leaving behind a slitlike cavity (slit hemorrhage) surrounded by brownish discoloration.
• Acute hypertensive encephalopathy most often is associated with sudden sustained rises in diastolic blood pressure to greater than 130 mm Hg. It is characterized by increased intracranial pressure and global cerebral dys- function, manifesting as headaches, confusion, vomit- ing, convulsions, and sometimes coma. Rapid therapeutic intervention to reduce the intracranial pressure is essen- tial. Postmortem examination may show brain edema, with or without transtentorial or tonsillar herniation. Petechiae and fibrinoid necrosis of arterioles in the gray and white matter may be seen microscopically.

SUMMARY
Cerebrovascular Diseases
• Stroke is the clinical term for acute-onset neurologic defi- cits resulting from hemorrhagic or obstructive vascular lesions.
• Cerebral infarction follows loss of blood supply and can be widespread or focal, or affect regions with the least robust vascular supply (“watershed” infarcts).
• Focal cerebral infarcts are most commonly embolic; with subsequent dissolution of an embolism and reperfusion, a nonhemorrhagic infarct can become hemorrhagic.
• Primary intraparenchymal hemorrhages typically are due to either hypertension (most commonly in white matter, deep gray matter, or posterior fossa contents) or cerebral amyloid angiopathy.
• Spontaneous subarachnoid hemorrhage usually is caused by a structural vascular abnormality, such as an aneurysm or arteriovenous malformation.