Nervous System Pathology Flashcards
What is the morphology of the patterns of injury in the nervous system
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.
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
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.
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
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.
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?)
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).
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
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
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?
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.”
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?
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.
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
. 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.
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?
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.
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?
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.
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 ?
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.
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
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.
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
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.
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)
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.
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?
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.
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?
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.
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?
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.
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?
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
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?
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;
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
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)
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?
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.
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.
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.
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
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).
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?
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
