Far Eastern University – Nicanor Nicanor Reyes Medical Foundation
Some degenerative CNS disease is associated with neuronal intracytoplasmic inclusions: Neurofibrillary tangles – tangles – Alzheimer disease Lewy bodies – bodies – Parkinson disease
Abnormal vacuolization of the perikaryon and neuronal cell process in the neuropil – Creutzfeldt-Jakob disease
Pathology B – B – Central Nervous System
Humphrey Bitun M.D.
CENTRAL NERVOUS SYSTEM
The principal functional unit of the CNS is the neuron. neuron.
These cells have the ability to receive and transmit information.
Neurons may show selective vulnerability to various insults because it shares one or more properties. Mature neurons are incapable of cell division.
CNS contain other cells such as:
Reactions of Neurons to Injury May be an acute process often consequence of depletion of oxygen or glucose, or trauma.
May be a slow process associated with accumulation of abnormal protein aggregates such as in degenerative disorders.
Many neurologic diseases result from the injurious effects of accumulated misfolded proteins ( proteinopathies). proteinopathies).
MORPHOLOGY Acute Neuronal Injury (Red Neurons)
Changes that accompany acute CNS hypoxia or ischemia.
Acute insults that reflect earliest morphologic markers of neuronal cell death. Evident by about 12-24 hours after an irreversible hypoxic irreversible hypoxic injury.
Astrocytes and Astrocytes and Oligodendrocytes which Oligodendrocytes which make up the glia. glia.
Cellular Pathology of CNS
Reactions of Astrocytes to Injury Gliosis is the most important histopathologic CNS indicator.
Shrinkage of cell body, pyknosis of nucleus, disappearance of nucleolus, loss of Nissl substance with intense eosinophilia.
Reactive glial changes are often best indicator of these diseases.
Evidence that cell loss occurs via apoptotic death.
In gliosis Nuclei become enlarged, vesicular, develop prominent nucleoli Cytoplasm becomes bright pink Irregular swath around the eccentric nucleus, from which emerge numerous stout, ramifying processes called gemistocytic astrocytes. Rosenthal fibers – thick elongated, brightly eosinophilic, irregular structures, occur within astrocytic processes, contain 2 heat-shock proteins (αβ-crystallin and hsp27) and ubiquitin.
In Alexander disease, disease, a leukodystrophy with mutations in GFAP, abundant Rosenthal fibers are seen periventricular, perivascular, and subpial locations. Corpora amylacea (Polyglucosan (Polyglucosan bodies) bodies)
Changed observed in the cell body during regeneration of axon.
Best seen in anterior horn cells of spinal cord.
Increased protein synthesis associated with axonal sprouting.
Enlargement and rounding up of cell body.
Peripheral displacement of nucleolus.
Occur in increasing numbers with advancing age, represent degenerative change in astrocytes. Lafora bodies
Reactions of Microglia to Injury Microglia are mesoderm-derived phagocytic cells that serve as resident macrophages of the CNS.
Dispersion of Nissl substance from center to periphery of the cell termed central chromatolysis.
Occur as manifestation of aging. aging.
There are intracytoplasmic accumulations of complex lipids (lipofuscin), lipofuscin), proteins, or carbohydrates.
Occurs in genetically determined disorders of metabolism in which substrates or intermediates accumulates.
Viral infections can lead to abnormal intranuclear inclusions: Cowdry Bodies – Bodies – Herpes infection
Negri Bodies – Bodies – Rabies infections
Nucleus and Cytoplasm – Cytoplasm – Cytomegalovirus
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Seen in cytoplasm of neurons (and other cells) in myoclonic epilepsy (Lafora (Lafora body myoclonus with epilepsy).
Neuronal Inclusions
More common, round, faintly basophilic, PAS-positive, concentrically-lamellated, located wherever there are astrocytic end processes.
Axonal Reaction
Typically found in regions with long standing gliosis Characteristic of a glial tumor – pilocytic astrocytoma
Neuronal death due to progressive disease of some duration. Cell loss, selectively involving functionally related groups of neurons and reactive gliosis.
They act as metabolic buffers and detoxifiers within the brain. Their foot processes surround capillaries and contribute to barrier functions controlling flow of macromolecules.
Subacute and Chronic Neuronal Injury (Degeneration)
Characterized by hypertrophy and hyperplasia of astrocytes. Astrocytes – A star-shaped, multipolar, branching cytoplasmic process that emanate from the cell body and contains glial fibrillary acidic protein (GFAP), an intermediate filament.
Responds to injury by:
Proliferating
Developing elongated nuclei (Rod (Rod cells) cells) – neurosyphilis Forming aggregates in foci of necrosis – microglial nodules
Congregating around dying neurons - neuronophagia
Reactions of other glial cells to Injury Oligodendrial nuclei may harbor viral inclusions in progressive multifocal leukoencephalopathy. Glial cytoplasmic inclusions – primarily composed of α-synuclein are found in oligodendrocytes in multiple system atrophy (MSA). (MSA). Ependymal cells – lines the ventricles, when there is inflammation or marked dilation of the ventricular system, disruption of the lining with paired proliferation of subependymal astrocytes (ependymal (ependymal granulations). granulations).
Cerebral Edema, Hydrocephalus and Raised Intracranial Pressure and Herniation
Hydrocephalus ex vacuo – compensatory increase in ventricular
volume secondary to loss of brain parenchyma.
Can arise in one of three commonly observed setting:
Generalized brain edema
Increased CSF volume Focally expanding mass lesions
Raised ICP and Herniation
Cerebral Edema
More precisely brain parenchymal edema edema is the result of increased fluid leakage from blood vessels to various cells of CNS
Two main pathways:
Vasogenic edema
Increase in extracellular fluid caused by BBB disruption and increased vascular permeability.
Allows fluid to shift from intravascular compartment to the intercellular spaces of the brain.
May either be localized (adjacent (adjacent to inflammation or tumor ) or generalized (ischemia (ischemia). ). Cytotoxic Edema
Increase in intracellular fluid secondary to neuronal, glial, or endothelial cell membrane injury.
– tumors, abscesses, hemorrhage Focal – 1. Subfalcine (Cingulate) Herniation
Gyri are flattened
Sulci are narrowed Ventricular cavities are compressed Interstitial edema (hydrocephalic edema) edema) occurs around the lateral ventricles when an increased intravascular pressure causes abnormal flow of fluid from CSF to the white matter.
Accumulation of excessive CSF within the ventricular system.
Most cases are a consequence of impaired flow and resorption.
Overproduction is a rare cause that can accompany tumors. Increased volume expands the ventricle, elevating ICP.
When it develops in infancy, before closure of the cranial sutures, sutures, there is enlargement of the head: increased head ci rcumference. Developing after this period, associated with expansion of ventricles and increased ICP, no changes in head circumference. Non-communicating or Obstructive Hydrocephalus
Ventricular system is obstructed.
Does not communicate with subarachnoid space
May occur because of a mass in the third ventricle Communicating Hydrocephalus
Posterior cerebral artery may may also be compressed; it supplies the primary visual cortex. Kernohan Notch – the contralateral cerebral peduncle may be compressed resulting to hemiparesis ipsilateral to the side of the herniation. Duret Hemorrhage – progression of herniation accompanied by secondary hemorrhagic lesions of midbrain and pons. 3. Tonsillar herniation
There is communication but there is enlargement of the whole ventricular system.
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Displacement of cerebellar tonsils through foramen magnum Brainstem compression compromises vital respiratory and cardiac centers in the medulla.
Malformation and Developmental Disorders Neural Tube Defects
Failure of a portion of the neural tube to close, or reopening of a region of the tube after successful closure. Most common NTD involving the spinal cord Spinal Dysraphism (Spina Bifida)
May be asymptomatic bony defect (spina (spina bifida occulta) occulta)
May be a severe malformation with flattened, disorganized segment of the spinal cord with meningeal outpouching. Myelomeningocele (Meningomyelocele)
Medial aspect of the temporal lobe is compressed against the free margin of the tentorium. rd 3 cranial nerve nerve is compressed – pupillary dilation and impairment of ocular movements on the side of the lesion.
Hydrocephalus
Occurs when unilateral or asymmetric expansion of cerebral hemisphere displaces the cingulate gyrus under the falx.
Compression of anterior cerebral artery and and its branches. 2. Transtentorial (Uncintae, Mesial Temporal) Herniation
May be encountered in generalized ischemia or metabolic derangements that prevent maintenance of normal ions.
Conditions associated with generalized edema both have the vasogenic and cytotoxic edema.
increased intracranial pressure. Mostly associated with mass effect Diffuse – generalized brain edema
Herniation is the displacement of brain tissue past rigid dural folds ( falx falx and tentorium and tentorium)) or through openings of the skull due to
Extension of CNS tissue through a defect in ver tebra. Meningocele – only meningeal extrusion
Most commonly occurs in the lumbosacral region.
Have motor and sensory deficits of lower extremities.
Commonly associated with epilepsy.
Disturbances in bowel and bladder control.
Complicated by infection of the overlying skin. Encephalocele
Presence of collections of neurons in inappropriate locations. Can be found on ventricular surfaces (periventricular heterotropias) can be caused by mutations on filamin A.
Diverticulum of malformed brain tissue. Most often in the posterior fossa.
May occur via the cribriform plate in the anterior fossa
st
Folate deficiency during 1 several weeks of gestation is a wellestablished risk factor. Neural Tube closure is normally completed by day 28 of embryonic development. Folic acid must be given throughout the reproductive years Anencephaly
Absence of white matter that carry cortical projections from one hemisphere to another.
What remains is the area cerebrovasculosa, a flattened remnant of disorganized brain tissue.
On radio: misshapen lateral ventricles or bat-wing deformity.
Associated with mental retardation
The pool of proliferating precursor cells in the developing brain lies adjacent to the ventricular system. Early on, most divisions yield 2 or more progenitor cells, and as it progresses, there are more asymmetric division yielding both progenitor and a cell that will undergo differentiation.
Posterior Fossa Anomalies Arnold-Chiari Malformation (Chiari Type II)
If too few cells exit during early divisions, the result is overproduction of neurons. Two migration patterns: Radial Migration – becomes excitatory neurons.
Tangential Migration – becomes inhibitory neurons Megalencephaly (abnormally large brain) or Microencephaly (abnormally small brain volume).
Associated with fetal alcohol syndrome, HIV infection in utero, and chromosomal abnormalities.
Reduction in the number of neurons that reach the neocortex, leads to simplification of gyral folding. Lissencephaly Characterized by reduction in the number of g yri.
In extreme cases may show no gyral patterns (agyria).
Two general patterns: Type 1 – smooth surface form Type 2 – rough, cobblestoned surface form
Type 1 is associated with mutations that disrupt signaling for migration of the cytoskeletal motor proteins.
Type 2 is associated with genetic alterations that disrupt the stop signal for migration. Polymicrogyria
Small, numerous, irregularly formed cerebral convolutions.
Gray matter is composed of four layers (or fewer) with entrapment of apparent meningeal tissues at points of fusion
Induced by localized tissue injury toward ends of m igration.
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Hydrocephalus and lumbar myelomeningocoele.
Caudal displacement of medulla, malformation of tectum, aqueductal stenosis, cerebral heteroropias, hydromyelia. Chiari Type I malformation Less severe, low-lying cerebellar tonsils extend downward into the vertebral canal.
Silent, may become symptomatic due to impaired CSF flow and medullary compression. Dandy-Walker malformation
Enlarged posterior fossa.
Cerebellar vermis is absent or present in rudimentary form.
Large midline cyst lined by ependymal and is continuous with leptomeninges on its outer surface.
Expanded, roofless fourth ventricle.
Dyplasias of brain stem nuclei are commonly associated. Joubert Syndrome
Microencephaly is more common.
Small posterior fossa, misshapen midline cerebellum with downward extension of vermis through foramen magnum.
If excess cells exit the pool too early, the overall generation of the neurons is decreased.
Associated with Trisomy 13 & mutations in sonic hedgehog. Agenesis of corpus callosum
Abnormalities in the generation and migration of neurons result in malformations of the forebrain.
Midline facial anomalies (cyclopia) in severe cases. Arrhinencephaly – absence of CN1.
Malformation of the anterior end of the tube, with absence of most of the brain and calvarium.
Incomplete separation of the cerebral hemispheres.
Forebrain Anomalies
Another microtubule-associated protein, double-cortin (DCX), is associated with lissencephaly in males, and subcortical band heterotropias in females. Holoprosencephaly
Neuronal Heterotropias
Hypoplasia of the cerebellar vermis with apparent elongation of the superior cerebellar peduncles. Altered shape of brain stem, gives rise to molar tooth sign.
Mutations affecting genes for primary non-motile cilia
Syringomyelia and Hydromyelia Characterized by expansion of the ependymal-lined canal of the cord (hydromyelia) or by formation of fluid-filled cleft-like cavity in the inner portion of the cord (syringomyelia, syrinx ) that may extend to the brainstem (syngobulbia).
Associated with Chiari malformations, intraspinal tumors or following traumatic injuries
Destruction of adjacent gray and white matter, surrounded by a dense feltwork of reactive gliosis.
Isolated loss of pain and temperature sensation in the upper extremities, due to predilection for early involvement of the crossing anterior spinal commissure.
Perinatal Brain Injury
Laceration – injury caused by penetration and tearing of tissues.
Important cause of childhood-onset neurologic disability. Cerebral palsy – refers to a non-progressive neurologic motor deficit characterized by combinations of spasticity, dystonia, ataxia/atheosis, and paresis. Intraparenchymal Hemorrhage
Leads to rapid tissue displacement, hemorrhage, edema.
The crests of the gyri are most susceptible.
Hemorrhage within the germinal matrix, often near the junction between the caudate nucleus and thalamus.
Most common locations for contusions correspond to the most frequent sites of direct impact and to regions of the brain that overlie rough irregular inner skull surface (frontal, temporal lobe) Coup injury – a person who suffers a blow that developed a contusion at point of contact. Contrecoup injury – contusion on surface diametrically opposite
May extend to ventricular system and cause hydrocephalus. Periventricular Leukomalacia
Infarct occurring in the supratentorial periventricular white matter, especially in premature infants.
Chalky, yellow plaques with regions of white matter necrosis and calcifications. When both gray and white matter are involved, large destructive cystic lesions develop throughout the hemispheres, a condition called multicystic encephalopathy . Gliotic Gyri (Ulegyria)
If head is immobile at time of trauma – coup injury If head is mobile – coup and contrecoup injuries
MORPHOLOGY
Contusions are wedge-shaped, with the broad base lying along the surface at the point of impact.
Early stages – hemorrhage and edema, often pericapillary. Next few hours, extravasation extends across the width of cerebral cortex, into the white matter and subarachnoid space.
In perinatal ischemia, the depths of sulci bear the brunt injury and result in thinned-out, gliotic gyri.
Neuronal injury (pyknosis, eosinophilia, disintegration)
Later, aberrant and irregular myelinization gives rise to marble-like appearance of deep nuclei (status marmoratus ).
Lesions are in the caudate, putamen, and thalamus, movement disorders (choreoathetosis) are common.
Axonal swelling develops in vicinity of adjacent neurons. Old lesions appear as depressed, retracted, yellowish brown patches involving the crests of gyri. Plaque Jaune – applied to old lesions, epileptic foci.
Diffuse Axonal Injury
Trauma
Axonal swelling, indicative of diffuse axonal injury. Axons are injured by direct action of mechanical f orces.
Injury of few cubic centimeters may be silent (if in frontal lobe), may be severely disabling (if in spinal cord ) or may be fatal (if in the brainstem).
Mechanical disruption can result from angular acceleration even in the absence of an impact.
Physical forces may result to skull fracture, parenchymal injury , and vascular injury and all three can co-exist.
Widespread, asymmetric axonal swelling. Best demonstrated with silver impregnation techniques or immunoperoxidase stains for axonally transported proteins.
Increased numbers of microglia are ssen in damaged areas. Degeneration of involved fiber tracts.
Skull Fractures
Bone is displaced into the cranial cavity by a distance greater than the thickness of the bone is called displaced skull fracture .
When an individual falls while awake (stepping of a ladder), the site of impact is often the occipital portion of the skull. A fall that follows syncope, commonly is a frontal impact .
Traumatic Vascular Injury
Symptoms referable to lower cranial nerves, cervicomedullary region, orbitoid or mastoid hematomas distant from point of impact may raise a suspicion of basal skull fracture. CSF discharge from nose or ear, infection may follow Fractures that cross sutures are termed diastatic.
Parenchymal Injuries Concussion Syndrome of altered consciousness secondary to head injury.
Brought about by a change in momentum of head (suddenly arrested by impact on a rigid surface).
Transient neurologic dysfunction, loss of consciousness, temporary respiratory arrest, loss of reflexes. Neurologic recovery is complete, amnesia of the event persists.
Involves dysregulation of reticular activating system in brainstem
It results from direct trauma and disruption of the vessel wall.
Depends on the position of the ruptured vessel.
Both epidural & subdural rarely occur outside setting of trauma Traumatic tear of the carotid artery traverses the carotid sinus, may lead to formation of arteriovenous fistula.
(See Table 28-1, page 1261 for patterns of CNS vascular injury)
Direct Parenchymal Injury
Contusions and lacerations are caused by transmission of kinetic energy to the brain. Contusion – similar to a bruise caused by blunt trauma.
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Epidural Hematoma Dural arteries, most importantly middle meningeal artery , are vulnerable to injury particularly with temporal skull fractures .
Extravasation of blood causes the dura to separate from the inner surface of the skull.
The expanding hematoma has smooth inner contour that compresses the brain surface.
Cerebrovascular Disease
Injury to the brain as a consequence of altered blood flow.
Can be grouped into: Ischemic or Hemorrhagic etiologies. Stroke applies to all these conditions, partcularly acute.
Cerebrovascular disease as two processes:
Hypoxia, ischemia, and infarction - embolism is a more common etiology than thrombosis.
Hemorrhage - common etiologies are hypertension and vascular anomalies (aneurysm and malformations).
Subdural Hematoma Dura has 2 layers:
External collagenous
Inner layer with scant fibroblast, space devoid of collagen.
When bleeding occurs between the 2 layers, it separates and creates the subdural space in which blood accumulates.
Brain is a highly aerobic tissue, in which oxygen rather than metabolic substrate is limiting.
Bridging veins travel through subarachnoid space and subdural space to empty into the superior sagittal sinus. The venous sinuses are fixed to the dura, so displacement of the brain can tear the veins at the point where they penetrate dura.
It may be deprived of oxygen by several mechanisms: Hypoxia caused by a low partial pressure of oxygen (PO2), impairment of the blood's oxygen-carrying capacity, or inhibition of oxygen use in tissue
MORPHOLOGY Acute Subdural Hematomas appear as collection of freshly clotted blood along the brain surface, without extension into the depths of sulci.
Underlying brain is flattened and subarachnoid space is clear. Venous bleeding is self-limited, hematoma is broken down.
Lysis of the clot (about 1 week)
Growth of fibroblasts from dural space to hematoma (2 wks).
Development of hyalinized connective tissue (1-3 months). Multiple recurrent episodes of bleeding occurs in Chronic subdural hematomas , presumably from thin-walled vessels of granulation tissues.
Hypoxia, ischemia, and infarction
caused
br
Cessation of blood flow can result from reduction in perfusion pressure (hypertension), small- large-vessel obstruction, or both. Survival of the brain tissue in reduced blood flow depends on the presence of collateral circulation, duration of ischemia, and magnitude and rapidity of the reduction flow.
With ischemia, there is depletion of ATP and loss of the membrane potential essential for neuronal electrical activity.
There is also, an elevation of cytoplasmic calcium levels, which activates a cascade of enzymatic processes.
Depletion of energy can result to inappropriate release of excitatory transmitter such as Glutamate, which contributes to damage by allowing excessive influx of Ca via NMDA receptors. Penumbra is an area of "at risk" tissue between necrotic and normal brain tissue.
Ischemia, either transient or permanent, interruption of normal circulatory flow.
CLINICAL FEATURES
Symptomatic manifest within 48 hours of injury. Most common over the lateral aspects of the hemispheres.
Global Cerebral Ischemia
10% of cases are bilateral.
Diffuse ischemic/ hypoxic encephalopathy
Neurologic signs attributed to pressure exerted.
Occurs when there is generalized reduction of cerebral perfusion
Sequelae of Brain Trauma
Posttraumatic Hydrocephalus – obstruction of CSF resorption. Chronic Traumatic Encephalopathy (CTE) – dementia pugilistica, a dementing illness, brain is atrophic, enlarged ventricle, accumulation of tau-containing neurofibrillary tangles. Epilepsy, Infection, Psychiatric disorders
Spinal Cord Injury
Most are associated with transient or permanent displacement. Level of cord injury determines the extent. Thoracic level below – paraplegia Cervical leions – quadriplegia
Above C4 – leads to respiratory compromise.
Localized gray matter damage at the level of impact is the principal cause of neurologic deficits.
Similar histology to CNS injury. Central areas of neuronal destruction becomes cystic and gliotic.
Cord section above and below the lesion show secondary ascending and descending Wallerian degeneration, involving the long white-matter tracts affected by trauma.
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Hierarchy of sensitivity among CNS cell: Neurons - most sensitive
Glial cells (oligodendrocytes, astrocytes) are also vulnerable
Most sensitive neurons are in the pyramidal cell layer of hippocampus (CA1, "Sommer sector" ), cerebellar Purkinje cells and pyramidal neurons in cerebral cortex . Severe global cerebral ischemia, widespread neuronal death. Patients who survive remain in a persistent vegetative state. Others have current clinical criteria for "brain death," including irreversible diffuse cortical injury and brainstem damage. When this pervasive form of injury is maintained on mechanical ventilation, brain gradually undergoes autolytic process with gradual liquefaction "respirator brain." Border zone ("watershed ") infarcts occur in regions of the brain or spinal cord that lay the most distal reach of the arterial blood. Damage to border zone between anterior and middle cerebral artery region produces a sickle-shaped band of necrosis. Border zone infarcts are usually seen after hypotensive episodes.
MORPHOLOGY Brain becomes edematous and swollen, producing widening of the gyri and narrowing of the sulci
Early changes, occurring 12 to 24 hours after the insult, are seen in neurons (red neurons) and consist of microvacuolization, eosinophilia of neuronal cytoplasm, and later nuclear pyknosis and karyorrhexis. Subacute changes, occurring at 24 hours to 2 weeks are tissue necrosis, macrophage influx, vascular proliferation, and gliosis. Repair , robust after 2 weeks, is characterized by removal of necrotic tissue, loss of normal CNS architecture, and gliosis. In cerebral neocortex the neuronal loss and gliosis are uneven, with preservation of some layers and destruction of others, producing a pattern of injury termed pseudolaminar necrosis .
As infarcts begin with loss of supply: initiallynon-hemorrhagic.
Secondary hemorrhage can occur from ischemiareperfusion injury, either through collaterals or following dissolution or fragmentation of the intravascular occlusive material.
The hemorrhages are petechial in nature, and may be multiple or even confluent. Management of patients with these two types of infarcts differs as thrombolytics are contraindicated in hemorrhagic infarcts.
MORPHOLOGY
Little change in the first 6 hours of irreversible injury.
By 48 hours, the tissue becomes pale, soft, and swollen, and the corticomedullary junction becomes indistinct.
From 2 to 10 days, the brain is gelatinous and friable, and infarcted tissue becomes more distinct as edema resolves. From 10 days to 3 weeks, the tissue liquefies, eventually leaving a fluid-filled cavity.
Focal Cerebral Ischemia
Follows reduction or cessation of blood flow to a localized area of the brain due to arterial occlusion or hypoperfusion.
When ischemia is sustained, infarction follows.
The major source of collateral flow is the circle of Willis (supplemented by the external carotidophthalmic pathway).
Occlusive vascular disease of severity sufficient to lead to cerebral infarction may be due to embolization from a distant source, in situ thrombosis, or various forms of vasculitides. Embolism to the brain occurs from a variety of sources.
Cardiac mural thrombi are among the most common culprits; myocardial infarct, valvular disease, and atrial fibrillation are important predisposing factors. Thromboemboli arising in arteries, often originating over atheromatous plaques within the carotid arteries. Paradoxical emboli in children with cardiac anomalies Emboli associated with cardiac surgery ; and emboli of other material (tumor, fat, or air). The distribution of the middle cerebral artery — the direct extension of the internal carotid artery — is most frequently affected by embolic infarction. “Shower embolization,” in fat embolism, occur after fractures
Thrombotic occlusions are most commonly associated with atherosclerosis and plaque rupture. The most common sites are the carotid bifurcation, the origin of the middle cerebral artery, and either end of the basilar artery. Inflammatory processes that involve blood vessels may also lead to luminal narrowing, occlusion and hence cerebral infarcts. Infectious vasculitis of small and large vessels occurs with syphilis and tuberculosis, common immunosuppression. Polyarteritis nodosa and other noninfectious vasculitides may involve cerebral vessels. Primary angiitis of the CNS is an inflammatory disorder that involves multiple small to mediumsized parenchymal and subarachnoid vessels and is characterized by chronic inflammation, multinucleated giant cells, and destruction of the vessel wall. As granulomas may be present, this disorder is also known as granulomatous angiitis of the nervous system. Infarcts are subdivided into two groups based on the presence of hemorrhage.
The gross appearance of a nonhemorrhagic infarct varies.
Microscopically, the tissue reaction evolves: After the first 12 hours, ischemic neuronal change (red neurons), cytotoxic and vasogenic edema predominate. Up to 48 hours, neutrophilic emigration progressively increases and then falls off.
Reactive astrocytes can be seen as early as 1 week after the insult. As the process of liquefaction/phagocytosis proceeds, astrocytes at the edges progressively enlarge, divide.
After several months, the astrocytic response recedes; leaving behind a dense meshwork of glial fibers admixed with new capillaries and some perivascular connective tissue. \ Spinal cord infarction may be seen in the setting of hypoperfusion or as a consequence of traumatic interruption of the feeding tributaries derived from the aorta.
CLINICAL FEATURES
Neurologic symptoms referable to the area of injury often develop rapidly, over minutes, and may evolve over hours.
In general, there is often a degree of slow improvement.
Hypertensive Cerebrovascular Disease Lacunar Infarcts
Hypertension affects arteries and arterioles that supply the basal ganglia and hemispheric white matter as well as the brainstem.
Cerebral vessels develop arteriolar sclerosis.
Important of CNS arterial lesions is the development of single or multiple, small, cavitary infarcts known as lacunes.
These are lake like spaces, arbitrarily defined as less than 15 mm wide, woccur in the lenticular nucleus, thalamus, internal capsule, deep white matter, caudate nucleus, and pons
Affected vessels may also be associated with widening of the perivascular spaces without tissue infarction (tat cribl).
Slit Hemorrhages
Hypertension also gives rise to rupture of the small caliber penetrating vessels and the development of small hemorrhages.
In time they resorb, leaving a slitlike cavity (slit hemorrhage) surrounded by brownish discoloration.
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Focal tissue destruction, pigmentladen macrophages, & gliosis.
Hypertensive Encephalopathy
Arise in malignant hypertension: diffuse cerebral dysfunction.
Such individuals may show an edematous brain with or without
commonly associated with lobar hemorrhages.
Amyloidogenic peptides are deposited in the walls of mediumand small-caliber meningeal and cortical vessels.
Petechiae and fibrinoid necrosis of arterioles.
Infarcts
These can weaken the vessel and lead to hemorrhage. Many have microbleeds (numerous small hemorrhages).
transtentorial or tonsillar herniation.
may
characterized
develop by
a
distinctive
dementia,
gait
clinical
syndrome
abnormalities,
and
pseudobulbar signs, often with superimposed focal deficits.
The syndrome, generally referred to as vascular (multi-infarct) dementia, is caused by
Cerebral Amyloid Angiopathy (CAA) is the risk factor most
An effect of the ApoE genotype on the risk of recurrence. Presence of ε2 or ε4 allele increases risk of repeat bleeding.
MORPHOLOGY Restricted to leptomeningeal and cerebral cortical arterioles and capillaries, molecular layer of cerebellum may be observed.
Cerebral atherosclerosis
Thrombosis or embolization from carotid vessels or heart.
Vessels are rigid, fail to collapse during processing and sectioning
Cerebral arteriolar sclerosis from chronic hypertension.
No fibrosis, rather a dense and uniform amyloid deposit.
When the pattern of injury preferentially involves large areas of the subcortical white matter with myelin and axon loss, the disorder is referred to as Binswanger disease
Other forms of small-vessel diseases of the CNS Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
Intracranial Hemorrhage
Autosomal dominant, mutations in NOTCH3 gene.
Hemorrhages may occur in any site of the CNS.
Causes vascular smooth muscle dysfunction.
Epidural and subdural are typically due to trauma.
Clinically recurrent strokes and dementia.
Hemorrhages within the parenchyma and subarachnoid space are more often due to underlying cerebrovascular disease
Arteries show concentric thickening of media and adventitia, loss of smooth muscle cells, presence of basophilic, PAS (+)
Intraparenchymal Hemorrhage
Rupture of small intraparenchymal vessel can result in hemorrhage within the brain associated with sudden onset of neurologic symptoms (stroke). Spontaneous (non-traumatic) intraparenchymal hemorrhage occur most commonly in middle to late adult (peak at 60 y/o) Ganglionic Hemorrhage – in the basal ganglia and thalamus, associated with hypertension. Lobar Hemorrhage – occur in the lobes of cerebrum associated with cerebral amyloid angiopathy (CAA).
CLINICAL FEATURES Intracerebral hemorrhage can be devastating since it affects large portions of the brain and extends to ventricular system.
Location of the hemorrhage determines the manifestations.
Subarachnoid Hemorrhage and Ruptured Saccular Aneurysms Most frequent cause of clinically significant subarachnoid hemorrhage is rupture of a saccular (berry) aneurysm .
Hypertension is the risk factor most commonly associated with deep brain parenchymal hemorrhages (50% of hemorrhages).
Typically in deep white matter or gray structures.
Followed by brainstem and cerebellum.
Causes atherosclerosis (large arteries) and hyaline arteriolosclerosis in smaller, which are weaker than normal vessels hence prone to rupture. Chronic hypertension is associated with minute aneurysms termed Charcot-Bouchard microaneurysms, occurs in vessels less than 300 um in diameter, most common in basal ganglia
Saccular is the most common type of intracranial aneurysm
Others include:
MORPHOLOGY
May originate in the putamen (50-60% of cases), thalamus, pons, cerebellar hemispheres, and other regions. Acute hemorrhage is characterized by extravasation of blood with compression of adjacent parenchyma. Early lesions consist of central core of clotted blood surrounded by a rim of brain tissue & anoxic neural/glial changes and edema Older hemorrhages show area of cavitary destruction of brain with a rim of brownish discoloration. Edema resolves, hemosiderin- and lipid-laden macrophages appear, proliferation of reactive astrocytes is seen at periphery
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Atherosclerotic (Fusiform) – mostly of the basilar artery
Mycotic
Traumatic
Dissecting
The last three are most often found in the anterior circulation but differ in that they more often cause infarction rather than subarachnoid hemorrhage.
90% of saccular aneurysm is found near major arterial branch points in the anterior circulation.
Multiple aneurysms exist in 20-30% of cases.
PATHOGENESIS Structural abnormality suggests developmental disorders.
Majority occurs sporadically.
Increased incidence in Mendelian disorders, Fibromuscular Dysplasia, and Coarctition of the Aorta. Other factors include smoking and hypertension.
Most often in cerebellum, pons, and subcortical regions.
Low-flow channels that do not have AV shunting.
3.) Capillary Telangiectasias
Microscopic foci of dilated, thin-walled vascular channels separated by relatively normal brain parenchyma Most occur in the pons.
MORPHOLOGY
Unruptured saccular aneurysm is a thin-walled outpouching usually at an arterial branch point along the circle of Willis.
4.) Venous Angioma (Varices)
Few mm to 2-3cm with bright red, shiny, thin, translucent wall. Rupture usually occurs at the apex of the sac and leads to extravasation of blood into the arachnoid space, the parenchyma of the brain or both.
Arterial wall adjacent to the neck may show intimal thickening and attenuation of the media. Smooth muscle and intimal elastic lamina fo not extend into the neck and are absent from the aneurysm sac itself. It is instead made up of thickened hyalinized intima and adventitia.
Aneurysms greater than 10mm have 50% risk of bleeding/yr.
Rupture may occur anytime, but in 1/3 of cases it is associated with acute increase in ICP, such as straining at stoo l or orgasms.
Sudden, excruciating headache (worst headache I’ve ever had) and rapidly lose consciousness.
25-50% of patients die with the first rpture.
Clinical consequences: Acute event (hours to days) – increased risk of additional ischemic injury, in basal subarachnoid hemorrhage, vasospasms involve major vessels. Healing phase (late sequelae) – meningeal fibrosis and scarring which may lead to obstruction of CSF flow.
Vascular Malformations
Classified into four: 1. Arteriovenous Malformations 2. Cavernous Malformations 3. Capillary Telangiectasias 4. Venous Angiomas First 2 are associated with risk of hemorrhage and development of neurologic symptoms.
Involve vessels in subarachnoid space, brain, or both.
Tangled network of worm-like vascular channels. Has prominent, pulsatile, AV shunting with high blood flow.
Greatly enlarged vessels separated by gliotic tissue.
Arteries with duplication and fragmentation of the internal elastic lamina, others have marked thickening or partial replacement of media by hyalinized tissue.
2.) Cavernous Malformations
Distended, loosely organized vascular channels arranged back to back with collagenized walls of variable thickness. No brain parenchyma in between vessels.
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Associated with ischemic injury to the spinal cord.
Slowly progressive neurologic symptoms.
Males are affected twice as females. Presents between ages 10-30 as a seizure disorder, intracerebral hemorrhage, and subarachnoid hemorrhage. Most common site is middle cerebral artery : posterior branches Large AVM in newborn can lead to CHF due to shunt effects especially if involves the vein of Galen. Cavernous malformations are unique, familial form is common. Multiplicity of lesions is hallmark of familial cases, inherited as highly penetrant autosomal dominant trait.
Infections
Four principal routes: Hematogenous – arterial circulation, retrograde venous
Direct implantation
Local extension
Peripheral nervous system – HSV, rabies
(See Table 28-2, page 1272 for common CNS infections)
Acute Meningitis
Inflammatory process of the leptomeninges and CSF within the subarachnoid space, usually caused by infection. Meningoencephalitis – meninges and brain parenchyma.
May also respond to non-bacterial irritants (chemical meningitis)
MORPHOLOGY 1.) Arteriovenous Malformations (AVM)
CLINICAL FEATURES AV malformations are the most common subtype.
CLINICAL FEATURES th Most frequent in 5 decade of life, more common in women
Consists of aggregates of ectatic venous channels Foix-Aljouanine Disease (Angiodysgenetic necrotizing myelopathy ) a venous angiomatous malformation of the spinal cord and overlying meninges. Most often in the lumbosacral region.
Broadly classified into: Acute Pyogenic – usually bacterial
Aseptic – acute or subacute viral Chronic – tuberculous, spirochetal, cryptococcal
Acute Pyogenic (Bacterial) Meningitis In neonates: E. coli , group B S. pneumoniae
In children and older: S. pneumoniae, L. monocytogenes
In adolescents and young adults: N. meningitidis
Systemic signs of infection superimposed on clinical evidence of meningeal irritation and neurologic impairments (headache, photophobia, irritability, clouding, and stiff neck).
CSF : cloudy, purulent CSF, ~90,000 neutrophils per mm , increased protein concentration, reduced glucose content.
3
Waterhouse-Friderichsen Syndrome – meningitis-associated septicemia with hemorrhagic infarction of adrenal glands and cutaneous petechiae, mostly in pneumococcal & meningococcal .
Patient is febrile, with headache and neck stiffness.
CSF profile is same as brain abscess.
In immunocompromised, Klebsiella & anaerobes, may have uncharacteristic CSF findings.
Extradural Abscess
Acute Aseptic (Viral) Meningitis Aseptic meningitis – absence of organism by bacterial culture in a patient with manifestations of meningitis. Generally of viral etiology (80% of cases of enteroviruses).
Associated with osteomyelitis, arises from adjacent infection. If occurs in spinal epidural space, may compress the co rd.
Chronic Bacterial Meningoencephalitis
May be caused by:
May be bacterial, rickettsial, or autoimmune.
Mycobacterium tuberculosis Treponema pallidum
Less fulminant clinical course than pyogenic meningitis.
Borrelia sp.
CSF : lymphocytic pleocytosis, moderate protein elevation, glucose content is nearly always normal. Chemical Meningitis – aseptic meningitis-like picture due to rupture of epidermoid cyst introducing chemical irritants. CSF is sterile, with pleocytosis with neutrophils, increased prot eins, and normal glucose content.
Tuberculosis May be part of active disease elsewhere. May involve meninges or the brain. CLINICAL FEATURES
Headache, malaise, confusion, vomiting.
CSF : Mononuclear pleocytosis, elevated proteins, moderately reduced or normal glucose.
Complications: Arachnoid fibrosis leading to hydrocephalus & obliterative endarteritis producing occlusion and infarction.
Tuberculomas may produce same space-occupying symptoms. HIV (+) – are at risk of M. avium-intracellulare, confluent sheets of macrophages filled with organisms, few or no granuloma.
MORPHOLOGY
Exudate is evident within the leptomeninges on brain surface. In H. influenzae, usually it is basal. In pneumococcal , usually densest over cerebral convexities near the sagittal sinus. Tracts of pus follow along blood vessels on surface of the brain. Ventriculitis – inflammation of ventricles on fulminant meningitis Neutrophils fill the subarachnoid space, premoninantly around the leptomeningeal blood vessels.
May extend to brain substance (Cerebritis).
Phlebitis may lead to venous thrombosis and hemorrhagic infarct
Leptomeningeal fibrosis may follow and cause hydrocephalus.
In pneumococcal meningitis, capsular polysaccharide of the organism produce a gelatinous exudate that promotes arachnoid fibrosis, called chronic adhesive arachnoiditis .
Acute Focal Suppurative Infections Brain Abscess
MORPHOLOGY Diffuse meningoencephalitis, most common pattern.
Subarachnoid space has gelatinous or fibrinous exudate, involves the base of the brain.
Discrete, white areas of inflammation scattered on meninges.
Mixed inflammatory infiltrates with well-formed granulomas and caseous necrosis and giant cells.
Arteries may show obliterative endarteritis and intima thickens.
Fibrous adhesive arachnoiditis may develop -> hydrocephalus. Tuberculomas may be present.
A localized focus of necrosis of brain tissue with inflammation.
Neurosyphilis
Direct implantation, local extension, or hematogenous route.
Predisposing conditions may give rise to multiple brain abscess:
Manifestation of tertiary stage of syphilis, occurs in 10%.
Right-to-left shunt CHD.
Major patterns are: Meningovascular Neurosyphilis
Bronchiectasis
Paretic Neurosyphilis
Systemic disease with immunosuppression
Tabes Dorsalis
Streptococcus and Staphylococcus are most common organisms.
CSF : high white count, increased protein, normal glucose.
Increased ICP may lead to fatal herniation.
MORPHOLOGY
Incomplete or mixed pictures, most commonly the combination of tabes dorsalis and paretic disease (taboparesis).
MORPHOLOGY Meningovascular Neurosyphilis
Central liquefactive necrosis surrounded by brain swelling.
At outer margin, exuberant granulation with neovascularization.
Abnormally permeable vessels account for vasogenic edema.
Involves base of the brain, cerebral convexities, spinal meninges. Associated obliterative endarteritis (Heubner arteritis) with a distinctive perivascular inflammatory reaction.
Cerebral Gummas (plasma-cell rich lesions) may also occur.
Collagenous capsule produced by fibroblasts derived from the blood vessel walls, outside is a zone of reactive gliosis. Subdural Empyema
Bacterial or Fungal infection of skull bones or air sinuses can spread to subdural space. Arachnoid and subarachnoid space is NOT affected.
The empyema may produce mass effect or thrombophlebitis.
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Paretic Neurosyphilis
Invasion of the brain by T. pallidum, insidious but progressive.
Cognitive impairment associated with mood alterations that may terminate in severe dementia (general paresis of the insane). Parenchymal damage is most common in frontal lobe.
Loss of neurons, proliferation of microglia (rod cells), gliosis, and iron deposits (demonstrated with Prussian blue) caused by small bleeds from damage to microcirculation.
Herpes Simplex Virus Type 2 In adults, it causes meningitis.
50% of neonates born by vaginal delivery with mothers with active primary HSV genital infection acquire infection.
HSV-2 may cause acute hemorrhage and necrosis in HIV patients.
Organisms may be demonstrated.
Tabes Dorsalis
Result of damage to sensory axons in the dorsal roots.
Impaired joint position sense and ataxia (locomotor).
Varicella-Zoster Virus (Herpes Zoster) Primary infection causes chickenpox without CNS involvement.
Loss of pain sensation leads to joint/skin damage (Charcot joints)
Lightning pains, absence of deep tendon reflexes. Loss of both axons and myelin in dorsal roots, with pallor and atrophy in the dorsal columns of the cord.
Organisms are not demonstrated.
Neuroborreliosis (Lyme Disease)
Caused by Borrelia burgdorferi transmitted by Ixodes tick.
Aseptic meningitis, facial nerve palsy, polyneuropathies.
Focal proliferation of microglia, scattered extracellular organisms
Viral Meningoencephalitis
Associated with meningeal inflammation (meningoencephalitis) and sometimes with cord involvement (encephalomyelitis). Some viruses have propensity to infect the nervous system, such neural tropism takes several forms. Latency is an important phase of severe vi ral infections of CNS.
Arhtropod-Borne Viral Encephalitis Arboviruses are importance cause especially in tropical regions.
Most important types in Western hemisphere are: Eastern and Western Equine, West Nile, Venezuelan, St. Louis, & La Crosse The rest of the world: Japanese B (Far East), Murray Valley (Australia and New Guinea), & Tick-borne (Russia, East Europe).
Generalized neurologic deficits, reflex asymmetry, ocular palsies.
Spinal cord involvement in West Nile encephalitis can lead to polio-like syndrome with paralysis. CSF : colorless, slightly elevated pressure, elevated proteins, normal glucose, initially neutrophilic but converts to lymphocytic
MORPHOLOGY
Meningoencephalitis with perivascular lymphocyte accumulation
Gray and white matter necrosis.
Single-cell neuronal necrosis with phagocytosis (neuronophagia). Microglial cells form aggregates – microglial nodules.
Occurs most commonly in children and young adults.
Alterations in mood, memory, and behavior.
Follow a sub-acute course of manifestations (weakness, lethargy, ataxia, seizures), evolve in a more protracted period (4-6 weeks). Increased incidence in patients with loss-of-function in TLR3.
CNS involvement characterized by numerous sharply circumscribed demyelinating lesions that undergo necrosis.
Cytomegalovirus
Occurs in fetuses and immunocompromised patients.
Outcome in utero is periventricular necrosis leading to brain destruction followed by microcephaly and ventricle calcification.
Common opportunistic pathogen in patients with AIDS.
MORPHOLOGY Most commonly causes subacute encephalitis .
CMV inclusion-bearing cells, localized in the paraventricular subependymal regions of the brain.
Results in severe hemorrhagic necrotizing ventriculoencephalitis and a choroid plexitis. Can attack the lower spinal cord and produce a painful radiculoneuritis.
Any cell may be infected, becomes enlarged with intranuclear and intracytoplasmic inclusions.
Poliomyelitis
Causes subclinical or mild gastroenteritis, the virus secondarily invades the nervous system.
MORPHOLOGY Mononuclear cell perivascular cuffs and neuronophagia of the anterior horn motor neurons of the spinal cord.
Usually confined to anterior horns.
Cranial motor nuclei are involved as well. Loss of neurons and gliosis in anterior horns.
Herpes Simplex Virus Type I
Virus enters latent phase within sensory neurons of the dorsal root or the trigeminal ganglia. Reactivation causes shingles, manifests as painful vesicular skin eruption confined to one or several dermatomes. Self-limited but there may be postherpetic neuralgia syndrome after age 60 years, characterized with persistent pain.
Atrophy of anterior spinal roots and neurogenic atrophy of the denervated muscles.
CLINICAL FEATURES
Initially manifests as meningeal irritation.
CSF picture consistent with aseptic meningitis. Produces flaccid paralysis associated with muscle wasting and hyporeflexia – permanent neurologic residue of poliomyelitis.
MORPHOLOGY
Starts in and most severe in inferior and medial regions of the temporal lobes and orbital gyri of frontal lobes.
When the diaphragm and intercostal muscles are affected, severe respiratory compromise may occur.
Necrotizing and hemorrhagic.
Perivascular inflammatory infiltrates. Cowdry Type A intranuclear inclusions in neurons and glia.
Slowly developing encephalitis have more diffuse involvement.
Myocarditis complicates infections. Postpolio syndrome – develops in patients 25-35 years after the resolution of disease, progressive weakness associated with decreased muscle mass and pain.
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Rabies Severe encephalitis transmitted by a bite of rabid animal.
Exposure to bats, even without a known bite, can cause rabies.
MORPHOLOGY Patches of irregular, ill-defined white matter injury.
Shows area of demyelination, most often subcortical, in the center are scattered lipid-laden macrophages and reduced number of axons.
At the edge of the lesion are enlarged oligodendrocyte nuclei with glassy amphophilic viral inclusions.
There may be bizarre giant astrocytes.
MORPHOLOGY
Intense edema and vascular congestion. Neuronal degeneration, inflammation, most severe in brainstem Negri bodies, pathognomonic microscopic finding, are round to oval, cytoplasmic, eosinophilic inclusions that can be found in pyramidal neurons of hippocampus & Purkinje cells of cerebellum, sites usually devoid of inflammation.
CLINICAL FEATURES
Subacute Sclerosing Panencephalitis
SSPE is charactertized by cognitive decline, spasticity of limbs, and seizures, occur in children and young adults. Occurs after initial, early-age acute measles infection.
Persistent, non-productive infection of CNS by altered virus.
Widespread gliosis, myelin degeneration, viral inclusions.
Enters the CNS by ascending along the peripheral nerves from wound site, incubation period of usually 1-3 months depending on the distance of the wound to the brain. Begins with non-specific symptoms.
Local paresthesia around the wound is diagnostic.
Usually involved following hematogenous spread.
Hyperalgesia, Violent motor response, convulsions.
Contracture of pharyngeal muscles on swallowing, producing foaming of the mouth, aversion to swallowing water.
Candida, Mucor, Aspergillus fumigatus, Cryptococcus neoformans, Histoplasma, Coccidioides, Blastomyces.
Meningeal irritation and flaccid paralysis.
Human Immunodeficiency Virus (HIV) CNS changes stem from direct effects of the virus to the CNS, opportunistic infections, and primary CNS lymphoma high fraction of which is EBV (+) B cell tumors.
HIV aseptic meningitis occurs within 1-2 weeks in 10% of cases.
Antibodies to HIV may be present in the CSF. In acute phase: mild lymphocytic meningitis, perivascular inflammation, and sometimes myelin loss. Only the microglia cells have CD4 co-receptor and chemokine receptor (CCR5, CXCR4) that required for efficient HIV infection. Immune Reconstitution Inflammatory Syndrome (IRIS) – occur in patients with AIDS after effective treatment, exuberant inflammatory response while on ART.
Fungal Meningoencephalitis
Intense inflammation with an influx of CD8+ lymphocytes HIV-associated dementia – cognitive changes, most closely related to inflammatory activation of microglial cells.
Three main forms: Chronic meningitis Vasculitis – most frequent in Mucromycosis, Aspergillosis Parenchymal infection – granuloma or abscess, most common in Candida and Cryptococcus. CSF may contain few cells but high concentration of prot eins.
MORPHOLOGY
Chronic meningitis affecting the basal leptomeninges, which are opaque and thickened. May obstruct CSF outflow, giving rise to hydrocephalus. Gelatinous material within the subarachnoid space and small cysts within the parenchyma (soap bubbles), prominent in the basal ganglia in the lentuculostriate arteries. Aggregates of organisms within expanded perivascular (VirchowRobin) spaces, with minimal or absent inflammation or gliosis.
Other Infectious Diseases of the Nervous System
MORPHOLOGY
Chronic inflammation with widely distributed microglia nodules, often with macrophage-derived multinucleated giant cells. Prominent in subcortical white matter, diencephalon, brainstem. White matter has multifocal or diffuse areas of myelin pallor, axonal swelling and gliosis.
Cerebral Toxoplasmosis
Opportunistic, most common in immunosuppressed.
Infection by T. gondii is subacute (1-2 weeks).
CT show multiple ring-enhancing lesions (non-specific).
Produce brain abscesses, most often in the cerebral cortex near gray-white junction and deep gray nuclei.
Free tachyzoites and encysted bradyzoites may be found. Cerebral Amebiasis
Progressive Multifocal Leukoencephalopathy PML is caused by JC polyomavirus, preferentially infecting oligodendrocytes, demyelination as its principal pathology.
Almost exclusive in immunosuppressed patients.
Primary infection is asymptomatic.
Imaging shows extensive, multifocal lesions in hemispheric or cerebellar white matter.
Chronic granulomatous meningoencephalitis is associated with Acanthamoeba. Cerebral Malaria
Complication of infection of Plasmodium falciparum with the highest mortality rate.
More likely result of vascular dysfunction.
Accompanied by reduced cerebral blood flow. Other infections:
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Rapidly fatal encephalitis results from infection ofNaegleria.
Trypanosomiasis
Rickettsial (Typhus, Rocky Mountain Spotted fever)
Metazoal (cysticerosis, echinococcosis)
Prion Disease
Prions are abnormal forms of cellular proteins that cause rapidly progressive neurodegenerative disorders that may be sporadic, familial, or transmitted. Associated with abnormal forms of specific protein termed prion protein (PrP), characterized by spongiform change caused by intracellular vacuoles in neurons and glia.
MORPHOLOGY Little gross evident brain atrophy due to rapid progression. Pathognomonic finding is spongiform transformation of the cortex, due to uneven small, empty, microscopic vacuoles. Expansion of vacuoles into cyst-like spaces (status spongiosus)
Kuru Plaques are extracellular deposits of aggregated abnormal
protein, Congo Red and PAS positive, usually in the cerebellum.
PATHOGENESIS
Normal PrP is 30kD, cytoplasmic protein present in neurons.
Disease occurs when PrP undergoes a conformational change C from its normal α-helix-containing isoform (PrP ) to an abnormal SC β-pleated sheet isoform (PrP ). It acquired resistance to digestion of proteases.
Accumulation of PrPSC seems to be the cause of pathologic change, but the development of cytoplasmic vacuoles and neuronal death is still unknown.
Western blotting extracts after partial digestion is diagnostic.
Conformational change may occur spontaneously at a low rate (sporadic cases), or at high rate such as in familial forms (Creutzfeldt-Jakob Disease [CJD] and Gerstmann-StrausserScheinker Syndrome [GSS] and Fatal Familial Insomnia [FFI])
SC
C
Fatal Familial Insomnia
Sleep disturbance caused by mutation in PRNP gene.
Leads to aspartate substitution at arginine residue 178. Lasts fewer than 3 years.
Does not shown spongiform pathology. Most striking is neuronal loss and reactive gliosis in the anterior ventral and dorsomedial nuclei of thalamus.
Demyelinating Diseases
Acquired conditions characterized by preferential damage to myelin with relative preservation of axons
Determined by limited capacity of CNS to regenerate normal myelin and degree of secondary damage to axons
SC
PrP can convert other PrP molecules to PrP , this propagation accounts for the transmissible nature of prion disease.
Abundant in cerebral cortex in vCJD.
In all forms of Prion disease, IHC demonstrates proteinase KSC resistant PrP in the tissue.
Multiple Sclerosis
Autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space
Most common of the demyelinating disorder
Clinically apparent at any age, onset in childhood and >50 years is rare; Women > Men
PATHOGENESIS
The gene encoding for PrP is PRNP , shows high degree of conservation across species.
Creutzfeldt-Jakob Disease (CJD)
Most common prion disease, rapidly progressive dementia.
Sporadic form incidence is 1 per 1,000,000 people.
Familial forms are due to mutations in PRNP.
Peak incidence in 7 decade.
Iatrogenic transmission by corneal implants. Subtle changes in memory and behavior followed by rapidly progressive dementia, associated with startle myoclonus.
Average survival is only 7 months after onset of symptoms.
Long surviving cases show extensive atrophy of gray matter. Variant Creutzfeldt-Jakob Disease
Affects young adults, behavioral disorders prominent in early stages, neurologic syndrome progressed more slowly.
vCJD is characterized by presence of extensive cortical plaques surrounded by a halo of spongiform change . No alterations in PRNP. Related to consumption of bovine spongiform encephalopathy agent in contaminated foods or blood transfusion.
Lesions are caused by autoimmune response (TH1 and TH17) directed against the components of the myelin sheath
Each inherited copy of DRB1*1501 allele in an individual brings a 3 fold increase in the risk of MS.
IL-2, IL-7, cytokines and their receptors, co-stimulatory molecules and cytoplasmic signaling molecules are also implicated
Virus infection (e.g. EBV) may be implicated Experimental autoimmune encephalomyelitis an experimental model in which demyelination and inflammation occur after immunization of myelin protein.
th
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MORPHOLOGY
White matter disease best appreciated in the brain and cord. Lesions are firmer than the surrounding white matter (sclerosis) and circumscribed depressed, glassy, gray-tan, irregular plaques Occur adjacent to the lateral ventricles, optic nerves and chiasm, brainstem, ascending, descending fiber tracts, cerebellum & cord Active plaque – ongoing myelin breakdown, abundant macrophages, lipid rich, (+) PAS debris. (+) lymphocytes, monocytes, perivascular cuffs.
Found on small veins
Preservation of axons and depletion of oligodendrocytes Astrocytes undergo reactive changes
Inflammatory cells slowly disappear
plaques – little to no myelin, reduction in oligodendrocyte nuclei, prominent astrocytic proliferation and gliosis, severe decrease and demyelination of axons Shadow plaques – partial and incomplete remyelination by surviving oligodendrocytes Inactive
Central Pontine Myelinolysis
Acute disorder characterized by loss of myelin in the basis pontis and portions of pontine tegmentum
Roughly symmetric pattern
Commonly arises 2-6 days after rapid correction of hyponatremia Osmotic Demyelination Disorder – CPM associated with severe electrolyte or osmolar disturbances
(-) Inflammation with well-preserved neurons and axons
Synchronous onset of damage, all lesions appear at the same stage of myelin loss and reaction Extra-pontine lesions may also occur
CLINICAL FEATURES
Unilateral visual impairment due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis) – frequent initial manifestation of MS Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus and internuclear ophthalmoplegia from interruption of medial longitudinal fasciculus. Spinal cord lesions: motor and sensory impairments, spasticity and difficulties in bladder control CSF: mild elevated protein level and moderate pleocytosis, increase IgG levels Immunoelectrophoresis: (+) IgG bands – indicative of activated B cell clones in the CNS
Neuromyelitis Optica (NMO)
Syndrome with synchronous (or near) bilateral optic neuritis and spinal cord demyelination
High incidence in women than in MS. Poor recovery from the first attack characterized by (+) antibodies against aquaporin-4 .
White cells are common in the CFS, often neutrophils
Necrosis in the damage areas of white matter, inflammatory infiltrates and vascular deposition of Ig and complement. Therapies reduce the antibody burden through plasmapheresis or depletion of B cells with anti-CD20 Ab
Acute Disseminated Encephalomyelitis (ADE) and Acute Necrotizing Hemorrhagic Encephalomyelitis (ANHE) ADE is a diffuse, monophasic demyelinating disease following a viral infection or immunization
Headache, lethargy and coma Rapid, 20% die, remaining recover completely
ANHE (also known as Acute Hemorrhagic Leukoencephalitis of Weston Hurst) – fulminant syndrome of CNS demyelination,
affecting young adults and children
Recent episode of URTI, most often of unknown cause Fatal in many patients.
MORPHOLOGY ADE – greyish discoloration around the WM vessels
Myelin loss with relative preservation of axons found throughout the white matter Early stages = neutrophils; later stages = mo nonuclears
Breakdown of myelin is due to accumulation of lipid-laden macrophages ANHE – shows histologic similarities with ADE like perivenular distribution of demyelination throughout the CNS. However:
Neurodegenerative Disorders
Damages is more severe
Destruction of small blood vessels, disseminated necrosis of white and gray matter with acute hemorrhage, fibrin deposition, and abundant neutrophils
Scattered lymphocytes are seen in foci of demyelination
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Disorders characterized by the progressive loss of neurons, typically affecting the groups of neurons with functional relationships even if they are not immediately adjacent The pathologic process that is common across most of the diseases is the accumulation of protein aggregates – hallmark Resulting to a “toxic” gain- or loss- of function
Capable of acting like prions giving rise to more aggregates Recognized as inclusions histologically
Basis for aggregation:
Directly related to an intrinsic feature of a mutated protein (e.g. expanded polyglutamine repeats in Huntington dse)
Intrinsic feature of a peptide derived from a larger precursor (e.g. Aβ in Alzheimer disease)
Unexplained alteration of a normal cellular protein (e.g. αsynuclein in sporadic Parkinson disease)
Approaches for neurodegenerative diseases:
Symptomatic/Anatomic: based on the anatomic regions affected which typically reflects the symptoms
Pathologic: inclusions or abnormal structures observed
(See Robbins, Table 28-3 page 1287 for summary of ND disorders)
Alzheimer Disease Most common cause of dementia in older adults
Insidious impairment of higher cognitive functions Disease progression: memory, visuo-spatial orientation, judgement, personality and language deficits are apparent
In 5-10 years, becomes disabled, mute and immobile
Rarely symptomatic before 50, incidence increases with ag e Familiar forms of AD (5-10%)
MOLECULAR GENETICS AND PATHOGENESIS
Periventricular and subpial regions of the brain are spared; extremely rare to extend below the ponto-medullary junction Rapidly evolving quadriplegia which may result to long term severe deficits including “locked-in” syndrome
The fundamental abnormality in AD is the accumulation of Aβ and tau in specific regions of the brain as a result of excessive production and defective removal
Pathologic hallmarks: Plaques – deposits of aggregated Aβ peptides in neuropils
Tangles – aggregates of microtubule binding protein tau, which develops intracellularly and persists extracellularly after neuronal death
Aβ generation is critical initiating event for development of AD
Mutations in protein where Aβ is derived (APP) - Familial AD
Mutations in the gene for Tau do not give rise to AD, instead it cause frontotemporal lobar degenerations
Neurofibrillary tangles – tau containing bundles of filaments in
the cytoplasm of the neurons that displace or encircle the nucleus Elongated “flame” shape, rounder cells, basket weave of fibers around the nucleus (globose tangles) Found in cortical neurons, entorhinal cortex, hippocampus, amygdala, basal forebrain and raphe nuclei Cerebral amyloid angiopathy – invariable accompaniment of AD
Role of Aβ
Generated in two potential pathways: non-amyloidogenic pathway and amyloidogenic pathway
Once generated, it is highly prone to aggregation
APP (precursor) is located at chromosome 21 Aβ generations and point mutations in APP are the initiating causes of familial AD Loci that cause majority of early-onset familial AD: PS1 (chromosome 14) and PS2 (chromosome 1) Leads to a gain-of-function that increases the amount of Aβ
May be found in brains without AD
CLINICAL FEATURES
Progression is slow but relentless Initial symptoms: forgetfulness and other memory disturbances. Final stages: incontinent, mute and unable to walk. Pneumonia is usually the terminal event.
Frontotemporal Lobar Degenerations (FTLDs) Role of Tau
With the development of tangles in AD, it shifts to a somaticdendritic distribution , becomes hyperphosphorylated and loses the ability to bind to microtubules Possible pathways: aggregates of tau protein elicit a stress response and microtubule stabilizing function of tau protein is lost
Other Genetic Factors Apolipoprotien E (ApoE) – chromosome 19, has a strong influence. ε4 allele increases the risk of AD and lowers the age of onset.
Heterogeneous set of disorders associated degeneration of frontal and/or temporal lobes.
Personality, behaviour and language precede memory loss.
Global dementia occurs with progressive disease.
One of the more common causes of early onset dementia.
Commonly referred to as frontotemporal dementia (FTD).
Two patterns: FTLD-tau and FTLD-TDP.
focal
FTLD-Tau
Role of Inflammation Aggregates of Aβ elicit an inflammatory response.
with
Progressive neuronal loss and reactive gliosis Presence of tau-containing inclusions in the cytoplasm Pick bodies – smooth controlled inclusions resemble tangles in AD
Stimulate secretion of mediators that cause damage.
MOLECULAR GENETICS AND PATHOGENESIS
Alterations in tau phosphorylation
Oxidative injury to the neurons
Sporadic or due to Tau mutations Missense point mutation affect tau phosphorylation and point mutations that affect splicing
Loss of function component : aggregation depletes neurons of tau
Gain of function component : aberrantly hyperphosphorylated aggregated protein in the neuron
Basis for Cognitive Impairment Presence of large burden of plaques and tangles is highly associated with severe cognitive dysfunction (tangles > plaques)
Loss of choline acetyltransferase, reactivity and amyloid burden.
synaptophysin
immuno-
Biomarkers Aβ deposition identified via 18F-labeled amyloid-binding cmpds. Increased phosphorylared tau and reduced Aβ in the CSF
MORPHOLOGY
Atrophy of frontal and temporal lobes.
Atrophic regions are marked by neuronal loss, gliosis and (+) taucontaining neurofibrillary tangles Pick disease – pronounced asymmetric, atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe
MORPHOLOGY
Variable degree of cortical atrophy marked by widening of the sulci (frontal, temporal and parietal lobes)
Compensatory ventricular enlargement (hydrocephalus ex vacuo) secondary to reduced brain volume Neuritic plaques – Dilated, tortuous, neuritic processes around a central amyloid core surrounded by a clear halo .
20-200µm in diameter
Microglial cells and reactive astrocytes in the periphery
Found in the hippocampus, amygdala and neocortex. (+) sparing of motor and sensory cortices Amyloid core – stained by Congo red, contains Aβ Diffuse plaques – deposition of Aβ peptides with staining characteristics of amyloid in the absence of the surrounding neuritic processes
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“Knife edge” appearance of the gyri due to severe atrophy
Surviving cells shows characteristic swelling (Pick cells) Pick bodies – cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods
FTLD-TDP
Localized cortical atrophy with TDP-43 inclusions
Behavioural or language complaints
MOLECULAR GENETICS AND PATHOGENESIS
Most common genetic form is the result of an expansion of a hexanucleoptide repeat in the 5’ UTR of C9orf72 (also in ALS)
Mutations in the gene encoding the TDP-43 protein are less common, also occurs in familial ALS Mutations in the gene encoding for progranulin
Atypical Parkinsonism Syndromes Progressive Supranuclear Palsy (PSP)
MORPHOLOGY
Similar to other forms of FLTD TDP-43 is found diffusely in the nucleus
Inclusions may be found in the cell body, nucleus or neurites
Taupathy in that affected individuals commonly develop progressive truncal rigidity, disequilibrium with frequent falls and difficulty with voluntary eye movements Other symptoms: nuchal dystonia, pseudobulbar palsy and a mild progressive dementia th
th
Males > Females, 5 -7 decade, fatal within 5-7 years onset
Pathologic hallmark: presence of tau-containing inclusions MORPHOLOGY
Parkinson Disease
Neurodegenerative disease marked by a prominent hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra Clinical syndrome: diminished facial expression (masked facies), stooped posture, slowing of voluntary movement, festinating gait, rigidity and “pill-rolling” tremor Seen in a number of conditions that have common damage to the nigrostriatal dopaminergic system Central triad: tremor, rigidity and Bradykinesia
MOLECULAR GENETICS AND PATHOGENESIS Protein accumulation and aggregation, mitochondrial abnormalities and neuronal loss in the substantia nigra and elsewhere in the brain α-synuclein
First gene to be identified as a cause of autosomal dominant PD encodes for this lipid binding protein Major component of the Lewy body – diagnostic hallmark of PD Aggregates in the form of Lewy bodies or neurites first appear in the medulla followed by the brain, ascending through the brainstem extending into the limbic structures and the neocortex
Widespread neuronal loss in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter and dentate nucleus of the cerebellum
(+) globose fibrillary tangles
Corticobasal Degeneration (CBD) Progressive taupathy characterized by extrapyramidal rigidity, asymmetric motor disturbances and impaired cortical function
Cognitive decline may occur
MORPHOLOGY
Cortical atrophy, severe loss of neurons, gliosis, and “ballooned” neurons (neuronal achromasia)
Tau immunoreactivity: Astrocytes – tufted astrocytes; Oligodendrocytes – coiled bodies
Tau + threads in G/W matter is most specific pathologic finding
Multiple System Atrophy (MSA)
Sporadic disorder that affects several brain functional systems. Cytoplasmic inclusions of α-synuclein in oligodendrocytes Primary pathologic hallmark is observed in glial cells and is commonly associated with degeneration of WM tracts
Neuroanatomic circuits that are commonly involved: Striatonigral circuit (leading to parkinsonism)
Mitochondrial dysfunction
Autosomal recessive forms of PD that are caused by mutations in genes the encodes for DJ-1, PINK1 and parkin DJ-1 – acts a transcriptional regulator which may have cytoprotective effects to the mitochondria in time of stress PINK1 – degraded in the mitochondria, recruits parkin Parkin – E3 ubiquitin ligase
Olivopontocerebellar circuit (leading to ataxia)
Autonomic
nervous system (leading to autonomic dysfunction) – orthostatic hypotension is prominent.
PATHOGENESIS α-synuclein is the major component of the inclusions
Burden of inclusions increases as the disease progresses
Mutations in LRRK2 (Leucine-rich repeat kinase 2)
More common cause of autosomal dominant PD and sporadic.
MORPHOLOGY Pallor of the substantia nigra and locus ceruleus
Lewy bodies in some remaining neurons, cholinergic cells of the basal nucleus of Meynert and in ot her brainstem nuclei Single or multiple cytoplasmic, eosinophilic, round to elongated inclusions with dense core surrounded by a pale halo
MORPHOLOGY
Cerebellar form: atrophy of the cerebellum, cerebellar peduncles, pons and medulla
Parkinsonian form: atrophy involves substantia nigra and striatum
Diagnostic glial cytoplasmic inclusions were originally demonstrated in oligodendrocytes with silver impregnation.
Huntington Disease
Dementia with Lewy Bodies
10-15% of PD patients develop dementia, particularly with advancing age
Fluctuating course, hallucinations, and prominent frontal signs
May have Alzheimer Disease
Most prominent finding is the presence of widespread Lewy bodies in the cortex and brainstem
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An autosomal dominant disease characterized by progressive movement disorders and dementia caused by degeneration of striatal neurons Jerky, hyperkinetic, dystonic movements involving all parts of the body (chorea) are characteristic May develop Bradykinesia and rigidity
MOLECULAR GENETICS AND PATHOGENESIS Prototype of polyglutamine tri-nucleotide repeat expansion dses.
HTT (gene for HD) located on 4p16.3 encodes for huntingtin
Stretch of CAG repeats that encodes for a polyglutamine regions near the N terminus of the protein (normal = 6-35 repeats, beyond is associated with HD) Anticipation – repeat expansion occur during spermatogenesis, paternal transmission is associated with early onset in the next generation
Joint position and vibratory sense are impaired
Loss of pain, temperature sensation and light touch.
Pes cavus and kyphoscoliosis may occur
Caused by expansion of a GAA tri-nucleotide repeat in the first intron of a gene on chromosome 9q13 ( frataxin)
MORPHOLOGY
Spinal cord shows loss of axons and gliosis in the posterior columns, distal portions of corticospinal tracts and spinocerebellar Degeneration in the Clarke column, cranial nerve VIII, X and XII, dentate nucleus, Purkinje cells and Betz cells of the motor cortex Heart is enlarged and may have adhesions
No sporadic form of HD
Other pathways: altered expression of BDNF and deleterious effects of protein aggregates which may disrupt both proteasomal and autophagic degradation pathways
Ataxia-Telangiectasia MORPHOLOGY
Autosomal recessive disorder characterized by an ataxicdyskinetic syndrome beginning in early childhood Telangiectasias in the conjunctiva and skin with immunodeficiency
Brain is small and shows striking atrophy of the caudate nucleus (putamen, globus pallidus, frontal>parietal lobe may also atrophy)
Profound loss of striatal neurons
Changes occur in a medial to lateral direction
MORPHOLOGY
Nucleus accumbens in the most preserved portion
Diaphorase (+) and cholinesterase (+) neurons are spared Aggregates containing huntingtin are found in neurons in the striatum and cerebral cortex
Abnormalities are predominantly in the cerebellum with loss of Purkinje and granule cells
Degeneration of dorsal columns, spinocerebellar tracts and anterior horn cells and peripheral neuropathy Amphicytes – bizarre enlargement of the nucleus 2-5x the normal size
CLINICAL FEATURES
Dysregulation of the basal ganglia circuit results to increased motor output (choreoathetosis) th th 4 – 5 decade, related to the length of CAG repeat
Writhing movements of the extremities are typical
May progress to severe dementia
Spinocerebellar Degenerations
Involves the cerebellum along with other components of the nervous system, commonly the spinal cord and peripheral nerve Cerebellar and sensory ataxia, spasticity and sensorimotor peripheral neuropathy
CLINICAL FEATURES
Presents with signs and symptoms referable to the cerebellum, brainstem, spinal cord and peripheral nerves
MOLECULAR GENETICS Polyglutamine diseases – linked to expansion of CAG repeats. SCA1, SCA2, SCA 3 (Machado-Joseph dse), SCA6, SCA7 (unique, visual impairment), SCA17 and dentatorubropallidoluysian atrophy (DRPLA) Expansion of non-coding region repeats – similar to myotonic dystrophy
SCA8, SCA10, SCA12, SCA31 and SCA36 Point mutations
Progressive disorder in which there is loss of UMN in the cerebral cortex, LMN in the spinal cord and brainstem
Denervation of muscles, producing weakness that becomes profound as the disease progresses
Men>women, 5 decade or later Sporadic is more common than Familial (FALS)
Majority are autosomal dominant disorders
Mutation in the gene encoding for copper-zinc superoxide dismutase (SOD1) on chromosome 21 (20% of FALS) A4V mutation is the most common in the US – associated with a rapid course and rare involvement of UMN
The most common mutation that gives rise to ALS and FTLD simultaneously is an expansion of C9orf72 (40% of FALS, small fraction of sporadic cases)
TDP-43 and FUS mutations may also occur
Friedreich Ataxia
Autosomal recessive disease with progressive ataxia, spasticity, weakness, sensory neuropathy and cardiomyopathy
Begins in the 1 decade of life with gait ataxia, followed by hand clumsiness and dysarthria
st
Deep tendon reflexes are depressed or absent Extensor plantar reflex is present
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th
Molecular Genetics and Pathogenesis Both sporadic and FALS are associated with degeneration of UMN and LMN, often associated with toxic protein accumulation
nd
Relentlessly progressive, death in the 2 decade Initial symptoms are commonly recurrent sinopulmonary infections and unsteadiness in walking Associated with T-cell Leukemias
Amyotrophic Lateral Sclerosis (ALS) (Lou-Gehrig Syndrome)
Spinocerebellar Ataxias
Lymph nodes, thymus and gonads are hypoplastic
Morphology
Anterior roots of the spinal cord are thin due to loss of LMN fibers and pre-central motor gyrus may be atrophic
Bunina bodies – PAS (+) cytoplasmic neurons, appear to be
remnants of autophagic vacuoles Skeletal muscles show neurogenic atrophy
Loss of UMN leads to degeneration of corticospinal tracts, resulting in volume loss and absence of myelinated fibers
Neuronal Storage Diseases
Disorders characterized by the accumulation of storage material within neurons, typically followed by death of the neurons.
Results to seizures and generalized loss of neurologic function Ex: Tay-Sachs, Niemann-Pick diseases , Mucopolysaccharidoses
Clinical Features
Early manifestations: asymmetric weakness of the hands and cramping and spasticity of the extremities Muscle strength and bulk diminish, involuntary contractions (fasciculations) may occur Progressive muscular atrophy – uncommon cases in which LMN involvement predominates Progressive bulbar palsy or bulbar ALS – degeneration of lower brains tem cranial motor nuclei occurs and progresses rapidly (abnormal deglutition and phonation dominate)
Ceroid lipofuscinoses - rare disorders in which lipid pigments accumulate in neurons.
Leukodystrophies
Disorders caused by mutations of genes whose products are involved in the generation, turnover, or maintenance of myelin
Often at younger ages
Caused by single enzyme defects resulting in altered metabolism of myelin associated lipids or by variety of genetic alternation
Krabbe disease
Familial cases occur much earlier than sporadic cases
Autosomal recessive leukodystrophy
FTLD is the clinical presentation of cerebral di sease in ALS
Deficiency of galactocerebroside β-galactosidase (Galactosylceramidase),
Other Motor Neuron Disease Spinal and Bulbar Muscular Atrophy (Kennedy Disease) X-linked polyglutamine repeat-expansion disease characterized by distal limb amyotrophy and bulbar signs associated with degeneration of LMN
Androgen sensitivity, gynecomastia, testicular atrophy and oligospermia Cellular injury depends on the binding of androgen to the abnormal receptor and the subsequent interaction with DNA
Spinal Muscle Atrophy Genetically linked disorders of childhood with marked loss of LMN resulting in progressive weakness SMA Type 1, Werdnig-Hoffman dse – most severe form with the st earliest onset occurring in the 1 year of life, and death in 2 years SMA Type 3 Kugelberg-Welander dse – motor disability emerges during later childhood and adolescence
Severity is related to the level of SMN that is involved in assembly of the spliceosome
All of the forms of SMA are associated with disruption of SMN1
enzyme for catabolism of galactocerebroside to ceramide and galactose
Alternative catabolic pathway shunts galactocerebroside to galactosylsphingosine, which is cytotoxic
Rapidly progressive clinical course, onset: ages of 3 to 6 months
Dominated by motor signs such as stiffness and weakness
Survival beyond 2 years of age is uncommon Shows loss of myelin and oligodendrocytes in the CNS and PNS
Neurons and axons are relatively spared
Diagnostic feature is the aggregation of engorged macrophages (globoid cells) in the brain parenchyma and around blood vessels
Metachromatic leukodystrophy
Autosomal recessive
Deficiency of the lysosomal enzyme arylsulfatase A, enzyme that cleaves sulfate from sulfate-containing lipids (sulfatides).
Accumulation of the sulfatides, especially cerebroside sulfate Sulfatides have biological actions that contribute to white matter injury by inhibiting differentiation of oligodendrocytes and eliciting a pro-inflammatory response in glial cells. Most striking histologic finding is demyelination with gliosis
Macrophages with vacuolated cytoplasm are scattered throughout the white matter Metachromasia - when the membrane-bound vacuoles with complex crystalloid structures when bound to toluidine blue, sulfatides shift the absorbance spectrum of the dye
Metachromatic material can also be detected in peripheral nerves and urine, latter being a sensitive met hod of diagnosis.
Genetic Metabolic Diseases
Disruption of metabolic process in neurons and glia, particularly those involved in synthetic or degradation
Manifest in post-natal period, or emerge later in development Neuronal Storage disease
Autosomal recessive disorder
Deficiency of enzymes in catabolism of sphingolipids, mucopolysaccharides or mucolipids
Leukodystrophies
Autosomal recessive disorder
Mutation in genes encoding enzymes for Myelin synthesis or catabolism, typically involve white matter. Mitochondrial encephalomyopathies
Adrenoleukodystrophy
X-linked recessive disease
Mutations in ATP binding cassette tra nsporter family of proteins (ABCD1), involved in transport of molecules into the peroxisome
Young males have behavioral changes and adrenal insufficiency
Characterized by the inability to catabolize very-long-chain fatty acids (VLCFAs) within peroxisomes.
Results to elevated levels of VL CFAs in serum.
Symptoms result from a progressive loss of myelin in the CNS and peripheral nerves, as well as adrenal insufficiency
Disorders of oxidative phosphorylation.
Gray matter is more severely affected, leading to greater metabolic requirements of neurons. May be caused by mutations in the mitochondrial or the nuclear genomes
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In the white matter, loss of myelin accompanied by gliosis and extensive lymphocytic infiltration
Atrophy of the adrenal cortex is present
Adrenomyeloneuropathy – allelic disorder in adults, slowly progressive predominantly peripheral nerve disorder, wherein symptoms in female carriers are usually more mild Pelizaeus-Merzbacher disease - have a mutations in genes that encode proteins required for myelin formation Alexander disease - mutation in the intermediate filament proteins such as GFAP Vanishing white matter leukoencephalopathy - mutation in genes for subunits of translation initiation factor eIF2B
Mitochondrial Encephalomyopathies
Disorders of energy generation
Mitochondrial genome, which is entirely inherited from the mother, encodes only 13 proteins, 22 tRNAs, and two rRNAs
The same mutation may manifest as different phenotypes, and the same phenotype may result from one of several mutations.
Cause by mutation in nuclear and mitochondrial DNA involving components of oxidative phosphorylation complexes and proteins involved in the assembly the electron transport chain.
Toxic and Acquired Metabolic Diseases Vitamin Deficiencies Thiamine (Vitamin B1) Deficiency Wernicke encephalopathy Acute appearance of psychotic symptoms and ophthalmoplegia.
Acute symptoms are reversible when treated with thiamine.
If unrecognized and untreated, may be followed by a prolonged and largely irreversible condition, called Korsakoff syndrome Korsakoff syndrome Disturbances of short term memory and confabulation.
Common in chronic alcoholism, but may also be encountered in individuals with thiamine deficiency resulting from GIT disorders
MORPHOLOGY
Foci of hemorrhage and necrosis in the mamillary bodies and the walls of the third and fourth ventricles.
Target tissues are neurons and gray matter .
Elevated lactate levels was caused by disruption of energy generation, demonstrated by spectroscopic imaging methods.
Early lesion - dilated capillaries with prominent endothelial cells.
At the histologic level, there is loss of staining for enzymatic activity of cytochrome C oxidase.
Capillaries become leaky, producing hemorrhagic areas. Infiltration of macrophages and development of a cystic space with hemosiderin-laden macrophages.
Heteroplasmy - condition in which cells have a mixture of normal and abnormal mitochondria
Chronic lesions in the dorsomedial nucleus of the thalamus seem to be the best correlate of the memory disturbance and confabulation predominate in individuals with Korsakoff.
Mitochondrial encephalomyopathy, Lactic acidosis, and Stroke-like Vitamin B12 Deficiency
episodes (MELAS)
Recurrent episodes of acute neurologic dysfunction, cognitive changes, muscle involvement with weakness and lactic acidosis. Most common mutation is mitochondrial tRNA leucine (MTTL1). Areas of infarction are observed, sometimes with vascular proliferation and focal calcification. Altered expression of cytochrome c oxidase in neurons and vascular smooth muscle cells suggest that the underlying pathogenesis is driven both by the metabolic changes in neurons as well as the ability of the cerebral vasculature to respond.
Subacute combined degeneration of the spinal cord
Degeneration of both ascending and descending spinal tracts.
Lesions are caused by a defect in myelin formation
Initially bilaterally symmetrical numbness, tingling and ataxia.
Progress to spastic weakness of lower extremities.
Complete paraplegia may occur, usually only later i n the course.
Swelling of myelin layers, producing vacuoles, in the affected tracts, with time, axons degenerate as well.
In the early stages of the disease the mid-thoracic level of the spinal cord is affected, from where the process may extend proximally and distally.
Myoclonic epilepsy and ragged red fibers (MERRF)
Maternally transmitted disease
Presents with myoclonus, seizure disorder, and myopathy.
Neurologic Sequelae of Metabolic Disturbances
Myopathy is characterized by ragged red fibers on muscle biopsy
Hypoglycemia
Ataxia: neuronal loss from the cerebellar system including the inferior olive in the medulla, cerebellar cortex, and deep nuclei.
Leigh syndrome
Disease of infancy
Characterized by:
Lactic Acidemia Feeding Problem
Arrest of psychomotor development Extraocular Palsies
Seizures
Weakness with hypotonia
Death usually occurs within 1 to 2 years.
Multifocal regions of destruction of brain tissue associated with a spongiform appearance and proliferation of blood vessels. Brainstem nuclei, thalamus, and hypothalamus are typically involved, usually in a symmetric manner.
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Glucose deprivation leads to selective injury to large pyramidal neurons of the cerebral cortex, which, if severe, may result in pseudolaminar necrosis of the cortex, especially the deep layers.
Hippocampus is also vulnerable to glucose depletion and may show a marked loss of pyramidal neurons in Sommer sector. Purkinje cells of the cerebellum are also sensitive to hypoglycemia, although to a lesser extent than to hypoxia.
Hyperglycemia
Most commonly associated with inadequately controlled diabetes mellitus and associated with either ketoacidosis or hyperosmolar coma, does not elicit morphologic changes.
Fluid depletion must be corrected gradually; otherwise, severe cerebral edema may follow.
Hepatic Encephalopathy
Encephalopathy with impaired liver function is accompanied by a glial response within the CNS.
Elevated ammonia levels and pro-inflammatory cytokines. Astrocytes with enlarged nuclei and minimal reactive cytoplasm, known as Alzheimer type II cells, appear in the cerebral cortex and basal ganglia and other subcortical gray matter regions.
Toxic Disorders Carbon Monoxide
Tumors
20% of all cancers of childhood (70% arise in the posterior fossa).
GLIOMAS
Most common group of primary brain tumors.
Arise from a progenitor cell that preferentially differentiates down one of the cellular lineages.
Astrocytoma
Two major categories:
Result of impaired oxygen carrying capacity of hemoglobin.
Local effects from interaction of CO with heme of cytochrome C oxidase, inhibiting electron transport in the mitochondria.
Selective injury of the neurons of layers III and V of the cerebral cortex, Sommer sector of the hippocampus, and Purkinje cells
Infiltrating Astrocytoma
Bilateral necrosis of the globus pallidus may also occur Demyelination of white matter tracts may be a later event.
Methanol
Mainly affects the retina, degeneration of retinal ganglion cells.
Selective bilateral necrosis of the putamen and focal whitematter necrosis also occur in severe exposure.
Formate and other metabolites of methanol appear to contribute to toxicity through disruption of oxidative phosphorylation and non-enzymatic protein modification.
Diffusely infiltrating astrocytoma
Localized astrocytoma (most common is pilocytic)
Found anywhere along the neuroaxis.
th
th
80% of adult primary brain tumors, 4 – 6 decades of life.
Usually found in the cerebral hemispheres.
Most common s/sx: seizures, headaches, focal neurologic deficits
Toxicity occurs by ingestion of illicit liquor (moonshine) contaminated with methanol or used as substitute for ethanol
Spectrum of histologic differentiation: Diffuse Astrocytoma – Grade II/ IV
Anaplastic Astrocytoma – Grade III/IV Glioblastoma – Grade IV/IV
No WHO Grade I infiltrating astrocytomas.
MOLECULAR GENETICS Occur in one of two clinical settings:
New onset disease, in older patients ( primary glioblastoma)
Less frequently, younger patients due to progression of a lower-grade astrocytoma (secondary glioblastoma) Four molecular subtypes: Classic Subtype
Ethanol
Acute ethanol intoxication are reversible, but chronic alcohol abuse is associated with a variety of neurologic sequelae,
Cerebellar dysfunction occurs in about 1% of chronic alcoholics, with syndrome of truncal ataxia, unsteady gait, and nystagmus.
Atrophy, loss of granule cells mainly in the anterior vermis
May also cause loss of Purkinje cells and proliferation of the adjacent astrocytes (Bergmann gliosis) between the depleted granular cell layer and the molecular layer of the cerebellum.
Mutations of PTEN, amplification of chromosome 10 & EGFR
Deletion of CDKN2A, another TSG.
Proneural Subtype
Most common associated with secondary glioblastoma.
Mutations in TP53, IDH1, IDH2, overexpression of PDGFRA Neural Subtype
Higher neuronal markers (NEFL, GABRA1, SYT1, SLC12A5) Mesenchymal Subtype
Radiation
Very high doses of radiation (>10 Gy) can cause intractable nausea, confusion, convulsions, and rapid onset of coma, followed by death. Delayed effects present with rapidly evolving symptoms, including headaches, nausea, vomiting, and papilledema that may appear months to years after irradiation.
Marked edema in the surrounding tissue, along with vascular fibrinoid necrosis and eventual sclerosis. Methotrexate may act synergistically wand cause tissue injury.
Lesions are often adjacent to the lateral ventricles but may be distributed throughout the white matter or in the brainstem.
Axons and cell bodies in the vicinity of the lesions undergo dystrophic mineralization, and there is adjacent gliosis. Radiation induce tumor: sarcomas, gliomas, and meningiomas
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Deletions of NF1 gene on chromosome 17.
Genes in TNF and NF-kB are highly expressed. Most affect two cancer hallmarks, sustain proliferative signaling and evasion of tumor growth suppressors.
Large areas of coagulative necrosis, primarily in white matter, with all tissue within the area undergoing necrosis
Pathologic findings:
Among higher grade astrocytomas (III, IV), presence of mutant form of IDH1 has better prognosis than wildtype IDH1, the mutant form creates 2-hydroxyglutarate that interferes enzymes that regulate DNA methylation.
MORPHOLOGY
Diffuse Astrocytoma
Poorly defined, gray, infiltrative that expand and distort.
Cystic degeneration may be seen.
Infiltration beyond the outer margins is always present.
Cellular density is greater than normal white matter.
Extensive feltwork of fine, GFAP (+), astrocytic processes that create a fibrillary background appearance.
Brainstem Glioma Occur most often in first 2 decades of life.
Anaplastic Astrocytoma
More dense, have greater pleomorphism and mitosis. Gemistocytic Asrocytoma – tumors in which the predominant neoplastic astrocyte shows a brightly eosinophilic cell body from which emanate abundant stout processes. Glioblastoma
GBM have variation in appearance (some are firm and white, some are yellow and necrotic, some have cystic degeneration).
Similar to anaplastic astrocytoma with additional feature of necrosis and vascular cell proliferation.
Necrosis is often in serpentine pattern in hypercellular areas. Tumors collect along edges producing pseudo-pallisading.
Vascular produce tufts of cells, minimal criteria are a double layer of endothelial cells. Gliomatosis Cerebri
Diffuse ganglioma w/ extensive infiltration of multiple areas
Follows an aggressive course, grade III/IV lesion.
Distinct anatomic patterns in pediatric age group: Intrinsic Pontine Gliomas (most common) – aggressive, short survival rate. Cervicomedullary junction – less aggressive, exophytic Dorsally exophytic gliomas – more benign course, arise from the tectum of midbrain, pons, or medulla.
Most affecting adults are intrinsic pontine gliomas.
Most have Lys to Met mutation at K27M in histone H3.1 or 3.3
Oligodendroma
Infiltrating gliomas with cells that resemble oligodendrocytes th th Most common in 4 – 5 decades.
Several years of neurologic complains, such as seizures.
Mostly in the cerebral hemisphere, predilection for white matter
MOLECULAR GENETICS CLINICAL FEATURES
Well-differentiated diffuse astrocytoma remain stable and slowly progress in a number of years.
Radiologic studies show mass effects as well as changes in the brain adjacent to the tumor. High-grade astrocytomas have abnormal leaky vessels with an abnormally permeable BBB, hence demonstrating contrasts.
Prognosis with glioblastoma is very poor.
Pilocytic Astrocytoma
Grade I/IV are distinguished from others by their gross and microscopic appearance and relatively benign behavior .
Occur in children and young adults, usually in the cerebellum but rd may also appear in floor and walls of 3 ventricle, optic nerves, and the cerebral hemispheres. Rarity of TP53 mutations or molecular signatures.
Those occurring in patients with neurofibromatosis 1 show loss of neurofibromin, not observed in sporadic forms. Two types of alterations in BRAF in pilocytic astrocytoma Translocation that separate kinase domain
Most common are mutations in IDH1 and IDH2.
Deletions in 1p and 19q occur together as co-deletion. Mutations in CKN2A, however EGFR amplification is absent.
MORPHOLOGY
Well-circumscribed, gelatinous, gray masses, often with cysts, focal hemorrhage, and calcifications, grade II/IV
Sheets of regular cells with spherical nuclei with finely granular chromatin surrounded by clear halo of vacuolated cytoplasm.
Contain delicate network of anastomosing capillaries.
Tumor cells infiltrating the cortex collect around neurons (perineuronal satellitosis)
Anaplastic Oligodendrocytoma Grade III/IV, higher cell density, anaplasia, mitosis, necrosis.
Found in nodules within an otherwise typical grade II.
CLINICAL FEATURES Better prognosis with astrocytomas.
Surgery, chemo, and radiation yield 5-10 years survival. Anaplastic oligodendrocytoma – worse prognosis.
Activating point mutation (V600E) Ependymoma and Paraventricular Mass Lesions
MORPHOLOGY Often cystic, if solid may be well circumscribed, less infiltrative.
Composed of bipolar cells with long thin hair-like processes that are GFAP (+) and form dense fibrillary meshworks. Rosenthal fibers and eosinophilic granular bodies. Often biphasic with both loose microcystic and fibrillary areas. Limited infiltration of the surrounding brain. Grow very slowly, may be treated with resection.
Ependymomas are tumors that most often arise the ependymallined ventricular system, including the oft-obliterated central canal of the spinal cord.
In the first 2 decades, occur near the 4 ventricle.
In adults, the spinal cord is the most common location, particularly in the setting of neurofibromatosis 2.
MOLECULAR GENETICS
Mutation in NF2 gene in spinal cord involvement. Do not share the genetic alterations in gliomas.
Two subtypes:
Pleomorphic Xanthoastrocytoma
Occurs most often in the temporal lobe of children.
Usually with a history of seizures. Consist of neoplastic, bizarre astrocytes filled with lipids.
Can express neuronal and glial markers.
Nuclear atypia is extreme
Presence of abundant reticulin deposits, circumscription, chronic inflammatory infiltrates, absence of necrosis and mitotic activity. Usually low-grade (grade II/IV) – 5 yr survival of 80%
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th
One expressing a mesenchymal phenotype, in young patients, higher propensity to develop metastasis.
Second with aberrations of large regions of chromosome or the whole chromosome, with better overall prognosis.
MORPHOLOGY th In 4 ventricle, typically solid or papillary masses from floor.
Proximity of vital pontine and medullary nuclei makes extirpation impossible. Cells with irregular, round-oval nuclei, granular chromatin. May form gland-like round or elongated capsules that resemble embryonal ependymal canal with long delicate processes extending the lumen (perivascular pseudorosettes ). GFAP expression is found in most ependymomas.
Slow growing, but glial component becomes anaplastic and the disease may progress rapidly.
Most have activating mutation in BRAF (V600E).
Most commonly found in temporal lobe and are cystic.
Neoplastic ganglion cells are irregularly clustered and have random orientation of neurites.
Binucleate forms are found.
Dysembryoplastic Neuroepithelial Tumor
Most are well-differentiated as grade II/IV, but anaplastic ependymomas (grade III/IV) have increased density and mitosis. Myxopapillary ependymomas Occur in the filum terminale of the cord.
Contain papillary elements in a myxoid background with ependymoma-like cells.
Cuboidal cells with clear cytoplasm arranged around papillary cores containing connective tissue and blood vessels.
Rare, low grade (grade I), tumor of childhood often presents with a seizure disorder. Good prognosis following surgical resection, low recurrence.
Located in the superficial temporal lobe.
Attenuation of the overlying skull.
Multiple, discrete, intracortical nodules of small, round cells arranged in columns around central cores of processs.
Well-differentiated floating neurons that sit in pools of mucopolysaccharide-rich fluid myxoid background.
Recurrence is likely if it has extended to subarachnoid space and surrounded the roots of cauda equina.
Central Neurocytoma CLINCAL FEATURES Posterior fossa ependymomas often manifest as hydrocephalus secondary to progressive obstruction of the fourth ventricle.
CSF dissemination is a common occurrence.
Posterior fossa lesions have the worst outcome.
Low grade (grade II) neuronal neoplasm in the ventricular sy stem
Most commonly the lateral or 3 ventricles.
Evenly spaced, round, uniform nuclei and islands of neuropil.
Resembles oligodendroglioma.
rd
POORLY DIFFERENTIATED NEOPLASMS
Other tumors
Subependymomas
Solid, calcified, slow-growing nodules attached to the lining of the ventricles protruding inside. Usually asymptomatic, incidental findings.
If large enough may cause hydrocephalus.
Medulloblastoma
Malignant embryonal tumor, predominantly in children and exclusively in the cerebellum.
Tumor is largely undifferentiated (Grade IV).
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Most often in the lateral and 4 ventricles, clusters of ependymal-appearing nuclei scattered in a dense, fine, glial fibrillary background. Choroid Plexus Papillomas Occur anywhere the choroid plexus, most common in children Usually found in the lateral ventricles.
Have connective tissue stalks covered with a cuboidal or columnar epithelium.
Clinically present with hydrocephalus.
MOLECULAR GENETICS
Choroid Plexus Carcinoma resembles adenocarcinoma. rd Colloid Cyst of the 3 Venticle
Non-neoplastic enlarging cysts mostly in young adults.
Attached to the roof of the 3 ventricle may obstruct one or both foramina of Monro and cause non-communicating hydrocephalus which may be rapidly fatal. Cyst has thin, fibrous capsule, and a lining of low to flat cuboidal epithelium, contains gelatinous protein material.
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NEURONAL TUMORS
More often seen in younger adults, present as seizures.
Neuroectodermal in origin but express few if any markers of mature neural cells, retains cellular features of primitive cells. Most common is medulloblastoma, 20% brain tumors in children
Can be divided into 4 groups: WNT type – occur in older children, classic histology, monosomy of chromosome 6, expression of B-catenin, prognosis is best, 90% 5-year survival. SHH Type – occur in infants or young adults, nodular desmoplastic histology, MYCN amplification. Group 3 – MYC amplification, isochrome 17, occurs in infants and young children, classic or large cell, worst prognosis.
Group 4 – i17q cytogenic alteration, classic or large cell.
Intermediate prognosis. MORPHOLOGY
Located in midline of cerebellum in children. Lateral locations are more often found in adults.
May occlude CSF flow and lead to hydrocephalus.
Densely cellular with sheets of anaplastic cells.
Cells are small with scant cytoplasm and hyperchromatic nuclei that are frequently elongated or crescent shaped.
Gangliomas
Mixture of mature neuronal and glial cells.
Superficial lesions that present with seizures. Most common of the neuronal tumors of the CNS.
Ki-67 are detected in high percentage of cells. May express neuronal granules, form Homer-Wright rosettes.
Nodular desmoplastic variant
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Areas of stromal response, collagen and reticulin deposits.
Nodules of cells form pale islands that have more neuropil and show greater expression of neuronal markers. Large cell variant
Large irregular nuclei, prominent nucleoli, frequent mitoses and apoptotic cells. Linear chains at the edge of the tumor.
Malignant cells infiltrate the parenchyma and accumulate around the blood vessels.
Reticulin staining demonstrates infiltrating cells are separated from one another, a pattern called hooping.
Express B cell markers such as CD20, EBV if infected.
Disseminate via CSF is common giving rise to nodular masses at some distance from the primary tumor, termed drop metastasis.
CLINICAL FEATURES
Highly malignant, prognosis is dismal. Exquisitely radiosensitive. May respond to inhibitors of hedgehog signaling pathway. CNS Supratentorial Primitive Neuroectodermal Tumors (CNS PNET) – resembles medulloblastoma in the cerebral hemisphere
Atypical Teratoid / Rhabdoid Tumor
Highly malignant occurring in young children (grade IV) occurs in the posterior fossa and supratentorial compartments.
Divergent differentiation with epithelial, mesenchymal, neuronal, and glial components and often includes r habdoid cells resembling those in rhabdomyosarcoma.
MOLECULAR GENETICS Consistent alteration in chromosome 22 is the hallmark.
Intravascular Lymphoma
Unusual large cell lymphoma that grows within small vessels.
The occlusion of the vessel can result in widespread infracts.
Often present with non-localizing neurologic symptoms.
Germ Cell Tumors
Primary Brain Germ Cell Tumors occur along the midline, most commonly in the pineal and suprasellar regions.
Tumors of the young, first 2 decades.
Teratomas are among the more common congenital tumors.
Those in the pineal region show strong male predominance.
Source of the germ cells is not clear, may be rests that remain or perhaps migrate from other sites.
Histologic classification is same that used in the testes.
Pineal Parenchymal Tumors
Arise from pineocytes, have features of neuronal differentiation. Well-differentiated (pineocytomas) with areas of neuropil, cells with small, round nuclei, no mitosis or necrosis, more often in adults. High-grade tumors (pineoblastomas) with evidence of neuronal differentiation, densely packed cells with necrosis and mitosis, more often in children.
Pineoblastoma spread via the CSF space, occurs increasingly in individuals with RB mutations.
Gliomas may also be seen in pineal region, often low grade may rd extend to posterior 3 ventricle.
The gene is hSNF5/INI1 encodes for protein part of remodeling.
MORPHOLOGY
Large, soft consistency along the surface of the brain. Cells have eosinophilic cytoplasm, sharp cell borders, and eccentrically located nuclei.
Immunoreactive for epithelial membrane antigen & vimentin
May also be reactive to actin and keratins.
Islands of tumor with rhabdoid cells are mixed with a small cell component as well as other patterns.
CLINICAL FEATURES
Highly aggressive, occur before 5 y/o and most patients live less than a year after diagnosis.
Tumor similar to seminoma is referred as germinoma in CNS.
CSF levels of tumor markers like AFP and β-hCG may be useful.
MENINGIOMAS
Predominantly benign tumors of adults, usually attached to the dura, arise from meningothelial cells of arachnoid.
Prior radiation therapy of head and neck is a risk factor.
OTHER PARENCHYMAL TUMORS
Primary CNS Lymphoma
2% of extranodal lymphomas, 1% of intracranial tumors. Most common CNS neoplasm in immunocompromised. Often multifocal within the parenchyma, yet involvement outside the CNS is rare and late complication.
Secondary involvement of CNS from a primary lymph node lymphoma is usually manifeated by the presence of malignant cells within the CSF and around intradural nerve roots. Vast majority are B-cell origin.
In immunocompromised, they are latently infected by EBV .
MORPHOLOGY Multiple, often involve deep gray matter as well as white matter and the cortex.
Periventricular spread is common. Diffuse Large-cell B-cell lymphoma is most common subtype.
MOLECULAR GENETICS
Most common is chromosome 22 loss, especially 22q (long arm) Deletions in 22q12 harboring the NF2 gene which encodes for the protein merlin are common in cases of NF Type 2.
Of sporadic type, 50-60% harbor NF2 mutation.
In meningiomas without NF2 mutations the most common mutation include TNF-receptor associated factor 7 ( TRAF7).
MORPHOLOGY
Round masses with well-defined dural bases that compress the underlying brain but are easily separated from it.
Usually encapsulated by thin, fibrous tissue. May also grow en plaque , tumors spreads in a sheet-like fashion, commonly associated with hyperostotic reactive changes in the adjacent bone.
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Necrosis and hemorrhage are absent, grade I/IV. Firm and fibrous to finely gritty, may contain psammoma bodies.
Various histologic patterns: Syncytial (Meningothelial) – whorled clusters
Fibroblastic – elongated cells with collagen deposits
Transitional – share features of first two types
Psammomatous – with psamomma bodies.
Secretory – PAS (+) intracytoplasmic droplets
Microcystic – loose, spongy appearance.
Xanthomatous degeneration, metaplasia pleomorphism are common in meningiomas. Atypical Meningiomas
Subacute Cerebellar Degeneration Destruction of Purkinje cells, gliosis, chronic inflammatory cells PCA-1 antibody (Anti-Yo) to Purkinje cells. and
nuclear
Grade II/IV, higher rate of recurrence, more aggressive locally Four or more mitoses in 10 hpf or at least 3 atypical features. Certain histologic patterns are considered II/Iv like clear cell and choroid due to more aggressive behavior. Anaplastic (Malignant) Meningioma
Grade III/IV, highly aggressive with sarcomatous appearance.
Mitotic rates are high >20/10hpf. Papillary meningioma – pleomorphic cells arranged around fibrovascular cores. Rhabdoid meningioma – sheets of tumor cells with hyaline eosinophilic cytoplasm with intermediate filaments. Meningioma is positive for CEA, secretory type is keratin (+).
Underlying mechanism appears to be development of an immune response against tumor antigens that cross-react with antigens in the CNS or PNS.
Predominantly in women with ovarian, breast, uterine CA.
Limbic Encephalitis
Subacute dementia and marked by perivascular inflammatory cuffs, microglial nodules, neuronal loss, and gliosis.
Most evident in anterior and medial portions of temporal lobe. Resembles an infectious process. Some have ANNA-1 antibody ( anti-Hu) that recognized neuronal nuclei in CNS and PNS. Most commonly associated with small cell CA of the lungs. Another antibody is those that recognize NMDA receptors and cross react with hippocampal neurons.
Identified in women with ovarian teratomas. Some have circulating VGKC-complex antibody that recognizes voltage-gated potassium channel, may be associated with peripheral neuropathy.
CLINICAL FEATURES
Usually slow-growing, present with vague non-localizing symptoms or with focal findings referable to brain compression.
Common sites:
Parasagittal aspect of brain convexity.
Dura over lateral convexity.
Wing of sphenoid Olfactory groove, sella turcica, foramen magnum
Uncommon in children, moderate female predominance.
In spinal meningiomas, it is commonly psammomatous.
Usually solitary, if multiple may be associated with NF2.
METASTATIC TUMORS
Mostly carcinomas, metastasis account for ¼ to ½ of intracranial tumors in hospitalized patients.
Lung
Breast
Skin (Melanoma)
Kidney
GIT
Some (Prostatic adenoma) almost never metastasize to the brain
Meninges are frequent involvement by metastatic disease. Present clinically as mass lesions.
MORPHOLOGY
Intraparenchymal metastasis form sharply demarcated mass often at the junction of gray and white matter, usually surrounded by zone of edema. Melanoma may not follow this rule, may invade the brain. Meningeal Carcinomatosis – tumor nodules studding the surface of the brain, cord, nerve roots associated with lung and breasts.
In children, most common in neuroblastoma with myoclonus.
Peripheral Nervous System
Subacute Sensory Neuropathy – associated with limbic encephalitis or in isolation, marked by loss of sensory neurons from dorsal root ganglia with lymphocytic inflammation. Lambert-Eaton Myasthenic Syndrome – antibodies against voltage-gated calcium channels in presynaptic NMJ.
FAMILIAL TUMOR SYNDROMES
5 most common primary sites:
Eye movement disorders Most commonly opsoclonus associated with cerebellar and brainstem dysfunction.
Cowden Syndrome
Dysplastic Gangliocytoma of cerebellum (Lhermitte-Duclos)
Mutations in PTEN lead to PI3K/AKT activity.
Li-Fraumeni Syndrome Medulloblastomas with mutations in TP53 Turcot Syndrome
Medulloblastoma or Glioblastoma
Mutations in APC or mismatch repair genes.
Gorlin Syndrome
Tuberous Sclerosis Complex
Autosomal dominant, development of hamartomas and benign neoplasms involving the brain and other tissues.
Present as seizures, autism, and mental retardation. Hamartomas in CNS take the form of cortical tubers and subependymal nodules.
Subependymal giant-cell astrocytomas are low grade
Cortical tubers are epileptogenic Elsewhere in the body, develop over childhood/adolescence:
PARANEOPLASTIC SYNDROMES
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Medulloblastoma, mutations in PCTH leads to upregulation of the SHH pathway
Renal Angiomyolipomas
Retinal Glial Hamartomas
Pulmonary Lymphangioleiomyomatosis
Cardiac Rhabdomyosarcomas
Cutaneous lesions include:
Angiofibromas Shagreen Patches – localized leathery thickenings. Ash-leaf Patches – hypopigmented areas
Subungual fibromas
TSC1 (tuberous sclerosis locus) found on 9q34 encodes for a protein known as hamartin, a more commonly mutated TSC2 at 16p13.3 encodes for tuberin.
These two form a complex that inhibits mTOR.
MORPHOLOGY Composed of haphazardly arranged neurons that lack the normal laminar organization of the neocortex.
Some large cells have appearances intermediate between glia and neurons, often express intermediate filaments of both neuronal (neurofilament ) and glial (GFAP). These cells usually stain for both tuberin and hamartin. Multiple drop-like masses that bulge into the ventricular system gave rise to the term candle-guttering.
Von Hippel-Lindau Disease
Autosomal dominant, develops hemangioblastomas of the CNS and cysts involving pancreas, liver, and kidneys with propensity to develop to RCC and pheochromocytoma.
Most common in cerebellum and retina.
VHL gene is a TSG, located in 3p25.3 encodes for VHL protein which is a component of a ubiquitin ligase complex that downregulated hypoxia-induced factor 1 (HIF-1).
MORPHOLOGY
Hemangioblastomas are highly vascular occurs as a mural nodule associated with a large fluid-filled cyst.
Variable portions of capillary-size or large thin-walled vessels and intervening stromal cells that are vacuolated, PAS (+), lipid-rich cytoplasm.
Neurofibromatosis
Two autosomal dominant disorders, NF1 and NF2, are familial tumors characterized by tumors both in CNS and PNS. NF1 is more common, neurofibromas of peripheral nerves, gliomas of optic nerves, pigmented nodules of the iris (Lisch nodules) and hyperpigmented macules (café au lait spots) NF2 is most commonly characterized by bilateral schwannomas of the CNVIII (vestibulocochlear) and multiple meningiomas.
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