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What are the three types of neuronal metabolic diseases?
- 1. Storage diseases
- 2. Leukodystrophies
- 3. Mitochondrial encephalomyopathies
What are the features of neuronal storage diseases?
- Deficiency of a specific enzyme involved in the catabolism of sphingolipids, mucopolysaccharides, or mucolipids.
- They are often characterized by the accumulation of the substrate of the enzyme within the lysosomes of neurons, leading to neuronal death.
- Cortical neuronal involvement leads to loss of cognitive function and may also cause seizures.
What are the features of leukodystrophies?
- Nyelin abnormalities (either abnormal synthesis or turnover) and generally lack neuronal storage defects.
- Some of these disorders involve lysosomal enzymes; others affect peroxisomal enzymes.
- Diffuse involvement of white matter leads to deterioration in motor skills, spasticity, hypotonia, or ataxia.
- Most are autosomal recessive disorders; adrenoleukodystrophy, an X-linked disease, is a notable exception.
What are the two important neuronal storage disease?
Neuronal Ceroid Lipofuscinoses, and Tay Sachs
What are the features of Neuronal Ceroid Lipofuscinoses?
- lysosomal storage diseases
- share the accumulation of lipofuscin—an autofluorescent substance with a variety of ultrastructural appearances—in neurons
- blindness, mental and motor deterioration, and seizures
- Abnormal regulation of membrane-associated palmitoylated proteins.
What is the genetic defect in Tay Sachs disease?
α-subunit locus on chromosome 15 that cause a severe deficiency of hexosaminidase A--> accumulation of GM2
What organs are mainly involved in Tay Sachs disease?
neurons in the central and autonomic nervous systems and retina
What is the histological finding in Tay Sachs disease?
- Neurons are ballooned with cytoplasmic vacuoles, each representing a markedly distended lysosome filled with gangliosides
- Stains for fat such as oil red O and Sudan black B are positive
- whorled configurations within lysosomes composed of onion-skin layers of membranes on EM
- A cherry-red spotthus appears in the macula, representing accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina
What are the clinical characteristics of Tay sachs disease?
- The affected infants appear normal at birth but begin to manifest signs and symptoms at about age 6 months.
- There is relentless motor and mental deterioration, beginning with motor incoordination, mental obtundation leading to muscular flaccidity, blindness, and increasing dementia.
- Sometime during the early course of the disease, the characteristic, but not pathognomonic, cherry-red spot appears in the macula of the eye in almost all patients.
- Over the span of 1 or 2 years a complete vegetative state is reached, followed by death at age 2 to 3 years.
What is the mechanism of neuronal injury in Tay Sachs disease?
- Most mutations affect protein folding. Such misfolded proteins trigger the “unfolded protein” response leading to apoptosis.
- These findings have given rise to the possibility of chaperone therapy of Tay-Sachs disease
What are the leukodystrophies?
- Krabbe Disease
- Metachromatic Leukodystrophy
- Pelizaeus-Merzbacher Disease
- Canavan Disease
- Alexander Disease
- Vanishing-White-Matter Leukodystrophy
What is the cause of Krabbe disease?
- deficiency of galactocerebroside β-galactosidase (galactosylceramidase), the enzyme required for the catabolism of galactocerebroside to ceramide and galactose
What causes injury in Krabbe disease?
While accumulation of galactocerebroside occurs, this is not the direct toxic agent in this disease. Instead, it seems that an alternative catabolic pathway removes a fatty acid from this molecule, generating galactosylsphingosine, which is a cytotoxic compound that may cause oligodendrocyte injury
What are the findings in Krabbe disease?
- The clinical symptoms are dominated by motor signs, including stiffness and weakness, with gradually worsening difficulties in feeding. The brain shows loss of myelin and oligodendrocytes in the CNS and a similar process in peripheral nerves
- Axons and neurons are spared
- Aggregation of engorged macrophages (globoid cells) in the parenchyma and around blood vessels
What is the pathognomonic feature of Krabbe disease?
Aggregation of engorged macrophages (globoid cells) in the parenchyma and around blood vessels
What is the cause of Metachromatic Leukodystrophy?
- lysosomal enzyme arylsulfatase A
- cleaves the sulfate from sulfate-containing lipids (sulfatides), the first step in their degradation.
- Enzyme deficiency leads to an accumulation of the sulfatides, especially cerebroside sulfate
What are the symptoms of metachromatic LD?
- Childhood--> begin with motor
- Adult--> begin with psychiatric
What are the diagnostic features of metachromatic LD?
- The most striking histologic finding is demyelination with resulting gliosis.
- Macrophages with vacuolated cytoplasm are scattered throughout the white matter. The membrane-bound vacuoles contain complex crystalloid structures composed of sulfatides; when bound to certain dyes such as toluidine blue, sulfatides shift the absorbance spectrum of the dye, a property called metachromasia.
- The detection of metachromatic material in the urine is also a sensitive method of establishing the diagnosis
What are the features of ALD?
- Progressive disease with symptoms referable to myelin loss from the CNS and peripheral nerves as well as adrenal insufficiency
- X-linked form usually presents in the early school years with neurologic symptoms and adrenal insufficiency and is rapidly progressive and fatal
- ATP-binding cassette transporter family of proteins, ABCD1
- Inability to properly catabolize very-long-chain fatty acids (VLCFAs) within peroxisomes, with elevated levels of VLCFAs in serum.
- There is loss of myelin, accompanied by gliosis and extensive lymphocytic infiltration.
- Atrophy of the adrenal cortex is present, and VLCFA accumulation can be seen in remaining cells
What is the major abnormality in ALD?
Inability to properly VLCFA within peroxisomes, with elevated levels of VLCFAs in serum.
What are the core features of four other LD?
- 1) Pelizaeus-Merzbacher Disease-->XL, Tigeroid appearance of the brain (patches of myelin)/ pendular eye movements, hypotonia, choreoathetosis, and pyramidal signs early in the disease, followed later by spasticity, dementia, and ataxia/mutation in myelin proteins
- 2) Canavan Disease--> megalocephaly, severe mental deficits, blindness, spongy degeneration of white mater, loss-of-function mutations in the gene encoding the deactylating enzyme aspartoacylase
- 3) Alexander Disease-->megalencephaly, seizures, and progressive psychomotor retardation, white-matter loss, typically with a frontal-to-occipital gradient, Even though Rosenthal fibers are primarily composed of various heat-shock proteins, including αB-crystallin, the basis of Alexander disease lies in mutations in the gene encoding glial fibrillary acid protein (GFAP)/exuberant accumulation of Rosenthal fibers around blood vessels/ dominant gain-of-function mutations associated with decreased capacity to form filaments as well as induction of stress responses
- 4) Vanishing-White-Matter Leukodystrophy-->genes encoding any of the five subunits of eukaryotic initiation factor 2B (eIF2B)/ataxia and seizures
What are types of MITOCHONDRIAL ENCEPHALOMYOPATHIES?
- Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes
- Myoclonic Epilepsy and Ragged Red Fibers
- Leigh Syndrome (Subacute Necrotizing Encephalopathy)
- Kearn-Sayre Syndrome
- Alpers Disease
What are the features of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes?
- most common neurologic syndrome caused by mitochondrial abnormalities
- The stroke-like episodes are often associated with reversible deficits that do not correspond well to specific vascular territories.
- Pathologically, areas of infarction are observed, often with vascular proliferation and focal calcification.
- The most prevalent mutations associated with MELAS occurs in tRNAs;
What are the features of Myoclonic Epilepsy and Ragged Red Fibers?
- maternally transmitted
- Ataxia, associated with neuronal loss from the cerebellar system (including the inferior olive in the medulla, cerebellar cortex, and deep nuclei), is also a common component
What are the features of Leigh Syndrome (Subacute Necrotizing Encephalopathy)?
- lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extra-ocular palsies, and weakness with hypotonia
- Death within 2 years
- multifocal, moderately symmetric regions of destruction of brain tissue with a spongiform appearance and proliferation of blood vessels.
- The areas that are most commonly affected include the periventricular gray matter of the midbrain, the tegmentum of the pons, and the periventricular regions of the thalamus and hypothalamus.both nuclear and mitochondrial DNA mutations
What are the features of Kearn-Sayre Syndrome?
- large mitochondrial DNA deletion/rearrangement
- cerebellar ataxia, progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects
- spongiform change in gray and white matter, with neuronal loss most evident in the cerebellum
What are the features of Alpers Disease?
- hepatic dysfunction and pathologic findings including hepatitis and bile duct proliferation
- Begin with severe intractable seizures, followed by developmental delay, hypotonia, ataxia, and cortical blindness.
- There is neuronal loss in cerebral cortex and throughout deeper structures, and spongiform degeneration of gray matter. Mutations in the nuclear gene encoding DNA polymerase γ—the isoform of DNA polymerase responsible for replication of the mitochondrial genome
What are the features of vitamin B1 deficiency?
- psychotic symptoms or ophthalmoplegia that begin abruptly (Wernicke encephalopathy)
- The acute stages, if unrecognized and untreated, may be followed by a prolonged and largely irreversible condition,Korsakoff syndrome, characterized clinically by memory disturbances and confabulationSeen in Gastric disorders and alcoholism
What are the histological findings of Wernicke encephalopathy?
- Foci of hemorrhage and necrosis in the mamillary bodies and the walls of the third and fourth ventricles.
- Early lesions show dilated capillaries with prominent endothelial cells. Subsequently, the capillaries become leaky, producing hemorrhagic areas. With time, there is infiltration of macrophages and development of a cystic space with hemosiderin-laden macrophages. These chronic lesions predominate in individuals with Korsakoff syndrome.
- Lesions in the dorsomedial nucleus of the thalamus seem to be the best correlate of the memory disturbance and confabulation
Lesions in the ................... seem to be the best correlate of the memory disturbance and confabulation in Korsakoff amnestic syndrome
dorsomedial nucleus of the thalamus
What is the hallmark of cerebellar dysfunction in chronic alcoholics?
- Truncal ataxia, unsteady gait, and nystagmusAtrophy and loss of granule cells predominantly in the anterior vermis
- In advanced cases there is 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
What is the early finding in alcoholic cerebellar degeneration?
Loss of granule cells in Anterior vermis
What is the clinical feature of vitamin B12 deficiency?
- The neurologic symptoms may present in the course of a few weeks, initially with numbness, tingling, and slight ataxia in the lower extremities, but may progress rapidly to include spastic weakness of the lower extremities.
- Complete paraplegia may occur, usually only later in the course. With prompt vitamin replacement therapy, clinical improvement occurs; however, if complete paraplegia has developed, recovery is poor
What is the histological feature of nerve involvement in B12 deficiency?
- swelling of myelin layers, producing vacuoles
- This begins segmentally at the midthoracic level of the spinal cord in the early stages. With time, axons in both the ascending tracts of the posterior columns and the descending pyramidal tracts degenerate
How can hypoglycemia affect neurological function?
- Like O2 deprivation.
- Some regions of the brain are more sensitive to hypoglycemia than are others. Glucose deprivation initially leads to selective injury to large pyramidal neurons of the cerebral cortex, which, if severe, may result in pseudolaminar necrosis of the cortex, predominantly involving deep layers.
- The hippocampus is also vulnerable to glucose depletion and may show a marked loss of pyramidal neurons in Sommer sector (area CA1 of the hippocampus).
- Purkinje cells of the cerebellum are also sensitive to hypoglycemia, although to a lesser extent than to hypoxia.
Glucose deprivation initially leads to ........................
selective injury to large pyramidal neurons of the cerebral cortex
What are the hallmarks of hepatic encephalopathy?
- The cellular response in the CNS is predominantly glial.
- Alzheimer type II cells are evident in the cortex and basal ganglia and other subcortical gray matter regions.
What are the features of CNS involvement in CO poisoning?
- Selective injury of the neurons of layers III and V of the cerebral cortex, Sommer sector of the hippocampus, and Purkinje cells is characteristic.
- Bilateral necrosis of the globus pallidus
- Demyelination of white matter tracts may be a later event
What is the hallmark of methanol toxicity?
- Methanol toxicity preferentially affects the retina, where degeneration of retinal ganglion cells may cause blindness.
- Selective bilateral putamenal necrosis and focal white-matter necrosis also occur when the exposure is severe.
- Formate, a major metabolite of methanol, may have a role in the retinal toxicity
What is the effect of radiation on CNS?
- Exposure to very high doses of radiation (>1000 rems) can cause intractable nausea, confusion, convulsions, and rapid onset of coma, followed by death.
- Delayed effects of radiation can also present with rapidly evolving symptoms, including headaches, nausea, vomiting, and papilledema that may appear months to years after irradiation.
- The pathologic findings consist of large areas of coagulative necrosis and adjacent edema. The typical lesion is restricted to white matter, and all elements within the area undergo necrosis, including astrocytes, axons, oligodendrocytes, and blood vessels. Adjacent to the area of coagulative necrosis, proteinaceous spheroids may be identified, and blood vessels show thickened walls with intramural fibrin-like material.
- Radiation can also induce tumors, which usually develop years after radiation therapy and include sarcomas, gliomas, and meningiomas
What are the features of Combined Methotrexate and Radiation-Induced Injury?
- Methotrexate toxicity most commonly develops when the drug has been administered in association with radiation therapy, either together or at separate times. The interval between the inciting events and the onset of symptoms varies considerably but may be as long as months
- Symptoms often begin with drowsiness, ataxia, and confusion, and may progress rapidly. While some affected individuals recover function, others may become comatose
- focal areas of coagulative necrosis within white matter, often adjacent to the lateral ventricles
- Surrounding axons are often dilated and form axonal spheroids. Axons and cell bodies in the vicinity of the lesions undergo dystrophic mineralization, and there is adjacent gliosis
What are the mcc of brain tumors?
What are the five common metastatic tumors to brain?
lung, breast, skin (melanoma), kidney, and gastrointestinal tract
Which common tumor does not metastasize to brain?
Which tumor is rare but commonly metastasize to brain?
What is the morphology of metastatic brain tumors?
- Intraparenchymal metastases form sharply demarcated masses, often at the junction of gray matter and white matter, usually surrounded by a zone of edema.
- The boundary between tumor and brain parenchyma is well defined microscopically as well, although melanoma is one tumor that does not always follow this rule.
- Nodules of tumor, often with central areas of necrosis, are surrounded by reactive gliosis.
- Meningeal carcinomatosis, with tumor nodules studding the surface of the brain, spinal cord, and intradural nerve roots, is associated particularly with carcinoma of the lung and the breast
What is the major mechanism for CNS paraneoplastic syndromes?
Development of an immune response against tumor antigens that cross-react with antigens in the central or peripheral nervous systems
What are the various paraneoplastic encephalomyelitis?
- Subacute cerebellar degeneration (Purkinje destruction)
- Limbic encephalitis, characterized by subacute dementia and marked by perivascular inflammatory cuffs, microglial nodules, some neuronal loss, and gliosis, most evident in the anterior and medial portions of the temporal lobe and resembling an infectious process.
- Eye movement disorders, most commonly opsoclonus. In children this is most commonly associated with neuroblastoma and is found along with myoclonus
What are the paraneoplastic syndromes involving the PNS?
- Subacute sensory neuropathy may be found in association with limbic encephalitis or in isolation. It is marked by loss of sensory neurons from dorsal root ganglia, in association with lymphocytic inflammation.
- Lambert-Eaton myasthenic syndrome, caused by antibodies against the voltage-gated calcium channel in the presynaptic elements of the neuromuscular junction. This can be seen in the absence of malignancy as well
.......................is associated with antibodies against voltage-gated potassium channels
What are the features of Schwann cells?
- presence of S-100 antigen
- potential for melanocytic differentiation
Why do peripheral nerve tumors can arise within the dura, as well as along the peripheral course of nerves?
There is a transition between myelination by oligodendrocytes (central myelin) and myelination by Schwann cells (peripheral myelin) that occurs within several millimeters of the substance of the brain
What is the pathogenesis of schwanomma?
- These benign tumors arise from the neural crest–derived Schwann cell.
- Schwannomas are a component of NF2, and even sporadic schwannomas are commonly associated with inactivating mutations in the NF2 gene on chromosome 22. Loss of expression of the NF2 gene product, merlin, is a consistent finding in all schwannomas.
- Merlin normally restricts the cell-surface expression of growth factor receptors, such as EGFR, through interactions involving the actin cytoskeleton; in its absence, cells hyperproliferate in response to growth factors
What is the consistent molecular abnormality in all schwannomas?
Loss of NF2 gene product merlin on chromosome 22
What is the function of Merlin?
Merlin normally restricts the cell-surface expression of growth factor receptors, such as EGFR, through interactions involving the actin cytoskeleton; in its absence, cells hyperproliferate in response to growth factors
What are the morphological features of Schwannomas ?
- Well-circumscribed, encapsulated masses that are attached to the nerve but can be separated from it
- Mixture of two growth patterns
- In the Antoni A pattern of growth, elongated cells with cytoplasmic processes are arranged in fascicles in areas of moderate to high cellularity and scant stromal matrix; the “nuclear-free zones” of processes that lie between the regions of nuclear palisading are termed Verocay bodies.
- In the Antoni B pattern of growth, the tumor is less densely cellular and consists of a loose meshwork of cells, microcysts and myxoid stroma.
- Electron microscopy shows basement membrane deposits encasing single cells and collagen fibers.
- Because the lesion displaces the nerve of origin as it grows, silver stains or immunostains for neurofilament proteins demonstrate that axons are largely excluded from the tumor, although they may become entrapped in the capsule.
- The Schwann cell origin of these tumors is borne out by their S-100 immunoreactivity.
- A variety of degenerative changes may be found in schwannomas, including nuclear pleomorphism, xanthomatous change, and vascular hyalinization
What is the symptom of schwannoma?
Cerebellopontine angle, where they are attached to the vestibular branch of the eighth nerve. Affected individuals often present with tinnitus and hearing loss
The presence of either multiple neurofibromas or plexiform neurofibromas strongly suggests the diagnosis of .............
neurofibromatosis type 1 (NF1).
What are the general features of neurofibroma?
- Neurofibromas can present as discrete localized masses—most commonly as a cutaneous neurofibroma or in peripheral nerve as a solitary neurofibroma—or as an infiltrative lesion growing within and expanding a peripheral nerve (plexiform neurofibroma).
- The presence of either multiple neurofibromas or plexiform neurofibromas strongly suggests the diagnosis of neurofibromatosis type 1 (NF1).
- Skin lesions grow as nodules, sometimes with overlying hyperpigmentation. The risk of malignant transformation of these tumors is extremely small.
- In contrast, plexiform tumors may result in significant neurologic deficits when they involve major nerve trunks, are difficult to remove because of their intraneural spread, and have a significant potential for malignant transformation
What is the morphology of Cutaneous Neurofibroma?
- Present in the dermis and subcutaneous fat, these well-delineated but unencapsulated masses are composed of spindle cells.
- Although they are not invasive, the adnexal structures are sometimes enwrapped by the edges of the lesion. The stroma of these tumors is highly collagenized and contains little myxoid material.
What are the morphological features of plexiform neurofibroma?
- Large nerve trunks are most commonly involved
- Unlike schwannomas, it is not possible to separate the lesion from the nerve
- The proximal and distal extremes of the tumor may have poorly defined margins, as fingers of tumor and individual neoplastic cells insert themselves between the nerve fibers
- Loose, myxoid background with a low cellularity
- Several cell types are present, including Schwann cells, multipolar fibroblastic cells, and inflammatory cells
- Although the myxoid stroma dominates, there are often areas of collagen bundles, which have a “shredded carrot” appearance.
- In contrast to schwannomas, axons can be demonstrated within the tumor.
What is the pathophysiology of plexiform neurofibroma?
- Alterations in both copies of the NF1 gene have been consistently observed in the Schwann cell components of plexiform neurofibromas, supporting a critical role for loss of NF1 function in the genesis of this tumor.
- The product of the NF1 gene (neurofibromin) stimulates the activity of a GTPase that inhibits RAS activity (recall that RAS is active only when bound to GTP).
What are the general features of Malignant Peripheral Nerve Sheath Tumor?
- highly malignant tumors that are locally invasive, frequently with multiple recurrences and eventual metastatic spread.
- medium to large nerves
- 50% of cases arise in the setting of NF1—either from transformation of a plexiform neurofibroma or following radiation therapy
- NF1 function is lost at an early stage of development of malignant peripheral nerve sheath tumors; subsequent alterations often disrupt both the p53- and RB-dependent pathways for regulation of cell proliferation
What are the histological finding in Malignant Peripheral Nerve Sheath Tumor?
- Poorly defined tumor masses that frequently infiltrate along the axis of the parent nerve and invade adjacent soft tissues
- Variable Histology (Schwann, Fibrosarcoma,...)