BMS 100 Neuropathology I PDF

Neuropathology I Headache disorders General Neurological Pathology BMS 100 Week 12 Video links Video 1 Boucher: https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.aspx?id =8882b947-805a-4357-9d80-afd000018ca4 Toronto: https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.aspx?id =f0a77f5d-b452-40d6-9d6f-af...

Neuropathology I Headache disorders General Neurological Pathology BMS 100 Week 12 Video links Video 1 Boucher: https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.aspx?id =8882b947-805a-4357-9d80-afd000018ca4 Toronto: https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.aspx?id =f0a77f5d-b452-40d6-9d6f-afd000019b2f Video 2 Boucher: https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.aspx?id =4de496ec-a00c-405a-b195-afd000018c85 Toronto: https://ccnm.ca.panopto.com/Panopto/Pages/Viewer.aspx?id =e0e8acf1-d092-45cd-81e4-afd000019b15 General Neuropathology – asynchronous e-learning Brain herniation General Cellular Neuropathology Acute ischemia Chronic findings in ischemia Neurodegeneration and neuronal inclusions Gliosis Review Moore’s Clinically-Oriented Anatomy, 7th ed., fig. 7.41, p. 870 Herniation due to increases in intracranial pressure Subfalcine herniation (most common herniation) expansion of one cerebral hemisphere “pushes” the cingulate gyrus under the falx cerebri § Cingulate gyrus is part of the limbic lobe – medial cortex within the medial longitudinal fissure Compression of this lobe or the nearby anterior cerebral artery can lead to: § “vascular symptoms” – weakness of the contralateral leg § “limbic symptoms” – apathy, difficulty making decisions, indifference Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 28.3, p. 1245 Herniation due to increases in intracranial pressure Transtentorial (uncinate, mesial temporal) herniation medial aspect of the temporal lobe is compressed downwards across the tentorium cerebelli à compression of midbrain and pons § 3rd cranial nerve palsy § compression of the contralateral cerebral peduncle (hemiparesis) § hemorrhagic lesions in midbrain and pons § Hydrocephalus due to obstruction of CSF flow Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 28.3, p. 1245 Herniation due to increases in intracranial pressure Tonsillar herniation Significant displacement of the cerebellar tonsils through the foramen magnum Acute, it can be life-threatening because it causes brainstem compression and compromises vital respiratory and cardiac centers in the medulla oblongata chronic often has less severe repercussions § Some congenital malformations of the contents of the posterior fossa can show tonsillar herniation, but with minimal clinical features Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 28.3, p. 1245 Necrotic cellular damage – focus on intracellular calcium Remember glutamate? § Most common excitatory neurotransmitter in the CNS § One of the ionotropic receptors for glutamate – NMDA receptor – is permeable to calcium Remember nitric oxide? § A free radical messenger that can be converted to a more toxic radical, peroxynitrite (ONOO-) if it is produced in high concentrations § Neuronal nitric oxide synthase is activated by elevations in intracellular calcium Necrotic cellular damage – focus on intracellular calcium Why would brain tissue deprived of blood flow (ischemia) become depolarized? How could depolarization be linked to “unregulated” neurotransmitter release How can this impact free radical production? Patterns of neuronal injury Acute neuronal injury – “red neurons” § on H&E stains, neurons look “redder” than usual due to increased eosinophilia § pyknosis (a type of nuclear condensation), eosinophilic cell body, cell shrinkage, disappearance of the nucleolus, loss of Nissl substance § Typically found 12-24 hours after hypoxic/ischemic insult Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 8th ed. Fig 28.3, p. 1281 Patterns of neuronal injury Subacute/chronic neuronal injury: § Often described as neuronal degeneration Typical of slower, progressive diseases such as ALS or Alzheimer disease § Cell loss and reactive gliosis proliferation, hypertrophy of astrocytes § Hyperproliferative, hyperplastic astrocytes = gemistocytic astrocytes activation of microglial cells § Activated microglial cells also change their morphology - their processes also get “fatter” and shorter neuronal cell loss can be difficult to detect – although neurons from certain functional areas are lost, they’re not usually lost “all at once” § Easier to see the gliosis than the cell loss § often cell loss is due to apoptosis, hence the absence of an inflammatory reaction and subtle histologic findings Astrocytic reaction to injury Gliosis (reactive gliosis): § hypertrophy and hyperplasia of astrocytes § nuclei enlarge and nucleoli become more prominent § cytoplasm becomes more eosinophilic, processes more stout Known as gemistocytic astrocytes Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 8th ed. Fig 28.3, p. 1281 Astrocytic reaction to injury Benefits of astrocytic gliosis § Help with synaptogenesis after injury? Controversial – likely more of a barrier than an aid in “reconnecting” the damaged brain § important in buffering excitotoxins (glutamate), acid, potassium § important in maintaining or re-establishing the BBB § Improved ability to support neuron energy metabolism increased Disadvantages of astrocytic gliosis § Axons have great difficulty navigating across the glial scar, may be a major barrier preventing regeneration of axons/tracts Reactions of other cells to injury Oligodendrocytes and ependymal cells exhibit minimal changes when tissue is damaged § any changes will be discussed in the relevant pathologies Microglial cells almost always exhibit changes § known as microglial activation (resident macrophages of the CNS) § cells lose their ramifications and become more “ameboid” secrete pro-inflammatory molecules and cytokines that recruit peripheral leukocytes and aid astroglial activation phagocytose dead or dying cells secrete free radicals and “overactivate” the immune response à worsened neuronal injury Patterns of neuronal injury Intracellular inclusions are common with a range of neurological diseases: § lipofuscin: accumulates with aging, “wear-and-tear” complex of lipids § viral inclusions Cowdry = intranuclear inclusion associated with herpes infection Negri body = intracytoplasmic inclusion associated with rabies § Neurofibrillary tangles (Alzheimer disease) § Lewy bodies in Parkinson disease Inclusions are often specific to a narrow range of diseases and will be discussed in the context of those diseases Infarction from Obstruction of Local Blood Supply (Focal Cerebral Ischemia) The general mechanisms of ischemic necrosis have been discussed earlier this semester § see next slide for key features There are, however, several special responses to ischemia in the central nervous system: § Excitatory amino acid neurotransmitters, such as glutamate, are released during ischemia may cause cell damage by overstimulation and persistent opening of NMDA receptor – glutamate ionotropic receptors § These receptors allow calcium influx § Calcium influx can increase nitric oxide production in neuronal cells General pathological sequences Ischemia (stroke) § Early insult (minutes – hours): loss of intracellular ATP à destabilization of membrane potentials, excitotoxicity, calcium influx and nitric oxide production à destruction of membranes and necrosis § Later insult (hours – a day): development of red neurons (dead, shrunken, eosinophilic, pyknotic cells) microglial activation, disruption of BBB at this time § Subacute phase of the insult (day – days): reactive astrocytes, reactive microglia, influx of leukocytes across BBB – known as liquefactive necrosis § Resolution – astrocytic “scar” develops, liquefied mass removed sometimes leaving a cavity bounded by scar Sometimes necrotic area is composed completely of gliotic tissue and new vascular elements (no neurons) Liquefactive necrosis: characterized by digestion of the dead cells à transformation of the tissue into a liquid viscous mass seen in focal bacterial or, occasionally, fungal infections à accumulation of leukocytes à purulent inflammation (pus) For unknown reasons, hypoxic death of cells within the central nervous system often manifests as liquefactive necrosis “glial scar” – hypertrophic astrocytes at the margins Re-establishment of BBB Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 8th ed. 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