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The Central Nervous System

The Central Nervous System. Cellular Responses to Injury. Reactions of neurons to injury Acute neuronal injury – “red neurons” Subacute and chronic neuronal injury – degeneration Axonal reaction – regeneration Neuronal inclusions. Cellular Responses to Injury.

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The Central Nervous System

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  1. The Central Nervous System

  2. Cellular Responses to Injury • Reactions of neurons to injury • Acute neuronal injury – “red neurons” • Subacute and chronic neuronal injury – degeneration • Axonal reaction – regeneration • Neuronal inclusions

  3. Cellular Responses to Injury • Reaction of astrocytes to injury • Metabolic buffers and detoxifiers • Gliosis • Gemistoytic astrocytes • Alzheimer type II astrocytes • Rosenthal fibers • Alexander disease • Lafora bodies

  4. Cellular Responses to Injury • Other glial cells – oligodendrocytes and ependyma • More limited repertoire of reactions • Inclusions • CMV – extensive ependymal injury

  5. Cellular Responses in Injury • Reactions of microglia to injury • Fixed macrophages in the CNS • Proliferation • Development of elongated nuclei • Formation of aggregates about small foci of tissue necrosis ( microglial nodules) • Congregation around cell bodies of dying neurons ( neuronophagia) • Blood-derived macrophages are principal phagocytic cells in inflammatory foci

  6. Cerebral Edema, Hydrocephalus, and Raised Intracranial Pressure and Herniation • Cerebral Edema • Vasogenic edema • Cytotoxic edema • Hydrocephalic edema • Hydrocephalus • Accumulation of excessive CSF within the ventricular system • Communicating • Noncommunicating • Hydrocephalus ex vacuo • Raised Intracranial pressure and herniation • Subfalcine ( cingulate) herniation • Transtentorial ( uncinate,mesial temporal) herniation • Tonsillar herniation

  7. Malformations and Developmental Diseases • Neural tube defects • Encephalocele • Spinal dysraphism ( spina bifida) • Myelomeningocele • Meningocele • Anencephaly • Folic acid, alpha-fetoprotein • Forebrain anomalies • Megaloencephaly or microencephaly • Lissencephaly ( agryia) • Polymicrogyria Neuronal heterotopias Holoproencephaly Agensis of the corpus callosum • Posterior fossa anomalies • Dandy-Walker malformation • Arnold-Chiari malformation ( Chiari type II), • Chiari I malformation • Syringomyelia and hydromyelia

  8. Perinatal Brain Injury • Brain injury occurring in the perinatal period is an important cause of childhood neurologic disability • Cerebral palsy • Intraparenchylmal hemorrhage within the germinal matrix • Periventricular leukomalacia • Multicystic encephalopathy • Ulegyria • Status marmoratus

  9. Trauma • Skull fractures • Parenchymal Injuries • Traumatic Vascular Injury • Sequelae of brain tumors • Spinal cord Trauma – level of lesion determines extent of neurologic manifestation

  10. Trauma • Anatomic location and limited capacity for functional repair – major determinants of consequences of trauma • Skull fractures, parenchymal injury, vascular injury or combination • Penetrating or blunt (open or closed) injury

  11. Trauma • Displaced skull fracture • Basal skull fracture – CSF leak • Diastatic

  12. Trauma • Parenchymal Injuries • Concussion – clinical syndrome of altered consciousness secondary to head injury typically brought about by a chance in the momentum of the head • Instantaneous LOC, temporary respiratory arrest, loss of reflexes, amnesia for the event, post-concussive neuropsychiatric syndromes

  13. Trauma • Direct parenchymal injury • Contusion • Laceration • Coup and contrecoup • Plaque jaune • Diffuse axonal injury

  14. Trauma • Traumatic vascular injury • Epidural hematoma – middle meningeal artery, temporal skull fractures, lucid interval • Subdural hematoma – bridging veins, infants and elderly, lysis -> growth of fibroblasts into the hematoma -> early development of hyalinized CT, chronic subdural – multiple episodes of repeat bleding

  15. Trauma • Sequelae of brain trauma • Post-traumatic hydrocephalus • Post-traumatic dementia • Punch-drunk syndrome • Post-traumatic epilepsy • Meningiomas • Infectious diseases • Psychiatric disorders

  16. Cerebrovascular Diseases • Hypoxia, Ischemia, and Infarction • Hypertensive cerebrovascular disease • Intracranial hemorrhage

  17. Cerebrovascular Diseases • Hypoxia, ischemia, and infarction • Global cerebral ischemia • Hypotension, hypoperfusion, low-flow states • Hierarchy of sensitivity to insult • Selective vulnerability • Border zone “watershed” infarcts • Focal cerebral ischemia • Adequacy of collateral flow • Majority of thrombotic occlusions are due to atherosclerosis • Emboli – mural thrombi, MI valvular disease, paradoxical • Vasculitis

  18. Hypertensive Cerebrovascular Disease • Lacunar infarcts • Slit hemorrhages • Hypertensive encephalopathy • Diffuse cerebral dysfunction • Headaches, confusion, vomiting, convulsions, coma • Increased intracranial pressure • Vascular dementia – Multi-infarct, dementia, gait abnormalities, pseudobulbar signs, superimposed focal defects, Binswanger disease – loss of large areas of white matter

  19. Intracranial Hemorrhage • Intracerebral (intraparenchymal) • Hypertension is the most common underlying cause of primary brain parenchymal hemorrhage • Cerebral amyloid angiopathy • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

  20. Intracranial Hemorrhage • Subarachnoid hemorrhage • Saccular (berry) aneurysm – most frequent cause, Table 28-19 – common sites, sporadic most common, also AD polycystic kidney disease, Ehlers-Danlos, type IV, NF type 1, Marfan), “Worst headache of my life”

  21. Intracranial Hemorrhage • Vascular malformations • Arteriovenous malformation • Cavernous malformation • Capillary telangiectasias • Venous angiomas

  22. Infections • Acute meningitis • Acute focal suppurative infections • Chronic bacterial meningoencephalitis • Viral meningoencephalitis • Fungal Meningoencephalitis • Other infectious diseases of the nervous system

  23. Principal routes of spread of microorganisms into the CNS Hematogenous spread Direct implantation Local extension Transport along the peripheral NS

  24. Meningitis Inflammatory process of the leptomeninges and CSF within the subarachnoid space Acute pyogenic (bacterial) Purulent CSF, exudate within the leptomeninges, pus tracts along blood vessels Aseptic (viral) less fulminant Chronic (TB, syphilis, cryptococcal, lyme disease

  25. Acute Focal Suppurative Infections • Brain abscess • Acute bacterial endocarditis, congenital heart disease, chronic pulmonary sepsis, immunosuppression • Subdural empyema • Extradural abscess

  26. Viral Meningoencephalitis • Arthropod-borne – West Nile • Herpes simplex type 1 and type 2 • Herpes Zoster • CMV • Poliomyelitis – anterior horn cells • Rabies – Negri bodies • HIV • Progressive multifocal leukoencephalopathy – JC polyomavirus • Subacutesclerosingpanencephalitis - measles

  27. Fungal Meningoencephalitis • Candida, Mucor, Aspergillus, Crytococcus • Chronic meningitis • Vasculitits • Parenchymal invasion

  28. Protozoal • Cerebral amebiasis fatal necrotizing encephalitis or chronic • Toxoplasmosis • Opportunistic • Immunosuppression or maternal infection • Multiple ring-enhancing lesions

  29. Transmissible Spongiform Encephalopathies (Prion diseases) • Creutzfeldt-Jacob disease • Gerstmann-Straussler-Scheinker syndrome • Fatal familial insomnia • Kuru • Figure 28-31

  30. Demyelinating Diseases • Multiple sclerosis • Neuromyelitisoptica – Devic disease • Bilateral optic neuritis and spinal cord demyelination • Acute disseminated encephalomyelitis and acute necrotizing hemorrhagic encephalomyelitis • Other diseases with demyelination • Central pontinemyelinolysis – rapid correction of hypomatremia

  31. 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 • Immune response against components of the myelin sheat • Plaques – active, inactive, shadow • Visual impairment, cranial nerve signs, ataxia, nystagmus, spinal cord lesions, • CSF – elevated protein, 1/3 pleocytosis, increased IgG

  32. Degenerative Diseases • Degenerative diseases affecting the cerebral cortex • Degenerative diseases of basal ganglia and brainstem • Spinocerebellar degenerations • Degenerative diseases affecting the motor neuron

  33. Degenerative Diseases affecting the Cerebral cortex • Alzheimer disease • Most common cause of dementia in the elderly • Most cases are sporadic, 10% familial • Cortical arophy • Neuritic plaques • Neurofibrillary tangles • Abeta peptides • Abnormal forms of protein tau • Neuropil threads • CAA • Frontotemporal dementias • Frontotemproal dementia with parkinsonisn linked to Tau mutations • Pick disease • Progressive supranuclear palsy • Corticobasaldegneration • Frontotemporal dementias withou tau pathology • Vascular dementia

  34. Degenerative Diseases of Basal Ganglia and Brainstem • Parkinsonism – diminished facial expression, stooped posture, slowness of voluntary movements, festinating gait, rigidity, “pill-rolling” tremor • Parkinson disease – dopamine, pallor of substantianigra, alpha-synuclein mutations, lewy bodies • Dementia with Lewy bodies • Multiple system atrophy – inclusions in oligodendrocytes • Huntington disease – progressive movement disorders, dementia, degeneration of striatal nuerons, atrophy of caudate nucleus,

  35. SpinocerebellarDegeneraitons • Spinocerebellar ataxia • Friedreich ataxia – frataxin mutations, GAA trinucleotide-repeat, cardiomyopathy • Ataxia-telangiectasia - immunodeficeincy

  36. Degenerative diseases affecting Motor Neurons • Amyotrophic lateral sclerosis – lower motor and upper motor neurons • Bulbospinal atrophy ( Kennedy syndrome) • Spinal muscle atrophy

  37. Genetic Metabolic Diseases • Neuronal Storage diseases • Neuronal ceroidlipofuscinoses • Tay-Sachs disease • Leukodystrophies • Krabbe disease - deficiency of galatocerebroside beta-galactosidase • Metachromicleukodystrophy – deficiency of lysosomal enzyme arylsulfatase • Adrenoleukosystrophy • Pelizaeus-Merzbacher disease • Canavan disease • Alexander disease • Vanisning-white-matter leukodystrophy • Mitochondrial encephalomyopathies • Mitochondrial encephalopathy, lactic acidosis, strokelike episodes (MELAS) • Myoclonic epilepsy and ragged red fibers (MERRF) • Leigh syndorme (subacute necrotizing encephalopathy • Kearn-Sayre syndrome • Alpers disease

  38. Toxic and Acquired Metabolic Diseases • Vitamin deficiencies • Vitamin B12 • Thiamine (B1) • Beriberi, Wenicke encephalopathy and Korsakoff syndrome • Neurologic sequelae of metabolic disturbances • Hypoglycemia • Hyperglycemia • Hepatic encephalopathy • Toxic disorders • Carbon monoxide • Methanol • Ethanol • Radiation • Combined radiation and methotrexate induced injury

  39. Tumors • Gliomas • Neuronal tumors • Poorly differentiated neoplasms • Other parenchymal tumors • Meningiomas • Paraneoplastic syndromes • Peripheral nerve sheath tumors • Familial tumor syndromes

  40. Tumors 20% of all childhood cancers are CNS tumors 70% of childhood tumors arise in the posterior fossa 70% of adult tumors arise in cerebral hemispheres, supratentorial Rarely metastasize outside of the CNS Symptoms – seizures, headaches, focal neurological deficits, hydrocephalus, ataxia

  41. Gliomas Astrocytomas Infiltrating vs non-infiltrating (pilocytic) Grade I – pilocytic – often cystic Grade II – diffuse astrocytoma Grade III – anaplastic astrocytoma Grade IV – glioblastoma (pseudopalisading) Oligodendrogliomas White matter Well-circumscribed, better prognosis Ependymomas NF2, ependyma-lined ventricular system Perivascular pseudorosettes Subepndymomas Choroid plexus papillomas/ carcinomas Colloid Cyst of third ventricle

  42. Medulloblastoma Poorly differentiated Well-circumscribed Midline of the cerebellum Desmoplastic variant Drop metastases – cauda equina

  43. Meningiomas Attached to the dura Usually benign En plaque Psammoma bodies Atypical Anaplastic

  44. Metastatic ¼ to ½ of intra-cranial tumors in hospitalized patients Five most common Lung Breast Melanoma Kidney GI

  45. Peripheral Nerve Sheath Tumors Schwannoma Neural crest-derived Schwann cell Acoustic neuroma – actually vestibular Neurofibroma Cutaneous Peripheral nerve – solitary or plexiform Malignant peripheral sheath tumors

  46. Familial Tumor Syndromes Neurofibromatosis Type I – AD, Lisch nodules, café au lait spots Neurofibromatosis Type II – AD, 8th nerve schannomas and multiple meningiomas Tuberous Sclerosis – AD, hamartomas ( cortical tubers) and benign neoplasms of the brain; seizures; liver, kidney, pancreas cysts; angifibromas, shagreen patches, ash-leaf spots, subungal fibromas Von Hippel – Lindau Disease – AD, hemangioblastomas (cerebellum and retina); cysts of liver, pancreas, kidney; renal cell carcinoma, pheochromocytomas

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