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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 Reaction of astrocytes to injury Metabolic buffers and detoxifiers Gliosis Gemistoytic astrocytes Alzheimer type II astrocytes Rosenthal fibers Alexander disease Lafora bodies Cellular Responses to Injury Other glial cells – oligodendrocytes and ependyma More limited repertoire of reactions Inclusions CMV – extensive ependymal injury 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 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 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 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 Trauma Skull fractures Parenchymal Injuries Traumatic Vascular Injury Sequelae of brain tumors Spinal cord Trauma – level of lesion determines extent of neurologic manifestation 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 Trauma Displaced skull fracture Basal skull fracture – CSF leak Diastatic 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 Trauma Direct parenchymal injury Contusion Laceration Coup and contrecoup Plaque jaune Diffuse axonal injury 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 Trauma Sequelae of brain trauma Post-traumatic hydrocephalus Post-traumatic dementia Punch-drunk syndrome Post-traumatic epilepsy Meningiomas Infectious diseases Psychiatric disorders Cerebrovascular Diseases Hypoxia, Ischemia, and Infarction Hypertensive cerebrovascular disease Intracranial hemorrhage 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 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 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 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” Intracranial Hemorrhage Vascular malformations Arteriovenous malformation Cavernous malformation Capillary telangiectasias Venous angiomas Infections Acute meningitis Acute focal suppurative infections Chronic bacterial meningoencephalitis Viral meningoencephalitis Fungal Meningoencephalitis Other infectious diseases of the nervous system Principal routes of spread of microorganisms into the CNS Hematogenous spread Direct implantation Local extension Transport along the peripheral NS 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 Acute Focal Suppurative Infections Brain abscess ○ Acute bacterial endocarditis, congenital heart disease, chronic pulmonary sepsis, immunosuppression Subdural empyema Extradural abscess 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 Subacute sclerosing panencephalitis measles Fungal Meningoencephalitis Candida, Mucor, Aspergillus, Crytococcus Chronic meningitis Vasculitits Parenchymal invasion Protozoal Cerebral amebiasis fatal necrotizing encephalitis or chronic Toxoplasmosis Opportunistic Immunosuppression or maternal infection Multiple ring-enhancing lesions Transmissible Spongiform Encephalopathies (Prion diseases) Creutzfeldt-Jacob disease Gerstmann-Straussler-Scheinker syndrome Fatal familial insomnia Kuru Figure 28-31 Demyelinating Diseases Multiple sclerosis Neuromyelitis optica – Devic disease Bilateral optic neuritis and spinal cord demyelination Acute disseminated encephalomyelitis and acute necrotizing hemorrhagic encephalomyelitis Other diseases with demyelination Central pontine myelinolysis – rapid correction of hypomatremia 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 Degenerative Diseases Degenerative diseases affecting the cerebral cortex Degenerative diseases of basal ganglia and brainstem Spinocerebellar degenerations Degenerative diseases affecting the motor neuron Degenerative Diseases affecting the Cerebral cortex Alzheimer disease Frontotemporal dementias 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 Frontotemproal dementia with parkinsonisn linked to Tau mutations Pick disease Progressive supranuclear palsy Corticobasal degneration Frontotemporal dementias withou tau pathology Vascular dementia 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 substantia nigra, 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, Spinocerebellar Degeneraitons Spinocerebellar ataxia Friedreich ataxia – frataxin mutations, GAA trinucleotide-repeat, cardiomyopathy Ataxia-telangiectasia - immunodeficeincy Degenerative diseases affecting Motor Neurons Amyotrophic lateral sclerosis – lower motor and upper motor neurons Bulbospinal atrophy ( Kennedy syndrome) Spinal muscle atrophy Genetic Metabolic Diseases Neuronal Storage diseases Leukodystrophies Neuronal ceroid lipofuscinoses Tay-Sachs disease Krabbe disease - deficiency of galatocerebroside beta-galactosidase Metachromic leukodystrophy – 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 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 Tumors Gliomas Neuronal tumors Poorly differentiated neoplasms Other parenchymal tumors Meningiomas Paraneoplastic syndromes Peripheral nerve sheath tumors Familial tumor syndromes 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 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 Medulloblastoma Poorly differentiated Well-circumscribed Midline of the cerebellum Desmoplastic variant Drop metastases – cauda equina Meningiomas Attached to the dura Usually benign En plaque Psammoma bodies Atypical Anaplastic Metastatic ¼ to ½ of intra-cranial tumors in hospitalized patients Five most common Lung Breast Melanoma Kidney GI 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 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