Central nervous system cellular injury and pathology can affect neurons, astrocytes, oligodendrocytes, ependymal cells, choroid plexus, microglia and blood vessels. Neurons are vulnerable to acute injury, neurodegenerative diseases, viral infections and aging. Astrocytes repair injury through gliosis. Oligodendrocytes produce myelin. Ependymal cells line ventricles and astrocyte proliferation can be triggered by disruption. Microglia are phagocytes that aggregate at injury sites. Cerebral edema, hydrocephalus, herniation, cerebrovascular diseases, intracranial hemorrhage and vascular malformations can all impact the central nervous system.
Central nervous system cellular injury and pathology can affect neurons, astrocytes, oligodendrocytes, ependymal cells, choroid plexus, microglia and blood vessels. Neurons are vulnerable to acute injury, neurodegenerative diseases, viral infections and aging. Astrocytes repair injury through gliosis. Oligodendrocytes produce myelin. Ependymal cells line ventricles and astrocyte proliferation can be triggered by disruption. Microglia are phagocytes that aggregate at injury sites. Cerebral edema, hydrocephalus, herniation, cerebrovascular diseases, intracranial hemorrhage and vascular malformations can all impact the central nervous system.
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Central nervous system cellular injury and pathology can affect neurons, astrocytes, oligodendrocytes, ependymal cells, choroid plexus, microglia and blood vessels. Neurons are vulnerable to acute injury, neurodegenerative diseases, viral infections and aging. Astrocytes repair injury through gliosis. Oligodendrocytes produce myelin. Ependymal cells line ventricles and astrocyte proliferation can be triggered by disruption. Microglia are phagocytes that aggregate at injury sites. Cerebral edema, hydrocephalus, herniation, cerebrovascular diseases, intracranial hemorrhage and vascular malformations can all impact the central nervous system.
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Download as PPTX, PDF, TXT or read online from Scribd
• Neurons – Acute neuronal injury • “Red neurons”, eosinophilic cytoplasm • Spheroids, disruption of axonal transport • Central chromatolysis, axonal injury – Neurodegenerative diseases • Intracellular inclusions • Dystrophic neurites – Viral infections—inclusions – Aging--lipofuscin Patterns of Cellular Injury • Astrocytes – Repair and scar formation (gliosis) • Hypertrophy and hyperplasia • Gemistocytic astrocyte, bright pink cytoplasm • Minimal extracellular matrix deposition • Limited fibroblast involvement • Long standing gliosis – Fibrillary astrocytes and Rosenthal fibers – Degenerative change • Corpora amylacea in astrocytic processes Patterns of Cellular Injury • Oligodendrocytes – Produce myelin – Multiple neurons per cell • Ependymal cells – Line ventricles – Disruption triggers subependymal astrocyte proliferation (ependymal granulations) • Choroid plexus – Secretes CSF Patterns of Cellular Injury • Microglia – Phagocytes • Bone marrow derived – Activated by tissue injury – Microglial nodules • Aggregates at site of tissue injury • Congregate around portions of dying neurons – Neuronophagia Cerebral Edema • Accumulation of excess fluid within the brain parenchyma – Vasogenic edema • Integrity of blood-brain barrier is disrupted • Fluid shifts from vascular compartment to intercellular spaces • Inflammation or tumors – Cytotoxic edema • Membrane injury • Increased intracellular fluid • Hypoxic/ischemic insult or toxins – Often occur together Hydrocephalus • Accumulation of excessive CSF within the ventricular system – Impaired flow – Impaired resorption – Excess production (rarely) • Before suture closure – Enlargement of head • After suture closure – Expansion of ventricles – Increased intracranial pressure Hydrocephalus • Noncommunicating hydrocephalus – Obstruction within ventricular system – Enlargement of ventricles proximal to block • Communicating hydrocephalus – Reduced resorption – All ventricles enlarged • Hydrocephalus ex vacuo – Secondary to loss of brain parenchyma Herniation • Focal expansion of brain causes it to be displaced in relation to dural folds or bony structures – Occurs when volume of brain exceeds limits permitted by compression of veins and displacement of CSF – Intracranial pressure rises – Usual result is compromise of blood supply to “pushed” tissue Herniation • Subfalcine (cingulate) herniation – Unilateral or asymmetric expansion of a cerebral hemisphere – Cingulate gyrus displaced under edge of falx cerebri – Associated with compression of anterior cerebral artery branches Herniation • Transtentorial (uncinate) herniation – Medial aspect of temporal lobe compressed against free edge of tentorium cerebelli – Oculomotor nerve is compromised on side of lesion (CN III palsy and “blown” pupil) – Posterior cerebral artery may be compressed • Primary visual cortex – May compress contralateral cerebral peduncle (hemiparesis ipsilateral to herniation) – Duret hemorrhages in midbrain and pons • Midline or paramedian hemorrhages from tearing of penetrating veins and arteries Herniation • Tonsilar herniation – Displacement of cerebellar tonsils through the foramen magnum – Brainstem compression – Compromises respiratory and cardiac centers in medulla Cerebrovascular Diseases • Any abnormality of the brain caused by a pathologic process involving blood vessels – Thrombotic occlusion of vessels – Embolic occlusion of vessels – Vascular rupture • Occlusion of vessels – Loss of oxygen and metabolic substrates resulting in infarction • Hemorrhage – Direct tissue damage and secondary ischemia Cerebrovascular Diseases • Brain requires a continuous supply of glucose and oxygen • Oxygen is the limiting substance – Functional hypoxia • Low partial pressure of oxygen • Impaired oxygen carrying capacity • Inhibition of oxygen use by tissues – Ischemia, transient or permanent • Interruption of normal circulatory flow – Reduced perfusion pressure – Vascular obstruction Global Cerebral Ischemia • Widespread ischemic/hypoxic injury resulting from a generalized reduction in cerebral perfusion • Outcome varies with severity of insult • Neurons are much more sensitive to hypoxia than glial cells • Most sensitive – Pyramidal cells of CA1 of hippocampus – Purkinje cells of the cerebellum – Pyramidal cells of neocortex • Border zone (“watershed”) infarcts – Wedge shaped infarcts at edge of arterial perfusion fields – ACA-MCA border Global Cerebral Ischemia • Morphology – Brain swollen, poor demarcation between gray and white matter – Microscopic of irreversible ischemic injury (infarction) • Early (12-24 hours): red neurons, infiltration of neutrophils • Subacute (24 hr-2wks): necrosis, macrophages, vascular proliferation, reactive gliosis • Repair (>2wks): removal of necrotic tissue, disorganization, gliosis Focal Cerebral Ischemia • Arterial occlusion leading to focal ischemia or infarction – Embolization • More common • Sources: cardiac mural thrombi, atheromatous plaques, paradoxical emboli, cardiac surgery, other material (tumor, fat, air) • Middle cerebral artery most frequently involved – Branch points, preexisting luminal stenoses Focal Cerebral Ischemia – In situ thrombosis • Atherosclerosis – Carotid bifurcation, origin of MCA, basilar artery
• Infarcts are divided into two large groups
– Nonhemorrhagic – Hemorrhagic • Hemorrhage is due to reperfusion of ischemic tissue Focal Cerebral Ischemia • Morphology – Macroscopic • 0-6 hrs: nothing • 6-48 hrs: pale, soft swollen, indistinct gray-white matter junction • 2-10 days: gelatinous, friable, affected area is defined as edema resolves • 10 days-3 wks: tissue liquefies leaving cavity – Microscopic (see previous) Intracranial Hemorrhage • Hemorrhage can occur at a variety of sites • Each site has associated causes Primary Brain Parenchymal Hemorrhage • Peak incidence at age 60 • Rupture of small intraparenchymal vessel • Hypertension is most common underlying cause (15% of deaths with chronic HTN) • Basal ganglia, thalamus, pons, cerebellum • Location and size determine clinical manifestations Cerebral Amyloid Angiopathy • Amyloidogenic peptides deposit in the walls of small and medium caliber meningeal and cortical vessels • Weakens vessel walls • Spares vasculature of white and deep gray matter • Often referred to as lobar hemorrhages due to involvement of cerebral cortex Saccular Aneurysms • Most frequent cause of clinically significant subarachnoid hemorrhage is rupture of a saccular aneurysm • 90% occur in the anterior circulation • Multiple aneurysms occur in 20-30% of cases • Associated with disorders of extracellular matrix proteins • Increased risk in individuals with autosomal dominant polycystic kidney disease Saccular Aneurysms • Overall, 1.3% per year rate of bleeding – Risk increases with size – 10mm has 50% per year rate of bleeding • Subarachnoid hemorrhage has additional acute risk of ischemia due to vasospasm of other vessels • Healing phase involves risk of obstruction of CSF flow and resorption • 25-50% of individuals die with first rupture • Sudden, excruciating headache Saccular Aneurysms • Morphology – Thin walled out-pouching of an artery – Muscular wall and internal elastic lamina are absent from the sac – Sac is thickened hyalinized intima Vascular Malformations • Arteriovenous malformations (AVM) – Enlarged blood vessels separated by gliotic tissue – M:F is 2:1 – Presents most often between 10 and 30 yrs of age • Seizure disorder, intracerebral hemorrhage, subarachnoid hemorrhage – Large AVM can cause high output heart failure in infants – Most dangerous vascular malformation – Can be in subarachnoid space, extend into brain, or entirely within brain Vascular Malformations • Cavernous hemangiomas – Distended loosely organized vascular channels without intervening nervous tissue – Occur in cerebellum, pons, subcortical regions – Low flow, no AV shunting • Capillary telangiectasias – Thin walled vascular channels separated by normal brain parenchyma – Pons • Venous angiomas – Ectatic venous channels Hypertensive Cerebrovascular Disease • Effects of hypertension on the brain – Massive hypertensive intracerebral hemorrhage – Lacunar infarcts – Slit hemorrhages – Hypertensive encephalopathy Hypertensive Cerebrovascular Disease • Arterio- and Arteriolo- sclerosis – Deep penetrating vessels of basal ganglia, white matter, and brain stem – Hyaline change makes vessel walls weaker – Charcot-Bouchard microaneurysms • Less than 300 microns in diameter • May rupture and bleed Hypertensive Cerebrovascular Disease • Lacunar infarcts – Small cavitary infarcts just a few millimeters wide – Deep gray matter, internal capsule, deep white matter, pons – Can be silent or cause significant neurological impairment • Slit hemorrhage – Small hemorrhage that heals leaving a slit-like cavity Hypertensive Cerebrovascular Disease • Acute hypertensive encephalopathy – Acute cerebral dysfunction – Increased intracranial pressure – Petechiae and fibrinoid necrosis of arterioles in gray and white matter Vasculitis • Infectious arteritis • Systemic vasculitis • Primary angiitis of the CNS – Involves multiple small to medium parenchymal and subarachnoid vessels – Diffuse encephalopathic picture – Steroids and immunosuppressive treatment Trauma • Significant cause of death and disability • Severity and site of injury affect outcome • Variables: shape of object, force of impact, head in motion • Penetrating or blunt, open or closed • External appearance doesn’t necessarily correlate with extent of brain injury • Parenchymal and/or vascular injury Traumatic Parenchymal Injury • Contusions – Brain impacts the skull • Coup and contrecoup • Rapid tissue displacement and vascular rupture – Hemorrhage, tissue injury, edema – Crests of gyri • Orbital gyri of frontal lobe, temporal lobe (esp. tips) • Laceration – Penetration of brain • Tissue tearing, vascular disruption, hemorrhage • Linear path Traumatic Parenchymal Injury • Diffuse axonal injury – Widespread damage to axons within the brain • Angles of lateral ventricles or brainstem most commonly affected – Movement of one region relative to another • Angular acceleration alone can cause this without impact • Axonal disruption (integrity or function) and hemorrhage – 50% of patients who develop coma shortly after trauma Traumatic Parenchymal Injury • Concussion – Reversible altered consciousness from head injury in the absence of contusion – Transient neurological dysfunction • Loss of consciousness • Temporary respiratory arrest • Loss of reflexes – Complete neurological recovery • Amnesia for the event – Pathogenesis unknown Traumatic Vascular Injury • Direct trauma and disruption of the vessel wall • May occur in one or more compartments – Epidural – Subdural – Subarachnoid – Intraparenchymal Traumatic Vascular Injury • Epidural hematoma – Torn vessel in the dura • Middle meningeal artery – Often with skull fracture – Blood under arterial pressure separates dura from the inner surface of the skull • Smooth inner contour that compresses brain – Patients can be lucid for several hours between trauma and development of neurological signs • Neurosurgical emergency Traumatic Vascular Injury • Subdural hematoma – Tearing of bridging veins caused by rapid movement of the brain • Bleed into the subdural space • Most common over lateral aspect of cerebral hemispheres • 10% bilateral – Increased risk • Brain atrophy—stretched veins • Infants—thin walled veins – Become manifest within 48 hours of injury • Signs attributable to pressure on the brain • Headache, confusion, sometimes localizing • Progressive neurological deterioration, rarely with acute decompensation Traumatic Vascular Injury • Subdural hematoma – Bleeding is usually self-limited – If not evacuated, hematoma will organize over time • Fibroblasts grow in from dura • Granulation tissue matures and forms “subdural membranes” – Subdural hematomas frequently rebleed becoming chronic subdural hematomas – Symptomatic subdural hematomas are treated by removing the organizing blood and tissue Malformations • Neural tube defects – Failure of a portion of the neural tube to close or reopening after successful closure – Involve some combination of neural tissue, meninges, and overlying bone or soft tissues – Most frequent CNS malformations – Folate deficiency during initial weeks of gestation is risk factor – Early detection by ultrasound and α-fetoprotein – 4-5% recurrence risk in subsequent pregnancies Neural Tube Defects • Spinal cord involvement most common – Spina bifida occulta • Asymptomatic bony defect – Myelomeningocele • Extension of CNS tissue through a defect in the vertebral column – Problems with motor and sensory in lower limbs, bowel/bladder control – Infection risk from thin or ulcerated overlying skin Neural Tube Defects • Brain end of neural tube – Anencephaly • Absence of brain and top of skull – Encephalocele • Diverticulum of malformed CNS tissue extending through a defect in the cranium – Posterior more common than anterior Forebrain Malformations • Microencephaly – Abnormally small brain – Associated with chromosome abnormalities, fetal alcohol syndrome, in utero HIV infection • Lissencephaly (agyria) – Absence of normal gyration and smooth surfaced brain – Disruption of normal neuronal migration and differentiation • Abnormally thickened cortex and only four layered – Pachygyria is a less widespread form Forebrain Malformations • Polymicrogyria – Increased number of irregularly formed gyri – Altered cortical architecture • Holoprosencephaly – Disruption of normal midline patterning • Mild forms may just have absence of olfactory bulbs and related structures • In severe forms the brain may not be divided into lobes or hemispheres – Midline facial defects • Mutations in sonic hedgehog linked to some cases Posterior Fossa Anomalies • Most commonly result in misplaced or absent cerebellum and hydrocephalus • Arnold-Chiari malformation – Chiari type II malformation • Small posterior fossa, misshapen midline cerebellum with downward extension of vermis through foramen magnum • Hydrocephalus and lumbar myelomeningocele are typically also present – Chiari I malformation • Low-lying cerebellar tonsils extend through the foramen magnum • Obstruction of CSF flow and compression of medulla • Headache and cranial nerve deficits Posterior Fossa Anomalies • Dandy-Walker malformation – Enlarged posterior fossa – Cerebellar vermis is absent (or rudimentary anterior portion) – Large midline cyst • Lined with ependyma and is contiguous with leptomeninges on its outer surface – Dysplasia of brainstem nuclei are commonly found Spinal Cord Abnormalities • Hydromyelia – Expansion of the central canal • Syringomyelia (syrinx) – Fluid filled cleft-like cavity in the inner portion of the spinal cord – May also be acquired • Associated with destruction of adjacent gray and white matter, surrounded by reactive gliosis • Cervical cord most often affected Perinatal Brain Injury • Cerebral palsy – Nonprogressive neurological motor disorder characterized by spasticity, dystonia, ataxia/athetosis, and paresis attributable to injury occurring during the prenatal and perinatal periods Perinatal Brain Injury • Intraparenchymal hemorrhage – Within germinal matrix of premature infants – May extend to ventricles and subarachnoid space – Sometimes leading to hydrocephalus • Periventricular leukomalacia – Infarcts in the supratentorial periventricular white matter, esp. in premature infants – Leaves chalky yellow plaques in white matter with calcifications – If involves gray matter too, large cystic lesions can develop throughout the hemispheres (multicystic encephalopathy) Infections • Nervous tissue damaged by – Direct injury of neurons or glia – Microbial toxins – Effects of inflammatory response – Immune-mediated mechanisms • Routes of entry – Hematogenous (most common) • Arterial or venous less commonly – Direct implantation • Post-traumatic – Local extension from skull, spine, or malformation – Peripheral nerves Epidural and Subdural Infections • Bacterial or fungal • Usually by direct local spread • Epidural abscess – Commonly associated with osteomyelitis – Spinal epidural abscess can cause cord compression • Subdural empyema – May produce a mass effect – Thrombophlebitis of bridging veins→infarction of brain Meningitis • Inflammatory process of leptomeninges and CSF in the subarachnoid space – Meningoencephalitis is spread of infection from the meninges to the underlying brain – Usually an infection, can be chemical – Infectious meningitis • Acute pyogenic • Aseptic • Chronic Acute Pyogenic Meningitis • Wide range of bacteria • Most likely depends on age – Neonates: E. coli, group B streptococci – Elderly: S. pneumoniae, Listeria monocytogenes – Adolescents/young adults: Neisseria meningitides • Systemic signs of infection superimposed on meningeal irritation and neurological impairment • CSF: neutrophils, ↑ protein, ↓glucose, bacteria • Exudate in leptomeninges over surface of brain Acute Pyogenic Meningitis • When fulminant, inflammatory cells may infiltrate leptomeningeal veins, spread to the brain, or extend to the ventricles • Phlebitis may lead to thrombosis and hemorrhagic infarction of the brain • Untreated, it may be fatal • Effective antimicrobial treatment greatly reduces mortality Aseptic Meningitis • Aseptic is a misnomer – Clinical term for an illness comprising meningeal irritation, fever, and alterations of consciousness of relatively acute onset without recognizable organisms • Less fulminant, usually self-limiting, and usually treated symptomatically • CSF: lymphocytosis, moderately elevated protein, normal glucose • Pathogen can be identified in about 70% of cases, usually an enterovirus Chronic Meningitis • Tuberculous meningitis – CSF: pleiocytosis (↑ leukocytes) of mononuclear cells or neutrophils and mononuclear cells, ↑ protein, ↓ glucose – May have an intraparenchymal mass (tuberculoma) – Usually affects basal meninges • Meninges contain infiltrate of lymphocytes, plasma cells, and macrophages • Possibly even well-formed granulomas – Cause of arachnoid fibrosis that may lead to hydrocephalus Chronic Meningitis • Neurosyphilis – Tertiary stage of syphilis, occurs in about 10% of untreated infections – Meningovascular neurosyphilis is a major manifestation • Chronic meningitis usually involving the base of the brain • Cerebral gummas may occur in relation to the meninges and extend into the brain – Paretic neurosyphilis is the parenchymal disease • Insidious progressive loss of mental and physical functions with mood alterations, terminating in dementia Chronic Meningitis – Tabes dorsalis • Damage to sensory nerves in dorsal roots – Impaired proprioception » Locomotor ataxia – Impaired pain sensation » Joint damage, skin damage – Lightning pains – Absence of deep tendon reflexes – HIV infection increases risk of neurosyphilis • Increased rate of progression and severity of disease Parenchymal Infections • Any type of microbial organism can potentially infect the brain • Different types of organisms generally have different patterns of involvement – Viruses are most diffuse – Bacteria (when not meningitis) are most localized – Other are more mixed – Immunosuppression leads to more widespread involvement of any particular agent Brain Abscess • Nearly always caused by bacteria • Destructive lesions – Progressive focal signs – Signs of increased intracranial pressure – CSF: ↑ WBC and protein, glucose normal • Complications – ICP, herniation can be fatal – Rupture, ventriculitis, meningitis, venous sinus thrombosis Viral Encephalitis • Parenchymal infection of brain that also always is associated with meningeal inflammation (meningoencephalitis) • Most show perivascular and parenchymal mononuclear infiltrates, microglial nodules, and neuronophagia • Various viruses may have – Inclusion bodies – Specific cell types or particular areas involved – Immune-mediated injury – Congenital malformation Arboviruses • Arthropod-borne viruses (mostly mosquitoes) – Eastern and Western equine encephalitis – West Nile virus • Patients develop generalized as well as focal signs Herpes Simplex Type 1 • Most common in children and young adults • Affects inferior and medial temporal lobes and orbital gyri of frontal lobe – Alterations in mood, memory, and behavior • Necrotizing and often hemorrhagic • Inclusions in neurons and glia Herpes Simplex Type 2 • Usually manifests in adults as meningitis • Disseminated severe encephalitis in neonates born by vaginal delivery to women with primary active genital infections Cytomegalovirus • Fetuses and immunocompromised individuals • Tends to localize in the paraventricular subependymal regions – Severe hemorrhagic necrotizing ventriculoencephalitis and choroid plexitis • In utero infection – Periventricular necrosis produces severe brain destruction – Microcephaly and periventricular calcification Rabies • Enters CNS by ascending along the peripheral nerves from the wound site – Incubation usually a few months • Initially, malaise, fever, headache • Advances to extreme CNS excitability – Slightest touch is painful – Violent motor responses – Aversion to swallowing (hydrophobia) • Progresses to alternating mania and stupor • Coma and death from respiratory center failure • Negri bodies: viral inclusions seen in pyramidal cells in the hippocampus and Purkinje cells of cerebellum HIV • Patterns of direct injury to brain – Aseptic HIV-1 meningitis • 10% of individuals 1-2 weeks after seroconversion – HIV-1 meningoencephalitis (subacute encephalitis) • AIDS-dementia complex • Microglial nodules, multinucleated giant cells • Neuronal death from cytokines and chemokines – Vacuolar myelopathy • Resembles combined subacute degeneration Progressive Multifocal Leukoencephalopathy • Caused by JC virus • Infects oligodendrocytes – Demyelination is primary effect • Immunocompromised individuals – Reactivation of virus • Focal and relentlessly progressive neurological symptoms and signs Fungal Encephalitis • Usually in the immunosuppressed • Granulomas or abscesses often with meningitis • Organisms – Candida albicans: microabscesses – Mucor: direct extension in diabetics with ketoacidosis – Aspergillus fumigatus: widespread hemorrhagic infarcts, angioinvasive – Cryptococcus neoformans: AIDS (can be fulminant or indolent), India ink prep of CSF to visualize – Also: Histoplasma, Coccidioides, Blastomyces Other Meningoencephalitides • Cerebral Toxoplasmosis – AIDS • Cysticercosis – Tenia solium (tapeworm) – Cysts in brain and meninges • Amebic – Naegleria • Swimming in non-flowing warm fresh water – Acanthamoeba • Chronic granulomatous meningoencephalitis Prion Diseases • Disorders associated with abnormal forms of a normal cellular protein called prion protein (PrPc) • Abnormal form acts as an infectious agent – It propagates itself and damages cells that contain it • Most cases are sporadic or associated with mutations in the gene that encodes PrPc Prion Diseases • PrPc changes conformation to PrPsc • PrPsc can then induce conformational change in other PrPc molecules to PrPsc • PrPsc is resistant to protease digestion • PrPsc aggregates and damages the cell • Leads to cytoplasmic vacuoles and eventual neuronal death • PrPc to PrPsc change occurs spontaneously at an extremely low rate (sporadic cases) • Mutation of gene for PrPc allows change at a high rate (familial cases) Prion Diseases • Creutzfeldt-Jakob Disease (CJD) – Rapidly progressive dementia • Begins with subtle changes in memory and behavior – 85% of cases are sporadic – 1 in 1 million annual incidence – Peak incidence in seventh decade – Uniformly fatal, average 7 months – Spongiform transformation of the cerebral cortex and deep gray matter Prion Diseases • Variant Creutzfeldt-Jakob Disease (vCJD) – Starting in 1995, a series of cases of a CJD-like illness appeared in the United Kingdom – Differed from CJD • Young adults • Behavioral disorders were prominent in early disease stages • Slower progression – New disease was the consequence of exposure to bovine spongiform encephalopathy – Spongiform change and absence of inflammation, like CJD, plus cortical amyloid plaques surrounded by spongiform change Tumors • ½ to ¾ are primary, the rest are metastatic – Annual incidence • 10-17/100,000 intracranial • 1-2/100,000 intraspinal – Larger proportion of childhood cancers (20%) • Adult and childhood tumors differ in histological subtype and location – Childhood: more likely posterior fossa – Adults: more likely supratentorial Tumors • Unique characteristics – Histological distinction between benign and malignant is more subtle – Low-grade lesions (low mitotic rate, cellular uniformity, slow growth) may still infiltrate large regions of the brain → serious deficits and poor prognosis – Anatomic site can have lethal consequences even if the tumor is benign histologically – Pattern of spread • Rarely metastasize outside of the CNS • Seeding through the subarachnoid space can occur Gliomas • Astrocytomas – Fibrillary astrocytomas • 80% of adult primary tumors • 4th through 6th decades • Cerebral hemispheres • Seizures, headache, focal deficits • Histological differentiation correlates with clinical course and outcome – Astrocytoma (grade I and II) – Anaplastic astrocytoma (grade III) – Glioblastoma multiforme (grade IV) Gliomas • Astrocytomas – Fibrillary astrocytomas • Well differentiated – Static or slowly progressive – Mean survival >5 years – Tumor usually progresses to higher grade with time • Gliobastoma – Mean survival 8-10 months – <10% at 2 years Gliomas • Astrocytomas – Fibrillary astrocytomas • Infiltrative tumors that extend beyond grossly apparent margins expanding and distorting brain • Gray, high grade tumors have necrosis and hemorrhage • High grade tumors are contrast enhancing on imaging studies Gliomas • Astrocytomas – Pilocytic astrocytomas • Relatively benign, often cystic tumors • Children and young adults • Cerebellum, usually • Also 3rd ventricle, optic nerves, occasionally cerebral hemispheres • Symptomatic recurrence is often due to cyst enlargement rather than solid component Gliomas • Oligodendroglioma – 5-15% of gliomas – 4th and 5th decades – Cerebral hemispheres, white matter preference – Several years of neurological complaints, often with seizures – Better prognosis than astrocytomas • Mean survival 5-10 years – “Fried egg” appearance of tumor cells, delicate network of capillaries – 90% have calcifications Gliomas • Ependymomas – Arise next to ventricular system and central canal of spinal cord – In 1st two decades, occur near 4th ventricle – Adults, occur in spinal cord most commonly • Neurofibromatosis type 2 association – CSF dissemination is common – Supratentorial and spinal cord tumors have better outcome than posterior fossa tumors – Solid or papillary mass – Rosettes and perivascular pseudorosettes Neuronal Tumors • Central neurocytoma – Low grade adjacent to ventricular system • Ganglioneuromas – Mature looking neurons with a mixture of glial elements • Dysembryoplastic neuroepithelial tumor – Distinctive low grade tumor of childhood – Superficial temporal lobe – “Floating neurons” in myxoid background Medulloblastoma • 20% of pediatric brain tumors • Occurs exclusively in the cerebellum – Children, midline tumors – Adults, lateral tumors • Largely undifferentiated, highly malignant • Untreated, dismal prognosis – Tumor is very radiosensitive – Resection and radiation, 75% 5 year survival • Similar tumors called CNS primitive neuroectodermal tumors can occur elsewhere in the CNS Primary CNS Lymphoma • 2% of extranodal lymphomas, 1% of intracranial tumors • Most common CNS neoplasm in immunosuppressed individuals – Nearly all EBV driven • Most are diffuse large B cell lymphomas • Aggressive, poor response to chemotherapy • Multiple sites within the CNS are often involved – Outside involvement is a rare and late complication Germ Cell Tumors • Primary brain germ cell tumors occur along the midline – Pineal (male predominance) and suprasellar region • 90% occur in first 2 decades • Classification is similar to that used in the testes (seminoma is called germinoma in CNS) Meningiomas • Benign tumors of adults • Attached to the dura usually, also can be seen in the ventricles • Derived from arachnoid meningothelial cells • Vague non-localizing or focal symptoms from brain compression • Prognosis depends on size, location, surgical accessibility, and histological grade • Many histological patterns – Psammoma bodies Metastatic Tumors • ¼ to ½ of intracranial tumors • Most common primaries (80%) – Lung, breast, skin (melanoma), kidney, GI tract • In the brain – Sharply demarcated masses – Often at gray matter-white matter junction – Usually surrounded by a zone of edema – Surrounded by reactive gliosis Paraneoplastic Syndromes • Most commonly associated with small cell carcinoma of the lung • Some characteristic patterns affecting the CNS and PNS – Subacute cerebellar degeneration → ataxia – Limbic encephalitis → subacute dementia – Subacute sensory neuropathy → altered pain sensation Diseases of Myelin • Most diseases of CNS myelin do not significantly involve the peripheral nerves, and vice versa • Two broad groups – Demyelinating diseases • Preferential damage to previously normal myelin – Dysmyelinating diseases (leukodystrophies) • Myelin is not properly formed or has abnormal turnover kinetics Multiple Sclerosis • Autoimmune demyelinating disorder • Distinct episodes of neurological deficits, separated in time, attributable to white matter lesions that are separated in space • Prevalence 1/1000 • Age of onset: young adulthood to 50 • Twice as common in women Multiple Sclerosis • Believed to be caused by a combination of environmental and genetic factors – 1st degree relative: 15x risk – 25% concordance rate among monozygotic twins – Link to HLA-DR2 • T cell mediated delayed type hypersensitivity reaction to myelin proteins is thought to be central to the pathogenesis of MS Multiple Sclerosis • Morphology – MS is a white matter disease – Affected areas show plaques • Well-circumscribed, glassy, gray-tan, irregularly- shaped lesions • Commonly occur beside ventricles • Also frequent in optic nerves, optic chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord Multiple Sclerosis • Clinical – Relapsing-remitting disease with gradual neurological deterioration – Common neurological symptoms and signs • Unilateral visual impairment (optic neuritis) • Cranial nerve signs • Ataxia • Disruption in conjugate eye movement (internuclear ophthalmoplegia) • Motor and sensory impairment of trunk and limbs • Problems with voluntary control of bladder function Multiple Sclerosis – CSF • Mildly elevated protein, increased gamma-globulin • Oligoclonal bands – Antibodies directed against a variety of targets – Marker of disease activity – Unclear of role in disease mechanism Other Acquired Demyelinating Diseases • Post-infectious immune-mediated demyelination – Acute disseminated encephalomyelitis • Acute onset, diffuse involvement a week or two after antecedent infection • May be fatal in 20% of cases – Acute necrotizing hemorrhagic encephalomyelitis • More devastating disorder • Young adults and children Other Acquired Demyelinating Diseases • Central pontine myelinolysis – Non-immune process resulting in loss of myelin in central pons – Most often due to rapid correction of hyponatremia – Seen in alcoholism and severe electrolyte or osmolar imbalance – Often presents with rapidly evolving quadraplegia Leukodystrophies • Inherited dysmyelinating diseases – Abnormal myelin synthesis or turnover – Lysosomal enzymes, peroxisomal enzymes, mutations in myelin proteins • Much of the pathology is found in the white matter • Affected children are normal at birth but then begin to miss developmental milestones – Wide range of problems develop due to diffuse involvement of white matter Nutritional Diseases • Thiamine deficiency – Wernicke encephalopathy • Abrupt development of confusion, abnormalities of eye movement, and ataxia • Hemorrhage and necrosis in mammillary bodies – Korsakoff syndrome • Consequence of untreated Wernicke encephalopathy • Profound memory disturbances • Largely irreversible • Lesions in medial dorsal nucleus of thalamus – Wernicke-Korsakoff syndrome is often applied because of the link – Chronic alcoholism association Nutritional Diseases • Vitamin B12 deficiency – Subacute combined degeneration of the spinal cord • Involves ascending and descending fiber bundles • Symptoms develop over weeks – Slight ataxia – Numbness and tingling in lower extremities – Can progress to spastic weakness of lower extremities – Complete paraplegia can occur – Improvement with vitamin replacement therapy – Poor recovery if complete paraplegia has developed Degenerative Diseases and Dementias • Dementia – Memory impairment and other cognitive deficits with preservation of a normal level of consciousness – Dementia always represents a pathologic process – Not all forms of dementia are degenerative • Degenerative disorders represent an underlying cellular degeneration of neurons in the brain • Vascular disorders are an important cause of dementia Alzheimer Disease • Most common cause of dementia in the elderly • Clinical course – Insidious impairment of higher intellectual functions, with alterations in mood and behavior – Progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction – Over the next 5 to 10 years, profoundly disabled, mute, immobile – Death usually occurs from pneumonia or other infection Alzheimer Disease • Incidence – 3% for age 65-74 – 19% for age 75-84 – 47% for age >85 • Clinical assessment and imaging allow for accurate diagnosis in 80-90% of cases – Pathological examination of brain needed for definitive diagnosis • Most cases are sporadic, some familial (5-10%) • Rarely symptomatic before age 50 Alzheimer Disease • Morphologic changes in brain and dementia are initiated by the accumulation of a peptide, β amyloid (Aβ) • Aβ is derived from a larger membrane protein, amyloid precursor protein (APP) – Two processing paths • Cleaved by α- and γ-secretase → no Aβ • Cleaved by β- and γ-secretase → Aβ • Generation and accumulation of Aβ occurs slowly with advancing age Alzheimer Disease • Familial – Mutations in APP or components of γ-secretase (presenilin-1 or presenilin-2) increase rate of Aβ accumulation • Alzheimer disease occurs in almost all individuals with trisomy 21 (Down syndrome) who survive beyond age 45 – APP gene is on chromosome 21 • Sporadic – Allele of apolipoprotein, ε4 (ApoE4), associated with 30% of cases—how is unknown – SORL1 associated with late onset, deficiency of SORL1 protein may alter intercellular trafficking of APP Alzheimer Disease • Affects of Aβ on neurons – Small aggregates alter neurotransmission and can be toxic to neurons and synaptic endings – Larger deposits, plaques, lead to neuronal death, inflammatory response, may have mechanical effects on axons and dendrites altering region to region communication – Leads neurons to hyperphosphorylate the microtubule binding protein tau Alzheimer Disease • Tau protein – Hyperphosphorylated tau redistributes within the neuron • From axon to dendrites and cell body • Aggregates into tangles • Results in neuronal dysfunction and cell death • Development of plaques and tangles occur in parallel are responsible for the development of the clinical signs and symptoms – They develop well in advance of clinical presentation Alzheimer Disease • Morphology – Neuritic plaques, diffuse plaques, neurofibrillary tangles, neuronal loss, and glial reaction – Pattern of progression • Entorhinal cortex, hippocampal formation and isocortex, then neocortex Frontotemporal Dementias • Degeneration and atrophy of the frontal and temporal lobes – Deterioration of language and changes in personality – Followed by memory disturbances • Some caused by mutations of gene for tau protein • Some have disease defining inclusions of abnormal accumulations of tau Parkinsonism • Clinical syndrome characterized by diminished facial expression (masked facies), stooped posture, slowness of voluntary movement, festinating gait (progressive, shortened, accelerated steps), rigidity, and “pill-rolling” tremor • Seen in a number of conditions that have damage to dopaminergic neurons in the substantia nigra or their projections to the striatum Idiopathic Parkinson Disease • Most common neurodegenerative disorder associated with Parkinsonism • Progressive Parkinsonism in absence of a toxic or other known etiology and clinical response to L- dihydroxyphenylalanine (L-DOPA) • Most cases are sporadic – Autosomal dominant and recessive forms exist – AD form associated with α-synuclein mutations • Lewy bodies – A diagnostic histological feature of Parkinson disease – Neuronal inclusions containing α-synuclein – Suggests defective degradation in the proteosome may play a role in the disease (other genes support this, parkin and UCHL- 1) Idiopathic Parkinson Disease • Morphology – Pallor of substantia nigra and locus ceruleus • Loss of pigmented neurons and gliosis – Lewy bodies • Contain α-synuclein and other proteins including neurofilament and ubiquitin • Seen in remaining neurons of substantia nigra and locus ceruleus • Also seen in cholinergic cells of basal nucleus of Meynert and other brain stem nuclei • Similar structures can be seen in cerebral cortical neurons, esp. cingulate and parahippocampal gyri Idiopathic Parkinson Disease • Clinical – L-DOPA is effective for symptomatic relief but doesn’t change progressive nature of the disease – 10-15 years of progressive motor slowing until near immobility – Death usually result of infection or trauma from falls – 10-15% develop dementia • Fluctuating course and hallucinations • Attributed to widely disseminated Lewy bodies in the cerebral cortex Huntington Disease • Inherited autosomal dominant disorder • Progressive movement disorders and dementia, with degeneration of striatum (caudate and putamen) – Chorea affecting all parts of the body – May develop Parkinsonism • Relentlessly progressive resulting in death after an average of 15 years Huntington Disease • All have a trinucleotide repeat expansion in the gene for huntingtin located on 4p16.3 • Polymorphic CAG trinucleotide repeat in the gene that encodes a polyglutamine tract in the protein – Normal alleles have 11 to 34 copies – Disease alleles this can increase to hundreds – More repeats earlier onset of disease Huntington Disease • Unclear how expanded polyglutamine tract causes disease – Binds to and sequesters transcription factors – Functional abnormalities in mitochondria – Aggregates of abnormal protein trigger apoptosis • Huntingtin is expressed widely throughout the body Huntington Disease • Morphology – Striking atrophy of the caudate nucleus – Less dramatic atrophy of putamen – Secondary ventricular dilation (lateral and 3rd) – Neurons that use GABA are especially affected Huntington Disease • Clinical – Onset in 4th or 5th decade – Motor symptoms precede cognitive impairment – Choreiform movements – Forgetfulness and thought and affective disorders, may progress to severe dementia – Increased risk of suicide – Infection most common cause of death Spinocerebellar Degenerations • Heterogeneous group of disorders – Includes several distinct diseases • Affects cerebellar cortex, spinal cord, other brain regions, and peripheral nerves • Degeneration of neurons without distinct pathological changes in the affected areas with mild gliosis • Many are caused by expansion of CAG repeats Friedreich Ataxia • Autosomal recessive • Begins in 1st decade with gait ataxia and followed by hand clumsiness and dysarthria – Deep tendon reflexes are diminished to absent, extensor plantar reflex is present – Loss of joint position and vibratory sense – Pain, temperature, and light touch may be diminished Friedreich Ataxia – High incidence of cardiac disease and diabetes – Most patients are wheelchair bound within 5 years • Caused by a GAA trinucleotide repeat expansion (intronic) in a protein that is involved in determining iron levels in cells – Results in low protein levels Motor Neuron Diseases • Series of diseases that affect lower motor neurons in the spinal cord and brain stem and upper motor neurons in the motor cortex • Sensory systems and cognitive functions are usually unaffected • Types with dementia do occur Amyotrophic Lateral Sclerosis • Most common form of neurodegeneration affecting the motor system – Loss of both upper and lower motor neurons – Men slightly more than women – Onset in 5th decade or later – Most are sporadic, 5-10% familial (AD) • Half of familial cases have mutation of superoxide dismutase, SOD1 Amyotrophic Lateral Sclerosis • Morphology – Loss of anterior horn neurons – Degeneration of lateral corticospinal tracts • Clinical – Weakness of hands – Cramping and spasticity of arms and legs – Diminished muscle strength and bulk with fasciculations – 50% 5 year survival Bulbospinal Atrophy • Kennedy disease • X-linked adult onset disease affecting lower motor neurons • Affected individuals manifest androgen insensitivity – Gynecomastia, testicular atrophy, oligospermia • Trinucleotide repeat disorder – Polyglutamine repeat in androgen receptor Spinal Muscular Atrophy • Distinctive group of autosomal recessive motor neuron diseases that begin in childhood and adolescence • Loss of motor neurons and weakness associated with muscle fiber atrophy that often involves entire fascicles • Werdnig-Hoffmann disease (SMA1) is the most common form – Onset at birth or within 4 months – Leads to death within 3 years • All forms are associated with mutations of SMN gene on chromosome 5 Familial Tumor Syndromes • Inherited diseases characterized by the development of hamartomas and neoplasms throughout the body • Those with particular involvement of the nervous system follow • Because of involvement of the nervous system and cutaneous manifestations, they have been grouped under the term “neurophakomatoses” • Most are linked to loss of tumor suppressor genes Neurofibromatosis Type 1 • Autosomal dominant • Characterized by – Neurofibromas (plexiform and solitary) – Gliomas of the optic nerve – Pigmented nodules of the iris (Lisch nodules) – Cutaneous hyperpigmented macules (café au lait spots) • One of the more common genetic disorders, 1 in 3000 Neurofibromatosis Type 1 • Neurofibromas have a propensity to undergo malignant change • NF1 gene is a tumor suppressor gene – Thought to be involved in G-protein dependent signal transduction pathways • Disease is highly variable – Individuals with a mutated gene may have no symptoms while others have progressive with spinal deformities, disfiguring lesions, and compression of vital structures including the spinal cord Neurofibromatosis Type 2 • Autosomal dominant • Tumors – Bilateral vestibular schwannomas (acoustic neuromas) – Multiple meningiomas – Gliomas (ependymomas) of spinal cord • Frequency of 1 in 40,000-50,000 • NF2 gene on chromosome 22 – Also mutated in sporadic meningiomas and schwannomas Tuberous Sclerosis • Autosomal dominant • Hamartomas and benign tumors – Cortical and subependymal hamartomas • Seizures are associated with cortical lesions – Renal angiomyolipomas – Retinal glial hamartomas – Pulmonary lesions – Cardiac rhabdomyomas Tuberous Sclerosis • Cysts of liver, kidneys, pancreas • Cutaneous lesions – Angiofibromas – Shagreen patches (leathery thickenings) – Hypopigmented areas (ash-leaf patches) – Subungual fibromas • Mutations of tumor suppressor genes, TSC1 (hamartin) and TSC2 (tuberin) – Interact and regulate signaling pathways von Hippel-Lindau Disease • Autosomal dominant • Hemangioblastomas involving the cerebellar hemispheres, retina, and less commonly the brain stem and spinal cord • Cysts of pancreas, liver, kidney • High risk of renal cell carcinoma • Frequency of 1 in 30,000-40,000 • Mutations in tumor suppressor gene VHL – Also associated with adrenal pheochromocytoma – Gene controls angiogenesis, esp. in response to hypoxia