Outline Introduction Cerebrovascular disease Traumatic Head and brain injury Infections Tumors Degenerative disorders Miscellaneous - Alcohol/Nutrition Demyelinating Disorders Congenital malformations Perinatal Brain Injury.

Introduction PATTERNS OF INJURY IN THE NERVOUS SYSTEM Acute neuronal injury becomes visible Within 12 hours of an irreversible hypoxic/ischemic episode. Areas of cerebral ischemia may progress to coagulative necrosis. Axonal injury also leads to cell body enlargement and rounding, peripheral displacement of the nucleus central chromatolysis

Introduction PATTERNS OF INJURY IN THE NERVOUS SYSTEM Neurodegenerative diseases are associated with specific intracellular inclusions that help in diagnosis. (e.g., Lewy bodies in Parkinson disease and tangles in Alzheimer disease). Viral infections can form inclusions. ageing neurons also accumulate complex lipids in their cytoplasm and lysosomes (lipofuscin).

Introduction Astrocytes PATTERNS OF INJURY IN THE NERVOUS SYSTEM They are responsible for repair and scar formation in the brain, a process termed gliosis. In response to injury, astrocytes undergo both hypertrophy and hyperplasia. The nucleus enlarges and becomes vesicular, and the nucleolus is prominent. Limited involvement of fibroblast in repair in the brain. In settings of long-standing gliosis, astrocytes have less distinct cytoplasm and appear more fibrillar (fibrillary astrocytes).

Introduction PATTERNS OF INJURY IN THE NERVOUS SYSTEM Rosenthal fibers are thick, elongated, brightly eosinophilic protein aggregates that can be found in astrocytic processes in chronic gliosis and in some low-grade gliomas. Microglia are bone marrow-derived cells that function as the phagocytes of the CNS. they proliferate in response to tissue injury and trauma affecting the brain. trauma,

Cerebrovascular disease Important cause of morbidity and mortality. Any abnormality of the brain caused by a pathologic process involving blood vessels. 3 causes (1) thrombotic occlusion (2) embolic occlusion and (3) vascular rupture.

Cerebrovascular disease Thrombosis and embolism cause ischemic injury or infarction of specific regions of the brain, Vascular rupture causes hemorrhage=> to direct tissue damage as well as secondary ischemic injury. • Stroke can be defined as a sudden onset of a rapidly evolving vascular disorder of the brain that lasts for more than 24hours and leaves a deficit. It can arise within the context of the lesions described above.

Cerebrovascular disease Tissue Hypoxia and Ischemia. Cessation of blood flow can result from a reduction in perfusion pressure, as in hypotension, or secondary to vascular obstruction, or both. Other causes of cerebral hypoxia includes: Functional hypoxia in a setting of a low partial pressure of oxygen; impaired oxygen- carrying capacity or inhibition of oxygen use by tissue.

Cerebrovascular disease 1. Global cerebral Ischemia. widespread ischemic/hypoxic injury occurs as a result of reduction of cerebral perfusion Systolic pressures may be as low as 50mmHg, May occur with: M.I,, shock, and hypotension. Outcome varies with the severity Neurons are more sensitive to hypoxia than are glial cells. Coma and severe neurological impairment may occur in survivors=> (persistent vegetative state).

Cerebrovascular disease Morphology: 3 types of Histopathologic changes in irreversible neuronal injury: Early changes, occurring 12 to 24 hours after the insult, include acute neuronal cell change (red neurons) Subacute changes, occurring at 24 hours to 2 weeks, include necrosis of tissue, influx of macrophages, vascular proliferation, and reactive gliosis . Repair, seen after 2 weeks, is characterized by removal of all necrotic tissue, loss of organized CNS structure, and gliosis .

Cerebrovascular disease Morphology: In the cerebral cortex the neuronal loss and gliosis leads to preservation of some layers and destruction of other areas. This is known as pseudo laminar necrosis. Border zone ("watershed") infarcts are wedge-shaped areas of infarction that occur in those regions of the brain and spinal cord that lie at the most distal fields of arterial perfusion.(ACA and MCA most susceptible)

Cerebrovascular disease Water shed areas between MCA and ACA and MCA and PCA

Watershed infarcts are due to systemic hypotension Watershed infarcts are due to systemic hypotension. The areas affected are the regions at the border zones between the vascular territories of the large vessels

Cerebrovascular disease Morphology: Border zone infarcts are usually seen after hypotensive episodes. The area between the anterior and middle cerebral artery distributions is at greatest risk. Damage in this area presents with necrosis close to the interhemispheric fissure. 2. Focal Cerebral Ischemia :Cerebral arterial occlusion leads to focal ischemia and-if sustained-to infarction of CNS tissue in the distribution of the compromised vessel. The presence or absence of collateral flow contributes to the morphological pattern .

Cerebrovascular disease Morphology: The circle of Willis is the main arterial collateral system in the brain. Partial collateralization is also provided over the surface of the brain through cortical- leptomeningeal anastomoses. There is no collateral supply for the areas supplied by the deep penetrating vessels supplying structures such as the thalamus, basal ganglia, and deep white matter. Hypotension may lead to necrosis affecting the cerebral cortex. Laminar necrosis.

Laminar Necrosis Laminar necrosis If someone survives an episode of severe systemic hypotension (e.g., cardiac arrest), laminar necrosis of the cortex may be seen at autopsy Recall that the deeper cortical layers are more sensitive to ischemia Normal cortex

Cerebrovascular disease cerebral infarction due to occlusive disease could be caused by: in situ thrombosis or embolization from a distant source. Overall, embolic infarctions are more common. Causes of cerebral thrombo/embolic phenomenon : Cardiac mural thrombi ; myocardial infarct valvular disease, and atrial fibrillation Atheromatous plaques within the carotid arteries Paradoxical emboli in cardiac anomalies Emboli associated with cardiac surgery

Cerebrovascular disease Morphology: The territory of distribution of the middle cerebral artery-is most frequently affected by embolic infarction; emboli tend to lodge where vessels branch or in areas of preexisting luminal stenosis. Atherosclerosis is responsible for most thrombotic occlusions leading to infarction.

Morphology: The most common sites of primary thrombosis are the carotid bifurcation, the origin of the middle cerebral artery, and at either end of the basilar artery.

Cerebrovascular disease Cerebral Infarcts: Two broad groups based on their macroscopic and radiologic appearance. Non-hemorrhagic infarcts can be treated with thrombolytic therapies, if identified early Hemorrhagic: multiple, petechial hemorrhages .Thrombolytic therapy is contraindicated.

Cerebrovascular disease Intracranial Hemorrhage Hemorrhage within the skull can occur in a variety of locations as a result of specific causes. Common causes of intraparenchymal hemorrhage includes: Hypertension or vascular wall injury Arteriovenous malformation, Cavernous malformation

Cerebrovascular disease Common causes of intraparenchymal hemorrhage: Intraparenchymal tumor. Subarachnoid hemorrhages are most commonly seen with berry aneurysms Hemorrhages associated with the dura (in either subdural or epidural spaces) make up a pattern associated with trauma

Cerebrovascular disease Cerebral Amyloid Angiopathy Amyloidogenic peptides-typically the same ones found in Alzheimer disease deposit in the walls of medium- and small-caliber meningeal and cortical vessels. Leads to weakening of the vessel wall and increases risk of hemorrhages.

Cerebrovascular disease Cerebral Amyloid Angiopathy Limited to leptomeningeal and cortical vessels Pattern of hemorrhage is different than of hypertension associated intraparenchymal bleeding The pattern is referred to as lobar hemorrhages because of the involvement of the cerebral cortex. Congo red staining for diagnosis

Cerebrovascular disease con’t Origins of major vessels Aorta  brachiocephalic  right CCA + right subclavian Left CCA arises from the aortic arch Vertebral arteries arise from the subclavian arteries. VAs join to form basilar artery after entering foramen magnum.

Cerebrovascular disease Gross: cortical infarct There are cortical hemorrhages in the right temporal lobe Hemorrhagic infarcts are often embolic.

Cerebrovascular disease Hypertension associated disorders common vascular anomalies associated with chronic hypertension: Intracerebral hemorrhage Charcort-Bouchard aneurysm Lacunar infarcts Slit hemorrhages Hypertensive encephaolopathy

Cerebrovascular disease Thrombosis of small vessels: Affects penetrating vessels End arteries Little collateral flow Associated with hypertension, diabetes mellitus, aging Predisposes to lacunar infarction and hemorrhage

Cerebrovascular disease Hypertension associated Intracerebral hemorrhage: Usually massive Due to rupture of small cerebral vessels Occurs in basal ganglia, thalamus, pons, and cerebellum Clinical picture depends on size and location of bleed.

Cerebrovascular disease con’t Gross: The most common cause of spontaneous intracerebral hemorrhage is hypertension The most common location is the basal ganglia, as seen here. The hemorrhage is the result of rupture of vessels rather than occlusion

Cerebrovascular disease Charcot-Bouchard Aneurysm Small aneurysmal dilation (micro- aneurysm) Caused by chronic hypertension They rupture easily=>intracerebral hemorrhage.

Cerebrovascular disease Lacunar infarcts: These are the effects of arteriolosclerosis of the small penetrating vessels. Commonly seen in the Basal ganglia, Thalamus,Internal capsule, Pons and Deep white matter. Morphology: Small cavitatory changes with tissue loss and areas of gliosis with associated lipid laden macrophages.

Cerebrovascular disease Acute hypertensive encephalopathy Seen in malignant hypertension A clinicopathologic syndrome of diffuse cerebral dysfunction presents with: headaches, confusion, vomiting, convulsions and coma. Pathology: edematous brain, with or without transtentorial or tonsillar herniation. Petechiae and fibrinoid necrosis of arterioles .

Cerebrovascular disease Subarachnoid hemorrhage Causes: Rupture of a saccular (berry) aneurysm. vascular malformation, Trauma Intracerebral hemorrhage Hematologic disturbances, and tumors. Rupture occurs during acute increases in intracranial pressure, such as with straining at stool or sexual orgasm. Sudden, excruciating headache (classically described as "the worst headache I've ever had")

Cerebrovascular disease Common sites of saccular (berry) aneurysms in the circle of Willis

Cerebrovascular disease Berry Aneursym: About 90% of saccular aneurysms occur in the anterior circulation occurs as a result of underlying congenital defect in the media of the cerebral vessels. There is a 1.3% per year rate of bleeding. probability of rupture increases with size of the lesion, ( greater than 10 mm have a 50% risk of bleeding per year.) .

Cerebrovascular disease Common Berry aneurysm Associations: APKD Ehlers –Danlos syndrome Coarctation of the aorta Bicuspid aortic valve Neuro-fibromatous -type 1

Cerebrovascular disease Other intracranial aneurysms, less common. Posterior circulation: Atherosclerotic (fusiform, basilar artery) Anterior circulation) Mycotic, Traumatic, Dissecting aneurysms. They seldom rupture and presents with cerebral infarction (from occlusion) and not SAH.

Cerebrovascular disease CNS trauma Hemorrhage related to trauma 2 main patterns: Epidural and subdural Suba-arachnoid and intraparenchymal injury Can also occur

Cerebrovascular disease Epidural Hemorrhage The middle meningeal rupture Severe trauma with or without skull fracture Initial transient loss of consciousness(due to diffuse axonal injury) followed by a lucid interval of up to 24 hrs as the hematoma develops. Neurosurgical emergency.

Cerebrovascular disease Sub-dural Hemorrhage Due to rupture of bridging veins that drains the neural tissue into the dura sinuses. Pathogenesis: Cerebral atrophy as a result of ageing or chronic alcoholism are risk factors Infants and children (thin walled veins ) The trauma may be severe or minimal. May be a component of child abuse in the shaken baby syndrome

Cerebrovascular Disease Sub-dural Hemorrhage Presents after 48 hrs of injury or much later May present with: Focal signs, seizures, LOC, or headache and confusion. Neurologic de-compensation is usually slow . They are most common over the lateral aspects of the cerebral hemispheres and are bilateral in only 10% of cases.

Cerebrovascular disease Sub-dural Hemorrhage: Morphology: In the acute phase, collection of fresh blood on the brain surface without sulci extension Organization occurs by lysis of the clot , growth of fibroblasts and connective tissue hyalinization Organized hematomas are attached to the inner surface of the dura and are not adherent to the underlying arachnoid. Bleeding from an organized lesion=>chronic SDH.

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Subdural hematoma

Epidural Subdural

Cerebrovascular disease CNS Parenchymal Trauma: Pattern of injury: Coup and countrecoup: coup injury : Injury occurs from impact of the brain to the skull at the site of impact. Contrecoup: Injury occurs from the impact of the skull to the brain at a site opposite the site of impact. Contusions are the common injury in both cases A contusion is caused by rapid tissue displacement, hemorrhage, tissue injury, and edema. Penetrating injuries causes lacerations. With tissue tearing, hemorrhage and linear injury.

Coup vs. contrecoup injury

Contusion

Diffuse Axonal Injury Injury of axons in deep white matter of brain Twisting/shearing of axons Can be caused by angular acceleration alone “Shaken baby” syndrome Common cause of coma after trauma(responsible for the initia loss of consciousness in patients with epidural bleeds)

Diffuse Axonal Injury

CNS Infections Review Bacterial Meningitis from Microbiology. Be able to make the distinction between Encephalitis Meningitis Brain abscess Know the common organisms responsible in different age groups.

CNS infections Morphology: Abscesses :Discrete lesions with central liquefactive necrosis and a surrounding fibrous capsule .Focus of suppurative necrosis in the brain. Viral encephalitis:Meningeal inflamation in the presence of parenchyma lesions. Exudates is mainly lymphocytic . Meningitis: Inflammation of the Lepto-meningitis

CNS infections Rabies Severe encephalitis Bite of a infected animal; various animals are the natural reservoir for the virus Exposure to bats without a bite can infect. (cave explorers) especially at risk. Long incubation period. May be shorter if bite is close to CNS. Organism travels along peripheral nerves. Malaise, headache, and fever, increased CNS excitability. Hydrophobia

CNS infections HIV associated Disorders Several disorders Either due to primary infection with HIV or opportunistic infections.

CNS infections Progressive Multifocal Leukoencephalopathy (PML) Caused by JC virus, a polyomavirus. The virus preferentially infects oligodendrocytes, presenting with demyelination Immunosuppression is the main risk factor. seen in Chronic leukemias, immunosuppressive therapy, and AIDS.

CNS infections Progressive Multifocal Leukoencephalopathy (PML) Reactivation of a latent infection because of immune-suppression. Patients develop focal and relentlessly progressive neurologic symptoms and signs, Imaging shows multifocal, ring-enhancing lesions in the hemispheric or cerebellar white matter.

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CNS infections Cryptococcus meningitis Common in AIDS. It can be fulminant and fatal in weeks, or it can evolve over years. The CSF may have few cells but a high level of protein. The mucoid encapsulated yeasts can be visualized in the CSF by India ink preparations and in tissue sections by PAS and mucicarmine as well as silver stains Best test is a polymerase based latex agglutination test.

CNS Tumors CNS tumor characteristics: More intracranial tumors than spinal cord tumors Tumors in children are more likely to be posterior fossa tumors while adults lesions are supratentorial Histological distinction between benign and malignant is not always precise.

CNS Tumors CNS tumor characteristics: Low grade lesions may still be associated with poor prognosis because of clinical deficit as a result of anatomic location. Location of CNS tumor may also limit the ability for surgical resection CNS tumors spread easily via the sub- arachnoid space and the CSF.

CNS Tumours Gliomas tumors of the brain parenchyma that histologically resemble different types of glial cells. Astrocytomas, oligodendrogliomas, and Ependymomas.

CNS tumours Astrocytoma : Two major categories of astrocytic tumors Fibrillary and pilocytic astrocytomas. Fibrillary Astrocytoma 80% of adult primary brain tumors. Located in the cerebral hemispheres Fourth to sixth decades of life. Presents with seizures, headaches, and focal neurologic deficits related to the anatomic site of involvement.

CNS tumours Divided into three, Based on the degree of differentiation, : Astrocytoma, Anaplastic astrocytoma, and glioblastoma multiforme Astrocytomas are the best differentiated tumors and patients may progress slowly. Most patients eventually deteriorate clinically and presents with anaplastic features.

CNS tumours Glioblastoma Multiformes: May be the initial presentation or progression of more differentiated tumor Mean survival of less than 10 months with the current state of the art management

CNS tumours Pathology: Astrocytomas generally shows: Poorly defined, gray, infiltrative tumor that expands and distorts the brain. Glioblastoma multiformes shows features of anaplasia with the addition of necrosis and vascular or endothelial cell proliferation and pseudo-palisading nuclei . High grade tumors shows contrast enhancement on imaging.

CNS tumors Pilocytic astrocytomas Relatively benign tumors, Typically occur in children and young adults and are Usually located in the cerebellum. But may also appear in the floor and walls of the third ventricle and optic nerves. Cerebral lesions are rare.

CNS tumors Pilocytic astrocytomas Morphology: A cystic tumor composed of areas with bipolar cells with long, thin "hairlike" processes that are GFAP positive; Rosenthal fibers microcysts are often present. Necrosis and mitoses are absent.

CNS tumors Ependymomas Arise in ventricular system Located in the fourth ventricle in pediatrics and young adults More common in the spinal cord in adults. CSF dissemination is common Morphology: perivascular pseudo-rosettes with tumor cells arranged around vessels.

CNS tumors Medulloblastomas: Considered a CNS PNET. Childhood tumor Located in the cerebellum Highly malignant but also radiosensitive 75% 5 year survival rate with treatment Histology:Small blue cells with scant cytoplasm and prominent nuclei.

CNS tumors Primary CNS lymphoma The most common CNS neoplasm in immunosuppressed individuals (including transplant recipients and persons with AIDS) Epstein-Barr virus is the principal etiology with immunosuppresion. Relatively poor response to chemotherapy compared with peripheral lymphomas. Multiple tumors within the parenchyma.

CNS tumors Meningiomas predominantly benign tumors of adults, Dural tumors that arise from the meningothelial cell of the arachnoid. may be found along the external surfaces of the brain as well as within the ventricular system, Presents with focal symptoms as a result of compression of the underlying brain. 50% of cases have the NF-2 gene

CNS tumors Meningiomas In a patient presenting with multiple meningiomas with eighth nerve schwannomas or glial tumors , the suspicion of Neurofibromatosis type 2 (NF2) should be considered

CNS tumors Meningiomas Pathology: Several histologic classification: Syncytial, Transitional,fibroblastic and the Psamommatous types. The psammomatous type is characterised by the presence of Psammomama bodies.

CNS tumors Metastatic tumors Multiple lesions Common Primaries: Lung, breast, skin (melanoma), kidney, and gastrointestinal Located in the grey/white matter boundary

Degenerative CNS disorders Degenerative disorders reflects an underlying cellular degeneration of neurons: Dementia 2 .Movement disorders Dementia Alzheimer's 75%, Lewy body disease 25%,fronto-temporal Vascular dementias. Not associated with degenerative changes

Degenerative CNS disorders Dementia Development of memory impairment and other cognitive deficits with preservation of a normal level of consciousness. not part of normal aging and always represents a pathologic process.

Degenerative CNS disorders Clinical features related to affected brain regions: Frontal lobe: Impaired judgment, strategic reasoning, abstract thinking, continence, control of appetite Parietal Lobe:agnosia and apraxia Medial temporal lobe: memory disturbances ,Hallucinations Neo-cortex: Receptive dysphasia and automatism Occipital Lobe: visual perception dysfunction

Degenerative CNS disorders Alzheimer's Dx. Most common cause of dementia in the elderly, Increasing incidence with age Insidious onset of cognitive decline with alteration in mood and behavior Most cases are sporadic Familial/genetics accounts for up to 10% and have earlier onset.

Degenerative CNS disorders Genetics in Alzheimer's ApoE4 Lipoprotein mutation seen in 30% Genetic mutations includes: Amyloid precursor protein (APP) gene on chromosome 21 - Presenilin 1 gene on chromosome 14 - Presenilin 2 gene on chromosome 1 Trisomy 21(Down syndrome);Extra copy of Gene .Early onset Alzheimers.

Degenerative CNS disorders A. Z Pathology: Deposition of intraneuronal or intracellular tau proteins (neurofibrillary tangles and Extra neuronal A β amyloids plaques Atrophy of frontal, temporal and parietal lobes Neuronal loss and secondary gliosis

Degenerative CNS disorders Pathogenesis of Alzheimer’s Several hypothesis: Cholinergic: Altered synthesis of acetylcholine Amyloid: Accumulation of Aβ amyloid triggers neuronal degeneration. Does not explain neurofibrillary tangles. Tau protein: Phosphorylated tau protein initiates a cascade that leads to formation of neurofibrillary tangles, and disintegration of microtubules.

Cerebral atrophy

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Degenerative CNS disorders Fronto-temporal dementias Progressive deterioration of language and changes in personality degeneration and atrophy of temporal and frontal lobes. symptoms occur before memory disturbance(clinical difference from Alzheimer’s disease) mutations in the gene encoding tau proteins.

Degenerative CNS disorders Disorders of movement: Parkinsonism Involuntary movement disorders: Huntinton disease Motor weakness: Amytropic lateral sclerosis Ataxia :Fredrick's ataxia

Degenerative CNS disorders Parkinsonism Clinical syndrome due to damage to the nigro-striatal groups of dopaminergic neurons Presents with gait and postural abnormalities and dementia(10-15%) Idiopathic Parkinson’s is the commonest cause Pathology: Pallor of the substantia nigra and locus ceruleus Presence of lewy bodies

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Degenerative CNS disorders Huntington Disease Autosomal dominant disorder Relentlessly progressive disorder consisting of chorea and dementia Trinucleaotide ,(CAG)repeat expansion of the huntingtin gene. Pathology: Degeneration of the caudate and Putamen(striatum) Huntingtin exhibits anticipation

Degenerative CNS disorders Amyotrophic Lateral Sclerosis(Lou Gehrig's Disease) Degenerative disorder affecting the motor neurones characterized by muscle atrophy ("amyotrophy") and hyper-reflexia due to loss of both upper and lower motor neurons. 90% of cases are sporadic. Familial cases are Autosomal dominant involving the gene for superoxide dismutase.

Stephen Hawking

Demyelinating Disorders Myelin in peripheral nerves is similar to the myelin in the CNS except for the following differences: Peripheral myelin is made by Schwann cells, not oligodendrocytes; each cell in the peripheral nerve contributes to only one internode, In CNS, many internodes comes from a single oligodendrocyte; Disruption of myelin in nerves leads to changes in nerve conduction and symptoms. Secondary damage to axons and the limited capacity of the CNS to regenerate myelin contribute to dx.

Demyelinating Disorders Demyelinating CNS disorders: Acquired conditions characterized by damage to previously normal myelin: Immune-mediated injury ,example multiple sclerosis (MS) and related disorders. Viral infection of oligodendrocytes as in progressive multifocal leukoencephalopathy drugs and other toxins.

Demyelinating Disorders Dysmyelinating/ leukodystrophy : Improperly formed or abnormal myelin. Mutations affecting the proteins required for myelin synthesis or degradation. Examples: Krabbe disease,

Demyelinating Disorders Multiple Sclerosis MS Autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space. Common, prevalence of 1/1000 in the U.S Any age group, F>M Relapsing and remitting episodes of neurologic deficits. Loss of tolerance to self myelin antigens. Genetics plays a role

Demyelinating Disorders Morphology : white matter disease; Affected areas show multiple, well- circumscribed, slightly depressed, glassy, gray-tan, irregularly shaped ,periventricular plaques . Plaques are commonly seen in optic nerves and chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord.

Demyelinating Disorders Multiple Sclerosis MS Pathology: CSF shows mildly elevated protein level with an increased proportion of γ-globulin; oligoclonal bands may be seen and represents antibodies against a variety of antigenic targets. .Magnetic Resonance Imaging: Shows the distribution of brain lesions.

Demyelinating Disorders Central pontine myelinolysis Nonimmune process characterized by loss of myelin involving the center of the pons, After rapid correction of hyponatremia. Severe electrolyte disturbance may be present. Presents with rapidly evolving quadriplegia.