outline introduction cerebrovascular disease traumatic head and brain injury infections tumors ...

Outline

Introduction Cerebrovascular

disease Traumatic Head and

brain injury Infections Tumors

Degenerative disorders

Miscellaneous -Alcohol/Nutrition

Demyelinating Disorders

Congenital malformations

Perinatal Brain Injury.

IntroductionPATTERNS 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

IntroductionPATTERNS 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

PATTERNS OF INJURY IN THE NERVOUS SYSTEM Astrocytes 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).

IntroductionPATTERNS 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.


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.


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 disease1. 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).


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)


Water shed areas between MCA and ACA and MCA and PCA

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


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

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

Laminar necrosis

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.


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.


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


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


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.


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

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.

Origins of major vessels


Gross: cortical infarct

There are cortical hemorrhages in the right temporal lobe

Hemorrhagic infarcts are often embolic.


Hypertension associated disorderscommon vascular anomalies

associated with chronic hypertension:

Intracerebral hemorrhage Charcort-Bouchard aneurysm Lacunar infarcts Slit hemorrhages Hypertensive encephaolopathy


Thrombosis of small vessels: Affects penetrating vessels

End arteries Little collateral flow

Associated with hypertension, diabetes mellitus, aging

Predisposes to lacunar infarction and hemorrhage


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


Charcot-Bouchard Aneurysm Small aneurysmal dilation

(micro-aneurysm) Caused by chronic hypertension They rupture

easily=>intracerebral hemorrhage.


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")

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.) .


Common Berry aneurysm Associations:

APKD Ehlers –Danlos syndrome Coarctation of the aorta Bicuspid aortic valve Neuro-fibromatous -type 1

Cerebrovascular diseaseOther 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.


CNS traumaHemorrhage related to trauma2 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 HemorrhageDue 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.


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.

Subdural hematoma

Epidural Subdural

Cerebrovascular diseaseCNS 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 infectionsRabies 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.

CNS infectionsCryptococcus 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 TumorsCNS 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 subarachnoid 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 tumorsEpendymomas 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 tumorsPrimary 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 disordersDegenerative disorders reflects an

underlying cellular degeneration of neurons:

1. 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 disordersClinical 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 disordersAlzheimer'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 disordersGenetics 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 disordersA. 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’sSeveral 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 disordersDisorders of movement: Parkinsonism Involuntary movement disorders:

Huntinton disease Motor weakness: Amytropic lateral

sclerosis Ataxia :Fredrick's ataxia

Degenerative CNS disordersParkinsonism 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

Degenerative CNS disordersHuntington 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 disordersAmyotrophic 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 DisordersDemyelinating 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.


Dysmyelinating/ leukodystrophy :

Improperly formed or abnormal myelin.

Mutations affecting the proteins required for myelin synthesis or degradation.

Examples: Krabbe disease,


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


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.


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.


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.

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