CNS pathology

Question 1

Stains for CNS cells

Answer 1

• H&E
• Luxol blue: stains myelin blue (white matter dark blue, gray matter very light blue)
• Silver stain: stains neurofilaments black
• Immunoperoxidase stains to stain for synaptic protein (synaptophysin), localized neurofilaments or NTs

Question 2

Ischemic cell change (red neuron)

Answer 2

• Red is dead, occurs in response to deprivation of O2
• Btwn 8-24hrs after insult, neuron shrinks and cytoplasm becomes eosinophilic (pink/red on H&E)
• Nucleus is darkly stained, then lost
• Changes are irreversible
• Insult requires deprivation of O2 to tissue for several minutes for irreversible damage, but then 8-24hrs is required for these changes to be observed
• Cellular changes: depletion of ATP, acidosis, impaired reuptake of GLU by glial cells and resulting excitotoxicity, accumulation of intracellular Ca, ROS generation

Question 3

Wallerian degeneration

Answer 3

• Occurs when an axon is transected by trauma
• Axon and myelin distal to transection degenerate, leading to impaired axonal transport
• Disappearance of neurofibrils and breaking of axon into short fragments (parts are phargocytosed)
• This occurs over weeks in PNS and months in CNS
• Sprouting of new axons from cell body possible in PNS, but not CNS

Question 4

Central chromatolysis

Answer 4

• Occurs after transection injury to neuron’s axon, usually seen in large motor neurons
• Consists of swelling of cell body, dissolution of nissl substance, and migration of nucleus to the periphery of the body
• Reversible

Question 5

Distal axonopathy

Answer 5

• Degeneration of the axon and myelin first develops in the most distal part of the axon
• The axon “dies back”
• Usually a result of toxins (pesticides, acrylamide, ect) or metabolic problems (diabetes, renal failure, alcoholism)
• When the metabolic needs of the cell are not met, the most distal part of the axon dies first

Question 6

Inclusion bodies

Answer 6

• Abnormal deposits in neurons
• Stains w/ silver stain: cytoplasmic neurofibrilary tangles (AD) and Pick bodies (Pick disease)
• Stains w/ H&E: cytoplasmic lewy bodies (PD) and negri bodies (rabies)
• Stains w/ H&E: nuclear cowdry type A (herpes and CMV)

Question 6

Oligodendrocytes

Answer 6

• All glia are neuroectodermal in origin (except for microglia, which are mesodermal- bone marrow- derived)
• Reside mostly in white matter (also some in grey) and myelin ate the axons
• Have small, round nuclei and no apparent cytoplasm

Question 7

Myelin loss (pathologic oligodendrocytes)

Answer 7

• Demonstrated by luxol stain, turing myelin blue
• Demyelinating disease such as MS (autoimmune) leave large plaques of absent blue color (axons left intact)
• MS plaques are usually periventricular, larger, and more confluent that PML
• Progressive multifocal leukoencephalopathy (PML) forms small plaques of demyelination (most severe at grey-white matter junctions) when oligodendrocytes die and myelin degenerates
• Oligodendrocytes can die from viruses, like the papova virus (causes PML). This virus results in a homogenous, glassy nuclear inclusion in the oligos
• Leukodystrophies are due to genetic mutations. Myelin is abnormally formed and is unstable so it breaks down

Question 9

Astrocytes 1

Answer 9

• Astrocytes present in gray and white matter, have large oval nuclei (larger than oligo’s) with more euchromatin than oligo’s
• Processes can only be seen when stained w/ glial fibrillary acidic protein (GFAP)
• These processes surround the small arteries of the brain and play a role in maintaining the BBB and ionic environment

Question 9

Astrogliosis (gliosis)

Answer 9

• Astrocytes respond to almost any brain injury by gliosis, which includes proliferation and hypertrophy
• Cytoplasm becomes very apparent and eosinophilic due to GFAP (referred to as gemistocytes)
• This process does not result in fibrosis

Question 10

Astrocytes 2

Answer 10

• Astrocytes present in gray and white matter, have large oval nuclei (larger than oligo’s) with more euchromatin than oligo’s
• Processes can only be seen when stained w/ glial fibrillary acidic protein (GFAP)

Question 11

Microglia

Answer 11

• Derived from bone marrow (mesoderm), infiltrate developing brain along w/ blood vessels
• Slow turnover during life
• Appear as small elongated, dark-staining nuclei
• Can respond to injury by differentiating and acting as macrophages

Question 12

Reactive microglial cell

Answer 12

• Activated microglia (due to brain injury or local immune response) look rod-shaped
• May up regulate expression of MHC and inflammatory cytokines

Question 13

Macrophage response

Answer 13

• Microglia may differentiate into macrophages, especially during brain necrosis
• The macrophages phagocytose the tissue debris (lipid-laden macrophages, or glitter cells)
• Monocytes may enter brain after injury, and differentiate into macrophages as they do so

Question 14

Microglial nodule

Answer 14

• Microglia may respond to single damaged neurons in encephalitis, by encircling the neuron and phagocytosing it (neurophagia)
• This results in the formation of a microglial nodule
• Microglial nodules may also be present in white mater, especially in HIV encephalitis

Question 15

Multinucleated giant cell reaction

Answer 15

• Formed either from fusion or failure to divide
• In HIV encephalitis groups of microglial cells may accumulate in the white matter
• Some will fuse to form the multinucleate giant cell
• Can often be seen in AIDS dementia pts

Question 16

Vasogenic edema

Answer 16

• Loss of integrity of BBB (broken tight junctions) may result in entrance of excess water and solutes into extracellular space of brain
• The fluid collect predominantly in white matter
• Results in increased brain volume and intracranial pressure, leads to mass effect

Question 18

Vasogenic edema

Answer 18

• Loss of integrity of BBB (broken tight junctions) may result in entrance of excess water and solutes into extracellular space of brain
• The fluid collect predominantly in white matter
• Results in increased brain volume and intracranial pressure (new water entering brain)

Question 18

Hypoxia vs ischemia

Answer 18

• When the brain is deprived of O2 (hypoxia) it is usually due to the brain being deprived of blood (ischemia)
• Pure hypoxia causes mostly reversible (to an extent) failure of electrical activity and synaptic transmission, and doesn’t cause necrosis
• Ischemia results in decreased O2, glc, and a build up of toxic metabolites and thus is much more damaging

Question 19

Cytotoxic edema

Answer 19

• Toxic or metabolic events that affect normal neuronal and glial membranes may result in intracellular accumulation of fluid, or lysing of cells
• More likely to affect cells in gray matter and usually do not lead to mass effect (not introducing any new water- just releasing the water from cytoplasm)

Question 20

Selective neuronal necrosis (global hypoxia-ischemia)

Answer 20

• Cells in the CNS have differing sensitivity to hypoxia-ischemia (during intermediate severity of ischemia)
• Neurons (especially cortical neurons) are more vulnerable to ischemia than glial cells and endothelial cells (most vulnerable layers in cortex: layers 3 and 5)
• Neurons in brainstem and spinal cord are more resistant to hypoxia-ischemia than neurons in the cortex
• Water-shed areas are first to be affected because they lack sufficient collateral circulation (i.e. hippocampus), usually btwn ACA, MCA, and PCA
• Histologic changes seen only after 12-24 hrs of insult
• Results in eosinophilic ischemic necrosis: neurons shrink, cyto becomes eosinophilic, nucleus becomes blurry. Eventually the neuron disappears

Question 21

Selective neuronal necrosis (global hypoxia-ischemia)

Answer 21

• Cells in the CNS have differing sensitivity to hypoxia-ischemia (during intermediate severity of ischemia)
• Neurons (especially cortical neurons) are more vulnerable to ischemia than glial cells and endothelial cells (most vulnerable layers in cortex: layers 3 and 5)
• Neurons in hippocampus most susceptible to hypoxia than another part of brain (lose recent memory)
• Neurons in brainstem and spinal cord are more resistant to hypoxia-ischemia than neurons in the cortex
• Water-shed areas are first to be affected because they lack sufficient collateral circulation (i.e. hippocampus), usually btwn ACA, MCA, and PCA
• Histologic changes seen only after 12-24 hrs of insult
• Results in eosinophilic ischemic necrosis: neurons shrink, cyto becomes eosinophilic, nucleus becomes blurry. Eventually the neuron disappears

Question 22

Focal ischemia and infarction

Answer 22

• Leads to deprivation of a specific area of blood, causing excitotoxicity (increased extracellular GLU and ASP), increased lactic acid and tissue acidosis
• The center of the infarct (core) is unsalvageable
• But btwn the core and the healthy tissue is the penumbra, an area of constrained blood but partially preserved metabolism
• The penumbra is at risk of infarction, yet potentially salvageable
• Requires 12-24hrs after insult for histologic changes to be seen

Question 23

Causes of CNS infarcts

Answer 23

• Atherosclerosis predominantly affects larger vessels (common carotid, especially at bifurcation, MCA, and basilar a)
• Atheroscelrotic plaques can lead to thrombotic occlusions, which do not move unless they embolize (form at site of infarction)
• Most large infarcts are caused by thromboembolisms of the MCA
• Hemorrhages are most often seen in infarcts of embolic origin

Question 24

Microscopic features of infarcts

Answer 24

- Earliest changes: pallor and vacuolization (falls apart) of neuropil, endothelial swelling and eosinophilic ischemic necrosis (EIN) - Next there are some PMNs infiltrating, followed by macrophages - Finally there is cavitation w/ surrounding gliosis - During gliosis and PMN/mac infiltration the brain appears hypercellular

Question 25

Embolic vs thrombotic infarction

Answer 25

- Embolic infarctions are more common, and the heart is frequently the source (arrhythmias such as a fib and vulvar disease) - Other sources: bits of thrombus, atherosclerotic plaque, talc protein, others - The MCA is most often affected by embolic infarcts - Embolisms are more likely to cause multiple infarcts than thrombotic - Embolic infarcts are more likely to be complicated by hemorrhage into infarcted tissue (blood is restored to dead tissue and the capillaries hemorrhage) - Always check for hemorrhage (indicates embolic) and multiple infarcts (indicates embolic)

Question 26

Vasculitis infarct

Answer 26

- Vasculitis (inflammation of blood vessels) can cause infarction - May be part of systemic vasculitis or isolated to CNS - May be multiple and hemorrhagic, and has many causes (such as infection) - Often suspected but rarely Dx - Vessel walls infiltrated by inflammatory cells, damage to vessel wall can result in thrombosis

Question 27

Lacunar infarcts

Answer 27

- Type of ischemic small vessel disease (HTN high risk factor for this and intracerebral hemorrhage) - Small infarcts (often multiple) due to small vessel atherosclerosis w/ chronic HTN and diabetes being major risk factors - Often found in pons and basal ganglia - May be asymptomatic, or isolated neurological deficits (or dementia if multiple)

Question 28

Intracerebral hemorrhage

Answer 28

- Associated with HTN and often occur in basal ganglia, thalamus, brainstem, or cerebellum - Will cause a mass effect - The ipsilateral ventricle will be small, while the contralateral one will be large due to obstruction of CSF flow - The obstruction to CSF flow and the mass affect both raise intracranial pressure

Question 29

Fibrinoid change

Answer 29

- Deposition of proteins in vessel walls, causes damage to the walls - Due to chronic HTN (less severe, more chronic than fibrinoid necrosis) - If extreme HTN, the vessels may undergo fibrinoid necrosis

Question 30

Amyloid angiopathy

Answer 30

- Amyloid stains w/ congo red, gives a green birefringence under polarized light - Deposition of amyloid in cerebral vessels is another way of developing intracerebral hemorrhage (sometimes multiple) - These hemorrhages are usually located superficially in the cerebral hemispheres, with a predilection for the occipital lobe - Common in AD

Question 31

Cerebral aneurysm

Answer 31

- Can cause excruciating headaches, loss of consciousness, stiff neck, subarachnoid hemorrhage - Blood in subarachnoid space causes: blockage to CSF flow, vasospasms (other vessels may hemorrhage) - Often arise at bifurcations, circle of willis and communicating arteries, basilar artery - Often are multiple and rebleed, often fatal - Can result in intraventricular and intracerebral hemorrhage

Question 31

Vascular malformations

Answer 31

- Congenital problems that cause abnormal flow, hemorrhage, seizures, and focal deficits - Usually superficial, typically over cerebral convexity - Can easily be seen on angiogram, where its a large bundle of unorganized vessels

Question 32

Cavernous hemangioma

Answer 32

- Back-back thin walled vessels - Located more deeply in the brain usually than AVMs - Most common symptom is seizure by also may bleed - Typically has less brain parenchyma btwn vessels than AVMs - Can often be asymptomatic

Question 33

Arteriovenous malformations (AVM)

Answer 33

- Congenital problems that cause abnormal flow, hemorrhage, seizures, and focal deficits - May be asymptomatic, but are more dangerous than cavernous hemangiomas - Usually superficial, typically over cerebral convexity - Can easily be seen on angiogram, where its a large bundle of unorganized vessels - Often will have arteries connecting to veins without going through a capillary bed (microscopically seen as many vessels of various sizes ) - Tend to bleed b/c arteriole blood under high pressure directly enters veinules that can't handle the pressure - The vessel walls and size of vessels vary btwn one another (can be fibrotic)

Question 34

Uncal herniation

Answer 34

- A complication of any space-occupying intracerebral lesion (mass affect), including hemorrhage and infarction - Uncus herniates thru the incisura of the tentorium and compresses the brainstem - Can lead to hemorrhages in the midline brainstem (duret hemorrhages- from shearing of other arteries) - PCA can be affected by duret hemorrhages

Question 35

Cavernous hemangioma

Answer 35

- Back-back thin walled vessels - Located more deeply in the brain usually than AVMs - Most common symptom is seizure by also may bleed - Typically has less brain parenchyma btwn vessels than AVMs, vessels tend to be thinner (fibrosis in the walls of vessels) - Can often be asymptomatic

Question 36

Types of hematomas

Answer 36

- Epidural: lesion in the middle meningeal artery, bleeds above the dura and causes mass effect - Subdural: lesion in the bridging vein, leads to slowly enlarging hematoma that causes mass effect - Subarachnoid: lesion in the cerebral arteries, causes blood to enter CSF (worst headache ever, drowsiness, confusion), no mass effect - Intracranial hemorrhage: lesion of a vessel within the brain tissue, causes mass effect