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Block 11 ASF
Terms in this set (208)
AKA Betz cells.
Blue clumps in cell bodies = Nissl (RNA).
Found in the cortex.
Neurons of the cerebellum
Deep layer = granule cells. Very small and dense. Clump together --> open spaces in between.
Surrounding this = purkinje cells.
Ischemic changes in neurons
Neurons are very sensitive to anoxia, especially purkinje cells in the cerebellum.
With anoxia, they become more eosinophilic, undergo pyknosis, and eventually die.
General response to injury in the CNS (replaces fibrosis that occurs everywhere else).
Usually astrocytes that are entering ('astrogliosis').
Astrocytes have lots of pink cytoplasm next to the nucleus (gemistocytes)
Alzheimer type II cells
Has nothing to do with alzheimer's.
Astrocytes that are no longer functioning.
Occur with metabolic derangement (liver or kidney failure).
Have enlarged nucleus with pale chromatin.
Myelinate in the CNS (one cell --> multiple neurons).
Tend to align in a straight line along white matter tracts.
Can contain viral inclusions (PML).
Lymphocyte-sized nucleus, dense chromatin, no visible cytoplasm.
Ciliated columnar cells lining the ventricles.
Joined by tight junctions and help circulate CSF.
With increased ventricular pressure, ependymal cells are lost. End up with subependymal glial proliferation (NOT Ependymal) under the injury.
These are monocyte lineage in the CNS.
Can be rod cells (in response to viral infection) or macrophage.
Can surround and eat neurons (neuronophagia) or form nodules.
Causes, sx, and signs of increased ICP
Caused by a focal or global lesion.
Sx = HA, nausea, vomiting.
Signs = papilledema (eye is a direct extension of the brain).
Biggest fear is that it will cause herniation.
Edema of the brain
Causes increased ICP.
Vasogenic (leaky vessels from infarct, tumor, infection). Tends to be in white matter. Extracellular.
Cytotoxic (cell swelling from anoxia, toxins, metabolic). Tends to be in cortex. Intracellular.
Grossly = flattened gyri, narrow sulci, compressed ventricles.
Histo = lighter staining, vacuolated areas.
Types of brain herniation
1) Subfalcine: under the falx cerebri. Compresses cingulate gyrus and ACA.
2) Transtentorial: Uncal herniaiton with CN3, PCA, and brainstem compression.
3) Tonsillar: Cerebellar tonsils through foramen magnum.
4) Skull defect 2/2 surgery.
Midline brainstem hemorrhage 2/2 transtentorial herniation.
Herniation puts pressure on brainstem and causes penetrating arteries from the basilar AA to sever.
This is an arterial bleed that progresses quickly.
Compress respiration centers leading to death.
Most is made in lateral ventricles at choroid plexus --> 3rd ventricle (through interventricular foramen) --> 4th ventricle (through cerebral aqueduct) --> subarachnoid space --> arachnoid granulations --> venous sinuses
Types of hydrocephalus
Decreased resorption (more common) = communicating (problem with arachnoid granulations. All ventricles communicate with each other properly).
noncommunicating (problem between ventricles)
Increased production from choroid tumor (rare).
Normal pressure hydrocephalus (misnomer. Pressure fluctuations).
Hydrocephalus ex-vacuo (loss of brain tissue --> ventricles expand to take up extra space).
Normal pressure hydrocephalus
If you do an LP, the pressure will probably be normal, but over 24 hours, you get pressure fluctuations (episodic).
The patient may look like they have dementia (gait disorder, impaired mental function, incontinence).
Tx = shunt. They generally get better.
Epidemiology of adult CNS tumors
As common as non-Hodgkin lymphomas, melanomas, and bladder cancer.
1/3 are malignant, 2/3 benign.
Glioblastoma (malignant) > other gliomas (malignant).
Meningiomas (benign) > pituitary tumors > nerve sheath tumors.
Features of glioblastoma
High grade astrocyte tumor or stem cell progenitor origin.
Rapidly growing, diffusely infiltrative, considerable mass effect.
High Ki67, lots of mitoses.
2 cell types: Bizarre multinucleated cells (no longer proliferating, so not a problem) and small bipolar cells (proliferative and infiltrative component).
Bipolar cells secrete glutamate which is excitotoxic --> seizures and kills adjacent neurons.
Pseudopalisades around region of necrosis. Necrotic region pushes normal cells to the periphery and causes them to align.
Associated with edema.
Necrosis (non enhancing) with ring enhancement around the edge (richly vascular with leaky vessels)
Changes in vascularity with glioblastoma
In the main tumor, rapid proliferation causes cells to outgrow blood supply --> infarct and necrosis.
Pseudopalisading cells around necrotic area.
The region around the necrosis is hypoxic, so VEGF is secreted.
Vascular endothelium proliferates --> glomeruloid bodies.
These new vessels are leaky. New vessels + leakiness --> contrast enhancement on imaging.
Grading of CNS tumors
Histological grading of tumors is more important than staging in the CNS.
Grade I - IV based on prognosis.
Can't use staging because lymph node mets and extraneural mets are extremely rare and don't correlate with prognosis.
Primary vs secondary glioblastoma
Different origins with different molecular mutations.
Primary = arise de novo as a grade IV lesion. Present in patients in 60s or 70s.
Secondary develop in stepwise fashion:
Begin as grade II (diffuse astrocytoma) presenting in 30s or 40s (no mitoses, VEGF production, or necrosis) -->grade III (anaplastic astrocytoma). Nuclear atypia, brisk mitotic activity, still no VEGF or necrosis --> grade IV with atypia, mitoses, VEGF, AND necrosis.
Any CNS tumor that arises from astrycytes, ependymal cells, or oligodendrocytes.
Glioblastoma/astrocytoma = 75% of gliomas in adults.
Oligodendrogliomas, mixed, and ependymomas = 25%.
Either grade II or III.
Arise from oligodendrocytes.
Diffusely infiltrating, but well-differentiated.
Typically found in cerebral hemispheres (NOT cerebellum) of adults. Radiology = calcifications in white matter.
Histo = fried egg appearance.
80% have co-deletion of 1p and 19q. Good prognosis/chemo response.
Grade II = NO atypia, mitoses, vascular proliferation, or necrosis.
Grade III (anaplastic) = atypia, mitoses, vascular proliferation, and necrosis. Contrast enhance.
Mixed gliomas AKA oligoastrocytoma
composed of mix of astrocytes and oligodendrocytes.
Occur as grade II or III only.
Behavior parallels whichever component predominates.
Little evidence that these are actually biphasic. All regions have a homogenous genetic profile.
Changes coming in how we diagnose brain tumors
The grading system based strictly on histology has been around for decades. Was designed by WHO for use everywhere even in regions with little technology.
We are now moving to an integrated diagnosis that uses histology and molecular findings. Better correlates with prognosis and treatment.
Primary CNS lymphomas
Prior to HAART tx, 2-12% of AIDS patients would get primary CNS lymphoma.
Overwhelming majority were B-cell lymphomas associated with EBV.
Perivascular pattern of growth.
Metastatic CNS cancer vs glioma
Well circumscribed on radiology, often multiple, often at gray-white junction, sharply demarcated, lots of mitoses.
Poorly circumscribed, usually single lesion, typically in white matter, lots of infiltration, fewer mitotic figures.
Most common benign CNS tumor in adults.
Arises from the meninges over the brain.
Often induce hyperostosis of overlying skull. Grade I don't invade the brain, but can invade bone and soft tissue.
Clinical findings are 2/2 compression of adjacent structures. Can have marked edema.
Tx = surgery.
Arise from arachnoid cap cells in leptomeninges.
Form whorls that can calcify --> psammoma bodies.
15-20% progress to grade II (atypical) with brain invasion.
1-2% progress to grade III (malignant meningioma). Highly aggressive with less than 2 year survival.
Intrasellar tumors arising from hormone-secreting cells of anterior pituitary.
Can secrete hormones or not.
Those that don't --> sx of mass effect (bitemporal hemianopsia, pituitary or hypothalamic dysfunction).
This is the one example in the CNS where stage is more important than grade for prognosis
Benign (Grade I) peripheral nerve sheath tumors.
Commonly occur on 8th cranial nerve and spinal nerve roots, but can occur on any nerve.
Clinically, sx are related to the nerve thats affected.
Composed exclusively of schwann cells. Don't infiltrate the nerve, but grow around it and damage it.
Do NOT transform into high grade tumors.
Tx = surgery.
Epidemiology of CNS tumors in kids
CNS tumors are the most common neoplasm in kids 0-19yo.
Order of commonness:
Gliomas (esp diffuse pontine gliomas) > pilocytic astrocytomas > ependymomas > embryonal tumors (medulloblastoma and primitive neuroectodermal tumors)
Most often in cerebellum in kids.
Radiologically = cyst with a mural nodule.
Have a biphasic histology with dense and loose areas.
Bipolar cells with rosenthal fibers in the astrocytes.
Grade I and do not progress to higher grade.
However, they DO have VEGF and contrast enhancement (enhancement does not = malignancy)
2nd most common CNS tumor in kids.
Grade II tumors arising in walls of ventricles.
Sx relate to obstruction of CSF flow (noncommunicating hydrocephalus).
Slow growing, no mitoses, VEGF, or necrosis.
Rarely, Grade II can progress to grade III. Unfavorable prognosis with more mitoses, VEGF, and necrosis.
High grade (grade IV) neoplasms primarily in kids.
2 most common types:
Primitive neuroectodermal tumors
Embryonal tumor. Grade IV in kids.
By definition, arise in cerebellum.
Most are sporadic, but <5% associated with syndromes.
Extend into 4th ventricle --> noncommunicating hydrocephalus and increased ICP.
Radiology = solid, contrast enhancing masses.
Can drop metastasize via CSF into the spinal cord, so staging is often done.
4 molecular subtypes with distinct prognoses:
WNT and SHH = better prognosis.
Group 3 and 4 = worse prognosis.
Primitive neuroectodermal tumors
Embryonal tumor. Grade IV in kids.
Arise in cerebral hemisphere.
Variably contrast enhance, may have cysts, calcification, or hemorrhage.
Histology is similar to medulloblastoma, but mutations are different. NOT associated with genetic syndromes.
Aggressive (only 50% survive 2 years)
Neurofibromatosis type I
2 high hypothesis for NF1 gene.
Most common genetic dz affecting nervous system.
CNS = optic glioma, pilocytic astrocytoma, glioblastoma.
Non-CNS neoplasms = sarcoma, pheo, juvenile CML (before age 6).
Pigmented lesions = cafe au lait macules, freckling, lisch nodules.
Learning disability (IQ = 90)
Dermal neurofibromas develop in skin, appear at puberty, not malignant.
Get plexiform neurofibromas and malignant peripheral nerve sheath tumors.
MPNST are most common malignancy and leading cause of death in NF1 patients.
Schwann cell derived malignancies
Plexiform neurofibromas occur in large nerve or nerve plexi. Often congenital with high malignant potential.
Neurofibromas have many cell types. Form when second NF1 gene is knocked out.
Can transform into aggressive Schwann-cell-only malignancies called malignant peripheral nerve sheath tumors. Form when NF1 negative cells acrue other mutations in cell cycle regulatory genes.
Neurofibromatosis type 2
AKA acoustic neurofibromatosis or central neurofibromatosis.
Development of multiple schwannomas.
AD inheritance of chromosome 22q.
NF2 encodes merlin or schwannomin gene that mediates communication between cell membrane and cytoskeletom.
Develop multiple meningiomas and ependymomas, meningioangiomatosis
May be familial, but 60% are sporadic.
TSC1 encoding hamartin, TSC2 encoding tuberin. Mutations = hyperactivity of mTOR pathway.
Seizures are most common CNS manifestation followed by mental retardation.
Hamartomas in brain and kidney most frequently
Brain lesions in tuberous sclerosis
Masses of dysplastic tissue in cortex. These are the seizure foci.
Candle gutterings form under ependymal cells in the ventricle (<1cm). Can progress to subependymal giant cell astrocytomas which can fill the ventricle. Contrast enhance and are often calcified.
Neural tube closure
Notochord is mesoderm.
Signals to overlying ectoderm to form the neural plate. Cells become more columnar, fold into grove --> close forming a tube.
Cells at top undergo EMT --> neural crest cells.
Groove fuses from cranial to caudal between 20-28 days.
Neural tube defects
Most common group of CNS malformations.
Encephalocele (closed. still skin over it).
Spina bifida occulta, meningocele, myelomeningocele
MOST COMMON CNS MALFORMATION.
Occurs at 28 days gestation.
Open, cranial NT defect.
Brain is exposed to harsh amniotic fluid.
Tissue becomes cerebrovasculosa with excess vascularity, disorganization.
Closed, cranial NT defect. Skin covers the protrusion.
Protrusion of CNS parenchyma through a defect in the skull.
Most commonly occipital/posterior fossa.
Protected from amniotic fluid, so histo is more normal than anencephaly.
Sx depend on whats in the malformation and what's missing in the skull.
Spinal neural tube defects
Spina bifida occulta = just dimple or patch of hair over defect. Occurs in 20% of population.
Meningocele = just meninges protrude.
Myelomeningocele = meninges AND spinal cord protrude.
Myelomeningocele > meningocele.
Myelomeningocele is associated with type II chiari malformation
Diagnosis of neural tube defects
If open, maternal serum AFP will be elevated.
AFP is made by the fetus. There shouldn't be any in the amniotic fluid or maternal serum unless its leaking out somehow (open defect).
Prevention with folate supplements.
Type I = cerebellar tonsils herniate through foramen magnum.
Type II = tonsils and vermis. Associated with myelomeningocele.
Type III = occipital encephalocele.
These can obstruct CSF flow --> hydrocephalus.
Dandy walker malformation
Failure of the cerebellar vermis to develop.
Massively dilated 4th ventricle with absent cerebellum.
Forms a large cyst that can obstruct CSF flow.
Enlarged posterior fossa, dysplasias of brainstem nuclei, non-patent 4th ventricular foramen.
Only issue is loss of olfactor nerves.
Forebrain anomaly (prosencephalon = forebrain)
Least --> most severe:
Lobar: Hemisphere division, lobe formation, but midline fusion.
Semi-lobar: Pseudodivision of hemispheres, no lobes.
Alobar: No hemispheres or lobe formation.
Underlying brain defect mirrors midline facial defects (cleft lip, cyclopia, proboscis)
Posterior fossa is usually normal
Normal neuronal migration
Cells of the cortex originate in periventricular zone and migrate outward.
Starts at 7 weeks.
Migrate out in successive waves --> cortical layering.
Travel along radial glia that extend from ventricle to surface.
Agyria of the brain.
Normal up to 22 weeks.
cortex is usually less than 4 layers.
Many pseudogyri with false sulci.
Usually 4 layers or less of cortex.
Can be global or focal.
Usually 4 layers or less.
Grey matter heterotopia
Periventricular gray matter that has matured in place (around the ventricle) instead of migrating.
Often a source of seizures.
Destructive lesion of the brain usually 2/2 a vascular problem.
Focal, may be bilateral.
secondary defect in hemispheres that communicate with subarachnoid space, ventricle, or both.
More exensive destructive lesion than proencephaly.
Effects most of the cerebrum, but inferior temporal lobe and occipital lobe may be spared.
Kink in positioning in utero occludes ACA and MCA bilaterally with complete loss of most of cortex.
Brainstem is intact, so they still have suckling reflex and cardiopulm functions.
Die of things like pneumonia.
Agenesis of corpus callosum
Total loss --> batwing appearance of imaging.
Can be partial if something disrupts growth (forms anterior --> posterior)
Germinal matrix hemorrhage
Hemorrhage of the vessels serving the periventricular/germinal matrix where cortex normally originates.
These vessels have peculiar right-angle branches that are prone to shear injury.
Blood dumps into the ventricular system and may end up subarachnoid.
More likely to occur in premature infants.
Premature infants have had less neuronal migration = more cells in periventricular area = more blood flow.
These vessels are very leaky and prone to damage.
Graded 1-4 clinically.
Spinal cord malformations
Dilated central canal of the spinal cord = hydromyelia.
Sx = loss of pain and temperature in upper extremities (loss of anterior white commissure).
Retention of position sense (dorsal columns) and motor abilities (anterior horn).
Syringomyelia = syrinx extends farther into the spinal cord.
Associated with type I chiari malformation.
Hypoxic/ischemic damage to developing brain
In premature infants, the cortex is most susceptible to hypoxia at the base of the sulcus.
Grossly = ulegyria/mushroom gyri. Loss preferentially of the base of the sulcus.
Histo = neuronal loss, gliosis worse in lower sulcus.
Bilirubin reaches the brain in infants because of less developed BBB.
Tends to collect in basal ganglia, thalamus, cerebellum, HC, brainstem nuclei --> yellow deposits.
Sx = dystonia, rigidity, bilateral deafness, upward gaze palsy.
3rd leading cause of death.
50% are severely disabled, 10% return to normal activity.
Abrupt onset of focal or global neurological symptoms caused by ischemia or hemorrhage lasting >24 hours.
Non-specific clinical term encompassing many pathologies.
Arterial supply of brain
Brain = 2.5% of body weight, but 15% of arterial supply.
Internal carotids supply above tentorium.
Vertebro-basilar system supplies below tentorium.
Temporal evolution of bland infarcts 2/2 thrombus or plaque
Acutely (1 day - 1 week): Area is soft, edematous, blurring between gray and white matter.
Subacute (1 week - 1 month): Obvious tissue destruction with liquefactive necrosis beginning.
Chronic (>1month): cavitation with surrounding gliosis.
Pathologic changes with acute infarct
1 day - 1 week.
Grossly discolored with minimal edema.
Neurons become eosinophilic from 0-48 hours (response to hypoxia).
Breakdown of blood brain barrier allows PMNs to enter and some edema occurs.
Pathologic changes with subacute infarct
1 week - 1 month.
The subacute period is the most critical time clinically. Time with most edema.
Breakdown of BBB allows more fluid to enter.
1-2 weeks out, neovascularization occurs --> leaky vessels --> contributes to edema.
Hematogenously-derived macrophage enter.
Pathologic changes with chronic infarct
Edema is largely resolved.
Macrophage remove dead brain leaving a cavity behind.
Cavity is surrounded by gliosis, but NO collagenous scar.
Start off as a bland ischemic infarct with thrombus occluding a major artery.
The thrombolytic system dissolves the clot, but the arterial walls distal to the clot have died. The high pressure arterial blood entering the area causes the vessels to rupture --> hemorrhage.
Microscopically, looks the same as a bland infarct except erythrocytes are now present.
Clinically, these are worse because the added component of blood in the area worsens the adema. More prone to herniation.
Major watershed infarcts
Watershed areas = regions where arterial supplies overlap at their distal ends.
Infarcts occur with GLOBAL drop in BP for long periods of time (ie, cardiac arrest).
When BP drops, arterial blood isn't forced into the distal arts of the arterial tree and watershed areas are under-perfused.
Minor watershed infarcts
Watershed areas are found at the base of cortical gyri.
Caused by same causes as major watershed infarcts.
Can result in ulegyria with "mushroom" gyri.
Can cause seizures.
Neurons that are particularly susceptible to hypoxia
Sommer sector of the hippocampus (results in hippocampal sclerosis and epilepsy).
Purkinje cells of cerebellum --> ataxia.
Cortical neurons in laminae III and V --> laminar necrosis.
Venous cerebral infarcts
Less common than arterial.
Occur when large thrombi form in major sinuses of the brain.
Arterial blood can't move because of back pressure.
Blood piles up in the WATERSHED regions.
Microscopically, looks the same as hemorrhagic infarct.
VENOUS in origin and evolve over days to weeks.
Occur with tearing of veins moving from brain to dural sinuses.
People with atrophy are more prone because brain can move more.
Common history is a fall striking their head days or weeks earlier. Slow bleed occurs. May increase intracranial pressure --> herniation.
Herniation pushes on CN3 and causes duret hemorrhage.
Typically arterial in origin, so evolve more quickly than subdural.
Arachnoid is adhered to the brain, so blood is trapped along the surface of the brain.
Arachnoid space is entirely open, so blood can spread long distances.
Most common cause = ruptured Berry aneurysm.
Sx = stiff neck (chemical meningitis), elevated BP, blood LP, lethargy, drowsiness. Can herniate.
Most common cause of subarachnoid hemorrhage.
Risk factors = HTN, genetic dz's affecting vessel wall strengths.
Blood breakdown products are toxic leading to vasospasms and new infarcts. These infarcts often become foci for seizures.
Irritaiton --> fibrosis of meninges trapping cranial nerves --> CN palsies.
Typically occur in the areas of the circle of willis supplying supratentorial brain.
They occur at branch points because there is a natural gap in tunica muscularis at this point.
HTN's affects on brain vasculature
HTN --> hyaline arteriosclerosis of the small vessels, particularly lenticulostriate vessels serving basal ganglia.
Arteriosclerosis can cause small/lacunar infarcts from ischemia with cystic change (clinically silent).
Arteriosclerosis can also weaken the walls of these small arteries --> Charcot-Bouchard aneurysms that can burst into parenchyma. These are arterial --> rapid death.
80% in basal ganglia. 10% in pons, 10% elsewhere.
Vascular malformations of brain
Arteriovenous malformations are common.
Arteries connect directly to veins without intervening arterioles or capillaries.
Arterioles are important in dampening down the pressure, so no blood flow through them --> increased pressure entering vessels with venous mural structure.
Prone to bleed due to high pressure.
Because of lack of capillaries, parenchyma isn't perfused --> death and atrophy of tissue.
Mechanisms of how microorganisms enter the CNS
1) Entry through defects in protective barriers (skull, dura, BBB).
2) Contiguous spread from infections close to the brain (otitis media --> abscess through bone).
3) Hematogenous spread. Attack BBB.
4) Pirating of retrograde axonal transport mechanisms (rabies)
5) Hiding inside a cell destined to enter CNS (HIV enters monocytes)
Inflammation of pia and arachnoid with spread through CSF in subarachnoid space.
What is generally meant by "meningitis"
May be caused by virus (acute and self-limiting), pyogenic bacteria (rapid), mycobacteria and fungi (subacute and slower growing).
Gross appearance of acute pyogenic meningitis
Pus settles in dependent areas such as depths of sulci and base of brain.
Because the infection is present in the CSF in the subarachnoid space, it can move into the ventricles and choroid plexus causing pus there.
Microscopic appearance and lab values of acute bacterial meningitis
CSF contains large numbers of PMN's (there shouldn't be any. The only WBCs should be microglia).
LP shows increased pressure (edema), increased PMNs, low glucose (increased brain utilization and bacterial utilization), increased protein (breakdown of BBB).
*When looking at protein and glucose, you must test the blood levels. CSF is an ultrafiltrate of blood, so problems systemically will reflect in the CSF.
Long-term sequelae following bacterial meningitis
While the brain doesn't usually undergo fibrosis, the leptomeninges can. The inflammation is very irritating.
1) Pus along sulci, in ventricles can cause fibrosis of arachnoid granulations (--> communicating hydrocephalus) or along ventricular pathway (--> noncommunicating hydrocephalus).
2) Pus accumulates along base of the brain --> encases cranial nerves and circle of willis. Tend to develop nerve deafness, vascular compromise --> strokes.
3) Strokes can --> seizure foci.
Subacute meningitis 2/2 slower growing.
Tends to accumulate in basal leptomeninges (gravity).
Granulomatous inflammation, acid-fast bacilli visible within giant cells.
Sequelae similar to acute bacterial meningitis.
Common in immunocompromised/HIV.
Doesn't cause typical pus. "Glazed donut" meninges.
Tends to travel along the arteries branching from MCA traveling to basal ganglia. Produces "soap bubbles." Mucicarmine stain within these soap bubbles --> organisms.
Tend to have less inflammation 2/2 immunocompromised state of patient.
Develop over time via process that begins with cerebritis.
Early abscesses have poorly formed, weak walls. With pressure from pus, the wall can rupture --> daughter abscesses.
Rupture of abscess into ventricles or subarachnoid space can kill the patient.
*This is one exception where you can get fibrosis within the brain parenchyma. Fibroblasts migrate from leptomeninges.
Structure of mature cerebral abscess
Center of liquefactive necrosis/acute inflammation.
Next layer is a wall of granulation tissue with fibroblasts, capillaries, lymphoplasmocytic infiltrate, and fibrosis.
Outer layer = reactive gliosis.
Focal process with localized suppurative destruction of brain tissue.
Typically forms from bacteria or fungi through hematogenous spread > otitis media.
Septic emboli of fungi/bacteria --> vasculature of brain --> bacteria break down vessel walls of arterioles --> edema.
Large numbers of PMNs in the brain parenchyma with dulling of gray-white junction.
With time, inflammation changes to lymphocytes and macrophages with neovascularization and worsening edema.
Cortical abscess caused by candida
Seeds gray matter (unusual as most seed gray-white junction).
Most commonly in patients with burn wounds.
Cortical abscesses caused by aspergillus
The large fungus lodges in mid-sized arteries.
Invades through artery walls --> infarct (infarct meets infection).
Most often in transplant patients.
Cortical abscesses caused by mucormycosis
Fungal infection commonly seen in diabetics.
Invades through cribriform plate of nose --> undersurface of frontal lobe of brain.
Produces localized abscesses.
Localized or diffuse inflammation of brain and overlying leptomeninges.
Acute viral encephalitis, acute postinfection encephalitis, subacute
Pathology of acute viral encephalitis
Most common cause of encephalitis.
Perivascular lymphatic cuff around vessels.
Dying neurons undergo neuronophagia by activated microglia.
Encountered in patients without obvious immunosuppression.
Mixed acute-chronic inflammatory reaction.
Involves underside of temporal lobe, usually --> patchy contrast enhancement.
Can have eosinophilic nuclear inclusions, but only EARLY.
Normal histology of white matter
Relatively low cellularity.
Contains axons, oligodendrocytes, non-reactive astrocytes, unactivated microglia.
Does NOT contain:
Neuron cell bodies, lymphocytes, activated macrophage, reactive astrocytes (gliosis)
Histology of biopsy of MS lesion
Well-demarcated lesion of white matter.
Perivascular lymphocytes and activated macrophage, gliosis.
Demyelination starts with activation of microglia which breakdown the BBB. Breakdown allows for CIRCULATING lymphocytes and macrophage to enter --> perivascular distribution.
Mixed infiltrate of T and B cells, macrophage.
OLIGOCLONAL bands of B-cells (differentiates from CNS lymphoma)
LFB-PAS stain shows loss of myelin (demyelinating condition).
But, neurofilament stain shows that axons are still in tact.
However, some neurons are damaged by bystander inflammation. Spheroids result. Overtime, leads to progressive neurodegenerating symptoms.
Normal luxol fast blue-PAS stain
Normal CNS myelin is turquoise.
Normal PNS myelin is violet.
With demyelination, you will see loss of this color.
Demyelinating vs dysmyelinating
Demyelinating: Myelin initially developed normally and was damaged later on.
Dysmyelinating: Myelination was never normal (leukodystrophies).
MS epidemiology and course
Mean age of onset is 30yo.
Women affected more than men.
Avg life expectancy after dx = 25 years.
Characterized by relapses and remissions of neurological disturbances with gradual accumulation of residual impairment (10% have gradual, steady progression).
Plaque = grossly visible foci of demyelination.
Active/new plaques are pinkish. Paler with indistinct borders.
Chronic ones are gray, gelatinous-appearing, and firm.
Tend to be found in periventricular white matter and at the junction between cortex and white matter. Tend to spare the white matter just next to the ventricles (U-fibers)
Dawson fingers = finger-like projections from chronic plaques traveling along veins.
Tend to also involve the optic nerves/chiasm (90%) and spinal cord (ascending and descending tracts, subpial regions)
Edematous, macrophage are present, preservation of axons, perivascular mononuclear cell infiltrates, oligo loss/proliferation/remyelination.
Remyelination of MS plaques after remission
As a plaque ages, inflammation decreases, macs clear, and remyelination occurs.
Eventually, however, remyelination fails. Mechanisms:
1) Persistent T-cell and ab responses inhibit oligo precursor cell differentiation.
2) Failure of lesions to repopulate with oligos
3) Inhibition of signaling cascades that drive myelin gene expression in oligos.
4) Increased neuronal expression of N-CAM which inhibits myelin
5) Formation of dense glial scar by astrocytes
6) ECM alterations that block oligo progenitor cell migration into plaque
Imaging, potential amplitude, and conduction abilities of neurons in relapse, remission, and remyelination phase of MS plaque and in chronic lesions
Relapse: MRI --> contrast enhancement indicating large surge of inflammation. Decrease in evoked potential amplitude (this is weird because it indicates a conduction block and axon damage. May be due to cytokines reducing ion channel expression).
Remission: MRI shows loss of enhancement (inflammation is removed), delayed evoked potentials (because demyelinated) but conduction block/neuronal damage is relieved (amplitude is normal, but slowed).
Remyelination: Secure conduction is restored, some axon loss has occurred, but sufficient reserves to offset this.
Chronic lesions: Repeated lesions --> loss of neurons and no more remyelination --> permanent function loss.
Chronic-relapsing (usual form) = charcot form.
Acute MS (Marburg dz) = monophasic that's fatal within days.
Devic's disease = acute MS that targets optic nerves and spinal cord. Often fatal.
Balo's concentric sclerosis = rapidly fatal acute MS with concentric wavelike patterns of myelin loss.
Schilder's disease = resembles acute MS but with large areas of demyelinatino.
Acute disseminated encephalomyelitis (ADEM)
Acute, monophasic demyelinative disease of kids and adults.
Develops 2-12 days after MMR infection or immunization for rabies or smallpox (this is why regular rabies vaccines aren't given)
Fever, HA, meningeal signs, decreased LOC, seizures, ataxia.
Recovery is usually complete and starts within 7 days.
Sleeve-like perivascular demyelination around small veins.
Acute hemorrhagic leukoencephalitis
Perivenous demyelination. Hyerpacute form of ADEM.
Typically fatal within 1-5 days.
Affects small veins which rupture --> petechial hemorrhages and marked edema.
Affected veins are necrotic and cuffed by reactive macrophage mixed with neutrophils.
Progressive multifocal leukoencephalopathy
Complication of an underlying disease process (immunocompromised).
Short (3-12mo) course of visual, motor, sensory, and personality changes that culminate in dementia and death.
Microscopically: Large numbers of macs with few lymphocytes. Bizarre oligodendrocytes with enlarged "plum-colored" nuclei packed with JC virus.
Subacute sclerosing panencephalitis
Occurs in some children with a history of early measles exposure.
Oligo's are infected with a defective virus --> extensive demyelination and death.
Pathology: Demyelination with gliosis, perivascular and parenchymal inflammation with prominent intranuclear viral inclusions.
Vacuolar myelopathy with HIV infection
Symmetrical sensory disturbance of feet that progresses to clumsiness and ataxia within weeks.
Multifocal, vacuolated and demyelinated lesions in posterior and lateral columns of spinal cord (brain is spared)
Variety of genetic dysmyelinating diseases.
Variable age of onset and rate of progression.
Result in diffuse dysfunction --> vegetative state.
Pathology: Gross demyelination in large confluent areas of hemispheres.
Loss of oligos and myelin with preservation of axons.
Often inclusions or cellular accumulations of specific materials specific for the specific defect.
Adrenoleukodystrophy (Schilder's disease)
X-linked mutation in ABCD1 transport protein.
Gets very long chain fatty acids into peroxisomes.
Without the transporter, build up in places like brain, leydig cells of testis, adrenal cortex.
In brain: Loss of myelin in occipital, parietal, and temporal lobes with sparing of frontal cortex.
Types of connective tissue
Classified by cells and fibers present in the tissue and the nature of the ground substance.
Dense CT (Tendons and ligaments)
Specialized CT (blood, bone, cartilage)
Extracellular matrix between the cellular components of connective tissues (collagen, fibrillin)
Major component of skin and other connective tissue.
Most abundant protein in the body.
Assembled as trimers in the golgi from pro-collagen made in the ER.
Each type of collagen has its own component alpha chain
Defect in type I collagen.
Type II osteogenesis imperfecta
Perinatal lethal type.
Severe short stature, bent limbs, untrauterine fractures, crumpled femurs, minimal calvarial ossification, blue sclera.
Skull is large for body size and soft to palpation.
Hips are flexed and abducted.
Some die in utero. 80% of others die within first few weeks usually from pulmonary insufficiency
Type IV osteogenesis imperfecta
Mild osteoporosis, normal sclera, abnormal dental enamel, short stature, hearing loss.
Type I osteogenesis imperfecta
Most common (90%).
AD, most cases inherited.
Osteopenia, bone fragility, recurring fractures with minimal trauma.
Wormian bones: Small islands of bone in the fontanels and sutures of skull of infants.
At risk for subdural hemorrhage and skull fractures.
Mild short stature.
Hearing loss (conductive from bone sclerosis).
Normal cognitive function.
Classic Ehlers Danlos Syndrome
Type 1 (Severe) or type 2 (mild).
Involves skin, joints, and cardiac valves.
Hyperelastic, velvety skin with "cigarette paper" scars and easy bruising.
Type III Ehlers Danlos syndrome
Joint hypermobility type.
Joint pain, mitral valve prolapse, easy bruising.
No good diagnostic criteria (joint hypermobility can be found in normal people). No gene identified, so this is over-diagnosed.
type IV Ehlers Danlos syndrome
Veins are visible under the skin, abnormal face, risk of rupture of large vessels and viscera.
Mutation in fibrillin gene (FBN1)
No specific ethnic or racial group or gender preference.
75% have affected parent. 25% new mutations (autosomal dominant).
Clinical phenotype = CV, ocular, skeletal, skin, lung, dura manifestations.
Criteria for dx of Marfans with a negative family history
1) Aortic root dilation + ectopia lentis
2) Aortic root dilatation + FBN1 mutation
3) Aortic root dilatation + systemic score > 7
4) Ectopia lentis + FBN1 mutation known to cause aortic root dilatation
Criteria for dx of Marfan's with a positive family history
1) Ectopia lentis
2) Systemic score > 7
3) Aortic root dilatation
Non-marfan phenotypes associated with FBN1 mutation
1) Mitral valve prolapse with skeletal features
2) MASS phenotype: Myopia, mitral valve prolapse, aortic enlargement (non-progressive), skin and skeletal features
3) Aortic aneurysm with other non-diagnostic features
4) predominant or isolated skeletal features
5) Familial ectopia lentis
Limitations of genetic testing
Locus heterogeneity may limit usefulness of test.
Sensitivity of each test must be known.
Specificity is not usually a problem.
Choice of testing method varies according to the gene being tested and types of mutation
Molecular genetic dx of osteogenesis imperfecta
COL1A1 and COL1A2 genes are associated with types I, II, III, and IV.
Type 1 = 100%. Type 2 = 98%. Type II and IV = 70-80%.
Used in cases of suspected child abuse.
Prenatal and pre-implantation dx
Molecular genetic dx of ehlers danlos syndrome
Each of the 4 types is associated with a different gene, so establishing a clinical dx before testing is important.
For type I and II, only 50% sensitive.
COL5A1 and COL 5A2
No genotype to phenotype correlation.
Type IV (vascular type):
AD, COL3A1 gene.
Identified in 98-99% of patients.
Dx based entirely on clinical findings.
Molecular genetic dx Marfan syndrome
Sn: Sequence analysis finds mutation in 70-93% of patients who meet clinical criteria.
No genotype-phenotype correlation.
Memory impairment + cognitive dysfunction.
Results from loss of cortical gray matter.
Idiopathic (AD, Pick's dz, Lewy body dementia).
Focal neurologic (vascular, MS, mass lesions, infections, toxins, inherited dz).
Most common cause of dementia.
Usually starts after 50yo.
Slow onset memory loss, disorientation, behavior changes.
Become mute and bedridden and usually die of infection.
Grossly, global cortical degeneration --> generalized atrophy, expanded ventricles (hydrocephalus ex-vacuo)
Amyloid precursor protein
APP = a neuronal receptor with no known function.
It normally is degraded by alpha cleavage which can be degraded.
If it undergoes beta cleavage, it forms Abeta amyloid --> plaques seen in Alz dz.
Encoded on chr 21, so Down's people usually have early onset Alz with excess Abeta production.
Found in alzheimer's plaques and deposits in the vessel walls. Can --> ischemia.
Neurofibrillary tangles in Alzheimer's
Intracellular neuronal inclusions.
Composed of hyperphosphorylated agregates of tau protein.
Tau normally helps to organize microtubules. When hyperphosphorylated, it can't do this, so the microtubules get tangled and aggregate in neurons.
Plaques in alzheimer's
Plaque has misfolded Abeta amyloid in the center surrounded by broken neuritic processes.
Second most common cause of dementia.
Due to ischemia and multiple infarcts.
Laminar necrosis and HC disease (layers 3 and 5 of cortex and Sommer sector of HC are most susceptible to hypoxia)
RF's = HTN, DM, atherosclerosis, vasculitis.
Fronto-temporal dementia. Parietal and occipital lobes are spared.
Predominately presents with behavioral problems, aphasia, memory loss.
Will see pick bodies in neurons and pick cell (enlarged neurons) within the cortex of frontal and temporal lobes.
Inclusions are aggregates of abnormal tau.
Histology of parkinson's disease
Lewy bodies, inclusions of alpha-synuclein, in the basal ganglia.
Aggregate within the pigmented neurons.
Parkinson's disease dementia vs Lewy body dementia
With normal parkinson's disease, you can see dementia very late in the course with cortical lewy bodies becoming present.
With Lewy body dementia, you get cortical lewy bodies and dementia very early in the presentation with the associated movement disorders of PD.
Progressive supranuclear palsy
Variant of parkinson's disease.
Instead of lewy bodies in the SN, you get tangles instead.
Feature = diplopia with gaze paralysis
Diffuse lewy body disease
Dementia and movement disorder.
Lewy bodies in substantia nigra and cortex.
Distinguished from late-stage parkinson's (which also has lewy bodies in cortex and SN) by the timing.
This will have cortical lewy bodies and dementia much earlier in the disease presentation than PD.
Cause = CAG repeats on Chr 4. AD inheritance with anticipation and earlier onset in subsequent generations.
Caudate > putamen are mostly affected with loss of myelin and neurons in these areas, gliosis.
Muscle fibers with denervation in adults vs kids
Adult form = ALS.
Child form = spinal muscular atrophy.
Adults: Get grouped atrophy where you lose groups of muscles while others are maintained.
Children get rare, very large fibers with many small muscle fibers intermingled.
Acute B1 deficiency.
Not seen much anymore because when people come in to the ER drunk, the IV contains vitamins.
Nystagmus, confusion, ocular palsy, ataxia, coma.
Hemorrhage, gliosis in mammilary bodies, floor of 3rd and 4th ventricles.
Long-term Wernicke's/hemorrhages leads to atrophy in affected places (mamillary bodies, floor of 3rd and 4th ventricles).
Loss of neurons and gliosis.
Confabulation (making up answers to questions).
Retrograde and anterograde amnesia.
Shrinkage with myelin loss.
Long-term, leads to anterior vermian degeneration with truncal ataxia,
Loss of PURKINJE cells
Osmotic demyelination syndrome
Seen with rapid correction of hyponatremia.
Demyelination in the center of the pons.
Leads to corticospinal and corticobulbar loss --> motor dysfunction.
Causes tetraplegia and bulbar paralysis.
Causes "locked in syndrome"
Subacute combined degeneration
Over months to years, causes demyelination of CST and posterior columns.
End up with paresthesia/anesthesia, ataxia, spasticity, weakness, and areflexia.
Diabetic hypoglycemia affects on the CNS
Similar distribution as hypoxia except with sparing of the purkinje cells of the cerebellum.
Affects all of the superficial cortex, hippocampus.
Not brainstem or brainstem.
Acutely, "red neurons" like hypoxia.
Chronically, laminar necrosis with gliosis.
Seen with liver failure --> fluid and electrolyte balance issues.
Alzheimer type II cells, demyelination.
Astrocytes have fluid collections and can no longer support neuronal function.
Seen in kids who have viral infections and take aspirin.
Fatty liver and swollen brain.
Autosomal recessive mutation on chromosome 13.
Can't make the copper transporter (ceruplasmin).
Copper deposits in the liver (cirrhosis), cornea (Kayser-Fleischer ring), basal ganglia.
Similar symptoms as Hungtington's but with earlier age of presentation.
Affects of arsenic on the CNS
Inorganic arsenic = affects the PNS.
Organic = acute hemorrhagic leukoencephalopathy with hemorrhages only in the white matter.
Mercury poisoning effects on the CNS
Inorganic = Peripheral neuropathy.
Organic = muscle weakness, ataxia, tunnel vision, slurred speech, hearing loss, sudden fits of laughter.
Loss of GRANULE cells of the cerebellum (specific).
Causes encephalopathy and peripheral neuropathy.
In children, causes mental retardation, cerebral edema, microcytic anemia.
In adults, causes microcytic anemia, peripheral neuropathy, gingival lead line, lead colic (abdominal pain)
Methanol effects on the CNS
Hemorrhagic leukoencephalopathy with putamen necrosis, retinal and optic nerve damage.
Carbon monoxide poisoning and the CNS
Changes in the globus pallidus with cherry red spots.
If they survive, GP will cavitate.
Demyelination of white matter.
Affects of radiation on the CNS
Coagulative necrosis, edema, fibrosis, vascular wall thickening, secondary tumors.
Signs of basilar skull fracture
Blood in ear.
Orbital or mastoid hematoma (raccoon eyes).
Typically follows impact to back or sides of head.
Arterial bleeding between the dura and skull, usually middle meningeal artery.
Get biconvex shape because of dural attachment to skull.
Usually occurs in younger males.
Arterial, so very fast onset. May have lucid interval.
Compresses gyri and displaces brain.
Crosses dural attachments, but not suture lines.
Tearing of bridging VEINS traveling from brain to dural sinuses.
Between dura and arachnoid.
Venous, so slower accumulation of blood.
Occurs more often in older people who have atrophied brains with more tension on veins.
Crosses sutures, but not dural attachments.
No flattening of gyri on affected side
Childhood nonaccidental trauma
Bilateral subdural hematomas. May be of different ages.
bilateral retinal hemorrhages.
Chronic traumatic encephalopathy
Repeated episodes of trauma such as in contact sports.
May have transient symptoms early on.
Get intraneuronal tau inclusions like in Alz.
Damage from boxing.
Atrophy with hydrocephalus ex vacuo.
Separation of leaflets of septum pellucidum.
Tangles like in Alz.
Diffuse axonal injury
Caused by sudden angular deceleration/acceleration leading to stretching and shearing of nerve cell processes in white matter.
Most commonly involves the corpus callosum, periventricular areas, or brainstem.
Can cause PVS or post-trauma dementia.
Can get bleeding from shearing of white matter vessels.
Get spheroids/areas of axonal swelling in the broken end of the axons.
Essentially bruises within the brain.
Most often inferior frontal and anterior temporal lobes.
End up with superficial punctate or lateral hemorrhages along gyral crests (only on the top. no deeper injury)
Can cause subarachnoid hemorrhage with tearing of bridging veins.
Acute vs subacute vs remote brain contusions
Subacute: Soft full of macrophages cleaning up.
Remove: Cyst formation, gliosis, hemosiderin-laden macrophages. Olf contusions have depressed, brown, firm edges and may adhere to dura.
Coup vs contre coup vs gliding contusions
Gliding contusions: The area of the brain near the falx cerebri is firmly adhered. This can lead to shearing injury to the subcortical tissue nearby
Coup = immobile head with blunt force. Worse contusion under the point of impact.
Contre coup = moving head, immobile surface. Severest opposite impact
Types of missile injury to the brain
Depressed = causes skull fracture without entering cranial cavity.
Penetrating = enters but doesn't exit.
Perforating = through and through.
Indications for nerve biopsy
Vasculitis (also get a muscle biopsy).
Confirm inflammatory process
Diabetic with atypical presentation
Dx with hereditary neuropathy
Usually diagnose the sural nerve (will have minimal deficit, will eventually regrow).
Histology of diabetic neuropathy
Loss of neurons 2/2 vascular insufficiency.
Thickening of vessel wall with collagen deposition --> loss of neurons.
Rapidly progressive, ascending, motor deficity (no sensory loss). Loss of myelin.
CSF shows increased protein, but no cells.
Etiology = probably autoimmune after a viral infection.
Tx: Supportive care, IVIg
Hereditary motor and sensory neuropathies
Tendency to demyelinate and remyelinate --> more schwann cells wrapped around.
On physical exam, you can feel their nerves.
Response of nerve to injury
In the periphery, the nerves can regenerate.
Wallerian degeneration = nerve is cut or crushed.
Nerve dies and degrades back to the most proximal node that is intact.
The nerve then regrows through sprouting.
Schwann cells remyelinate the axon.
Type I vs Type II fibers
Type I = slow twitch. More NADH/mitochondria for oxidative capacity.
Type II = fast twitch. Stain with ATPase stain (more ATP).
Normal muscles contain a mixture of these intermingled.
Neurogenic muscle atrophy stages
Starts with a mosaic of Type I and type II fibers.
Nerve loss --> angular atrophy of the fibers innervated by that nerve. Fibers become compressed.
Reinnervation can occur from the next nerve over. It is the nerve that determines the fiber type, so you then get type grouping with too many of one type grouped together.
Loss of the nerve supplying the whole group --> grouped atrophy. The groups progressively get larger leading to muscle atrophy.
May also see central nuclei instead of subsarcolemmal.
Neuromuscular junction disorder.
Don't need a muscle bx to diagnose.
Small muscles tire easily. Often get weakness with repetition of movement.
Thymus is often abnormal with hyperplasia.
Can test for AchR antibodies.
EMG can be characteristic.
Histological changes seen with myopathy
Phagocytosis with macrophage infiltration
Atrophy --> ROUND (not angular)
Inflammation with motheaten changes (motheaten indicates inflammation used to be present).
Examples of myopathies: Inflammatory myopathies, dystrophies, congenital myopathies, metabolic myopathies.
Signs of muscle regeneration
Can happen with myopathies.
Nuclei migrate in from the edges of the fibres.
They will have a bluer cytoplasm than normal because they increase their amount of RNA to make new proteins and replace to myofibrils that were lost.
Polymyositis and dermatomyositis = proximal muscle weakness, inflammatory infiltrate.
Dermatomyositis will have heliotrope rash, periFASCICULAR inflammation.
Inclusion body myositis
Type of inflammatory myositis.
Presents with distal weakness.
Will have rimmed vacuoles within the muscle fibers.
Little inflammation, doesn't respond to steroids.
Histology of muscular dystrophies
Fibrosis, phagocytosis, atrophy, hypertrophy, dense fibers.
Scraping of superficial layers of epidermis or destruction of superficial layers by compression.
Bruises that result from hemorrhage into soft tissue due to rupture of vessels caused by blunt trauma.
Tissue tears caused by blunt trauma which causes the skin to split open.
Tend to have abraded or contused margins.
Tissue bridging across the wound because of greater tensile strengths of the blood vessels and nerves.
Produced by sharp edged weapons.
Wound whose length is greater than its depth.
No tissue bridging because sharp edge cuts the vessels and nerves.
Depth into the body exceeds the length on the skin.
No tissue bridging because sharp edge cuts the vessels and nerves.
Produced by heavy instruments with a cutting edge like axes, machetes, meat cleavers, and propellers.
Combination of cutting and blunt force trauma.
Aortic tear in a MVC
Tends to tear right after the aortic arch near the ligamentum arteriosum.
The ligamentum holds the aorta in place, so it tends to tear right after it in the area thats more mobile.
Ways that you can tell where a victim was sitting in a car accident
Look at the direction of the seatbelt injury.
Look for dicing injuries/angulated cuts from shattering of tempered glass on the side windows. The side of the face can help determine where they were sitting.
Fracture on the lower legs that indicates that a pedestrian was walking on the road when they were hit.
Can be at different heights on the legs because of gait.
With getting hit by a car, more likely to die from head trauma (not aortic tear)
Difference between adults and kids who get hit by cars
Adults tend to be hit below the center of gravity, so they fly OVER the car.
Kids are hit above center of gravity so they get run over.
Common cause of death in these injuries = separation of the atlanto-occipital joint.
Partial vs full thickness burn
Partial thickness only gets the epidermis and superficial dermis.
Very painful because nerves are intact. Forms blisters.
Full thickness has loss of epidermis and dermis including the dermal appendages. Tends to be white/charred and anesthetic because of nerve damage.
Inhalation injury following a fire
May not be seen for 24-48 hours.
Direct effect of heat or toxic component.
Water-soluble toxic gases cause upper airway damage.
lipid soluble cause deeper airway damage.
Secondary burn infections
Most common = pseudomonas aeruginosa.
Burn sepsis with organ failure is the leading cause of death in burn patients.
Heat cramps vs heat exhaustion vs heat stroke
Heat cramps caused by loss of electrolytes from sweating.
Heat exhaustion = sudden onset prostration, collapse from hypovolemia due to water depletion.
For heat cramps and exhaustion, you maintain thermoregulatory mechanisms.
Heat stroke = you STOP sweating causing a rapid increase in body temp. With temps over 106F, 50% mortality. Mechanism = peripheral vasodilation, pooling of blood, muscle necrosis, arrhythmias, DIC.
Findings of an electrical burn
Crater at the center, white rim around that, then red rim on the outside.
Burns are more common with high voltage currents. Usually cause medullary center paralysis, V.fib.
Low voltage currents may not produce current, but may cause V. fib, tetanic muscle spasms (preventing you from letting go), or paralysis of respiratory muscles
Blood smear findings of lead poisoning
Microcytic, hypochromic, hemolytic anemia.
Basophilic stippling (denatured RNA).
Lead has a high affinity for sulfhydryl groups impairing heme synthesis. Inhibits ALA dehydratase and ferrochelatase. End up with Zn protoprophyrin instead, thus hypochromic.
Lead also interfers with the Na/K ATPase which results in fragility and lysis.
Effects of lead poisoning
CNS = encephalopathy, mental deterioration, often irreversible (kids have more permeable BBB).
Blood = anemia, basophilic stippling.
Kidney = chronic tubulointerstitial dz.
GI Tract = abdominal pain. Kids absorb more from the GI tract.
CNS = headache, memory loss.
Blood = same.
Peripheral nerves = demyelination with wrist or foot drop.
Kidney and GI tract = same.
Can get lead lines on bones and teeth.
Acceptable lead levels
Current amount allowable is 5micrograms/L.
Removed lead from pain in 1978 and from gas in 1986.
Can still be found in soil.
0.9% have levels that exceed those allowable.
Cause of lead lines on bones
Lead interferes with normal remodeling of calcified cartilage and bony trabeculae in the epiphysis.
Leads to increased bone density at the epiphysis.
NOT actual lead deposits.
Carbon monoxide poisoning
Hemoglobin has a 200x higher affinity for CO vs oxygen.
Hypoxia occurs at 20-30% saturation, Death at over 50%.
Causes cherry red color to occur at the skin and mucus membranes, cherry red lividity.
Chronic CO poisoning --> hypoxic changes in the basal ganglia with cavitation.
Overdose causes N/V/D, liver failure, jaundice.
15-25g needed for toxicity (normal dose = 0.5g).
5% is metabolized by P450s to NAPQI which depletes GSH.
Antidote = N-acetylcysteine which is the precursor for GSH.
Excessive drinking can induce the P450s that break down acetaminophen --> more conversion to NAPQI and more toxicity (CYP2E1).
Can lead to metabolic acidosis, opposes GNG (hypoglycemia), inhibits fatty acid oxidation --> fatty liver.
Boerhaave syndrome, Mallory Weiss tear
Boerhaave syndrome = through and through tear of esophagus.
Mallory weiss tear = not all the way through.
These are associated with forceful vomiting (not specific for, but often associated with alcohol)
FX of NATURAL estrogens used for HRT on breast and endometrial cancer risk, thromboembolism, CV dz
CV dz risk = no change (even though it increases HDL and decreases LDL).
Endometrial carcinoma = increased risk, but no increased risk if you add progesterone.
Breast cancer = increased risk if you add progesterone.
Thromboembolism = increased risk.
Fx of OCPs (synthetic E + P) on breast, endometrial, ovarian, and cervical cancer, thromboembolism, CV dz, and hepatic adenoma
Breast cancer = no increased risk (controversial).
Endometrial cancer = protective.
Thromboembolism = increased risk.
Ovarian cancer = protective.
Cervical cancer = increased risk in those with HPV.
CV dz = no increased risk if less than 30, but increased risk in those over 35, especially who smoke.
Hepatic adenoma = increased risk.
Toxicity occurs with 2-4g in kids or 10-30g in adults.
Respiratory alkalosis with metabolic acidosis
Death occurs from dose-related pulmonary edema.
Chronic IV use --> talc deposits in the interstitium of the lung (used to cut the heroin).
Stimulates the Mu receptor.
Can occur with aspirin + acetaminophen.
End up with tubulointerstitial nephritis with renal papillary necrosis.
Renal findings in heroin/IVDA
Chronic skin infections --> amyloidosis which can affect the kidneys.
Heroin users are susceptible to focal segmental glomerular sclerosis.
Both --> nephrotic syndrome.
Blocks reuptake of NE/Epi and stimulates the release of more of it.
Leads to tachycardia, arrhythmias, HTN, MI, peripheral vasoconstriction, cerebral hemorrhage, infarct, or rhabdomyolysis (2/2 ischemia from vasoconstriction).
These are not necessarily dose-dependent.
Physiological fx of marijuana use
Reduces intraocular pressure (glaucoma).
Treats nausea associated with chemo.
CNS: Distorts sensory perceptions and impairs motor coordination for 4-5 hours.
Pulmonary complications: laryngitis, pharyngitis, bronchitis. Inhale 3x more tar.
CV: Increased HR.
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