Pathoma Ch 4,5, 16, 17 (Hemostasis, RBC, Breast, CNS) Flashcards
4. Hemostasis and Related D/o 5. RBC D/o 16. Breast 17. CNS
Distinguish primary and secondary hemostasis
Primary hemostasis = formation of weak plt plug
-involves plt, fibrin
Secondary hemostasis = use of coagulation cascade to stabilize plt plug
First thing to happen after BV wall damage
(a) 2 mediators
BV wall damage => Immediate reflexive vasoconstriction
a) Mediated by both neural impulse and endothelin (from endothelial cells
Differentiate receptors/factors used for plt adhesion and plt aggregation
Steps of primary hemostasis (forming weak plt plug): vasoconstriction, plt adhesion, plt degranulation, finally plt aggregation
Plt aggregation = plts bind to subendothelial collagen by binding to vWF via GP1b receptor
Then plt aggregation for plts to clump together mediated by Gp3a2b receptor using fibrinogen
Name the 2 key molecules released by platelet degranulation in primary hemostasis
Plt degranulation (after adhesion, before aggregation) releases
- ADP (from plt dense granules) that promotes exposure of Gp2b3a receptors
- TXA2 (from plt COX) that stimulates plts aggregation
2 places where vWF is made/released from
- Weibel-Palade bodies of endothelial cells (main source)
- this is why ADH (that stimulates Weibel-Palade body release of vWF) is used in the tx of vWD - Alpha-granules of plts
Differentiate the types of bleeding seen in d/o of primary vs. secondary hemostasis
Primary hemostasis = formation of weak platelet plug with plts and fibrin
-d/o => mucosal and skin bleeding = epistaxis, hemoptysis, GI bleed, hematuria, petechiae, purpura
Secondary hemostasis = stabilization of plt plug via coagulation cascade
-d/o (coag factor deficiencies) => deep tissue bleeds in joints and muscles, also rebleeding after surgical procedures (classically wisdom teeth)
Differentiate ecchymoses, purpura, and petechiae
All skin (superficial) bleeds, differentiated by size
Ecchymoses = superficial bleed over 1cm
Purpura: over 3mm
Petechiae: 1-2mm (indicative of thrombocytopenia
Clinical sign that can help distinguish thrombocytopenia from poor quality of plts
Petechiae (1-2mm skin bruises) indicate thrombocytopenia (low number of plts)
-while petechiae are not seen in d/o of plt quality (usually d/o of plt receptors such as Gp1b needed for adhesion, Gp2b3a for aggregation
Bone marrow biopsy expected in ITP
Immune thrombocytopenic purpura (IgG against plts)- see megakaryocyte hyperplasia b/c megakaryocytes trying to compensate for low plts
Name 2 general categories of d/o of primary hemostasis
D/o primary hemostasis = d/o of plts
- Immune thrombocytopenic purpura (ITP) = IgG against plts
- Microangiopathic hemolytic anemia (includes HUS and TTP) = pathologic formation of plt microthrombi in small vessels 2/2 either E. Coli O157:H7 or ADAMTS13 deficiency
Differentiate acute and chronic ITP
Acute ITP seen in children s/p viral illness or vaccination, get self-limited disease
Chronic form in adults (often women of childbearing age, aka same ppl who get AI d/o)
Plt count and PT/PTT values expected in
(a) ITP
(b) HUS
(c) TTP
(a) ITP: reduced plts (2/2 presence of anti-plt IgG so plts destroyed in spleen), PT/PTT normal b/c coagulation cascade (clotting factors) are unaffected
(b) HUS and TTP = microangiopathic hemolytic anemias (meaning pathology of the small HVs that causes hemolytic anemia): reduced plt count (b/c plts used up in microthrombi) and normal PT/PTT
Explain how IVIG aids in the tx of ITP
IVIG = intravenous immunoglobulin
Basically give the spleen another immunoglublin to worry about, so it has a decreased capacity to destroy IgG marked plts
-uesd as very acute/transient therapy during symptomatic bleed
Give 2 mechanisms by which splenectomy treats ITP
ITP = IgG against antibodies
- These antibodies are produced by the spleen
- The spleen is where the plts are destroyed once they become bound to the IgGs
So splenectomy removes both the source of the Ab and the site of plt degradation
HUS vs. TTP
(a) Etiology
(b) MC organ system involved
HUS and TTP are both microangiopathic hemolytic anemias (pathology of small BVs where plt microthrombi are produced causing hemolytic anemia)
HUS = hemolytic uremic syndrome
(a) Etiology = infection w/ E. Coli 0157:H7
(b) MC involves kidney (umm hence uremic in name)
TTP = thrombotic thrombocytopenic purpura
(a) Etiology = deficiency in ADAMTS13 = enzyme needed to cleave vWF into active form => plts abnormal adhere and form microthrombi
(b) MC see CNS abnormalities (thrombi involving vessels of the CNS)
Name the activating substance of the intrinsic and extrinsic pathways of the coagulation cascade
Intrinsic pathway (12 –> 11 –> 9 –> 8 –> X) activates by tissue thromboplastic factor
Extrinsic pathway (7 –> X) activated by subendothelial collagen
Hemophilia A
(a) What is it?
(b) Etiology
(c) Lab findings
Hemophilia A
(a) X-linked recessive deficiency in factor VIII (A ‘eight’)
(b) Etiology: usually X-linked recessive but can be 2/2 de novo mutation
(c) Normal bleeding time (b/c primary hemostasis of weak plt plug is normal, normal plt count), prolonged PTT w/ normal PT
Hemophilia A vs. hemophilia B
Hemophilia A = deficiency in factor VIII
Hemophilia B = deficiency in factor IX (just one back in the cascade): affects same pathway (intrinsic pathway) => both have the same findings of
- prolonged PTT, normal PT
- normal bleeding time b/c plts unaffected
How to differentiate hemophilia A from acquired coagulation factor inhibitor
Hemophilia A = deficiency in factor VIII
Acquired (autoimmune usually) inhibition of factor VIII (ex: IgG against factor VIII)
Same clinical and lab findings (deep joint bleeds and prolonged PTT), but different mixing study
-mixing study (mix pt blood w/ normal plasma): PTT corrects in hemophilia A, PTT does NOT correct in acquired inhibitor (b/c there’s an inhibitor present…)
von Willebrand disease: Lab findings
von Willebrand disease = deficiency in vWF, factor that binds to subendothelial collagen in damaged endothelium and binds plts via receptor Gp1b
Lab findings: prolonged bleeding time (b/c plt activity is impacted), prolonged PTT b/c factor VIII needs vWF to be stable
Abnormal ristocetin test
Ristocetin induces plt agglutination by causing vWF to bind to plt Gp1b (receptor for adhesion).
In vonWillebrand disease, ristocetin won’t cause agglutination (b/c no vWF present) => abnormal test
Explain why the following populations may be deficient in vitamin K
(a) Newborns
(b) Long term abx takers
(c) Malabsorption
(a) Newborns have immature gut flora
- hence why nerborns are prophylactically given vitK injection at birth to prevent hemorrhagic disease of newborn
(b) Long term abx kills the gut flora that normal synthesize vitK
(c) Malabsorption of fat-soluble vitamins (ADEK)
Epoxide reductase function
(a) Effect of inhibition
Epoxide reductase is the liver enzyme that activates vitamin K
(a) When vitK isn’t active, factors X, IX, VII, II, protein C and S don’t get gamma carboxylated => factors aren’t active
What value is followed to monitor effect of liver failure on coagulation
Follow PT: tracks extrinsic pathway (factor VII –> X) and common pathway
- factor VII produced in the liver, so PT is pretty specific
- vs. PTT which counts on factors 12, 11, 9, and 8
What is HIT (heparin induced thrombocytopenia)?
HIT = development of anti-PF-4 (plt factor 4) in response to plt therapy
So plts get destroyed (prolonged bleeding time) and then plt fragments activate remaining plts and cause thrombosis
-so get both bleeding clotting (uhoh)
Tx for heparin induced thrombocytopenia
Tx for HIT (anti-PF4 causing both thrombocytopenia and increased thrombosis)
- Stop the heparin!
- Add an anticoagulant
- DONT use coumadin 2/2 icnreased risk of coumadin necrosis
- first line usually argatroban (direct thrombin inhibitor)
Give some causes of DIC
Disseminated intravascular coagulation: always develops 2/2 something else
- sepsis (especially E. coli or N. meningitidis)
- obstetric complications 2/2 tissue thromboplastin (activates extrinsic coagulation cascade) in amniotic fluid
- adenocarcinoma: mucin activates coagulation
- acute promyelocytic leukemia
- rattlesnake bit: venom activates coagulation
Explain the physiology of DIC and the following lab results
(a) Plt count
(b) PT/PTT
(c) fibrinogen
(d) Hb
DIC = disseminated intravascular coagulation, 2/2 pathologic activation of the coagulation cascade
-then plts consumed => bleeding from skin and mucosal surfaces
(a) Reduced plt count: b/c used up in clots
(b) PT/PTT both elevated b/c coag cascade activated so clotting factors are used up
(c) Fibrinogen decreased b/c used up in clots
(d) Hb reduced b/c intravascular microthrombi causes microangiopathic hemolytic anemia (RBC get sheared in BV as move past clot)
Best screening test for DIC
Best screening test for DIC = D-dimer
D-dimer = fibrin degradation product, so elevated means a mature clot is formed and broken down
Key: D-dimer is produced from splitting of fibrin (stable cross linked clot), NOT from splitting of fibrinogen (weak plt plug not yet undergone secondary hemostasis of coagulation cascade)
Tx for DIC
DIC- it’s not its own entity, need to address the underlying cause
-sepsis, obstetric complication, adenocarcinoma, APL, rattlestnake venom
In the meantime can give supportive care by transfusion of blood products and cryo
Oral agent for tx of vonWillebrand disease
Deficiency in vWF (causing prolonged bleeding time and prolonged PTT) can be tx w/ desmopressin (ADH analogu)
Desmopressin stimulates release of vWF from Weibel-Palade bodies of the endothelial cells
Explain how cirrhosis could disrupt fibrinolysis
Liver produced alpha2-antiplasmin (enzyme that inactivates plasmin, recall plasmin breaks up fibrin in clots)
So w/o alpha2-antitripsin, plasmin remains active breaking up clots => presents similar to DIC
Pt presenting w/ apparent DIC (oozing from IV site, very low plt and fibrinogen serum results), but D-dimer is negative
Dx?
D-dimer is the best screening test for DIC, if D-dimer not positive pt is not in DIC
D/o of fibrinolysis (ex: no aplha2-antitplasmin needed to inactivate plasmin, so plasmin jsut goes around breaking down clots) will present similar to DIC, but coag cascade is not active so no fibrin => no D-dimer
(b/c recall that D-dimer is not produced by breakdown of fibrinogen which is what the immature clots will be in d/o of fibrinolysis)
Name some of the products produced by the endothelium to protect against thrombus formation
- Endothelium blocks collagen exposure
- Produced PGI1 and NO (NO vasodilates)
- Produces tPA to break up clots locally and inactivate coag factors
- Produces heparin-like molecules that augment antithrombin III activity
- Secretes thrombomodulin which modulates thrombin activity so that thrombin activates protein C instead of converting fibrinogen –> fibrin
Thrombomodulin
(a) Secreted by what?
(b) Fxn
Thrombomodulin
(a) Secreted by vascular endothelium
(b) Fxns to change/modulate the fxn of thrombin. So instead of catalyzing fibrinogen–>fibrin (stabilizes clot), thrombin activates protein C (that inactivates factors V and VIII)
Fxn of protein C and S
Both protein C and S inactivate coagulation factors V and VIII
(V involved in common pathway, VIII involved in intrinsic pathway)
Explain why pts are kept on heparin while bridging to warfarin/coumadin therapy
Protein C/S have a shorter half life than factors 1972 => when first started on coumadin therapy there is a short stage of hypercoagulability where protein C/S are deficient but factors 1972 are still present
So keep pt on heparin for that window period where C/S are inactive and 1972 are active
Describe diagnostic finding of ATIII deficiency
Antithrombin III (inactivates thrombin and coagulation factors) increases risk for thrombosis
-especially intravascular b/c ATIII is stimulated/activated by heparin-like molecules produced by endothelium
Diagnostic finding = PTT does not rise in response to heparin
-b/c heparin work by activating ATIII
Antithrombin III
(a) Location of production
(b) Fxn
(c) Key finding of deficiency
ATIII
(a) produced in the liver
(b) Inhibits thrombin and coagulation factors
(c) PTT does not rise in response to heparin b/c heparin works by activating/binding to ATIII
Clinical features of amniotic fluid embolus in mother during labor or delivery
SOB (embolus to lungs), neurologic symptoms (embolus up to brain), DIC (b/c amniotic fluid has a lot of tissue thromboplastin that activates extrinsic pathway of coag cascade)
Based on the components of hemoglobin, name the 4 causes of microcytic anemia
Hb = heme and globin, while heme is iron and protoporphyrin
Reduced iron: (1) iron deficiency anemia (2) anemia of chronic disease
Defective protoporphyrin production (3) sideroblastic anemia
Defective or reduced globin formation (4) thalasesmia
Location of absorption of
(a) Iron
(b) Folate
(a) Iron absorbed in the duodenum by DMT1 transporters, then into blood via ferroportin
(b) Folate absorbed in the jejunum
Why is iron always transported bound to something?
Transported bound to transferrin, stored as ferritin, always bound b/c of Fenton reaction = ability to produce free radicals that cause peroxidation of membranes and oxidation of proteins/DNA
Differentiate bloodwork seen in early iron deficiency vs. uncompensated chronic iron deficiency
Early in iron deficiency anemia there is a normocytic anemia: BM makes normal RBCs just fewer of them. Storage iron gets depleted so ferritin reduces and TIBC increases
Then can no longer compensate and you get microcytic hypochromic anemia: fewer, smaller, lack central pallor
Explain the physiology of anemia of chronic disease
Chronic inflammation => chronic elevation in acute phase reactants from liver including hepcidin
Hepcidin sequesters iron away from bacteria, but also prevents us from using our iron stores => despite high ferritin there is low serum iron and low percent saturation
Name 3 causes of acquired sideroblastic anemia
MC cause is congenital mutation in ALAS (RLS of protoporphyrin synthesis) but 3 acquired causes
- vitamin B6 deficiency (cofactor required for ALAS), can see in isoniazid tx
- alcoholism (mitochondrial poison)
- Pb poisoning (lead denatures two enzymes used after ALAS in protoporphyrin synthesis)
What type of anemia has an elevated serum iron
Serum iron is elevated (above 100) in sideroblastic anemia: b/c iron accessibility isn’t the problem (as it is in iron deficiency or anemia of chrnoic disease), instead there is not enough protoporphyrin for iron to bind to make heme => elevated serum iron and elevated percent saturation
Clinical presentation of 1-4 deletions in alpha globin chain
4 alleles for alpha globin
- 1 deleted = asymptomatic
- 2 deleted = mild anemia w/ elevated RBC count, cis in Asians vs. trans in Africans
- 3 deleted = severe anemia, HbH (beta tetramers)
- 4 deleted = hydrops fetalis lethal in utero, Hb barts (gamma tetramers)
Differentiate cause of alpha and beta thalassemia
Alpha thal due to deletions of 2 to 4 of the alpha globin chains, while beta thal is usually due to mutation of the beta globin gene
So deletion vs. mutation
Differentiate Hb electrophoresis seen in beta thal minor and beta thal major
Beta thal minor: usually asymptomatic w/ increased RBC count
-Slightly decreased HbA w/ increased HbA2 (5% while normal is 2.5%), and HbF (2% while normal is 1%)
Beta thal major: severe anemia starting a few months after birth
-NO HbA, HbA2 (alpha2delta2) and HbF (alpha2gamma2)
Increased risk of parvovirus aplastic crisis
- Beta thal major
- Hereditary spherocytosis
Parvovirus B19 infects erythroid precursors, therefore any disease where it’s hard for pt to tolerate temporary halt in erythropoiesis => increased risk of parvovirus aplastic crisis
Name 2 anemias w/ target cells on peripheral smear
- beta thal minor: see target cell ‘bleb’ due to excess membrane
- Sickle cell: cell continuously sickle and de-sicle thru microcirculation causing reduced cytoplasm => extra membrane causes blebs
Also the two anemias where you get ‘crewcut appearance’ of skull on Xray and ‘chipmunk facies’ due to expansion of hematopoiesis into skull and facial bonesa
Explain how pancreatic insufficiency can cause vit B12 deficiency
Pancreas produces enzyme that cleaves R-binder from B12 so that instrinic factor can bind B12 and aid absorption
In a normocytic anemia how can you differentiate peripheral destruction vs. central underproduction
Reticulocyte count
Retic under 3% suggests poor marrow response = underproduction
While retic count over 3% suggests good marrow response and peripheral destruction
Describe the breakdown of RBC components
Heme –> iron and protoporphyrin
- iron recycled
- protoporphyrin –> unconjugated bilirubin
Globin –> amino acid precursors
Hereditary Spherocytosis
(a) Etiology
(b) Explain the shape of RBCs
(c) What causes the anemia?
HS
(a) Mutation in RBC cytoskeleton-membrane tethering protein
(b) Loss of RBC membrane renders cell spheroid shape (spherocyte) instead of disc shaped
(c) Its not that fewer cells are produced, but the abnormally shaped cells can’t maneuver the splenic sinusoids => RBCs destroyed by splenic macrophages
What is the osmotic fragilty test used to dx?
Osmotic fragilty test- put RBCs in hypotonic solution, normal RBCs have discoid shape that can adapt to a bit of water intake
while spherocytes (seen in hereditary spherocytosis 2/2 defect in RBC cytoskeleton-membrane tethering proteins) have increased fragility in hypotonic solution
Tx for hereditary spherocytosis
Tx is splenectomy- if you remove the spleen there is nothing to remove the oddly shaped RBCs => no more anemia
Mutation in SCD
(a) Mutation in HbC
SIngle amino acid change replaces normal glutamic acid (hydrophilic) w/ valine (hydrophobic) => beta chain of Hb is defective
(a) Hb C due to autosomal recessive mutation of beta chain where normal glutamic acid is replaced by lysin
Differentiate
(a) HbS
(b) HbA
(c) HbA2
(d) HbF
(e) HbH
(f) Hb barts
Hbs
(a) HbS (SCD) = alpha2betaS2
- betaS polymerizes/sickles in hypoxia, acidosis, and dehydration
(b) HbA = adult Hb, alpha2beta2
(c) HbA2 = alpha2delta2
(d) HbF = alpha2gamma2
(e) HbH (seen in alpha thal when 3 of the 4 globin genes are deleted) = beta tetramer
(f) Hb bart (seen in alpha thal when 4 of 4 globin genes are deleted- fetal hydrops) = gamma tetramers
Mechanism of disease in SCD
When both beta globin genes are mutated, 90% of Hb is HbS which polymerizes/sickles w/ hypoxia, dehydration, or acidosis
SCD
(a) Common presenting features in infants
(b) MC cause of death in adults
(a) Dactylitis in child- b/c of vaso-occlusion (causing infarction) in extremities
(b) MC cause of death in adults = acute chest syndrome 2/2 vaso-occlusion in the pulmonary microcirculation
Differentiate Hb electrophoresis in sickle cell disease vs. sickle cell trait
SCD: 90% HbS, 8% HbF (up from normal 1%), 2% HbA2 (normal)
-key here is no HbA (b/c no normal beta globin gene
Sickle cell trait: 55% HbA (higher percent despite equal genes b/c it’s more efficiently made), 43% HbS, 2% HbA2
Clinical presentation of sickle cell trait
Sickle cell trait is usually asymptomatic b/c RBCs with under 50% HbS don’t sickle, except in the renal medulla
Overtime can lead to medullary microinfarctions => microscopic hematuria and eventually decreased ability to concentrate urine
Predominantly intravascular or extravascular hemolysis?
(a) Hereditary spherocytosis
(b) Paroxysmal Nocturnal Hemoglobinuria
(c) SCD
(d) G6PD deficiency
(e) Malaria
Hereditary spherocytosis and sickle cell disease are normocytic anemias w/ predominantly extravascular hemolysis
PNH, G6PD deficiency, and malaria are normocytic anemias w/ predominantly intravascular hemolysis
Explain pathophysiology of paroxysmal noctural hemoglobinuria
PNH: acquired defect in myeloid stem cell (so it’s one line of cells not all cells) causing absent GPI = anchor protein needed for DAF (decay accelerating factor) on surface to protect against complement-mediated damage by inhibiting C3 convertase
No GPI = no DAF = RBC gets damaged by C3 convertase (intravascular hemolysis)
Lysis of RBC, WBC, and plts (b/c all come from the same myeloid stem line!)
Paroxysmal noturnal hemoglobinuria
(a) Main cause of death
(b) Increased risk of what malignancy?
(c) Why happens at night
PNH
(a) Main cause of death = thrombosis of portal, hepatic, or cerebral veins
- plts destroyed (by complement b/c don’t have GPI to bind DAF to prevent destruction by C3 convertase) release cytoplasmic contents in circulation and induce thrombosis
(b) Increased risk of AML (acute myeloid leukemia) b/c PNH is due to acquired mutation in myeloid stem cell
(c) During sleep breathing becomes shallow => mild respiratory acidosis develops that activates complement
Differentiate the African and Mediterranean variant of G6PD deficiency
G6PD deficiency = less NADPH to reduce glutathione and protect RBC from oxidative injury from H2O2 => intravascular hemolysis
African variant- G6PD has only mildly reduced t1/2 => mild intravascular hemolysis w/ oxidative stress
Mediterranean variant- G6PD t1/2 is markedly reduced => severe intravascular hemolysis w/ oxidative stress
Clinical presentation of G6PD deficiency after sulfa drugs or fava beans
Sulfa drugs, fava beans, primaquine, dapsone, infections (things that cause oxidative stress) => intravascular hemolysis of RBCs that presents as hemoglobinuria and back pain (b/c Hb is nephrotoxic) hours after exposure to oxidative stress
What is aplastic anemia?
(a) Biopsy finding
Damage to hematopoietic stem cell => pancytopenia
(a) Bone marrow biopsy shows empty, fatty marrow
Differentiate use of direct vs. indirect Coombs test in diagnosis of autoimmune hemolytic anemia
Direct Coomb’s asks if there are immunoglobulins already bound to RBCs
Indirect Coomb’s asks if the pt has anti-RBC antibodies in their serum
MC cause of warm agglutinin autoimmune hemolytic anemia
MC cause of warm agglutinin (IgG mediated) AI hemolytic anemia = SLE
2 infections associated w/ cold agglutinin autoimmune hemolytic anemia
IgM binds RBCs and fixes complement in relatively cold temperature of the extremities
Associated w/ mycoplasma pneumoniae and infectious mono
Differentiate warm vs. cold agglutinin autoimmune hemolytic anemia
Warm agglutinin = IgG binds RBCs in relatively warm temp of central body
Cold agglutinin = IgM binds and fixes complement in relatively cold temperature of the extremities
Ideal time to supplement mother to prevent neural tube defects
Failure of neural tube to fuse is associated w/ low folate PRIOR to conception
So ideally is best to supplement mother w/ folate before conception
Name of d/o when neural tube fails is disrupted
(a) On the cranial plane
(b) On the caudal plane
Neural tube defects
(a) Anencephaly = absence of skull and brain 2/2 disruption of cranial end of the neural tube
(b) Spina bifida = failure of posterior vertebral arch to close, disruption at caudal end of the neural tube
Differentiate the following
(a) Meningocele
(b) Spina bifida occulta
(c) Meningomyelocele
Spectrum of spina bifida
(a) Meningocele = when just meninges protrude thru vertebral defect
(b) Spina bifida occulta = mildest form, presents as a dimple or patch of underlying tissue thru the vertebral defect
(c) Meningomyelocele = both meninges and spinal cord protrude thru vertebral defect
Clinical presentation of cerebral aqueduct stenosis
Enlarging head circumference 2/2 dilation of lateral ventricles b/c CSF cannot flow from 3rd to 4th ventricle
Dandy-Walker Malformation vs. Arnold-Chiari malformation
Dandy-Walker malformation = congenital failure of cerebellar vermis to develop => get massive dilation of 4th ventricle
Arnold-Chiari type II = congenital downward displacement of cerebellar vermis and tonsils thru foramen magnum which obstructs CSF flow => hydrocephalus
UMN vs. LMN signs
UMN signs: hyperreflexia, upgoing (positive) Babinski, spastic paralysis, hypertonia
LMN signs: hyporeflexia, atrophy and weakness, downgoing (negative) Babinski, flaccid paralysis, fasciculations, hypotonia
Clinical presentation of poliomyelitis vs. amyotrophic lateral sclerosis
Polio- only LMN signs: hyporeflexia, flaccid paralysis w/ atrophy, negative Babinski, fasciculations, hypotonia
While ALS classically presents w/ mix of both LMN and UMN signs
How to differentiate ALS from syringomyelia
ALS only affects corticostpinal tract (voluntary movement) while syringomyelia has sensory findings (classically loss of pain and temp in cape like distribution)
Classic early sign of ALS
Atrophy and weakness of hands
Explain the mutation involved in familial cases of amyotrophic lateral sclerosis
Most cases of ALS are sporadic, but familial cases can be due to zinc-copper superoxide dismutase mutation
Need superoxide dismutase to catalyze O2- –> H2O2, so w/ this mutation pt gets free radical injury to neurons
Friedreich ataxia
(a) Mode of inheritance
(b) Mutated gene and its function
Friedreich ataxia
(a) Autosomal recessive trinucleotide repeat d/o (GAA repeats) in frataxin gene
(b) Frataxin gene is essential for mitochondrial iron regulation, so loss of frataxin gene => iron buildup => free radical damage of neurons via Fenton rxn
Name the 3 spinal tracts and their function
- Spinothalamic tract for pain and temperature sensation
- lateral corticospinal tract for motor control (voluntary movement)
- dorsal column for pressure, touch, vibration, and proprioception
Spinothalamic tract
(a) Fxn
(b) Location of synapses
(c) Location of decussation
Spinothalamic tract
(a) Pain and temperature
(b) Synapse in posterior horn
(c) Second order neuron decussates in anterior white commisure then continues up to thalamus
- 2nd synapse in the thalamus, then continues up to cortex
Lateral corticospinal tract
(a) Fxn
(b) Location of synapses
(c) Location of decussation
Lateral corticospinal tract
(a) Voluntary movement control
Pyramidal nerves start by (c) decussating in medullary pyramids, then (b) synapse on anterior motor horn of the spinal cord
-2nd order neuron synapse out at the muscle at nmj
Only 2 neurons
Dorsal column tract
(a) Fxn
(b) Location of synapses
(c) Location of decussation
Dorsal column tract
(a) Vibration, proprioception
(b) Synapses first in inferior medulla, then (c) crosses over in medulla and ascends via medial lemniscus to the thalamus where synapses again then up to cortex
What is a syringomyelia?
(a) Associated condition
(b) MC location
Syringomyelia = generic term for cyst of cavity within the spinal cord
(a) Associated w/ Arnold-chiari malformations
(b) MC located C8-T1 => causes cape like distribution of loss of pain/temp sensation
Clinical presentation of Friedreich ataxia
(a) Associated cardiac condition
Freidreich ataxia = autosomal recessive loss of fritaxin gene (mitochondrial protein) causing iron free radical damage that degenerates the cerebellum and spinal cord
Cerebellar degeneration => ataxia
Spinal cord degeneration (multiple tracts) => loss of vibratory sense, proprioception, muscle weakness, loss of DTRs
Presents in early childhood, wheelchair bound in a few years
(a) Hypertrophic cardiomyopathy
Which layers of the meninges are involved in meningitis
Only the pia and arachnoid (not the dura) make up the leptomeninges which are involved in meningitis
-dura matter is “dura-ble”
MC infectious agent causing meningitis by age group
(a) Neonates
(b) Children and teenagers
(c) Adults and elderly
Meningitis by age groups
(a) Neonates = GBS, E. coli, and listeria monocytogenes
- GBS and E. Coli thru vaginal canal
(b) Children and teenagers = N. meningitidis
(c) Adults and elderly = Strep pneumo
Classic organism responsible for meningitis in unvaccinated child
H. influenza in nonvaccinated infants
Pathway that neisseria meningitides takes to get to the brain
N. meningitides enters thru the nasopharynx, then into the blood stream to hematgenously spread to the leptomeninges
Lumbar puncture
(a) Performed at what vertebral level
(b) Poke thru what layers?
LP
(a) Ideally btwn L4-L5 (at the level of the iliac crest)
(b) Poke thru skin, epidural space, dura, arachnoid to get into subarachnoid space
- doesn’t poke thru pia!!!
CSF findings that differentiate
(a) Bacterial and viral meningitis
(b) Viral and fungal meningitis
LP findings
(a) Bacterial meningitis- neutrophilia w/ reduced CSF glucose (then can use gram stain and culture to identify organism)
- Viral meningitis = leukocytes elevated and normal CSF glucose (viruses are debatedly not alive, they don’t consume glucose!)
(b) Both viral and fungal meningitis have elevated lymphocytes in CSF, but viral will have normal glucose while fungal will have reduced glucose
Normal CSF glucose
Normal CSF glucose = 2/3 (serum glucose)
So if serum glucose is 100, expect CSF glucose in mid 60s
Differentiate etiology of pale vs. hemorrhagic cerebral infarct
Pale cerebral infarct from thrombotic disease (ex: atherosclerosis) b/c atherosclerotic plaque can’t be degraded => blood doesn’t return to area
Hemorrhagic infarct from embolic disease (ex: AFib to MCA), clot lysed and blood re-enters so area becomes hemorrhagic
Etiology of lacunar strokes
(a) Explain why deep brain structures are the MC affected
Lacunar strokes: chronic HTN causes hyaline arteriolosclerosis of cerebral vessels which narrows vessels
(a) MC affects deep brain structures b/c it’s the small perforating branches off the MCA (lenticulostriate vessels) that are smallest and easily narrow
Involvement of what location leads to
(a) Pure motor stroke
(b) Pure sensory stroke
(a) Pure motor stroke 2/2 lacunar stroke of internal capsule
(b) Pure sensory stroke 2/2 lacunar stroke of thalamus
Explain how chronic HTN increases risk of intracerebral hemorrhage
Chronic HTN => hyaline arteriolosclerosis that can narrow vessels (cause lacunar stroke) but also can weaken vessel wall, forming Charcot-Bouchard microaneurysms of the lenticulostriate vessels (perforating branches off MCA)
Subarachnoid hemorrhage
(a) LP finding
(b) MC cause
SAH
(a) Xanthochromia (yellow hue of CSF 2/2 bilirubin) due to blood in the subarachnoid space
(b) MC cause = berry aneurysm
MC location of SAH
(a) Why
MC location = branching points of the anterior communicating artery (anterior circle of Willis)
(a) B/c at these branch points the media fails to develop = weaker wall => wall balloons out
- berry aneurysm = thin-walled saccular outpouchings that lack media layer
Epidural vs. subdural hematoma
(a) Etiology
(b) Shape on CT
(c) Clinical presentation
Epidural hematoma
(a) 2/2 skull fracture injuring middle meningeal artery
(a) Lens shape on CT
(b) Can present w/ lucid interval before blood accumulates
Subdural hematoma
(a) From rupture of bridging veins
(b) Crescent shaped on CT
(c) Progressive neurologic signs
Complication of tonsillar herniation vs. subfalcine herniation
Tonsillar herniation = cerebellar tonsil thru foramen magnum. Compression of brain stem => cardiopulmonary arrest
Subfalcine herniation = cingulate gyrus displaced under falx cerebri. Causes compression of anterior cerebral artery => infarction
3 consequences of uncal herniation
Uncus lobe of the temporal lobe herniates under the tentorium cerebelli
- Compression of CN III => eyes ‘down and out’ w/ dilated pupil
- Compression of posterior cerebral artery => occipital lobe infarction => contralateral homonymous hemianopsia
- Rupture of paramedian artery => Duret (brainstem) hemorrhage
What are leukodystrophies?
Leukodystrophy = d/o of the white matter (aka myelinated tissue) due to mutation in enzymes necessary for production or maintenance of myelin
MC leukodystrophy
MC leukodystrophy (aka mutation cuasing defective production or maintenance of myelin) = metachromatic leukodystrophy
= lysosomal storage disease b/c sulfatides cannot be degraded so they accumulate in the lysosomes of oligodendocytes
Subacute sclerosing panencephalitis
(a) Part of brain affected
(b) Etiology
Subacute sclerosing panencephalitis
(a) Both white and gray matter (hence ‘pan’ encephalitis)
(b) Etiology = measles virus
- persistent brain infection by measles virus, infection in infancy then neurologic signs arise in childhood
Progressive multifocal leukoencephalopathy
(a) Etiology
(b) Clinical presentation
PML
(a) Reactivation of the JC virus
- usually due to immunosuppression allowing for reactivation
(b) Rapidly progressive neurologic signs leading to death
Central pontine myelinolysis
(a) Physiology
(b) Etiology
(c) Clinical presentation
CPM
(a) Focal demyelination (destruction of the white matter) of the pons
(b) Too rapid correction of hyponatremia, usually in the severe malnourished
- give Na+ which draws water out of the brain
(c) Acute b/l paralysis- “locked in” syndrome- paralyzed except for eyes
Distinguish degenerative d/o of cortex vs. basal ganglia
Degeneration of cortex => dementia
- Alzheimers
- Lewy Body dementia
While degeneration of the basal ganglia (deeper structures) => movement d/o
- Parkinsons
- Huntingtons
2 MC cause of dementia
Dementia defined as memory loss w/ cognitive dysfunction w/o LOC
1st MC = Alzheimers
2nd MC = Vascular dementia
Allele associated w/
(a) Increased
(b) Decreased
risk of Alzheimers
(a) ApoE4 allele increases risk for Alzheimers- b/c E4 allele increased breakdown of amyloid precursor protein into Abeta protein (that can’t be excreted and therefore gets deposited)
(b) ApoE2 (lower number) allele conveys lower risk of Alzheimers
- ApoE2 allele is protective
Explain why Down syndrome is a model of early onset Alzheimers
Downs = 3 copies of chrom 21, chrom 21 contains amyloid precursor protein (APP), which gets broken down into Abeta protein that can’t be excreted => deposits in tissues and causes Alzheimers
So pts w/ an extra copy of APP allele make extra APP => more Abeta protein to accumulate
Two dementia d/o w/ tau deposits and how to distinguish them
Tau = microtubule-associated protein
Neurofibrillary tangles = intracellular aggregates of fibers composed of hyperphosphorylated tau protein seen in Alzheimer
While round aggregates of tau protein deposit in the cortex neurons in Pick disease (frontotemporal dementia)
List the TRAP mneumonic for the clinical features of Parkinson disease
Clinical features of Parkinson disease
Tremor- pill rolling tremor at rest
Rigidity- cogwheel rigidity of extremities
Akinesia/bradykinesia- slowing of voluntary movement, expressionless face
Postural instability and shuffling gait
Parkinson disease vs. Lewy-body dementia
(a) Clinical distinguish
(b) Histologic finding
Parkinson disease
(a) Starts w/ movement features, dementia comes later
(b) Histologically: lewy bodies (round, eosinophilic inclusions of alpha-synuclein) in the substantia nigra of the basal ganglia
Lewy-body dementia
(a) Early onset dementia w/ movement features next or simultaneously (key is that dementia is not delayed)
(b) Lewy bodies (round, eosinophilic inclusions of alpha-synuclein) in the cortex
Recall overall principle:
- cortical degeneration => dementia
- basal ganglia degeneration => movement d/o
2 diseases that contain Lewy bodies
- Parkinson disease: Lewy bodies (round eosinophilic inclusions) in the deep nuclei of the substantia nigra
- Lewy Body dementia: Lewy bodies in the cortex (peripherally)
Explain where anticipation of Huntington disease occurs
Further trinucleotide expansion occurs in spermatogenesis, increasing repeats = anticipation
Huntington disease
(a) Average age of presentation
(b) Differentiate chorea and athetosis
Huntington disease
(a) 40 yoa
(b) Chorea = rapid involuntary contractions, while athetosis are slow involuntary snake-like movements of fingers
Explain the physiology of Huntington disease
(a) Degeneration of what neurons?
(b) Mode of inheritance
(c) Location of mutated gene
Huntingtons: loss of GABAergic inhibition on the cortex => get random uncontrolled neuronal firing
(a) Degeneration of GABAergic neurons in the caudate nucleus of the basal ganglia
(b) Aut dom of CAG trinucleotide repeats
(c) Huntington gene on chromosome 4
Explain the physiology of spongiform encephalopathy
(a) Configuration of prion proteins
Spongiform encephalopathy- prior proteins are usually in alpha-helical configuration
(a) Can convert to beta-pleated conformation (not degradable) sporadically, inherited, or transmitted (exposure to human infected tissue)
- vicious cycle b/c beta-pleated conformation (pathologic protein) converts normal protein into more pathologic form
CNS tumor: what percent are mets vs. primary?
(a) Typical location of metastatic tumors
50% of CNS tumors are mets, while 50% are primary (so 50/50 shot!)
(a) Mets: multiple, well-circumscribed lesions at the gray-white jxn
MC = lung, breast, kidney
Differentiate the fxn of these CNS cells
(a) Astrocytes
(b) Meningothelial cells
(c) Ependymal cells
(d) Oligodendrocytes
CNS cell in addition to neurons
(a) Astrocytes form BBBB
(b) Meningothelial cells form the meninges
(c) Ependymal cells line the ventricles
(d) Oligodendrocytes myelinate CNS neurons
Differentiate location of CNS tumors in adults vs. children
Adult- most CNS tumors are supratentorial, while in children primary CNS tumors are usually infratentorial
CNS tumors of the following cells occur in children or adults?
(a) Astrocytes
(b) Oligodendrocytes
(c) Ependymal cells
(d) Meningothelial cells
(a) Astrocyte tumors
- malignant glioblastoma multiform (GBM) in adults
- benign pilocytic astrocytoma in children
(b) Oligodendrocytes
- malignant oligodendroglioma in adults
(c) Ependymal cells
- malignant ependymoma in children
(d) Meningiothelial cells
- meningioma in adults
MC primary CNS tumor
(a) malignant in adults
(b) benign in adults
(c) benign in children
MC primary CNS tumor
(a) MC primary malignant CNS tumor in adults = GBM (glioblastoma multiforme) of astrocytes
(b) MC primary benign CNS tumor in adults = meningioma
(c) MC primary benign CNS tumor in children = pilocytic astrocytoma from astrocytes
Glioblastoma multiforme
(a) Cell of origin
(b) Classic gross pathology finding
(c) Histologic stain
(d) Prognosis
MC primary CNS tumor in adults = GBM
(a) Arises from astrocytes, high-grade malignant tumor of astocytes = GBM
(b) Butterfly lesion
(c) Tumor cells are GFAP positive
- GFAP is the intermediate filament in glial cells
(d) Poor prognosis
Meningioma
(a) RF
(b) Classic clinical presentation
(c) Attached to what layer?
Meningioma
(a) RF: female!! Tumor expresses estrogen receptor
(b) Seizures b/c tumor compresses (w/o invading) the cortex
(c) Tumor as a round mass attached to the dura
Intracerebral tumor removed and tumor cells stain S-100 positive
Dx?
S-100 positive cells = cells derived from the neural crest, MC Schwann cells (won’t find melanocytes in the head)
Dx = Schwannoma = benign tumor of schwann cells
Oligodendroglioma
(a) Benign?
(b) Imaging
(c) MC location
Oligodendroglioma
(a) Malignant tumor of the oligodendrocytes (cells that myelinate CNS neurons)
(b) On imaging: calcified tumor in the white matter
(c) Usually involving the frontal lobe
GFAP positive tumor cells ddx
GFAP is the intermediate filament used in glial cells, esp astrocytes => tumor cells of glioblastoma multiforme (malignant high grade tumor of astrocytomas) and pilocytic astrocytoma (benign tumor of astrocytes) are both GFAP positive
Primary CNS tumor in children w/ the worse prognosis
Medulloblastoma = malignant tumor derived from neuroectoderm
Medulloblastoma
(a) Cells of origin
(b) Histologic finding
(c) Explain drop metastasis
Medulloblastoma
(a) Arises from neuroectoderm (granular cells of the cerebellum)
(b) Histology: small round blue cells
(c) Drop metastasis = mets to the cauda equina
Craniopharyngioma
(a) Cells of origin
(b) Classic clinical presentation
(c) Imaging finding
Craniopharyngioma
(pharynx in name b/c arises from Rathke’s pouch which is from the floor of the mouth or pharynx)
(a) Rathke’s pouch (give rise to anterior pituitary, part of the surface ectoderm)
(b) Bitemporal hemianopsia 2/2 mass effect in the sella turcica on optic chiasm just above
(c) Calcified tumor in sella turcica
(remember calcified b/c derived from mouth, or ‘tooth-like’ tissue)
MC clinical presentation of ependymoma
Ependymoma = malignant tumor of ependymal cells (line ventricular space), seen in children
MC arise in the 4th ventricle and obstruct CSF flow => p/w hydrocephalus
2 non-cancerous causes of calcification on mammography
- fat necrosis- get saponification
2. sclerosing adenosis in fibrocystic change
Distinguish the two layers of epithelium that line lobules and ducts of breast tissue
2 layers: both which line the lobules and ducts of breast tissue
Inner luminal cell layer- produces milk
Outer myoepithelial layer- contracts to propel milk towards the nipple
Why is breast cancer MC found in the upper outer quadrant
B/c lobules and ducts (functional units of the breast) are present at highest density in the upper outer quadrant
Highest density of tissue = more tissue to become cancerous
Name fibrocystic-related changes of the breast that do increase risk for invasive carcinoma
Atypical hyperplasia- 5x increased risk
Ductal hyperplasia and sclerosing adenosis- 2x increased risk
Butttttt apocrine metaplasia doesn’t infer increased risk!
Differentiate intraductal papilloma and papillary carcnioma
Intraductal papilloma (benign papillary growth): fibrovascular changes that maintains the two standard epithelial layers (both luminal and myoepithelial) -seen in younger F
While papillary carcinoma (malignant) has fibrovascular projections that are lined by epithelial (luminal) cells W/O myoep cells
-risk increases w/ age
Both present w/ bloody nipple discharge
Clinical presentation of intraductal papilloma
Intraductal papilloma = benign fibrovascular growth that maintains the two standard epithelial layers of lining presents w/ bloody nipple discharge
Its malignant counterpart (papillary carcinoma) also p/w bloody nipple discharge
What is a fibroadenoma?
Fibroadenoma = MC tumor in pre-menopausal F
-benign breast tumor of both fibrous tissue and glands
Differentiate fibroadenoma and Phyllodes tumor
Fibroadenoma = benign breast mass of both fibrous and glandular tissue
While Phyllodes tumor has an overgrowth of the fibrous component
-MC in postmenopausal and can be malignant
How are the following most commonly detected
(a) DCIS
(b) Large vs. small IDC
(c) LCIS
(a) DCIS often detected as calcification on mammography, doesn’t usually produce a mass
(b) IDC over 2cm detected by palpation of mass, IDC btwn 1-2cm detected by mammography
(c) LCIS usually discovered incidentally on biopsy (biopsy for something else and find LCIS) b/c it doesn’t produce a mass or calcification
Differentiate DCIS and IDC
Both are malignant cells, difference is if invaded basement membrane
DCIS = malignant prolif of cells in ducts w/o invasion of BM
What type of cancer is Paget’s disease of the breast?
(a) Clinical presentation
(b) Clinical relevance
Paget’s disease of the breast = DCIS that extends up to the ducts to involve the skin of the nipple
(a) Nipple ulceration and erythema
(b) Almost always associated w/ underlying carcinoma
- while extramammary paget’s is not associated w/ underlying carcinoma
Briefly describe differentiating features of the 4 subtypes of invasive ductal carcinoma
(a) Tubular carcinoma
(b) Mucinous carcinoma
(c) Medullary carcinoma
(d) Inflammatory carcinoma
Invasive ductal carcinoma
(a) Tubular- tubules lacking myoepithelial cells
(b) Mucinous- abundant extracellular mucin “tumor cells floating in mucus pool”
(c) BRCA1 carriers, high grade malignant cells in inflammatory background (lymphocytes and plasma cells)
(d) Inflammatory- can be mistaken for acute mastitis b/c presents as inflamed, swollen breast b/c cancer is in the dermal lymphatics (lymphatic drainage is blocked)
MC type of invasive breast cancer
80% of invasive carcinomas of the breast are IDC (invasive ductal carcinoma), so much more common than ILC (invasive lobular carcinoma)
Tx of LCIS
LCIS often tx w/ tamoxifen and close f/u
-tamoxifen decreases growth response to hormones and decreases the already low risk of progression to invasive carcinoma
Explain the histological finding of invasive lobular carcinoma
ILC- cells characteristically grow in single-file pattern b/c they lack E-cadherin that keeps them stuck together
-the key here is that these cells don’t form ducts (therefore are in the lobules) b/c they lack E-cadherin adhesion protein
Cancers associated w/
(a) BRCA1
(b) BRCA2
(a) BRCA1 = breast cancer (esp medullary subtype of invasive ductal carcinoma) and ovarian carcinoma (classically serous carcinoma)
(b) BRCA2 associated w/ breast carcinoma in males
In males what type of breast cancer develops?
(a) Location
Males don’t develop lobules (don’t make milk…) so they develop invasive ductal carcinoma
(a) Subareolar mass b/c the highest density of breast tissue in males is under the nipple
