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Hematology and Oncology hematology and oncology—Physiology SECT ION III 377 ``HEMATOLOGY AND ONCOLOGY —PHYSIOLOGY Blood groups A A antigen on RBC surface and anti-B antibody in plasma. Incompatible blood transfusions can cause immunologic response, hemolysis, renal failure, shock, and death. Note: anti-A and anti-B antibodies—IgM (do not cross placenta); anti-Rh—IgG (cross placenta). B B antigen on RBC surface and anti-A antibody in plasma. AB A and B antigens on RBC surface; no antibodies in plasma; “universal recipient” of RBCs, “universal donor” of plasma. O Neither A nor B antigen on RBC surface; both antibodies in plasma; “universal donor” of RBCs, “universal recipient” of plasma. Rh Rh antigen on RBC surface. Rh- mothers exposed to fetal Rh+ blood (often during delivery) may make anti-Rh IgG. In subsequent pregnancies, anti-Rh IgG crosses the placenta, causing hemolytic disease of the newborn (erythroblastosis fetalis) in the next fetus that is Rh+. Treatment: Rho(D) immune globulin for mother during every pregnancy to prevent initial sensitization of Rh- mother to Rh antigen. Coagulation, complement, and kinin pathways XII XIIa XIa IXa Xa XI IX VIIIa IIa IIa VIII * = require Ca2+, phospholipid Fibrin Fibrinogen monomers Fibrin degradation products (aggregation) Ca2+ Fibrin mesh acts to stabilize platelet plug Collagen, basement membrane, activated platelets Intrinsic coagulation pathway Extrinsic coagulation pathway VII VIIa X II (prothrombin) IIa (thrombin) Thromboplastin (= tissue factor) * * * * * Va V XIIIa XIII HMWK Kinin cascade vasodilation permeability pain Plasminogen Plasmin C3 C3a Complement cascade Prekallikrein Kallikrein Bradykinin Fibrinolytic system Note: Kallikrein activates bradykinin; ACE inactivates bradykinin. Hemophilia A: deficiency of factor VIII. Hemophilia B: deficiency of factor IX. Hematology and Oncology 378 SECT ION III hematology and oncology—Physiology Coagulation cascade components Procoagulation Warfarin inhibits the enzyme vitamin K epoxide reductase. Neonates lack enteric bacteria, which produce vitamin K. Vitamin K deficiency: synthesis of factors II, VII, IX, X, protein C, protein S. vWF carries/protects VIII. Oxidized vitamin K reduced vitamin K epoxide reductase (acts as cofactor) + mature II, VII, IX, X, C, S precursors of II, VII, IX, X, C, S Protein C activated protein C (APC) cleaves and inactivates Va, VIIIa protein S; thrombomodulin (endothelial cells) Plasminogen plasmin cleavage of fibrin mesh tPA Anticoagulation Antithrombin inhibits activated forms of factors II, VII, IX, X, XI, XII. Heparin enhances the activity of antithrombin. Principal targets of antithrombin: thrombin and factor Xa. Factor V Leiden mutation produces a factor V resistant to inhibition by activated protein C. tPA is used clinically as a thrombolytic. Platelet plug formation (primary hemostasis) Temporary plug stops bleeding AGGREGATION Fibrinogen binds GpIIb/IIIa receptors and links platelets Balance between ACTIVATION ADP binding to receptor induces GpIIb/IIIa expression at platelet surface ADP helps platelets adhere to endothelium Platelets release ADP and Ca2+ (necessary for coagulation cascade) ADHESION Platelets bind vWF via GpIb receptor at the site of injury only (specific) INJURY vWF binds to exposed collagen upon endothelial damage Anti-aggregation factors: PGI2 and NO (released by endothelial cells) blood flow platelet aggregation Pro-aggregation factors: TXA2 (released by platelets) blood flow platelet aggregation Q R S Vitamin K activated vitamin K epoxide reductase (acts as cofactor) + mature II, VII, IX, X, C, S precursors of II, VII, IX, X, C, S Protein C activated protein C cleaves and inactivates Va, VIIIa thrombin-thrombomodulin complex (endothelial cells) Plasminogen plasmin Fibrinolysis: 1. cleavage of fibrin mesh 2. destruction of coagulation factors tPA Protein S Hematology and Oncology hematology and oncology—Physiology SECT ION III 379 Thrombogenesis Formation of insoluble fibrin mesh. Aspirin inhibits cyclooxygenase (TXA2 synthesis). Ticlopidine and clopidogrel inhibit ADPinduced expression of GpIIb/IIIa. Abciximab inhibits GpIIb/IIIa directly. Ristocetin activates vWF to bind to GpIb. Useful for diagnosis: normal platelet aggregation response is not seen in von Willebrand disease. Erythrocyte sedimentation rate Acute-phase reactants in plasma (e.g., fibrinogen) can cause RBC aggregation, thereby RBC sedimentation rate (RBC aggregates have a higher density than plasma). ESR Ž infections, autoimmune diseases (e.g., SLE, rheumatoid arthritis, temporal arteritis), malignant neoplasms, GI disease (ulcerative colitis), pregnancy. ESR Ž polycythemia, sickle cell anemia, CHF, microcytosis, hypofibrinogenemia. Platelet ADP receptor GpIIb/IIIa insertion Subendothelial collagen GpIb GpIIb/IIIa Fibrinogen vWF Thrombomodulin Protein C Activated protein C Vascular endothelial cells Inside endothelial cells (vWF) thromboplastin tPA, PGI2 Arachidonic acid COX TXA2 Platelet phospholipid (vWF) (fibrinogen) Inside platelets Irreversibly blocked by clopidogrel and ticlopidine Deficiency: Bernard- Soulier syndrome Deficiency: Glanzmann thrombasthenia Deficiency: von Willebrand disease Blocked by abciximab Hematology and Oncology 380 SECT ION III hematology and oncology—Pathology ``HEMATOLOGY AND ONCOLOGY —PAT HOLOGY Pathologic RBC forms TY PE EXAM PLE ASSOCIATED PAT HOLOGY NOTES Acanthocyte (spur cell) A Liver disease, abetalipoproteinemia (states of cholesterol dysregulation). Acantho = spiny. Basophilic stippling B Anemia of Chronic Disease, alcohol abuse, Lead poisoning, Thalassemias. Basically, ACiD alcohol is LeThal. Bite cell C G6PD deficiency. Elliptocyte D Hereditary elliptocytosis. Macro-ovalocyte E Megaloblastic anemia (also hypersegmented PMNs), marrow failure. Ringed sideroblast F Sideroblastic anemia. Excess iron in mitochondria = pathologic. Schistocyte, helmet cell G DIC, TTP/HUS, traumatic hemolysis (i.e., mechanical heart valve prosthesis). Hematology and Oncology hematology and oncology—Pathology SECT ION III 381 Pathologic RBC forms (continued) TY PE EXAM PLE ASSOCIATED PAT HOLOGY NOTES Sickle cell H Sickle cell anemia. Spherocyte I Hereditary spherocytosis, autoimmune hemolysis. Teardrop cell J Bone marrow infiltration (e.g., myelofibrosis). RBC “sheds a tear” because it’s been forced out of its home in the bone marrow. Target cell K HbC disease, Asplenia, Liver disease, Thalassemia. “HALT,” said the hunter to his target. Other RBC pathologies TY PE EXAM PLE PROCESS ASSOCIATED PAT HOLOGY Heinz bodies A Oxidation of hemoglobin sulfhydryl groups Ž denatured hemoglobin precipitation and phagocytic damage to RBC membrane Ž bite cells. Visualized with special stains such as crystal violet. Seen in G6PD deficiency; Heinz body–like inclusions seen in α-thalassemia. Howell-Jolly bodies B Basophilic nuclear remnants found in RBCs. Howell-Jolly bodies are normally removed from RBCs by splenic macrophages. Seen in patients with functional hyposplenia or asplenia. Hematology and Oncology 382 SECT ION III hematology and oncology—Pathology Anemias ANEMIAS MCV (80–100 fL) (Normocytic) aACD and iron deficiency anemia may first present as a normocytic anemia and then progress to a microcytic anemia. bCopper deficiency can cause a microcytic sideroblastic anemia. MCV (< 80 fL) (Microcytic) Iron deficiency (late) ACDa Thalassemias Lead poisoning Sideroblastic anemiab ACDa NONHEMOLYTIC (Reticulocyte count normal or ) Aplastic anemia Chronic kidney disease Iron deficiency (early) HEMOLYTIC (Reticulocyte count ) INTRINSIC RBC membrane defect: hereditary spherocytosis RBC enzyme deficiency: G6PD, pyruvate kinase HbC defect Sickle cell anemia Paroxysmal nocturnal hemoglobinuria EXTRINSIC Autoimmune Microangiopathic Macroangiopathic Infections MCV (> 100 fL) (Macrocytic) MEGALOBLASTIC Folate deficiency B12 deficiency Orotic aciduria NONMEGALOBLASTIC Liver disease Alcoholism Reticulocytosis Microcytic, hypochromic (MCV < 80 fL) anemia DESC RIPTION FINDINGS Iron deficiency iron due to chronic bleeding (GI loss, menorrhagia), malnutrition/absorption disorders or demand (e.g., pregnancy) Ž final step in heme synthesis. iron, TIBC, ferritin. Fatigue, conjunctival pallor A. Microcytosis and hypochromia B. May manifest as Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal webs, and atrophic glossitis). A Conjunctival pallor in anemia. B Iron deficiency. Note microcytosis and hypochromia (central pallor, arrows). α-thalassemia Defect: α-globin gene deletions Ž α-globin synthesis. cis deletion prevalent in Asian populations; trans deletion prevalent in African populations. 4 allele deletion: No α-globin. Excess γ-globin forms γ4 (Hb Barts). Incompatible with life (causes hydrops fetalis). 3 allele deletion: HbH disease. Very little α-globin. Excess β-globin forms β4 (HbH). 1–2 allele deletion: no clinically significant anemia. Hematology and Oncology hematology and oncology—Pathology SECT ION III 383 Microcytic, hypochromic (MCV < 80 fL) anemia (continued) DESC RIPTION FINDINGS β-thalassemia Point mutations in splice sites and promoter sequences Ž β-globin synthesis. Prevalent in Mediterranean populations. C b-thalassemia major. Note anisocytosis, poikilocytosis, target cells (arrows 1 and 2), microcytosis (arrow 3), and schistocytes (arrow 4). 4 1 3 2 β-thalassemia minor (heterozygote): ƒƒ β chain is underproduced. ƒƒ Usually asymptomatic. ƒƒDiagnosis confirmed by HbA2 (> 3.5%) on electrophoresis. β-thalassemia major (homozygote): ƒƒ β chain is absent Ž severe anemia C requiring blood transfusion (2° hemochromatosis). ƒƒMarrow expansion (“crew cut” on skull x-ray) Ž skeletal deformities. “Chipmunk” facies. ƒƒ Extramedullary hematopoiesis (leads to hepatosplenomegaly). risk of parvovirus B19- induced aplastic crisis. Major Ž HbF (α2γ2). HbF is protective in the infant and disease only becomes symptomatic after 6 months. HbS/β-thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of β-globin production. Lead poisoning D Lead inhibits ferrochelatase and ALA dehydratase Ž heme synthesis and RBC protoporphyrin. Also inhibits rRNA degradation, causing RBCs to retain aggregates of rRNA (basophilic stippling). High risk in old houses with chipped paint. LEAD: Lead Lines on gingivae (Burton lines) and on metaphyses of long bones D on x-ray. Encephalopathy and Erythrocyte basophilic stippling. Abdominal colic and sideroblastic Anemia. Drops—wrist and foot drop. Dimercaprol and EDTA are 1st line of treatment. Succimer used for chelation for kids (It “sucks” to be a kid who eats lead). Sideroblastic anemia E Defect in heme synthesis. Hereditary: X-linked defect in δ-ALA synthase gene. Causes: genetic, acquired (myelodysplastic syndromes), and reversible (alcohol is most common, lead, vitamin B6 deficiency, copper deficiency, and isoniazid). Ringed sideroblasts ( E with iron-laden mitochondria) seen in bone marrow. iron, normal TIBC, ferritin. Treatment: pyridoxine (B6, cofactor for δ-ALA synthase). Hematology and Oncology 384 SECT ION III hematology and oncology—Pathology Macrocytic (MCV > 100 fL) anemia DESC RIPTION FINDINGS Megaloblastic anemia Impaired DNA synthesis Ž maturation of nucleus of precursor cells in bone marrow delayed relative to maturation of cytoplasm. Abnormal cell division Ž pancytopenia. Folate deficiency Causes: malnutrition (e.g., alcoholics), malabsorption, antifolates (e.g., methotrexate, trimethoprim, phenytoin), requirement (e.g., hemolytic anemia, pregnancy). Hypersegmented neutrophils, glossitis, folate, homocysteine but normal methylmalonic acid. No neurologic symptoms (distinguishes from B12 deficiency). B12 deficiency (cobalamin) A Causes: insufficient intake (e.g., strict vegans), malabsorption (e.g., Crohn disease), pernicious anemia, Diphyllobothrium latum (fish tapeworm), proton pump inhibitors. Hypersegmented neutrophils A, glossitis, B12, homocysteine, methylmalonic acid. Neurologic symptoms: subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis): ƒƒ Peripheral neuropathy with sensorimotor dysfunction ƒƒDorsal columns (vibration/proprioception) ƒƒ Lateral corticospinal (spasticity) ƒƒDementia Orotic aciduria Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of defect in UMP synthase. Autosomal recessive. Presents in children as megaloblastic anemia that cannot be cured by folate or B12 with failure to thrive. No hyperammonemia (vs. ornithine transcarbamylase deficiency— orotic acid with hyperammonemia). Hypersegmented neutrophils, glossitis, orotic acid in urine. Treatment: uridine monophosphate to bypass mutated enzyme. Nonmegaloblastic macrocytic anemias Macrocytic anemia in which DNA synthesis is unimpaired. Causes: liver disease; alcoholism; reticulocytosis Ž MCV; drugs (5-FU, zidovudine, hydroxyurea). Macrocytosis and bone marrow suppression can occur in the absence of folate/B12 deficiency. Normocytic, normochromic anemia Normocytic, normochromic anemias are classified as nonhemolytic or hemolytic. The hemolytic anemias are further classified according to the cause of the hemolysis (intrinsic vs. extrinsic to the RBC) and by the location of the hemolysis (intravascular vs. extravascular). Intravascular hemolysis Findings: haptoglobin, LDH, schistocytes and reticulocytes on peripheral blood smear; and urobilinogen in urine (e.g., paroxysmal nocturnal hemoglobinuria, mechanical destruction [aortic stenosis, prosthetic valve], microangiopathic hemolytic anemias). Extravascular hemolysis Findings: macrophage in spleen clears RBC. Spherocytes in peripheral smear, LDH plus unconjugated bilirubin, which causes jaundice (e.g., hereditary spherocytosis). Hematology and Oncology hematology and oncology—Pathology SECT ION III 385 Nonhemolytic, normocytic anemia DESC RIPTION FINDINGS Anemia of chronic disease Inflammation Ž hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport) Ž release of iron from macrophages. iron, TIBC, ferritin. Can become microcytic, hypochromic Aplastic anemia A Caused by failure or destruction of myeloid stem cells due to: ƒƒ Radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites) ƒƒ Viral agents (parvovirus B19, EBV, HIV, HCV) ƒƒ Fanconi anemia (DNA repair defect) ƒƒ Idiopathic (immune mediated, 1° stem cell defect); may follow acute hepatitis Pancytopenia characterized by severe anemia, leukopenia, and thrombocytopenia. Normal cell morphology, but hypocellular bone marrow with fatty infiltration A (dry bone marrow tap). Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection. Treatment: withdrawal of offending agent, immunosuppressive regimens (antithymocyte globulin, cyclosporine), allogeneic bone marrow transplantation, RBC and platelet transfusion, G-CSF, or GM-CSF. Chronic kidney disease EPO Ž hematopoiesis. Hematology and Oncology 386 SECT ION III hematology and oncology—Pathology Intrinsic hemolytic normocytic anemia E = extravascular; I = intravascular. DESC RIPTION FINDINGS Hereditary spherocytosis (E) Defect in proteins interacting with RBC membrane skeleton and plasma membrane (e.g., ankyrin, band 3, protein 4.2, spectrin). Less membrane causes small and round RBCs with no central pallor ( MCHC, red cell distribution width) Ž premature removal of RBCs by spleen. Splenomegaly, aplastic crisis (parvovirus B19 infection). Labs: osmotic fragility test . Eosin-5- maleimide binding test useful for screening. Normal to MCV with abundance of cells; masks microcytia. Treatment: splenectomy. G6PD deficiency (I/E) Most common enzymatic disorder of RBCs. X-linked recessive. Defect in G6PD Ž glutathione Ž RBC susceptibility to oxidant stress. Hemolytic anemia following oxidant stress (classic causes: sulfa drugs, antimalarials, infections, fava beans). Back pain, hemoglobinuria a few days after oxidant stress. Labs: blood smear shows RBCs with Heinz bodies and bite cells. “Stress makes me eat bites of fava beans with Heinz ketchup.” Pyruvate kinase deficiency (E) Autosomal recessive. Defect in pyruvate kinase Ž ATP Ž rigid RBCs. Hemolytic anemia in a newborn. HbC defect (E) Glutamic acid-to-lysine mutation at residue 6 in β-globin. Patients with HbSC (1 of each mutant gene) have milder disease than have HbSS patients. Paroxysmal nocturnal hemoglobinuria (I) complement-mediated RBC lysis (impaired synthesis of GPI anchor for decay-accelerating factor that protects RBC membrane from complement). Acquired mutation in a hematopoietic stem cell. Increased incidence of acute leukemias. Triad: Coombs hemolytic anemia, pancytopenia, and venous thrombosis. Labs: CD55/59 RBCs on flow cytometry. Treatment: eculizumab. Sickle cell anemia (E) A HbS point mutation causes a single amino acid replacement in β chain (substitution of glutamic acid with valine) at position 6. Pathogenesis: low O2, dehydration, or acidosis precipitates sickling (deoxygenated HbS polymerizes), which results in anemia and vaso-occlusive disease. Newborns are initially asymptomatic because of HbF and HbS. Heterozygotes (sickle cell trait) have resistance to malaria. 8% of African Americans carry the HbS trait. Sickled cells are crescent-shaped RBCs A. “Crew cut” on skull x-ray due to marrow expansion from erythropoiesis (also in thalassemias). Complications in sickle cell disease (SS): ƒƒ Aplastic crisis (due to parvovirus B19). ƒƒ Autosplenectomy (Howell-Jolly bodies) Ž risk of infection with encapsulated organisms; early splenic dysfunction occurs in childhood. ƒƒ Splenic sequestration crisis. ƒƒ Salmonella osteomyelitis. ƒƒ Painful crisis (vaso-occlusive): dactylitis. (painful hand swelling), acute chest syndrome (most common cause of death in adults), avascular necrosis, stroke. ƒƒ Renal papillary necrosis (due to low O2 in papilla; also seen in heterozygotes) and microhematuria (medullary infarcts). Diagnosis: hemoglobin electrophoresis. Treatment: hydroxyurea ( HbF) and bone marrow transplantation. Hematology and Oncology hematology and oncology—Pathology SECT ION III 387 Extrinsic hemolytic normocytic anemia DESC RIPTION FINDINGS Autoimmune hemolytic anemia Warm agglutinin (IgG)—chronic anemia seen in SLE, CLL, or with certain drugs (e.g., α-methyldopa) (“warm weather is GGGreat”). Cold agglutinin (IgM)—acute anemia triggered by cold; seen in CLL, Mycoplasma pneumonia infections, or infectious mononucleosis (“cold ice cream—yuMMM”). Many warm and cold AIHA are idiopathic in etiology. Autoimmune hemolytic anemias are usually Coombs . Direct Coombs test—anti-Ig antibody (Coombs reagent) added to patient’s blood. RBCs agglutinate if RBCs are coated with Ig. Indirect Coombs test—normal RBCs added to patient’s serum. If serum has anti-RBC surface Ig, RBCs agglutinate when anti-Ig antibodies (Coombs reagent) added. Microangiopathic anemia Pathogenesis: RBCs are damaged when passing through obstructed or narrowed vessel lumina. Seen in DIC, TTP-HUS, SLE, and malignant hypertension. Schistocytes (helmet cells) are seen on blood smear due to mechanical destruction of RBCs. Macroangiopathic anemia Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia 2° to mechanical destruction. Schistocytes on peripheral blood smear. Infections destruction of RBCs (e.g., malaria, Babesia). Lab values in anemia Iron deficiency Chronic disease Hemochromatosis Pregnancy/ OCP use Serum iron (1°) (1°) — Transferrin or TIBC (indirectly measures transferrin) a (1°)b Ferritin (1°) — % transferrin saturation (serum iron/TIBC) — Transferrin—transports iron in blood. Ferritin—1° iron storage protein of body. a Evolutionary reasoning—pathogens use circulating iron to thrive. The body has adapted a system in which iron is stored within the cells of the body and prevents pathogens from acquiring circulating iron. b Transferrin production is in pregnancy and by OCPs. Leukopenias CELL TY PE CELL CO UNT CA USES Neutropenia Absolute neutrophil count < 1500 cells/mm3 Sepsis/postinfection, drugs (including chemotherapy), aplastic anemia, SLE, radiation Lymphopenia Absolute lymphocyte count < 1500 cells/mm3 (< 3000 cells/mm³ in children) HIV, DiGeorge syndrome, SCID, SLE, corticosteroids,a radiation, sepsis, postoperative Eosinopenia Cushing syndrome, corticosteroidsa aCorticosteroids cause neutrophilia, but eosinopenia and lymphopenia. Corticosteroids activation of neutrophil adhesion molecules, impairing migration out of the vasculature to sites of inflammation. In contrast, corticosteroids sequester eosinophils in lymph nodes and cause apoptosis of lymphocytes. Hematology and Oncology 388 SECT ION III hematology and oncology—Pathology Heme synthesis, porphyrias, and lead poisoning The porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis, leading to a similar condition. CONDITION AFFECTED ENZYME ACC UMULATED SUBST RATE PRESENTING SYM PTOMS Lead poisoning Ferrochelatase and ALA dehydratase Protoporphyrin, δ-ALA (blood) Microcytic anemia, GI and kidney disease. Children—exposure to lead paint Ž mental deterioration. Adults—environmental exposure (battery/ ammunition/radiator factory) Ž headache, memory loss, demyelination. Acute intermittent porphyria Porphobilinogen deaminase Porphobilinogen, δ-ALA, coporphobilinogen (urine) Symptoms (5 P’s): ƒƒ Painful abdomen ƒƒ Port wine–colored urine ƒƒ Polyneuropathy ƒƒ Psychological disturbances ƒƒ Precipitated by drugs, alcohol, and starvation Treatment: glucose and heme, which inhibit ALA synthase. Porphyria cutanea tarda A Uroporphyrinogen decarboxylase Uroporphyrin (teacolored urine) Blistering cutaneous photosensitivity A. Most common porphyria. Glycine + succinyl-CoA B6 -aminolevulinic acid Porphobilinogen Hydroxymethylbilane Uroporphyrinogen III Coproporphyrinogen III Ferrochelatase Lead poisoning Lead poisoning Porphyria cutanea tarda Acute intermittent porphyria -aminolevulinic acid synthase: rate-limiting step -aminolevulinic acid dehydratase Uroporphyrinogen decarboxylase Heme heme ALA synthase activity heme ALA synthase activity Fe2+ Protoporphyrin Sideroblastic anemia (X-linked) Porphobilinogen deaminase Mitochondria Mitochondria Cytoplasm Location Intermediates Enzymes Diseases Glucose, heme Hematology and Oncology hematology and oncology—Pathology SECT ION III 389 Coagulation disorders PT—tests function of common and extrinsic pathway (factors I, II, V, VII, and X). Defect Ž PT. PTT—tests function of common and intrinsic pathway (all factors except VII and XIII). Defect Ž PTT. DISO RDE R PT PTT MEC HANISM AND COMMENTS Hemophilia A or B — Intrinsic pathway coagulation defect. ƒƒ A: deficiency of factor VIII Ž PTT. ƒƒ B: deficiency of factor IX Ž PTT. Macrohemorrhage in hemophilia—hemarthroses (bleeding into joints), easy bruising, PTT. Treatment: recombinant factor VIII (in hemophilia A). Vitamin K deficiency General coagulation defect. Bleeding time normal. synthesis of factors II, VII, IX, X, protein C, protein S. Platelet disorders Defects in platelet plug formation Ž bleeding time (BT). Platelet abnormalities Ž microhemorrhage: mucous membrane bleeding, epistaxis, petechiae, purpura, bleeding time, possible platelet count (PC). DISO RDE R PC BT MEC HANISM AND COMMENTS Bernard-Soulier syndrome Defect in platelet plug formation. GpIb Ž defect in platelet-to-vWF adhesion. Glanzmann thrombasthenia – Defect in platelet plug formation. GpIIb/IIIa Ž defect in platelet-to-platelet aggregation. Labs: blood smear shows no platelet clumping. Immune thrombocytopenia Defect: anti-GpIIb/IIIa antibodies Ž splenic macrophage consumption of platelet/antibody complex. May be triggered by viral illness. platelet survival. Labs: megakaryocytes on bone marrow biopsy. Thrombotic thrombocytopenic purpura Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease) Ž degradation of vWF multimers. Pathogenesis: large vWF multimers Ž platelet adhesion Ž platelet aggregation and thrombosis. platelet survival. Labs: schistocytes, LDH. Symptoms: pentad of neurologic and renal symptoms, fever, thrombocytopenia, and microangiopathic hemolytic anemia. Treatment: exchange transfusion and steroids. Hematology and Oncology 390 SECT ION III hematology and oncology—Pathology Mixed platelet and coagulation disorders DISO RDE R PC BT PT PTT MEC HANISM AND COMMENTS von Willebrand disease — — — or Intrinsic pathway coagulation defect: vWF Ž normal or PTT (depends on severity; vWF acts to carry/protect factor VIII). Defect in platelet plug formation: vWF Ž defect in platelet-to-vWF adhesion. Mild but most common inherited bleeding disorder. Autosomal dominant. Diagnosed in most cases by ristocetin cofactor assay ( agglutination is diagnostic). Treatment: DDAVP, which releases vWF stored in endothelium. DIC Widespread activation of clotting leads to a deficiency in clotting factors, which creates a bleeding state. Causes: Sepsis (gram-negative), Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome, Transfusion (STOP Making New Thrombi). Labs: schistocytes, fibrin split products (d-dimers), fibrinogen, factors V and VIII. Hereditary thrombosis syndromes leading to hypercoagulability DISEASE DESC RIPTION Factor V Leiden Production of mutant factor V that is resistant to degradation by activated protein C. Most common cause of inherited hypercoagulability in whites. Prothrombin gene mutation Mutation in 3′ untranslated region Ž production of prothrombin Ž plasma levels and venous clots. Antithrombin deficiency Inherited deficiency of antithrombin: has no direct effect on the PT, PTT, or thrombin time but diminishes the increase in PTT following heparin administration. Can also be acquired: renal failure/nephrotic syndrome Ž antithrombin loss in urine Ž factors II and X. Protein C or S deficiency ability to inactivate factors V and VIII. risk of thrombotic skin necrosis with hemorrhage following administration of warfarin. Skin and subcutaneous tissue necrosis after warfarin administration Ž think protein C deficiency. “Protein C Cancels Coagulation.” Hematology and Oncology hematology and oncology—Pathology SECT ION III 391 Blood transfusion therapy COM PONENT DOSAGE EFFECT CLINICAL USE Packed RBCs Hb and O2 carrying capacity Acute blood loss, severe anemia Platelets platelet count ( ~5000/mm3/unit) Stop significant bleeding (thrombocytopenia, qualitative platelet defects) Fresh frozen plasma coagulation factor levels DIC, cirrhosis, warfarin overdose, exchange transfusion in TTP/HUS Cryoprecipitate Contains fibrinogen, factor VIII, factor XIII, vWF, and fibronectin Treat coagulation factor deficiencies involving fibrinogen and factor VIII Blood transfusion risks include infection transmission (low), transfusion reactions, iron overload, hypocalcemia (citrate is a calcium chelator), and hyperkalemia (RBCs may lyse in old blood units). Leukemia vs. lymphoma Leukemia Lymphoid or myeloid neoplasms with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood. Lymphoma Discrete tumor masses arising from lymph nodes. Presentations often blur definitions. Leukemoid reaction Acute inflammatory response to infection. WBC count with neutrophils and neutrophil precursors such as band cells (left shift); leukocyte ALP. Contrast with CML (also WBC count with left shift, but leukocyte ALP). Hodgkin vs. non‑Hodgkin lymphoma Hodgkin Non-Hodgkin Localized, single group of nodes; extranodal rare; contiguous spread (stage is strongest predictor of prognosis). Prognosis is much better than with non-Hodgkin lymphoma. Multiple, peripheral nodes; extranodal involvement common; noncontiguous spread Characterized by Reed-Sternberg cells Majority involve B cells (except those of lymphoblastic T-cell origin) Bimodal distribution–young adulthood and > 55 years; more common in men except for nodular sclerosing type Peak incidence for certain subtypes at 20–40 years old 50% of cases associated with EBV May be associated with HIV and immunosuppression Constitutional (“B”) signs/symptoms—lowgrade fever, night sweats, weight loss Fewer constitutional signs/symptoms Hematology and Oncology 392 SECT ION III hematology and oncology—Pathology Reed-Sternberg cells Distinctive tumor giant cell seen in Hodgkin disease; binucleate or bilobed with the 2 halves as mirror images (“owl eyes” A). RS cells are CD15+ and CD30+ B-cell origin. Necessary but not sufficient for a diagnosis of Hodgkin disease. Better prognosis with strong stromal or lymphocytic reaction against RS cells. Nodular sclerosing form most common (affects women and men equally). Lymphocyte-rich form has best prognosis. Lymphocyte mixed or depleted forms have poor prognosis. 2 owl eyes × 15 = 30. A Reed-Sternberg cell. Non-Hodgkin lymphoma TY PE OCC URS IN GENETICS COMMENTS Neoplasms of mature B cells Burkitt lymphoma A Adolescents or young adults B t(8;14)—translocation of c-myc (8) and heavy-chain Ig (14) “Starry sky” appearance A, sheets of lymphocytes with interspersed macrophages (arrows). Associated with EBV. Jaw lesion B in endemic form in Africa; pelvis or abdomen in sporadic form. Diffuse large B-cell lymphoma Usually older adults, but 20% in children t(14;18) Most common type of non-Hodgkin lymphoma in adults. Mantle cell lymphoma Older males t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14) CD5+. Follicular lymphoma Adults t(14;18)—translocation of heavy-chain Ig (14) and bcl-2 (18) Indolent course; bcl-2 inhibits apoptosis. Presents with painless “waxing and waning” lymphadenopathy. Neoplasms of mature T cells Adult T-cell lymphoma Adults Caused by HTLV-1 (associated with IV drug abuse) Adults present with cutaneous lesions; especially affects populations in Japan, West Africa, and the Caribbean. Lytic bone lesions, hypercalcemia. Mycosis fungoides/ Sézary syndrome Adults C Adults present with cutaneous patches C / plaques/tumors with potential to spread to lymph nodes and viscera. Circulating malignant cells seen in Sézary syndrome. Indolent, CD4+. Hematology and Oncology hematology and oncology—Pathology SECT ION III 393 Multiple myeloma A Monoclonal plasma cell (“fried egg” appearance) cancer that arises in the marrow and produces large amounts of IgG (55%) or IgA (25%). Most common 1° tumor arising within bone in the elderly (> 40–50 years old). Associated with: ƒƒ susceptibility to infection ƒƒ Primary amyloidosis (AL) ƒƒ Punched-out lytic bone lesions on x-ray A ƒƒM spike on serum protein electrophoresis ƒƒ Ig light chains in urine (Bence Jones protein) ƒƒ Rouleaux formation (RBCs stacked like poker chips in blood smear) Numerous plasma cells with “clock face” chromatin and intracytoplasmic inclusions containing immunoglobulin B. Distinguish from Waldenström macroglobulinemia Ž M spike = IgM (Ž hyperviscosity symptoms); no lytic bone lesions. Monoclonal gammopathy of undetermined significance (MGUS)—monoclonal expansion of plasma cells with serum monoclonal protein < 3g/dL (“M spike”) and bone marrow with < 10% monoclonal plasma cells. Asymptomatic precursor to multiple myeloma. Patients with MGUS develop multiple myeloma at a rate of 1–2% per year. Think CRAB: HyperCalcemia Renal insufficiency Anemia Bone lytic lesions/Back pain Multiple Myeloma: Monoclonal M protein spike Albumin 1 2 M spike B Multiple myeloma smear. Plasma cells with large eccentric nuclei (arrow). Myelodysplastic syndromes Stem cell disorders involving ineffective hematopoiesis Ž defects in cell maturation of all non-lymphoid lineages. Caused by de novo mutations or environmental exposure (e.g., radiation, benzene, chemotherapy). Risk of transformation to AML. Pseudo–Pelger-Huet anomaly—neutrophils with bilobed nuclei (two nuclear masses connected with a thin filament of chromatin) typically seen after chemotherapy. Hematology and Oncology 394 SECT ION III hematology and oncology—Pathology Leukemias Unregulated growth of leukocytes in bone marrow Ž or number of circulating leukocytes in blood and marrow failure Ž anemia ( RBCs), infections ( mature WBCs), and hemorrhage ( platelets); leukemic cell infiltrates in liver, spleen, and lymph nodes are possible. TY PE PERIPHERAL BLOOD SMEA R COMMENTS Lymphoid neoplasms Acute lymphoblastic leukemia/lymphoma (ALL) A Age: < 15 years. T-cell ALL can present as mediastinal mass (leukemic infiltration of the thymus). Associated with Down syndrome. Peripheral blood and bone marrow have lymphoblasts A. TdT+ (marker of pre-T and pre-B cells), CD10+ (pre-B cells only). Most responsive to therapy. May spread to CNS and testes. t(12;21) Ž better prognosis. Small lymphocytic lymphoma (SLL)/ chronic lymphocytic leukemia (CLL) B Age: > 60 years. CD20+, CD5+ B-cell neoplasm. Often asymptomatic, progresses slowly; smudge cells B in peripheral blood smear; autoimmune hemolytic anemia. SLL same as CLL except CLL has peripheral blood lymphocytosis or bone marrow involvement. Hairy cell leukemia C Age: Adults. Mature B-cell tumor in the elderly. Cells have filamentous, hair-like projections C . Stains TRAP (tartrate-resistant acid phosphatase ). TRAP stain largely replaced with flow cytometry. Causes marrow fibrosis Ž dry tap on aspiration. Treatment: cladribine (2-CDA), an adenosine analog (inhibits adenosine deaminase). Hematology and Oncology hematology and oncology—Pathology SECT ION III 395 Leukemias (continued) TY PE PERIPHERAL BLOOD SMEA R COMMENTS Myeloid neoplasms Acute myelogenous leukemia (AML) D Age: median onset 65 years. Auer rods D; peroxidase cytoplasmic inclusions seen mostly in M3 AML; circulating myeloblasts on peripheral smear; adults. Risk factors: prior exposure to alkylating chemotherapy, radiation, myeloproliferative disorders, Down syndrome. t(15;17) Ž M3 AML subtype responds to all-trans retinoic acid (vitamin A), inducing differentiation of myeloblasts; DIC is a common presentation in M3 AML and can be induced by chemotherapy due to release of Auer rods. Chronic myelogenous leukemia (CML) E Age: peak incidence 45–85 years, median age at diagnosis 64 years. Defined by the Philadelphia chromosome (t[9;22], bcr-abl); myeloid stem cell proliferation; presents with neutrophils, metamyelocytes, basophils E ; splenomegaly; may accelerate and transform to AML or ALL (“blast crisis”). Very low leukocyte alkaline phosphatase (LAP) as a result of low activity in mature granulocytes (vs. leukemoid reaction, in which LAP is ). Responds to imatinib (a small-molecule inhibitor of the bcr-abl tyrosine kinase). Chromosomal translocations TRANSLOCATION ASSOCIATED DISO RDE R t(9;22) (Philadelphia chromosome) CML (bcr-abl hybrid) Philadelphia CreaML cheese. t(8;14) Burkitt lymphoma (c-myc activation) t(11;14) Mantle cell lymphoma (cyclin D1 activation) t(14;18) Follicular lymphomas (bcl-2 activation) t(15;17) M3 type of AML (responsive to all-trans retinoic acid) Hematology and Oncology 396 SECT ION III hematology and oncology—Pathology Langerhans cell histiocytosis B Proliferative disorders of dendritic (Langerhans) cells from monocyte lineage. Presents in a child as lytic bone lesions A and skin rash or as recurrent otitis media with a mass involving the mastoid bone. Cells are functionally immature and do not efficiently stimulate primary T lymphocytes via antigen presentation. Cells express S-100 (mesodermal origin) and CD1a. Birbeck granules (“tennis rackets” on EM) are characteristic B. A Langerhans cell histiocytosis. Lytic lesion (arrow) in the skull. Hematology and Oncology hematology and oncology—Pathology SECT ION III 397 Chronic myeloproliferative disorders The myeloproliferative disorders represent an often-overlapping spectrum, but the classic findings are described below. JAK2 is involved in hematopoietic growth factor signaling. Mutations are implicated in myeloproliferative disorders other than CML. Polycythemia vera A Hematocrit > 55%, somatic (non-hereditary) mutation in JAK2 gene. Often presents as intense itching after hot shower. Rare but classic symptom is erythromelalgia (severe, burning pain and reddish or bluish coloration) due to episodic blood clots in vessels of the extremities A. 2° polycythemia is via natural or artificial in EPO levels. Essential thrombocytosis B Similar to polycythemia vera, but specific for overproduction of abnormal platelets Ž bleeding, thrombosis. Bone marrow contains enlarged megakaryocytes B. Myelofibrosis C Fibrotic obliteration of bone marrow C . Teardrop RBCs and immature forms of the myeloid line. “Bone marrow is crying because it’s fibrosed.” CML bcr-abl transformation leads to cell division and inhibition of apoptosis. Treatment: imatinib (Gleevec). RBCs WBCs PLATELETS PHILADEL PHIA CHROMOSOME JAK2 MUTATIONS Polycythemia vera Essential thrombocytosis - - (30–50%) Myelofibrosis Variable Variable (30–50%) CML Hematology and Oncology 398 SECT ION III hematology and oncology—ph armacology Polycythemia PLASMA VOLUME RBC MASS O2 SAT URATION EPO LE VELS ASSOCIATIONS Relative – – – plasma volume (dehydration, burns). Appropriate absolute – Lung disease, congenital heart disease, high altitude. Inappropriate absolute – – Renal cell carcinoma, Wilms tumor, cyst, hepatocellular carcinoma, hydronephrosis. Due to ectopic EPO. Polycythemia vera – Due to negative feedback. ``HEMATOLOGY AND ONCOLOGY —PHARMACOLOGY Heparin MEC HANISM Cofactor for the activation of antithrombin, thrombin, and factor Xa. Short half-life. CLINICAL USE Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT. Used during pregnancy (does not cross placenta). Follow PTT. TO XICITY Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin). NOTES Low-molecular-weight heparins (e.g., enoxaparin, dalteparin) act more on factor Xa, have better bioavailability and 2–4 times longer half-life. Can be administered subcutaneously and without laboratory monitoring. Not easily reversible. Heparin-induced thrombocytopenia (HIT)—development of IgG antibodies against heparin bound to platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets Ž thrombosis and thrombocytopenia. Argatroban, bivalirudin Derivatives of hirudin, the anticoagulant used by leeches; inhibit thrombin directly. Used instead of heparin for anticoagulating patients with HIT. Hematology and Oncology hematology and oncology—ph armacology SECT ION III 399 Warfarin (Coumadin) MEC HANISM Interferes with normal synthesis and γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, and X and proteins C and S. Metabolized by the cytochrome P-450 pathway. In laboratory assay, has effect on EXtrinsic pathway and PT. Long halflife. The EX-PresidenT went to war(farin). CLINICAL USE Chronic anticoagulation (after STEMI, venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation). Not used in pregnant women (because warfarin, unlike heparin, can cross the placenta). Follow PT/ INR values. TO XICITY A Bleeding, teratogenic, skin/tissue necrosis A, drug-drug interactions. For reversal of warfarin overdose, give vitamin K. For rapid reversal of severe warfarin overdose, give fresh frozen plasma. Direct factor Xa inhibitors Apixaban, rivaroxaban. MEC HANISM Bind and directly inhibit the activity of factor Xa. CLINICAL USE Treatment and prophylaxis of DVT and PE (rivaroxaban), stroke prophylaxis in patients with atrial fibrillation. Oral agents do not usually require coagulation monitoring. TO XICITY Bleeding (no specific reversal agent available). Hematology and Oncology 400 SECT ION III hematology and oncology—ph armacology Heparin vs. warfarin Heparin Warfarin ST RUCT URE Large anionic, acidic polymer Small lipid-soluble molecule ROUTE OF ADMINIST RATION Parenteral (IV, SC) Oral SITE OF ACTION Blood Liver ONSET OF ACTION Rapid (seconds) Slow, limited by half-lives of normal clotting factors MEC HANISM OF ACTION Activates antithrombin, which the action of IIa (thrombin) and factor Xa Impairs the synthesis of vitamin K–dependent clotting factors II, VII, IX, and X (vitamin K antagonist) DURATION OF ACTION Acute (hours) Chronic (days) IN HIBITS COAG ULATION IN VIT RO Yes No TREATMENT OF AC UTE OVERDOSE Protamine sulfate IV vitamin K and fresh frozen plasma MONITO RING PTT (intrinsic pathway) PT/INR (extrinsic pathway) CROSSES PLACENTA No Yes (teratogenic) Thrombolytics Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA). MEC HANISM Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. PT, PTT, no change in platelet count. CLINICAL USE Early MI, early ischemic stroke, direct thrombolysis of severe PE. TO XICITY Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies. Aspirin (ASA) MEC HANISM Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) enzyme by covalent acetylation. Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced: bleeding time, TXA2 and prostaglandins. No effect on PT or PTT. CLINICAL USE Antipyretic, analgesic, anti-inflammatory, antiplatelet ( aggregation). TO XICITY Gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Reye syndrome in children with viral infection. Overdose causes respiratory alkalosis initially, which is then superimposed by metabolic acidosis. ADP receptor inhibitors Clopidogrel, ticlopidine, prasugrel, ticagrelor. MEC HANISM Inhibit platelet aggregation by irreversibly blocking ADP receptors. Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa from binding to fibrinogen. CLINICAL USE Acute coronary syndrome; coronary stenting. incidence or recurrence of thrombotic stroke. TO XICITY Neutropenia (ticlopidine). TTP/HUS may be seen. Hematology and Oncology hematology and oncology—ph armacology SECT ION III 401 Cilostazol, dipyridamole MEC HANISM Phosphodiesterase III inhibitor; cAMP in platelets, thus inhibiting platelet aggregation; vasodilators. CLINICAL USE Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), angina prophylaxis. TO XICITY Nausea, headache, facial flushing, hypotension, abdominal pain. GP IIb/IIIa inhibitors Abciximab, eptifibatide, tirofiban. MEC HANISM Bind to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abciximab is made from monoclonal antibody Fab fragments. CLINICAL USE Unstable angina, percutaneous transluminal coronary angioplasty. TO XICITY Bleeding, thrombocytopenia. Cancer drugs—cell cycle Bleomycin Etoposide Vinca alkaloids and taxols Antimetabolites Synthesis of components needed for DNA synthesis Synthesis of components needed for mitosis DNA synthesis G1 S G2 Differentiation Resting G0 – – – – – M Hematology and Oncology 402 SECT ION III hematology and oncology—ph armacology Antineoplastics Nucleotide synthesis DNA RNA Cellular division MTX, 5-FU: thymidine synthesis 6-MP: purine synthesis Alkylating agents, cisplatin: cross-link DNA Dactinomycin, doxorubicin: DNA intercalators Etoposide: inhibits topoisomerase II Vinca alkaloids: inhibit microtubule formation Paclitaxel: inhibits microtubule disassembly Protein Hematology and Oncology hematology and oncology—ph armacology SECT ION III 403 Antimetabolites DRUG MEC HANISM a CLINICAL USE TO XICITY Methotrexate (MTX) Folic acid analog that inhibits dihydrofolate reductase Ž dTMP Ž DNA and protein synthesis. Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas. Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis, IBD. Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue.” Macrovesicular fatty change in liver. Mucositis. Teratogenic. 5-fluorouracil (5-FU) Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase Ž dTMP Ž DNA and protein synthesis. Colon cancer, pancreatic cancer, basal cell carcinoma (topical). Myelosuppression, which is not reversible with leucovorin. Overdose: “rescue” with uridine. Photosensitivity. Cytarabine (arabinofuranosyl cytidine) Pyrimidine analog Ž inhibition of DNA polymerase. Leukemias, lymphomas. Leukopenia, thrombocytopenia, megaloblastic anemia. CYTarabine causes panCYTopenia. Azathioprine 6-mercaptopurine (6-MP) 6-thioguanine (6-TG) Purine (thiol) analogs Ž de novo purine synthesis. Activated by HGPRT. Preventing organ rejection, RA, SLE (azathioprine). Leukemia, IBD (6-MP, 6-TG). Bone marrow, GI, liver. Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have toxicity with allopurinol, which inhibits their metabolism. aAll are S-phase specific. 5-FU Thymidylate synthase dUMP dTMP CH2-THF DHF THF DHF reductase MTX Hematology and Oncology 404 SECT ION III hematology and oncology—ph armacology Antitumor antibiotics DRUG MEC HANISM CLINICAL USE TO XICITY Dactinomycin (actinomycin D) Intercalates in DNA. Wilms tumor, Ewing sarcoma, rhabdomyosarcoma. Used for childhood tumors (“children act out”). Myelosuppression. Doxorubicin (Adriamycin), daunorubicin Generate free radicals. Intercalate in DNA Ž breaks in DNA Ž replication. Solid tumors, leukemias, lymphomas. Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. Toxic to tissues following extravasation. Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity. Bleomycin Induces free radical formation, which causes breaks in DNA strands. Testicular cancer, Hodgkin lymphoma. Pulmonary fibrosis, skin changes, mucositis. Minimal myelosuppression. Alkylating agents DRUG MEC HANISM CLINICAL USE TO XICITY Cyclophosphamide, ifosfamide Covalently X-link (interstrand) DNA at guanine N-7. Require bioactivation by liver. Solid tumors, leukemia, lymphomas, and some brain cancers. Myelosuppression; hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolites). Nitrosoureas (carmustine, lomustine, semustine, streptozocin) Require bioactivation. Cross blood-brain barrier Ž CNS. Cross-links DNA. Brain tumors (including glioblastoma multiforme). CNS toxicity (convulsions, dizziness, ataxia). Busulfan Cross-links DNA. CML. Also used to ablate patient’s bone marrow before bone marrow transplantation. Severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation. Hematology and Oncology hematology and oncology—ph armacology SECT ION III 405 Microtubule inhibitors DRUG MEC HANISM CLINICAL USE TO XICITY Vincristine, vinblastine Vinca alkaloids that bind β-tubulin, inhibit its polymerization into microtubules, thereby preventing mitotic spindle formation (M-phase arrest). Solid tumors, leukemias, and lymphomas. Vincristine—neurotoxicity (areflexia, peripheral neuritis), paralytic ileus. Vinblastine blasts bone marrow (suppression). Paclitaxel, other taxols Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur). “It is taxing to stay polymerized.” Ovarian and breast carcinomas. Myelosuppression, alopecia, hypersensitivity. Cisplatin, carboplatin MEC HANISM Cross-link DNA. CLINICAL USE Testicular, bladder, ovary, and lung carcinomas. TO XICITY Nephrotoxicity and acoustic nerve damage. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride diuresis. Etoposide, teniposide MEC HANISM Etoposide inhibits topoisomerase II Ž DNA degradation. CLINICAL USE Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas. TO XICITY Myelosuppression, GI irritation, alopecia. Irinotecan, topotecan MEC HANISM Inhibit topoisomerase I and prevent DNA unwinding and replication. CLINICAL USE Colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan). TO XICITY Severe myelosuppression, diarrhea. Hydroxyurea MEC HANISM Inhibits ribonucleotide reductase Ž DNA Synthesis (S-phase specific). CLINICAL USE Melanoma, CML, sickle cell disease ( HbF). TO XICITY Bone marrow suppression, GI upset. Hematology and Oncology 406 SECT ION III hematology and oncology—ph armacology Prednisone, prednisolone MEC HANISM May trigger apoptosis. May even work on nondividing cells. CLINICAL USE Most commonly used glucocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin lymphomas (part of combination chemotherapy regimen). Also used as immunosuppressants (e.g., autoimmune diseases). TO XICITY Cushing-like symptoms; weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis. Tamoxifen, raloxifene MEC HANISM Selective estrogen receptor modulators (SERMs)—receptor antagonists in breast and agonists in bone. Block the binding of estrogen to ER cells. CLINICAL USE Breast cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent osteoporosis. TO XICITY Tamoxifen—partial agonist in endometrium, which the risk of endometrial cancer; “hot flashes.” Raloxifene—no in endometrial carcinoma because it is an endometrial antagonist. Trastuzumab (Herceptin) MEC HANISM Monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill breast cancer cells that overexpress HER-2, through inhibition of HER2-initiated cellular signaling and antibody-dependent cytotoxicity. CLINICAL USE HER-2 breast cancer and gastric cancer (tras2zumab). TO XICITY Cardiotoxicity. “HEARTceptin” damages the HEART. Imatinib (Gleevec) MEC HANISM Tyrosine kinase inhibitor of bcr-abl (Philadelphia chromosome fusion gene in CML) and c-Kit (common in GI stromal tumors). CLINICAL USE CML, GI stromal tumors. TO XICITY Fluid retention. Rituximab MEC HANISM Monoclonal antibody against CD20, which is found on most B-cell neoplasms. CLINICAL USE Non-Hodgkin lymphoma, rheumatoid arthritis (with MTX), ITP. TO XICITY risk of progressive multifocal leukoencephalopathy. Vemurafenib MEC HANISM Small molecule inhibitor of forms of the B-Raf kinase with the V600E mutation. CLINICAL USE Metastatic melanoma. Hematology and Oncology hematology and oncology—ph armacology SECT ION III 407 Bevacizumab MEC HANISM Monoclonal antibody against VEGF. Inhibits angiogenesis. CLINICAL USE Solid tumors (colorectal cancer, renal cell carcinoma). TO XICITY Hemorrhage and impaired wound healing. Common chemotoxicities CHEMO-TOX MAN T Cisplatin/Carboplatin Ž acoustic nerve damage (and nephrotoxicity) Vincristine Ž peripheral neuropathy Bleomycin, Busulfan Ž pulmonary fibrosis Doxorubicin Ž cardiotoxicity Trastuzumab Ž cardiotoxicity Cisplatin/Carboplatin Ž nephrotoxic (and acoustic nerve damage) CYclophosphamide Ž hemorrhagic cystitis 5-FU Ž myelosuppression 6-MP Ž myelosuppression Methotrexate Ž myelosuppression SECT ION III 408 Hematology and Oncology ``NOTES 409 ``Anatomy and Physiology 410 ``Pathology 419 ``Pharmacology 439 HI G H -Y I ELD SYSTEMS “Rigid, the skeleton of habit alone upholds the human frame.” —Virginia Woolf “Beauty may be skin deep, but ugly goes clear to the bone.” —Redd Foxx “The function of muscle is to pull and not to push, except in the case of the genitals and the tongue.” —Leonardo da Vinci Musculoskeletal, Skin, and Connective Tissue Musculoskeletal, Skin, and Connective 410 SECTION III Tissue anatomy and physiology ``MUSCULOS KELETAL , SKIN , AND CONN ECTIVE TISS UE—ANATOMY AND PHYSIOLOGY Epidermis layers From surface to base: ƒƒ Stratum Corneum (keratin) ƒƒ Stratum Lucidum ƒƒ Stratum Granulosum ƒƒ Stratum Spinosum (spines = desmosomes) ƒƒ Stratum Basale (stem cell site) Californians Like Girls in String Bikinis. A Epidermis layers. A, Stratum corneum; B, stratum lucidum; C, stratum granulosum; D, stratum spinosum; E, stratum basale. A B C D E Epithelial cell junctions Tight junction (zonula occludens)—prevents paracellular movement of solutes; composed of claudins and occludins. Adherens junction (zonula adherens)—below tight junction, forms “belt” connecting actin cytoskeletons of adjacent cells with CADherins (Ca2+-dependent adhesion proteins). Loss of E-cadherin promotes metastasis. Desmosome (macula adherens)—structural support via keratin interactions. Autoantibodies pemphigus vulgaris. Gap junction—channel proteins called connexons permit electrical and chemical communication between cells. Hemidesmosome—connects keratin in basal cells to underlying basement membrane. Autoantibodies bullous pemphigoid. (Hemidesmosomes are down “bullow”). Integrins—membrane proteins that maintain integrity of basolateral membrane by binding to collagen and laminin in basement membrane. Cell membrane Basolateral Basement membrane Apical E-cadherin Desmoplakin Keratin Connexon with central channel Actin filaments Musculoskeletal, Skin, and Connective Tissue anatomy and physiology SECTION III 411 Knee injury Presents with acute knee pain and signs of joint injury/instability: ƒƒ Anterior drawer sign Ž ACL injury ƒƒ Posterior drawer sign Ž PCL injury ƒƒ Abnormal passive abduction (valgus stress) Ž MCL injury ƒƒ Abnormal passive adduction (varus stress) Ž LCL injury ƒƒMcMurray test: pain on external rotation Ž medial meniscus; pain on internal rotation Ž lateral meniscus. Unhappy triad—common injury in contact sports due to lateral force applied to a planted leg. Classically, consists of damage to the ACL, MCL, and medial meniscus (attached to MCL); however, lateral meniscus injury is more common. “Anterior” and “posterior” in ACL and PCL refer to sites of tibial attachment. Medial condyle Medial meniscus Tibia PCL MCL Femur Fibula Lateral condyle Lateral meniscus ACL LCL Clinically important landmarks Pudendal nerve block (to relieve pain of delivery)—ischial spine. Appendix—2/3 of the distance between the umbilicus and the anterior superior iliac spine (ASIS), just proximal to the ASIS (McBurney point). Lumbar puncture—iliac crest. Rotator cuff muscles Shoulder muscles that form the rotator cuff: ƒƒ Supraspinatus (suprascapular nerve)— abducts arm initially (before the action of the deltoid); most common rotator cuff injury. ƒƒ Infraspinatus (suprascapular nerve)— laterally rotates arm; pitching injury. ƒƒ Teres minor (axillary nerve)—adducts and laterally rotates arm. ƒƒ Subscapularis (subscapular nerve)—medially rotates and adducts arm. Innervated primarily by C5-C6. SItS (small t is for teres minor). Biceps tendon Posterior Anterior Subscapularis Acromion Infraspinatus Teres minor Supraspinatus Coracoid Musculoskeletal, Skin, and Connective 412 SECTION III Tissue anatomy and physiology Wrist bones Scaphoid, Lunate, Triquetrum, Pisiform, Hamate, Capitate, Trapezoid, Trapezium A . (So Long To Pinky, Here Comes The Thumb). Scaphoid (palpated in anatomical snuff box) is the most commonly fractured carpal bone and is prone to avascular necrosis owing to retrograde blood supply. Dislocation of lunate may cause acute carpal tunnel syndrome. A fall on an outstretched hand that damages the hook of the hamate can cause ulnar nerve injury. Carpal tunnel syndrome: entrapment of median nerve in carpal tunnel; nerve compression Ž paresthesia, pain, and numbness in distribution of median nerve. Guyon canal syndrome: Compression of the ulnar nerve at the wrist or hand, classically seen in cyclists due to pressure from handlebars. A Bones of wrist. Trapezium Base of thumb Distal radius Ulnar styloid Base 5th MC Trapezoid Scaphoid Capitate Lunate Hamate Triquetrum Pisiform Musculoskeletal, Skin, and Connective Tissue anatomy and physiology SECTION III 413 Brachial plexus lesions C5 C6 C7 C8 T1 Long thoracic Musculocutaneous Median Ulnar Axillary Radial Roots Trunks Divisions Upper Middle Lower Lateral Posterior Medial Cords Branches (Extensors) (Flexors) 1. Erb palsy (“waiter’s tip”) 2. Claw hand (Klumpke palsy) 3. Wrist drop 4. Winged scapula 5. Deltoid paralysis 6. “Saturday night palsy” (wrist drop) 7. Difficulty flexing elbow, variable sensory loss 8. Decreased thumb function, “Pope’s blessing” 9. Intrinsic muscles of hand, claw hand CONDITION IN JURY CAUSES MUSCLE DEFICIT FUNCTIONAL DEFICIT PRESENTATION Erb palsy (“waiter’s tip”) Traction or tear of upper (“Erb-er”) trunk: C5-C6 roots Infants—lateral traction on neck during delivery Adults—trauma Deltoid, supraspinatus Abduction (arm hangs by side) Erb-Duchenne palsy (”waiter’s tip”) Infraspinatus Lateral rotation (arm medially rotated) Biceps brachii Flexion, supination (arm extended and pronated) Klumpke palsy Traction or tear of lower trunk: C8-T1 root Infants—upward force on arm during delivery Adults—trauma (e.g., grabbing a tree branch to break a fall) Intrinsic hand muscles: lumbricals, interossei, thenar, hypothenar Total claw hand: lumbricals normally flex MCP joints and extend DIP and PIP joints Thoracic outlet syndrome Compression of lower trunk and subclavian vessels Cervical rib injury; Pancoast tumor Same as Klumpke palsy Atrophy of intrinsic hand muscles; ischemia, pain, and edema due to vascular compression Winged scapula Lesion of long thoracic nerve Axillary node dissection after mastectomy, stab wounds Serratus anterior Inability to anchor scapula to thoracic cage Ž cannot abduct arm above horizontal position Randy Travis Drinks Cold Beer Musculoskeletal, Skin, and Connective 414 SECTION III Tissue anatomy and physiology Upper extremity nerves NERVE CAUSES OF IN JURY PRESENTATION Axillary (C5-C6) Fractured surgical neck of humerus; anterior dislocation of humerus Flattened deltoid Loss of arm abduction at shoulder (> 15 degrees) Loss of sensation over deltoid muscle and lateral arm Musculocutaneous (C5-C7) Upper trunk compression Loss of forearm flexion and supination Loss of sensation over lateral forearm Radial (C5-T1) Midshaft fracture of humerus; compression of axilla (e.g., due to crutches or sleeping with arm over chair (“Saturday night palsy”) Wrist drop: loss of elbow, wrist, and finger extension grip strength (wrist extension necessary for maximal action of flexors) Loss of sensation over posterior arm/forearm and dorsal hand Median (C5-T1) Supracondylar fracture of humerus (proximal lesion); carpal tunnel syndrome and wrist laceration (distal lesion) “Ape hand” and “Pope’s blessing” Loss of wrist and lateral finger flexion, thumb opposition, lumbricals of 2nd and 3rd digits Loss of sensation over thenar eminence and dorsal and palmar aspects of lateral 31⁄2 fingers with proximal lesion Tinel sign (tingling on percussion) in carpal tunnel syndrome Ulnar (C8-T1) Fracture of medial epicondyle of humerus “funny bone” (proximal lesion); fractured hook of hamate (distal lesion) “Ulnar claw” on digit extension Radial deviation of wrist upon flexion (proximal lesion) Loss of flexion of wrist and medial fingers, abduction and adduction of fingers (interossei), actions of medial 2 lumbrical muscles Loss of sensation over medial 11/2 fingers including hypothenar eminence Recurrent branch of median nerve (C5-T1) Superficial laceration of palm “Ape hand” Loss of thenar muscle group: opposition, abduction, and flexion of thumb No loss of sensation Axillary nerve Musculocutaneous nerve Radial nerve Median nerve Ulnar nerve Median nerve Ulnar nerve Radial nerve in spiral groove Radial nerve Recurrent branch of median nerve Ulnar nerve Dorsum of hand Median nerve Radial nerve (superficial branch) Ulnar nerve Palm of hand Median nerve Radial nerve (superficial branch) Musculoskeletal, Skin, and Connective Tissue anatomy and physiology SECTION III 415 Distortions of the hand At rest, a balance exists between the extrinsic flexors and extensors of the hand, as well as the intrinsic muscles of the hand—particularly the lumbrical muscles (flexion of MCP, extension of DIP and PIP joints). “Clawing”—seen best with distal lesions of median or ulnar nerves. Remaining extrinsic flexors of the digits exaggerate the loss of the lumbricals Ž fingers extend at MCP, flex at DIP and PIP joints. Deficits less pronounced in proximal lesions; deficits present during voluntary flexion of the digits. PRESENTATION CONT EXT Extending fingers/at rest Making a fist Extending fingers / at rest Making a fist LO CATION OF LESION Distal ulnar nerve Proximal median nerve Distal median nerve Proximal ulnar nerve SIGN “Ulnar claw” “Pope’s blessing” “Median claw” “OK gesture” (with digits 1–3 flexed) Note: Atrophy of the thenar eminence (unopposable thumb Ž “ape hand”) can be seen in median nerve lesions, while atrophy of the hypothenar eminence can be seen in ulnar nerve lesions. Hand muscles Thenar eminence Hypothenar eminence Thenar (median)—Opponens pollicis, Abductor pollicis brevis, Flexor pollicis brevis. Hypothenar (ulnar)—Opponens digiti minimi, Abductor digiti minimi, Flexor digiti minimi brevis. Dorsal interosseous muscles—abduct the fingers. Palmar interosseous muscles—adduct the fingers. Lumbrical muscles—flex at the MCP joint, extend PIP and DIP joints. Both groups perform the same functions: Oppose, Abduct, and Flex (OAF). DAB = Dorsals ABduct. PAD = Palmars ADduct. Musculoskeletal, Skin, and Connective 416 SECTION III Tissue anatomy and physiology Lower extremity nerves NERVE CAUSE OF IN JURY PRESENTATION Obturator (L2–L4) Pelvic surgery thigh sensation (medial) and adduction. Femoral (L2–L4) Pelvic fracture thigh flexion and leg extension. Common peroneal (L4–S2) Trauma or compression of lateral aspect of leg, fibular neck fracture Foot drop—inverted and plantarflexed at rest, loss of eversion and dorsiflexion. “Steppage gait.” Loss of sensation on dorsum of foot. Tibial (L4–S3) Knee trauma, Baker cyst (proximal lesion); tarsal tunnel syndrome (distal lesion) Inability to curl toes and loss of sensation on sole of foot. In proximal lesions, foot everted at rest with loss of inversion and plantarflexion. Superior gluteal (L4–S1) Posterior hip dislocation, polio Trendelenburg sign/gait—pelvis tilts because weight-bearing leg cannot maintain alignment of pelvis through hip abduction (superior nerve Ž medius and minimus). Lesion is contralateral to the side of the hip that drops, ipsilateral to extremity on which the patient stands. Inferior gluteal (L5–S2) Posterior hip dislocation Difficulty climbing stairs, rising from seated position. Loss of hip extension (inferior nerve Ž maximus). PED = Peroneal Everts and Dorsiflexes; if injured, foot dropPED. TIP = Tibial Inverts and Plantarflexes; if injured, can’t stand on TIPtoes. Sciatic nerve (L4–S3)—posterior thigh, splits into common peroneal and tibial nerves. Neurovascular pairing Nerves and arteries are frequently named together by the bones/regions with which they are associated. The following are exceptions to this naming convention. LO CATION NERVE ARTERY Axilla/lateral thorax Long thoracic Lateral thoracic Surgical neck of humerus Axillary Posterior circumflex Midshaft of humerus Radial Deep brachial Distal humerus/ cubital fossa Median Brachial Popliteal fossa Tibial Popliteal Posterior to medial malleolus Tibial Posterior tibial Musculoskeletal, Skin, and Connective Tissue anatomy and physiology SECTION III 417 Muscle conduction to contraction T tubule M line Z line Sarcoplasm Myosin Sarcoplasmic reticulum Actin Mitochondrion Sarcomere A band H band Myofibril I band Ryanodine receptor Cytosol T-tubule membrane Ca2+ Dihydropyridine receptor Sarcoplasmic reticulum Exterior Muscle contraction 1. Action potential depolarization opens presynaptic voltage-gated Ca2+ channels, inducing neurotransmitter release. 2. Postsynaptic ligand binding leads to muscle cell depolarization in the motor end plate. 3. Depolarization travels along muscle cell and down the T tubule. 4. Depolarization of the voltage-sensitive dihydropyridine receptor, mechanically coupled to the ryanodine receptor on the sarcoplasmic reticulum, induces a conformational change, causing Ca2+ release from sarcoplasmic reticulum. 5. Released Ca2+ binds to troponin C, causing a conformational change that moves tropomyosin out of the myosin-binding groove on actin filaments. 6. Myosin releases bound ADP and subsequently, inorganic PO4 3– Ž displacement of myosin on the actin filament (power stroke). Contraction results in shortening of H and I bands and between Z lines (HIZ shrinkage), but the A band remains the same length (A band is Always the same length). Types of muscle fibers Type 1 muscle Slow twitch; red fibers resulting from mitochondria and myoglobin concentration ( oxidative phosphorylation) Ž sustained contraction. Think “1 slow red ox.” Type 2 muscle Fast twitch; white fibers resulting from mitochondria and myoglobin concentration ( anaerobic glycolysis); weight training results in hypertrophy of fast-twitch muscle fibers. Musculoskeletal, Skin, and Connective 418 SECTION III Tissue anatomy and physiology Smooth muscle contraction Ca2+–calmodulin complex cGMP GTP Myosin–light-chain phosphatase (MLCP) L-type voltage gated Ca2+ channel Ca2+ Ca2+ CONTRACTION RELAXATION Myosin + actin CONTRACTION (via cross-bridging) Myosin-P + actin – – – Membrane depolarization Action potential Guanylate cyclase Smooth muscle cell Myosin–light-chain kinase (MLCK) Ca2+ Nitric oxide Nitric oXide RELAXATION Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 419 Bone formation Endochondral ossification Bones of axial and appendicular skeleton, and base of the skull. Cartilaginous model of bone is first made by chondrocytes. Osteoclasts and osteoblasts later replace with woven bone and then remodel to lamellar bone. In adults, woven bone occurs after fractures and in Paget disease. Membranous ossification Bones of calvarium and facial bones. Woven bone formed directly without cartilage. Later remodeled to lamellar bone. Cell biology of bone Osteoblasts Build bone by secreting collagen and catalyzing mineralization. Differentiate from mesenchymal stem cells in periosteum. Osteoclasts Multinucleated cells that dissolve bone by secreting acid and collagenases. Differentiate from monocytes/macrophages. Parathyroid hormone At low, intermittent levels, exerts anabolic effects (building bone) on osteoblasts and osteoclasts (indirect). Chronic high PTH levels (1° hyperparathyroidism) cause catabolic effects (osteitis fibrosa cystica). Estrogen Estrogen inhibits apoptosis in bone-forming osteoblasts and induces apoptosis in bone-resorbing osteoclasts. Under estrogen deficiency (surgical or postmenopausal), excess remodeling cycles and bone resorption lead to osteoporosis. ``MUSCULOS KELETAL , SKIN , AND CONN ECTIVE TISS UE—PATHOLOGY Achondroplasia Failure of longitudinal bone growth (endochondral ossification) Ž short limbs. Membranous ossification is not affected Ž large head relative to limbs. Constitutive activation of fibroblast growth factor receptor (FGFR3) actually inhibits chondrocyte proliferation. > 85% of mutations occur sporadically and are associated with advanced paternal age, but the condition also demonstrates autosomal dominant inheritance. Common cause of dwarfism. Normal life span and fertility. Osteoporosis Trabecular (spongy) bone loses mass and interconnections despite normal bone mineralization and lab values (serum Ca2+ and PO4 3-). Diagnosis by a bone mineral density test (DEXA) with a T-score of ≤ -2.5. Can be caused by long-term exogenous steroid use. Can lead to vertebral crush fractures—acute back pain, loss of height, kyphosis. Type I Postmenopausal: bone resorption due to estrogen levels. Femoral neck fracture, distal radius (Colles) fracture. Type II Senile osteoporosis: affects men and women > 70 years old. Mild compression fracture Normal vertebrae Prophylaxis: regular weight-bearing exercise and adequate calcium and vitamin D intake throughout adulthood. Treatment: bisphosphonates, PTH, SERMs, rarely calcitonin; denosumab (monoclonal antibody against RANKL). Musculoskeletal, Skin, and Connective 420 SECTION III Tissue Pathology Osteopetrosis (marble bone disease) Failure of normal bone resorption due to defective osteoclasts Ž thickened, dense bones that are prone to fracture. Bone fills marrow space Ž pancytopenia, extramedullary hematopoiesis. Mutations (e.g., carbonic anhydrase II) impair ability of osteoclast to generate acidic environment necessary for bone resorption. X-rays show bone-inbone appearance A. Can result in cranial nerve impingement and palsies as a result of narrowed foramina. Bone marrow transplant is potentially curative as osteoclasts are derived from monocytes. A Osteopetrosis. Radiograph of the pelvis shows diffusely dense bones. Osteomalacia/rickets Vitamin D deficiency. Osteomalacia in adults; rickets in children. Due to defective mineralization/ calcification of osteoid Ž soft bones that bow out. vitamin D Ž serum calcium Ž PTH secretion Ž serum PO4 3-. Hyperactivity of osteoblasts Ž ALP (osteoblasts require alkaline environment). Paget disease of bone (osteitis deformans) Common, localized disorder of bone remodeling caused by in both osteoblastic and osteoclastic activity. Serum Ca2+, phosphorus, and PTH levels are normal. ALP. Mosaic pattern of woven and lamellar bone A ; long bone chalk-stick fractures. blood flow from arteriovenous shunts may cause high-output heart failure. risk of osteogenic sarcoma. Hat size can be increased B; hearing loss is common due to auditory foramen narrowing. Stages of Paget disease: ƒƒ Lytic—osteoclasts ƒƒMixed—osteoclasts + osteoblasts ƒƒ Sclerotic—osteoblasts ƒƒQuiescent—minimal osteoclast/osteoblast activity A Paget disease of bone. H&E stain shows osteocytes within lacunae (scattered small white dots) and chaotic, mosaic pattern (lacy purple lines) of bone remodeling. B Paget disease of bone. Note marked thickening of calvarium. Osteonecrosis (avascular necrosis) Infarction of bone and marrow, usually very painful. Caused by trauma, high-dose corticosteroids, alcoholism, sickle cell. Most common site is femoral head (due to insufficiency of medial circumflex femoral artery). Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 421 Lab values in bone disorders DISO RDER SERUM Ca2+ PO4 3- ALP PTH COMM ENTS Osteoporosis — — — — bone mass Osteopetrosis —/ — — — Dense, brittle bones. Ca2+ in severe, malignant disease Paget disease — — — Abnormal “mosaic” bone architecture Osteomalacia/rickets Soft bones Hypervitaminosis D — Caused by over-supplementation or granulomatous disease (e.g., sarcoidosis) Osteitis fibrosa cystica 1° hyperparathyroidism 2° hyperparathyroidism “Brown tumors” due to fibrous replacement of bone, subperiosteal thinning Idiopathic or parathyroid hyperplasia, adenoma, carcinoma Often as compensation for ESRD ( PO4 3- excretion and production of activated vitamin D) Musculoskeletal, Skin, and Connective 422 SECTION III Tissue Pathology Primary bone tumors TUMOR TYP E EPID EMIOLOGY /LO CATION CHA RACTERISTI CS Benign tumors Giant cell tumor A 20–40 years old. Epiphyseal end of long bones. Locally aggressive benign tumor often around knee. “Soap bubble” appearance on x-ray A. Multinucleated giant cells. Osteochondroma (exostosis) Most common benign tumor. Males < 25 years old. Mature bone with cartilaginous cap. Rarely transforms to chondrosarcoma. Malignant tumors Osteosarcoma (osteogenic sarcoma) B 2nd most common 1° malignant bone tumor (after multiple myeloma). Bimodal distribution: 10–20 years old (1°), > 65 (2°). Predisposing factors: Paget disease of bone, bone infarcts, radiation, familial retinoblastoma, Li-Fraumeni syndrome (germline P53 mutation). Metaphysis of long bones, often around knee B C . Codman triangle (from elevation of periosteum) or sunburst pattern on x-ray. Aggressive. Treat with surgical en bloc resection (with limb salvage) and chemotherapy. C Osteosarcoma. Lucent lesion on x-ray B now better seen on MRI as heterogeneous mass with periosteal elevation. Ewing sarcoma D Boys < 15 years old. Commonly appears in diaphysis of long bones, pelvis, scapula, and ribs. Anaplastic small blue cell malignant tumor D. Extremely aggressive with early metastases, but responsive to chemotherapy. “Onion skin” appearance in bone. Associated with t(11;22) translocation. 11 + 22 = 33 (Patrick Ewing’s jersey number). Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 423 Primary bone tumors (continued) TUMOR TYP E EPID EMIOLOGY /LO CATION CHA RACTERISTI CS Malignant tumors (continued) Chondrosarcoma Rare, malignant, cartilaginous tumor. Men 30–60 years old. Usually located in pelvis, spine, scapula, humerus, tibia, or femur. Malignant cartilaginous tumor. May be of 1° origin or from osteochondroma. Expansile glistening mass within the medullary cavity. Benign Malignant Epiphysis Metaphysis Diaphysis Metaphysis Epiphysis Ewing sarcoma Chondrosarcoma Osteosarcoma (Codman triangle) Osteochondroma (exostosis) Giant cell tumor (soap bubble) Musculoskeletal, Skin, and Connective 424 SECTION III Tissue Pathology Osteoarthritis and rheumatoid arthritis Osteoarthritis Rheumatoid arthritis ETIOLOGY Mechanical—joint wear and tear destroys articular cartilage. Autoimmune—inflammatory destruction of synovial joints. Mediated by cytokines and type III and type IV hypersensitivity reactions. JOINT FINDINGS Subchondral cysts, sclerosis A , osteophytes (bone spurs), eburnation (polished, ivorylike appearance of bone), Heberden nodes (DIP), and Bouchard nodes (PIP). No MCP involvement. Pannus formation in joints (MCP, PIP), subcutaneous rheumatoid nodules (fibrinoid necrosis), ulnar deviation of fingers, subluxation B , Baker cyst (in popliteal fossa). No DIP involvement. PREDISPOSING FACTO RS Age, obesity, joint deformity, trauma. Females > males. 80% have rheumatoid factor (anti-IgG antibody); anti–cyclic citrullinated peptide antibody is more specific. Strong association with HLA-DR4. CLASSI C PRESENTATION Pain in weight-bearing joints after use (e.g., at the end of the day), improving with rest. Knee cartilage loss begins medially (“bowlegged”). Noninflammatory. No systemic symptoms. Morning stiffness lasting > 30 minutes and improving with use, symmetric joint involvement, systemic symptoms (fever, fatigue, pleuritis, pericarditis). TREATM ENT NSAIDs, intra-articular glucocorticoids. NSAIDs, glucocorticoids, disease-modifying agents (methotrexate, sulfasalazine, TNF-α inhibitors). Thickened capsule Slight synovial hypertrophy Osteophyte Ulcerated cartilage Sclerotic bone Joint space narrowing Subchondral bone cyst Synovial cavity Cartilage Normal Osteoarthritis Bone and cartilage erosion Increased synovial fluid Pannus formation Joint capsule and synovial lining Joint capsule and synovial lining Normal Rheumatoid arthritis Cartilage Synovial cavity B Rheumatoid arthritis. Note boutonnière deformities of PIP joints with ulnar deviation. A Osteoarthritis. X-rays of the knee show joint space narrowing and sclerosis (arrows). Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 425 Sjögren syndrome Autoimmune disorder characterized by destruction of exocrine glands (especially lacrimal and salivary). Predominantly affects females 40–60 years old. Findings: ƒƒ Xerophthalmia ( tear production and subsequent corneal damage) ƒƒ Xerostomia ( saliva production) ƒƒ Presence of antinuclear antibodies: SS-A (anti-Ro) and/or SS-B (anti-La) ƒƒ Bilateral parotid enlargement Can be a 1° disorder or a 2° syndrome associated with other autoimmune disorders (e.g., rheumatoid arthritis). Complications—dental caries; mucosaassociated lymphoid tissue (MALT) lymphoma (may present as unilateral parotid enlargement). Gout FINDINGS Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in joints A. Associated with hyperuricemia, which can be caused by: ƒƒ Underexcretion of uric acid (90% of patients)—largely idiopathic; can be exacerbated by certain medications (e.g., thiazide diuretics). ƒƒOverproduction of uric acid (10% of patients)—Lesch-Nyhan syndrome, PRPP excess, cell turnover (e.g., tumor lysis syndrome), von Gierke disease. Crystals are needle shaped and birefringent (yellow under parallel light, blue under perpendicular light). More common in males. SYMPTOMS Asymmetric joint distribution. Joint is swollen, red, and painful B. Classic manifestation is painful MTP joint of the big toe (podagra). Tophus formation (often on external ear, olecranon bursa, or Achilles tendon). Acute attack tends to occur after a large meal or alcohol consumption (alcohol metabolites compete for same excretion sites in kidney as uric acid, causing uric acid secretion and subsequent buildup in blood). TREATM ENT Acute: NSAIDs (e.g., indomethacin), glucocorticoids, colchicine. Chronic (preventive): xanthine oxidase inhibitors (e.g., allopurinol, febuxostat). A Tophi in joints. Aggregates of urate crystals surrounded by inflammation. B Gout. Left big toe (podagra) is swollen and red. Musculoskeletal, Skin, and Connective 426 SECTION III Tissue Pathology Pseudogout A Presents with pain and effusion in a joint, caused by deposition of calcium pyrophosphate crystals within the joint space (chondrocalcinosis on x-ray). Forms basophilic, rhomboid crystals that are weakly positively birefringent A. Usually affects large joints (classically the knee). > 50 years old; both sexes affected equally. Diseases that may be associated with pseudogout include hemochromatosis, hyperparathyroidism, and hypoparathyroidism. Treatment includes NSAIDs for sudden, severe attacks; steroids; and colchicine. Gout—crystals are yellow when parallel (||) to the light. Pseudogout—crystals are blue when parallel (||) to the light. Infectious arthritis S. aureus, Streptococcus, and Neisseria gonorrhoeae are common causes. Gonococcal arthritis is an STD that presents as a migratory arthritis with an asymmetric pattern. Affected joint is swollen, red, and painful. STD = Synovitis (e.g., knee), Tenosynovitis (e.g., hand), and Dermatitis (e.g., pustules). Seronegative spondyloarthropathies Arthritis without rheumatoid factor (no anti-IgG antibody). Strong association with HLA-B27 (gene that codes for HLA MHC class I). Occurs more often in males. PAIR Psoriatic arthritis Joint pain and stiffness associated with psoriasis. Asymmetric and patchy involvement. Dactylitis (“sausage fingers” A), “pencil-incup” B deformity on x-ray. Seen in fewer than 1 ⁄3 of patients with psoriasis. Ankylosing spondylitis Chronic inflammatory disease of spine and sacroiliac joints Ž ankylosis (stiff spine due to fusion of joints), uveitis, and aortic regurgitation. Bamboo spine (vertebral fusion) C . Inflammatory bowel disease Crohn disease and ulcerative colitis are often accompanied by ankylosing spondylitis or peripheral arthritis. Reactive arthritis (Reiter syndrome) Classic triad: ƒƒConjunctivitis and anterior uveitis ƒƒUrethritis ƒƒ Arthritis “Can’t see, can’t pee, can’t bend my knee.” Post-GI (Shigella, Salmonella, Yersinia, Campylobacter) or Chlamydia infections. A B C Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 427 Systemic lupus erythematosus SYMPTOMS A Classic presentation: rash, joint pain, and fever, most commonly in a female of reproductive age and African descent. Libman-Sacks endocarditis—wart-like vegetations on both sides of valve. Lupus nephritis (type III hypersensitivity reaction): ƒƒNephritic—diffuse proliferative glomerulonephritis. ƒƒNephrotic—membranous glomerulonephritis. RASH OR PAIN: Rash (malar A or discoid) Arthritis Soft tissues/serositis Hematologic disorders (e.g., cytopenias) Oral/nasopharyngeal ulcers Renal disease, Raynaud phenomenon Photosensitivity, Positive VDRL/RPR Antinuclear antibodies Immunosuppressants Neurologic disorders (e.g. seizures, psychosis) Common causes of death in SLE: ƒƒ Cardiovascular disease ƒƒ Infections ƒƒ Renal disease FINDINGS Antinuclear antibodies (ANA)—sensitive, not specific. Anti-dsDNA antibodies—specific, poor prognosis (renal disease). Anti-Smith antibodies—specific, not prognostic (directed against snRNPs). Antihistone antibodies—sensitive for drug-induced lupus. Anticardiolipin antibodies—false positive on tests for syphilis, prolonged PTT (paradoxically, risk of arteriovenous thromboembolism). C3, C4, and CH50 due to immune complex formation. TREATM ENT NSAIDs, steroids, immunosuppressants, hydroxychloroquine. Musculoskeletal, Skin, and Connective 428 SECTION III Tissue Pathology Sarcoidosis Characterized by immune-mediated, widespread noncaseating granulomas A and elevated serum ACE levels. Common in black females. Often asymptomatic except for enlarged lymph nodes. Incidental findings on CXR of bilateral hilar adenopathy and/or reticular opacities B. Associated with restrictive lung disease (interstitial fibrosis), erythema nodosum, lupus pernio, Bell palsy, epithelioid granulomas containing microscopic Schaumann and asteroid bodies, uveitis, and hypercalcemia (due to 1α-hydroxylase–mediated vitamin D activation in macrophages). Treatment: steroids. A Sarcoidosis. B Sarcoidosis. Bilateral suprahilar adenopathy (arrows) and right upper lung reticular opacity on CXR. Polymyalgia rheumatica SYMPTOMS Pain and stiffness in shoulders and hips, often with fever, malaise, and weight loss. Does not cause muscular weakness. More common in women > 50 years old; associated with temporal (giant cell) arteritis. FINDINGS ESR, C-reactive protein, normal CK. TREATM ENT Rapid response to low-dose corticosteroids. Fibromyalgia Most commonly seen in females 20–50 years old. Chronic, widespread musculoskeletal pain associated with stiffness, paresthesias, poor sleep, and fatigue. Treat with regular exercise, antidepressants (TCAs, SNRIs), and anticonvulsants. Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 429 Polymyositis/dermatomyositis SYMPTOMS A Polymyositis—progressive symmetric proximal muscle weakness, characterized by endomysial inflammation with CD8+ T cells. Most often involves shoulders. Dermatomyositis—similar to polymyositis, but also involves malar rash (similar to SLE), Gottron papules A , heliotrope (erythematous periorbital) rash, “shawl and face” rash B, “mechanic’s hands.” risk of occult malignancy. Perimysial inflammation and atrophy with CD4+ T cells. B Dermatomyositis rash. Shawl and face distribution. FINDINGS CK, ANA, anti-Jo-1, anti-SRP, anti-Mi-2 antibodies. TREATM ENT Steroids. Neuromuscular junction diseases Myasthenia gravis Lambert-Eaton myasthenic syndrome FREQUENCY Most common NMJ disorder Uncommon PATHOPHYSIOLOGY Autoantibodies to postsynaptic ACh receptor Autoantibodies to presynaptic Ca2+ channel Ž ACh release CLINI CAL Ptosis, diplopia, weakness Worsens with muscle use Proximal muscle weakness, autonomic symptoms (dry mouth, impotence) Improves with muscle use ASSO CIAT ED WITH Thymoma, thymic hyperplasia Small cell lung cancer AChE INHI BITO R ADMINIST RATION Reversal of symptoms Minimal effect Myositis ossificans Metaplasia of skeletal muscle to bone following muscular trauma A. Most often seen in upper or lower extremity. May present as suspicious “mass” at site of known trauma or as incidental finding on radiography. A Myositis ossificans. Heterotopic ossification of elbow (arrows) after injury and prosthetic radial head replacement. Musculoskeletal, Skin, and Connective 430 SECTION III Tissue Pathology Scleroderma (systemic sclerosis) B Excessive fibrosis and collagen deposition throughout the body. Commonly sclerosis of skin, manifesting as puffy and taut skin A B with absence of wrinkles. Also sclerosis of renal, pulmonary (most common cause of death), cardiovascular, and GI systems. 75% female. 2 major types: ƒƒ Diffuse scleroderma—widespread skin involvement, rapid progression, early visceral involvement. Associated with anti- Scl-70 antibody (anti-DNA topoisomerase I antibody). ƒƒ Limited scleroderma—limited skin involvement confined to fingers and face. Also with CREST involvement: Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia. More benign clinical course. Associated with antiCentromere antibody (C for CREST). A Scleroderma. Note digital pitting and distal ulcerations (arrows). Dermatologic macroscopic terms (morphology) LESION CHA RACTERISTI CS EXAMPL ES Macule Flat lesion with well-circumscribed change in skin color < 1 cm Freckle, labial macule A Patch Macule > 1 cm Large birthmark (congenital nevus) B Papule Elevated solid skin lesion < 1 cm Mole (nevus) C , acne Plaque Papule > 1 cm Psoriasis D Vesicle Small fluid-containing blister < 1 cm Chickenpox (varicella), shingles (zoster) E Bulla Large fluid-containing blister > 1 cm Bullous pemphigoid F Pustule Vesicle containing pus Pustular psoriasis G Wheal Transient smooth papule or plaque Hives (urticaria) H Scale Flaking off of stratum corneum Eczema, psoriasis, SCC I Crust Dry exudate Impetigo J A B C D E F G H I J Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 431 Dermatologic microscopic terms LESION CHA RACTERISTI CS EXAMPL ES Hyperkeratosis thickness of stratum corneum Psoriasis, calluses Parakeratosis Hyperkeratosis with retention of nuclei in stratum corneum Psoriasis Spongiosis Epidermal accumulation of edematous fluid in intercellular spaces Eczematous dermatitis Acantholysis Separation of epidermal cells Pemphigus vulgaris Acanthosis Epidermal hyperplasia ( spinosum) Acanthosis nigricans Pigmented skin disorders Albinism Normal melanocyte number with melanin production A due to tyrosinase activity or defective tyrosine transport. Can also be caused by failure of neural crest cell migration during development. risk of skin cancer. Melasma (chloasma) Hyperpigmentation associated with pregnancy (“mask of pregnancy” B) or OCP use. Vitiligo Irregular areas of complete depigmentation C . Caused by autoimmune destruction of melanocytes. A B C Musculoskeletal, Skin, and Connective 432 SECTION III Tissue Pathology Common skin disorders Verrucae Warts; caused by HPV. Soft, tan-colored, cauliflower-like papules A. Epidermal hyperplasia, hyperkeratosis, koilocytosis. Condyloma acuminatum on genitals B. Melanocytic nevus Common mole. Benign, but melanoma can arise in congenital or atypical moles. Intradermal nevi are papular C . Junctional nevi are flat macules D. Urticaria Hives. Pruritic wheals that form after mast cell degranulation E . Characterized by superficial dermal edema and lymphatic channel dilation. Ephelis Freckle. Normal number of melanocytes, melanin pigment F . Atopic dermatitis (eczema) Pruritic eruption, commonly on skin flexures. Often associated with other atopic diseases (asthma, allergic rhinitis). Usually starts on the face in infancy G and often appears in the antecubital fossae H thereafter. Allergic contact dermatitis Type IV hypersensitivity reaction that follows exposure to allergen. Lesions occur at site of contact (e.g., nickel I , poison ivy, neomycin J ). Psoriasis Papules and plaques with silvery scaling K, especially on knees and elbows. Acanthosis with parakeratotic scaling (nuclei still in stratum corneum). stratum spinosum, stratum granulosum. Auspitz sign (arrow in L )—pinpoint bleeding spots from exposure of dermal papillae when scales are scraped off. Can be associated with nail pitting and psoriatic arthritis. Seborrheic keratosis Flat, greasy, pigmented squamous epithelial proliferation with keratin-filled cysts (horn cysts) M. Looks “stuck on” N O. Lesions occur on head, trunk, and extremities. Common benign neoplasm of older persons. Leser-Trélat sign—sudden appearance of multiple seborrheic keratoses, indicating an underlying malignancy (e.g., GI, lymphoid). A F K B G L C H M D I N E J O Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 433 Infectious skin disorders Impetigo Very superficial skin infection. Usually from S. aureus or S. pyogenes. Highly contagious. Honeycolored crusting A. Bullous impetigo B has bullae and is usually caused by S. aureus. Cellulitis Acute, painful, spreading infection of dermis and subcutaneous tissues. Usually from S. pyogenes or S. aureus. Often starts with a break in skin from trauma or another infection C . Necrotizing fasciitis Deeper tissue injury, usually from anaerobic bacteria or S. pyogenes. Results in crepitus from methane and CO2 production. “Flesh-eating bacteria.” Causes bullae and a purple color to the skin D. Staphylococcal scalded skin syndrome Exotoxin destroys keratinocyte attachments in the stratum granulosum only (vs. toxic epidermal necrolysis, which destroys the epidermal-dermal junction). Characterized by fever and generalized erythematous rash with sloughing of the upper layers of the epidermis that heals completely. Seen in newborns and children E . Hairy leukoplakia White, painless plaques on the tongue that cannot be scraped off F . EBV mediated. Occurs in HIV‑positive patients. A B D C E F Musculoskeletal, Skin, and Connective 434 SECTION III Tissue Pathology Blistering skin disorders Pemphigus vulgaris B Potentially fatal autoimmune skin disorder with IgG antibody against desmoglein (component of desmosomes). Flaccid intraepidermal bullae A caused by acantholysis (keratinocytes in stratum spinosum are connected by desmosomes); oral mucosa also involved. Immunofluorescence reveals antibodies around epidermal cells in a reticular (net-like) pattern B. Nikolsky sign (separation of epidermis upon manual stroking of skin). Bullous pemphigoid D Less severe than pemphigus vulgaris. Involves IgG antibody against hemidesmosomes (epidermal basement membrane; antibodies are “bullow” the epidermis). Tense blisters C containing eosinophils affect skin but spare oral mucosa. Immunofluorescence reveals linear pattern at epidermal-dermal junction D. Nikolsky sign . C Bullous pemphigoid. Note multiple intact, tense bullae. Dermatitis herpetiformis Pruritic papules, vesicles, and bullae (often found on elbows) E . Deposits of IgA at the tips of dermal papillae. Associated with celiac disease. A Pemphigus vulgaris. Note multiple crusty and weepy erythematous erosions where blisters have broken. E Dermatitis herpetiformis. Papules and vesicles on an erythematous base. Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 435 Blistering skin disorders (continued) Erythema multiforme Associated with infections (e.g., Mycoplasma pneumoniae, HSV), drugs (e.g., sulfa drugs, β-lactams, phenytoin), cancers, and autoimmune disease. Presents with multiple types of lesions—macules, papules, vesicles, and target lesions (look like targets with multiple rings and a dusky center showing epithelial disruption) F . Stevens-Johnson syndrome Characterized by fever, bulla formation and necrosis, sloughing of skin, and a high mortality rate. Typically 2 mucous membranes are involved G, and skin lesions may appear like targets as seen in erythema multiforme. Usually associated with adverse drug reaction. A more severe form of Stevens-Johnson syndrome with > 30% of the body surface area involved is toxic epidermal necrolysis H I . F Erythema multiforme. Note target lesions in patient with erythema multiforme secondary to HSV. I Toxic epidermal necrolysis. Large bullae with skin sloughing in sheets. H Toxic epidermal necrolysis. Note epidermal sloughing of skin leading to depigmentation. G Stevens-Johnson syndrome. Mucosal involvement of the eye (left) and lips (right). , Musculoskeletal, Skin, and Connective 436 SECTION III Tissue Pathology Miscellaneous skin disorders Acanthosis nigricans Epidermal hyperplasia causing symmetrical, hyperpigmented, velvety thickening of skin, especially on neck or in axilla A. Associated with hyperinsulinemia (e.g., diabetes, obesity, Cushing syndrome) and visceral malignancy (e.g., gastric adenocarcinoma). A Acanthosis nigricans. Note multiple skin tags on left, and velvety appearance on right. , Actinic keratosis Premalignant lesions caused by sun exposure. Small, rough, erythematous or brownish papules or plaques B. Risk of squamous cell carcinoma is proportional to degree of epithelial dysplasia. B Actinic keratosis. Large actinic keratosis (AK) over the eyebrow (left). Multiple AKs on hands and forearms (right). Erythema nodosum Painful inflammatory lesions of subcutaneous fat, usually on anterior shins. Often idiopathic, but can be associated with sarcoidosis, coccidioidomycosis, histoplasmosis, TB, streptococcal infections, leprosy, and Crohn disease C . C Erythema nodosum Lesions on leg in patient with streptococcal infection (left) and patient with leprosy and erythema nodosum leprosum (right). , Musculoskeletal, Skin, and Connective Tissue Pathology SECTION III 437 Miscellaneous skin disorders (continued) Lichen Planus Pruritic, Purple, Polygonal Planar Papules and Plaques are the 6 P’s of lichen Planus D. Mucosal involvement manifests as Wickham striae (reticular white lines). Sawtooth infiltrate of lymphocytes at dermal-epidermal junction. Associated with hepatitis C. D Lichen planus. Appearance on light skin (left) and dark skin (right). , Pityriasis rosea “Herald patch” followed days later by “Christmas tree” distribution E . Multiple plaques with collarette scale. Self-resolving in 6–8 weeks. E Pityriasis rosea. Herald patch (left, arrow) and Christmas tree distribution (right). , Sunburn Acute cutaneous inflammatory reaction due to excessive UV irradiation. Causes DNA mutations, inducing apoptosis of keratinocytes. UVA is dominant in tanning and photoaging, UVB in sunburn. Can lead to impetigo F and skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma). F Sunburn with impetigo. Disruption of normal skin integrity led to secondary bacterial infection (impetigo). Musculoskeletal, Skin, and Connective 438 SECTION III Tissue Pathology Skin cancer Basal cell carcinoma Most common skin cancer. Found in sun-exposed areas of body. Locally invasive, but almost never metastasizes. Pink, pearly nodules, commonly with telangiectasias, rolled borders, and central crusting or ulceration A. BCCs also appear as nonhealing ulcers with infiltrating growth B or as a scaling plaque (superficial BCC) C . Basal cell tumors have “palisading” nuclei D. Squamous cell carcinoma Second most common skin cancer. Associated with excessive exposure to sunlight, immunosuppression, and occasionally arsenic exposure. Commonly appears on face E , lower lip F , ears, and hands. Locally invasive, but may spread to lymph nodes and will rarely metastasize. Ulcerative red lesions with frequent scale. Associated with chronic draining sinuses. Histopathology: keratin “pearls” G. Actinic keratosis, a scaly plaque, is a precursor to squamous cell carcinoma. Keratoacanthoma is a variant that grows rapidly (4–6 weeks) and may regress spontaneously over months H. Melanoma Common tumor with significant risk of metastasis. S-100 tumor marker. Associated with sunlight exposure; fair-skinned persons are at risk. Depth of tumor correlates with risk of metastasis. Look for the ABCDEs: Asymmetry, Border irregularity, Color variation, Diameter > 6 mm, and Evolution over time. At least 4 different types of melanoma I J K L . Often driven by activating mutation in BRAF kinase. Primary treatment is excision with appropriately wide margins. Metastatic or unresectable melanoma in patients with BRAF V600E mutation may benefit from vemurafenib, a BRAF kinase inhibitor. Basal cell carcinoma. Appearance includes A rolled borders, B nonhealing ulcer, or C scaling plaque. Histology D reveals nests of basaloid cells in dermis. A B C D Squamous cell carcinoma. Commonly seen on faces E and lips F . Histology reveals keratin “pearls” G. Keratoacanthoma H is a variant. E F G H Melanoma. Multiple variants, including superficial spreading melanoma I , nodular melanoma J , lentigo maligna melanoma K, and acrolentiginous melanoma L . I J K L Musculoskeletal, Skin, and Connective Tissue pharmacology SECTION III 439 ``MUSCULOS KELETAL , SKIN , AND CONN ECTIVE TISS UE—PHA RMACOLOGY Arachidonic acid products Lipoxygenase pathway yields Leukotrienes. LTB4 is a neutrophil chemotactic agent. LTC4, D4, and E4 function in bronchoconstriction, vasoconstriction, contraction of smooth muscle, and vascular permeability. PGI2 inhibits platelet aggregation and promotes vasodilation. L for Lipoxygenase and Leukotriene. Neutrophils arrive “B4” others. Platelet-Gathering Inhibitor. Membrane lipid (e.g., phosphatidylinositol) NSAIDS, aspirin, acetaminophen, COX-2 inhibitors Cyclooxygenase (COX-1, COX-2) Protein synthesis Corticosteroids Endoperoxides (PGG2, PGH2) Thromboxane (TXA2) Prostaglandins (PGE2, PGF2 ) Prostacyclin (PGI2Zafirlukast, ) montelukast (LTC4, LTD4, LTE4) Hydroperoxides (HPETES) Zileuton Arachidonic acid Lipoxygenase Phospholipase A2 Platelet aggregation Bronchial tone Vascular tone Bronchial tone Uterine tone Bronchial tone Uterine tone Bronchial tone Vascular tone Platelet aggregation − − − − Leukotrienes (LTB4) Neutrophil chemotaxis − Aspirin MECHANISM Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) by covalent acetylation, which synthesis of both thromboxane A2 (TXA2) and prostaglandins. bleeding time until new platelets are produced (~ 7 days). No effect on PT, PTT. A type of NSAID. CLINI CAL USE Low dose (< 300 mg/day): platelet aggregation. Intermediate dose (300–2400 mg/day): antipyretic and analgesic. High dose (2400–4000 mg/day): anti-inflammatory. TO XICITY Gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Risk of Reye syndrome in children treated with aspirin for viral infection. Also stimulates respiratory centers, causing hyperventilation and respiratory alkalosis. Musculoskeletal, Skin, and Connective 440 SECTION III Tissue pharmacology NSAIDs Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac. MECHANISM Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block PG synthesis. CLINI CAL USE Antipyretic, analgesic, anti-inflammatory. Indomethacin is used to close a PDA. TO XICITY Interstitial nephritis, gastric ulcer (PGs protect gastric mucosa), renal ischemia (PGs vasodilate afferent arteriole). COX-2 inhibitors (celecoxib) MECHANISM Reversibly inhibit specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares COX-1, which helps maintain the gastric mucosa. Thus, should not have the corrosive effects of other NSAIDs on the GI lining. Spares platelet function as TXA2 production is dependent on COX-1. CLINI CAL USE Rheumatoid arthritis and osteoarthritis; patients with gastritis or ulcers. TO XICITY risk of thrombosis. Sulfa allergy. Acetaminophen MECHANISM Reversibly inhibits cyclooxygenase, mostly in CNS. Inactivated peripherally. CLINI CAL USE Antipyretic, analgesic, but not anti-inflammatory. Used instead of aspirin to avoid Reye syndrome in children with viral infection. TO XICITY Overdose produces hepatic necrosis; acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue adducts in liver. N-acetylcysteine is antidote—regenerates glutathione. Bisphosphonates Alendronate, other -dronates. MECHANISM Pyrophosphate analogs; bind hydroxyapatite in bone, inhibiting osteoclast activity. CLINI CAL USE Osteoporosis, hypercalcemia, Paget disease of bone. TO XICITY Corrosive esophagitis (patients are advised to take with water and remain upright for 30 minutes), osteonecrosis of the jaw. Musculoskeletal, Skin, and Connective Tissue pharmacology SECTION III 441 Gout drugs Chronic gout drugs (preventive) Allopurinol Inhibits xanthine oxidase, conversion of xanthine to uric acid. Also used in lymphoma and leukemia to prevent tumor lysis– associated urate nephropathy. concentrations of azathioprine and 6-MP (both normally metabolized by xanthine oxidase). Do not give salicylates; all but the highest doses depress uric acid clearance. Even high doses (5–6 g/day) have only minor uricosuric activity. Diet Purines Nucleic acids Hypoxanthine Allopurinol, Febuxostat Xanthine oxidase Xanthine oxidase Urate crystals deposited in joints Xanthine Plasma Gout uric acid Urine Probenecid and high-dose salicylates Tubular reabsorption Diuretics and low-dose salicylates Tubular secretion Febuxostat Inhibits xanthine oxidase. Probenecid Inhibits reabsorption of uric acid in PCT (also inhibits secretion of penicillin). Acute gout drugs NSAIDs Naproxen, indomethacin. Glucocorticoids Oral or intraarticular. Colchicine Binds and stabilizes tubulin to inhibit microtubule polymerization, impairing leukocyte chemotaxis and degranulation. Acute and prophylactic value. GI side effects. TNF-α inhibitors All TNF-α inhibitors predispose to infection, including reactivation of latent TB, since TNF blockade prevents activation of macrophages and destruction of phagocytosed microbes. DRUG MECHANISM CLINI CAL USE Etanercept Fusion protein (receptor for TNF-α + IgG1 Fc), produced by recombinant DNA. Etanercept is a TNF decoy receptor. Rheumatoid arthritis, psoriasis, ankylosing spondylitis Infliximab, adalimumab Anti-TNF-a monoclonal antibody IBD, rheumatoid arthritis, ankylosing spondylitis, psoriasis Musculoskeletal, Skin, an 442 SECTION III d Connective Tissue ``NOTES 443 “Estimated amount of glucose used by an adult human brain each day, expressed in M&Ms: 250.” —Harper’s Index “He has two neurons held together by a spirochete.” —Anonymous “I never came upon any of my discoveries through the process of rational thinking.” —Albert Einstein “I like nonsense; it wakes up the brain cells.” —Dr. Seuss ``Embryology 444 ``Anatomy and Physiology 447 ``Pathology 483 ``Pharmacology 490 HI G H -Y I ELD SYSTEMS Neurology 444 SECTION III Neurology neurology—Embryology ``NEUROLOGY —EMBRYOLOGY Neural development Day 18 Day 21 Neural plate Neural crest Neural crest cells Neural tube Notochord Notochord induces overlying ectoderm to differentiate into neuroectoderm and form the neural plate. Neural plate gives rise to the neural tube and neural crest cells. Notochord becomes nucleus pulposus of the intervertebral disc in adults. Alar plate (dorsal): sensory Same orientation as spinal cord. Basal plate (ventral): motor Regional specification of developing brain Forebrain (prosencephalon) Three primary vesicles Wall Cavity Midbrain (mesencephalon) Hindbrain (rhombencephalon) Telencephalon Diencephalon Mesencephalon Metencephalon Myelencephalon Cerebral hemispheres Thalamus Midbrain Pons Cerebellum Medulla Spinal cord Lateral ventricles Third ventricle Aqueduct Upper part of fourth ventricle Lower part of fourth ventricle Five secondary vesicles Adult derivatives of: Walls Cavities CNS/PNS origins Neuroectoderm—CNS neurons; ependymal cells (inner lining of ventricles, make CSF); oligodendroglia; astrocytes. Neural crest—PNS neurons, Schwann cells. Mesoderm—Microglia (like Macrophages, originate from Mesoderm). Neurology neurology—Embryology SECTION III 445 Neural tube defects Neuropores fail to fuse (4th week) Ž persistent connection between amniotic cavity and spinal canal. Associated with low folic acid intake before conception and during pregnancy. Elevated α-fetoprotein (AFP) in amniotic fluid and maternal serum. acetylcholinesterase (AChE) in amniotic fluid is a helpful confirmatory test (fetal AChE in CSF transudates across defect into the amniotic fluid). Spina bifida occulta Failure of bony spinal canal to close, but no structural herniation. Usually seen at lower vertebral levels. Dura is intact. Associated with tuft of hair or skin dimple at level of bony defect. Meningocele Meninges (but not the spinal cord) herniate through spinal canal defect. Normal AFP. Meningomyelocele Meninges and spinal cord herniate through spinal canal defect. Subarachnoid space Transverse process Skin Tuft of hair Dura Spinal cord Leptomeninges Normal Spina bifida occulta Meningocele Meningomyelocele Forebrain anomalies Anencephaly Malformation of anterior neural tube resulting in no forebrain, open calvarium (“frog-like appearance”). Clinical findings: AFP; polyhydramnios (no swallowing center in brain). Associated with maternal diabetes (type I). Maternal folate supplementation risk. Holoprosencephaly Failure of left and right hemispheres to separate; usually occurs during weeks 5–6. Complex multifactorial etiology that may be related to mutations in sonic hedgehog signaling pathway. Moderate form has cleft lip/palate, most severe form results in cyclopia. Posterior fossa malformations Chiari II (Arnold-Chiari malformation) Significant herniation of cerebellar tonsils and vermis through foramen magnum with aqueductal stenosis and hydrocephalus. Often presents with lumbosacral myelomeningocele and paralysis below the defect. Dandy-Walker Agenesis of cerebellar vermis with cystic enlargement of 4th ventricle (fills the enlarged posterior fossa). Associated with hydrocephalus and spina bifida. 446 SECTION III Neurology neurology—Embryology Syringomyelia Cystic cavity (syrinx) within the spinal cord A (if central canal Ž hydromyelia). Crossing anterior spinal commissural fibers are typically damaged first. Results in a “cape-like,” bilateral loss of pain and temperature sensation in upper extremities (fine touch sensation is preserved). Syrinx = tube, as in syringe. Most common at C8–T1. Associated with Chiari I malformation (> 3–5 mm cerebellar tonsillar ectopia; congenital, usually asymptomatic in childhood, manifests with headaches and cerebellar symptoms). Syrinx Chiari I malformation A Syringomyelia. MRI of cervical spine shows low-lying cerebellar tonsils (Chiari I, red arrow) and fluid-filled cavity in spinal cord (syrinx, yellow arrow). Tongue development 1st and 2nd branchial arches form anterior 2/3 (thus sensation via CN V3, taste via CN VII). 3rd and 4th branchial arches form posterior 1/3 (thus sensation and taste mainly via CN IX, extreme posterior via CN X). Motor innervation is via CN XII. Muscles of the tongue are derived from occipital myotomes. Taste—CN VII, IX, X (solitary nucleus). Pain—CN V3, IX, X. Motor—CN XII. Anterior tongue Posterior tongue Arches 1 and 2 Taste and sensation IX Arches 3, 4 X X X Sensation via V3 Taste via VII Neurology neurology—Anatomy and Physiology SECTION III 447 `` NEUROLOGY —ANATOMY AND PHYSIOLOGY Neurons Signal-transmitting cells of the nervous system. Permanent cells—do not divide in adulthood (and, as a general rule, have no progenitor stem cell population). Signal-relaying cells with dendrites (receive input), cell bodies, and axons (send output). Cell bodies and dendrites can be stained via the Nissl substance (stains RER). RER is not present in the axon. If an axon is injured, it undergoes Wallerian degeneration—degeneration distal to the injury and axonal retraction proximally; allows for potential regeneration of axon (if in PNS). Astrocytes Physical support, repair, K+ metabolism, removal of excess neurotransmitter, component of bloodbrain barrier, glycogen fuel reserve buffer. Reactive gliosis in response to neural injury. Astrocyte marker—GFAP. Derived from neuroectoderm. Microglia CNS phagocytes. Mesodermal origin. Not readily discernible in Nissl stains. Have small irregular nuclei and relatively little cytoplasm. Scavenger cells of the CNS. Respond to tissue damage by differentiating into large phagocytic cells. Part of the mononuclear phagocyte system. HIV-infected microglia fuse to form multinucleated giant cells in the CNS. Myelin conduction velocity of signals transmitted down axons. Results in saltatory conduction of action potential between nodes of Ranvier, where there are high concentrations of Na+ channels. CNS—oligodendrocytes; PNS— Schwann cells. Wraps and insulates axons: space constant and conduction velocity. Oligodendroglia Myelinates the axons of neurons in the CNS. Each oligodendrocyte can myelinate many axons (~30). Predominant type of glial cell in white matter. Derived from neuroectoderm. “Fried egg” appearance on H&E stain. Injured in multiple sclerosis, progressive multifocal leukoencephalopathy (PML), and leukodystrophies. Node of Ranvier Axon Oligodendrogliocyte Neurology 448 SECTION III neurology—Anatomy and Physiology Schwann cells Schwann cell Nucleus Node of Ranvier Myelin sheath Each Schwann cell myelinates only 1 PNS axon. Also promote axonal regeneration. Derived from neural crest. conduction velocity via saltatory conduction between nodes of Ranvier, where there are high concentrations of Na+ channels. Destroyed in Guillain-Barré syndrome. Acoustic neuroma—type of schwannoma. Typically located in internal acoustic meatus (CN VIII). If bilateral, strongly associated with neurofibromatosis type 2. Sensory corpuscles RE CEPTOR TY PE DES CRI PTION LO CATION SENSES Free nerve endings C—slow, unmyelinated fibers Aδ—fast, myelinated fibers All skin, epidermis, some viscera Pain and temperature Meissner corpuscles Large, myelinated fibers; adapt quickly Glabrous (hairless) skin Dynamic, fine/light touch; position sense Pacinian corpuscles Large, myelinated fibers; adapt quickly Deep skin layers, ligaments, and joints Vibration, pressure Merkel discs Large, myelinated fibers; adapt slowly Basal epidermal layer, hair follicles Pressure, deep static touch (e.g., shapes, edges), position sense Peripheral nerve Endoneurium—invests single nerve fiber layers (inflammatory infiltrate in Guillain-Barré syndrome). Perineurium (Permeability barrier)—surrounds a fascicle of nerve fibers. Must be rejoined in microsurgery for limb reattachment. Epineurium—dense connective tissue that surrounds entire nerve (fascicles and blood vessels). Endo = inner. Peri = around. Epi = outer. Nerve fibers Epineurium Perineurium Endoneurium Nerve trunk Neurology neurology—Anatomy and Physiology SECTION III 449 Neurotransmitters TY PE CHANGE IN DISE ASE LO CATIONS OF SYNTHESIS a Norepinephrine in anxiety in depression Locus ceruleus (pons) Dopamine in Huntington disease in Parkinson disease in depression Ventral tegmentum and SNc (midbrain) 5-HT in Parkinson disease in anxiety in depression Raphe nucleus (pons, medulla, midbrain) ACh in Parkinson disease in Alzheimer disease in Huntington disease Basal nucleus of Meynert GABA in anxiety in Huntington disease Nucleus accumbens aLocus ceruleus— stress and panic. Nucleus accumbens and septal nucleus—reward center, pleasure, addiction, fear. Blood-brain barrier Prevents circulating blood substances from reaching the CSF/CNS. Formed by 3 structures: ƒƒ Tight junctions between nonfenestrated capillary endothelial cells ƒƒ Basement membrane ƒƒ Astrocyte foot processes Glucose and amino acids cross slowly by carriermediated transport mechanism. Nonpolar/lipid-soluble substances cross rapidly via diffusion. A few specialized brain regions with fenestrated capillaries and no blood-brain barrier allow molecules in the blood to affect brain function (e.g., area postrema—vomiting after chemo, OVLT—osmotic sensing) or neurosecretory products to enter circulation (e.g., neurohypophysis—ADH release). Other notable barriers include: ƒƒ Blood-testis barrier ƒƒMaternal-fetal blood barrier of placenta Infarction and/or neoplasm destroys endothelial cell tight junctions Ž vasogenic edema. Hypothalamic inputs and outputs permeate the blood-brain barrier. Helps prevent bacterial infection from spreading into the CNS. Also restricts drug delivery to brain. Astrocyte foot processes Tight junction Capillary lumen Basement membrane Neurology 450 SECTION III neurology—Anatomy and Physiology Hypothalamus The hypothalamus wears TAN HATS—Thirst and water balance, Adenohypophysis control (regulates anterior pituitary), Neurohypophysis releases hormones produced in the hypothalamus, Hunger, Autonomic regulation, Temperature regulation, Sexual urges. Inputs (areas not protected by blood-brain barrier): OVLT (organum vasculosum of the lamina terminalis; senses change in osmolarity), area postrema (responds to emetics). Supraoptic nucleus makes ADH. Paraventricular nucleus makes oxytocin. ADH and oxytocin: made by hypothalamus but stored and released by posterior pituitary. Lateral area Hunger. Destruction Ž anorexia, failure to thrive (infants). Inhibited by leptin. If you zap your lateral nucleus, you shrink laterally. Ventromedial area Satiety. Destruction (e.g., craniopharyngioma) Ž hyperphagia. Stimulated by leptin. If you zap your ventromedial nucleus, you grow ventrally and medially. Anterior hypothalamus Cooling, parasympathetic. Anterior nucleus = cool off (cooling, pArasympathetic). A/C = anterior cooling. Posterior hypothalamus Heating, sympathetic. Posterior nucleus = get fired up (heating, sympathetic). If you zap your posterior hypothalamus, you become a poikilotherm (cold-blooded, like a snake). Suprachiasmatic nucleus Circadian rhythm. You need sleep to be charismatic (chiasmatic). Neurology neurology—Anatomy and Physiology SECTION III 451 Sleep physiology Sleep cycle is regulated by the circadian rhythm, which is driven by SCN of hypothalamus. Circadian rhythm controls nocturnal release of ACTH, prolactin, melatonin, and norepinephrine: Suprachiasmatic nucleus (SCN) Ž norepinephrine release Ž pineal gland Ž melatonin. SCN is regulated by environment (e.g., light). Two stages: rapid-eye movement (REM) and non-REM. Extraocular movements during REM sleep due to activity of PPRF (paramedian pontine reticular formation/conjugate gaze center). REM sleep occurs every 90 minutes, and duration through the night. Alcohol, benzodiazepines, and barbiturates are associated with REM sleep and delta wave sleep; norepinephrine also REM sleep. Treat bedwetting (sleep enuresis) with oral desmopressin acetate (DDAVP), which mimics ADH; preferred over imipramine because of the latter’s adverse effects. Benzodiazepines are useful for night terrors and sleepwalking. SLEE P ST AGE (% OF TOT AL SLEE P TIME IN YOUNG ADULTS ) DES CRI PTION EEG WAVEFORM Awake (eyes open) Alert, active mental concentration Beta (highest frequency, lowest amplitude) Awake (eyes closed) Alpha Non-REM sleep Stage N1 (5%) Light sleep Theta Stage N2 (45%) Deeper sleep; when bruxism occurs Sleep spindles and K complexes Stage N3 (25%) Deepest non-REM sleep (slow-wave sleep); when sleepwalking, night terrors, and bedwetting occur Delta (lowest frequency, highest amplitude) REM sleep (25%) Loss of motor tone, brain O2 use, and variable pulse and blood pressure; when dreaming and penile/clitoral tumescence occur; may serve a memory processing function Beta At night, BATS Drink Blood Awake Stage N1 Stage N2 Stage N3 REM 50 μV 1 s EEG Kcomplex Sleep spindle Posterior pituitary (neurohypophysis) Receives hypothalamic axonal projections from supraoptic (ADH) and paraventricular (oxytocin) nuclei. Oxytocin: oxys = quick; tocos = birth. Adenohypophysis = Anterior pituitary. Neurology 452 SECTION III neurology—Anatomy and Physiology Thalamus Major relay for all ascending sensory information except olfaction. NU CLEUS IN PUT IN FO DESTIN ATION MNEMONI C VPL Spinothalamic and dorsal columns/medial lemniscus Pain and temperature; pressure, touch, vibration, and proprioception 1° somatosensory cortex VPM Trigeminal and gustatory pathway Face sensation and taste 1° somatosensory cortex Makeup goes on the face (VPM) LGN CN II Vision Calcarine sulcus Lateral = Light MGN Superior olive and inferior colliculus of tectum Hearing Auditory cortex of temporal lobe Medial = Music VL Basal ganglia, cerebellum Motor Motor cortex Limbic system Collection of neural structures involved in emotion, long-term memory, olfaction, behavior modulation, and autonomic nervous system function. Structures include hippocampus, amygdala, fornix, mammillary bodies, and cingulate gyrus. Responsible for Feeding, Fleeing, Fighting, Feeling, and Sex. The famous 5 F’s. Cerebellum Modulates movement; aids in coordination and balance. Input: ƒƒ Contralateral cortex via middle cerebellar peduncle. ƒƒ Ipsilateral proprioceptive information via inferior cerebellar peduncle from the spinal cord (input nerves = climbing and mossy fibers). Output: ƒƒ Sends information to contralateral cortex to modulate movement. Output nerves = Purkinje cells Ž deep nuclei of cerebellum Ž contralateral cortex via the superior cerebellar peduncle. ƒƒDeep nuclei (lateral Ž medial)—Dentate, Emboliform, Globose, Fastigial (“Don’t Eat Greasy Foods”). Lateral lesions—voluntary movement of extremities; when injured, propensity to fall toward injured (ipsilateral) side. Medial lesions—Lesions involving midline structures (vermal cortex, fastigial nuclei) and/or the flocculonodular lobe result in truncal ataxia, nystagmus, and head tilting. These patients also may have a wide-based (cerebellar) gait and deficits in truncal coordination. Generally, midline lesions result in bilateral motor deficits affecting axial and proximal limb musculature. Neurology neurology—Anatomy and Physiology SECTION III 453 Basal ganglia Important in voluntary movements and making postural adjustments. Receives cortical input, provides negative feedback to cortex to modulate movement. Striatum = putamen (motor) + caudate (cognitive). Lentiform = putamen + globus pallidus. D1-Receptor = D1Rect pathway. Indirect = Inhibitory. Dopamine Spinal cord From SNc GPi Putamen Direct GPe Thalamus Input from SNc Motor cortex Direct pathway facilitates movement Indirect pathway inhibits movement Indirect STN Pedunculopontine nucleus D1 D2 Stimulatory Inhibitory SNc Substantia nigra pars compacta GPe Globus pallidus externus GPi Globus pallidus internus STN Subthalamic nucleus D1 Dopamine D1 receptor D2 Dopamine D2 receptor Excitatory pathway—cortical inputs stimulate the striatum, stimulating the release of GABA, which disinhibits the thalamus via the GPi/SNr ( motion). Inhibitory pathway—cortical inputs stimulate the striatum, which disinhibits STN via GPe, and STN stimulates GPi/SNr to inhibit the thalamus ( motion). Dopamine binds to D1, stimulating the excitatory pathway, and to D2, inhibiting the inhibitory pathway Ž motion. Parkinson disease Degenerative disorder of CNS associated with Lewy bodies (composed of α-synuclein— intracellular eosinophilic inclusion) and loss of dopaminergic neurons (i.e., depigmentation) of the substantia nigra pars compacta. Parkinson TRAPS your body—Tremor (at rest— e.g., pill-rolling tremor), cogwheel Rigidity, Akinesia (or bradykinesia), Postural instability and Shuffling gait. Neurology 454 SECTION III neurology—Anatomy and Physiology Huntington disease Autosomal dominant trinucleotide repeat disorder on chromosome 4. Symptoms manifest between ages 20 and 50; characterized by choreiform movements, aggression, depression, and dementia (sometimes initially mistaken for substance abuse). levels of GABA and ACh in the brain. Neuronal death via NMDA-R binding and glutamate toxicity. Atrophy of caudate nuclei can be seen on imaging. Expansion of CAG repeats (anticipation). Caudate loses ACh and GABA. Movement disorders DISORDER PRESENT ATION CHARACTERISTI C LESION NOTES Hemiballismus Sudden, wild flailing of 1 arm +/- ipsilateral leg Contralateral subthalamic nucleus (e.g., lacunar stroke) “Half-of-body ballistic.” Contralateral lesion. Chorea Sudden, jerky, purposeless movements Basal ganglia (e.g., Huntington) Chorea = dancing. Athetosis Slow, writhing movements; especially seen in fingers Basal ganglia (e.g., Huntington) Writhing, snake-like movement. Myoclonus Sudden, brief, uncontrolled muscle contraction Jerks; hiccups; common in metabolic abnormalities such as renal and liver failure. Dystonia Sustained, involuntary muscle contractions Writer’s cramp; blepharospasm (sustained eyelid twitch). Essential tremor (postural tremor) Action tremor; exacerbated by holding posture/limb position Genetic predisposition. Patients often self-medicated with EtOH, which tremor amplitude. Treatment: b-blockers, primidone. Resting tremor Uncontrolled movement of distal appendages (most noticeable in hands); tremor alleviated by intentional movement Parkinson disease Occurs at rest; “pill-rolling tremor” of Parkinson disease. Intention tremor Slow, zigzag motion when pointing/extending toward a target Cerebellar dysfunction Neurology neurology—Anatomy and Physiology SECTION III 455 Cerebral cortex functions Premotor area (part of extrapyramidal circuit) Sylvian fissure Motor speech (Broca area; dominant hemisphere) Frontal eye fields Principal motor area Principal sensory areas Principal visual cortex Central sulcus Parietal lobe Occipital lobe Frontal lobe Temporal lobe Associative auditory cortex (Wernicke area; dominant hemisphere) Arcuate Frontal association fasciculus areas Primary auditory cortex Homunculus Medial Lateral Salivation Tongue Mastication Vocalization Knee Ankle Toes Hip Neck Shoulder Elbow Wrist Hand Little Ring Middle Index Thumb Face Trunk Eyelid and eyeball Brow Lips Jaw Fingers Swallowing Topographical representation of motor (shown) and sensory areas in the cerebral cortex. Distorted appearance is due to certain body regions that are more richly innervated and thus have cortical representation. Neurology 456 SECTION III neurology—Anatomy and Physiology Common brain lesions ARE A OF LESION CONSE QUEN CE NOTES Amygdala (bilateral) Klüver-Bucy syndrome (hyperorality, hypersexuality, disinhibited behavior) Associated with HSV-1. Frontal lobe Disinhibition and deficits in concentration, orientation, and judgment; may have reemergence of primitive reflexes Right parietal-temporal cortex Spatial neglect syndrome (agnosia of the contralateral side of the world) Left parietal-temporal cortex Agraphia, acalculia, finger agnosia, and left-right disorientation Gerstmann syndrome. Reticular activating system (midbrain) Reduced levels of arousal and wakefulness (e.g., coma) Mammillary bodies (bilateral) Wernicke-Korsakoff syndrome: confusion, ophthalmoplegia, ataxia; memory loss (anterograde and retrograde amnesia), confabulation, personality changes Associated with thiamine (B1) deficiency and excessive EtOH use; can be precipitated by giving glucose without B1 to a B1-deficient patient. Wernicke problems come in a CAN of beer: Confusion, Ataxia, Nystagmus. Basal ganglia May result in tremor at rest, chorea, or athetosis Parkinson disease. Cerebellar hemisphere Intention tremor, limb ataxia, and loss of balance; damage to the cerebellum results in ipsilateral deficits; fall toward side of lesion Cerebellar hemispheres are laterally located— affect lateral limbs. Cerebellar vermis Truncal ataxia, dysarthria Vermis is centrally located—affects central body. Subthalamic nucleus Contralateral hemiballismus Hippocampus (bilateral) Anterograde amnesia—inability to make new memories Paramedian pontine reticular formation Eyes look away from side of lesion Frontal eye fields Eyes look toward lesion Neurology neurology—Anatomy and Physiology SECTION III 457 Central pontine myelinolysis A variant of the osmotic demyelination syndrome. Acute paralysis, dysarthria, dysphagia, diplopia, and loss of consciousness. Can cause “locked-in syndrome.” Massive axonal demyelination in pontine white matter tracts A 2° to osmotic forces and edema. Commonly iatrogenic, caused by overly rapid correction of hyponatremia. Correcting serum Na+ too fast: ƒƒ “From low to high, your pons will die” (CPM) ƒƒ “From high to low, your brain will blow” (cerebral edema/herniation) A Central pontine myelinolysis. Axial MRI with FLAIR shows abnormal increased signal in central pons (arrow). Aphasia Aphasia = higher-order inability to speak (language deficit). Dysarthria = motor inability to speak (movement deficit). Broca Nonfluent aphasia with intact comprehension. Broca area—inferior frontal gyrus of frontal lobe. Broca Broken Boca (boca = mouth in Spanish). Wernicke Fluent aphasia with impaired comprehension and repetition. Wernicke area—superior temporal gyrus of temporal lobe. Wernicke is Wordy but makes no sense. Wernicke = “What?” Global Nonfluent aphasia with impaired comprehension. Both Broca and Wernicke areas affected. Conduction Poor repetition but fluent speech, intact comprehension. Can be caused by damage to left superior temporal lobe and/or left supramarginal gyrus. Can’t repeat phrases such as, “No ifs, ands, or buts.” Transcortical motor Nonfluent aphasia with good comprehension and repetition. Transcortical sensory Poor comprehension with fluent speech and repetition. Mixed transcortical Nonfluent speech, poor comprehension, good repetition. Neurology 458 SECTION III neurology—Anatomy and Physiology Circle of Willis System of anastomoses between anterior and posterior blood supplies to brain. Anterior choroidal Lenticulostriate Pontine Optic chiasm ICA VA Subclavian Aorta Brachiocephalic CCA ECA OBLIQUE-LATERAL VIEW A2 A1 P1 P2 M1 BA ACA MCA PCom PCA OF Anterior ACA cerebral Middle MCA cerebral Posterior PCom communicating Anterior ACom communicating Posterior PCA cerebral Internal carotid ICA Basilar BA Vertebral VA Anterior spinal ASA Superior SCA cerebellar Anterior inferior AICA cerebellar Posterior inferior PICA cerebellar INFERIOR VIEW Posterior circulation ICA MCA ACA Anterior circulation Neurology neurology—Anatomy and Physiology SECTION III 459 Cerebral arteries—cortical distribution Anterior cerebral artery (supplies anteromedial surface) Middle cerebral artery (supplies lateral surface) Posterior cerebral artery (supplies posterior and inferior surfaces) Watershed zones Between anterior cerebral/middle cerebral, posterior cerebral/middle cerebral arteries. Damage in severe hypotension Ž upper leg/upper arm weakness, defects in higher-order visual processing. Regulation of cerebral perfusion Brain perfusion relies on tight autoregulation. Cerebral perfusion is primarily driven by Pco2 (Po2 also modulates perfusion in severe hypoxia). Therapeutic hyperventilation ( Pco2) helps intracranial pressure in cases of acute cerebral edema (stroke, trauma) via cerebral perfusion by vasoconstriction. Cerebral blood flow Hypoxemia increases cerebral perfusion pressure only when PO2 < 50 mmHg Cerebral perfusion pressure PCO2 until PCO2 > 90 mmHg Arterial gas 50 100 150 pressure (mmHg) Arterial gas 40 80 120 pressure (mmHg) Normal Cerebral blood flow Normal normal PO2 normal PCO2 O2 CO2 Neurology 460 SECTION III neurology—Anatomy and Physiology Effects of strokes ARTERY ARE A OF LESION SYM PTOMS NOTES Anterior circulation MCA Motor cortex—upper limb and face. Sensory cortex—upper limb and face. Temporal lobe (Wernicke area); frontal lobe (Broca area). Contralateral paralysis—upper limb and face. Contralateral loss of sensation— upper and lower limbs, and face. Aphasia if in dominant (usually left) hemisphere. Hemineglect if lesion affects nondominant (usually right) side. ACA Motor cortex—lower limb. Sensory cortex—lower limb. Contralateral paralysis—lower limb. Contralateral loss of sensation— lower limb. Lenticulostriate artery Striatum, internal capsule. Contralateral hemiparesis/ hemiplegia. Common location of lacunar infarcts, 2° to unmanaged hypertension. Posterior circulation ASA Lateral corticospinal tract. Medial lemniscus. Caudal medulla—hypoglossal nerve. Contralateral hemiparesis—upper and lower limbs. contralateral proprioception. Ipsilateral hypoglossal dysfunction (tongue deviates ipsilaterally). Stroke commonly bilateral. Medial medullary syndrome— caused by infarct of paramedian branches of ASA and vertebral arteries. PICA Lateral medulla—vestibular nuclei, lateral spinothalamic tract, spinal trigeminal nucleus, nucleus ambiguus, sympathetic fibers, inferior cerebellar peduncle. Vomiting, vertigo, nystagmus; pain and temperature sensation from ipsilateral face and contralateral body; dysphagia, hoarseness, gag reflex; ipsilateral Horner syndrome; ataxia, dysmetria. Lateral medullary (Wallenberg) syndrome. Nucleus ambiguus effects are specific to PICA lesions. “Don’t pick a (PICA) horse (hoarseness) that can’t eat (dysphagia).” AICA Lateral pons—cranial nerve nuclei; vestibular nuclei, facial nucleus, spinal trigeminal nucleus, cochlear nuclei, sympathetic fibers. Middle and inferior cerebellar peduncles. Vomiting, vertigo, nystagmus. Paralysis of face, lacrimation, salivation, taste from anterior 2⁄3 of tongue, corneal reflex. Face— pain and temperature sensation. Ipsilateral hearing. Ipsilateral Horner syndrome. Ataxia, dysmetria. Lateral pontine syndrome. Facial nucleus effects are specific to AICA lesions. “Facial droop means AICA’s pooped.” PCA Occipital cortex, visual cortex. Contralateral hemianopia with macular sparing. Basilar artery Pons, medulla, lower midbrain, corticospinal and corticobulbar tracts, ocular cranial nerve nuclei, paramedian pontine reticular formation. Preserved consciousness and blinking, quadriplegia, loss of voluntary facial, mouth, and tongue movements. “Locked-in syndrome.” Neurology neurology—Anatomy and Physiology SECTION III 461 Effects of strokes (continued) ARTERY ARE A OF LESION SYM PTOMS NOTES Communicating arteries ACom Most common lesion is aneurysm. Can lead to stroke. Saccular (berry) aneurysm can impinge cranial nerves. Visual field defects. Lesions are typically aneurysms, not strokes. PCom Common site of saccular aneurysm. CN III palsy—eye is “down and out” with ptosis and pupil dilation. Lesions are typically aneurysms, not strokes. Aneurysms In general, an abnormal dilation of artery due to weakening of vessel wall. Berry aneurysm Occurs at the bifurcations in the circle of Willis A. Most common site is junction of the anterior communicating artery and anterior cerebral artery. Rupture (most common complication) leads to subarachnoid hemorrhage (“worst headache of life”) or hemorrhagic stroke. Can also cause bitemporal hemianopia via compression of optic chiasm. Associated with ADPKD, Ehlers-Danlos syndrome, and Marfan syndrome. Other risk factors: advanced age, hypertension, smoking, race ( risk in blacks). A Berry aneurysm. Coronal (left) and sagittal (right) contrast CT shows berry aneurysm (arrows). Charcot-Bouchard microaneurysm Associated with chronic hypertension; affects small vessels (e.g., in basal ganglia, thalamus). Central post-stroke pain syndrome Neuropathic pain due to thalamic lesions. Initial sensation of numbness and tingling followed in weeks to months by allodynia (ordinarily painless stimuli cause pain) and dysaesthesia. Occurs in 10% of stroke patients. Neurology 462 SECTION III neurology—Anatomy and Physiology Intracranial hemorrhage Epidural hematoma Rupture of middle meningeal artery (branch of maxillary artery), often 2° to fracture of temporal bone. Lucid interval. Rapid expansion under systemic arterial pressure Ž transtentorial herniation, CN III palsy. CT shows biconvex (lentiform), hyperdense blood collection A not crossing suture lines. Can cross falx, tentorium. A Epidural hematoma. Axial CT of the brain shows lensshaped collection of epidural blood (left, arrows), with bone windows showing associated skull fracture (right, circle) and scalp hematoma (arrows). , Subdural hematoma Rupture of bridging veins. Slow venous bleeding (less pressure = hematoma develops over time). Seen in elderly individuals, alcoholics, blunt trauma, shaken baby (predisposing factors: brain atrophy, shaking, whiplash). Crescent-shaped hemorrhage that crosses suture lines B. Midline shift. Cannot cross falx, tentorium. B Subdural hematoma. Axial CTs show crescent-shaped subdural blood collections. Left image shows acute bleed with midline shift (subfalcine herniation, arrows). Right image shows “acute on chronic” hemorrhage (red arrows, acute; blue arrow, chronic). Subarachnoid hemorrhage Rupture of an aneurysm (such as a berry [saccular] aneurysm, as seen in Marfan, Ehlers-Danlos, ADPKD) or an AVM. Rapid time course. Patients complain of “worst headache of my life (WHOML).” Bloody or yellow (xanthochromic) spinal tap. 2–3 days afterward, risk of vasospasm due to blood breakdown (not visible on CT, treat with nimodipine) and rebleed (visible on CT) C . C Subarachnoid hemorrhage. Axial CT of the brain shows subarachnoid blood in the sulci (left, arrows) and intraventricular blood (right, arrows) layering in the posterior horn of the lateral ventricles. , . Intraparenchymal (hypertensive) hemorrhage Most commonly caused by systemic hypertension D. Also seen with amyloid angiopathy, vasculitis, and neoplasm. Typically occurs in basal ganglia and internal capsule (Charcot-Bouchard aneurysm of lenticulostriate vessels), but can be lobar. D Hypertensive hemorrhage. Axial CT of the brain shows intraparenchymal hemorrhage in the basal ganglia (left) and cerebellum (right). , Neurology neurology—Anatomy and Physiology SECTION III 463 Ischemic brain disease/stroke Irreversible damage begins after 5 minutes of hypoxia. Most vulnerable—hippocampus, neocortex, cerebellum, watershed areas. Irreversible neuronal injury. Stroke imaging: bright on diffusion-weighted MRI in 3–30 minutes (highest sensitivity for early ischemia), dark abnormality on noncontrast CT in ~ 12–24 hours. Absence of bright areas on noncontrast CT highly accurate to exclude hemorrhage (contraindication for tPA). Ischemic hypoxia—“hypocampus” is most vulnerable. TIME SIN CE IS CHEMI C EVENT 12–48 HOURS 24–72 HOURS 3–5 DAYS 1–2 WEEKS > 2 WEE KS Histologic features Red neurons Necrosis + neutrophils Macrophages Reactive gliosis + vascular proliferation Glial scar Hemorrhagic stroke Intracerebral bleeding, often due to hypertension, anticoagulation, and cancer (abnormal vessels can bleed). May be 2° to ischemic stroke followed by reperfusion ( vessel fragility). Basal ganglia are most common site of intracerebral hemorrhage. Ischemic stroke A Acute blockage of vessels Ž disruption of blood flow and subsequent ischemia. Results in liquefactive necrosis. 3 types: ƒƒ Thrombotic—due to a clot forming directly at the site of infarction (commonly the MCA A), usually over an atherosclerotic plaque. ƒƒ Embolic—an embolus from another part of the body obstructs a vessel. Can affect multiple vascular territories. Often cardioembolic. ƒƒHypoxic—due to hypoperfusion or hypoxemia. Common during cardiovascular surgeries, tends to affect watershed areas. Treatment—tPA (if within 3–4.5 hr of onset and no hemorrhage/risk of hemorrhage). Reduce risk with medical therapy (e.g., aspirin, clopidogrel); optimum control of blood pressure, blood sugars, and lipids; and treat conditions that risk (e.g., atrial fibrillation). Transient ischemic attack Brief, reversible episode of focal neurologic dysfunction lasting < 24 hours without acute infarction ( MRI), with the majority resolving in < 15 minutes; deficits due to focal ischemia. Dural venous sinuses Large venous channels that run through the dura. Drain blood from cerebral veins and receive CSF from arachnoid granulations. Empty into internal jugular vein. Superior sagittal sinus (main location of CSF return via arachnoid granulations) Inferior sagittal sinus Great cerebral vein of Galen Straight sinus Confluence of the sinuses Sigmoid sinus Internal jugular vein Jugular foramen Cavernous sinus Sphenoparietal sinus Superior ophthalmic vein Transverse sinus Occipital sinus Neurology 464 SECTION III neurology—Anatomy and Physiology Ventricular system Lateral ventricles Posterior horn Cerebral aqueduct of Sylvius Foramen of Magendie Foramen of Luschka Third ventricle Fourth ventricle Foramen of Monro Anterior horn Lateral ventricle Ž 3rd ventricle via right and left interventricular foramina of Monro. 3rd ventricle Ž 4th ventricle via cerebral aqueduct (of Sylvius). 4th ventricle Ž subarachnoid space via: ƒƒ Foramina of Luschka = Lateral. ƒƒ Foramen of Magendie = Medial. CSF is made by ependymal cells of choroid plexus; it is reabsorbed by arachnoid granulations and then drains into dural venous sinuses. Hydrocephalus Communicating (nonobstructive) Communicating hydrocephalus CSF absorption by arachnoid granulations, which can lead to intracranial pressure, papilledema, and herniation (e.g., arachnoid scarring post-meningitis). Normal pressure hydrocephalus A Does not result in increased subarachnoid space volume. Expansion of ventricles A distorts the fibers of the corona radiata and leads to clinical triad of urinary incontinence, ataxia, and cognitive dysfunction (sometimes reversible). “Wet, wobbly, and wacky.” Hydrocephalus ex vacuo Appearance of CSF in atrophy (e.g., Alzheimer disease, advanced HIV, Pick disease). Intracranial pressure is normal; triad is not seen. Apparent increase in CSF observed on imaging is actually result of neural tissue due to neuronal atrophy. Noncommunicating (obstructive) Noncommunicating hydrocephalus Caused by a structural blockage of CSF circulation within the ventricular system (e.g., stenosis of the aqueduct of Sylvius). Spinal nerves There are 31 spinal nerves in total: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 1 coccygeal. Nerves C1–C7 exit above the corresponding vertebra. All other nerves exit below (e.g., C3 exits above the 3rd cervical vertebra; L2 exits below the 2nd lumbar vertebra). 31, just like 31 flavors of Baskin-Robbins ice cream! Vertebral disc herniation—nucleus pulposus (soft central disc) herniates through annulus fibrosus (outer ring); usually occurs posterolaterally at L4–L5 or L5–S1. Neurology neurology—Anatomy and Physiology SECTION III 465 Spinal cord—lower extent In adults, spinal cord extends to lower border of L1–L2 vertebrae. Subarachnoid space (which contains the CSF) extends to lower border of S2 vertebra. Lumbar puncture is usually performed between L3–L4 or L4–L5 (level of cauda equina). Goal of lumbar puncture is to obtain sample of CSF without damaging spinal cord. To keep the cord alive, keep the spinal needle between L3 and L5. Spinal cord and associated tracts Legs (Lumbosacral) are Lateral in Lateral corticospinal, spinothalamic tracts. Dorsal column is organized as you are, with hands at sides. Arms outside, legs inside. Dorsal column (pressure, vibration, touch, proprioception) DESCENDING ASCENDING ASCENDING Lateral corticospinal tract (voluntary motor) Anterior corticospinal tract (voluntary motor) Anterior spinothalamic tract (crude touch, pressure) Lateral spinothalamic tract (pain, temperature) • Fasciculus gracilis (lower body, legs) • Sacral • Cervical Gray matter Posterior horn Cervical Thoracic Lumbar Sacral • Cervical • Sacral Intermediate horn sympathetics (T1 - L2/L3) • Fasciculus cuneatus (upper body, arms) White matter Anterior horn Neurology 466 SECTION III neurology—Anatomy and Physiology Spinal tract anatomy and functions Remember, ascending tracts synapse and then cross. TR ACT AND FUNCTION 1ST -ORDER NEURON SYN APSE 1 2ND -ORDER NEURON SYN APSE 2 3RD-ORDER NEURON Dorsal column Ascending: pressure, vibration, fine touch, and proprioception Sensory nerve ending Ž cell body in dorsal root ganglion Ž enters spinal cord, ascends ipsilaterally in dorsal column Ipsilateral nucleus cuneatus or gracilis (medulla) Decussates in medulla Ž ascends contralaterally in medial lemniscus VPL (thalamus) Sensory cortex Spinothalamic tract Ascending Lateral: pain, temperature Anterior: crude touch, pressure Sensory nerve ending (Ad and C fibers) (cell body in dorsal root ganglion) Ž enters spinal cord Ipsilateral gray matter (spinal cord) Decussates at anterior white commissure Ž ascends contralaterally VPL (thalamus) Sensory cortex Lateral corticospinal tract Descending: voluntary movement of contralateral limbs UMN: cell body in 1° motor cortex Ž descends ipsilaterally (through internal capsule), most fibers decussate at caudal medulla (pyramidal decussation) Ž descends contralaterally Cell body of anterior horn (spinal cord) LMN: leaves spinal cord NMJ Motor neuron signs SIGN UMN LESION LMN LESION COMMENTS Weakness + + Lower MN = everything lowered (less muscle mass, muscle tone, reflexes, downgoing toes). Upper MN = everything up (tone, DTRs, toes). Fasciculations = muscle twitching. Positive Babinski is normal in infants. Atrophy - + Fasciculations - + Reflexes Tone Babinski + - Spastic paralysis + - Flaccid paralysis - + Clasp knife spasticity + - Neurology neurology—Anatomy and Physiology SECTION III 467 Spinal cord lesions AREA AFFECTED DISE ASE CHARACTERISTI CS Poliomyelitis and spinal muscular atrophy (Werdnig-Hoffmann disease) LMN lesions only, due to destruction of anterior horns; flaccid paralysis. Multiple sclerosis Due to demyelination; mostly white matter of cervical region; random and asymmetric lesions, due to demyelination; scanning speech, intention tremor, nystagmus. Amyotrophic lateral sclerosis Combined UMN and LMN deficits with no sensory, cognitive, or oculomotor deficits; both UMN and LMN signs. Can be caused by defect in superoxide dismutase 1. Commonly presents as fasciculations with eventual atrophy and weakness of hands; fatal. Riluzole treatment modestly survival by presynaptic glutamate release. Commonly known as Lou Gehrig disease. Stephen Hawking is a well-known patient who highlights the lack of cognitive deficit. For Lou Gehrig disease, give rilouzole. Anterior spinal artery Posterior spinal arteries Complete occlusion of anterior spinal artery Spares dorsal columns and Lissauer tract; upper thoracic ASA territory is a watershed area, as artery of Adamkiewicz supplies ASA below ~T8. Tabes dorsalis Caused by 3° syphilis. Results from degeneration (demyelination) of dorsal columns and roots Ž impaired sensation and proprioception and progressive sensory ataxia (inability to sense or feel the legs Ž poor coordination). Associated with Charcot joints, shooting pain, Argyll Robertson pupils (small bilateral pupils that further constrict to accommodation and convergence, not to light). Exam will demonstrate absence of DTRs and Romberg. Syringomyelia Syrinx expands and damages anterior white commissure of spinothalamic tract (2nd-order neurons) Ž bilateral loss of pain and temperature sensation (usually C8–T1); seen with Chiari I malformation; can expand and affect other tracts. Vitamin B12 or vitamin E deficiency Subacute combined degeneration—demyelination of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts; ataxic gait, paresthesia, impaired position and vibration sense. Neurology 468 SECTION III neurology—Anatomy and Physiology Poliomyelitis Caused by poliovirus (fecal-oral transmission). Replicates in the oropharynx and small intestine before spreading via the bloodstream to the CNS. Infection causes destruction of cells in anterior horn of spinal cord (LMN death). SYM PTOMS LMN lesion signs—weakness, hypotonia, flaccid paralysis, fasciculations, hyporeflexia, and muscle atrophy. Signs of infection—malaise, headache, fever, nausea, etc. FINDINGS CSF with WBCs and slight of protein (with no change in CSF glucose). Virus recovered from stool or throat. Spinal muscular atrophy (Werdnig- Hoffmann disease) Congenital degeneration of anterior horns of spinal cord Ž LMN lesion. “Floppy baby” with marked hypotonia and tongue fasciculations. Infantile type has median age of death of 7 months. Autosomal recessive inheritance. Friedreich ataxia Autosomal recessive trinucleotide repeat disorder (GAA) on chromosome 9 in gene that encodes frataxin (iron binding protein). Leads to impairment in mitochondrial functioning. Degeneration of multiple spinal cord tracts Ž muscle weakness and loss of DTRs, vibratory sense, and proprioception. Staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes, hypertrophic cardiomyopathy (cause of death). Presents in childhood with kyphoscoliosis. Friedreich is Fratastic (frataxin): he’s your favorite frat brother, always stumbling, staggering, and falling, but has a big heart. Brown-Séquard syndrome Lesion Hemisection of spinal cord. Findings: ƒƒ Ipsilateral UMN signs below the level of the lesion (due to corticospinal tract damage) ƒƒ Ipsilateral loss of tactile, vibration, proprioception sense 1–2 levels below the level of the lesion (due to dorsal column damage) ƒƒ Contralateral pain and temperature loss below the level of the lesion (due to spinothalamic tract damage) ƒƒ Ipsilateral loss of all sensation at the level of the lesion ƒƒ Ipsilateral LMN signs (e.g., flaccid paralysis) at the level of the lesion If lesion occurs above T1, patient may present with Horner syndrome due to damage of oculosympathetic pathway. Loss of all sensation Level of lesion Impaired proprioception, vibration, 2-point discrimination, and joint and position sensation Impaired pain and temperature sensation Neurology neurology—Anatomy and Physiology SECTION III 469 Horner syndrome Sympathectomy of face: ƒƒ Ptosis (slight drooping of eyelid: superior tarsal muscle) ƒƒ Anhidrosis (absence of sweating) and flushing (rubor) of affected side of face ƒƒ Miosis (pupil constriction) Associated with lesion of spinal cord above T1 (e.g., Pancoast tumor, Brown-Séquard syndrome [cord hemisection], late-stage syringomyelia). PAM is horny (Horner). Ptosis, anhidrosis, and miosis (rhyming). Second neuron Spinal cord First neuron Internal carotid artery C2 T1 Hypothalamus Synapse is in lateral horn Ophthalmic division of trigeminal nerve Long ciliary nerve To sweat glands of forehead To smooth muscle of eyelid To pupillary dilator To sweat glands of face External carotid artery Third neuron Superior cervical ganglion The 3-neuron oculosympathetic pathway projects from the hypothalamus to the intermediolateral column of the spinal cord, then to the superior cervical (sympathetic) ganglion, and finally to the pupil, the smooth muscle of the eyelids, and the sweat glands of the forehead and face. Interruption of any of these pathways results in Horner syndrome. Landmark dermatomes C2—posterior half of a skull “cap.” C3—high turtleneck shirt. C4—low-collar shirt. T4—at the nipple. T 7—at the xiphoid process. T10—at the umbilicus (important for early appendicitis pain referral). L1—at the inguinal ligament. L4—includes the kneecaps. S2, S3, S4—erection and sensation of penile and anal zones. Diaphragm and gallbladder pain referred to the right shoulder via the phrenic nerve. T4 at the teat pore. T10 at the belly butten. L1 is IL (Inguinal Ligament). Down on ALL 4’s (L4). “S2, 3, 4 keep the penis off the floor.” C3 C6 C2 V3 V2 V1 C8 C8 C7 L5 C6 S2 S3 L4 C4 C5 T1 T4 T6 T10 T8 L1 T12 Neurology 470 SECTION III neurology—Anatomy and Physiology Clinical reflexes Biceps = C5 nerve root. Triceps = C7 nerve root. Patella = L4 nerve root. Achilles = S1 nerve root. Reflexes count up in order: S1, 2—“buckle my shoe” (Achilles reflex) L3, 4—“kick the door” (patellar reflex) C5, 6—“pick up sticks” (biceps reflex) C7, 8—“lay them straight” (triceps reflex) Additional reflexes: L1, L2—“testicles move” (cremaster reflex) S3, S4—“winks galore” (anal wink reflex) C5, 6 L3, 4 C7, 8 S1, 2 Primitive reflexes CNS reflexes that are present in a healthy infant, but are absent in a neurologically intact adult. Normally disappear within 1st year of life. These “primitive” reflexes are inhibited by a mature/ developing frontal lobe. They may reemerge in adults following frontal lobe lesions Ž loss of inhibition of these reflexes. Moro reflex “Hang on for life” reflex—abduct/extend limbs when startled, and then draw together Rooting reflex Movement of head toward one side if cheek or mouth is stroked (nipple seeking) Sucking reflex Sucking response when roof of mouth is touched Palmar reflex Curling of fingers if palm is stroked Plantar reflex Dorsiflexion of large toe and fanning of other toes with plantar stimulation Babinski sign—presence of this reflex in an adult, which may signify a UMN lesion Galant reflex Stroking along one side of the spine while newborn is in ventral suspension (face down) causes lateral flexion of lower body toward stimulated side Brain stem—ventral view CNs that lie medially at brain stem: III, VI, XII. 3(×2) = 6(×2) = 12 (Motor = Medial). Olfactory bulb (CN I) Olfactory tract Optic chiasm Anterior perforated substance Infundibulum Tuber cinereum Mammillary body Cerebral peduncle (crus cerebri) Pons Middle cerebellar peduncle Pyramid Pyramidal decussation C1 CN II Optic tract CN III CN IV (arises dorsally and immediately decussates) CN V CN VI CN VII CN VIII CN IX CN X CN XI CN XII Neurology neurology—Anatomy and Physiology SECTION III 471 Brain stem—dorsal view (cerebellum removed) 4th ventricle Medulla Pineal body Superior colliculi Inferior colliculi Superior cerebellar peduncles Middle cerebellar peduncles Pineal gland—melatonin secretion, circadian rhythms. Superior colliculi—conjugate vertical gaze center. Inferior colliculi—auditory. Parinaud syndrome—paralysis of conjugate vertical gaze due to lesion in superior colliculi (e.g., pinealoma). Your eyes are above your ears, and the superior colliculus (visual) is above the inferior colliculus (auditory). Neurology 472 SECTION III neurology—Anatomy and Physiology Cranial nerves NER VE CN FUNCTION TY PE MNEMONI C Olfactory I Smell (only CN without thalamic relay to cortex) Sensory Some Optic II Sight Sensory Say Oculomotor III Eye movement (SR, IR, MR, IO), pupillary constriction (sphincter pupillae: Edinger-Westphal nucleus, muscarinic receptors), accommodation, eyelid opening (levator palpebrae) Motor Marry Trochlear IV Eye movement (SO) Motor Money Trigeminal V Mastication, facial sensation (ophthalmic, maxillary, mandibular divisions), somatosensation from anterior 2/3 of tongue Both But Abducens VI Eye movement (LR) Motor My Facial VII Facial movement, taste from anterior 2/3 of tongue, lacrimation, salivation (submandibular and sublingual glands), eyelid closing (orbicularis oculi), stapedius muscle in ear (note: nerve courses through the parotid gland, but does not innervate it) Both Brother Vestibulocochlear VIII Hearing, balance Sensory Says Glossopharyngeal IX Taste and somatosensation from posterior 1/3 of tongue, swallowing, salivation (parotid gland), monitoring carotid body and sinus chemo- and baroreceptors, and stylopharyngeus (elevates pharynx, larynx) Both Big Vagus X Taste from epiglottic region, swallowing, soft palate elevation, midline uvula, talking, coughing, thoracoabdominal viscera, monitoring aortic arch chemo- and baroreceptors Both Brains Accessory XI Head turning, shoulder shrugging (SCM, trapezius) Motor Matter Hypoglossal XII Tongue movement Motor Most Cranial nerve nuclei Located in tegmentum portion of brain stem (between dorsal and ventral portions): ƒƒMidbrain—nuclei of CN III, IV ƒƒ Pons—nuclei of CN V, VI, VII, VIII ƒƒMedulla—nuclei of CN IX, X, XII ƒƒ Spinal cord—nucleus of CN XI Lateral nuclei = sensory (aLar plate). —Sulcus limitans— Medial nuclei = Motor (basal plate). Cranial nerve reflexes RE FLE X AFFERENT EFFERENT Corneal V1 ophthalmic (nasociliary branch) VII (temporal branch: orbicularis oculi) Lacrimation V1 (loss of reflex does not preclude emotional tears) VII Jaw jerk V3 (sensory—muscle spindle from masseter) V3 (motor—masseter) Pupillary II III Gag IX X Neurology neurology—Anatomy and Physiology SECTION III 473 Vagal nuclei Nucleus Solitarius Visceral Sensory information (e.g., taste, baroreceptors, gut distention). VII, IX, X. Nucleus aMbiguus Motor innervation of pharynx, larynx, and upper esophagus (e.g., swallowing, palate elevation). IX, X, XI (cranial portion) Dorsal motor nucleus Sends autonomic (parasympathetic) fibers to heart, lungs, and upper GI. X. Cranial nerve and vessel pathways Cribriform plate (CN I). Middle cranial fossa (CN II–VI)—through sphenoid bone: ƒƒOptic canal (CN II, ophthalmic artery, central retinal vein) ƒƒ Superior orbital fissure (CN III, IV, V1, VI, ophthalmic vein, sympathetic fibers) ƒƒ Foramen Rotundum (CN V2) ƒƒ Foramen Ovale (CN V3) ƒƒ Foramen spinosum (middle meningeal artery) Posterior cranial fossa (CN VII–XII)—through temporal or occipital bone: ƒƒ Internal auditory meatus (CN VII, VIII) ƒƒ Jugular foramen (CN IX, X, XI, jugular vein) ƒƒHypoglossal canal (CN XII) ƒƒ Foramen magnum (spinal roots of CN XI, brain stem, vertebral arteries) Divisions of CN V exit owing to Standing Room Only. Neurology 474 SECTION III neurology—Anatomy and Physiology Cavernous sinus A collection of venous sinuses on either side of the pituitary. Blood from eye and superficial cortex Ž cavernous sinus Ž internal jugular vein. CN III, IV, V1, V2, and VI and postganglionic sympathetic fibers en route to the orbit all pass through the cavernous sinus. Cavernous portion of internal carotid artery is also here. The nerves that control extraocular muscles (plus V1 and V2) pass through the cavernous sinus. Cavernous sinus syndrome (e.g., due to mass effect, fistula, thrombosis)—ophthalmoplegia and corneal and maxillary sensation with normal visual acuity. CN VI commonly affected. Dura Abducens (VI) nerve Sphenoid sinus Hypophysis Optic chiasm Anterior cerebral artery Internal carotid artery Anterior clinoid process Subarachnoid space Oculomotor (III) nerve Trochlear (IV) nerve Ophthalmic (V1) nerve Maxillary (V2) nerve Pia Arachnoid Common cranial nerve lesions CN V motor lesion Jaw deviates toward side of lesion due to unopposed force from the opposite pterygoid muscle. CN X lesion Uvula deviates away from side of lesion. Weak side collapses and uvula points away. CN XI lesion Weakness turning head to contralateral side of lesion (SCM). Shoulder droop on side of lesion (trapezius). The left SCM contracts to help turn the head to the right. CN XII lesion (LMN) Tongue deviates toward side of lesion (“lick your wounds”) due to weakened tongue muscles on the affected side. Auditory physiology Outer ear Visible portion of ear (pinna), includes auditory canal and eardrum. Transfers sound waves via vibration of eardrum. Middle ear Air-filled space with three bones called the ossicles (malleus, incus, stapes). Ossicles conduct and amplify sound from eardrum to inner ear. Inner ear Snail-shaped, fluid-filled cochlea. Contains basilar membrane that vibrates 2° to sound waves. Vibration transduced via specialized hair cells Ž auditory nerve signaling Ž brainstem. Each frequency leads to vibration at specific location on the basilar membrane (tonotopy): ƒƒ Low frequency heard at apex near helicotrema (wide and flexible). ƒƒHigh frequency heard best at base of cochlea (thin and rigid). Neurology neurology—Anatomy and Physiology SECTION III 475 Hearing loss RINNE TEST WEBER TEST Conductive Abnormal (bone > air) Localizes to affected ear Sensorineural Normal (air > bone) Localizes to unaffected ear Noise-induced Damage to stereocilliated cells in organ of Corti; loss of high-frequency hearing 1st; sudden extremely loud noises can produce hearing loss due to tympanic membrane rupture. Facial lesions UMN lesion Lesion of motor cortex or connection between cortex and facial nucleus. Contralateral paralysis of lower face; forehead spared due to bilateral UMN innervation. Upper division Lower division Face area of motor cortex Corticobulbar tract (UMN lesion = Central facial) Facial nucleus LMN lesion CN VII (LMN lesion = Facial nerve palsy) LMN lesion Ipsilateral paralysis of upper and lower face. Facial nerve palsy A Complete destruction of the facial nucleus itself or its branchial efferent fibers (facial nerve proper). Peripheral ipsilateral facial paralysis (drooping smile A) with inability to close eye on involved side. Can occur idiopathically (called Bell palsy A); gradual recovery in most cases. Associated with Lyme disease, herpes simplex and (less common) herpes zoster, sarcoidosis, tumors, and diabetes. Treatment includes corticosteroids. Mastication muscles 3 muscles close jaw: Masseter, teMporalis, Medial pterygoid. 1 opens: lateral pterygoid. All are innervated by the trigeminal nerve (V3). M’s Munch. Lateral Lowers (when speaking of pterygoids with respect to jaw motion). “It takes more muscle to keep your mouth shut.” Neurology 476 SECTION III neurology—Anatomy and Physiology Eye and retina Vitreous chamber (posterior segment) Hyaloid canal CN II (optic) Optic disc Fovea centralis Ciliary muscle Ciliary process Canal of Schlemm Anterior chamber Posterior chamber Cornea Pupil Iris Capsule of lens Lens Limbus Zonular fibers Sphincter pupillae Dilator pupillae Ora serrata Retina Choroid Sclera Ciliary body Anterior segment Central retinal artery Central retinal vein Neurology neurology—Anatomy and Physiology SECTION III 477 Common eye conditions Refractive errors Impaired vision that improves with glasses. Hyperopia Eye too short for refractive power of cornea and lens Ž light focused behind retina. Myopia Eye too long for refractive power of cornea and lens Ž light focused in front of retina. Astigmatism Abnormal curvature of cornea resulting in different refractive power at different axes. Presbyopia Decrease in focusing ability during accommodation due to sclerosis and elasticity. Uveitis Inflammation of anterior uvea and iris, with hypopyon (sterile pus), accompanied by conjunctival redness A). Often associated with systemic inflammatory disorders (e.g., sarcoid, rheumatoid arthritis, juvenile idiopathic arthritis, TB, HLA-B27–associated conditions). Retinitis Retinal edema and necrosis leading to scar B. Often viral (CMV, HSV, HZV). Associated with immunosuppression. Central retinal artery occlusion Acute, painless monocular vision loss. Retina cloudy with attenuated vessels and “cherry-red” spot at the fovea C . Retinal vein occlusion Blockage of central or branch retinal vein due to compression from nearby arterial atherosclerosis. Retinal hemorrhage and edema in affected area. Diabetic retinopathy Retinal damage due to chronic hyperglycemia. Two types: Non-proliferative—damaged capillaries leak blood Ž lipids and fluid seep into retina Ž hemorrhages and macular edema. Treatment: blood sugar control, macular laser. Proliferative—chronic hypoxia results in new blood vessel formation with resultant traction on retina. Treatment: peripheral retinal photocoagulation, anti-VEGF injections. A B C Neurology 478 SECTION III neurology—Anatomy and Physiology Aqueous humor pathway Glaucoma Optic disc atrophy with characteristic cupping, usually with intraocular pressure (IOP) and progressive peripheral visual field loss. Open angle Associated with age, African-American race, family history. Painless, more common in U.S. Primary—cause unclear. Secondary—blocked trabecular meshwork from WBCs (e.g., uveitis), RBCs (e.g., vitreous hemorrhage), retinal elements (e.g., retinal detachment). Closed/narrow angle Primary—enlargement or forward movement of lens against central iris (pupil margin) leads to obstruction of normal aqueous flow through pupil Ž fluid builds up behind iris, pushing peripheral iris against cornea and impeding flow through trabecular meshwork. Secondary—hypoxia from retinal disease (e.g., diabetes, vein occlusion) induces vasoproliferation in iris that contracts angle. Chronic closure—often asymptomatic with damage to optic nerve and peripheral vision. Acute closure—true ophthalmic emergency. IOP pushes iris forward Ž angle closes abruptly. Very painful, sudden vision loss, halos around lights, rock-hard eye, frontal headache. Do not give epinephrine because of its mydriatic effect. Cataract A Painless, often bilateral, opacification of lens A Ž in vision. Risk factors: age, smoking, EtOH, excessive sunlight, prolonged corticosteroid use, classic galactosemia, galactokinase deficiency, diabetes (sorbitol), trauma, infection. Ciliary muscle (M3) Ciliary epithelium ( ) (produces aqueous humor) Anterior chamber Dilator ( 1) Sphincter (M3) Lens Trabecular meshwork (collects aqueous humor that flows through anterior chamber) Canal of Schlemm (collects aqueous humor from trabecular meshwork) Iris Sclera Cornea Posterior chamber Neurology neurology—Anatomy and Physiology SECTION III 479 Papilledema A Optic disc swelling (usually bilateral) due to intracranial pressure (e.g., 2° to mass effect). Enlarged blind spot and elevated optic disc with blurred margins seen on fundoscopic exam A. Extraocular muscles and nerves Trochlea Medial rectus m. (CN III) Superior rectus m. (CN III) Lateral rectus m. (CN VI) Inferior rectus m. (CN III) Superior oblique m. (CN IV) Inferior oblique m. (CN III) CN VI innervates the Lateral Rectus. CN IV innervates the Superior Oblique. CN III innervates the Rest. The “chemical formula” LR6SO4R3. The superior oblique abducts, intorts, and depresses while adducted. CN III damage—eye looks down and out; ptosis, pupillary dilation, loss of accommodation. CN IV damage—eye moves upward, particularly with contralateral gaze and head tilt toward the side of the lesion (problems going down stairs, may present with compensatory head tilt in the opposite direction). CN VI damage—medially directed eye that cannot abduct. Testing extraocular muscles To test the function of each muscle, have the patient look in the following directions (e.g., to test SO, have patient depress eye from adducted position): IOU: to test Inferior Oblique, have patient look Up. Obliques move the eye in the Opposite direction. SR IR SO IO LR (temporal) MR (nasal) Neurology 480 SECTION III neurology—Anatomy and Physiology Pupillary control Miosis (constriction, parasympathetic): ƒƒ 1st neuron: Edinger-Westphal nucleus to ciliary ganglion via CN III ƒƒ 2nd neuron: short ciliary nerves to pupillary sphincter muscles Mydriasis (dilation, sympathetic) ƒƒ 1st neuron: hypothalamus to ciliospinal center of Budge (C8–T2) ƒƒ 2nd neuron: exit at T1 to superior cervical ganglion (travels along cervical sympathetic chain near lung apex, subclavian vessels) ƒƒ 3rd neuron: plexus along internal carotid, through cavernous sinus; enters orbit as long ciliary nerve to pupillary dilator muscles Pupillary light reflex Light in either retina sends a signal via CN II to pretectal nuclei (dashed lines) in midbrain that activates bilateral Edinger-Westphal nuclei; pupils contract bilaterally (consensual reflex). Result: illumination of 1 eye results in bilateral pupillary constriction. Marcus Gunn pupil (afferent pupillary defect)—due to optic nerve damage or severe retinal injury. bilateral pupillary constriction when light is shone in affected eye relative to unaffected eye. Tested with the “swinging flashlight test.” Edinger-Westphal nucleus Ciliary ganglion Optic tract Lateral geniculate nucleus Oculomotor nerve Light Optic nerve Pretectal nucleus Pupillary constrictor muscle Cranial nerve III CN III CN III has both motor (central) and parasympathetic (peripheral) components. Motor output to ocular muscles—affected primarily by vascular disease (e.g., diabetes: glucose Ž sorbitol) due to diffusion of oxygen and nutrients to the interior fibers from compromised vasculature that resides on outside of nerve. Signs: ptosis, “down and out” gaze. Parasympathetic output—fibers on the periphery are 1st affected by compression (e.g., posterior communicating artery aneurysm, uncal herniation). Signs: diminished or absent pupillary light reflex, “blown pupil” often with “down-and-out” gaze. Retinal detachment Separation of neurosensory layer of retina (photoreceptor layer with rods and cones) from outermost pigmented epithelium (normally shields excess light, supports retina) Ž degeneration of photoreceptors Ž vision loss. May be 2° to retinal breaks, diabetic traction, inflammatory effusions. Breaks more common in patients with high myopia and are often preceded by posterior vitreous detachment (flashes and floaters) and eventual monocular loss of vision like a “curtain drawn down.” Surgical emergency. Neurology neurology—Anatomy and Physiology SECTION III 481 Age-related macular degeneration A Degeneration of macula (central area of retina). Causes distortion (metamorphopsia) and eventual loss of central vision (scotomas). ƒƒDry (nonexudative, > 80%)—deposition of yellowish extracellular material in and beneath Bruch membrane and retinal pigment epithelium (“drusen”) A with gradual in vision. Prevent progression with multivitamin and antioxidant supplements. ƒƒWet (exudative, 10–15%)—rapid loss of vision due to bleeding 2° to choroidal neovascularization. Treat with anti-vascular endothelial growth factor injections (anti-VEGF) or laser. Visual field defects 1. Right anopia 2. Bitemporal hemianopia (pituitary lesion, chiasm) 3. Left homonymous hemianopia 4. Left upper quadrantic anopia (right temporal lesion, MCA) 5. Left lower quadrantic anopia (right parietal lesion, MCA) 6. Left hemianopia with macular sparing (PCA infarct), macula Ž bilateral projection to occiput 7. Central scotoma (macular degeneration) Meyer loop—inferior retina; loops around inferior horn of lateral ventricle. Dorsal optic radiation—superior retina; takes shortest path via internal capsule. 4 Optic chiasm Optic nerve Optic tract Meyer loop (temporal lobe) Calcarine fissure Visual cortex 1 5 3 2 Dorsal optic radiation (parietal lobe) Lt. Rt. 3 (6 if PCA infarct) Lateral geniculate body Defect in visual field of 1 2 3 4 5 6 L eye R eye 7 7 Macula Note: When an image hits 1° visual cortex, it is upside down and left-right reversed. Neurology 482 SECTION III neurology—Anatomy and Physiology Internuclear ophthalmoplegia (INO) Medial longitudinal fasciculus (MLF): pair of tracts that allows for crosstalk between CN VI and CN III nuclei. Coordinates both eyes to move in same horizontal direction. Highly myelinated (must communicate quickly so eyes move at same time). Lesions seen in patients with demyelination (e.g., multiple sclerosis). Lesion in MLF = INO: lack of communication such that when CN VI nucleus activates ipsilateral lateral rectus, contralateral CN III nucleus does not stimulate medial rectus to fire. Abducting eye gets nystagmus (CN VI overfires to stimulate CN III). Convergence normal. MLF in MS. When looking left, the left nucleus of CN VI fires, which contracts the left lateral rectus and stimulates the contralateral (right) nucleus of CN III via the right MLF to contract the right medial rectus. Directional term (e.g., right INO, left INO) refers to which eye is paralyzed. Medial recti Right MLF Medial rectus subnucleus of CN III Lateral recti Nuclei of CN VI L R Left MLF Left gaze Right INO (right MLF lesion) Impaired adduction Nystagmus Neurology neurology—Pathology SECTION III 483 ``NEUROLOGY —PATHOLOGY Dementia A in cognitive ability, memory, or function with intact consciousness. DISE ASE DES CRI PTION HISTOLOGI C/GROSS FINDINGS Alzheimer disease A Most common cause in elderly. Down syndrome patients have an risk of developing Alzheimer. Familial form (10%) associated with the following altered proteins (respective chromosomes in parentheses): ƒƒ Early onset: APP (Chr 21), presenilin-1 (Chr 14), presenilin-2 (Chr 1) ƒƒ Late onset: ApoE4 (Chr 19) ApoE2 (Chr 19) is protective. Widespread cortical atrophy. Narrowing of gyri and widening of sulci ACh Senile plaques A: extracellular β-amyloid core; may cause amyloid angiopathy Ž intracranial hemorrhage; Aβ (amyloid-β) synthesized by cleaving amyloid precursor protein (APP) Neurofibrillary tangles: intracellular, hyperphosphorylated tau protein = insoluble cytoskeletal elements; tangles correlate with degree of dementia Pick disease (frontotemporal dementia) Dementia, aphasia, parkinsonian aspects; change in personality. Spares parietal lobe and posterior 2 ⁄3 of superior temporal gyrus. Pick bodies: spherical tau protein aggregates Frontotemporal atrophy Lewy body dementia Initially dementia and visual hallucinations followed by parkinsonian features. α-synuclein defect Creutzfeldt-Jakob disease Rapidly progressive (weeks to months) dementia with myoclonus (“startle myoclonus”). Spongiform cortex Prions (PrPc Ž PrPsc sheet [b-pleated sheet resistant to proteases]) Other causes Multi-infarct (2nd most common cause of dementia in elderly); syphilis; HIV; vitamins B1, B3, or B12 deficiency; Wilson disease; and NPH. 484 SECTION III Neurology neurology—Pathology Multiple sclerosis Autoimmune inflammation and demyelination of CNS (brain and spinal cord). Patients can present with optic neuritis (sudden loss of vision resulting in Marcus Gunn pupils) internuclear ophthalmoplegia, hemiparesis, hemisensory symptoms, or bladder/bowel incontinence. Relapsing and remitting course. Most often affects women in their 20s and 30s; more common in whites. Charcot classic triad of MS is a SIN: ƒƒ Scanning speech ƒƒ Intention tremor (also Incontinence and Internuclear ophthalmoplegia) ƒƒNystagmus A Multiple sclerosis. FLAIR MRI shows typical plaques (arrows). FINDINGS protein (IgG) in CSF. Oligoclonal bands are diagnostic. MRI is gold standard. Periventricular plaques A (areas of oligodendrocyte loss and reactive gliosis) with destruction of axons. Multiple white matter lesions separated in space and time. TRE ATMENT β-interferon, immunosuppression, natalizumab. Symptomatic treatment for neurogenic bladder (catheterization, muscarinic antagonists), spasticity (baclofen, GABA receptor agonist), pain (opioids). Acute inflammatory demyelinating polyradiculopathy Most common variant of Guillain-Barré syndrome. Autoimmune condition that destroys Schwann cells Ž inflammation and demyelination of peripheral nerves and motor fibers. Results in symmetric ascending muscle weakness/paralysis beginning in lower extremities. Facial paralysis in 50% of cases. Autonomic function may be severely affected (e.g., cardiac irregularities, hypertension, or hypotension). Almost all patients survive; the majority recover completely after weeks to months. Findings: CSF protein with normal cell count (albuminocytologic dissociation). protein Ž papilledema. Associated with infections (Campylobacter jejuni and CMV) Ž autoimmune attack of peripheral myelin due to molecular mimicry, inoculations, and stress, but no definitive link to pathogens. Respiratory support is critical until recovery. Additional treatment: plasmapheresis, IV immune globulins. Neurology neurology—Pathology SECTION III 485 Other demyelinating and dysmyelinating diseases Progressive multifocal leukoencephalopathy Demyelination of CNS due to destruction of oligodendrocytes. Associated with JC virus. Seen in 2–4% of AIDS patients (reactivation of latent viral infection). Rapidly progressive, usually fatal. risk associated wtih natalizumab. Acute disseminated (postinfectious) encephalomyelitis Multifocal perivenular inflammation and demyelination after infection (commonly measles or VZV) or certain vaccinations (e.g., rabies, smallpox). Metachromatic leukodystrophy Autosomal recessive lysosomal storage disease, most commonly due to arylsulfatase A deficiency. Buildup of sulfatides Ž impaired production of myelin sheath. Findings: central and peripheral demyelination with ataxia, dementia. Charcot-Marie-Tooth disease Also known as hereditary motor and sensory neuropathy (HMSN). Group of progressive hereditary nerve disorders related to the defective production of proteins involved in the structure and function of peripheral nerves or the myelin sheath. Typically autosomal dominant inheritance pattern and associated with scoliosis and foot deformities (high or flat arches). Krabbe disease Autosomal recessive lysosomal storage disease due to deficiency of galactocerebrosidase. Buildup of galactocerebroside and psychosine destroys myelin sheath. Findings: peripheral neuropathy, developmental delay, optic atrophy, globoid cells. Adrenoleukodystrophy X-linked genetic disorder typically affecting males. Disrupts metabolism of very-long-chain fatty acids Ž excessive buildup in nervous system, adrenal gland, and testes. Progressive disease that can lead to long-term coma/death and adrenal gland crisis. Seizures Characterized by synchronized, high-frequency neuronal firing. Variety of forms. Partial (focal) seizures Affect 1 area of the brain. Most commonly originate in medial temporal lobe. Often preceded by seizure aura; can secondarily generalize. Types: ƒƒ Simple partial (consciousness intact)— motor, sensory, autonomic, psychic ƒƒ Complex partial (impaired consciousness) Epilepsy—a disorder of recurrent seizures (febrile seizures are not epilepsy). Status epilepticus—continuous seizure for > 30 min or recurrent seizures without regaining consciousness between seizures for > 30 min. Medical emergency. Causes of seizures by age: ƒƒ Children—genetic, infection (febrile), trauma, congenital, metabolic ƒƒ Adults—tumors, trauma, stroke, infection ƒƒ Elderly—stroke, tumor, trauma, metabolic, infection Generalized seizures Diffuse. Types: ƒƒ Absence (petit mal)—3 Hz, no postictal confusion, blank stare ƒƒMyoclonic—quick, repetitive jerks ƒƒ Tonic-clonic (grand mal)—alternating stiffening and movement ƒƒ Tonic—stiffening ƒƒ Atonic—“drop” seizures (falls to floor); commonly mistaken for fainting 486 SECTION III Neurology neurology—Pathology Differentiating headaches Pain due to irritation of structures such as the dura, cranial nerves, or extracranial structures. CLASSI FICATION LO CALI ZATION DUR ATION DES CRI PTION TRE ATMENT Clustera Unilateral 15 min–3 hr; repetitive Repetitive brief headaches. Excruciating periorbital pain with lacrimation and rhinorrhea. May induce Horner syndrome. More common in males. Inhaled oxygen, sumatriptan Tension Bilateral > 30 min (typically 4–6 hr); constant Steady pain. No photophobia or phonophobia. No aura. Analgesics, NSAIDs, acetaminophen; amitriptyline for chronic pain Migraine Unilateral 4–72 hr Pulsating pain with nausea, photophobia, or phonophobia. May have “aura.” Due to irritation of CN V, meninges, or blood vessels (release of substance P, CGRP, vasoactive peptides). Abortive therapies (e.g., triptans, NSAIDs) and prophylactic (propranolol, topiramate, calcium channel blockers, amitriptyline). POUND–Pulsatile, One-day duration, Unilateral, Nausea, Disabling Other causes of headache include subarachnoid hemorrhage (“worst headache of life”), meningitis, hydrocephalus, neoplasia, and arteritis. a Cluster headaches can be differentiated from trigeminal neuralgia based on duration. Trigeminal neuralgia produces repetitive shooting pain in the distribution of CN V that lasts (typically) for < 1 minute. The pain from cluster headaches lasts considerably longer (> 15 minutes). Vertigo Sensation of spinning while actually stationary. Subtype of “dizziness,” but distinct from “lightheadedness.” Peripheral vertigo More common. Inner ear etiology (e.g., semicircular canal debris, vestibular nerve infection, Ménière disease). Positional testing Ž delayed horizontal nystagmus. Central vertigo Brain stem or cerebellar lesion (e.g., stroke affecting vestibular nuclei or posterior fossa tumor). Findings: directional change of nystagmus, skew deviation, diplopia, dysmetria. Positional testing Ž immediate nystagmus in any direction; may change directions. Focal neurological findings. Neurology neurology—Pathology SECTION III 487 Neurocutaneous disorders Sturge-Weber syndrome Congenital, non-inherited (somatic), developmental anomaly of neural crest derivatives (mesoderm/ectoderm) due to activating mutation of GNAQ gene. Affects small (capillarysized) blood vessels Ž port-wine stain of the face A (non-neoplastic “birthmark” in CN V1/V2 distribution); ipsilateral leptomeningeal angioma B Ž seizures/epilepsy; intellectual disability; and episcleral hemangioma Ž IOP Ž early-onset glaucoma. STURGE-Weber: Sporadic, port-wine Stain; Tram track Ca2+ (opposing gyri); Unilateral; Retardation, Glaucoma, GNAQ gene; Epilepsy. Tuberous sclerosis HAMARTOMAS: Hamartomas in CNS and skin; Angiofibromas C ; Mitral regurgitation; Ash-leaf spots; cardiac Rhabdomyoma; (Tuberous sclerosis); autosomal dOminant; Mental retardation; renal Angiomyolipoma D; Seizures, Shagreen patches. incidence of subependymal astrocytomas and ungual fibromas. Neurofibromatosis type I (von Recklinghausen disease) Café-au-lait spots E , Lisch nodules (pigmented iris hamartomas F ), neurofibromas in skin, optic gliomas, pheochromocytomas. Mutated NF1 tumor suppressor gene (neurofibromin, a negative regulator of Ras) on chromosome 17. Skin tumors of NF-1 are derived from neural crest cells. von Hippel-Lindau disease Cavernous hemangiomas in skin, mucosa, organs; bilateral renal cell carcinomas; hemangioblastoma (high vascularity with hyperchromatic nuclei G) in retina, brain stem, cerebellum H; and pheochromocytomas. Autosomal dominant; mutated VHL tumor suppressor gene on chromosome 3, which results in constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors. A E B C G D F H 488 SECTION III Neurology neurology—Pathology Adult primary brain tumors Glioblastoma multiforme (grade IV astrocytoma) Common, highly malignant 1° brain tumor with ~ 1-year median survival. Found in cerebral hemispheres A. Can cross corpus callosum (“butterfly glioma”). Stain astrocytes for GFAP. “Pseudopalisading” B pleomorphic tumor cells—border central areas of necrosis and hemorrhage. Meningioma Common, typically benign 1° brain tumor. Most often occurs in convexities of hemispheres (near surfaces of brain) and parasagittal region. Arises from arachnoid cells, is extra-axial (external to brain parenchyma), and may have a dural attachment (“tail” C ). Often asymptomatic; may present with seizures or focal neurological signs. Resection and/or radiosurgery. Spindle cells concentrically arranged in a whorled pattern; psammoma bodies (laminated calcifications D). Hemangioblastoma Most often cerebellar E . Associated with von Hippel-Lindau syndrome when found with retinal angiomas. Can produce erythropoietin Ž 2° polycythemia. Closely arranged, thin-walled capillaries with minimal interleaving parenchyma F . Schwannoma Usually found at cerebellopontine angle G. Schwann cell origin H, S-100 ; often localized to CN VIII Ž acoustic schwannoma (aka acoustic neuroma). Resectable or treated with stereotactic radiosurgery. Bilateral acoustic schwannomas found in NF-2. Oligodendroglioma Relatively rare, slow growing. Most often in frontal lobes I . Chicken-wire capillary pattern. Oligodendrocytes = “fried egg” cells—round nuclei with clear cytoplasm J . Often calcified in oligodendroglioma. Pituitary adenoma Most commonly prolactinoma K. Bitemporal hemianopia ( L shows normal visual field above, patient’s perspective below) due to pressure on optic chiasm. Hyper- or hypopituitarism are sequelae. A I B F J G K D H L C E Neurology neurology—Pathology SECTION III 489 Childhood primary brain tumors Pilocytic (low-grade) astrocytoma Usually well circumscribed. In children, most often found in posterior fossa A (e.g., cerebellum). May be supratentorial. GFAP . Benign; good prognosis. Rosenthal fibers—eosinophilic, corkscrew fibers B. Cystic + solid (gross). Medulloblastoma Highly malignant cerebellar tumor C . A form of primitive neuroectodermal tumor. Can compress 4th ventricle, causing hydrocephalus. Can send “drop metastases” to spinal cord. Homer-Wright rosettes. Solid (gross), small blue cells D (histology). Ependymoma Ependymal cell tumors most commonly found in 4th ventricle E . Can cause hydrocephalus. Poor prognosis. Characteristic perivascular rosettes F . Rodshaped blepharoplasts (basal ciliary bodies) found near nucleus. Craniopharyngioma Benign childhood tumor, may be confused with pituitary adenoma (both can cause bitemporal hemianopia). Most common childhood supratentorial tumor. Derived from remnants of Rathke pouch. Calcification is common G, H (tooth enamel– like). E B F C G D H A Herniation syndromes Cingulate (subfalcine) herniation under falx cerebri Can compress anterior cerebral artery. Falx cerebri Lateral ventricles Supratentorial mass Uncus Tentorium cerebelli Downward transtentorial (central) herniation Uncal herniation Uncus = medial temporal lobe. Compresses ipsilateral CN III (blown pupil, “down-andout” gaze), ipsilateral PCA (contralateral homonymous hemianopsia), contralateral crus cerebri (ipsilateral paralysis, “false localization” sign). Cerebellar tonsillar herniation into the foramen magnum Coma and death result when these herniations compress the brain stem (and inhibit respiration). Neurology 490 SECTION III neurology—Pharmac ology ``NEUROLOGY —PHARM ACOLOGY Glaucoma drugs IOP via amount of aqueous humor (inhibit synthesis/secretion or drainage). DRUG ME CHANISM SIDE EFFECTS α-agonists Epinephrine Brimonidine (α2) aqueous humor synthesis via vasoconstriction aqueous humor synthesis Mydriasis; do not use in closed-angle glaucoma Blurry vision, ocular hyperemia, foreign body sensation, ocular allergic reactions, ocular pruritus β-blockers Timolol, betaxolol, carteolol aqueous humor synthesis No pupillary or vision changes Diuretics Acetazolamide aqueous humor synthesis via inhibition of carbonic anhydrase No pupillary or vision changes Cholinomimetics Direct (pilocarpine, carbachol) Indirect (physostigmine, echothiophate) outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork Use pilocarpine in emergencies—very effective at opening meshwork into canal of Schlemm Miosis and cyclospasm (contraction of ciliary muscle) Prostaglandin Latanoprost (PGF2α) outflow of aqueous humor Darkens color of iris (browning) Opioid analgesics Morphine, fentanyl, codeine, loperamide, methadone, meperidine, dextromethorphan, diphenoxylate. ME CHANISM Act as agonists at opioid receptors (mu = morphine, delta = enkephalin, kappa = dynorphin) to modulate synaptic transmission—open K+ channels, close Ca2+ channels Ž synaptic transmission. Inhibit release of ACh, norepinephrine, 5-HT, glutamate, substance P. CLINI CAL USE Pain, cough suppression (dextromethorphan), diarrhea (loperamide and diphenoxylate), acute pulmonary edema, maintenance programs for heroin addicts (methadone). TO XICITY Addiction, respiratory depression, constipation, miosis (pinpoint pupils), additive CNS depression with other drugs. Tolerance does not develop to miosis and constipation. Toxicity treated with naloxone or naltrexone (opioid receptor antagonist). Neurology neurology—Pharmac ology SECTION III 491 Butorphanol ME CHANISM Mu-opioid receptor partial agonist and kappa-opioid receptor agonist; produces analgesia. CLINI CAL USE Severe pain (migraine, labor, etc.). Causes less respiratory depression than full opioid agonists. TO XICITY Can cause opioid withdrawal symptoms if patient is also taking full opioid agonist (competition for opioid receptors). Overdose not easily reversed with naloxone. Tramadol ME CHANISM Very weak opioid agonist; also inhibits serotonin and norepinephrine reuptake (works on multiple neurotransmitters—“tram it all” in with tramadol). CLINI CAL USE Chronic pain. TO XICITY Similar to opioids. Decreases seizure threshold. Serotonin syndrome. Neurology 492 SECTION III neurology—Pharmac ology Epilepsy drugs PARTI AL (FOCAL) GENER ALIZED ME CHANISM SIDE EFFECTS NOTES SIM PLE COM PLE X TONI C-CLONI C ABSEN CE ST ATUS EPILE PTI CUS Ethosuximide * ✓ Blocks thalamic T-type Ca2+ channels GI, fatigue, headache, urticaria, Steven-Johnson syndrome. EFGHIJ—Ethosuximide causes Fatigue, GI distress, Headache, Itching, and Stevens-Johnson syndrome Sucks to have Silent (absence) Seizures Benzodiazepines (diazepam, lorazepam) ** ✓ GABAA action Sedation, tolerance, dependence, respiratory depression Also for eclampsia seizures (1st line is MgSO4) Phenytoin ✓ ✓ * ✓ *** ✓ Na+ channel inactivation; zero-order kinetics Nystagmus, diplopia, ataxia, sedation, gingival hyperplasia, hirsutism, peripheral neuropathy, megaloblastic anemia, teratogenesis (fetal hydantoin syndrome) SLE-like syndrome, induction of cytochrome P-450, lymphadenopathy, Stevens- Johnson syndrome, osteopenia Fosphenytoin for parenteral use Carbamazepine * ✓ * ✓ * ✓ Na+ channel inactivation Diplopia, ataxia, blood dyscrasias (agranulocytosis, aplastic anemia), liver toxicity, teratogenesis, induction of cytochrome P-450, SIADH, Stevens-Johnson syndrome 1st line for trigeminal neuralgia Valproic acid ✓ ✓ * ✓ ✓ Na+ channel inactivation, GABA concentration by inhibiting GABA transaminase GI, distress, rare but fatal hepatotoxicity (measure LFTs), neural tube defects in fetus (spina bifida), tremor, weight gain, contraindicated in pregnancy Also used for myoclonic seizures, bipolar disorder Gabapentin ✓ ✓ ✓ Primarily inhibits highvoltage- activated Ca2+ channels; designed as GABA analog Sedation, ataxia Also used for peripheral neuropathy, postherpetic neuralgia, migraine prophylaxis, bipolar disorder Phenobarbital ✓ ✓ ✓ GABAA action Sedation, tolerance, dependence, induction of cytochrome P-450, cardiorespiratory depression 1st line in neonates Topiramate ✓ ✓ ✓ Blocks Na+ channels, GABA action Sedation, mental dulling, kidney stones, weight loss Also used for migraine prevention Lamotrigine ✓ ✓ ✓ ✓ Blocks voltage-gated Na+ channels Stevens-Johnson syndrome (must be titrated slowly) Levetiracetam ✓ ✓ ✓ Unknown; may modulate GABA and glutamate release Tiagabine ✓ ✓ GABA by inhibiting re-uptake Vigabatrin ✓ ✓ GABA by irreversibly inhibiting GABA transaminase Stevens-Johnson syndrome Prodrome of malaise and fever followed by rapid onset of erythematous/purpuric macules (oral, ocular, genital). Skin lesions progress to epidermal necrosis and sloughing. * = 1st line; ** = 1st line for acute; *** = 1st line for prophylaxis. Neurology neurology—Pharmac ology SECTION III 493 Barbiturates Phenobarbital, pentobarbital, thiopental, secobarbital. ME CHANISM Facilitate GABAA action by duration of Cl- channel opening, thus neuron firing (barbidurates duration). Contraindicated in porphyria. CLINI CAL USE Sedative for anxiety, seizures, insomnia, induction of anesthesia (thiopental). TO XICITY Respiratory and cardiovascular depression (can be fatal); CNS depression (can be exacerbated by EtOH use); dependence; drug interactions (induces cytochrome P-450). Overdose treatment is supportive (assist respiration and maintain BP). Benzodiazepines Diazepam, lorazepam, triazolam, temazepam, oxazepam, midazolam, chlordiazepoxide, alprazolam. ME CHANISM Facilitate GABAA action by frequency of Cl- channel opening. REM sleep. Most have long half-lives and active metabolites (exceptions: triazolam, oxazepam, and midazolam are short acting Ž higher addictive potential). “Frenzodiazepines” frequency. Benzos, barbs, and EtOH all bind the GABAA receptor, which is a ligand-gated Clchannel. CLINI CAL USE Anxiety, spasticity, status epilepticus (lorazepam and diazepam), detoxification (especially alcohol withdrawal–DTs), night terrors, sleepwalking, general anesthetic (amnesia, muscle relaxation), hypnotic (insomnia). TO XICITY Dependence, additive CNS depression effects with alcohol. Less risk of respiratory depression and coma than with barbiturates. Treat overdose with flumazenil (competitive antagonist at GABA benzodiazepine receptor). Nonbenzodiazepine hypnotics Zolpidem (Ambien), Zaleplon, esZopiclone. “All ZZZs put you to sleep.” ME CHANISM Act via the BZ1 subtype of the GABA receptor. Effects reversed by flumazenil. CLINI CAL USE Insomnia. TO XICITY Ataxia, headaches, confusion. Short duration because of rapid metabolism by liver enzymes. Unlike older sedative-hypnotics, cause only modest day-after psychomotor depression and few amnestic effects. dependence risk than benzodiazepines. Anesthetics—general principles CNS drugs must be lipid soluble (cross the blood-brain barrier) or be actively transported. Drugs with solubility in blood = rapid induction and recovery times. Drugs with solubility in lipids = potency = 1 MAC MAC = Minimal Alveolar Concentration (of inhaled anesthetic) required to prevent 50% of subjects from moving in response to noxious stimulus (e.g., skin incision). Examples: N2O has blood and lipid solubility, and thus fast induction and low potency. Halothane, in contrast, has lipid and blood solubility, and thus high potency and slow induction. Neurology 494 SECTION III neurology—Pharmac ology Inhaled anesthetics Halothane, enflurane, isoflurane, sevoflurane, methoxyflurane, nitrous oxide. ME CHANISM Mechanism unknown. EFFECTS Myocardial depression, respiratory depression, nausea/emesis, cerebral blood flow ( cerebral metabolic demand). TO XICITY Hepatotoxicity (halothane), nephrotoxicity (methoxyflurane), proconvulsant (enflurane), expansion of trapped gas in a body cavity (nitrous oxide). Can cause malignant hyperthermia—rare, life-threatening hereditary condition in which inhaled anesthetics (except nitrous oxide) and succinylcholine induce fever and severe muscle contractions. Treatment: dantrolene. Intravenous anesthetics Barbiturates Thiopental—high potency, high lipid solubility, rapid entry into brain. Used for induction of anesthesia and short surgical procedures. Effect terminated by rapid redistribution into tissue (i.e., skeletal muscle) and fat. cerebral blood flow. B. B. King on OPIOIDS PROPOses FOOLishly. Benzodiazepines Midazolam most common drug used for endoscopy; used adjunctively with gaseous anesthetics and narcotics. May cause severe postoperative respiratory depression, BP (treat overdose with flumazenil), and anterograde amnesia. Arylcyclohexylamines (Ketamine) PCP analogs that act as dissociative anesthetics. Block NMDA receptors. Cardiovascular stimulants. Cause disorientation, hallucination, and bad dreams. cerebral blood flow. Opioids Morphine, fentanyl used with other CNS depressants during general anesthesia. Propofol Used for sedation in ICU, rapid anesthesia induction, and short procedures. Less postoperative nausea than thiopental. Potentiates GABAA. Neurology neurology—Pharmac ology SECTION III 495 Local anesthetics Esters—procaine, cocaine, tetracaine. Amides—lIdocaIne, mepIvacaIne, bupIvacaIne (amIdes have 2 I’s in name). ME CHANISM Block Na+ channels by binding to specific receptors on inner portion of channel. Preferentially bind to activated Na+ channels, so most effective in rapidly firing neurons. 3° amine local anesthetics penetrate membrane in uncharged form, then bind to ion channels as charged form. PRIN CIPLE Can be given with vasoconstrictors (usually epinephrine) to enhance local action— bleeding, anesthesia by systemic concentration. In infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate membrane effectively Ž need more anesthetic. Order of nerve blockade: small-diameter fibers > large diameter. Myelinated fibers > unmyelinated fibers. Overall, size factor predominates over myelination such that small myelinated fibers > small unmyelinated fibers > large myelinated fibers > large unmyelinated fibers. Order of loss: (1) pain, (2) temperature, (3) touch, (4) pressure. CLINI CAL USE Minor surgical procedures, spinal anesthesia. If allergic to esters, give amides. TO XICITY CNS excitation, severe cardiovascular toxicity (bupivacaine), hypertension, hypotension, and arrhythmias (cocaine). Neuromuscular blocking drugs Used for muscle paralysis in surgery or mechanical ventilation. Selective for motor (vs. autonomic) nicotinic receptor. Depolarizing Succinylcholine—strong ACh receptor agonist; produces sustained depolarization and prevents muscle contraction. Reversal of blockade: ƒƒ Phase I (prolonged depolarization)—no antidote. Block potentiated by cholinesterase inhibitors. ƒƒ Phase II (repolarized but blocked; ACh receptors are available, but desensitized)—antidote consists of cholinesterase inhibitors. Complications include hypercalcemia, hyperkalemia, and malignant hyperthermia. Nondepolarizing Tubocurarine, atracurium, mivacurium, pancuronium, vecuronium, rocuronium—competitive antagonists—compete with ACh for receptors. Reversal of blockade—neostigmine (must be given with atropine to prevent muscarinic effects such as bradycardia), edrophonium, and other cholinesterase inhibitors. Dantrolene ME CHANISM Prevents the release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle. CLINI CAL USE Used to treat malignant hyperthermia and neuroleptic malignant syndrome (a toxicity of antipsychotic drugs). Neurology 496 SECTION III neurology—Pharmac ology Parkinson disease drugs Parkinsonism is due to loss of dopaminergic neurons and excess cholinergic activity. STR ATEGY AGENTS Dopamine agonists Bromocriptine (ergot), pramipexole, ropinirole (non-ergot); non-ergots are preferred BALSA: Bromocriptine Amantadine Levodopa (with carbidopa) Selegiline (and COMT inhibitors) Antimuscarinics For essential or familial tremors, use a β-blocker (e.g., propranolol). dopamine Amantadine (may dopamine release); also used as an antiviral against influenza A and rubella; toxicity = ataxia l-dopa/carbidopa (converted to dopamine in CNS) Prevent dopamine breakdown Selegiline (selective MAO type B inhibitor); entacapone, tolcapone (COMT inhibitors— prevent l-dopa degradation Ž dopamine availability) Curb excess cholinergic activity Benztropine (Antimuscarinic; improves tremor and rigidity but has little effect on bradykinesia) Park your Mercedes-Benz. l-dopa (levodopa)/carbidopa ME CHANISM level of dopamine in brain. Unlike dopamine, l-dopa can cross blood-brain barrier and is converted by dopa decarboxylase in the CNS to dopamine. Carbidopa, a peripheral decarboxylase inhibitor, is given with l-dopa to the bioavailability of l-dopa in the brain and to limit peripheral side effects. CLINI CAL USE Parkinson disease. TO XICITY Arrhythmias from peripheral formation of catecholamines. Long-term use can lead to dyskinesia following administration (“on-off” phenomenon), akinesia between doses. Selegiline ME CHANISM Selectively inhibits MAO-B, which preferentially metabolizes dopamine over norepinephrine and 5-HT, thereby the availability of dopamine. CLINI CAL USE Adjunctive agent to l-dopa in treatment of Parkinson disease. TO XICITY May enhance adverse effects of l-dopa. Alzheimer drugs Memantine ME CHANISM NMDA receptor antagonist; helps prevent excitotoxicity (mediated by Ca2+). TO XICITY Dizziness, confusion, hallucinations. Donepezil, galantamine, rivastigmine ME CHANISM AChE inhibitors. TO XICITY Nausea, dizziness, insomnia. Neurology neurology—Pharmac ology SECTION III 497 Huntington drugs Neurotransmitter changes in Huntington disease: GABA, ACh, dopamine. Treatments: ƒƒ Tetrabenazine and reserpine—inhibit vesicular monoamine transporter (VMAT); limit dopamine vesicle packaging and release. ƒƒHaloperidol—dopamine receptor antagonist. Sumatriptan ME CHANISM 5-HT1B/1D agonist. Inhibits trigeminal nerve activation; prevents vasoactive peptide release; induces vasoconstriction. Half-life < 2 hours. A SUMo wrestler TRIPs ANd falls on your head. CLINI CAL USE Acute migraine, cluster headache attacks. TO XICITY Coronary vasospasm (contraindicated in patients with CAD or Prinzmetal angina), mild tingling. 498 SECTION III NEUROLOGY ``NOTES 499 `` Psychology 500 ``Pathology 502 ``Pharmacology 516 HI G H -Y I ELD P R I NCI P L E S IN “A Freudian slip is when you say one thing but mean your mother.” —Anonymous “Men will always be mad, and those who think they can cure them are the maddest of all.” —Voltaire “Anyone who goes to a psychiatrist ought to have his head examined.” —Samuel Goldwyn The DSM-5 was released by the American Psychiatric Association in 2013, reclassifying several psychiatric conditions and updating diagnostic criteria. We have updated this chapter to reflect certain DSM-5 revisions. Psychiatry Psychiatry 500 SECTI ON III Psychiatry—PSYCH ology ``PSYCHIATRY —PSYCHOLOGY Classical conditioning Learning in which a natural response (salivation) is elicited by a conditioned, or learned, stimulus (bell) that previously was presented in conjunction with an unconditioned stimulus (food). Usually deals with involuntary responses. Pavlov’s classical experiments with dogs— ringing the bell provoked salivation. Operant conditioning Learning in which a particular action is elicited because it produces a punishment or reward. Usually deals with voluntary responses. Positive reinforcement Desired reward produces action (mouse presses button to get food). Negative reinforcement Target behavior (response) is followed by removal of aversive stimulus (mouse presses button to turn off continuous loud noise). Punishment Repeated application of aversive stimulus extinguishes unwanted behavior. Extinction Discontinuation of reinforcement (positive or negative) eventually eliminates behavior. Can occur in operant or classical conditioning. Transference and countertransference Transference Patient projects feelings about formative or other important persons onto physician (e.g., psychiatrist is seen as parent). Countertransference Doctor projects feelings about formative or other important persons onto patient (e.g., patient reminds physician of younger sibling). Ego defenses Unconscious mental processes used to resolve conflict and prevent undesirable feelings (e.g., anxiety, depression). IMMAT URE DEFENSES DESCRI PTIO N EXAMPLE Acting out Expressing unacceptable feelings and thoughts through actions. Tantrums. Dissociation Temporary, drastic change in personality, memory, consciousness, or motor behavior to avoid emotional stress. Extreme forms can result in dissociative identity disorder (multiple personality disorder). Denial Avoiding the awareness of some painful reality. A common reaction in newly diagnosed AIDS and cancer patients. Displacement Transferring avoided ideas and feelings to some neutral person or object (vs. projection). Mother yells at her child, because her husband yelled at her. Fixation Partially remaining at a more childish level of development (vs. regression). Men fixating on sports games. Identification Modeling behavior after another person who is more powerful (though not necessarily admired). Abused child identifies with an abuser. Isolation (of affect) Separating feelings from ideas and events. Describing murder in graphic detail with no emotional response. Psychiatry Psychiatry—PSYCH ology SECTI ON III 501 Ego defenses (continued) IMMAT URE DEFENSES DESCRI PTIO N EXAMPLE Projection Attributing an unacceptable internal impulse to an external source (vs. displacement). A man who wants another woman thinks his wife is cheating on him. Rationalization Proclaiming logical reasons for actions actually performed for other reasons, usually to avoid self-blame. After getting fired, claiming that the job was not important anyway. Reaction formation Replacing a warded-off idea or feeling by an (unconsciously derived) emphasis on its opposite (vs. sublimation). A patient with libidinous thoughts enters a monastery. Regression Turning back the maturational clock and going back to earlier modes of dealing with the world (vs. fixation). Seen in children under stress such as illness, punishment, or birth of a new sibling (e.g., bedwetting in a previously toilet-trained child when hospitalized). Repression Involuntary withholding an idea or feeling from conscious awareness (vs. suppression). Not remembering a conflictual or traumatic experience; pressing bad thoughts into the unconscious. Splitting Believing that people are either all good or all bad at different times due to intolerance of ambiguity. Commonly seen in borderline personality disorder. A patient says that all the nurses are cold and insensitive but that the doctors are warm and friendly. MAT URE DEFENSES Altruism Alleviating guilty feelings by unsolicited generosity toward others. Mafia boss makes large donation to charity. Humor Appreciating the amusing nature of an anxietyprovoking or adverse situation. Nervous medical student jokes about the boards. Sublimation Replacing an unacceptable wish with a course of action that is similar to the wish but does not conflict with one’s value system (vs. reaction formation). Teenager’s aggression toward his father is redirected to perform well in sports. Suppression Intentional withholding of an idea or feeling from conscious awareness (vs. repression). Choosing to not worry about the big game until it is time to play. Mature adults wear a SASH: Sublimation, Altruism, Suppression, Humor. 502 SECTI ON III Psychiatry Psychiatry—Pathology ``PSYCHIATRY —PATHOLOGY Infant deprivation effects Long-term deprivation of affection results in: ƒƒ muscle tone ƒƒ Poor language skills ƒƒ Poor socialization skills ƒƒ Lack of basic trust ƒƒ Anaclitic depression (infant withdrawn/ unresponsive) ƒƒWeight loss ƒƒ Physical illness The 4 W’s: Weak, Wordless, Wanting (socially), Wary. Deprivation for > 6 months can lead to irreversible changes. Severe deprivation can result in infant death. Child abuse Physical abuse Sexual abuse EVIDENCE Healed fractures on x-ray (e.g., spiral fractures are highly suggestive of abuse), burns (e.g., cigarette, scalding), subdural hematomas, pattern marks/bruising (e.g., belts, electrical cords), rib fractures, retinal hemorrhage or detachment Genital, anal, or oral trauma; STDs; UTIs ABUSER Usually biological mother Known to victim, usually male EPIDEMIOLOGY ~3000 deaths/yr in U.S., 80% < 3 yr old Peak incidence 9–12 years old Child neglect Failure to provide a child with adequate food, shelter, supervision, education, and/or affection. Most common form of child maltreatment. Evidence: poor hygiene, malnutrition, withdrawal, impaired social/emotional development, failure to thrive. As with child abuse, child neglect must be reported to local child protective services. Childhood and early-onset disorders Attention-deficit hyperactivity disorder Onset before age 12. Limited attention span and poor impulse control. Characterized by hyperactivity, impulsivity, and/or inattention in multiple settings (school, home, places of worship, etc.). Normal intelligence, but commonly coexists with difficulties in school. Continues into adulthood in as many as 50% of individuals. Associated with frontal lobe volume/metabolism. Treatment: methylphenidate, amphetamines, atomoxetine, behavioral interventions (reinforcement, reward). Conduct disorder Repetitive and pervasive behavior violating the basic rights of others (e.g., physical aggression, destruction of property, theft). After age 18, many of these patients will meet criteria for diagnosis of antisocial personality disorder. Oppositional defiant disorder Enduring pattern of hostile, defiant behavior toward authority figures in the absence of serious violations of social norms. Tourette syndrome Onset before age 18. Characterized by sudden, rapid, recurrent, nonrhythmic, stereotyped motor and vocal tics that persist for > 1 year. Lifetime prevalence of 0.1–1.0% in the general population. Coprolalia (involuntary obscene speech) found in only 10–20% of patients. Associated with OCD and ADHD. Treatment: antipsychotics and behavioral therapy. Separation anxiety disorder Common onset at 7–9 years. Overwhelming fear of separation from home or loss of attachment figure. May lead to factitious physical complaints to avoid going to or staying at school. Treatment: SSRIs and relaxation techniques/behavioral interventions. Psychiatry Psychiatry—Pathology SECTI ON III 503 Pervasive developmental disorders Characterized by difficulties with language and failure to acquire or early loss of social skills. Autism spectrum disorder Characterized by poor social interactions, communication deficits, repetitive/ritualized behaviors, and restricted interests. Must present in early childhood. May or may not be accompanied by intellectual disability; rarely accompanied by unusual abilities (savants). More common in boys. Rett disorder X-linked disorder seen almost exclusively in girls (affected males die in utero or shortly after birth). Symptoms usually become apparent around ages 1–4, including regression characterized by loss of development, loss of verbal abilities, intellectual disability, ataxia, and stereotyped handwringing. Neurotransmitter changes with disease DISOR DER NEUROTRA NSMITT ER CHA NGES Alzheimer disease ACh Anxiety norepinephrine, GABA, 5-HT Depression norepinephrine, 5-HT, dopamine Huntington disease GABA, ACh, dopamine Parkinson disease dopamine, 5-HT, ACh Schizophrenia dopamine Understanding these changes can help guide pharmacologic treatment choice. Orientation Patient’s ability to know who he or she is, where he or she is, and the date and time. Common causes of loss of orientation: alcohol, drugs, fluid/electrolyte imbalance, head trauma, hypoglycemia, infection, nutritional deficiencies. Order of loss: 1st—time; 2nd—place; last— person. Often abbreviated in the medical chart as “alert and oriented × 3” (AO×3). Amnesias Retrograde amnesia Inability to remember things that occurred before a CNS insult. Anterograde amnesia Inability to remember things that occurred after a CNS insult (no new memory). Korsakoff amnesia Classic anterograde amnesia caused by thiamine deficiency and the associated destruction of mammillary bodies. May also include some retrograde amnesia. Seen in alcoholics, and associated with confabulations. Dissociative amnesia Inability to recall important personal information, usually subsequent to severe trauma or stress. May be accompanied by dissociative fugue (abrupt travel or wandering during a period of dissociative amnesia, associated with traumatic circumstances). 504 SECTI ON III Psychiatry Psychiatry—Pathology Cognitive disorder Significant change in cognition (memory, attention, language, judgment) from previous level of functioning. Associated with abnormalities in CNS, a general medical condition, medications, or substance use. Includes delirium and dementia. Delirium “Waxing and waning” level of consciousness with acute onset; rapid in attention span and level of arousal. Characterized by disorganized thinking, hallucinations (often visual), illusions, misperceptions, disturbance in sleepwake cycle, cognitive dysfunction. Usually 2° to other illness (e.g., CNS disease, infection, trauma, substance abuse/withdrawal, metabolic/electrolyte disturbances, hemorrhage, urinary/fecal retention). Most common presentation of altered mental status in inpatient setting. Abnormal EEG. Treatment: ƒƒ Identify and address underlying cause. ƒƒOptimize brain condition (O2, hydration, pain, etc.). ƒƒ Antipsychotics (mainly haloperidol). Delirium = changes in sensorium. Check for drugs with anticholinergic effects. Often reversible. T-A-DA approach (Tolerate, Anticipate, Don’t Agitate) helpful for management. Dementia Gradual in intellectual ability or “cognition” without affecting level of consciousness. Characterized by memory deficits, aphasia, apraxia, agnosia, loss of abstract thought, behavioral/personality changes, impaired judgment. A patient with dementia can develop delirium (e.g., patient with Alzheimer disease who develops pneumonia is at risk for delirium). Irreversible causes: Alzheimer disease, Lewy body dementia, Huntington disease, Pick disease, cerebral infarcts, Creutzfeldt-Jakob disease, chronic substance abuse (due to neurotoxicity of drugs). Reversible causes: NPH, vitamin B12 deficiency, hypothyroidism, neurosyphilis, HIV (partially). incidence with age. EEG usually normal. “Dememtia” is characterized by memory loss. Usually irreversible. In elderly patients, depression may present like dementia (pseudodementia). Psychiatry Psychiatry—Pathology SECTI ON III 505 Psychosis A distorted perception of reality (psychosis) characterized by delusions, hallucinations, and/or disorganized thinking. Psychosis can occur in patients with medical illness, psychiatric illness, or both. Hallucinations Perceptions in the absence of external stimuli (e.g., seeing a light that is not actually present). Delusions Unique, false beliefs about oneself or others that persist despite the facts (e.g., thinking aliens are communicating with you). Disorganized speech Words and ideas are strung together based on sounds, puns, or “loose associations.” Hallucination types Visual More commonly a feature of medical illness (e.g., drug intoxication) than psychiatric illness. Auditory More commonly a feature of psychiatric illness (e.g., schizophrenia) than medical illness. Olfactory Often occur as an aura of psychomotor epilepsy and in brain tumors. Gustatory Rare. Tactile Common in alcohol withdrawal (e.g., formication—the sensation of bugs crawling on one’s skin). Also seen in cocaine abusers (“cocaine crawlies”). HypnaGOgic Occurs while GOing to sleep. HypnoPOMPic Occurs while waking from sleep (“POMPous upon awakening”). Schizophrenia Chronic mental disorder with periods of psychosis, disturbed behavior and thought, and decline in functioning that lasts > 6 months. Associated with dopaminergic activity, dendritic branching. Genetics and environment contribute to the etiology of schizophrenia. Frequent cannabis use is associated with psychosis/schizophrenia in teens. Lifetime prevalence—1.5% (males = females, blacks = whites). Presents earlier in men (late teens to early 20s vs. late 20s to early 30s in women). Patients are at risk for suicide. Diagnosis requires 2 or more of the following (first 4 in this list are “positive symptoms”): ƒƒDelusions ƒƒHallucinations—often auditory ƒƒDisorganized speech (loose associations) ƒƒDisorganized or catatonic behavior ƒƒ “Negative symptoms”—flat affect, social withdrawal, lack of motivation, lack of speech or thought Brief psychotic disorder—< 1 month, usually stress related. Schizophreniform disorder—1–6 months. Schizoaffective disorder—at least 2 weeks of stable mood with psychotic symptoms, plus a major depressive, manic, or mixed (both) episode. 2 subtypes: bipolar or depressive. Delusional disorder Fixed, persistent, untrue belief system lasting > 1 month. Functioning otherwise not impaired. Example: a woman who genuinely believes she is married to a celebrity when, in fact, she is not. 506 SECTI ON III Psychiatry Psychiatry—Pathology Dissociative disorders Dissociative identity disorder Formerly known as multiple personality disorder. Presence of 2 or more distinct identities or personality states. More common in women. Associated with history of sexual abuse, PTSD, depression, substance abuse, borderline personality, and somatoform conditions. Depersonalization/ derealization disorder Persistent feelings of detachment or estrangement from one’s own body, thoughts, perceptions, and actions (depersonalization) or one’s environment (derealization). Mood disorder Characterized by an abnormal range of moods or internal emotional states and loss of control over them. Severity of moods causes distress and impairment in social and occupational functioning. Includes major depressive disorder, bipolar disorder, dysthymic disorder, and cyclothymic disorder. Psychotic features (delusions or hallucinations) may be present. Manic episode Distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy lasting at least 1 week. Often disturbing to patient. Diagnosis requires hospitalization or at least 3 of the following (manics DIG FAST): ƒƒDistractibility ƒƒ Irresponsibility—seeks pleasure without regard to consequences (hedonistic) ƒƒGrandiosity—inflated self-esteem ƒƒ Flight of ideas—racing thoughts ƒƒ in goal-directed Activity/psychomotor Agitation ƒƒ need for Sleep ƒƒ Talkativeness or pressured speech Hypomanic episode Like manic episode except mood disturbance is not severe enough to cause marked impairment in social and/or occupational functioning or to necessitate hospitalization. No psychotic features. Lasts at least 4 consecutive days. Bipolar disorder Bipolar I defined by the presence of at least 1 manic episode with or without a hypomanic or depressive episode. Bipolar II defined by the presence of a hypomanic and a depressive episode. Patient’s mood and functioning usually return to normal between episodes. Use of antidepressants can lead to mania. High suicide risk. Treatment: mood stabilizers (e.g., lithium, valproic acid, carbamazepine), atypical antipsychotics. Cyclothymic disorder—dysthymia and hypomania; milder form of bipolar disorder lasting at least 2 years. Psychiatry Psychiatry—Pathology SECTI ON III 507 Major depressive disorder May be self-limited disorder, with major depressive episodes usually lasting 6–12 months. Episodes characterized by at least 5 of the following 9 symptoms for 2 or more weeks (symptoms must include patientreported depressed mood or anhedonia and occur more frequently as the disorder progresses). Persistent depressive disorder (dysthymia)— depression, often milder, lasting at least 2 years. Seasonal affective disorder—symptoms usually associated with winter season; improves in response to full-spectrum brightlight exposure. SIG E CAPS: ƒƒ Sleep disturbance ƒƒ Loss of Interest (anhedonia) ƒƒGuilt or feelings of worthlessness ƒƒ Energy loss and fatigue ƒƒConcentration problems ƒƒ Appetite/weight changes ƒƒ Psychomotor retardation or agitation ƒƒ Suicidal ideations ƒƒDepressed mood Patients with depression typically have the following changes in their sleep stages: ƒƒ slow-wave sleep ƒƒ REM latency ƒƒ REM early in sleep cycle ƒƒ total REM sleep ƒƒ Repeated nighttime awakenings ƒƒ Early-morning awakening (important screening question) Atypical depression Differs from classical forms of depression. Characterized by mood reactivity (being able to experience improved mood in response to positive events, albeit briefly), “reversed” vegetative symptoms (hypersomnia and weight gain), leaden paralysis (heavy feeling in arms and legs), and long-standing interpersonal rejection sensitivity. Most common subtype of depression. Treatment: MAO inhibitors, SSRIs. Postpartum mood disturbances Onset within 4 weeks of delivery. Maternal (postpartum) “blues” 50–85% incidence rate. Characterized by depressed affect, tearfulness, and fatigue starting 2–3 days after delivery. Usually resolves within 10 days. Treatment: supportive. Follow-up to assess for possible postpartum depression. Postpartum depression 10–15% incidence rate. Characterized by depressed affect, anxiety, and poor concentration starting within 4 weeks after delivery. Lasts 2 weeks to a year or more. Treatment: antidepressants, psychotherapy. Postpartum psychosis 0.1–0.2% incidence rate. Characterized by delusions, hallucinations, confusion, unusual behavior, and possible homicidal/suicidal ideations or attempts. Usually lasts days to 4–6 weeks. Treatment: antipsychotics, antidepressants, possible inpatient hospitalization, assessment of child safety. 508 SECTI ON III Psychiatry Psychiatry—Pathology Pathologic grief Normal bereavement characterized by shock, denial, guilt, and somatic symptoms. Duration varies widely, up to 6–12 months. May experience simple hallucinations (e.g., hearing name called). Pathologic grief includes excessively intense grief; prolonged grief lasting > 6–12 months; or grief that is delayed, inhibited, or denied. May experience depressive symptoms, delusions, and hallucinations. Electroconvulsive therapy Treatment option for major depressive disorder refractory to other treatment and for pregnant women with major depressive disorder. Also considered when immediate response is necessary (acute suicidality), in depression with psychotic features, and for catatonia. Produces a relatively painless seizure in an anesthetized patient. Adverse effects include disorientation, temporary headache, and partial anterograde/retrograde amnesia usually fully resolving in 6 months. Risk factors for suicide completion Sex (male), Age (teenager or elderly), Depression, Previous attempt, Ethanol or drug use, loss of Rational thinking, Sickness (medical illness, 3 or more prescription medications), Organized plan, No spouse (divorced, widowed, or single, especially if childless), Social support lacking. Women try more often; men succeed more often. SAD PERSONS are more likely to complete suicide. Anxiety disorder Inappropriate experience of fear/worry and its physical manifestations (anxiety) when the source of the fear/worry is either not real or insufficient to account for the severity of the symptoms. Symptoms interfere with daily functioning. Lifetime prevalence of 30% in women and 19% in men. Includes panic disorder, phobias, and generalized anxiety disorder. Panic disorder Defined by the presence of recurrent panic attacks (periods of intense fear and discomfort peaking in 10 minutes with at least 4 of the following): Palpitations, Paresthesias, Abdominal distress, Nausea, Intense fear of dying or losing control, lIght-headedness, Chest pain, Chills, Choking, disConnectedness, Sweating, Shaking, Shortness of breath. Strong genetic component. Treatment: cognitive behavioral therapy, SSRIs, venlafaxine, benzodiazepines (risk of tolerance, physical dependence). PANICS. Diagnosis requires attack followed by 1 month (or more) of 1 (or more) of the following: persistent concern of additional attacks, worrying about consequences of the attack, or behavioral change related to attacks. Symptoms are the systemic manifestations of fear. Psychiatry Psychiatry—Pathology SECTI ON III 509 Specific phobia Fear that is excessive or unreasonable and interferes with normal function. Cued by presence or anticipation of a specific object or situation. Person recognizes fear is excessive. Can treat with systematic desensitization. Social anxiety disorder—exaggerated fear of embarrassment in social situations (e.g., public speaking, using public restrooms). Treatment: SSRIs. Agoraphobia—exaggerated fear of open or enclosed places, using public transportation, being in line or in crowds, or leaving home alone. Generalized anxiety disorder Pattern of uncontrollable anxiety for at least 6 months that is unrelated to a specific person, situation, or event. Associated with sleep disturbance, fatigue, GI disturbance, and difficulty concentrating. Treatment: SSRIs, SNRIs, buspirone, cognitive behavioral therapy. Adjustment disorder—emotional symptoms (anxiety, depression) causing impairment following an identifiable psychosocial stressor (e.g., divorce, illness) and lasting < 6 months (> 6 months in presence of chronic stressor). Obsessive-compulsive disorder Recurring intrusive thoughts, feelings, or sensations (obsessions) that cause severe distress; relieved in part by the performance of repetitive actions (compulsions). Ego dystonic: behavior inconsistent with one’s own beliefs and attitudes (vs. obsessive-compulsive personality disorder). Associated with Tourette disorder. Treatment: SSRIs, clomipramine. Body dysmorphic disorder—preoccupation with minor or imagined defect in appearance, leading to significant emotional distress or impaired functioning; patients often repeatedly seek cosmetic surgery. Post-traumatic stress disorder Persistent reexperiencing of a previous traumatic event (e.g., war, rape, robbery, serious accident, fire). May involve nightmares or flashbacks, intense fear, helplessness, or horror. Leads to avoidance of stimuli associated with the trauma and persistently arousal. Disturbance lasts > 1 month, with onset of symptoms beginning anytime after event, and causes significant distress, negative cognitive alterations, and/or impaired functioning. Treatment: psychotherapy, SSRIs. Acute stress disorder—lasts between 3 days and 1 month. 510 SECTI ON III Psychiatry Psychiatry—Pathology Malingering Patient consciously fakes, profoundly exaggerates, or claims to have a disorder in order to attain a specific 2° (external) gain (e.g., avoiding work, obtaining compensation). Poor compliance with treatment or follow-up of diagnostic tests. Complaints cease after gain (vs. factitious disorder). No conscious attempt to deceive Conscious attempt to deceive Somatoform disorders Factitious disorder Malingering Chief goal is psychological (1° gain) Chief goal is external (2° gain) Unexplained symptoms or complaints Factitious disorders Patient consciously creates physical and/or psychological symptoms in order to assume “sick role” and to get medical attention (1° [internal] gain). Munchausen syndrome Chronic factitious disorder with predominantly physical signs and symptoms. Characterized by a history of multiple hospital admissions and willingness to receive invasive procedures. Munchausen syndrome by proxy When illness in a child or elderly patient is caused by the caregiver. Motivation is to assume a sick role by proxy. Form of child/elder abuse. Somatic symptom and related disorders Category of disorders characterized by physical symptoms with no identifiable physical cause. Both illness production and motivation are unconscious drives. Symptoms not intentionally produced or feigned. More common in women. Somatic symptom disorder Variety of complaints in one or more organ systems lasting for months to years. Associated with excessive, persistent thoughts and anxiety about symptoms. May co-occur with medical illness. Conversion disorder Sudden loss of sensory or motor function (e.g., paralysis, blindness, mutism), often following an acute stressor; patient is aware of but sometimes indifferent toward symptoms (“la belle indifférence”); more common in females, adolescents, and young adults. Illness anxiety disorder (hypochondriasis) Preoccupation with and fear of having a serious illness despite medical evaluation and reassurance. Personality Personality trait An enduring, repetitive pattern of perceiving, relating to, and thinking about the environment and oneself. Personality disorder Inflexible, maladaptive, and rigidly pervasive pattern of behavior causing subjective distress and/ or impaired functioning; person is usually not aware of problem. Usually presents by early adulthood. Three clusters, A, B, and C; remember as Weird, Wild, and Worried based on symptoms. Psychiatry Psychiatry—Pathology SECTI ON III 511 Cluster A personality disorders Odd or eccentric; inability to develop meaningful social relationships. No psychosis; genetic association with schizophrenia. “Weird” (Accusatory, Aloof, Awkward). Paranoid Pervasive distrust and suspiciousness; projection is the major defense mechanism. Schizoid Voluntary social withdrawal, limited emotional expression, content with social isolation (vs. avoidant). Schizoid = distant. Schizotypal Eccentric appearance, odd beliefs or magical thinking, interpersonal awkwardness. Schizotypal = magical thinking. Cluster B personality disorders Dramatic, emotional, or erratic; genetic association with mood disorders and substance abuse. “Wild” (Bad to the Bone). Antisocial Disregard for and violation of rights of others, criminality, impulsivity; males > females; must be > 18 years old and have history of conduct disorder before age 15. Conduct disorder if < 18 years old. Antisocial = sociopath. Borderline Unstable mood and interpersonal relationships, impulsiveness, self-mutilation, boredom, sense of emptiness; females > males; splitting is a major defense mechanism. Histrionic Excessive emotionality and excitability, attention seeking, sexually provocative, overly concerned with appearance. Narcissistic Grandiosity, sense of entitlement; lacks empathy and requires excessive admiration; often demands the “best” and reacts to criticism with rage. Cluster C personality disorders Anxious or fearful; genetic association with anxiety disorders. “Worried” (Cowardly, Compulsive, Clingy). Avoidant Hypersensitive to rejection, socially inhibited, timid, feelings of inadequacy, desires relationships with others (vs. schizoid). Obsessive-compulsive Preoccupation with order, perfectionism, and control; ego-syntonic: behavior consistent with one’s own beliefs and attitudes (vs. OCD). Dependent Submissive and clinging, excessive need to be taken care of, low self-confidence. 512 SECTI ON III Psychiatry Psychiatry—Pathology Keeping “schizo-” straight Schizoid < Schizotypal < Schizophrenic < Schizoaffective (schizoid + odd thinking) (greater odd thinking than schizotypal) (schizophrenic psychotic symptoms + bipolar or depressive mood disorder) Schizophrenia time course: < 1 mo—brief psychotic disorder, usually stress related 1–6 mo—schizophreniform disorder > 6 mo—schizophrenia Eating disorders Anorexia nervosa Excessive dieting +/− purging; intense fear of gaining weight, body image distortion, and exercise, leading to a body weight well below ideal (≈ BMI < 17 kg/m2). Associated with bone density. Severe weight loss, metatarsal stress fractures, amenorrhea, lanugo (fine body hair), anemia, and electrolyte disturbances. Osteoporosis caused in part by estrogen over time. Seen primarily in adolescent girls. Commonly coexists with depression. Bulimia nervosa Binge eating +/− purging; often followed by self-induced vomiting or use of laxatives, diuretics, or emetics. Body weight often maintained within normal range. Associated with parotitis, enamel erosion, electrolyte disturbances, alkalosis, dorsal hand calluses from induced vomiting (Russell sign). Seen predominantly in adolescent girls. Gender dysphoria Strong, persistent cross-gender identification. Characterized by persistent discomfort with one’s sex assigned at birth, causing significant distress and/or impaired functioning. Affected individuals are often referred to as transgender. Transsexualism—desire to live as the opposite sex, often through surgery or hormone treatment. Transvestism—paraphilia, not gender dysphoria. Wearing clothes (e.g., vest) of the opposite sex (cross-dressing). Sexual dysfunction Includes sexual desire disorders (hypoactive sexual desire or sexual aversion), sexual arousal disorders (erectile dysfunction), orgasmic disorders (anorgasmia and premature ejaculation), and sexual pain disorders (dyspareunia and vaginismus). Differential diagnosis includes: ƒƒDrugs (e.g., antihypertensives, neuroleptics, SSRIs, ethanol) ƒƒDiseases (e.g., depression, diabetes, STDs) ƒƒ Psychological (e.g., performance anxiety) Sleep terror disorder Periods of terror with screaming in the middle of the night; occurs during slow-wave sleep. Most common in children. Occurs during non-REM sleep (no memory of arousal) as opposed to nightmares that occur during REM sleep (memory of a scary dream). Cause unknown, but triggers may include emotional stress, fever, or lack of sleep. Usually self limited. Psychiatry Psychiatry—Pathology SECTI ON III 513 Narcolepsy Disordered regulation of sleep-wake cycles; 1° characteristic is excessive daytime sleepiness. Caused by orexin production in lateral hypothalamus. Also associated with: ƒƒHypnagogic (just before sleep) or hypnopompic (just before awakening) hallucinations. ƒƒNocturnal and narcoleptic sleep episodes that start off with REM sleep. ƒƒ Cataplexy (loss of all muscle tone following a strong emotional stimulus, such as laughter) in some patients. Strong genetic component. Treatment: daytime stimulants (e.g., amphetamines, modafinil) and nighttime sodium oxybate (GHB). Hypnagogic—going to sleep Hypnopompic—post-sleep Substance use disorder Maladaptive pattern of substance use defined as 2 or more of the following signs in 1 year: ƒƒ Tolerance—need more to achieve same effect ƒƒWithdrawal ƒƒ Substance taken in larger amounts, or over longer time, than desired ƒƒ Persistent desire or unsuccessful attempts to cut down ƒƒ Significant energy spent obtaining, using, or recovering from substance ƒƒ Important social, occupational, or recreational activities reduced because of substance use ƒƒ Continued use in spite of knowing the problems that it causes ƒƒ Craving ƒƒ Recurrent use in physically dangerous situations ƒƒ Failure to fulfill major obligations at work, school, or home due to use ƒƒ Social or interpersonal conflicts related to substance use Stages of change in overcoming substance addiction 1. Precontemplation—not yet acknowledging that there is a problem 2. Contemplation—acknowledging that there is a problem, but not yet ready or willing to make a change 3. Preparation/determination—getting ready to change behavior 4. Action/willpower—changing behaviors 5. Maintenance—maintaining the behavior change 6. Relapse—returning to old behaviors and abandoning new changes 514 SECTI ON III Psychiatry Psychiatry—Pathology Psychoactive drug intoxication and withdrawal DRUG INTO XICATIO N WITH DRA WAL Depressants Nonspecific: mood elevation, anxiety, sedation, behavioral disinhibition, respiratory depression. Nonspecific: anxiety, tremor, seizures, insomnia. Alcohol Emotional lability, slurred speech, ataxia, coma, blackouts. Serum γ-glutamyltransferase (GGT)—sensitive indicator of alcohol use. Lab AST value is twice ALT value. Mild alcohol withdrawal: symptoms similar to other depressants. Severe alcohol withdrawal can cause autonomic hyperactivity and DTs (5–15% mortality rate). Treatment for DTs: benzodiazepines. Opioids (e.g., morphine, heroin, methadone) Euphoria, respiratory and CNS depression, gag reflex, pupillary constriction (pinpoint pupils), seizures (overdose). Treatment: naloxone, naltrexone. Sweating, dilated pupils, piloerection (“cold turkey”), fever, rhinorrhea, yawning, nausea, stomach cramps, diarrhea (“flu-like” symptoms). Treatment: long-term support, methadone, buprenorphine. Barbiturates Low safety margin, marked respiratory depression. Treatment: symptom management (assist respiration, BP). Delirium, life-threatening cardiovascular collapse. Benzodiazepines Greater safety margin. Ataxia, minor respiratory depression. Treatment: supportive care; consider flumazenil (competitive benzodiazepine antagonist). Sleep disturbance, depression, rebound anxiety, seizure (can be triggered by reversal with flumazenil). Stimulants Nonspecific: mood elevation, psychomotor agitation, insomnia, cardiac arrhythmias, tachycardia, anxiety. Nonspecific: post-use “crash,” including depression, lethargy, weight gain, headache. Amphetamines Euphoria, grandiosity, pupillary dilation, prolonged wakefulness and attention, hypertension, tachycardia, anorexia, paranoia, fever. Severe: cardiac arrest, seizure. Anhedonia, appetite, hypersomnolence, existential crisis. Cocaine Impaired judgment, pupillary dilation, hallucinations (including tactile), paranoid ideations, angina, sudden cardiac death. Treatment: benzodiazepines. Hypersomnolence, malaise, severe psychological craving, depression/suicidality. Caffeine Restlessness, diuresis, muscle twitching. Lack of concentration, headache. Nicotine Restlessness. Irritability, anxiety, craving. Treatment: nicotine patch, gum, or lozenges; bupropion/ varenicline. Psychiatry Psychiatry—Pathology SECTI ON III 515 Psychoactive drug intoxication and withdrawal (continued) DRUG INTO XICATIO N WITH DRA WAL Hallucinogens PCP Belligerence, impulsiveness, fever, psychomotor agitation, analgesia, vertical and horizontal nystagmus, tachycardia, homicidality, psychosis, delirium, seizures. Treatment: benzodiazepines, rapid-acting antipsychotic. Depression, anxiety, irritability, restlessness, anergia, disturbances of thought and sleep. LSD Perceptual distortion (visual, auditory), depersonalization, anxiety, paranoia, psychosis, possible flashbacks. Marijuana (cannabinoid) Euphoria, anxiety, paranoid delusions, perception of slowed time, impaired judgment, social withdrawal, appetite, dry mouth, conjunctival injection, hallucinations. Prescription form is dronabinol (tetrahydrocannabinol isomer): used as antiemetic (chemotherapy) and appetite stimulant (in AIDS). Irritability, depression, insomnia, nausea, anorexia. Most symptoms peak in 48 hours and last for 5–7 days. Generally detectable in urine for 4–10 days. Heroin addiction Users at risk for hepatitis, abscesses, overdose, hemorrhoids, AIDS, and right-sided endocarditis. Look for track marks (needle sticks in veins). Treatments described below. Methadone Long-acting oral opiate; used for heroin detoxification or long-term maintenance. Naloxone + buprenorphine Partial agonist; long acting with fewer withdrawal symptoms than methadone. Naloxone is not active when taken orally, so withdrawal symptoms occur only if injected (lower abuse potential). Naltrexone Long-acting opioid antagonist used for relapse prevention once detoxified. Alcoholism Physiologic tolerance and dependence with symptoms of withdrawal (tremor, tachycardia, hypertension, malaise, nausea, DTs) when intake is interrupted. Complications: alcoholic cirrhosis, hepatitis, pancreatitis, peripheral neuropathy, testicular atrophy. Treatment: disulfiram (to condition the patient to abstain from alcohol use), naltrexone, supportive care. Alcoholics Anonymous and other peer support groups are helpful in sustaining abstinence. Wernicke-Korsakoff syndrome Caused by thiamine deficiency. Triad of confusion, ophthalmoplegia, and ataxia (Wernicke encephalopathy). May progress to irreversible memory loss, confabulation, personality change (Korsakoff psychosis). Associated with periventricular hemorrhage/necrosis of mammillary bodies. Treatment: IV vitamin B1 (thiamine). Mallory-Weiss syndrome Longitudinal partial thickness tear at the gastroesophageal junction caused by excessive vomiting. Often presents with hematemesis. Associated with pain (vs. esophageal varices). Delirium tremens (DTs) Life-threatening alcohol withdrawal syndrome that peaks 2–5 days after last drink. Symptoms in order of appearance: autonomic system hyperactivity (tachycardia, tremors, anxiety, seizures), psychotic symptoms (hallucinations, delusions), confusion. Treatment: benzodiazepines. Psychiatry 516 SECTI ON III Psychiatry—Pharmacology ``PSYCHIATRY —PHARMACOLOGY Treatment for selected psychiatric conditions PSYCHIATRIC CO NDITIO N PREFERR ED DRUGS ADHD Methylphenidate Alcohol withdrawal Benzodiazepines Anxiety SSRIs, SNRIs, buspirone Bipolar disorder “Mood stabilizers” (e.g., lithium, valproic acid, carbamazepine), atypical antipsychotics Bulimia SSRIs Depression SSRIs, SNRIs, TCAs, bupropion, mirtazapine (especially with insomnia) Obsessive-compulsive disorder SSRIs, clomipramine Panic disorder SSRIs, venlafaxine, benzodiazepines PTSD SSRIs Schizophrenia Antipsychotics Social phobias SSRIs, β-blockers Tourette syndrome Antipsychotics (e.g., haloperidol, risperidone) CNS stimulants Methylphenidate, dextroamphetamine, methamphetamine, phentermine. MECHA NIS M catecholamines at the synaptic cleft, especially norepinephrine and dopamine. CLI NICAL USE ADHD, narcolepsy, appetite control. Psychiatry Psychiatry—Pharmacology SECTI ON III 517 Antipsychotics (neuroleptics) Haloperidol, trifluoperazine, fluphenazine, thioridazine, chlorpromazine (haloperidol + “-azines”). MECHA NIS M All typical antipsychotics block dopamine D2 receptors ( [cAMP]). High potency: Trifluoperazine, Fluphenazine, Haloperidol (Try to Fly High)—neurologic side effects (EPS symptoms). Low potency: Chlorpromazine, Thioridazine (Cheating Thieves are low)—non-neurologic side effects (anticholinergic, antihistamine, and α1-blockade effects). Chlorpromazine—Corneal deposits; Thioridazine—reTinal deposits; haloperidol— NMS, tardive dyskinesia. Evolution of EPS side effects: ƒƒ 4 hr acute dystonia (muscle spasm, stiffness, oculogyric crisis) ƒƒ 4 day akathisia (restlessness) ƒƒ 4 wk bradykinesia (parkinsonism) ƒƒ 4 mo tardive dyskinesia For NMS, think FEVER: Fever Encephalopathy Vitals unstable Enzymes Rigidity of muscles CLI NICAL USE Schizophrenia (primarily positive symptoms), psychosis, acute mania, Tourette syndrome. TO XICITY Highly lipid soluble and stored in body fat; thus, very slow to be removed from body. Extrapyramidal system side effects (e.g., dyskinesias). Treatment: benztropine or diphenhydramine. Endocrine side effects (e.g., dopamine receptor antagonism Ž hyperprolactinemia Ž galactorrhea). Side effects arising from blocking muscarinic (dry mouth, constipation), α1 (hypotension), and histamine (sedation) receptors. OTH ER TO XICITI ES Neuroleptic malignant syndrome (NMS)— rigidity, myoglobinuria, autonomic instability, hyperpyrexia. Treatment: dantrolene, D2 agonists (e.g., bromocriptine). Tardive dyskinesia—stereotypic oralfacial movements as a result of long-term antipsychotic use. Potentially irreversible. Atypical antipsychotics Olanzapine, clozapine, quetiapine, risperidone, aripiprazole, ziprasidone. It’s atypical for old closets to quietly risper from A to Z. MECHA NIS M Not completely understood. Varied effects on 5-HT2, dopamine, and α- and H1-receptors. CLI NICAL USE Schizophrenia—both positive and negative symptoms. Also used for bipolar disorder, OCD, anxiety disorder, depression, mania, Tourette syndrome. TO XICITY Fewer extrapyramidal and anticholinergic side effects than traditional antipsychotics. Olanzapine/clozapine may cause significant weight gain. Clozapine may cause agranulocytosis (requires weekly WBC monitoring) and seizure. Risperidone may increase prolactin (causing lactation and gynecomastia) Ž GnRH, LH, and FSH (causing irregular menstruation and fertility issues). Ziprasidone may prolong the QT interval. Must watch clozapine clozely! Psychiatry 518 SECTI ON III Psychiatry—Pharmacology Lithium MECHA NIS M Not established; possibly related to inhibition of phosphoinositol cascade. LMNOP: Lithium side effects— Movement (tremor) Nephrogenic diabetes insipidus HypOthyroidism Pregnancy problems CLI NICAL USE Mood stabilizer for bipolar disorder; blocks relapse and acute manic events. Also SIADH. TO XICITY Tremor, sedation, edema, heart block, hypothyroidism, polyuria (ADH antagonist causing nephrogenic diabetes insipidus), teratogenesis. Fetal cardiac defects include Ebstein anomaly and malformation of the great vessels. Narrow therapeutic window requires close monitoring of serum levels. Almost exclusively excreted by the kidneys; most is reabsorbed at the proximal convoluted tubules following Na+ reabsorption. Buspirone MECHA NIS M Stimulates 5-HT1A receptors. I’m always anxious if the bus will be on time, so CLI NICAL USE Generalized anxiety disorder. Does not cause I take buspirone. sedation, addiction, or tolerance. Takes 1–2 weeks to take effect. Does not interact with alcohol (vs. barbiturates, benzodiazepines). Antidepressants MAO inhibitors SEROTONERGIC AXON NORADRENERGIC POST-SYNAPTIC NEURON Mirtazapine TCAs, SSRIs, SNRIs, trazodone TCAs, SNRIs Metabolites MAO - + Bupropion - - - NE NE reuptake α2 (autoreceptor) adrenergic receptor Metabolites 5-HT 5-HT reuptake 5-HT receptor NE receptor - MAO AXON - Psychiatry Psychiatry—Pharmacology SECTI ON III 519 SSRIs Fluoxetine, paroxetine, sertraline, citalopram. Flashbacks paralyze senior citizens. MECHA NIS M 5-HT–specific reuptake inhibitors. It normally takes 4–8 weeks for antidepressants CLI NICAL USE Depression, generalized anxiety disorder, panic to have an effect. disorder, OCD, bulimia, social phobias, PTSD. TO XICITY Fewer than TCAs. GI distress, sexual dysfunction (anorgasmia and libido). Serotonin syndrome with any drug that 5-HT (e.g., MAO inhibitors, SNRIs, TCAs)—hyperthermia, confusion, myoclonus, cardiovascular collapse, flushing, diarrhea, seizures. Treatment: cyproheptadine (5-HT2 receptor antagonist). SNRIs Venlafaxine, duloxetine. MECHA NIS M Inhibit 5-HT and norepinephrine reuptake. CLI NICAL USE Depression. Venlafaxine is also used in generalized anxiety and panic disorders; duloxetine is also indicated for diabetic peripheral neuropathy. TO XICITY BP most common; also stimulant effects, sedation, nausea. Tricyclic antidepressants Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin, amoxapine (all TCAs end in -iptyline or -ipramine except doxepin and amoxapine). MECHA NIS M Block reuptake of norepinephrine and 5-HT. CLI NICAL USE Major depression, OCD (clomipramine), fibromyalgia. TO XICITY Sedation, α1-blocking effects including postural hypotension, and atropine-like (anticholinergic) side effects (tachycardia, urinary retention, dry mouth). 3° TCAs (amitriptyline) have more anticholinergic effects than 2° TCAs (nortriptyline) have. Desipramine is less sedating, but has a higher seizure incidence. Tri-C’s: Convulsions, Coma, Cardiotoxicity (arrhythmias); also respiratory depression, hyperpyrexia. Confusion and hallucinations in elderly due to anticholinergic side effects (use nortriptyline). Treatment: NaHCO3 for cardiovascular toxicity. Monoamine oxidase (MAO) inhibitors Tranylcypromine, Phenelzine, Isocarboxazid, Selegiline (selective MAO-B inhibitor). (MAO Takes Pride In Shanghai). MECHA NIS M Nonselective MAO inhibition levels of amine neurotransmitters (norepinephrine, 5-HT, dopamine). CLI NICAL USE Atypical depression, anxiety, hypochondriasis. TO XICITY Hypertensive crisis (most notably with ingestion of tyramine, which is found in many foods such as wine and cheese); CNS stimulation. Contraindicated with SSRIs, TCAs, St. John’s wort, meperidine, and dextromethorphan (to prevent serotonin syndrome). Psychiatry 520 SECTI ON III Psychiatry—Pharmacology Atypical antidepressants Bupropion Also used for smoking cessation. norepinephrine and dopamine via unknown mechanism. Toxicity: stimulant effects (tachycardia, insomnia), headache, seizure in bulimic patients. No sexual side effects. Mirtazapine α2-antagonist ( release of norepinephrine and 5-HT) and potent 5-HT2 and 5-HT3 receptor antagonist. Toxicity: sedation (which may be desirable in depressed patients with insomnia), appetite, weight gain (which may be desirable in elderly or anorexic patients), dry mouth. Trazodone Primarily blocks 5-HT2 and α1-adrenergic receptors. Used primarily for insomnia, as high doses are needed for antidepressant effects. Toxicity: sedation, nausea, priapism, postural hypotension. Called trazobone due to male-specific side effects. 521 “But I know all about love already. I know precious little still about kidneys.” —Aldous Huxley, Antic Hay “This too shall pass. Just like a kidney stone.” —Hunter Madsen “I drink too much. The last time I gave a urine sample it had an olive in it.” —Rodney Dangerfield ``Embryology 522 ``Anatomy 524 ``Physiology 525 ``Pathology 534 ``Pharmacology 546 HI G H -Y I ELD SYSTEMS Renal 522 SECTION III Renal RENAL—Embryology ``RENAL—EMB RYO LOGY Kidney embryology Pronephros—week 4; then degenerates. Mesonephros—functions as interim kidney for 1st trimester; later contributes to male genital system. Metanephros—permanent; first appears in 5th week of gestation; nephrogenesis continues through 32–36 weeks of gestation. ƒƒ Ureteric bud—derived from caudal end of mesonephric duct; gives rise to ureter, pelvises, calyces, and collecting ducts; fully canalized by 10th week ƒƒMetanephric mesenchyme—ureteric bud interacts with this tissue; interaction induces differentiation and formation of glomerulus through to distal convoluted tubule ƒƒ Aberrant interaction between these 2 tissues may result in several congenital malformations of the kidney Ureteropelvic junction—last to canalize Ž most common site of obstruction (hydronephrosis) in fetus. Urogenital sinus Mesonephric duct Metanephros Mesonephros Degenerated pronephros Potter sequence (syndrome) A Oligohydramnios Ž compression of developing fetus Ž limb deformities, facial anomalies (low-set ears and retrognathia [arrows in A]), and compression of chest Ž pulmonary hypoplasia (cause of death). Causes include ARPKD, posterior urethral valves, bilateral renal agenesis. Babies who can’t “Pee” in utero develop Potter syndrome. POTTER syndrome associated with: Pulmonary hypoplasia Oligohydramnios (trigger) Twisted face Twisted skin Extremity defects Renal failure (in utero) Renal RENAL—Embryology SECTION III 523 Horseshoe kidney Aorta Renal artery Horseshoe kidney Ureter Inferior mesenteric artery Inferior poles of both kidneys fuse A. As they ascend from pelvis during fetal development, horseshoe kidneys get trapped under inferior mesenteric artery and remain low in the abdomen. Kidney functions normally. risk for ureteropelvic junction obstruction, hydronephrosis, renal stones, and rarely renal cancer (Wilms tumor). Associated with Turner syndrome. A Horseshoe kidney. Axial CT of abdomen with contrast shows enhancing midline fused kidney (arrows). Multicystic dysplastic kidney Due to abnormal interaction between ureteric bud and metanephric mesenchyme. This leads to a nonfunctional kidney consisting of cysts and connective tissue. If unilateral (most common), generally asymptomatic with compensatory hypertrophy of contralateral kidney. Often diagnosed prenatally via ultrasound. 524 SECTION III Renal RENAL—Anatomy ``RENAL—ANATOMY Kidney anatomy and glomerular structure Cortex Medulla Medullary pyramids (papillae) Renal pelvis Renal artery Segmental artery Interlobular artery Interlobar artery Arcuate artery Ureter Cross-section of kidney Cross-section of glomerulus Endothelial cells Parietal layer of Bowman capsule Podocytes (visceral layer) Mesangial cells Basement membrane Renal vein Distal renal tubule Macula densa Juxtaglomerular cells A The left kidney is taken during living donor transplantation because it has a longer renal vein. A Normal glomerulus. Showing (A) macula densa, (B) afferent arteriole, (C) efferent arteriole, and (D) Bowman capsule. Ureters: course Ureters pass under uterine artery and under ductus deferens (retroperitoneal). “Water (ureters) under the bridge (uterine artery, vas deferens).” Gynecologic procedures involving ligation of the uterine vessels may damage the ureter Ž ureteral obstruction or ureteral leak. Ureter Vas deferens (in male) Uterine artery (in female) Trigone Ureteral orifice Internal urethral orifice Renal RENAL—Physiology SECTION III 525 ``RENAL—PHYSIO LOGY Fluid compartments Total body weight 40% nonwater mass 60% total body water 1/3 extracellular fluid (20% total body weight) 2/3 intracellular fluid (40% total body weight) 1/4 plasma volume (5% total body weight) 3/4 interstitial volume (15% total body weight) HIKIN’: HIgh K INtracellular. 60–40–20 rule (% of body weight): ƒƒ 60% total body water ƒƒ 40% ICF ƒƒ 20% ECF Plasma volume measured by radiolabeled albumin. Extracellular volume measured by inulin. Osmolarity = 290 mOsm/L. Glomerular filtration barrier Responsible for filtration of plasma according to size and net charge. Composed of: ƒƒ Fenestrated capillary endothelium (size barrier) ƒƒ Fused basement membrane with heparan sulfate (negative charge barrier) ƒƒ Epithelial layer consisting of podocyte foot processes The charge barrier is lost in nephrotic syndrome, resulting in albuminuria, hypoproteinemia, generalized edema, and hyperlipidemia. Renal clearance Cx = UxV/Px = volume of plasma from which the substance is completely cleared per unit time. Cx < GFR: net tubular reabsorption of X. Cx > GFR: net tubular secretion of X. Cx = GFR: no net secretion or reabsorption. Be familiar with calculations. Cx = clearance of X (mL/min). Ux = urine concentration of X (mg/mL). Px = plasma concentration of X (mg/mL). V = urine flow rate (mL/min). Glomerular filtration rate Inulin clearance can be used to calculate GFR because it is freely filtered and is neither reabsorbed nor secreted. GFR = Uinulin × V/Pinulin = Cinulin = Kf [(PGC – PBS) – (πGC – πBS)]. (GC = glomerular capillary; BS = Bowman space.) πBS normally equals zero. Normal GFR ≈ 100 mL/min. Creatinine clearance is an approximate measure of GFR. Slightly overestimates GFR because creatinine is moderately secreted by the renal tubules. Incremental reductions in GFR define the stages of chronic kidney disease. Effective renal plasma flow Effective renal plasma flow (ERPF) can be estimated using para-aminohippuric acid (PAH) clearance because it is both filtered and actively secreted in the proximal tubule. Nearly all PAH entering the kidney is excreted. ERPF = UPAH × V/PPAH = CPAH. RBF = RPF/(1 - Hct). ERPF underestimates true renal plasma flow (RPF) by ~10%. 526 SECTION III Renal RENAL—Physiology Filtration Filtration fraction (FF) = GFR/RPF. Normal FF = 20%. Filtered load (mg/min) = GFR (mL/min) × plasma concentration (mg/mL). GFR can be estimated with creatinine clearance. RPF is best estimated with PAH clearance. Prostaglandins dilate afferent arteriole ( RPF, GFR, so FF remains constant) Angiotensin ll preferentially constricts efferent arteriole ( RPF, GFR, so FF increases) NSAIDs ACE inhibitor Blood Afferent arteriole Juxtaglomerular cells Efferent arteriole Parietal layer of glomerular (Bowman) capsule Proximal convoluted tubule Changes in glomerular dynamics Effect RPF GFR FF (GFR/RPF) Afferent arteriole constriction Efferent arteriole constriction plasma protein concentration plasma protein concentration Constriction of ureter — — — — Calculation of reabsorption and secretion rate Filtered load = GFR × Px. Excretion rate = V × Ux. Reabsorption = filtered – excreted. Secretion = excreted – filtered. Renal RENAL—Physiology SECTION III 527 Glucose clearance Glucose at a normal plasma level is completely reabsorbed in proximal tubule by Na+/glucose cotransport. At plasma glucose of ~200 mg/dL, glucosuria begins (threshold). At ~375 mg/dL, all transporters are fully saturated (Tm). Glucosuria is an important clinical clue to diabetes mellitus. Normal pregnancy reabsorption of glucose and amino acids in the proximal tubule Ž glucosuria and aminoaciduria. Amino acid clearance Sodium-dependent transporters in proximal tubule reabsorb amino acids. Hartnup disease—autosomal recessive disorder. Deficiency of neutral amino acid (e.g., tryptophan) transporters in proximal renal tubular cells and on enterocytes. Leads to neutral aminoaciduria and absorption from the gut; results in pellagra-like symptoms; treat with high-protein diet and nicotinic acid. 528 SECTION III Renal RENAL—Physiology Loop of Henle Nephron physiology ATP Lumen– urine Proximal convoluted tubule Interstitium– blood Angiotensin II Carbonic anhydrase inhibitors Base− Na+ K+ Cl− Na+ Na+ Glucose H+ + HCO3 − HCO3 − + H+ H2CO3 H2O + CO2 H2CO3 CO2 + H2O + CA CA Thiazide diuretics Cl− channel diffusion PTH Ca2+ Ca2+ Cl− Lumen– urine Distal convoluted tubule Interstitium– blood Na+ Na+ Cl− Na+ K+ R ATP Loop diuretics Diffusion down the electrochemical gradient Lumen– urine Thick ascending limb Interstitium– blood Na+ Na+ K+ K+ K+ K+ Cl− 2Cl− (+) Potential Mg2+, Ca2+ ATP Amiloride, triamterene Aldosterone ADH Cl− Lumen– urine Collecting tubule Interstitium– blood Na+ K+ Cl− Na+ K+ R Principal cell Aquaporins in vesicles H2O V2 -intercalated cell H+ H+ K+ HCO3 − ATP ATP ATP Early proximal convoluted tubule (PCT)— contains brush border. Reabsorbs all of the glucose and amino acids and most of the HCO3 –, Na+, Cl–, PO4 3–, K+, and H2O. Isotonic absorption. Generates and secretes NH3, which acts as a buffer for secreted H+. PTH—inhibits Na+/PO4 3– cotransport → PO4 3– excretion. AT II—stimulates Na+/H+ exchange → ↑ Na+, H2O, and HCO3 - reabsorption (permitting contraction alkalosis). 65–80% Na+ reabsorbed. Early distal convoluted tubule (DCT)— actively reabsorbs Na+, Cl-. Makes urine hypotonic. PTH—↑ Ca2+/Na+ exchange → Ca2+ reabsorption. 5–10% Na+ reabsorbed. Thin descending loop of Henle—passively reabsorbs H2O via medullary hypertonicity (impermeable to Na+). Concentrating segment. Makes urine hypertonic. Thick ascending loop of Henle—actively reabsorbs Na+, K+, and Cl-. Indirectly induces the paracellular reabsorption of Mg2+ and Ca2+ through (+) lumen potential generated by K+ backleak. Impermeable to H2O. Makes urine less concentrated as it ascends. 10–20% Na+ reabsorbed. Collecting tubule—reabsorbs Na+ in exchange for secreting K+ and H+ (regulated by aldosterone). Aldosterone—acts on mineralocorticoid receptor Ž insertion of Na+ channel on luminal side. ADH—acts at V2 receptor Ž insertion of aquaporin H2O channels on luminal side. 3–5% Na+ reabsorbed. Renal RENAL—Physiology SECTION III 529 Renal tubular defects Fanconi syndrome Reabsorptive defect in PCT. Associated with excretion of nearly all amino acids, glucose, HCO3 –, and PO4 3–. May result in metabolic acidosis (proximal renal tubular acidosis). Causes include hereditary defects (e.g., Wilson disease), ischemia, and nephrotoxins/drugs. The kidneys put out FABulous Glittering Liquid: FAnconi syndrome is the 1st defect (PCT) Bartter syndrome is next (thick ascending loop of Henle) Gitelman syndrome is after Bartter (DCT) Liddle syndrome is last (collecting tubule) Bartter syndrome Reabsorptive defect in thick ascending loop of Henle. Autosomal recessive, affects Na+/ K+/2Cl– cotransporter. Results in hypokalemia and metabolic alkalosis with hypercalciuria. Gitelman syndrome Reabsorptive defect of NaCl in DCT. Autosomal recessive. Less severe than Bartter syndrome. Leads to hypokalemia and metabolic alkalosis, but without hypercalciuria. Liddle syndrome Na+ reabsorption in distal and collecting tubules ( activity of epithelial Na+ channel). Autosomal dominant. Results in hypertension, hypokalemia, metabolic alkalosis, aldosterone. Treatment: Amiloride. Relative concentrations along proximal tubules Tubular inulin in concentration (but not amount) along the proximal tubule as a result of water reabsorption. Cl- reabsorption occurs at a slower rate than Na+ in early proximal tubule and then matches the rate of Na+ reabsorption more distally. Thus, its relative concentration before it plateaus. 3.0 2.0 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Amino acids Glucose Net secretion Net reabsorption Percent distance along proximal tubule [Tubular fluid] [Plasma] 25 50 75 100 Inulina Cl− K+ Osmolarity Pi HCO3 − TF P PAH Creatinine TF P Na+ = TF/P > 1 when: Solute is reabsorbed less quickly than water TF/P = 1 when: Solute and water are reabsorbed at same rate TF/P < 1 when: Solute is reabsorbed more quickly than water Urea aNeither secreted nor reabsorbed; concentration increases as water is reabsorbed. 530 SECTION III Renal RENAL—Physiology Renin-angiotensin-aldosterone system Thirst Renin FF to preserve renal function (GFR) in low-volume states (i.e., when RBF ) Angiotensinogen Na+, HCO3 −, and H2O reabsorption (can permit contraction alkalosis) Angiotensin I Angiotensin II BP (JG cells) Na+ delivery (macula densa cells) Vasoconstriction sympathetic tone ( 1-receptors) + H2O channel insertion in principal cells H2O reabsorption Na+ channel and Na+/K+ pump insertion in principal cells; enhances K+ and H+ excretion (upregulates principal cell K+ channels and intercalated cell H+ ATPases) Creates favorable Na+ gradient for Na+ and H2O reabsorption BP ACE Bradykinin breakdown Constricts efferent arteriole of glomerulus Proximal tubule Na+/H+ activity Acts at AT I receptors on vascular smooth muscle Stimulates hypothalamus Aldosterone (adrenal gland) ADH (posterior pituitary) + + AT II Affects baroreceptor function; limits reflex bradycardia, which would normally accompany its pressor effects. Helps maintain blood volume and blood pressure. ANP Released from atria in response to volume; may act as a “check” on renin-angiotensin-aldosterone system; relaxes vascular smooth muscle via cGMP, causing GFR, renin. ADH Primarily regulates osmolarity; also responds to low blood volume states. Aldosterone Primarily regulates ECF Na+ content and volume; responds to low blood volume states. Juxtaglomerular apparatus Consists of JG cells (modified smooth muscle of afferent arteriole) and the macula densa (NaCl sensor, part of the distal convoluted tubule). JG cells secrete renin in response to renal blood pressure, NaCl delivery to distal tubule, and sympathetic tone (β1). JGA defends GFR via renin-angiotensinaldosterone system. b-blockers can decrease BP by inhibiting b1‑receptors of the JGA, causing renin release. Juxta = close by. Renal RENAL—Physiology SECTION III 531 Kidney endocrine functions Erythropoietin Released by interstitial cells in the peritubular capillary bed in response to hypoxia. 1,25-(OH)2 vitamin D Proximal tubule cells convert 25-OH vitamin D to 1,25-(OH)2 vitamin D (active form). 25-OH vitamin D 1,25-(OH)2 vitamin D 1 -hydroxylase PTH Renin Secreted by JG cells in response to renal arterial pressure and renal sympathetic discharge (β1 effect). Prostaglandins Paracrine secretion vasodilates the afferent arterioles to RBF. NSAIDs block renal-protective prostaglandin synthesis Ž constriction of the afferent arteriole and GFR; this may result in acute renal failure. Hormones acting on kidney Atrial natriuretic peptide (ANP) Secreted in response to atrial pressure. Causes GFR and Na+ filtration with no compensatory Na+ reabsorption in distal nephron. Net e ect: Na+ loss and volume loss. Parathyroid hormone (PTH) Secreted in response to plasma [Ca2+], plasma [PO43–], or plasma 1,25-(OH)2 vitamin D. Causes [Ca2+] reabsorption (DCT), [PO43–] reabsorption (PCT), and 1,25-(OH)2 vitamin D production ( Ca2+ and PO43– absorption from gut via vitamin D). Aldosterone Secreted in response to blood volume (via AT II) and plasma [K+]; causes Na+ reabsorption, K+ secretion, H+ secretion. ADH (vasopressin) Secreted in response to plasma osmolarity and blood volume. Binds to receptors on principal cells, causing number of water channels and H2O reabsorption. Angiotensin II (AT II) Synthesized in response to BP. Causes e erent arteriole constriction GFR and FF but with compensatory Na+ reabsorption in proximal and distal nephron. Net e ect: preservation of renal function in lowvolume state ( FF) with simultaneous Na+ reabsorption (both proximal and distal) to maintain circulating volume. 532 SECTION III Renal RENAL—Physiology Potassium shifts SHI FTS K+ OUT OF CELL (CAUSI NG HY PERKALEMI A) SHI FTS K+ INTO CELL (CAUSI NG HY POKALEMI A) Digitalis HyperOsmolarity Hypo-osmolarity Insulin deficiency Insulin ( Na+/K+ ATPase) Lysis of cells Acidosis Alkalosis b-adrenergic antagonist β-adrenergic agonist ( Na+/K+ ATPase) Patient with hyperkalemia? DO Insulin LAb work. Insulin shifts K+ into cells Electrolyte disturbances ELECTROLYT E LOW SERUM CONCENTRATIO N HIGH SERUM CONCENTRATIO N Na+ Nausea and malaise, stupor, coma Irritability, stupor, coma K+ U waves on ECG, flattened T waves, arrhythmias, muscle weakness Wide QRS and peaked T waves on ECG, arrhythmias, muscle weakness Ca2+ Tetany, seizures, QT prolongation Stones (renal), bones (pain), groans (abdominal pain), psychiatric overtones (anxiety, altered mental status), but not necessarily calciuria Mg2+ Tetany, torsades de pointes DTRs, lethargy, bradycardia, hypotension, cardiac arrest, hypocalcemia PO4 3− Bone loss, osteomalacia Renal stones, metastatic calcifications, hypocalcemia Acid-base physiology pH Pco2 [HCO3 –] COM PENSATO RY RESPONSE Metabolic acidosis Hyperventilation (immediate) Metabolic alkalosis Hypoventilation (immediate) Respiratory acidosis renal [HCO3 –] reabsorption (delayed) Respiratory alkalosis renal [HCO3 –] reabsorption (delayed) Key: = 1º disturbance; = compensatory response. Henderson-Hasselbalch equation: pH = 6.1 + log 0.03 PCO2 [HCO3 −] The predicted respiratory compensation for a simple metabolic acidosis can be calculated using the Winters formula. If the measured Pco2 differs significantly from the predicted Pco2, then a mixed acid-base disorder is likely present: Pco2 = 1.5 [HCO3 –] + 8 2 Renal RENAL—Physiology SECTION III 533 Acidosis/alkalosis pH < 7.4 Acidemia pH > 7.4 Alkalemia > 40 mmHg < 40 mmHg Respiratory acidosis Metabolic acidosis with compensation (hyperventilation) Chec k anion gap anion gap MUDPILES: Methanol (formic acid) Uremia Diabetic ketoacidosis Propylene glycol Iron tablets or INH Lactic acidosis Ethylene glycol (oxalic acid) Salicylates (late) Normal anion gap (8−12 mEq/L) HARD-ASS: Hyperalimentation Addison disease Renal tubular acidosis Diarrhea Acetazolamide Spironolactone Saline infusion P CO 2 P CO 2 P CO 2 < 40 mmHg Respirator y alkalosis Hyperventilation –Hysteria –Hypoxemia (e.g., high altitude) –Salicylates (early) –Tumor –Pulmonary embolism P CO 2 > 40 mmHg Metabolic alkalosis with compensation (hypoventilation) –V omiting –Loop diuretics –Antacid use –Hyperaldosteronism Chec k ar terial pH Anion gap = Na+ – (Cl– + HCO3 –) Hypoventilation –Airway obstruction –Acute lung disease –Chronic lung disease –Opioids, sedatives –Weakening of respiratory muscles 534 SECTION III Renal RENAL—Pathology Renal tubular acidosis A disorder of the renal tubules which leads to non-anion gap hyperchloremic metabolic acidosis. RTA TY PE NOTES Type 1 (distal, pH > 5.5) Defect in ability of α intercalated cells to secrete H+. Thus, new HCO3 - is not generated Ž metabolic acidosis. Associated with hypokalemia, risk for calcium phosphate kidney stones (due to urine pH and bone turnover). Causes—amphotericin B toxicity, analgesic nephropathy, multiple myeloma (light chains), and congenital anomalies (obstruction) of the urinary tract. Type 2 (proximal, pH < 5.5) Defect in proximal tubule HCO3 - reabsorption results in excretion of HCO3 - in urine and subsequent metabolic acidosis. Urine is acidified by α intercalated cells in collecting tubule. Associated with hypokalemia, risk for hypophosphatemic rickets. Causes—Fanconi syndrome (e.g., Wilson disease), chemicals toxic to proximal tubule (e.g., lead, aminoglycosides), and carbonic anhydrase inhibitors. Type 4 (hyperkalemic, pH < 5.5) Hypoaldosteronism, aldosterone resistance, or K+-sparing diuretics. The resulting hyperkalemia impairs ammoniagenesis in the proximal tubule Ž buffering capacity and H+ excretion into urine. ``RENAL—PATHOLOGY Casts in urine Presence of casts indicates that hematuria/pyuria is of renal (vs. bladder) origin. RBC casts Glomerulonephritis, ischemia, or malignant hypertension. Bladder cancer, kidney stones Ž hematuria, no casts. WBC casts Tubulointerstitial inflammation, acute Acute cystitis Ž pyuria, no casts. pyelonephritis, transplant rejection. Fatty casts (“oval fat bodies”) Nephrotic syndrome. Granular (“muddy brown”) casts Acute tubular necrosis. Waxy casts Advanced renal disease/chronic renal failure. Hyaline casts Nonspecific, can be a normal finding, often seen in concentrated urine samples. Renal RENAL—Pathology SECTION III 535 Nomenclature of glomerular disorders TY PE CHARACTERISTI CS EXAMPLE Focal < 50% of glomeruli are involved Focal segmental glomerulosclerosis Diffuse > 50% of glomeruli are involved Diffuse proliferative glomerulonephritis Proliferative Hypercellular glomeruli Mesangial proliferative Membranous Thickening of glomerular basement membrane Membranous nephropathy 1° glomerular disease Involves only glomeruli, thus a 1° disease of the kidney Minimal change disease 2° glomerular disease Involves glomeruli and other organs, thus a disease of another organ system, or a systemic disease that has impact on the kidney SLE, diabetic nephropathy Glomerular diseases Acute poststreptococcal glomerulonephritis Diffuse proliferative glomerulonephritis Membranoproliferative glomerulonephritis Nephritic syndrome* Nephrotic syndrome Both Rapidly progressive glomerulonephritis Berger disease (IgA glomerulonephropathy) Alport syndrome Focal segmental glomerulosclerosis Membranous nephropathy Minimal change disease Amyloidosis Diabetic glomerulonephropathy *Note that classic nephritic disorders can exhibit nephrotic features. 536 SECTION III Renal RENAL—Pathology Nephrotic syndrome NephrOtic syndrome presents with massive prOteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Associated with thromboembolism (hypercoagulable state due to AT III loss in urine) and risk of infection (loss of immunoglobulins). Focal segmental glomerulosclerosis LM—segmental sclerosis and hyalinosis A. IF . EM—effacement of foot process similar to minimal change disease. Most common cause of nephrotic syndrome in African Americans and Hispanics. Can be idiopathic or associated with HIV infection, sickle cell disease, heroin abuse, massive obesity, interferon treatment, and chronic kidney disease due to congenital absence or surgical removal. Inconsistent response to steroid therapy and may progress to chronic renal disease. A Focal segmental glomerulosclerosis. Membranous nephropathy LM—diffuse capillary and GBM thickening B. IF—granular as a result of immune complex deposition. Nephrotic presentation of SLE. EM—“spike and dome” appearance with subepithelial deposits. Most common cause of 1° nephrotic syndrome in Caucasian adults. Can be idiopathic or associated with antibody to phospholipase A2 receptor, drugs (e.g., NSAIDs, penicillamine), infections (e.g., HBV, HCV), SLE, or solid tumors. Poor response to steroid therapy and may progress to chronic renal disease. B Membranous nephropathy. Minimal change disease (lipoid nephrosis) LM—normal glomeruli (lipid may be seen in PCT cells). IF . EM—effacement of foot processes C . Most common in children. May be triggered by recent infection, immunization, or immune stimulus. May be associated with Hodgkin lymphoma (e.g., cytokine-mediated damage). Excellent response to corticosteroids. C Minimal change disease (lipoid nephrosis). Note effacement of foot processes on EM (arrow). Amyloidosis LM—Congo red stain shows apple-green birefringence under polarized light. Kidney is the most commonly involved organ (systemic amyloidosis). Associated with chronic conditions (e.g., multiple myeloma, TB, rheumatoid arthritis). Renal RENAL—Pathology SECTION III 537 Nephrotic syndrome (continued) Membranoproliferative glomerulonephritis Type I—subendothelial immune complex (IC) deposits with granular IF; “tram-track” appearance due to GBM splitting caused by mesangial ingrowth D. Type II—intramembranous IC deposits; “dense deposits.” MPGN is a nephritic syndrome that can also present with nephrotic syndrome. Type I is associated with HBV, HCV. May also be idiopathic. Type II is associated with C3 nephritic factor (stabilizes C3 convertase Ž serum C3 levels). D Membranoproliferative glomerulonephritis. H&E (right) and PAS (left) stain showing thickened “tram tracks.” Diabetic glomerulonephropathy LM—mesangial expansion, GBM thickening, eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) E . Nonenzymatic glycosylation of GBM Ž permeability, thickening. Nonenzymatic glycosylation of efferent arterioles Ž GFR Ž mesangial expansion. E Diabetic glomerulosclerosis. Arrows point to one of several Kimmelstiel-Wilson lesions. Note the light pink diffuse mesangial expansion. LM = light microscopy; EM = electron microscopy; IF = immunofluorescence. 538 SECTION III Renal RENAL—Pathology Nephritic syndrome NephrItic syndrome = an Inflammatory process. When it involves glomeruli, it leads to hematuria and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to salt retention), and proteinuria (< 3.5 g/day). Acute poststreptococcal glomerulonephritis LM—glomeruli enlarged and hypercellular. IF—(“starry sky”) granular appearance (“lumpybumpy”) due to IgG, IgM, and C3 deposition along GBM and mesangium. EM—subepithelial immune complex (IC) humps. Most frequently seen in children. Occurs ~2 weeks after group A streptococcal infection of the pharynx or skin. Resolves spontaneously. Type III hypersensitivity reaction. Presents with peripheral and periorbital edema, dark urine (cola-colored), and hypertension. anti-DNase B titers and complement levels. Rapidly progressive (crescentic) glomerulonephritis (RPGN) A LM and IF—crescent-moon shape A. Crescents consist of fibrin and plasma proteins (e.g., C3b) with glomerular parietal cells, monocytes, and macrophages. Several disease processes may result in this pattern, including: ƒƒ Goodpasture syndrome—type II hypersensitivity; antibodies to GBM and alveolar basement membrane Ž linear IF ƒƒGranulomatosis with polyangiitis (Wegener) ƒƒMicroscopic polyangiitis Poor prognosis. Rapidly deteriorating renal function (days to weeks). Hematuria/hemoptysis. PR3-ANCA/c-ANCA. MPO-ANCA/p-ANCA. Diffuse proliferative glomerulonephritis (DPGN) Due to SLE or MPGN. LM—“wire looping” of capillaries. EM—subendothelial and sometimes intramembranous IgG-based ICs often with C3 deposition. IF—granular. Most common cause of death in SLE. DPGN and MPGN can present as nephrotic syndrome and nephritic syndrome concurrently. IgA nephropathy (Berger disease) LM—mesangial proliferation. EM—mesangial IC deposits. IF—IgA-based IC deposits in mesangium. Seen with Henoch-Schönlein purpura. Often presents/flares with a URI or acute gastroenteritis. Episodic hematuria with RBC casts. Alport syndrome Mutation in type IV collagen Ž thinning and splitting of the glomerular basement membrane. Most commonly X-linked. Glomerulonephritis, deafness, and, less commonly, eye problems. Renal RENAL—Pathology SECTION III 539 Kidney stones Can lead to severe complications, such as hydronephrosis and pyelonephritis. Presents with unilateral flank tenderness, colicky pain radiating to groin, and hematuria. Treat and prevent by encouraging fluid intake. CONTENT PRECIPIT ATES AT X-RAY FINDINGS URINE CRYST AL NOTES Calcium (80%) pH (calcium phosphate) pH (calcium oxalate) Radiopaque Envelope A or dumbbell shaped A Calcium oxalate, calcium phosphate, or both. Promoted by hypercalciuria (idiopathic or 2° to conditions that cause hypercalcemia, such as cancer and PTH). Oxalate crystals can result from ethylene glycol (antifreeze), vitamin C abuse, or Crohn disease. Treatments for recurrent stones include thiazides and citrate. Most common kidney stone presentation: calcium oxalate stone in a patient with hypercalciuria and normocalcemia. Ammonium magnesium phosphate (15%) C pH Radiopaque Coffin lid B B Also known as struvite. Caused by infection with urease bugs (Proteus mirabilis, Staphylococcus, Klebsiella) that hydrolyze urea to ammonia Ž urine alkalinization. Can form staghorn calculi C that can be a nidus for UTIs. Treatment: eradication of underlying infection and surgical removal of stone. Uric acid (5%) pH RadiolUcent Rhomboid or rosettes D D Risk factors: urine volume, arid climates, and acidic pH. Visible on CT and ultrasound, but not x-ray. Strong association with hyperuricemia (e.g., gout). Often seen in diseases with cell turnover, such as leukemia. Treatment: alkalinization of urine. Cystine (1%) pH Radiopaque Hexagonal E E Mostly seen in children, 2° to cystinuria. Can form staghorn calculi. Sodium nitroprusside test . Treatment: alkalinization of urine and hydration. 540 SECTION III Renal RENAL—Pathology Hydronephrosis B Distention/dilation of the renal pelvis and calyces A B. Usually caused by urinary tract obstruction (e.g., renal stones, BPH, cervical cancer, injury to ureter); other causes include retroperitoneal fibrosis and vesicoureteral reflux. Dilation occurs proximal to site of pathology. Only impairs renal function if bilateral or patient only has one kidney. Leads to compression atrophy of renal cortex and medulla. A Hydronephrosis. Markedly dilated right renal collecting system with cortical atrophy (chronic hydronephrosis, arrows). Renal cell carcinoma C Originates from proximal tubule cells Ž polygonal clear cells A filled with accumulated lipids and carbohydrates. Most common in men 50–70 years old. incidence with smoking and obesity. Manifests clinically with hematuria, palpable mass B C , 2° polycythemia, flank pain, fever, and weight loss. Invades renal vein then IVC and spreads hematogenously; metastasizes to lung and bone. Most common 1° renal malignancy. Associated with gene deletion on chromosome 3 (sporadic or inherited as von Hippel-Lindau syndrome). RCC = 3 letters = chromosome 3. Associated with paraneoplastic syndromes (ectopic EPO, ACTH, PTHrP). “Silent” cancer because commonly presents as a metastatic neoplasm. Treatment: resection if localized disease. Immunotherapy or targeted therapy for advanced/metastatic disease. Resistant to chemotherapy and radiation therapy. A Renal cell carcinoma (histology). B Renal cell carcinoma (gross). Large, aggressive tumor with peripheral rim of displaced renal parenchyma (arrows). Renal RENAL—Pathology SECTION III 541 Renal oncocytoma A Benign epithelial cell tumor (arrows in A point to a well-circumscribed mass with a central scar). Large eosinophilic cells with abundant mitochondria without perinuclear clearing B (vs. chromophobe renal cell carcinoma). Presents with painless hematuria, flank pain, and abdominal mass. Treatment: nephrectomy. B Renal oncocytoma. H&E stain shows round to polygonal cells with granular eosinophilic cytoplasm and round nuclei. Wilms tumor (nephroblastoma) Most common renal malignancy of early childhood (ages 2–4). Contains embryonic glomerular structures. Presents with huge, palpable flank mass and/or hematuria. “Loss of function” mutations of tumor suppressor genes WT1 or WT2 on chromosome 11. May be part of Beckwith-Wiedemann syndrome or WAGR complex: Wilms tumor, Aniridia, Genitourinary malformation, and mental Retardation (intellectual disability). Transitional cell carcinoma Most common tumor of urinary tract system (can occur in renal calyces, renal pelvis, ureters, and bladder) A. Painless hematuria (no casts) suggests bladder cancer. Associated with problems in your Pee SAC: Phenacetin, Smoking, Aniline dyes, and Cyclophosphamide. Squamous cell carcinoma of the bladder Chronic irritation of urinary bladder Ž squamous metaplasia Ž dysplasia and squamous cell carcinoma. Risk factors include Schistosoma haematobium infection (Middle East), chronic cystitis, smoking, and chronic nephrolithiasis. Presents with painless hematuria. A Transitional cell carcinoma. Papillary growth lined by transitional epithelium with mild nuclear atypia and pleomorphism. 542 SECTION III Renal RENAL—Pathology Acute infectious cystitis Inflammation of urinary bladder. Presents as suprapubic pain, dysuria, urinary frequency, and urgency. Systemic signs (e.g., fever, chills) are usually absent. Risk factors include female gender (short urethra), sexual intercourse (“honeymoon cystitis”), and indwelling catheters. Causes: ƒƒ E. coli (most common). ƒƒ Staphylococcus saprophyticus—seen in sexually active young women (E. coli is still more common in this group). ƒƒ Klebsiella. ƒƒ Proteus mirabilis—urine has ammonia scent. ƒƒ Adenovirus—hemorrhagic cystitis. Lab findings—positive for leukocyte esterase . Nitrites appear for gram-negative organisms (especially E. coli). Sterile pyuria and urine cultures suggest urethritis by Neisseria gonorrhoeae or Chlamydia trachomatis. Pyelonephritis Acute B Affects cortex with relative sparing of glomeruli/ vessels A. Presents with dysuria, fever, costovertebral angle tenderness, nausea, and vomiting. Causes include ascending UTI (E. coli is most common), vesicoureteral reflux, and hematogenous spread to kidney. Often presents with white cell casts in urine. CT shows striated parenchymal enhancement (arrow in B). Risk factors include indwelling urinary catheter, urinary tract obstruction, diabetes mellitus, and pregnancy. Complications include chronic pyelonephritis, renal papillary necrosis, and perinephric abscess. Treatment: antibiotics. A Acute pyelonephritis. Neutrophilic infiltration (arrows) into renal interstitium. Chronic The result of recurrent episodes of acute pyelonephritis. Typically requires predisposition to infection such as vesicoureteral reflux or chronically obstructing kidney stones. Coarse, asymmetric corticomedullary scarring, blunted calyx. Tubules can contain eosinophilic casts resembling thyroid tissue C (thyroidization of kidney). C Chronic pyelonephritis. Lymphocytic infiltrate (tiny purple debris); arrows indicate eosinophilic casts within the tubules (thyroidization). Renal RENAL—Pathology SECTION III 543 Drug-induced interstitial nephritis (tubulointerstitial nephritis) Acute interstitial renal inflammation. Pyuria (classically eosinophils) and azotemia occurring after administration of drugs that act as haptens, inducing hypersensitivity. Nephritis typically occurs 1–2 weeks after certain drugs (e.g., diuretics, penicillin derivatives, sulfonamides, rifampin), but can occur months after starting NSAIDs. Associated with fever, rash, hematuria, and costovertebral angle tenderness, but can be asymptomatic. Diffuse cortical necrosis Acute generalized cortical infarction of both kidneys. Likely due to a combination of vasospasm and DIC. Associated with obstetric catastrophes (e.g., abruptio placentae) and septic shock. Acute tubular necrosis Most common cause of intrinsic renal failure. Self-reversible in some cases, but can be fatal if left untreated. Death most often occurs during initial oliguric phase. Key finding: granular (“muddy brown”) casts A. 3 stages: 1. Inciting event 2. Maintenance phase—oliguric; lasts 1–3 weeks; risk of hyperkalemia, metabolic acidosis 3. Recovery phase—polyuric; BUN and serum creatinine fall; risk of hypokalemia Can be caused by ischemic or nephrotoxic injury: ƒƒ Ischemic—2° to renal blood flow (e.g., hypotension, shock, sepsis, hemorrhage, CHF). Results in death of tubular cells that may slough into tubular lumen B (proximal tubule and thick ascending limb are highly susceptible to injury). ƒƒNephrotoxic—2° to injury resulting from toxic substances (e.g., aminoglycosides, radiocontrast agents, lead, cisplatin), crush injury (myoglobinuria), hemoglobinuria. Proximal tubule is particularly susceptible to injury. A Muddy brown casts in acute tubular necrosis. Inset shows magnified image of cast. B Acute tubular necrosis. Renal papillary necrosis Sloughing of renal papillae Ž gross hematuria and proteinuria. May be triggered by a recent infection or immune stimulus. Associated with: ƒƒDiabetes mellitus ƒƒ Acute pyelonephritis ƒƒ Chronic phenacetin use (acetaminophen is phenacetin derivative) ƒƒ Sickle cell anemia and trait 544 SECTION III Renal RENAL—Pathology Acute kidney injury (acute renal failure) In normal nephron, BUN is reabsorbed (for countercurrent multiplication), but creatinine is not. Acute kidney injury is defined as an abrupt decline in renal function with creatinine and BUN over a period of several days. Prerenal azotemia As a result of RBF (e.g., hypotension) Ž GFR. Na+/H2O and urea retained by kidney in an attempt to conserve volume, so BUN/creatinine ratio . Intrinsic renal failure Generally due to acute tubular necrosis or ischemia/toxins; less commonly due to acute glomerulonephritis (e.g., RPGN). Patchy necrosis leads to debris obstructing tubule and fluid backflow across necrotic tubule Ž GFR. Urine has epithelial/granular casts. BUN reabsorption is impaired Ž BUN/creatinine ratio. Postrenal azotemia Due to outflow obstruction (stones, BPH, neoplasia, congenital anomalies). Develops only with bilateral obstruction. Variable Prerenal Intrinsic Renal Postrenal Urine osmolality (mOsm/kg) > 500 < 350 < 350 Urine Na+ (mEq/L) < 20 > 40 > 40 FENa < 1% > 2% > 1% (mild) > 2% (severe) Serum BUN/Cr > 20 < 15 > 15 Consequences of renal failure Inability to make urine and excrete nitrogenous wastes. Consequences (MAD HUNGER): ƒƒMetabolic Acidosis ƒƒDyslipidemia (especially triglycerides) ƒƒHyperkalemia ƒƒUremia—clinical syndrome marked by BUN and creatinine ƒƒNausea and anorexia ƒƒ Pericarditis ƒƒ Asterixis ƒƒ Encephalopathy ƒƒ Platelet dysfunction ƒƒNa+/H2O retention (CHF, pulmonary edema, hypertension) ƒƒGrowth retardation and developmental delay (in children) ƒƒ Erythropoietin failure (anemia) ƒƒ Renal osteodystrophy 2 forms of renal failure—acute (e.g., ATN) and chronic (e.g., hypertension, diabetes, congenital anomalies). Renal osteodystrophy Failure of vitamin D hydroxylation, hypocalcemia, and hyperphosphatemia Ž 2° hyperparathyroidism. Hyperphosphatemia also independently serum Ca2+ by causing tissue calcifications, whereas 1,25-(OH)2 vitamin D Ž intestinal Ca2+ absorption. Causes subperiosteal thinning of bones. Renal RENAL—Pathology SECTION III 545 Renal cyst disorders ADPKD B Formerly adult polycystic kidney disease. Innumerable cysts A causing bilateral enlarged kidneys (arrows in B), ultimately destroy the kidney parenchyma. Presents with flank pain, hematuria, hypertension, urinary infection, progressive renal failure. Autosomal Dominant; mutation in PKD1 (85% of cases, chromosome 16) or PKD2 (15% of cases, chromosome 4). Death from complications of chronic kidney disease or hypertension (caused by renin production). Associated with berry aneurysms, mitral valve prolapse, benign hepatic cysts. ARPKD Formerly infantile polycystic kidney disease. Infantile presentation in parenchyma. Autosomal Recessive. Associated with congenital hepatic fibrosis. Significant renal failure in utero can lead to Potter sequence. Concerns beyond neonatal period include hypertension, portal hypertension, and progressive renal insufficiency. Medullary cystic disease C Inherited disease causing tubulointerstitial fibrosis C and progressive renal insufficiency with inability to concentrate urine. Medullary cysts usually not visualized; shrunken kidneys on ultrasound. Poor prognosis. Simple vs. complex renal cyst Simple cysts usually found in outer cortex filled with ultrafiltrate D. Very common, and account for majority of all renal masses. Found incidentally and typically asymptomatic. Complex cysts, including those that are septated, enhanced, or have solid components as seen on CT, require follow-up or removal due to risk of renal cell carcinoma. D Simple vs complex renal cyst. Coronal CT on the left shows 2-cm, low-density, non-enhancing, homogeneous simple cyst on the lower pole. Axial CT on the right shows multi-septated complex cyst with nodule (white arrow) that requires follow-up. A ADPKD. Distended kidney with multiple fluid-filled cysts. 546 SECTION III Renal RENAL—Pharmac ology ``RENAL—PHARMACOLOGY Diuretics: site of action NaCl NaCl Ca2+ Ca2+ Collecting duct Proximal convoluted tubule Glomerulus Outer medulla Cortex NaHCO3 Proximal straight tubule Distal convoluted tubule K+ K+ K+ K+ K+ H+ H+ NaCl (+aldosterone) Thin descending limb Loop of Henle Thick ascending limb (H2O impermeable) Collecting tubule H2O H2O (+ADH) Na+ Na+ Mg2+ 2Cl– 2Cl– (+PTH) Acetazolamide Mannitol Thiazides Potassium-sparing diuretics ADH antagonists Loop diuretics Inner medulla Renal RENAL—Pharmac ology SECTION III 547 Mannitol MECHANISM Osmotic diuretic, tubular fluid osmolarity, producing urine flow, intracranial/ intraocular pressure. CLINICAL USE Drug overdose, intracranial/intraocular pressure. TO XICITY Pulmonary edema, dehydration. Contraindicated in anuria, CHF. Acetazolamide MECHANISM Carbonic anhydrase inhibitor. Causes selflimited NaHCO3 diuresis and total-body HCO3 - stores. CLINICAL USE Glaucoma, urinary alkalinization, metabolic alkalosis, altitude sickness, pseudotumor cerebri. TO XICITY Hyperchloremic metabolic acidosis, paresthesias, NH3 toxicity, sulfa allergy. “ACID”azolamide causes ACIDosis. Loop diuretics Furosemide MECHANISM Sulfonamide loop diuretic. Inhibits cotransport system (Na+/K+/2 Cl-) of thick ascending limb of loop of Henle. Abolishes hypertonicity of medulla, preventing concentration of urine. Stimulates PGE release (vasodilatory effect on afferent arteriole); inhibited by NSAIDs. Ca2+ excretion. Loops Lose calcium. CLINICAL USE Edematous states (CHF, cirrhosis, nephrotic syndrome, pulmonary edema), hypertension, hypercalcemia. TO XICITY Ototoxicity, Hypokalemia, Dehydration, Allergy (sulfa), Nephritis (interstitial), Gout. OH DANG! Ethacrynic acid MECHANISM Phenoxyacetic acid derivative (not a sulfonamide). Essentially same action as furosemide. CLINICAL USE Diuresis in patients allergic to sulfa drugs. TO XICITY Similar to furosemide; can cause hyperuricemia; never use to treat gout. 548 SECTION III Renal RENAL—Pharmac ology Hydrochlorothiazide MECHANISM Thiazide diuretic. Inhibits NaCl reabsorption in early distal tubule, diluting capacity of the nephron. Ca2+ excretion. HyperGLUC. CLINICAL USE Hypertension, CHF, idiopathic hypercalciuria, nephrogenic diabetes insipidus, osteoporosis. TO XICITY Hypokalemic metabolic alkalosis, hyponatremia, hyperGlycemia, hyperLipidemia, hyperUricemia, and hyperCalcemia. Sulfa allergy. K+-sparing diuretics Spironolactone and eplerenone; Triamterene, and Amiloride. The K+ STAys. MECHANISM Spironolactone and eplerenone are competitive aldosterone receptor antagonists in the cortical collecting tubule. Triamterene and amiloride act at the same part of the tubule by blocking Na+ channels in the CCT. CLINICAL USE Hyperaldosteronism, K+ depletion, CHF. TO XICITY Hyperkalemia (can lead to arrhythmias), endocrine effects with spironolactone (e.g., gynecomastia, antiandrogen effects). Diuretics: electrolyte changes Urine NaCl (all diuretics except acetazolamide). Serum NaCl may as a result. Urine K+ with loop and thiazide diuretics. Serum K+ may as a result. Blood pH (acidemia): carbonic anhydrase inhibitors— HCO3 - reabsorption. K+ sparing—aldosterone blockade prevents K+ secretion and H+ secretion. Additionally, hyperkalemia leads to K+ entering all cells (via H+/K+ exchanger) in exchange for H+ exiting cells. (alkalemia): loop diuretics and thiazides cause alkalemia through several mechanisms: ƒƒ Volume contraction Ž AT II Ž Na+/H+ exchange in proximal tubule Ž HCO3 - reabsorption (“contraction alkalosis”) ƒƒ K+ loss leads to K+ exiting all cells (via H+/K+ exchanger) in exchange for H+ entering cells ƒƒ In low K+ state, H+ (rather than K+) is exchanged for Na+ in cortical collecting tubule, Ž alkalosis and “paradoxical aciduria” Urine Ca2+ with loop diuretics: paracellular Ca2+ reabsorption Ž hypocalcemia. with thiazides: Enhanced paracellular Ca2+ reabsorption in distal tubule. Renal RENAL—Pharmac ology SECTION III 549 ACE inhibitors Captopril, enalapril, lisinopril. MECHANISM Inhibit ACE Ž angiotensin II Ž GFR by preventing constriction of efferent arterioles. Levels of renin as a result of loss of feedback inhibition. Inhibition of ACE also prevents inactivation of bradykinin, a potent vasodilator. Angiotensin II receptor blockers (-sartans) have effects similar to ACE inhibitors but do not bradykinin Ž risk of cough or angioedema. CLINICAL USE Hypertension, CHF, proteinuria, diabetic nephropathy. Prevent unfavorable heart remodeling as a result of chronic hypertension. TO XICITY Cough, Angioedema (contraindicated in C1 esterase inhibitor deficiency), Teratogen (fetal renal malformations), Creatinine ( GFR), Hyperkalemia, and Hypotension. Avoid in bilateral renal artery stenosis, because ACE inhibitors will further GFR Ž renal failure. Captopril’s CATCHH. 550 SECTION III RENAL ``NOTES 551 ``Embryology 552 ``Anatomy 563 ``Physiology 567 ``Pathology 574 ``Pharmacology 589 HI G H -Y I ELD SYSTEMS “Artificial insemination is when the farmer does it to the cow instead of the bull.” —Student essay “Whoever called it necking was a poor judge of anatomy.” —Groucho Marx “See, the problem is that God gives men a brain and a penis, and only enough blood to run one at a time.” —Robin Williams Reproductive Reproductive 552 SECTIO N III REPRODUCTIVE—Embryology ``REPRODUCTIVE—EMB RYOLOGY Important genes of embryogenesis Sonic hedgehog gene Produced at base of limbs in zone of polarizing activity. Involved in patterning along anteriorposterior axis. Involved in CNS development; mutation can cause holoprosencephaly. Wnt-7 gene Produced at apical ectodermal ridge (thickened ectoderm at distal end of each developing limb). Necessary for proper organization along dorsal-ventral axis. FGF gene Produced at apical ectodermal ridge. Stimulates mitosis of underlying mesoderm, providing for lengthening of limbs. Homeobox (Hox) genes Involved in segmental organization of embryo in a craniocaudal direction. Hox mutations Ž appendages in wrong locations. Early fetal development DAY 0 Fertilization by sperm, forming zygote, initiating embryogenesis. Day 5 Blastocyst Day 7–10 Implantation Day 18 Day 21 Morula Endometrium Neural plate Neural crest Neural crest cells Neural tube Uterine wall Notochord Day 0 Fertilization Day 3 Day 2 Zygote WITHIN WEEK 1 hCG secretion begins around the time of implantation of blastocyst. WITHIN WEEK 2 Bilaminar disc (epiblast, hypoblast). 2 weeks = 2 layers. WITHIN WEEK 3 Trilaminar disc. 3 weeks = 3 layers. Gastrulation. Primitive streak, notochord, mesoderm and its organization, and neural plate begin to form. WEEKS 3–8 (EMB RYONIC PERIOD) Neural tube formed by neuroectoderm and closes by week 4. Organogenesis. Extremely susceptible to teratogens. WEEK 4 Heart begins to beat. Upper and lower limb buds begin to form. 4 weeks = 4 limbs. WEEK 6 Fetal cardiac activity visible by transvaginal ultrasound. WEEK 10 Genitalia have male/female characteristics. Gastrulation Process that forms the trilaminar embryonic disc. Establishes the ectoderm, mesoderm, and endoderm germ layers. Starts with the epiblast invaginating to form the primitive streak. Reproductive REPRODUCTIVE—Embryology SECTIO N III 553 Embryologic derivatives Ectoderm Surface ectoderm Adenohypophysis (from Rathke pouch); lens of eye; epithelial linings of oral cavity, sensory organs of ear, and olfactory epithelium; epidermis; anal canal below the pectinate line; parotid, sweat, and mammary glands. Craniopharyngioma—benign Rathke pouch tumor with cholesterol crystals, calcifications. Neuroectoderm Brain (neurohypophysis, CNS neurons, oligodendrocytes, astrocytes, ependymal cells, pineal gland), retina and optic nerve, spinal cord. Neuroectoderm—think CNS. Neural crest PNS (dorsal root ganglia, cranial nerves, celiac ganglion, Schwann cells, ANS), melanocytes, chromaffin cells of adrenal medulla, parafollicular (C) cells of thyroid, pia and arachnoid, bones of the skull, odontoblasts, aorticopulmonary septum. Neural crest—think PNS and non-neural structures nearby. Mesoderm Muscle, bone, connective tissue, serous linings of body cavities (e.g., peritoneum), spleen (derived from foregut mesentery), cardiovascular structures, lymphatics, blood, wall of gut tube, vagina, kidneys, adrenal cortex, dermis, testes, ovaries. Notochord induces ectoderm to form neuroectoderm (neural plate). Its only postnatal derivative is the nucleus pulposus of the intervertebral disc. Mesodermal defects = VACTERL: Vertebral defects Anal atresia Cardiac defects Tracheo-Esophageal fistula Renal defects Limb defects (bone and muscle) Endoderm Gut tube epithelium (including anal canal above the pectinate line), most of urethra (derived from urogenital sinus), luminal epithelial derivatives (e.g., lungs, liver, gallbladder, pancreas, eustachian tube, thymus, parathyroid, thyroid follicular cells). Types of errors in organ morphogenesis Agenesis Absent organ due to absent primordial tissue. Aplasia Absent organ despite presence of primordial tissue. Hypoplasia Incomplete organ development; primordial tissue present. Deformation Extrinsic disruption; occurs after the embryonic period. Disruption 2° breakdown of a previously normal tissue or structure (e.g., amniotic band syndrome). Malformation Intrinsic disruption; occurs during the embryonic period (weeks 3–8). Sequence Abnormalities result from a single 1° embryological event (e.g., oligohydramnios Ž Potter sequence). Reproductive 554 SECTIO N III REPRODUCTIVE—Embryology Teratogens Most susceptible in 3rd–8th weeks (embryonic period—organogenesis) of pregnancy. Before week 3: all-or-none effects. After week 8: growth and function affected. TERATOGEN EFFECTS ON FETUS NOTES Medications ACE inhibitors Renal damage Alkylating agents Absence of digits, multiple anomalies Aminoglycosides CN VIII toxicity A mean guy hit the baby in the ear. Carbamazepine Neural tube defects, craniofacial defects, fingernail hypoplasia, developmental delay, IUGR Diethylstilbestrol (DES) Vaginal clear cell adenocarcinoma, congenital Müllerian anomalies Folate antagonists Neural tube defects Lithium Ebstein anomaly (atrialized right ventricle) Methimazole Aplasia cutis congenita Phenytoin Fetal hydantoin syndrome: microcephaly, dysmorphic craniofacial features, hypoplastic nails and distal phalanges, cardiac defects, IUGR, intellectual disability Tetracyclines Discolored teeth “Teethracyclines” Thalidomide Limb defects (phocomelia, micromelia— “flipper” limbs) Limb defects with “tha-limb-domide.” Valproate Inhibition of maternal folate absorption Ž neural tube defects Valproate inhibits folate absorption Warfarin Bone deformities, fetal hemorrhage, abortion, ophthalmologic abnormalities Do not wage warfare on the baby; keep it heppy with heparin (does not cross placenta). Substance abuse Alcohol Common cause of birth defects and intellectual disability; fetal alcohol syndrome Cocaine Abnormal fetal growth and fetal addiction; placental abruption Smoking (nicotine, CO) A leading cause of low birth weight in developed countries; associated with preterm labor, placental problems, IUGR, ADHD Other Iodine (lack or excess) Congenital goiter or hypothyroidism (cretinism) Maternal diabetes Caudal regression syndrome (anal atresia to sirenomelia), congenital heart defects, neural tube defects Vitamin A (excess) Extremely high risk for spontaneous abortions and birth defects (cleft palate, cardiac abnormalities) X-rays Microcephaly, intellectual disability Fetal infections and certain antibiotics can also cause congenital malformations (see the Microbiology chapter). Reproductive REPRODUCTIVE—Embryology SECTIO N III 555 Fetal alcohol syndrome One of the leading causes of congenital malformations in the United States. Newborns of mothers who consumed significant amounts of alcohol during pregnancy have an incidence of congenital abnormalities, including intellectual disability, pre- and postnatal developmental retardation, microcephaly, holoprosencephaly, facial abnormalities, (smooth philtrum, thin upper lip, small palpebral fissures, hypertelorism), limb dislocation, and heart defects. Twinning Dizygotic twins arise from 2 eggs that are separately fertilized by 2 different sperm (always 2 zygotes), and will have 2 separate amniotic sacs and 2 separate placentas (chorions). Monozygotic twins arise from 1 fertilized egg (1 egg + 1 sperm) that splits into 2 zygotes in early pregnancy. The degree of separation between monozygotic twins depends on when the fertilized egg splits into 2 zygotes. The timing of this separation determines the number of chorions and the number of amnions. Monochorionic monoamniotic Monochorionic diamniotic Separate placenta Fused placenta Dichorionic diamniotic Dichorionic diamniotic Cleavage or 2-cell stage 2-cell stage 2-cell stage Morula Blastocyst Blastocyst Formed embryonic disc Formed embryonic disc No twinning if no cleavage Formed embryonic disc Monozygotic (20%) Dizygotic (80%) Morula Morula Blastocyst Amniotic cavity Chorionic cavity Amnion (inner) Chorion (outer) 8–12 days (< 1%) > 13 days 4–8 days (~75%) 0–4 days (~25%) Cleavage Cleavage Cleavage Monochorionic monoamniotic conjoined twins Reproductive 556 SECTIO N III REPRODUCTIVE—Embryology Placental development 1º site of nutrient and gas exchange between mother and fetus. Fetal component Cytotrophoblast Inner layer of chorionic villi. Cytotrophoblast makes Cells. Syncytiotrophoblast Outer layer of chorionic villi; secretes hCG (structurally similar to LH; stimulates corpus luteum to secrete progesterone during first trimester). Maternal component Decidua basalis Derived from the endometrium. Maternal blood in lacunae. Maternal artery Decidua Cytotropho- basalis blast Syncytiotrophoblast Branch villus Fetal artery Fetal vein Amnion Maternal vein Maternal blood Reproductive REPRODUCTIVE—Embryology SECTIO N III 557 Umbilical cord Umbilical arteries (2)—return deoxygenated blood from fetal internal iliac arteries to placenta A. Umbilical vein (1)—supplies oxygenated blood from placenta to fetus; drains into IVC via liver or via ductus venosus. Single umbilical artery is associated with congenital and chromosomal anomalies. Umbilical arteries and veins are derived from allantois. Vitelline duct Allantois Umbilical ring Stomach Liver bud Primitive intestine Hindgut Umbilical arteries Umbilical Allantoic duct vein Amniotic epithelium Wharton jelly A Cross-section of umbilical cord. Urachus In the 3rd week the yolk sac forms the allantois, which extends into the urogenital sinus. Allantois becomes the urachus, a duct between fetal bladder and yolk sac. Failure of urachus to obliterate results in: ƒƒ Patent urachus—urine discharge from umbilicus. ƒƒ Urachal cyst—partial failure of urachus to obliterate; fluid-filled cavity lined with uroepithelium, between umbilicus and bladder. Can lead to infection, adenocarcinoma. ƒƒ Vesicourachal diverticulum—outpouching of bladder. Vitelline duct 7th week—obliteration of vitelline duct (omphalo-mesenteric duct), which connects yolk sac to midgut lumen. Failure of vitelline duct to close results in: ƒƒ Vitelline fistula Ž meconium discharge from umbilicus. ƒƒ Meckel diverticulum— partial closure, with patent portion attached to ileum (true diverticulum). May have ectopic gastric mucosa and/or pancreatic tissue Ž melena, periumbilical pain, and ulcers. Reproductive 558 SECTIO N III REPRODUCTIVE—Embryology Aortic arch derivatives Develop into the arterial system. 1st Part of maxillary artery (branch of external carotid). 1st arch is maximal. 2nd Stapedial artery and hyoid artery. Second = Stapedial. 3rd Common Carotid artery and proximal part of internal Carotid artery. C is 3rd letter of alphabet. 4th On left, aortic arch; on right, proximal part of right subclavian artery. 4th arch (4 limbs) = systemic. 6th Proximal part of pulmonary arteries and (on left only) ductus arteriosus. 6th arch = pulmonary and the pulmonary-tosystemic shunt (ductus arteriosus). Left recurrent laryngeal nerve gets caught here by the ductus arteriosus; ductus arteriosus turns into the ligamentum arteriosum shortly after birth Right recurrent laryngeal nerve loops around here 6 months postnatal 3rd 3rd 4th 4th 6th 6th Branchial apparatus Also called pharyngeal apparatus. Composed of branchial clefts, arches, and pouches. Branchial clefts—derived from ectoderm. Also called branchial grooves. Branchial arches—derived from mesoderm (muscles, arteries) and neural crest (bones, cartilage). Branchial pouches—derived from endoderm. CAP covers outside to inside: Clefts = ectoderm Arches = mesoderm Pouches = endoderm Branchial cleft derivatives 1st cleft develops into external auditory meatus. 2nd through 4th clefts form temporary cervical sinuses, which are obliterated by proliferation of 2nd arch mesenchyme. Persistent cervical sinus Ž branchial cleft cyst within lateral neck. Primitive esophagus Arch Epicardial ridge Pouch Primitive pharynx Cleft Pharyngeal arches 1st 2nd 3rd 4th Reproductive REPRODUCTIVE—Embryology SECTIO N III 559 Branchial arch derivatives ARCH CARTILAGE MUSCLES NERVESa ABNORMALITIES/COMM ENTS 1st arch Meckel cartilage: Mandible, Malleus, incus, spheno- Mandibular ligament Muscles of Mastication (temporalis, Masseter, lateral and Medial pterygoids), Mylohyoid, anterior belly of digastric, tensor tympani, tensor veli palatini CN V2 and V3 chew Treacher Collins syndrome: 1st-arch neural crest fails to migrate Ž mandibular hypoplasia, facial abnormalities 2nd arch Reichert cartilage: Stapes, Styloid process, lesser horn of hyoid, Stylohyoid ligament Muscles of facial expression, Stapedius, Stylohyoid, platySma, belly of digastric CN VII (facial expression) smile Congenital pharyngocutaneous fistula: persistence of cleft and pouch Ž fistula between tonsillar area and lateral neck 3rd arch Cartilage: greater horn of hyoid Stylopharyngeus (think of stylopharyngeus innervated by glossopharyngeal nerve) CN IX (stylopharyngeus) swallow stylishly 4th–6th arches Cartilages: thyroid, cricoid, arytenoids, corniculate, cuneiform 4th arch: most pharyngeal constrictors; cricothyroid, levator veli palatini 6th arch: all intrinsic muscles of larynx except cricothyroid 4th arch: CN X (superior laryngeal branch) simply swallow 6th arch: CN X (recurrent laryngeal branch) speak Arches 3 and 4 form posterior 1⁄3 of tongue; arch 5 makes no major developmental contributions aThese are the only CNs with both motor and sensory components (except V2, which is sensory only). When at the restaurant of the golden arches, children tend to first chew (1), then smile (2), then swallow stylishly (3) or simply swallow (4), and then speak (6). Reproductive 560 SECTIO N III REPRODUCTIVE—Embryology Branchial pouch derivatives 1st pouch Develops into middle ear cavity, eustachian tube, mastoid air cells. 1st pouch contributes to endoderm-lined structures of ear. Ear, tonsils, bottom-to-top: 1 (ear), 2 (tonsils), 3 dorsal (bottom for inferior parathyroids), 3 ventral (to = thymus), 4 (top = superior parathyroids). 2nd pouch Develops into epithelial lining of palatine tonsil. 3rd pouch Dorsal wings—develops into inferior parathyroids. Ventral wings—develops into thymus. 3rd pouch contributes to 3 structures (thymus, left and right inferior parathyroids). 3rd-pouch structures end up below 4th-pouch structures. 4th pouch Dorsal wings—develops into superior parathyroids. DiGeorge syndrome Aberrant development of 3rd and 4th pouches Ž T-cell deficiency (thymic aplasia) and hypocalcemia (failure of parathyroid development). Associated with cardiac defects (conotruncal anomalies). MEN 2A Mutation of germline RET (neural crest cells): ƒƒ Adrenal medulla (pheochromocytoma). ƒƒ Parathyroid (tumor): 3rd/4th pharyngeal pouch. ƒƒ Parafollicular cells (medullary thyroid cancer): derived from neural crest cells; associated with the 4th/5th pharyngeal pouches. Cleft lip and cleft palate Cleft lip Cleft lip—failure of fusion of the maxillary and medial nasal processes (formation of 1° palate). Cleft palate—failure of fusion of the two lateral palatine processes or failure of fusion of lateral palatine processes with the nasal septum and/ or median palatine process (formation of 2° palate). Cleft lip and cleft palate have two distinct etiologies, but often occur together. Uvula Cleft palate (partial) Nasal cavity Roof of mouth Palatine shelves (2° palate) Reproductive REPRODUCTIVE—Embryology SECTIO N III 561 Genital embryology Female Default development. Mesonephric duct degenerates and paramesonephric duct develops. Gubernaculum Mesonephros Indifferent gonad Paramesonephric duct Mesonephric duct Urogenital sinus Male SRY gene on Y chromosome—produces testisdetermining factor (testes development). Sertoli cells secrete Müllerian inhibitory factor (MIF) that suppresses development of paramesonephric ducts. Leydig cells secrete androgens that stimulate the development of mesonephric ducts. Paramesonephric (Müllerian) duct Develops into female internal structures— fallopian tubes, uterus, and upper portion of vagina (lower portion from urogenital sinus). Müllerian duct abnormalities result in anatomical defects that may present as 1° amenorrhea in females with fully developed 2° sexual characteristics (indicator of functional ovaries). Mesonephric (Wolffian) duct Develops into male internal structures (except prostate)—Seminal vesicles, Epididymis, Ejaculatory duct, and Ductus deferens (SEED). Bicornuate uterus Results from incomplete fusion of the paramesonephric ducts (vs. complete failure of fusion, resulting in double uterus and vagina). Can lead to anatomic defects Ž recurrent miscarriages. SRY gene No Sertoli cells or lack of Müllerian inhibitory factor: develop both male and female internal genitalia and male external genitalia 5α-reductase deficiency: inability to convert testosterone into DHT; male internal genitalia, ambiguous external genitalia until puberty (when testosterone levels cause masculinization) SRY gene on Y chromosome Testis-determining factor Testes Sertoli cell Müllerian inhibitory factor Leydig cell Wolffian duct Genital tubercle, urogenital sinus Male external genitalia, prostate Degeneration of paramesonephric (Müllerian) duct (female internal genitalia) Male internal genitalia (except prostate) Testosterone DHT Reproductive 562 SECTIO N III REPRODUCTIVE—Embryology Male/female genital homologs Labia minora Genital tubercle Genital groove Dihydrotestosterone Estrogen Glans penis Genital tubercle Glans clitoris Corpus cavernosum Genital tubercle Vestibular bulbs and spongiosum Urogenital sinus Greater vestibular glands (of Bartholin) Bulbourethral glands (of Cowper) Urogenital sinus Urethral and paraurethral Prostate gland glands (of Skene) Ventral shaft of penis Urogenital folds Labia minora (penile urethra) Scrotum Labioscrotal swelling Labia majora Urogenital fold Urogenital sinus Labioscrotal swelling Anus Clitoris Female Opening of urethra Opening of vagina Labia majora Penis Male Undifferentiated Scrotum Urethral closure Congenital penile abnormalities Hypospadias Abnormal opening of penile urethra on inferior (ventral) side of penis due to failure of urethral folds to close. Hypospadias is more common than epispadias. Fix hypospadias to prevent UTIs. Hypo is below. Hypospadias EpispaEpdispiaadisas Abnormal opening of penile urethra on superior (dorsal) side of penis due to faulty positioning of genital tubercle. Exstrophy of the bladder is associated with Epispadias. When you have Epispadias, you hit your Eye when you pEE. Hypospadias Epispadias Descent of testes and ovaries MALE REMNANT FEMALE REMNANT Gubernaculum (band of fibrous tissue) Anchors testes within scrotum. Ovarian ligament + round ligament of uterus. Processus vaginalis (evagination of peritoneum) Forms tunica vaginalis. Obliterated. Reproductive REPRODUCTIVE—Anato my SECTIO N III 563 ``REPRODUCTIVE—ANATOMY Gonadal drainage Venous drainage Left ovary/testis Ž left gonadal vein Ž left renal vein Ž IVC. Right ovary/testis Ž right gonadal vein Ž IVC. “Left gonadal vein takes the Longest way.” Because the left spermatic vein enters the left renal vein at a 90° angle, flow is less continuous on the left than on the right. Ž left venous pressure > right venous pressure Ž varicocele more common on the left. Lymphatic drainage Ovaries/testes Ž para-aortic lymph nodes. Distal vagina/vulva/scrotum Ž superficial inguinal nodes. Proximal vagina/uterus Ž obturator, external iliac and hypogastric nodes. Female reproductive anatomy Vagina Urethra Bladder Round ligament of the uterus Labia majora Labia minora Rectum Ovary Fallopian tube Uterus Vagina Fornix Uterine artery Endometrium Myometrium Cervix Os Mesometrium (of broad ligament) Ureter Ovary Fallopian tube Fimbriae Ovarian ligament Fundus Ovarian artery Uterosacral ligament Mesosalpinx (of broad ligament) Infundibulopelvic ligament Mesovarium (of broad ligament) Posterior view Sagittal view LIGAMENT CONNECTS STRUCTURES CONTAINED NOTES Infundibulopelvic ligament (suspensory ligament of the ovaries) Ovaries to lateral pelvic wall Ovarian vessels Ligate vessels during oophorectomy to avoid bleeding. Ureter courses retroperitoneally, close to gonadal vessels. At risk of injury during ligation of ovarian vessels. Cardinal ligament (not labeled) Cervix to side wall of pelvis Uterine vessels Ureter at risk of injury during ligation of uterine vessels in hysterectomy. Round ligament of the uterus Uterine fundus to labia majora Derivative of gubernaculum. Travels through round inguinal canal; above the artery of Sampson. Broad ligament Uterus, fallopian tubes, and ovaries to pelvic side wall Ovaries, fallopian tubes, and round ligaments of uterus Mesosalpinx, mesometrium, and mesovarium are the components of the broad ligament. Ovarian ligament Medial pole of ovary to lateral uterus — A derivative of the gubernaculum. Ovarian Ligament Latches to Lateral uterus. 564 SECTIO N III Re productive REPRODUCTIVE—Anato my Female reproductive epithelial histology TISSUE HISTOLOGY /NOTES Vagina Stratified squamous epithelium, nonkeratinized Ectocervix Stratified squamous epithelium, nonkeratinized Endocervix Simple columnar epithelium Transformation zone Squamocolumnar junction (most common area for cervical cancer) Uterus Simple columnar epithelium with long tubular glands Fallopian tube Simple columnar epithelium, many ciliated cells, a few secretory (peg) cells Ovary, outer surface Simple cuboidal epithelium (germinal epithelium covering surface of ovary) Female sexual response cycle Most commonly described as phase of excitement (uterus elevates, vaginal lubrication), plateau (expansion of inner vagina), orgasm (contraction of uterus), and resolution; mediated by autonomic nervous system. Also causes tachycardia and skin flushing. Male reproductive anatomy Pathway of sperm during ejaculation— SEVEN UP: Seminiferous tubules Epididymis Vas deferens Ejaculatory ducts (Nothing) Urethra Penis Bladder Ureter Vas deferens Vas deferens Head of epididymis Tail of epididymis Seminiferous tubules Tunica albuginea Septa Rete testis Urethra Symphysis pubis Glans Prepuce Epididymis Testis Scrotum Cowper (bulbourethral) gland Ejaculatory duct Prostate Seminal vesicle Reproductive REPRODUCTIVE—Anato my SECTIO N III 565 Autonomic innervation of the male sexual response Erection—Parasympathetic nervous system (pelvic nerve): ƒƒNO Ž cGMP Ž smooth muscle relaxation Ž vasodilation Ž proerectile. ƒƒNorepinephrine Ž [Ca2+]in Ž smooth muscle contraction Ž vasoconstriction Ž antierectile. Emission—Sympathetic nervous system (hypogastric nerve). Ejaculation—visceral and somatic nerves (pudendal nerve). Point and Shoot. Sildenafil and vardenafil inhibit cGMP breakdown. 566 SECTIO N III Re productive REPRODUCTIVE—Anato my Seminiferous tubules CELL FUNCTION LOCATION/NOTES Spermatogonia (germ cells) Maintain germ pool and produce 1° spermatocytes Line seminiferous tubules A Sertoli cells (non–germ cells) Secrete inhibin Ž inhibit FSH Secrete androgen-binding protein Ž maintain local levels of testosterone Tight junctions between adjacent Sertoli cells form blood-testis barrier Ž isolate gametes from autoimmune attack Support and nourish developing spermatozoa Regulate spermatogenesis Produce MIF Temperature sensitive; sperm production and inhibin with temperature Line seminiferous tubules Convert testosterone and androstenedione to estrogen via aromatase Sertoli cells Support Sperm Synthesis temperature seen in varicocele, cryptorchidism Leydig cells (endocrine cells) Secrete testosterone in the presence of LH; testosterone production unaffected by temperature Interstitium Also contain aromatase Lumen of seminiferous tubule Spermatozoon Sertoli cell Spermatids Secondary spermatocyte Tight junction Spermatogonium Primary spermatocyte A Seminiferous tubules. Reproductive REPRODUCTIVE—Physio logy SECTIO N III 567 ``REPRODUCTIVE—PHYSIOLOGY Estrogen SOURCE Ovary (17β-estradiol), placenta (estriol), adipose tissue (estrone via aromatization) Potency: estradiol > estrone > estriol FUNCTION Development of genitalia and breast, female fat distribution Growth of follicle, endometrial proliferation, myometrial excitability Upregulation of estrogen, LH, and progesterone receptors; feedback inhibition of FSH and LH, then LH surge; stimulation of prolactin secretion transport proteins, SHBG; HDL; LDL Pregnancy: ƒƒ 50-fold in estradiol and estrone ƒƒ 1000-fold in estriol (indicator of fetal wellbeing) Estrogen receptors expressed in the cytoplasm; translocate to the nucleus when bound by ligand Estrogens Androstenedione Aromatase Androstenedione Cholesterol Desmolase FSH + Pulsatile GnRH + LH Estrogen Granulosa cell Theca cell Progesterone SOURCE Corpus luteum, placenta, adrenal cortex, testes Fall in progesterone after delivery disinhibits prolactin Ž lactation. progesterone is indicative of ovulation. Progesterone is pro-gestation. Prolactin is pro-lactation. FUNCTION Stimulation of endometrial glandular secretions and spiral artery development Maintenance of pregnancy myometrial excitability Production of thick cervical mucus, which inhibits sperm entry into the uterus body temperature Inhibition of gonadotropins (LH, FSH) Uterine smooth muscle relaxation (preventing contractions) estrogen receptor expressivity Prevents endometrial hyperplasia Reproductive 568 SECTIO N III REPRODUCTIVE—Physio logy Tanner stages of sexual development A Tanner stage is assigned independently to genitalia, pubic hair, and breast (e.g., a person can have Tanner stage 2 genitalia, Tanner stage 3 pubic hair). I. Childhood (prepubertal) II. Pubic hair appears (pubarche); breast buds form (thelarche) III. Pubic hair darkens and becomes curly; penis size/length ; breasts enlarge IV. Penis width , darker scrotal skin, development of glans; raised areolae V. Adult; areolae are no longer raised Menstrual cycle Maturing graafian follicle Ovulation Corpus luteum Regressing corpus luteum Proliferative phase (follicular) Secretory phase (luteal) Menstruation Endometrium 0 7 14 Days Blood hormone levels 21 28 FSH LH Progesterone Estrogen Ovulation Follicular phase can vary in length. Luteal phase is usually a constant 14 days. Ovulation day + 14 days = menstruation. Follicular growth is fastest during 2nd week of proliferative phase. Estrogen stimulates endometrial proliferation. Progesterone maintains endometrium to support implantation. progesterone Ž fertility. Oligomenorrhea: > 35-day cycle. Polymenorrhea: < 21-day cycle. Metrorrhagia (intermenstrual bleeding): frequent but irregular menstruation. Menorrhagia (heavy menstrual bleeding): > 80 mL blood loss or > 7 days of menses. Menometrorrhagia: heavy, irregular menstruation at irregular intervals. estrogen LH surge Ovulation Progesterone (from corpus luteum) Progesterone levels fall Menstruation (via apoptosis of endometrial cells) Reproductive REPRODUCTIVE—Physio logy SECTIO N III 569 Oogenesis 1° oocytes begin meiosis I during fetal life and complete meiosis I just prior to ovulation. Meiosis I is arrested in prOphase I for years until Ovulation (1° oocytes). Meiosis II is arrested in metaphase II until fertilization (2° oocytes). An egg met a sperm. If fertilization does not occur within 1 day, the 2° oocyte degenerates. Meiosis II Oogonium Diploid (2N, 2C) 1° oocyte Diploid (2N, 4C) 2° oocyte Haploid (1N, 2C) Ovum Haploid (1N, 1C) 23 sister chromatids 46 sister chromatids Arrested in prophase I until ovulation Arrested in metaphase II until fertilization 23 single chromatids 46 single chromosomes Polar body Polar body Polar body Ovum Polar body (can degenerate or give rise to 2 polar bodies) Replication (interphase) Meiosis I N = ploidy C = # of chromatids Reproductive 570 SECTIO N III REPRODUCTIVE—Physio logy Ovulation estrogen, GnRH receptors on anterior pituitary. Estrogen surge then stimulates LH release Ž ovulation (rupture of follicle). Mittelschmerz refers to transient mid-cycle ovulatory pain; classically associated with peritoneal irritation (e.g., follicular swelling/rupture, fallopian tube contraction). Can mimic appendicitis. temperature (progesterone induced). Pregnancy Fertilization most commonly occurs in upper end of fallopian tube (the ampulla). Occurs within 1 day of ovulation. Weeks Hormone Corpus luteum Placenta hCG Prolactin Progesterone Estriol 10 20 30 40 Implantation within the wall of the uterus occurs 6 days after fertilization. Syncytiotrophoblasts secrete hCG, which is detectable in blood 1 week after conception and on home test in urine 2 weeks after conception. Lactation After labor, the in progesterone and estrogen disinhibits lactation. Suckling is required to maintain milk production, since nerve stimulation oxytocin and prolactin. Prolactin—induces and maintains lactation and reproductive function. Oxytocin—assists in milk letdown; also promotes uterine contractions. Breastmilk is the ideal nutrition for infants < 6 months old. Contains maternal immunoglobulins (conferring passive immunity; mostly IgA), macrophages, and lymphocytes. Breastmilk reduces infant infections and is associated with risk for the child to develop asthma, allergies, diabetes mellitus, and obesity. Exclusively breastfed infants require vitamin D supplementation. Breastfeeding maternal risk of breast and ovarian cancer, and facilitates mother-child bonding. hCG SOURCE Syncytiotrophoblast of placenta. FUNCTION Maintains the corpus luteum (and thus progesterone) for the 1st trimester by acting like LH (otherwise no luteal cell stimulation, and abortion results). In the 2nd and 3rd trimesters, the placenta synthesizes its own estriol and progesterone and the corpus luteum degenerates. Used to detect pregnancy because it appears early in the urine (see above). α subunit structurally identical to α subunits of LH, FSH, and TSH. β subunit is unique (pregnancy tests detect β subunit). hCG is in multiple gestations and pathologic states (e.g., hydatidiform mole, choriocarcinoma). Reproductive REPRODUCTIVE—Physio logy SECTIO N III 571 Menopause estrogen production due to age-linked decline in number of ovarian follicles. Average age at onset is 51 years (earlier in smokers). Hormonal changes: estrogen, FSH, LH (no surge), GnRH. Menopause causes HAVOCS: Hot flashes, Atrophy of the Vagina, Osteoporosis, Coronary artery disease, Sleep disturbances. Menopause before age 40 can indicate premature ovarian failure. Usually preceded by 4–5 years of abnormal menstrual cycles. Source of estrogen (estrone) after menopause becomes peripheral conversion of androgens, androgens Ž hirsutism. FSH is specific for menopause (loss of negative feedback on FSH due to estrogen). Reproductive 572 SECTIO N III REPRODUCTIVE—Physio logy Spermatogenesis Spermatogenesis begins at puberty with spermatogonia. Full development takes 2 months. Occurs in seminiferous tubules. Produces spermatids that undergo spermiogenesis (loss of cytoplasmic contents, gain of acrosomal cap) to form mature spermatozoon. “Gonium” is going to be a sperm; “Zoon” is “Zooming” to egg. Spermatogonium Diploid (2N, 2C) 1° spermatocyte Diploid (2N, 4C) 2° spermatocyte Haploid (1N, 2C) Spermatid Haploid (1N, 1C) Mature spermatozoon Haploid (1N, 1C) Blood-testis barrier Meiosis I Meiosis II 46 single chromosomes (sex= X-Y) Sperm 23 single (sex= X) 23 single (sex= X) 23 single (sex= Y) 23 single (sex= Y) 23 sister chromatids (sex= X-X) 23 sister chromatids (sex= Y-Y) 46 sister chromatids (sex= X-X ) Y-Y Tight junction Replication (interphase) Note: Impaired tail mobility can lead to infertility (seen in ciliary dyskinesia/Kartagener syndrome). Acrosome Middle piece Head Tail Neck Nucleus Spermiogenesis N = ploidy C = # of chromatids Reproductive REPRODUCTIVE—Physio logy SECTIO N III 573 Androgens Testosterone, dihydrotestosterone (DHT), androstenedione. SOURCE DHT and testosterone (testis), AnDrostenedione (ADrenal) Potency: DHT > testosterone > androstenedione. FUNCTION Testosterone: ƒƒDifferentiation of epididymis, vas deferens, seminal vesicles (genitalia, except prostate) ƒƒGrowth spurt: penis, seminal vesicles, sperm, muscle, RBCs ƒƒDeepening of voice ƒƒ Closing of epiphyseal plates (via estrogen converted from testosterone) ƒƒ Libido DHT: ƒƒ Early—differentiation of penis, scrotum, prostate ƒƒ Late—prostate growth, balding, sebaceous gland activity Testosterone is converted to DHT by the enzyme 5α-reductase, which is inhibited by finasteride. In the male, androgens are converted to estrogen by cytochrome P-450 aromatase (primarily in adipose tissue and the testis). Aromatase is the key enzyme in the conversion of androgens to estrogen. Exogenous testosterone Ž inhibition of hypothalamic–pituitary–gonadal axis Ž intratesticular testosterone Ž testicular size Ž azoospermia. 574 SECTIO N III Re productive reproductive —Patho logy ``REPRODUCTIVE—PATHOLOGY Sex chromosome disorders of sexual development Klinefelter syndrome [male] (XXY), 1:850 Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia, female hair distribution A. May present with developmental delay. Presence of inactivated X chromosome (Barr body). Common cause of hypogonadism seen in infertility work-up. Dysgenesis of seminiferous tubules Ž inhibin Ž FSH. Abnormal Leydig cell function Ž testosterone Ž LH Ž estrogen. A Turner syndrome [female] (XO) Short stature (if untreated), ovarian dysgenesis (streak ovary), shield chest, bicuspid aortic valve, preductal coarctation (femoral < brachial pulse, notched ribs), lymphatic defects (result in webbed neck or cystic hygroma; lymphedema in feet, hands), horseshoe kidney B. Most common cause of 1° amenorrhea. No Barr body. “Hugs and kisses” (XO) from Tina Turner. Menopause before menarche. estrogen leads to LH, FSH. Can result from mitotic or meiotic error. Can be complete monosomy (45,XO) or mosaicism (e.g., 45,XO/46,XX). Pregnancy is possible in some cases (oocyte donation, exogenous estradiol-17β and progesterone). B Double Y males [male] (XYY), 1:1000 Phenotypically normal, very tall, severe acne, antisocial behavior (seen in 1–2% of XYY males). Normal fertility. Small percentage diagnosed with autism spectrum disorders. True hermaphroditism (46,XX or 47,XXY) Also called ovotesticular disorder of sex development. Both ovary and testicular tissue present (ovotestis); ambiguous genitalia. Very rare. Reproductive reproductive —Patho logy SECTIO N III 575 Diagnosing disorders of sex hormones Testosterone LH Diagnosis Defective androgen receptor Testosterone-secreting tumor, exogenous steroids 1° hypogonadism Hypogonadotropic hypogonadism Other disorders of sex development Include terms pseudohermaphrodite, hermaphrodite, and intersex. Disagreement between the phenotypic (external genitalia) and gonadal (testes vs. ovaries) sex. Female pseudohermaphrodite (XX) Ovaries present, but external genitalia are virilized or ambiguous. Due to excessive and inappropriate exposure to androgenic steroids during early gestation (e.g., congenital adrenal hyperplasia or exogenous administration of androgens during pregnancy). Male pseudohermaphrodite (XY) Testes present, but external genitalia are female or ambiguous. Most common form is androgen insensitivity syndrome (testicular feminization). Aromatase deficiency Inability to synthesize estrogens from androgens. Masculinization of female (46,XX) infants (ambiguous genitalia), and serum testosterone and androstenedione. Can present with maternal virilization during pregnancy (fetal androgens cross the placenta). Androgen insensitivity syndrome (46,XY) Defect in androgen receptor resulting in normal-appearing female; female external genitalia with rudimentary vagina; uterus and fallopian tubes generally absent; presents with scant sexual hair; develops testes (often found in labia majora; surgically removed to prevent malignancy). testosterone, estrogen, LH (vs. sex chromosome disorders). 5α-reductase deficiency Autosomal recessive; sex limited to genetic males (46,XY). Inability to convert testosterone to DHT. Ambiguous genitalia until puberty, when testosterone causes masculinization/ growth of external genitalia. Testosterone/estrogen levels are normal; LH is normal or . Internal genitalia are normal. Kallmann syndrome Failure to complete puberty; a form of hypogonadotropic hypogonadism. Defective migration of GnRH cells and formation of olfactory bulb; synthesis of GnRH in the hypothalamus; anosmia; GnRH, FSH, LH, testosterone, and infertility (low sperm count in males; amenorrhea in females). 576 SECTIO N III Re productive reproductive —Patho logy Hydatidiform mole A B Cystic swelling of chorionic villi and proliferation of chorionic epithelium (only trophoblast). Treatment—dilation and curettage and methotrexate. Monitor β-hCG. Complete mole Partial mole KARYOTYPE 46,XX; 46,XY 69,XXX; 69,XXY; 69,XYY hCG UTERINE SIZE — CONVERT TO CHORIOCARCINOMA 2% Rare FETAL PARTS No Yes (partial = fetal parts) COMPONENTS Enucleated egg + single sperm (subsequently duplicates paternal DNA); empty egg + 2 sperm is rare 2 sperm + 1 egg RISK OF COMPLICATIONS 15–20% malignant trophoblastic disease Low risk of malignancy (< 5%) SYM PTOMS Vaginal bleeding, enlarged uterus, hyperemesis, preeclampsia, hyperthyroidism Vaginal bleeding, abdominal pain IMAGING Honeycombed uterus or “clusters of grapes” A, “snowstorm” on ultrasound B Fetal parts Reproductive reproductive —Patho logy SECTIO N III 577 Hypertension in pregnancy Gestational hypertension (pregnancy-induced hypertension) BP > 140/90 mmHg after the 20th week of gestation. No pre-existing hypertension. No proteinuria or end-organ damage. Treatment: antihypertensives (α-methyldopa, labetalol, hydralazine, nifedipine), deliver at 39 weeks. Preeclampsia Defined as hypertension (> 140/90 mmHg) and proteinuria (> 300 mg/24 hr) after 20th week of gestation to 6 weeks postpartum (< 20 weeks suggests molar pregnancy). Severe features include BP > 160/110 mmHg with or without end-organ damage, e.g., headache, scotoma, oliguria, AST/ALT, thrombocytopenia. Caused by abnormal placental spiral arteries, results in maternal endothelial dysfunction, vasoconstriction, or hyperreflexia. Incidence in patients with preexisting hypertension, diabetes, chronic renal disease, or autoimmune disorders. Complications: placental abruption, coagulopathy, renal failure, uteroplacental insufficiency, or eclampsia. Treatment: antihypertensives, deliver at 34 weeks (severe) or 37 weeks (mild), IV magnesium sulfate to prevent seizure. Eclampsia Preeclampsia + maternal seizures. Maternal death due to stroke Ž intracranial hemorrhage or ARDS. Treatment: antihypertensives, IV magnesium sulfate, immediate delivery. HELLP syndrome Hemolysis, Elevated Liver enzymes, Low Platelets. A manifestation of severe preeclampsia, although may occur without hypertension. Treatment: immediate delivery.
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