Imatinib mesylate a specific tyrosine kinase inhibitor, has revolutionized the management o f CML. It is more effective than the previous gold standard therapy for CML, -interferon , plus or minus cytarabine, in chronic-phase patients. Imatinib therapy produced complete h emato- logic responses, major cytogenetic responses, and complete cytoge- netic responses i n the majority of patients treated in chronic phase and improved survival over interferon w hen compared using historical controls. The drug is also effective in patients who have fai led inter- feron and to some extent in both accelerated phase and blast crisis. Side effect s include nausea, cramps, edema, skin rash, cytopenias, and abnormal LFTs. 628 II The use of interferon in CML has declined dramatically with the intro- duction of tyrosi ne kinase inhibitors (imatinib, desatinib), but it may still have a role in combination the rapy. III The role of allogeneic transplantation from a HLA matched sibling or unrelated donor mu st be reconsidered given the success of tyrosine kinase inhibitors. This approach should be considered as first-line ther- apy in patients in whom trans-plant-related mortality is es timated to be very low. Other patients should be offered a trial of a tyrosine kinase inhib itor first. y g o o t a m e H l IV Treatment of transformed CML is difficult. Although patients may respond to imatinib, th is is temporary. Some patients who develop a lymphoblastic transformation may respond to th erapy as for ALL. Patients who develop a myeloblastic transformation rarely achieve lasting remission, and allogeneic transplant offers the only hope of long-term survival. Chronic lymphocytic leukemia CLL is a monoclonal proliferation of small lymphocytes that ar e most fre- quently of B-cell origin. CLL typically occurs in adults >40 yrs, with men more frequently affected than women. CLL comprises 25% of all leukemias and is the most common hematopoietic malignancy. Staging correlates with survival: 0 I II III IV Absolute lymphocytosis >15,000/mcL Stage 0 + enlarged lymph nodes Stage I + enlarged liver or spleen Stage II + anemia Stage III + thrombocytopenia Symptoms None in 25%; weight loss, bleeding, infection, anorexia. Signs Enlarged nontender nodes, hepatosplenomegaly Blood smear This is a diagnosis made by observing small, normal-a ppearing lymph nodes, many of which fracture on the smear and are termed \200\234smudge ce lls. \200\235 May also be signs of autoimmune hemolytic anemia (spherocytes) or autoimmune thrombocytopenia (large platelets). Complications (1) Autoimmune hemolytic anemia; (2) infe ction, either bacterial of the respiratory tract due to low immunoglobulin levels or viral due to altered cell-mediated immunity; (3) bone marrow failure; (4) immune-mediated thrombo cytopenia. Natural history Some remain in Stage 0 for years without progressing. Usually, n odes slowly enlarge. Death is often via infection (pneumococcus, haemophilus, meningococcus , candida, aspergillosis) or transformation to aggressive lymphoma (Richter \200\231s syndr ome). Treatment Chemotherapy is often not required initially. Chlorambucil, effective in re ducing WBC and node size, was the mainstay of therapy, but is now being supplanted by ritux imab, fludarabine, bendamustine, other monoclonal antibody therapies, and other agents in c linical trials. Steroids are useful in controlling autoimmune processes. Radiotherapy can b e used for relief of lymphadenopathy or splenomegaly. Supportive care: Transfusions, prophy lactic antibiotics, immune globulin. Prognosis is often good, depending on stage, age, and molecular/ immuno-logical factors such as ZAP70 or CD38. 629 Hodgkin \200\231s lymphoma Hodgkin \200\231s lymphoma (HL) is a cancer characterized by the presence of clonal malignant Reed \200\223Sternberg cells within a reactive cellular backg round comprised of variable numbers of granulocytes, plasma cells, and lympho- cytes. Reed \200\223Sternberg cells are transformed B lymphocytes, many of which contain Epstein \200 \223Barr genome, suggesting an association of previous infec- tion in the pathogenesis of H L in many patients. Classification (in order of incidence) Nodular sclerosing Mixed cellularity* Lymphocyte pre dominant Lymphocyte depleted* Prognosis: Good Good Good Poor Higher incidence and worse prognosis if HIV positive. Clinical features The usual presentation is with enlarged, painless lymph nodes, usually in the neck or axillae. Rarely, there may be alcohol-induced pain or features due to the mass effect of the nodes. 25% have constitutional symptoms such as fever, weight loss, night sw eats (often drenching), pruritus, and loss of energy. If the fever alternates with long per iods (15 \200\22328 d) of normal or low temperature, it is termed a Pel \200\223Ebstein fev er (other causes of this rare fever: TB, renal cell cancer). Signs: Lymphadenopathy (note p osition, consistency, mobility, size, tenderness). Look for weight loss, anemia, hepatosple nomegaly. Tests Lymph node biopsy for diagnosis. CBC, smear, ESR, LFTs, CXR, bone marrow bi opsy, abdominal or magnetic resonance imaging (MRI) scan. Lymphangiography is no longer use d routinely. Staging laparotomy is performed if finding abdominal disease will change the t herapy. It involves splenectomy with liver and lymph node biopsy. Staging influences treatm ent and prognosis. I Confined to single lymph node region II Involvement of \211 2 region s on same side of diaphragm III Involvement of nodes on both sides of diaphragm IV Spread b eyond the lymph nodes Each stage is subdivided into A (no systemic symptoms) or B (presence of weight loss >10% in last 6 months, unexplained fever >38 C, or night sweats). These in dicate more extensive disease. Pruritus is not a B symp- tom. Extranodal disease is indicat ed by a subscripted \200\234E \200\235 (e.g., IA e ). Treatment XRT for stages IA and (IA, chemotherapy for IIA \206\222 IVB). HA patients with very large mediastinal masses also r eceive chemotherapy. Chemotherapy is given with an \200\234*ABVD \200\235-type regimen (Ad riamycin, bleomycin, vinblastine, dacarbazine). Regimens containing nitrogen mustard such a s MOPP are less common because of the risk of sterility and secondary AML. Recently, more i ntensive regimens have been used, particularly for advanced disease. Peripheral stem-cell t ransplantation: Autologous or allogeneic transplantation of blood progenitor cells helps re store marrow function after myeloablative therapy, as do agents that stimulate progenitor c ells (e.g., filgrastim). Complications of treatment: Radiation-induced lung fibrosis and hy pothy- roidism. Chemotherapy \200\224nausea, alopecia, infertility in men, infection due to myelosuppression, mucositis, and second malignancies, especially AML, breast cancer, and n on-Hodgkin \200\231s lymphoma (NHL). Autologous marrow transplant may help in relapses afte r chemotherapy or in previously irradi- ated sites. 630 5-yr survival Depends on stage and grade, ranging from >90% in IA lymphocyte-predominant di sease to <40% with IVB lymphocyte depletion. Emergency presentations SVC obstruction presen ts with JVP \206\221 , a sensation of fullness in the head, dyspnea, blackouts, and facial edema. Arrange urgent radiotherapy (XRT). High-dose corticosteroids may also be useful. y g o o t a m e H l Non-Hodgkin \200\231s lymphoma This group includes all lymphomas without the Reed \200\223S ternberg cell and is a very diverse group. Classification is now based on cell of origin an d integrates histology, immunophenotype, and molecular studies. Historically, NHL was clini cally classified by grade of tumor, given the observations that low-grade lymphomas are mor e indolent but incurable whereas the high-grade types are more aggressive, but long-term cu re is achievable. The low-grade group includes CLL/SLL, follicular lymphoma, mantle cell, m arginal zone, splenic marginal zone, and others whereas the high-grade lymphomas include ce ntroblastic, immunoblastic, and lymphoblastic. Incidence has doubled since 1970 (to 1:10,00 0), perhaps from immunosup- pression in the setting of chronic viral infections (HIV, HTLV- I, and EBV) or transplant. The patient \212 \212 Typically an adult with lymphadenopathy Extranodal spread occurs early, so presentation may be in skin, bone, gut, CNS, or lung. Often asymptomatic. Pancytopenia occurs (marrow dyspl asia) hemolysis Infection is common. Systemic symptoms as in Hodgkin \200\231s. Examine all over. Note nodes (if any is >10 cm across, staging is advanced). Do ear-nose-throat (EN T) exam if GI lymphoma (GI and ENT lymphoma often coexist). \212 \212 \212 Tests, diagnosis, and staging As for Hodgkin \200\231s (staging is less important as 70% ha ve widespread disease at presentation). Always do node biopsy, CXR, abdomen + pelvis CT, CB C, LFT, cytology of a pleural or peritoneal effusion, CSF cytology if CNS signs, highly agg ressive phenotype or HIV positive. NB : Survival is worse if elderly or symptomatic. Treatm ent Asymptomatic low-grade tumors may not need treatment remission; chlorambucil or and occ asionally enter cyclophosphamide may control symptoms. Radiation therapy can be used for lo cal bulky disease. More aggressive disease requires combination chemotherapy, CHOP with Rit uxan. Lymphoblastic lymphoma ; treat as for ALL. Small noncleaved lymphomas are very aggres sive and require extremely intensive therapy. Burkitt \200\231s leukemia/lymphoma Endemic i n African children, also associated with HIV and sporadic forms and is associated with chro mosomal translocations involving immunoglobulin loci and the myc oncogene. Jaw tumors are c ommon, usually with GI involvement. Histology shows a \200\234starry sky \200\235 appearan ce (isolated histiocytes on background of abnormal lymphoblasts). Spectacular remission may result from a single dose of a cytotoxic drug (e.g., cyclophosphamide). spontaneous 631 Bone marrow failure The bone marrow is responsible for hematopoiesis and, in adults, is fou nd in the vertebrae, sternum, ribs, skull, and proximal long bones, although it may expand in anemia (e.g., thalassemia). All blood cells are thought to arise from an early, pluripot ent stem cell that divides in an asymmetric fash- ion to provide a committed progenitor and other stem cells. Committed progenitors then undergo further differentiation before releas ing formed elements into the blood. Bone marrow failure usually produces a pancy- topenia, often with sparing of the lymphocyte count. Aplastic anemia, hypersplenism, SLE, Causes of pancytopenia megaloblastic anemia, paroxysmal nocturnal hemoglobinuria, leukemia, myelodysp lasia, drugs, liver disease. Causes of marrow failure Stem cell or erythroblast loss: (1) A plastic anemia; this can be toxic (e.g., drug, benzene), immunologic, congenital, viral (es p. hepatitis B and parvoviruses), or idiopathic (most common). (2) In \201 ltration: From malignancy, infection (TB, M. avium intracellulare [MAI]). (3) Fibrosis: Primary myelofibro sis, HIV, SLE. (4) Abnormal differentiation of a genetically damaged clone of cells, such a s myelodysplastic syndromes, acute leukemia. Aplastic anemia This presents as pancytopenia with a hypoplastic marrow (i.e., the marrow stops producing cells). Causes are idiopathic ( 50%), radiation, drugs (e.g., cytotoxics, chloramphenicol, anticonvulsants and gold), virus es, congenital. Incidence: 10 \200\22320 per million per year. Presents as bleeding, anemia , or infec- tion. In 50% of cases there is response to immunosuppressive therapy. Treatmen t of aplastic anemia: Marrow transplantation is the best treatment for younger patients if there is a histocompatible sibling donor. In patients in whom transplantation is not feasib le, immunosuppressive regimens are effective. Many patients respond to regimens incorporati ng cyclosporine, antithymocyte globulin, or high-dose cyclophosphamide. Responses to an- dr ogens are rare. Bone marrow support The symptoms of bone marrow failure are due to the panc ytopenia. Red cells survive for \211\210 120 d, platelets for an average 10 d, and neutrop hils for 1 \200\2232 d, so early problems are mainly from neutropenia and thrombocytopenia. Erythrocytes: A 1 unit transfusion should raise the Hb by about 1 \200\2242 g/dL assuming that there are no antibodies. Platelets: Spontaneous bleeding is unlikely if platelets >20, 000/dL. Platelets require irradiation or leukocyte depletion prior to transfusion. Indicati ons for transfusion are counts <10,000/dL and bleeding. One unit of fresh plate- lets shoul d raise the count to >10,000/dL unless the patient is alloimmu- nized or febrile. Neutrophi ls: Use \200\234neutropenic precautions \200\235 if the count is <500/dL. There is no role for neutrophil transfusions typically, although active fungal pro- cesses are exceptions. Bone marrow biopsy Ideally, an aspirate and biopsy should be taken. Biopsies may be taken f rom the posterior iliac crest, aspirates may be taken from anterior iliac crest or sternum. Thrombocytopenia is rarely a contraindication. Severe coagulation disorders may need to be corrected. Apply pressure afterward (lie on that side for 1 \200\2232 h if platelets are l ow). 632 The myeloproliferative disorders Polycythemia vera, essential thrombocytosis, and idiopathi c myelofibrosis are bone marrow disorders characterized by excess proliferation of myeloid elements \200\224RBC, WBC, and platelets. These disorders are clonal hematopoi- etic stem c ell disorders in which all of the circulating cells are derived from a transformed stem cel l clone. The progeny of the aberrant stem cell dif- ferentiate and function normally. The t hree disorders share several features, including the fact that all may present with constit utional symptoms such as fever, weight loss, night sweats, pruritus, and malaise, and have vary- ing degrees of extramedullary hematopoiesis, myelofibrosis, and leukemic transformati on. These disorders are closely related pathogenetically, many associated with a mutation i n the JAK2 gene. These disorders are closely related clinically, with frequent disease evol ution between different MPN subtypes over the years in a single patient. Often these diseas es are a \200\234panmyelosis \200\235 indicating that more than one cell line is increased . This may generate diagnostic confusion, especially between essential thrombocytosis and p olycythemia vera. Erythrocytosis may be relative (plasma volume contraction) or absolute (i ncreased red cell mass). This distinction is made by red cell mass estimation using radioac tive chromium. Relative erythrocytosis is often due to dehydration (alcohol or diuretics). Absolute polycythemia may be primary (polycythemia vera) or secondary from smoking, sleep a pnea, chronic lung disease, tumors (fibroids, hepatoma, renal cell cancer), altitude, or ra rely from high-affinity Hb. Polycythemia rubra vera Incidence: 1.5/100,000/yr, peaks at 45 \200\22360 yrs. Signs: \212 \212 \212 Presentation is determined by hyperviscosity (CNS signs [p. 636]; angina; itching \200\224typically after a hot bath) and WBC turnover (gout) . It may also present with bruising or be detected incidentally after a routine CBC. Diagno sis: Red cell mass >125% of predicted ( 51 Cr studies). JAK2 mutation test is positive in > 95% with PV clinical phenotype. Erythropoietin levels are normal or low, O 2 saturation is normal. Treatment: Keep HCT <42% by phlebotomy. Iron deficiency may result from repeated ph lebotomies. Myelosuppressive agents (hydroxyurea, interferon) may be required to control ex tramedullary disease or blood counts. Prognosis: Variable; many often remain well for decad es, but complications include extramedullary hematopoiesis, myelofibrosis, marrow failure, or even leukemia. A particu- lar risk is from thrombotic disorders that may derive from \206\221 HCT and viscosity and/or activated white cells or platelets. Essential thrombocyto sis is defined as thrombocytosis (>600,000/ mcL) in the absence of a defined stimulus, such as iron deficiency, inflammation, polycythemia vera or primary myelofibrosis. Platelet fun ction can be abnormal, and presentation may be by bleeding or thrombosis. Microvascular occ lusion may lead to erythromelalgia (painful burning and erythema in fingertips and toes). T reatment: Hydroxyurea, interferon, or anagrelide may be needed for symp- toms or in high-ri sk patients (age >60, previous thrombosis history, hy- pertension, coronary artery disease) ; however, platelet count correlates poorly with the risk of thrombosis. Aspirin is useful, especially if there is any evidence of a thrombotic diathesis. Causes of a raised platelet count: Other myeloproliferative or inflammatory disorders, bleeding, malignancy, post-sple nectomy, Kawasaki disease. y g o o t a m e H l Elevated hemoglobin, white cells, or platelets variably affected MCV normal or microcytic S plenomegaly (60%) 633 Primary myelofibrosis There is marrow fibrosis with associated hematopoiesis in the spleen and liver (myeloid metaplasia, extramedullary hematopoiesis) associated with significant de grees of anemia and wasting. Clinical features: Variable \200\224constitutional, splenomega ly, bone marrow failure. Smear: Leukoerythroblastic; teardrop RBCS. Marrow tap: Often dry. Treatment is supportive, iron and folate supplements splenectomy, consideration of stem cell transplantation, interferon or JAK2 inhibitor trials. Other causes of marrow fibrosis Any myeloproliferative disorder, lymphoma, secondary carcinoma, TB, leukemia (especially, m egakaryoblastic [M7]) irradiation, SLE, HIV. Myeloma Myeloma is a plasma cell neoplasm that produces diffuse bone marrow infil- tration and focal osteolytic lesions. An M component (M for monoclonal \200\224 not IgM) is seen on serum and/or urine electrophoresis. Incidence 5/100,000. Peak age: 70 yrs. Classification Based on the principal neoplastic cell product: IgG \212 IgA \212 \212 55% 25% 20% Light chain disease IgD, IgE, and nonsecretory types are less common. 60% of IgG and IgA myelomas also produce free light chains that are filtered by the kidney and may be detectable as Bence Jones prot ein (these precipi- tate on heating and redissolve on boiling). They may cause renal damage or amyloidosis. Clinical features \212 Bone pain/tenderness is common, often postural (e.g., back ribs, long bones, and shoulder). Occasionally presents as pathological fracture (but 25% have no clinical or x-ray signs of bone disease at presentation). Fatigue (anemia, renal failure or dehydration). Infection ( poor Ig production). Amyloid Neuropathy Viscosity Visual acuity-I hemorrhages/exudates o n funduscopy Bleeding \212 \212 \212 \212 \212 \212 \212 Diagnosis Abundant, clonally restricted plasma ce lls in marrow. Component M or urinary light chains on serum/urine electrophoresis (Bence Jo nes proteins) and abnormal serum; free light chain ratios are supportive evidence. Other te sts: CBC, ESR \206\221 , alk phos usually normal (unless healing fracture). Nonmyeloma imm unoglobulins can be suppressed; urea, creatinine, urate + Ca 2+ \206\221 in 30 \200\22350% . Bone x-rays: Punched-out lesions, osteoporosis. Treatment Supportive: Bone pain, anemia, and renal failure cause most symptoms. Give analgesia and transfusions PRN. Advise high flu id intake. Solitary lesions can be given XRT and may heal. Bed rest tends to exacerbate hyp ercalcemia, so mobilization is important \200\224this may require surgical stabilization of lytic lesions and analgesia. Pamidronate (and other newer bisphosphonates) and erythropoie tin are promising for reducing bone pain, hypercalcemia, and transfusion requirements. 634 Chemotherapy None may be needed (none is curative) unless: HCT \206\223 or: \212 \212 \212 \212 \212 \212 \212 Optimal therapy is evolving but includes combinations of stero ids, mel- phalan, and thalidomide or bortezomib and other intensive chemotherapeu- tic regi mens. Autologous bone marrow transplant may offer an advantage after induction therapy for many patients who are suitable candidates and have high-risk disease. Survival worse if blo od urea nitrogen (BUN) >28 mg/ dL or Hb <7.5 g/dL. Dangers 1 Hypercalcemia: Use IV normal s aline (NS) 4 \200\2236 L/d with careful fluid bal- ance and furosemide. Consider steroids; e.g., hydrocortisone 100 mg IV q8h; bisphosphonates may be needed in refractory disease, ca lcitonin, mithramycin, and gallium nitrate also may be useful. y g o o t a m e H Troublesome symptoms Many osteolytic lesions Impending fracture Creatinine >1.5 mg/dL Marro w >30% plasma cells Serum \222 More light chains in urine than creatinine (mcg/mL) l 2 micro-globulin >4 mcg/mL. 2 Hyperviscosity: May need plasmapheresis 3 Acute renal failure may be precipitated by IVP; therefore avoid IV contrast. Paraproteinemia Paraproteinemia refers to the presence in the circulation of immunoglobu- l in produced by a single clone of plasma cells or their precursors. The paraprotein is recog nized as a sharp M component (M for monoclonal, not IgM) on serum electrophoresis. There ar e six major categories: 1 Multiple myeloma (p. 634) 2 Waldenstr m \200\231s macroglobuli nemia: This is a lymphoplasmacytoid malig- nancy producing an IgM paraprotein, lymphadenopa thy, and splenomegaly. CNS and ocular symptoms of hyperviscosity may occur. Chemotherapy an d plasmapheresis (p. 637) may help. 3 Primary amyloidosis: See below. 4 Monoclonal gammopathy (monoclonal gammopathy of unknown signifi- cance or MGUS) is common (3% >70 yr). In contrast to myeloma, in MGUS the parapro tein level is stable, immunosuppression and urine light chains are absent and there is litt le plasma cell marrow infiltrate. 5 Paraproteinemia in lymphoma or leukemia: CLL 6 Heavy chain disease: Production of free he avy chains, causing malabsorp- tion from infiltration of small bowel wall. It may terminate in lymphoma. Amyloidosis This is characterized by extracellular deposits of an abnormal protein resis- t ant to degradation called amyloid. Various proteins, under a range of stim- uli, may polyme rize to form amyloid fibrils. They are shown with Congo Red staining (apple-green birefring ence in polarized light). Classification 1 Systemic: 635 Immune dyscrasia (fibrils of immunoglobulin light chain fragments, known as \200\234AL \200\235 amyloid) Reactive amyloid ( \200\234AA \200\235 amyloid; nonglycosylated protein) Hereditary amyloid (type I familial amyloid polyneuropathy) 2 Localized: Most often cutaneo us; or cerebral, cardiac, endocrine \212 \212 \212 AL amyloid (primary amyloidosis) is associated with monoclonal proliferation of plasma cell s (e.g., in myeloma). Clinical features include carpal tunnel syndrome, peripheral neuropat hy, purpura, cardiomyopathy, and macro- glossia (a large tongue). AA amyloid (secondary amy loidosis) is associated with chronic infections (e.g., TB, bronchiectasis), inflammation (e specially rheumatoid arthritis), and neoplasia. It may affect kidneys, liver, and spleen. P resents as proteinuria, nephrotic syndrome, and/or hepatosplenomegaly. The diagnosis of amy loidosis is made after Congo Red staining of affected tissue. The rectum is a common site f or biopsy. Treatment rarely helps, but AA amyloid may improve with treatment of the underly ing disease. A rare complication of amyloid is the intravascular adsorption of factor X, re sulting in a prolonged PT and a serious coagulopathy. Inflammatory markers The ESR is a nonspecific indicator of the presence of inflammation. It mea- sures the rate of sedimentation of RBCs in anticoagulated blood over 1 h. If red cell s are coated by proteins (such as IgG or fibrinogen), then the normal negative charge on th e cell surface is masked and the cells will tend to stick to each other in columns (the sam e phenomenon as rouleaux on the blood smear [p. 612]),and so they will fall faster. The ESR rises with age and anemia. It is reduced in polycythemia, CHF, sickle-cell anemia, trichin o- sis. Patients with a markedly raised ESR (>100 mm/h) may have a serious malignancy, conn ective tissue diseases (e.g., giant cell arteritis), rheumatoid arthritis, renal disease, s arcoidosis, or infection. C-reactive protein (CRP) is an acute-phase protein that is very h elpful in the monitoring of inflammation. The best test is quantitative, normal <0.80 mg/L. Like the ESR, it is raised in many inflammatory conditions but is much less sluggish in it s response and falls within 2 \200\2233 d of the inciting event. Therefore, it can be used to follow the response to therapy (e.g., antibiot- ics) or activity of disease (e.g., in Cr ohn \200\231s disease). If the CRP has fallen 3 d after the onset of treatment for infectio n then the choice of antibiotics is probably appropriate. CRP is raised by active rheumatic disease (rheumatoid arthritis, rheumatic fever, seronegative arthritis, vasculitis), tissu e injury or necrosis (acute MI, transplanted kidney or bone marrow rejection, malignancies \200\224esp. breast, lung, GI), burns, infection (bacterial more than viral). It is very us eful for diagnosis of postoperative or intercurrent infections when the ESR may still be el evated. If the CRP has not started to fall 3 d after surgery then compli- cations must be c onsidered (e.g., infection, PE). CRP is NOT raised by SLE, leukemia (fever, blast crisis, o r cytotoxins), ulcerative colitis, osteoarthritis, anemia, polycythemia, or CHF. Its highes t levels are seen in bacterial infec- tions. Absence of an elevated CRP significantly reduc es the pretest prob- ability of other investigations for bacterial infection (e.g., bone or gallium scan) and so may be a cheaper, more comfortable alternative. 636 Hyperviscosity syndromes These occur if the plasma viscosity rises to such a point that the microcir- culation is impaired. Usually relative viscosity >4 (four times the viscosity of water) is necessary to produce symptoms. Causes Myeloma (p. 634) (IgM and IgA \206\221 vi scosity more than the same amount of IgG because they are multimeric), Waldenstr m \200 \231s macroglobulinemia, polycythemia. High leukocyte counts in leukemia may produce leukostasis, which differs from hyperviscosity per se. Presentation Visual disturba nce, retinal hemorrhages, headaches, coma, and GU or GI bleeding. The visual symptoms ( \200\234slow-flow retinopathy \200\235) may be described as \200\234look- ing through a wa tery windshield. \200\235 Other causes of slow-flow retinopathy are carotid occlusive disea se and Takayasu \200\231s disease. Treatment Removal of as little as 1 L of blood may relie ve symptoms. Plasmapheresis is useful in the paraproteinemias, especially IgM, since it is mostly intravascular. Plasmapheresis for hyperviscosity due to IgG is usually less effectiv e as it is deposited extravascularly. y g o o t a m e H l The spleen and splenectomy Splenomegaly is not uncommon and the differential diagnosis can be divided on the basis of the degree of splenic enlargement. (CML, PV, Massive splenomegal y primary myelofibrosis), malaria (hyperreactive malarial splenomegaly), schistosomiasis, l eishmaniasis, kala-azar, \200\234tropical splenomegaly \200\235 (idiopathic, in Africa and SE Asia) Moderate splenomegaly Infection (malaria, EBV, subacute bacterial endocarditis [S BE], TB), portal hypertension, hemolytic anemia, hematologic malignancy (leukemia, lymphoma ), splenic lymphoma, connective tissue disease (rheumatoid arthritis [RA], SLE), glycogen s torage diseases, common variable immunodeficiency, splenic cysts, idiopathic. Splenomegaly can cause abdominal discomfort or more commonly pain in the left shoulder (because of the e mbryologic origin of the organ). It may lead to hypersplenism, defined as pancytopenia due to cells becoming trapped in the reticuloendothelial system (symptoms of anemia, infection, and bleeding). When faced with a mass in the left upper quadrant, it is important to be ab le to recognize the spleen. The spleen moves with inspi- ration, enlarges toward the umbili cus, may have a notch, and \200\234you can \200\231t get above it \200\235 (the top margin disappears under the ribs). Ultrasound or CT may help in evaluation of the spleen. When hu nting for the cause for enlargement, look for lymphadenopathy and liver disease. Appropriat e tests are CBC, ESR, LFTs and liver, lymph node or marrow biopsy. Aspiration or biopsy of the spleen is not commonly performed. Splenectomy may be indicated for splenic trauma or sp lenic cysts, or as therapy for autoimmune thrombocytopenia and autoimmune hemolytic anemia, or for the diagnosis and treatment of splenic lymphomas. Post-splenectomy, there may be a prompt, dramatic, and transient rise in the platelet count, so patients should be mobilized early. All patients, especially children, remain at increased risk of infection, particula rly pneu- mococcal septicemia. Most children are advised to take daily penicillin V until a ged 20 yrs. In adults, prophylaxis of 2 \200\2235 yrs is recommended unless there is coexis ting hematologic disease; broader spectrum agents such as amoxicillin may be more appropria te. Give adults and unvaccinated children pneumococcal (Pneumovax , haemophilus (HiB), and meningococcal A & C (Mengivac ) 2 wks preoperatively. Warn asplenic travelers that they f ace an increased risk of tropical infections, and to adhere closely to antimalarial prophyl axis, while recognizing that this may not be effective. Counsel the patient to have standby amoxicillin to start at once if any symptoms of infection present, and to seek urgent hosp ital care. Myeloproliferative neoplasms 637 Thrombophilia Thrombophilia is a primary coagulopathy resulting in a propensity to thrombos is, and can be due to genetic predisposition or to acquired fac- tors, or both. Thrombophil ia is not rare and needs special precautions in surgery, pregnancy, and immobilization. Ris k factors associated with venous thrombosis include stasis, inflamma- tion, endothelial inj ury, and an imbalance between activated clotting factors and anticoagulants \200\224these t ypes of risk factors are primarily acquired and transient. Although many genetic risk facto rs for thrombosis have been identified, they do not exert a strong effect in healthy indivi duals; in the setting of other acquired risks, however, they will strongly increase the ris k of venous thrombosis. Suspect a primary hypercoagulable state in a young patient presenti ng with unprovoked thrombosis. Suspicion grows if there is a personal or family history of recurrent arterial or venous thrombosis or first-trimester spon- taneous abortion. Inherite d thrombophilia Activated protein C resistance (APC resistance) is the most common inherite d risk for venous thrombosis. APC resistance is overwhelmingly due to a single nucleotide p olymorphism in the factor V gene (Factor V Leiden) present in the carrier state in 5% of in dividuals of Northern European descent. Factor V Leiden renders factor Va resistant to clea vage by activated protein C and is associated with an mildly increased risk of deep venous thrombosis in the heterozygous state and a marked increase in the homozygous state. The pro thrombin 20210 polymorphism is present in 2% of the Mediterranean population (carrier stat e) and is less strongly associated with increased risk of DVT than is Factor V Leiden. Far less common are inherited deficiency states of antithrombin III, protein S, and protein C. Treatment: Those with a history of thrombosis and with inherited abnormalities should be co nsidered for long-term anticoagulation. Acquired thrombophilia Common risk factors include venous stasis (after knee or hip replacement surgery), endothelial injury, congestive heart failure, bed rest, obesity, the postoperative state, indwelling catheters, cancer, heparin -induced thrombocytopenia, and certain blood disorders including myeloproliferative neoplas ms, sickle cell anemia, paroxysmal nocturnal hemoglobinuria (PNH), and hemolytic anemias. C ancer: There is a high risk of occult malignancy becoming evident within a year of seemingl y unprovoked thrombotic events in patients <60 yrs of age. It is not current practice, howe ver, to investigate aggressively in a search for cancer in all patients with DVT, but rathe r to limit the investigation to age-appropriate cancer screening. Trousseau \200\231s syndr ome \200\224migratory throm- bophlebitis associated with visceral carcinoma \200\224classic ally resists treat- ment with warfarin and requires unfractionated or low-molecular-weight heparin. Antiphospholipid antibody syndrome is recurrent venous and/ or arterial thrombotic events in association with an antiphospholipid antibody. There are two well-recognized aPL antibodies and three common ways of measuring them: The anticardiolipin antibody (measured with an enzyme-linked immunosorbent assay [ELISA] or the dilute Russell \200\231s viper ve nom time [RVVT]) and the lupus anticoagulant (a misnomer, it falsely prolongs the aPTT by i nterfering with the assay in vitro but is a procoagulant nonetheless) measured by the aPTT. aPL syndrome can be primary or associated with autoimmune disorders such as SLE. The annua l risk of recurrent thrombosis after a confirmed thrombotic event in patients with an antip hospholipid antibody is 30%. Warfarin anticoagulation with 638 a target INR >3 is effective in reducing thrombotic recurrences. Treatment during pregnancy includes both aspirin and heparin. NB: Hypercoagulable studies performed at the time of a thrombosis can be misleading because of alterations of clotting factors due to acute illnes s or the thrombosis itself and should be avoided. y g o o t a m e H l Immunosuppressive drugs Immunosuppressive drugs are used in organ and marrow transplants, r heu- matoid arthritis, psoriasis, chronic hepatitis, asthma, giant cell arteritis, polymyal gia, SLE, PAN, and inflammatory bowel disease and many other autoimmune diseases. Prednison e Steroids can be life-saving, but a number of points should be taken into consideration be fore initiating treatment. \212 Hypertension, osteoporosis, and diabetes may be exacerbated by steroids. Do not stop steroi ds suddenly. Adrenal insufficiency may result, as endog- enous production takes time to res tart (p. 312). Increase steroid dosing at times of illness/stress (e.g., flu or preop). Min imize side effects by using the lowest dose possible for the shortest amount of time. Give doses in the morning, and alternate days if possible, to minimize adrenal suppression. Befo re starting steroid treatment, extensively counsel your patient regard- ing the risks and b enefits of steroids and the impact of steroids on their comorbidities. Avoid concurrent dru gs bought over the counter (e.g., aspirin, ibuprofen); the danger is steroid-associated GI bleeds: If NSAIDs are essential ask the patient to come to you for advice. You might consid er an NSAID com- bined with misoprostol, a prostaglandin analog. Interactions: Antiepilepti cs (below) and rifampin. Strongly consider pneumocystic pneumonia (PCP) prophylaxis in pati ents who are on other chemotherapeutic regimens, who require moderate steroid dosing for lo ng periods of time, or in patients who are otherwise immunocompromised. \212 \212 \212 \212 \212 \212 \212 \212SE: TB reactivation, edema, osteoporosis, cataracts, euphoria, elevated glucose, Pneum ocystis , urinary tract infection (UTI), toxoplasmosis, asper- gillus, serious chicken pox/ zoster, so avoid contacts (and so the need for varicella zoster immunoglobulin). Avoid preg nancy. \212 Azathioprine SE: Peptic ulcer, marrow suppression, reduced WBC. Do CBCs. Interactions : Mercaptopurine and azathioprine (which metabolized to mercaptopurine) are metabolized by xanthine oxidase (XO). Azathioprine toxicity results if XO inhibitors (allopurinol) are coa dministered. Genotype testing for thiopurine methyltransferase (TPMT) should be done prior to initiating azathioprine. Patients with low enzyme activity have increased risk of toxici ty. Cyclosporine Transplant patients usually require 6 mg/kg/d; in other patients, keep the dose <4 mg/kg/d. Monitor urine (UA) and creatinine every 2 wks for the first 3 months, the n monthly if dose >2.5 mg/kg/d (every 2 months if less than this). Reduce the dose if creat inine rises by >30% on two measurements even if the creatinine is still in the normal range . Stop if the abnormality persists. Monitor blood levels in transplant patients. SE: Nephro toxicity, hepatotoxicity, edema, gum hyperplasia, tremor, paresthesia, hypertension, confus ion, seizures, lymphoma, skin cancer. Interactions are legion. Cyclosporine levels are incr eased by ketoconazole, diltiazem, nicardipine, verapamil, oral contraceptives, erythromycin . Cyclosporine levels are reduced by barbiturates, carbamazepine, phenytoin, rifampin. 639 Avoid concurrent nephrotoxics: Gentamicin, amphotericin. Concurrent NSAIDs augment nephroto xicity: Monitor LFTs. Methotrexate Inhibits dihydrofolate reductase, which is involved in t he synthesis of purines and pyrimidines. SE: Hepatitis, lung fibrosis, CNS signs, teratogen icity. Methotrexate \200\231s action is increased by NSAIDs, aspirin, penicillin, probeneci d. Cyclophosphamide SE: Carcino- and teratogenic, hemorrhagic cystitis, marrow suppression. 640 This page intentionally left blank Geriatric medicine Colleen Christmas , M.D. e n i c i d e m c i r t a i r e Contents What is special about geriatric patients? 642 The elderly patient in the hospital 642 Frail ty, falls, and postural hypotension 644 Impairment, disability, and stroke rehabilitation 6 45 Urinary incontinence 646 Polypharmacy 648 Examination of mental state 648 Approach to de mentia 649 Alzheimer dementia 651 Preventive geriatrics 651 G What is special about geriatric patients? Many aspects regarding older adults make them a c hallenging and rewarding patient population to work with. Most of the care of older adults consists of simultanous management of multiple chronic diseases. The course of their medica l conditions will be punctuated by episodes of exacerbation of acute illness. With each suc cessive exacerbation, prognosticating the amount of recovery becomes increasingly difficult . Another challenge in providing care to geriatric patients is that quality of life, risks of treatment, and functional disability take on greater importance in making treatment deci sions. Geriatric patients represent an incredibly heterogeneous group demograph- ically and physiologically. From person to person the effects of lifestyle, genetic, and environmenta l factors produce variable results in aging of dif- ferent organ systems. While one octogen arian may be active, driving, caring for grandchildren, and have well-controlled chronic co nditions, the next may be severely debilitated, dependent on others for most of his or her care needs, and profoundly cognitively impaired. Thus, the approach to geriatric patients m ust be highly individualized. The final principle to be considered in caring for older adul ts is that of intrinsic vulnerability. Although exercise may ameliorate some of the adverse effects of aging on most organ systems, even the very healthy aged suffer from a reduced a bility to withstand physiologic perturbation. Examples of this may include glucose metaboli sm that appears normal during usual situ- ations but becomes abnormal with mild disturbance , such as a urinary tract infection. This dictates a requirement to \200\234stay on your t oes, \200\235 treat gingerly, and frequently reassess the impact of interventions in geriat ric patients. 6 1