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TABLE OF CONTENTS 1 CARDIOLOGY Atrial fibrillation ......................................14 */Cardiolo,14/Emergenc,37/Endocrin,57/ Control of ventricular response ........................14 */Gastroen,79/Gynecolo,103/Hematolo,115/ Restoring sinus rhythm .................................15 */Infectio,134/Nephrolo,173/Neurolog,193/ Decreasing embolic risk ................................17 */Orthoped,200/Pulmonar,206/Rheumato,226/ Maintenance of sinus rhythm ............................17 Atrial myxoma ............................................18 Clinical ...............................................18 Laboratory .............................................20 Treatment ..............................................21 Abdominal aortic aneurysm ................................21 Laboratory .............................................21 Preoperative workup ....................................22 Operative indications ..................................23 Screening for aneurysms ................................23 Rupture of abdominal aortic aneurysms ..................24 Results after aortic reconstruction ....................24 Cardiomyopathy (dilated) .................................25 Symptoms and signs .....................................25 Laboratory .............................................26 Causes .................................................27 Treatment ..............................................27 Myocardial infarction in the elderly .....................33 Beta blocker therapy ...................................33 Thrombolytic therapy ...................................34 PTCA and CABG ..........................................35 Anticoagulants .........................................35 ACE inhibitors .........................................36 Nitrates ...............................................36 Calcium channel blockers ...............................36 ASA ....................................................36 Flosequinan 175 ........................................37 Wolf-Parkinson-White syndrome ............................28 Orthodromic AV re-entrant tachycardia ..................29 Antidromic tachycardia .................................30 Atrial fibrillation and a wide QRS interval ............30 Chronic drug therapy for WPW ...........................32 2 EMERGENCY Adrenal insufficiency ..................................48 Causes .................................................48 Clinical diagnosis .....................................49 Laboratory .............................................50 Treatment ..............................................51 Ciguatara poisoning ......................................55 Clinical ...............................................56 Treatment ..............................................57 Clostridium myonecrosis .................................51 Clinical ...............................................54 Treatment ..............................................54 Hypertensive crisis ......................................41 Nitroprusside ..........................................41 Labetalol ..............................................42 Phentolamine ...........................................43 Enalaprilat ............................................44 Hydralazine ............................................44 Nitroglycerin .........................................45 Nifedipine .............................................45 Clonidine ..............................................46 Captopril ..............................................46 Minoxidil ..............................................47 Diazoxide ..............................................47 Trimethaphan camsylate .................................47 Poisoning ................................................37 Seizures ...............................................38 Investigations .........................................38 Antidotes ..............................................40 3 ENDOCRINOLOGY Cushing's syndrome .......................................69 Clinical ...............................................70 Testing in Cushing's syndrome ..........................71 Treatment ..............................................73 Gynecomastia .............................................57 Causes .................................................58 Laboratory .............................................59 Specific workup ........................................59 Treatment ..............................................60 Hirsutism ................................................73 Drugs causing hirsutism ................................76 Laboratory .............................................76 Treatment ..............................................78 Hypercalcemia ............................................65 Symptoms ...............................................66 Causes .................................................66 Treatment ..............................................66 Solitary thyroid nodule ..................................61 Treatment of malignant nodules .........................64 Treatment for indeterminate nodules ....................64 Treatment for cystic nodules ...........................65 Treatment for benign nodules ...........................65 4 GASTROENTEROLOGY Chronic active autoimmune hepatitis ......................97 Clinical ...............................................97 Laboratory .............................................100 Differential diagnosis .................................100 Course and prognosis ...................................102 Treatment ..............................................103 Diabetic diarrhea ........................................82 Causes .................................................82 Treatment ..............................................83 Hemochromatosis ..........................................79 Clinical ...............................................80 Laboratory .............................................80 Treatment ..............................................81 Ischemic colitis .........................................91 Clinical ...............................................92 Laboratory .............................................92 Treatment ..............................................93 Mesenteric ischemia ......................................88 Clinical ...............................................88 Laboratory .............................................89 Treatment ..............................................90 Primary biliary cirrhosis ................................84 Clinical ...............................................84 Complications ..........................................85 Laboratory .............................................85 Treatment ..............................................87 Spontaneous bacterial peritonitis ........................93 Clinical ...............................................94 Paracentesis ...........................................95 Diagnosis ..............................................96 Differential diagnosis .................................96 5 GYNECOLOGY Contraception - Newer Methods ............................111 Norplant ...............................................111 Depo-Provera ...........................................112 Post coital morning after protection ...................114 Hematologic disorders in pregnancy .......................103 Idiopathic thrombocytopenic purpura ....................103 Von Willebrands's disease ..............................105 Lupus anticoagulant ....................................106 Antithrombin III deficiency ............................106 Disseminated intravascular coagulation .................108 Abruptio placentae .....................................109 Fetal death syndrome ...................................109 Amniotic fluid embolus .................................110 Sepsis .................................................110 Preeclampsia and eclampsia .............................110 6 HEMATOLOGY & ONCOLOGY Carcinoma with unknown primary site ......................130 Multiple myeloma .........................................119 Clinical ...............................................119 Laboratory .............................................120 Treatment ..............................................122 Prognosis ..............................................123 Polycythemia vera ........................................115 Causes .................................................115 Laboratory .............................................116 Diagnosis ..............................................117 Symptoms and signs .....................................117 Complications ..........................................118 Treatment ..............................................118 Sickle cell anemia .......................................123 Laboratory .............................................126 Treatment ..............................................126 7 INFECTIOUS DISEASE Babesiosis ...............................................168 Clinical ...............................................169 Laboratory .............................................170 Treatment ..............................................171 Blastomycosis ............................................151 Pulmonary blastomycosis ................................152 Cutaneous blastomycosis ................................152 Osseous blastomycosis ..................................153 Genitourinary blastomycosis ............................153 Laboratory .............................................153 Treatment ..............................................154 Prognosis ..............................................155 Cat scratch disease ......................................171 Clinical ...............................................171 Laboratory .............................................172 Treatment ..............................................172 Coccidioidomycosis .......................................155 Pulmonary form .........................................156 Disseminated form ......................................156 Laboratory .............................................157 Treatment ..............................................158 Histoplasmosis ...........................................158 Acute pulmonary form ...................................159 Chronic cavitary form ..................................159 Disseminated form ......................................159 Laboratory .............................................160 Treatment ..............................................161 HIV and the lung .........................................161 Clinical ...............................................162 Laboratory .............................................163 Differential diagnosis .................................164 Treatment ..............................................165 Prophylaxis ............................................167 HIV and the CNS ..........................................134 Cryptococcal meningitis ................................134 Toxoplasmosis ..........................................135 CNS syphilis ...........................................136 HIV dementia ...........................................136 Cytomegalovirus encephalitis ...........................136 CNS lymphoma ...........................................137 Progressive multifocal leukoencephalopathy .............137 Kawasaki's disease .......................................145 Symptoms and signs .....................................146 Laboratory .............................................147 Differential diagnosis .................................148 Prognosis ..............................................148 Therapy ................................................148 Lyme disease .............................................137 Differential diagnosis .................................138 Treatment ..............................................140 Sporotrichosis ...........................................149 Clinical ...............................................149 Laboratory .............................................150 Treatment ..............................................150 Differential diagnosis .................................151 Toxic shock syndrome .....................................141 Criteria for diagnosis of Toxic Shock syndrome .........142 Differential diagnosis .................................143 Laboratory .............................................144 Prognosis ..............................................144 Complications ..........................................145 Treatment ..............................................145 8 NEPHROLOGY & UROLOGY Benign prostatic hypertrophy .............................173 Finasteride ............................................173 Terazosin ..............................................174 Doxazosin ..............................................175 Transurethral resection ................................176 Erectile dysfunction .....................................182 Endocrine causes .......................................182 Neuropathic causes .....................................182 Trauma and surgery .....................................182 Medication causes ......................................183 History and physical ...................................183 Laboratory .............................................184 Treatment ..............................................185 Nephrotic syndrome .......................................176 Signs and symptoms .....................................177 Laboratory .............................................177 Special laboratory tests ...............................178 Evaluation .............................................178 Primary diseases .......................................179 Secondary diseases .....................................179 Renal biopsy ...........................................179 Complications ..........................................180 Histology and disease ..................................180 Treatment (non-specific ) ..............................180 Specific therapy .......................................181 Urinary incontinence .....................................187 Urge incontinence (Detrusor instability) ...............188 Stress incontinence ....................................188 Overflow incontinence ..................................188 Functional incontinence ................................189 Laboratory .............................................189 Medications causing incontinence .......................190 Treatment ..............................................190 9 NEUROLOGY Cervical syndromes .......................................195 Clinical ...............................................196 Cervical radiculopathies ...............................197 Treatment of cervical radiculopathies ..................198 Cervical spondylotic myelopathies ......................199 Treatment of cervical spondylotic myelopathies .........199 Instability of the cervical spine ......................200 Stroke in the young ......................................193 Drugs causing strokes ..................................193 Carotid dissection .....................................193 Fibromuscular dysplasia ................................194 Other causes of strokes ................................194 10 ORTHOPEDIC MEDICINE Osteonecrosis ............................................200 Causes .................................................200 Clinical ...............................................201 Laboratory .............................................201 Treatment ..............................................201 Paget's disease of the bone ..............................201 Clinical ...............................................202 Laboratory .............................................203 Treatment ..............................................204 Summary of specific treatment ..........................206 11 PULMONARY MEDICINE Allergic bronchopulmonary aspergillosis ..................219 Clinical ...............................................219 Laboratory .............................................220 Diagnosis ..............................................221 Treatment ..............................................223 Invasive aspergillosis ...................................223 Clinical ...............................................224 Treatment ..............................................225 Pneumonia in the aged ....................................215 Clinical ...............................................215 Laboratory .............................................215 Types of pneumonia in the aged .........................216 Treatment of community acquired pneumonia ..............217 Specific pneumonias in the aged ........................218 Sarcoidosis ..............................................206 Clinical ...............................................208 Laboratory .............................................209 Treatment ..............................................210 Wegener's granulomatosis .................................211 Clinical ...............................................212 Laboratory .............................................213 Differential diagnosis .................................214 Treatment ..............................................214 12 RHEUMATOLOGY/IMMUNOLOGY Cryoglobulinemia .........................................232 Clinical ...............................................232 Laboratory .............................................234 Treatment ..............................................236 Leukocytoclastic vasculitis ..............................226 Causes .................................................226 Clinical ...............................................227 Laboratory .............................................227 Treatment ..............................................228 Systemic lupus erythematosus .............................236 Clinical ...............................................236 Laboratory .............................................237 Subsets of lupus .......................................238 Treatment ..............................................242 Vasculitis - An overview .................................228 Clinical ...............................................229 Laboratory .............................................231 Treatment ..............................................232 ~card.bin~ ■ ATRIAL FIBRILLATION ■ There are several causes of paroxysmal or chronic AF and include mitral valve disease, acute and chronic coronary disease, cardiomyopathy, hypertensive cardiovascular disease, chronic sinoatrial disease, hyperthyroidism (1%), pulmonary embolism (2.5%), alcohol, drugs as cocaine, caffeine, cholinergic stimulation and cardiothoracic surgery. The prevalence of AF is 2% in the general population and 5% in person >60 years old. « Control of ventricular response » May use IV digoxin, verapamil, diltiazem and esmolol. Digoxin will slow the rate in about 2 hours. Give 0.25 mg-.5 mg IV then 0.25 mg IV q4h up to 1-2 mg in the first 24 hours, then maintain with 0.125-0.375 mg po qd. Watch for AV block, ventricular arrhythmias, nausea, anorexia & yellow vision. Direct current cardioversion should be done if the AF is associated with CHF, hypotension and persistent ischemia. Diltiazem given as a bolus of 0.25 mg/kg IV over 2 min. Repeat if necessary after 15 min as 0.35 mg/kg over 2 min. This can be followed with maintenance of 5-15 mg/hr IV or 30-90 mg po qid. Watch for heart failure, bradycardia and hypotension. Don't use in pre-excitation syndromes or if mechanism of wide QRS is unknown. Reduction of ventricular response will occur in about 5 minutes and can last up to 10 hr after infusion is stopped. Verapamil can be used but its effect is short. Give 2.5-10 mg IV over 2 min then .005 mg/kg/min or 5-10 mg boluses every 30 minutes or 80-160 mg tid. Watch for bradycardia, hypotension, heart failure. Should not be used in pre-excitation syndromes. The digoxin level will increase. Esmolol could be used, but the effect is extremely short. Give 500 ug/kg IV over 1 minute, then 50 ug/kg IV for 4 min. If necessary may repeat the loading dose and increase the maintenance dose by 25-50 ug/kg/min q 10 min. Watch for hypotension, heart failure, bronchospasm, local irritation and use judiciously in renal failure. « Restoring sinus rhythm » For the acute situation use DC cardioversion or IV procainamide. For elective cardioversion use IV procainamide, quinidine, disopyramide, propafenone, flecainide, amiodarone, or sotalol. Not all patients need to be restored to sinus rhythm. One reason is that about 50% of patients restored to sinus rhythm and treated with Class 1A drugs, will revert to AF. If the patient has had AF for 2 years or more then it is unlikely that they will maintain sinus rhythm. If left atrial enlargement is present, then success is less likely. If patient has severe systolic or diastolic dysfunction, a dilated hypokinetic heart, severe ventricular hypertrophy, then they need the added atrial impetus afforded by sinus rhythm. Procainamide 10-15 mg/kg IV at 50 mg/min should be given. Observe for heart failure, hypotension and widening of the QRS. Up to 50% will convert with pharmacologic drugs. Quinidine 200-400 mg qid may be tried. Side effects include proarrhythmia, increased digoxin levels, nausea and diarrhea. Disopyramide 100-300 mg bid is another alternative. Be aware of anticholinergic effects, proarrhythmia, and heart failure. Flecanide 50-100 mg bid may be used if no contraindications. Side effects are heart failure and proarrhythmia. Propafenone 150-100 mg tid may be effective and the side effects are proarrhythmia and heart failure. Sotalol 80-320 mg bid is another possibility. Observe for heart failure, proarrhythmia and bradycardia. Propafenone and Sotalol have equal efficacy. Amiodarone 100-400 mg qd may be used but this drug has many side effects as bradycardia, hyper/hypo thyroidism, pulmonary and hepatic toxicity, nausea and as of this writing has NOT been approved for this indication. However, success rates of 60% have been reported in patients that were in resistant AF. DIRECT CURRENT CARDIOVERSION The longer the patient has had the AF the greater the energy required to convert. The smaller the left atria (<4.0 cm) and the more coarse the fibrillatory waves (>2mm), the less energy required. Start at 100 Joules. If unsuccessful increase to 200 J after a Class I agent as procainamide or quinidine has been given. This will result in restoration of 75% of patients. New studies have shown that if the serum digoxin level is therapeutic, and not toxic, then no need to withhold digoxin for 48-72 hours as previously done. If possible give warfarin for 3 weeks prior to conversion to avert embolization. « Decrease of embolic risk » For acute protection give IV heparin if AF is greater than 24 hours duration & warfarin for 3 weeks prior to cardioversion. For chronic protection of stroke, anticoagulate with warfarin. You can start warfarin at 5 mg daily and check PT 4-6 days later and monitor to keep the INR at 2.0-3.0. If mechanical valves are in place then keep INR at 2.5-3.5. In pregnancy warfarin should not be used in first trimester and preferably not during the entire duration of gestation. Heparin is the preferred agent. Warfarin doesn't cause an anticoagulant effect in nursing infants. There is some controversy for anticoagulation use in lone atrial fibrillation < 60 years of age and paroxysmal AF. ASA 325 mg daily will offer some protection if unable to anticoagulate with warfarin because of bleeding disorders, active peptic ulcer, alcoholism, gait disorders, severe renal or liver disease, previous hemorrhage, uncontrolled hypertension and non-compliance. « Maintenance of sinus rhythm » If patients are not maintained on antiarrhythmic drugs, only about 15-30% will remain in sinus rhythm 6 months after cardioversion. About 50-60% will stay in sinus rhythm for 1 year if quinidine is used post-conversion. Drugs in the Class 1A, 1C, or III may be used. « Wolff-Parkinson-White syndrome and Atrial fibrillation » This situation requires a special approach when there is rapid conduction over the accessory pathway which may lead to a fatal ventricular arrhythmias. Digoxin, verapamil or diltiazem should not be used because they preferentially suppress conduction over the AV node, and thus may speed conduction over the accessory pathway. Procainamide IV is the drug of choice as it slows conduction through the accessory pathway and will frequently reestablish sinus rhythm. If the patient is unstable, then DC cardioversion is in order. To prevent recurrences of AF, quinidine, procainamide, disopyramide, flecainide and propafenone may be used, as these drugs suppress antegrade travel over the accessory pathway and keep the patient in sinus rhythm. Also, for long term prevention of recurrences radiofrequency ablation of the accessory pathway by catheter is effective in over 90% of patients. If this fails, then surgical interruption can be done. ■ ATRIAL MYXOMA ■ « Clinical » Myxomas are the most common cardiac tumors and account for 25% of all tumors and cysts of the heart and pericardium. Myxomas have been reported in ages from 3 to 83, but the mean age is 56 years. Females are affected in a 3:1 ratio. About 86 percent involve the left atrium and they are attached by a stalk near the fossa ovalis. They are typically 6-8 cm in size and histology reveals myxoma, fibroblastic and endothelial cells in an acid mucopolysaccharide matrix. The right atrium is the next most common site, and rarely the ventricles. They are very friable and gelatinous and therefore can embolize very easily after battering against the mitral valve. They can contain calcium; especially right atrial myxomas. They protrude through the mitral valve during diastole. If they become entrapped in the mitral valve they can cause syncope. Symptoms can be more severe when standing or during exercise, and the murmurs can come and go depending on posture. Myxomas can become infected and cause a bacteremia which would make it difficult to distinguish from endocarditis, particularly if the attachment could not be visualized by echocardiogram and it was thought the mass was a vegetation of the mitral valve. The presenting symptoms can mimic mitral valve disease, primary pulmonary hypertension, connective tissue disease, CVA & endocarditis. Myxomas can simulate polymyositis and polyarteritis and systemic amyloidosis. About 7 percent have a family history of myxoma, or the syndrome myxoma, which can include primary nodular adrenocortical hyperplasia, myxomatous mammary fibroadenomas, testicular Sertoli cell tumors, pituitary adenomas with excessive growth hormone production, and pigmented cutaneous lesions. Right atrial myxomas can embolize to the lungs and so can left atrial myxomas if there is a left to right shunt. Left atrial tumors embolize peripherally and can be found in surgically removed embolus. Left atrial myxomas can cause CHF and hemoptysis (15%), murmurs of mitral stenosis, such as an increased first heart sound, diastolic murmur (70%), tumor plop (33%) which is similar to the opening snap of mitral stenosis, and mitral insufficiency due to damage to the mitral leaflets by the myxoma, producing a systolic murmur (50%). Syncope can occur. About 25% of patients have friction rubs. Patients can have weight loss (25%), fever (50%), arthralgias, fatigue, sweating, Raynaud's phenomenon, clubbing, and anemia, which can be hemolytic. Hemoptysis occurs in 15 percent of patients. « Laboratory » There is elevation of the ESR (33%); sometimes very high, leukocytosis, thrombocytopenia, thrombocytosis, and erythrocytosis. The EKG is usually normal but occasionally there may be p wave abnormalities. Usually there is sinus rhythm. The chest x-ray is usually normal as is the heart size. Suspect myxoma if the heart size normal and there is CHF. Right atrial myxomas show calcification on fluoroscopy. Transesophageal echocardiogram is the method of choice for diagnosis. There may be irregular echogenicity secondary to cysts in the tumor. Retrograde extension of the tumor into the pulmonary veins or invasion of ventricular or valvular tissue would suggest a carcinoma. CT and MRI are also of value in diagnosing myxoma. Embolized tumor recovered for histologic examination can show the myxoma origin. Blood cultures are negative. Hyperglobulinemia and IgG elevation are common. « Treatment » Treatment is surgical excision and the results are good with excellent long term survival and low recurrence. ■ ABDOMINAL AORTIC ANEURYSM ■ If a person has an abdominal aortic aneurysm and lives long enough rupture is inevitable. Studies with CT and ultrasonography have shown expansion rates of about 0.4 cm per year. However, large aneurysms expand faster than the smaller ones. With aneurysms less than 4.0 cm in diameter the risk of rupture is about 2 percent. About 25-41% of aneurysms greater than 5 cm will rupture within 5 years. « Laboratory » ABDOMINAL ULTRASONOGRAPHY Abdominal ultrasonography is about 100% sensitive, but depends on the technician's expertise. Advantages include the following: no contrast material is needed, longitudinal and transverse sections are available and reproducibility of size is fairly good. If the patient is obese and there is inordinate gas, this will preclude a good exam. The exam does not give accurate data for the surgeon, because it can't evaluate the proximal and distal aortic extent of the aneurysm. The visceral vessels are not evaluated either. However, despite these, US should be used for screening detection and sequential follow up. COMPUTERIZED TOMOGRAPHY CT is very specific and has a high sensitivity and may be more precise in estimating size than US. CT also gives data on the shape of the aneurysm and relation of visceral and renal vessels. Arguments against using CT includes the following: radiation and contrast has to be used, is more costly than US and is not as available as US. CT is not recommended as a screen or preoperative study. MAGNETIC RESONANCE IMAGING MRI is not used much because it is expensive, is contraindicated in patients with pacemakers and those patients that have clips, doesn't provide accurate associated occlusive arterial disease, and is not widely available. AORTOGRAPHY OR INTRA-ARTERIAL DIGITAL SUBTRACTION The use of these tests pre-operatively is controversial. Some surgeons use them and some don't. Mural thrombosis will give a false estimation of the diameter of the aneurysm. If supra-renal or juxta-renal aneurysm, mesenteric stenosis, associated iliofemoral arterial occlusive disease, renal arterial stenosis and hypertension are suspected, then aortography should be done pre-operatively. « Preoperative workup » Coronary artery disease is the main disease that must be corrected prior to repair of abdominal aortic aneurysm. About 35% of EARLY deaths after repair of the aneurysm can be attributed to myocardial infarction and 39% of deaths 5 years later can be due to coronary artery disease. In patients that have coronary artery clinically, coronary arteriography may or may not be done before myocardial revascularization. If patient has no symptoms of coronary artery disease then possibly stress ekg tests with or without thallium, and echocardiography may be done to determine status of heart. If the patient has < 50% of predicted FEV1, and vital capacity, this may interdict aortic reconstruction. Renal artery occlusive disease and creatinine elevations above 3 mg/dl must be addressed and corrected. Absolute contraindications to elective aortic reconstruction include intractable CHF and angina, myocardial infarction within the last 6 months, severe renal and pulmonary disease with dyspnea at rest, stroke patients that are severely impaired and a life expectancy of only about 2 years. « Operative Indications » As a general consensus, all asymtomatic aneurysms > 5 cm should have surgery. All ruptured and symptomatic abdominal aortic aneurysms should have surgery. Aneurysms between the 4-5 cm size is controversial, but occasionally the rupture rate may approach 6% per year in this group. If elective repair is indicated later for aneurysms between the 4-5 cm range, then US should be done every 6 months. If for some reason aneurysms > 5 cm do not come to surgery then these should be followed every 3 months via US. « Screening for Aneurysm » Screening may be cost effective if one selects out those patients that are susceptible to aneurysm. These would include patients between the ages of 55-80, hypertension, those that have associated aneurysms of popliteal or femoral area, and families that have a history of aneurysm. « Rupture of Abdominal Aortic Aneurysms » The overall mortality is 90%. About 50% who reach the hospital will survive. First, one must make the diagnosis, and this may not be clear. Differential would include diverticulitis, renal colic, and GI hemorrhage. Most textbooks give the triad of hypotension, abdominal pulsatile mass and back pain as the presentation. Most aneurysm rupture into the left retroperitoneum. However, the pain can be in the back, buttocks or testicular area, and the pain can be colicky. Rupture can occur into the bowel, peritoneal cavity, and vena cava. It has been shown that resuscitating the patient with fluids and raising the blood pressure before definitive surgery can result in loss of the retroperitoneal tamponade. Thus, these measures should be deferred until the rupture is controlled. « Results after Aortic Reconstruction » Excision and prosthetic dacron graft replacement is the standard approach. Mortality has steadily improved since the first successful aortic resection was carried out in Paris in 1951. The mortality has been reduced over the last 4 decades from about 20 to 4 percent, but these figures are tempered with many variables as condition of patient, etc. Early complications after elective surgery include: cardiac arrhythmia, ischemia and CHF (15%), pulmonary insufficiency (8%), renal damage (6%), distal thromboembolism (3%), bleeding (4%), wound infection (2%). Rare complications include paraplegia, stroke, ischemic colitis and sexual dysfunction. Late postoperative complications that usually occur 3-5 years after surgery include graft occlusion, infection, and aortic - enteric fistulae. ■ CARDIOMYOPATHY (Dilated) ■ Dilated cardiomyopathy was formerly known as congestive cardiomyopathy and is characterized by poor systolic function. The onset may occur at any age and afflicts men more often than women.The course is usually one of progressive deterioration with 75% dying within five years of onset of the symptoms. In those over age 55 most die within two years of symptom onset. « Symptoms and Signs » Symptoms and signs usually develop gradually and include dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue and in 25-50% of cases, chest pain. There also is an increased incidence of pulmonary emboli. Physical exam reveals moderate to severe cardiomegaly, S3 or S4 gallop, and a systolic murmur caused by mitral regurgitation, jugular venous distention and hepatic engorgement. There may be, in severe cases, pulsus alternans and a narrow pulse pressure secondary to decreased stroke volume. « Laboratory » CHEST X-RAY Cardiac enlargement is seen in the majority of cases and there are increased vascular markings in the upper lobes indicating elevated pulmonary venous pressure. There may be diffuse densities in the hilar areas and pleural effusions and curly B lines indicating engorged pulmonary lymphatics. EKG EKG may show sinus tachycardia, atrial and or ventricular dysrhythmias, non-specific ST-T abnormalities, intraventricular conduction defects, left ventricular strain pattern, left and right atrial enlargement and in ischemic cardiomyopathy evidence of previous myocardial infarctions. MUGA MUGA studies usually reveal a reduced left ventricular ejection fraction of less than 40%. ANGIOGRAPHY Angiography reveals a diffuse hypokinetic left ventricle, often with mitral regurgitation. Cardiac catheterization may help differentiate between ischemic and other types of cardiomyopathies. It can show intracavitary pressures, cardiac output, left ventricular function and coronary anatomy. Also, one can obtain pulmonary artery pressures and pulmonary vascular resistance. ECHOCARDIOGRAM Echocardiography shows 4 chamber cardiac dilatation, normal left ventricular wall thickness with global hypokinesis and abnormal diastolic mitral valve motion. OTHER LAB If patient is being considered for cardiac transplantation then CT of the chest and abdomen, 24 hour creatinine clearance, serologies for Toxoplasma, HIV, Cytomegalic inclusion virus and Epstein-Barr virus, hepatitis A,B,C serology, liver and renal function and dental x-rays. Endocardial biopsies may be indicated. « Causes » Toxins: such as alcohol, daunomycin, cobalt in beer and arsenic. Neurological causes: would include Refsum's disease, myotonic muscular dystrophy, limb girdle muscular dystrophy and Friedreich's ataxia. Collagen vascular causes: SLE, polyarteritis nodosa, endocardial fibroelastosis (occasionally seen in children due to a treatable inherited carnitine deficiency. Other causes: would include thyrotoxicosis, pheochromocytoma, homocystinuria, hypophosphatemia, beriberi, diabetes mellitus, peripartum, idiopathic (50% of which 20% are familial if relatives are tested) and ischemic. Infectious causes: especially coxsackie B in the USA, meningoocccal, diphtheria, mycoplasma, influenza, echovirus, yellow fever, mumps, polio, rubella, Chaga's disease, toxoplasmosis and other parasites, and HIV. « Treatment » Digoxin, furosemide, potassium chloride, ACE inhibitors, as captopril and enalapril, Isosorbide dinitrate, Hydralazine, continuous IV infusion of dobutamine, and cardiac transplantation which has a 75% 5 year survival. Digoxin has several drug interactions with antibiotics, quinidine, verapamil, cholestyramine and amiodarone. If the cardiomyopathy is due to alcohol then abstinence may halt the progression or even reverse the progression of alcoholic cardiomyopathy. Anticoagulation is recommended for all patients even in the absence of atrial fibrillation or a history of thromboembolic events. Warfarin is preferred with maintenance of the PT at 1.3- 1.5 times the control. Antiarrhythmic agents should be utilized only for symptomatic or serious dysrhythmias, since most of these have negative inotropic properties that will worsen the CHF and even induce proarrhythmias. Salt restriction and attention to electrolytes and magnesium are also important. ■ WOLFF-PARKINSON-WHITE SYNDROME ■ (WPW) In 1930, Dr Paul Dudley White, together with John Parkinson reported several similar cases of healthy young people prone to paroxysmal tachycardia. The resting EKG features include a short PR interval, delta wave (slurred upstroke at the beginning of the QRS) and a prolonged QRS interval (caused by the delta wave). WPW is the most common form of ventricular pre-excitation and is due to an accessory pathway of Kent. Sometimes, WPW is associated with hypertrophic cardiomyopathy and Ebsteins's anomaly. Approximately 50% of WPW patients will experience tachycardias that are associated with 3 main types of tachycardia as follows. « Orthodromic AV Re-Entrant Tachycardia » Orthodromic AV re-entrant tachycardia is the most common (about 95%). In this tachycardia the wave front travels down the AV node into the ventricles and retrogradely to the atrium by way of the Bundle of Kent. This results in a narrow QRS with rates between 160 and 220/minute. There is no pre-excitation or delta wave. The P waves follow the QRS very closely with the RP interval shorter than the PR interval. This type of tachycardia may be confused with the classic form of AV nodal re-entrant tachycardia, a circus movement within the AV node. This latter type of tachycardia will partially or completely hide the P wave. The treatment of orthodromic tachycardia consists of the Valsalva maneuver, facial immersion in ice cold water or sinus massage. These maneuvers will block the antegrade propagation. If these fail, then IV adenosine (Adenocard) 6 mg IV over 1-2 seconds followed by a saline flush is given. This may be repeated using 12 mg IV after 2-3 minutes up to a maximum of 30 mg. Also, Verapamil may also be used by giving 10 mg IV slowly which will block the AV node. Alternatively, Procainamide may be used by giving 15 mg/kg IV as a total loading dose. This is achieved by giving 20 mg/min. After the loading dose, an infusion may be given at 2-6 mg/min IV maintenance. The procainamide usually takes longer to work. Procainamide blocks the retrograde path. If verapamil or procainamide are used, watch for hypotension. « Antidromic Tachycardia » Antidromic tachycardia occurs in less than 5% of cases. In this type, the wave front travels down the accessory pathway to the ventricle and then back up the AV node. This leads to a wide QRS. There is a P wave preceding each QRS if not obscured by the wide QRS. If you have a previous EKG to compare with, you will find that the orientation and morphology of the WPW complexes resemble those during sinus rhythm. This will help to distinguish it from Ventricular tachycardia. Treatment of antidromic tachycardia in the hemodynamically stable patient is done by trying vagal maneuvers or IV adenosine as they may terminate the antidromic tachycardia, but have no effect on Ventricular tachycardia. If this fails, then give IV procainamide as for Orthodromic tachycardia. Also, you may use 2-3 boluses of 50 mg of LIdocaine over 15 minute periods followed by a 2-4 mg/min infusion. Both these drugs work by blocking the accessory pathway. If the patient is hemodynamically unstable, then DC cardioversion should be used. DO NOT USE IV VERAPAMIL OR DIGOXIN IN WIDE QRS TACHYCARDIAS. « Atrial Fibrillation and a Wide QRS Interval » In this type of wide QRS tachycardia, multiple wavepoints of depolarization in the atria bombard the AV node and the accessory pathway at rates up to 600/min. Because the AV node has a relatively long refractory period, it can only conduct a portion of these impulses and therefore can activate the ventricles at a slower rate of 100- 150, as opposed to the accessory pathway which can conduct beats to the ventricles between 200-400/min. The QRS is wide and must be differentiated from ventricular tachycardia. In atrial fibrillation the rhythm is regularly irregular as opposed to ventricular tachycardia. The Delta waves vary in size and there may be an occasional narrow QRS conducted through the AV node. Again, if a previous EKG is available, the complexes will resemble the WPW ekg that was in sinus rhythm, in orientation and morphologically. This type of tachycardia can lead to ventricular tachycardia and ventricular fibrillation and sudden death. Also, in the differential would be atrial fibrillation with ventricular aberration, but this usually presents as a classic right bundle branch block pattern and Ashman's phenomenon. Treatment of atrial fibrillation with WPW is with IV procainamide or Lidocaine which may slow accessory pathways, but in general, accessory pathways conducting at a high rate are not very susceptible when procainamide or lidocaine are used. Procainamide may also convert the atrial fibrillation to sinus rhythm. If the patient is hemodynamically unstable as hypotensive or dyspneic, then DC conversion is needed. Again, DO NOT USE VERAPAMIL OR DIGOXIN because these may accelerate the accessory pathways. In summary, if presented with a wide QRS tachycardia, first try the vagal maneuvers of carotid stimulation, Valsalva or facial immersion in ice water or IV Adenocard, keeping the thought in mind, that this may be an antidromic presentation of WPW. If it is, then you may get a conversion to sinus rhythm. However, if the rhythm is ventricular tachycardia then there will be no effect with Adenocard. If that is the case, proceed to Procainamide or Lidocaine. If these are ineffective, then proceed to DC cardioversion. Do not use verapamil or digoxin in wide QRS tachycardia. « Chronic Drug Therapy for WPW » If the patient has atrial fibrillation and WPW, the accessory pathway should be blocked with Class IA agents as quinidine, procainamide and disopyamide. Class 1C agents as flecainide, encainide and propafenone are all highly efficacious in blocking the accessory pathway. Flecainide can probably be used safely for WPW in patients with no other organic heart disease. Propafenone has a mild beta blocking effect that may be helpful in cases of catecholamine sensitive arrhythmias. Amiodarone, a Class III agent can suppress arrhythmias even in patients who have failed therapy with Class I agents. However, side effect of pulmonary fibrosis, hepatic toxicity, neurologic toxicity, photosensitivity and thyroid dysfunction are always a reason for consideration to have electrical physiologic studies performed, and then proceed to radiofrequency current ablation. Patients that have WPW and are in sinus rhythm, may be treated if they have symptomatic tachycardia, with digoxin and verapamil. Common errors occur in diagnosing WPW. Because the delta wave distorts the QRS pattern, the resting EKG of a patient who has WPW can be misread as simulating an old myocardial infarction or bundle branch block. Also, patients that have WPW have a high rate, of greater than 50%, false positive treadmill tests. If you miss the typical findings of WPW on an EKG and that patient has atrial fibrillation and is treated with digoxin or verapamil, there is increased risk of ventricular fibrillation. The risk for ventricular fibrillation is increased if the accessory AV pathway is < 270 milliseconds. One can clinically assess this accessory pathway by performing serial EKGs. If the WPW pattern is intermittent, the refractory period is likely to be long. An exercise test that causes the delta wave and short PR interval to disappear is associated with a long refractory period. If infusion of IV procainamide at 10 mg/kg over 5 minutes abolishes the pre-excitation pattern the refractory period is probably long. If any of these tests indicate a short refractory period, then the patient should be referred for electrophysiologic studies. ■ MYOCARDIAL INFARCTION IN THE ELDERLY ■ This topic will deal with the various therapeutic modalities that can be used in patients with myocardial infarction. Although the treatment is somewhat standardized in those patients under 75 years of age, the treatment of patients > 75 has been more tenuous, because of complications that can be incurred in this group. « Beta Blocker Therapy » The ISIS-1 showed a 22.7% reduction in mortality in older patients that were treated with atenolol. The Goteborg trial showed a 45% reduction with metoprolol. These studies for EARLY treatment in MI with beta blockade is much better for older than younger patients, who obtained no mortality benefit from beta blockers. Three pooled studies for LONG TERM reduction in mortality from beta blockers in the 65-75 year-old group have demonstrated a 40.1% reduction in mortality. The reduction for younger patients was only 28.3%. Also, diabetic patients that have MI will benefit from beta blockers. With the proven benefits in beta blockade then why isn't the therapy used more in older patients? There are several side effects that may not be tolerated in older patients, even though it is known that some patients in congestive heart failure may benefit from beta blockers. « Thrombolytic Therapy » Older patients can derive benefit from thrombolysis as much as younger patients. There is a slight rise in hemorrhage in the elderly, but overall, the benefits are greater in the elderly than in the young. In the ISIS-2 study, treatment with streptokinase accounted for a 15.7% reduction in mortality in those > 70. If the streptokinase was combined with ASA the mortality was reduced to 33.7%. There was a 41.2% reduction in those > 80 years of age when streptokinase was used. The GISSI study also demonstrated a reduction in mortality with streptokinase in the elderly that was greater than younger patients. Pooled data from the GISSI-1 study for patients 75 years and older AND the ISIS-2 study, for patients 80 years and older, showed a reduced mortality of 19.7. The ASSET and the AIMS trials showed similar survival with thrombolysis in the elderly. Only one study, the ISAM study, showed an increase in mortality of 35.4% in the elderly using thrombolysis. The pooled data from the above would indicate that thrombolysis decreased mortality from 8.4% to 6.2% in younger patients and a reduction in mortality from 20.7% to 17.2% in the elderly. « PTCA and CABG » The incidence of peri-infarction complications with emergency CABG is fairly high in the elderly with, strokes, infections, renal insufficiency and arrhythmias. Complications are more common in women. In spite of this, CABG may be used in preference to PTCA in some subsets of patients, because of increased tortuosity of the coronary vessels, multivessel disease and low ejection fractions. If there is one significant lesion seen with multi-vessel disease, then PTCA may be more appropriate. Emergency CABG has a very high morbidity and mortality in the elderly. It is much better, if feasible, to stabilize the elderly patient and then possibly proceed with coronary artery bypass grafting. « Anticoagulants » Since Heparin has been used with different thrombolytics and antiplatelet agents, and Heparin has been used both subcutaneously and intravenously, there is much ambiguity as to its utility in treatment of acute myocardial infarction. In the GUSTO trial the best results were seen in patients treated with accelerated t-PA and immediate and continuous IV heparin. Long term therapy with oral warfarin has yielded good benefits. In the Warfarin Re-infarction study, whose mean age was 62, mortality was reduced by 24%, reinfarction by 34% and cerebrovascular events by 55%. The question is whether these patients would have the same benefit with low dose oral aspirin. « ACE Inhibitors » It is well known that angiotensin II can constrict coronary arteries which will increase afterload. Without ACE inhibitors, the post MI heart can dilate, and become more ischemic because of the wall stress secondary to the increased afterload. The SAVE trial showed a significant reduction in post MI mortality with captopril. ACE inhibitors are useful for reducing post-infarction remodeling and subsequent heart failure. « Nitrates » Nitrates, in many trials, have shown benefit for decreasing ischemia and altering the hemodynamic response in patients with MI. They can be used to advantage, but one should be aware of possible hypotension in the aged. « Calcium Channel Blockers » Most studies indicate no clear benefit by using calcium channel blockers in MI patients. There have been 18 clinical studies where calcium channel blockers were used early and late in MI patients, and there was no decrease in mortality, infarctions, reinfarctions or infarct size. The main benefit for calcium channel blockers is in non-Q wave infarction patients, and in patients without impaired systolic or diastolic function. The Danish Verapamil infarction trial II study, however, showed decreased 16 month re-infarction and mortality in non-Q wave and Q wave MI patients. Patients were not taking beta blockers in this study that has obscured the results of other trials. « ASA » Using ASA in the elderly is associated with a higher incidence of side effects than the younger patient. Using low dose ASA has however, circumvented some of these side effects, yet still preventing thrombus formation. There was a decrease in mortality of 21% in the ISIS-2 study, and a decrease of non-fatal re-infarction of 44% when ASA was given at a dose of 160 mg/day for 30 days after MI. The RISC trial has shown that even reducing the ASA to 75 mgt/day resulted in a decreased rate of non-Q MI and unstable angina. « Flosequinan 175 » This is a new medication that is used in the management of heart failure. It is a once daily direct acting arterial-venous dilator that can be used in addition to digitalis, ACE inhibitors and diuretics. It should not be used in high doses because of adverse effects. ~emer.bin~ ■ POISONING ■ [Initial management] Provide airway, ventilation and vital signs. Protect yourself from organophosphate & carbamate insecticides and cyanide. If the patient is unconscious and convulsing, give Dextrose, and naloxone (2 mg in child or adult. If there is ingestion of propoxyphene, pentazocine or butorphanol then more than 2 mg may be required), and Oxygen. If the patient is alcoholic, give Thiamine 100 mg IV or IM before dextrose. If unable to give drug IV then may give atropine, epinephrine, lidocaine and naloxone through an endotracheal tube. Diazepam can be given rectally. « Seizures » If the seizures are due to theophylline then they may be refractory to usual therapeutic medications, and the patient may need general anesthesia. Seizures due to hypoglycemia must be treated immediately with glucose. Seizures due to isoniazid will respond to pyridoxine. Seizures related to anticholinergic agents may respond to physostigmine, if the usual anticonvulsants are not effective. Hemodialysis may be needed for seizures due to salicylates or lithium. Be aware that alcoholic withdrawal may cause seizures. Tricyclic seizures may need bicarbonate. « Investigations » EKG (for dysrhythmias or conduction defects from tricyclics). Chest x-ray (for aspirations & non cardiogenic pulmonary edema). Measure the anion gap and electrolytes (salicylates, methanol, ethylene glycol, carbon monoxide, toluene, cyanide, and hydrogen sulfide). Get serum osmolality & calculate the osmolality (2x sodium) + (glucose/18) + (BUN/2.8). The difference between these two is the osmolar gap. If more than 10 mOsm/liter then think methanol, ethylene glycol, or isopropanol poisoning. UA (for crystals of ethylene glycol) Qualitative drug screening of urine, serum & possibly gastric contents). Specific drug levels are useful in acetaminophen, anticonvulsants, digoxin, aspirin, ethanol, methanol, ethylene glycol, iron, isopropyl alcohol, lithium & theophylline overdoses. Contact the poison center. For salicylates & ethanol treat with urine alkalinization & hemodialysis. For methanol & ethylene glycol treat with hemodialysis. Breath analysis will reveal clues. Petroleum distillates have a characteristic odor, fruity odor (ketoacidosis & ketones of ethanol and isopropyl alcohol), almond odor (cyanide), garlic odor (arsenic or organophosphates), glue odor (chronic toluene abuse) and rotten egg odor (hydrogen sulfide or disulfiram). Do a physical exam to look for focal neurological signs (CVA, subdural hematoma), nuchal rigidity (meningitis), needle tracts (arms, feet, groin, under the tongue, neck, supraclavicular), drugs in the rectum, vagina & swallowed drug packets, and cardiac arrest (cocaine). Get family members to bring in prescription bottles and call the pharmacy to get a list of drugs. Search the clothing, home & garbage. Look for drug paraphernalia. « Antidotes » 1....Benzodiazepines [Flumazenil] 0.2 mg over 30 seconds. If ineffective after 30 seconds give .3 mg over 30 seconds. If no response after 30 seconds give .5 mg over 30 seconds at 1 minute intervals up to a total dose of 3 mg. Flumazenil should not be given if benzodiazepines are being given for convulsions or there is simultaneous ingestion of tricyclics. 2....Tricyclics antidepressants [Bicarbonate] 3....Digitalis [Digoxin specific antibody fragments] If the amount ingested and the serum digoxin concentration are both unknown then given 10-20 vials IV if there is a life threatening dysrhythmia. If the number of milligrams is known then divide that by 0.6 to ascertain the number of vials to give OR if the serum digoxin concentration is known, the number of vials = the digoxin concentration in ng/ml x 5.6 x weight in kg/600. 4....Opiates [Naloxone] Start at 2 mg IV. Less may be needed to prevent withdrawal symptoms. More may be needed if synthetic narcotics have been taken as propoxyphene, pentazocine & butorphanol. 5....Anticholinergic agents [Physostigmine] 1-2 mg IV over 5 minutes. May be useful to treat tachydysrhythmias or seizures. Should only be used for severe delirium. 6....Methanol, ethylene glycol [Ethanol] Give loading dose of 10 ml of 10% solution /kg of body weight. Maintenance dose 0.15 ml/kg/hr. If the patient is on dialysis, double the maintenance dose. Titrate to blood ethanol level of 100 mg/dl. 7....Calcium channel blockers, hydrofluoric acid, and fluorides [Calcium] 1 g calcium chloride given over 5 min by IV infusion with cardiac monitoring. Monitor the calcium level. 8....Organophosphate or carbamate insecticides [Atropine] Give an initial test dose of 2 mg IV. Repeat in larger doses until there is drying of pulmonary secretions. 9....Isoniazid, hydrazine, monomethylhydrazine in gyromitra species mushrooms [Pyridoxine]. If the amount of ingestion is unknown, start with 5 g IV. Overdose can cause neuropathy. If amount ingested is known then given gram per gram equivalent of pyridoxine. 10....Beta blockers [Glucagon] Start with 5-10 mg IV. Titrate to keep vital signs normal. May use maintenance dose of 2-10 mg/hr. ■ HYPERTENSIVE CRISIS ■ « Nitroprusside » Give 0.5-1.5 ug/kg/min to start with, then maintenance up to 10 ug/kg/min. Add 50 mg of reconstituted sodium nitroprusside to 250 ml of either 5% dextrose in water or normal saline. The solution should be covered with an aluminum foil or paper bag to protect it from light. Nitroprusside has its onset of action within 3-5 min. It acts directly on vascular smooth muscle producing mostly arterial, and to a lesser extent, venous dilation. The heart rate (HR), cardiac output (CO) and extracellular fluid (ECF) all may increase or have no change. There is a decrease of systemic resistance (SVR). The pulmonary capillary wedge pressure (PCWP) will decrease or have no change. There will be an increase of the plasma renin activity (PRA), and angiotension II (ANG II). SIDE EFFECTS Side effects are cyanide and thiocyanate toxicity. Clinical signs of thiocyanate toxicity include headache, nausea and vomiting, tremulousness, confusion, drowsiness, psychosis and coma. Deaths due to cyanide poisoning are extremely rare. If the patient is given an infusion of nitroprusside for more than 24 hours, serum thiocyanate levels should be done daily. Concentration > 10 mg/dL are associated with toxicity; > 20 mg/dL could be fatal. Always monitor the renal status as thiocyanate is excreted via the kidney. Oral antihypertensives should be started as soon as possible; usually when the diastolic reaches 100 mm Hg. If needed hemodialysis is used for treating thiocyanate toxicity. Nitroprusside is indicated for hypertension associated with CNS events, CHF, and aortic dissection and hypertensive encephalopathy. « Labetalol » Use 20 mg IV over 2 minutes to start with by bolus. If a response is not seen, then double the dose q 10 min to a total of 300 mg. Onset of action is in minutes and lasts for 4-6 hours. A labetalol infusion may be prepared by adding 200 mg of labetalol (40 mL) to 160 mL of either 5% dextrose in water or normal saline. The infusion rate is 0.5 mg/min. This is then titrated to obtain the desired blood pressure. In most cases, hypertension is under control when labetalol is given at a dose of 2 mg/min. Infusion rates up to 4 mg/min may be used. There is a decrease or no change in the HR and CO. There is a decrease of the SVR. The PCWP and ECF may either increase or have no change. There is a decrease in both the PRA and ANG II. Labetalol is a sympatholytic agent and is unique in that there is both post synaptic non-cardioselective Beta blockade and Alpha1 blockade. Since there is an oral form, the patient can be switched to oral labetalol after BP is controlled. SIDE EFFECTS There is a relative contraindication in patients with CHF, bradydysrhythmias, and bronchospastic lung disease. Watch for paradoxical hypertension that occasionally happens. Also, there may be orthostatic dizziness. Labetalol is useful in hypertensive encephalopathy, angina, renal failure, pheochromocytoma, antihypertensive withdrawal, and interactions between monamine oxidase inhibitors and drugs or food. « Phentolamine » Give a test dose of 1 mg IV over 2 minutes. If there is no marked hypotension then give 5-10 mg (.1-.2 mg/kg IV) over the next 4 minutes. It can be given every 5-15 minutes. Phentolamine is useful in hyperadrenergic states such as pheochromocytoma, but has a very short half life and the BP will start to rise again in 10 minutes, at which time the phentolamine can be given in intermittent boluses or a drip of 100 mg/hr. Because of a reflex tachycardia, a beta blocker should be used. « Enalaprilat (Vasotec) » Start with 1.25 mg (1 ml of a 2 ml vial) given over a 5 minute period. Increase to 5-10 mg as needed, then give q 6 hours. The peak effect usually is seen in 30 minutes, but may not be until 4 hours. Hypotension is very infrequent but can be treated with fluids. Diuretics will enhance the effect. Enalaprilat has no effect on the HR but does cause a decrease in the SVR, PCWP, and ECF. The CO is increased. The PRA is increased and the ANG II is decreased. Enalaprilat is excreted primarily by the kidneys. Enalaprilat is useful in CHF. « Hydralazine » The initial dose is 10-20 mg IV ever 20 minutes as needed or 10-50 mg IM (onset of action in 30 minutes) every 6 hours IM. The peak effect occurs at about 60 minutes. If hydralazine is used as a continuous infusion, 200 mg of drug is added to 1 liter of 5% dextrose in water or normal saline, and infused at 0.2 mg/min initially, and subsequently titrated. The onset of action by continuous infusion occurs within 10 to 20 minutes. Peak effect is seen at 20-40 minutes with continuous infusion. Hydralazine should not be used in myocardial ischemia. It is most useful in pre-eclampsia and eclampsia. Hydralazine is a direct acting arterial vasodilator. It exerts little effect on the venous system. Reflex tachycardia, increased myocardial oxygen consumption and increased cardiac output are the major effects. There is a decreased SVR and increase in PCWP and ECF. The PRA and ANG II are both increased. Hydralazine is metabolized primarily by the liver by acetylation. Some patients, genetically, are rapid acetylators and metabolize hydralazine rapidly, and therefore a more frequent dosing schedule may be needed. SIDE EFFECTS Side effects include headache, palpitations, orthostatic dizziness and edema. There may be exacerbation of angina. Drug induced lupus erythematosus occurs rarely with parenteral administration and much more commonly with oral hydralazine. In this syndrome there may be rash, fever, arthralgias, arthritis, serositis, elevated sedimentation rate and antinuclear antibodies. « Nitroglycerin » Nitroglycerin is given as an infusion of 5-100 ug/min by adding 50 mg/250 ml of 5% dextrose and water and then titrating to desired BP. Can give up to 300ug/min. Nitroglycerin is useful in myocardial infarction, pulmonary edema, and unstable angina. « Nifedipine » Can be given as 10 mg, and then biting and swallowing or sublingually. The peak effect is seen in 30-45 minutes. Nifedipine should be avoided in unstable angina or evolving MI as it may lower perfusion pressure. Nifedipine maintains or increases the cerebral blood flow. Nifedipine causes an increase or no effect in the cardiac output, and conduction in the sinoatrial node and atrioventricular node. There is an increase in the HR and coronary blood flow. There is a decrease or no change of myocardial contractility. There is a fairly marked decreased in PVR and an increase in sodium retention. There is a lack of a predictable response to nifedipine. The duration of response is 2-6 hours. « Clonidine » Clonidine is given initially as .1-.2 mg orally followed by .1 mg/hr to a total dose of 0.6 - 0.7 mg over 6-7 hours. The onset of action is at 30-60 min and peaks at 2-4 hours. It does not cause reflex tachycardia and can be used in CHF and myocardial ischemia. It can be useful in hyperadrenergic states as cocaine toxicity, clonidine withdrawal, MAO inhibitors with tyramine ingestion and phenylpropanolamine. The major disadvantage is sedation. Therefore, it shouldn't be used in hypertensive encephalopathy, stroke, or subarachnoid hemorrhage. It can cause significant bradycardia and rebound hypertension if stopped abruptly. « Captopril » Give as a 25 mg tablet and onset will occur in 15 minutes and peak in 2-3 hours. There may be a precipitous drop if used in patients with CHF, scleroderma crisis, renovascular disease and those on diuretics and vasodilators. Lisinopril and enalapril have slower onsets and shouldn't be used when a rapid reduction is needed. It doesn't cause reflex tachycardia or salt retention. It will maintain cerebral blood flow. It is useful in malignant hypertension, CHF, renovascular and cerebrovascular disease. There is an increase in the CO and PRA and a decrease in SVR, PCWP, ECF and ANG II. Side effects are rash, agranulocytosis, and angioedema. « Minoxidil » The initial dose is 5 mg with a repeat dose in 6 hours if needed. It should be used with a beta blocker and diuretic. It doesn't cause a rapid decrease in blood pressure and should not be used with CHF, myocardial ischemia or pheochromocytoma because of the reflex tachycardia. « Diazoxide » Diazoxide can be given at 50-150 mg (1-2 mg/kg) IV over a 5-10 second period, and can be repeated every 10-15 minutes as needed, or can be given as a 7.5-30 mg/min IV infusion. Diazoxide acts directly on vascular smooth muscle. There is an increase of HR, CO, PCWP, ECF, PRA and ANG II. There is a decrease in SVR. There is onset of action within 5 minutes and a peak effect within 3-5 minutes if given as an IV bolus. The duration of effect ranges from 4-12 hours. SIDE EFFECTS The most serious effect is prolonged hypotension. This occurs less frequently when mini boluses are given rather than the full 300 mg given as a bolus. There may be palpitations and tachyarrhythmias and peripheral edema. It may produce hyperglycemia by inhibiting Beta islet cell function. If extravasation occurs there may be superficial thrombophlebitis, cellulitis and necrosis as diazoxide is very alkaline. « Trimethaphan Camsylate » Trimethaphan can be started as a .3 -.5 mg/min IV infusion by adding 500 mg in 500 ml of 5% dextrose in water and then titrating to the desired level. In most patients the hypertension is controlled by giving 1-4 mg/min. Trimethaphan is a ganglionic blocking agent and will decrease the HR, CO, SVR, PCWP and increase the ECF. SIDE EFFECTS Trimethaphan can cause postural hypotension and patients should be kept at bed rest and may be placed in a 15 degree reverse Trendelenburg position to optimize the hypotensive effect. Other side effects include adynamic ileus, urinary retention and mydriasis. In very high doses of greater than 5 mg/min trimethaphan may produce neuromuscular blockade with resultant respiratory muscle paralysis. If the drug is used for more than 3 days tachyphylaxis may be induced. ■ ADRENOCORTICAL INSUFFICIENCY ■ Adrenal insufficiency (AI) can be a medical emergency and the failure to recognize it could have catastrophic consequences. The incidence of AI may be rising with AIDS and the increasing use of steroids. « Causes » The causes can be divided into two categories: primary adrenal disease and secondary. PRIMARY can be caused by the following: Granulomatous disease (TB, Histoplasmosis and other fungal infections, and sarcoidosis), Neoplastic infiltration, Amyloidosis, Hemochromatosis, Drugs (ketoconazole, mifepristone, anticoagulants), meningococcemia with Friderichsen-Waterhouse syndrome, adrenal hemorrhage, adrenoleukodystrophy in boys, autoimmune adrenalitis, and acquired immunodeficiency syndrome. SECONDARY hypothalamic and or pituitary disorders can be caused by pituitary and hypothalamic tumors, lymphocytic hypophysitis, and withdrawal from glucocorticoid therapy. Idiopathic autoimmune adrenalitis is the most common cause accounting for 80% of adrenocortical insufficiency. There are several endocrine disorders associated with this disease: (diabetes mellitus, thyrotoxicosis, thyroiditis, alopecia, vitiligo, myasthenia gravis, hypoparathyroidism, pernicious anemia, ovarian failure, hypercalcemia, chronic moniliasis, and Schmidt's syndrome). Several antibodies are often found as; gastric antibodies (20%), parathyroid antibodies (20%), adrenal antibodies (60%) and thyroid antibodies (40%). Metastatic disease involves the adrenal glands in 25% of oncologic patients. Ninety percent of the adrenal gland has to be destroyed before a patient is symptomatic. Most cancer patients don't have this amount of involvement. AIDS can cause adrenocortical insufficiency by infiltration with Mycobacterium avium-intracellulare, Cytomegalovirus, Kaposi's sarcoma, and Cryptococcus. Ketoconazole can also cause AI. « Clinical Diagnosis » Weakness and fatigue are the most frequent findings (94%) followed by the following in decreasing frequency: Skin hyperpigmentation manifested as tanning, freckles, vitiligo, blue-black discolorations of the areolas and mucous membranes (91%), Anorexia and weight loss (88%), Postural hypotension (81%), Hyponatremia (67%), Nausea and vomiting (66%), Hyperkalemia (55%), Azotemia (52%), Diarrhea and abdominal pain (23%) and hypoglycemia (19%. Dermal hyperpigmentation is seen in primary adrenocortical insufficency, but is not seen in secondary insufficiency. Look especially at the palmar creases and in scars where there is increased pigmentation. The entire body can be affected but look especially at the face, neck, upper extremities, scrotum, penis, axillary areas and the periumbilical area. Dilutional hyponatremia is more common in secondary insufficency than primary. It is caused by increased arginine vasopressin secretion and reduced free water elimination by the kidneys. Hyperkalemia only occurs in primary adrenocortical insufficiency because of the aldosterone deficiency. « Laboratory » RAPID ACTH TEST- Give cosyntropin 250 ug IV and measure plasma cortisol and aldosterone levels at baseline and after 30 min. The normal response at 30 min should be an increase of > 7 ug/dL of cortisol and aldosterone OR double the baseline value OR an absolute value of 20 ug/dL of cortisol and aldosterone. In primary AI there is a decreased cortisol and aldosterone level. In secondary, there is a decreased cortisol level and increased aldosterone level. PLASMA ACTH- Measure the ACTH at baseline before the rapid ACTH test is done. The normal diurnal plasma ACTH level is 0-70 pg/ml. In primary AI there is increased ACTH level and in secondary AI there is decreased ACTH levels. If you suspect acute adrenal insufficiency, baseline levels of cortisol, aldosterone and ACTH should be done along with routine blood chemistries. Give 5% dextrose in normal saline, about 2 liters in the first 6 hours. Give dexamethasone, 4 mg IV initially then 4 mg every 6 hours. Next, for diagnosis, give cosyntropin, 250 ug IV and determine the plasma cortisol after 30 minutes. Investigate the possible causes, get TB skin test and cultures and MRI of the adrenals. « Treatment » Give 20 to 30 mg of hydrocortisone daily, 2/3 in the early AM and the remainder in the early afternoon. If there is primary insufficency give .05 to .3 mg of fludrocortisone daily to maintain fluid and electrolyte balance. Before surgery and major stress give hydrocortisone 100 mg IV followed by 10 mg/hour during the procedure and postoperatively give 100 mg of hydrocortisone every 8 hours until the patient is stable; then taper the dose over 3-5 days. ■ CLOSTRIDIUM MYONECROSIS ■ Clostridium myonecrosis can be divided into two categories. The FIRST CATEGORY is related to the traumatic contamination of tissue with clostridium spores. This type of myonecrosis is secondary to septic abortion, penetrating wounds, open fractures, and colon and biliary surgery. In one series, compound fractures, gastrointestinal trauma and criminal abortions accounted for 50% of cases of Clostridial myonecrosis. Surgical procedures accounted for 34% and 16 percent were probably spontaneous. The traumatic category is usually caused by Clostridium perfringens. The disease course can be extremely swift, culminating in death if intervention does not ensue. Other organisms that are capable of producing aggressive infection are Streptococcus pneumoniae, Strep pyogenes, and Neisseria. Less frequent causes are gram negative enteric bacilli and Staphylococcus aureus. If the patient is asplenic, Capnocytophaga canimorsus can also cause an explosive infection. Organisms that can cause gas production include Clostridia, facultative gram negative enteric bacilli, beta hemolytic streptococci, Staphylococcal aureus and several anaerobic organisms. Gas formation is common in diabetic patients. The SECOND CATEGORY of Clostridial myonecrosis is that which arises spontaneously or atraumatically. It is usually caused by Clostridium septicum, but Clostridium perfringens may be the causative agent. Clostridium septicum is more aerotolerant than C. perfringens which allows it to survive better than C. perfringens. The inoculum required to initiate an infection is usually lower with C. septicum. There is a significant association of this organism with cancer of the gastrointestinal tract or a hematologic malignancy, diabetes mellitus and acyclic neutropenia. Most of the hematologic malignancies are not occult, but readily apparent. The cancer of the GI tract is usually localized in the distal ileum and cecum. Necrosis of the tumor is an important factor needed for Clostridia to initiate an infection. Chemotherapeutic agents and neutropenia are additional factors that may be operative in causing mucosal ulceration and neutropenia which then sets the stage for the myonecrosis. The increased incidence in diabetic patients may be explained by accompanying vascular disease, which triggers devitalization and necrosis. Carriage rates for Clostridium septicum in the feces is only 2 percent of human beings, but the appendix carrier rate is much higher, ranging from 10-63 percent. It is interesting to note that one other organism, Strep bovis, has been associated with carcinomas of the colon. This usually occurs in the setting of bacterial endocarditis. The death rate for spontaneous clostridial myonecrosis is higher than for other clostridial infections. Clostridia species are ubiquitous. They can be found in the feces, vagina and skin of humans and are widespread in the soil.The most common organism in human feces is C. ramosum and then C. perfringens. They are obligate anaerobes, but some species such as C. septicum, C. histolyticum, C. tertium and C. perfringes are aerotolerant and can live for years as spores. Clostridia can grow with amazing speed with the generation time of C. perfringes as short as eight minutes. Clostridium perfringes, C. septicum and C. novyi can produce toxins and proteolytic enzymes which can cause local and systemic injury, and because of this are the most virulent. Clostridium histolyticum and C. bifermentans cause more of a bland infection as they produce only proteolytic enzymes. « Clinical » The onset is sudden with hypotension, tachycardia, and fever. Terminally there is stupor, delirium, prostration and coma. The wound is swollen with surrounding skin that is pale. There is a foul smelling brown, blood tinged discharge. Later, there is formation of reddish bullae. Gas may be felt in the tissues. Hemolysis and jaundice may be present and later, acute renal failure and DIC may develop. A rapid diagnosis can be made by the gram stain which will yield gram positive rods with a paucity of neutrophils. Anaerobic culture will confirm the diagnosis. X-rays may show the gas. « Treatment » The patient should be treated aggressively with volume replacement, early surgical debridement of devitalized tissue until healthy, bleeding tissue is seen. Fasciotomy may be required and surgical reinspection is often done in 24 hours. The best combination of antibiotics is not known. A reasonable approach would be to start with IV penicillin G 12 million units in divided doses daily, Gentamicin or Tobramycin 1.5 mg/kg every 8 hours and Clindamycin 600 mg every 6 hours. Serum levels of aminoglycosides must be followed to avert toxicity and ensure that the Gentamicin is effective. Hyperbaric oxygen might be beneficial in gas gangrene. Oxygen is bactericidal on most species of clostridia and is required for killing by neutrophils. (a tissue partial pressure of oxygen of 30 mm Hg is needed for normal function of neutrophils). The partial pressure in tissues can be lower than this in infected tissues. If a partial pressure of 250 mm Hg can be achieved, then there is inhibition of alpha toxin which is elaborated by Clostridium perfringens. There is data from uncontrolled case series that have shown a reduction in the rate of spread, mortality and edema when hyperbaric oxygen was incorporated into therapy with antibiotics and surgery. ■ CIGUATERA FISH POISONING ■ Many patients with Ciguatera fish poisoning that seek medical attention from symptoms of gastroenteritis are missed. A patient that presents with nausea, vomiting, diarrhea, diaphoresis and numbness and tingling, particularly around the mouth, may be mis-diagnosed as hyperventilation syndrome plus viral gastroenteritis. Key points to differentiate Ciguatera fish poisoning from the garden variety gastroenteritis are: Ciguatera fish poisoning produces a phenomenon known as sensory reversal dysesthesia, whereby a patient perceives cold objects as warm and vice versa. The second key point is that alcohol will produce a return of the symptoms or a worsening of the symptoms. The third point is that Ciguatera fish poisoning will last for about 1-2 weeks and about 50% of patients will still have symptoms at 2 months. The neurologic symptoms persist much longer than the gastrointestinal symptoms. Ciguatera poisoning is contracted by eating fish that harbor the single cell toxic producing parasite, Ganbierdiscus toxicus. There are more than 400 fish species that live around coral reefs and harbor the parasite. Ganbierdiscus toxicus attaches itself to marine algae, and small fish will eat the algae. Larger fish will eat the smaller fish and thus a poisoning chain is set up. In particular, grouper, red snapper, amberjack, barracuda, sturgeon fish, jack tuna, sea bass, moray eels and king mackerel are the common fish involved with this infestation. The larger the fish, the larger the concentration of the poisonous toxin, and the greater the magnitude of the symptoms. Fish under 5 pounds are relatively safer to eat than those over 25 pounds. Ciguatoxin cannot be deactivated by cooking, freezing, drying, smoking, marinating, salting, or pickling, and gastric enzymes and acids will not inactivate it. The toxin is tasteless and odorless. The toxin doesn't cause any ill affects in the fish, even though there are high concentration in the viscera such as the gonads and liver. Florida and Hawaii are common states that have a higher incidence, but with modern transportation any state can be affected. Ciguatera fish poisoning is endemic in tropical regions as the Caribbean and the Indo-Pacific islands. « Clinical » Approximately 2-24 hours after ingesting the affected fish, nausea, vomiting, watery diarrhea, abdominal cramps, myalgias and diaphoresis will begin. The abdominal symptoms usually last about 3 days but can be longer. Eighty percent of patients will develop paresthesias of the extremities, numbness and tingling around the mouth and hot and cold reversal as mentioned above. The patient may also have dizziness, ataxia, pruritus, facial pain, rash, tremors, nuchal rigidity, and rarely audio and visual perturbations, confusion and coma. « Treatment » Treatment is mainly supportive with IV fluids and electrolyte replacement. The pruritus may be managed with terfenadine 60 mg bid. Amitriptyline, 25 mg bid may help the pruritus and the dysesthesias. Mannitol 20%, 1 gram/kg given over 30 minutes may help in the severe cases. The patient should be told to avoid alcohol and further fish ingestion. ~endo.bin~ ■ GYNECOMASTIA ■ Gynecomastia is a benign enlargement of the male breast but can coexist with numerous other conditions. Initially, there is ductal proliferation with epithelial hyperplasia and an increase in the periductal connective and stromal tissue. Later, after about 1 year, there is stromal hyalinization and less epithelial proliferation. The breast enlargement can be unilateral, bilateral, painless or painful. Differentiation from fatty breast tissue is made by the presence of a disc like mass underneath the breast. Gynecomastia occurs at 3 times during the life of man. In 60-90% of cases, neonatally, there is transient enlargement due to transplacental transfer of estrogens. During puberty, with a peak at 13-14 years of age, there is enlargement. The last peak is between 50-80 years of age. « Causes » Hematomas, dermoid cysts, lipomas, lymphangiomas, neurofibromas are uncommon causes. Male breast cancer needs to be ruled out, which presents usually as an eccentric unilateral, hard mass that is fixed. It can be associated with retraction, crusting or nipple discharge, dimpling and axillary lymph nodes. Other causes include hyperthyroidism, liver disease, primary and secondary hypogonadism, ectopic production of human chorionic gonadotropin from kidney, lung and liver. Additional causes include testicular tumors ( Leydig cell, Sertoli cell and germ cell), adrenal adenomas or carcinomas, starvation, kidney disease and dialysis, idiopathic, Klinefelter's syndrome (In Klinefelter's there is an increase risk of breast cancer 16 times higher than normal men.) The following drugs can cause gynecomastia: verapamil, nifedipine, enalapril, captopril, amiodarone, digitoxin, methyldopa, reserpine, diazepam, phenothiazines, tricyclic antidepressants, haloperidol, alcohol, amphetamines, marijuana, heroin, penicillamine, phenytoin, ranitidine, cimetidine, omeprazole, metronidazole, ketoconazole, isoniazid, cyproterone, flutamide, estrogens and estrogen agonists, chorionic gonadotropin, androgens and anabolic steroids, amphetamines, cytotoxic drugs, isoniazid and spironolactone. « Lab « All of the following tests may be done depending upon the circumstances: Serum chorionic gonadotropin, testosterone, estradiol, luteinizing hormone, mammography, fine needle biopsy of the breast, surgical biopsy of the breast, prolactin, liver and thyroid function, chromosomal analysis, chest x-ray, CT of chest and abdomen, testicular ultrasound, and CT of the pituitary. During puberty, workup should be limited and dictates palpation of the testes and history and physical and follow-up. The gynecomastia usually resolves in a year or so. In adults, get history of alcohol, drugs, chest symptoms to rule out cancer, testes hypofunction (decreased libido and impotence), symptoms of thyrotoxicosis, liver and kidney function. If these are all negative then recheck in about 6 months. If suspicious, proceed to other lab tests listed above. If a drug is suspected, remove the drug and re-evaluate in one month at which time there should be less pain. « Specific Workup » Measure serum hCG, LH, Testosterone, Estradiol. If hCG is elevated, get ultrasound of testes and if this is positive, rule out germ cell tumor. If normal, rule out an extragonadal germ cell hCG secreting non-trophoblastic tumor and proceed with a CT of chest and abdomen. If LH is increased and testosterone decreased, rule out primary hypogonadism. If LH is decreased or normal and testosterone is decreased, measure the serum prolactin and if elevated there is a chance of a prolactin secreting pituitary tumor which would trigger a CT or MRI of the pituitary. If the prolactin is normal, then rule out secondary hypogonadism. If both LH and testosterone are elevated, get T4 and TSH. If there is increase of T4 and decrease of TSH, hyperthyroidism is likely. If T4 and TSH are both normal there is probable androgen resistance. If estradiol is increased and there is a normal LH, perform testicular ultrasound. If a mass is seen then there could be a Leydig or Sertoli cell tumor. If ultrasound is normal, get an adrenal CT or MRI. If mass is seen then probable adrenal neoplasm. If normal there may be increased extraglandular aromatase activity causing the gynecomastia. « Treatment » The underlying disorder should be corrected. Discontinue drugs that may be causing the gynecomastia. Give reassurance for benign disorders. Cosmetic surgery. If prostatic cancer is present and, patients are to receive estrogens for treatment, then low dose radiation may be given prophylactically. Tamoxifen 10 mg bid may be given a 3 month trial. Side effects are low and Tamoxifen seems to be safe. There may not be complete regression, but an 80% complete response has been noted. Other drugs that have been used, but are not as effective, include Clomiphene, Danazol and Testolactone. ■ SOLITARY THYROID NODULE ■ Benign nodules consist of colloid (adenomatous) nodules that may present as a dominant nodule but with scanning, ultrasound and surgery they are in reality multinodular. Most of these are hypofunctioning by scan, but some may be hyperfunctioning. The cytology reveals colloid and benign follicular cells, but some are hemorrhagic nodules. On the other hand, the second type of benign tumor (follicular adenomas) are usually single lesions with well a defined capsule. Malignant nodules consist of papillary tumors which are very cellular with large nuclei and a pale ground glass appearance. Medullary , anaplastic and lymphomas are the other types of malignant tumors. The annual incidence of thyroid nodules in the USA is .1%. The main concern is that the nodule may be malignant but only a small number are malignant. Even if you can only feel one nodule, there may be others, and this may not represent a solitary nodule, but indeed a multinodular goiter which is only rarely malignant. Seek out key questions, as the younger the patient, the more the probability that the nodule will be malignant (The incidence of cancer in surgically excised solitary nodules ranges from 14- 61%). The risk of malignancy is increased if the patient is male and the nodule has been growing. Check for the hardness of the nodule and if there is any associated lymphadenopathy. Prior radiation, particularly a high dose in a young patient, increases the chance for cancer. Radiation will also, however, increase benign nodules. Check thyroid function with TSH, T3, T4 to see if there is a hyperfunctioning nodule which is uncommon. These hyperfunctioning nodules are hot autonomous nodules that suppress TSH. Hot nodules are not malignant very often. Other tests that can be done include thyroid scans, ultrasound exam and fine needle aspiration. Radioiodine 131 or 123 is preferable to the technetium scan, but in fact Technetium is used more often. Radionuclide scans are useful mainly for identifying hyperfunctioning nodules in patients with indeterminate or suspicious biopsy who don't have thyrotoxicosis. About 85% of nodules are cold and 10% warm and 5% hot. Most malignant solitary nodules are cold (15%), but in general, most cold nodules will turn out to be benign. Hot nodules are rarely malignant (1%). About 9% of warm nodules are cancerous. Ultrasonography of the thyroid can detect 2-3 mm nodules, but can only determine whether they are solid or cystic. About 70% of thyroid nodules are solid and 30% cystic or mixed. About 20% of the solid tumors turn out to be malignant and 10 % of the mixed. Therefore, US doesn't add that much at a cost of about $250.00 per exam. US is sometimes useful for following proven benign nodules for an increase in size. In recent years, it has been found that suppression of TSH with thyroid hormone, and then observing the gland for resolution of the nodule or growth is not reliable. In the past, it has been thought that if the nodule was benign, the nodule would shrink, and if there was no change in size or growth, then the nodule was malignant. Now it is known that malignant nodules may regress, and some benign tumors may not decrease in size. Fine needle aspiration is the most important procedure to be done. The cost of about $150.00-$200.00 is well worth the information that it provides. The accuracy of the biopsy (if an experienced cytopathologist interprets the slide) is 95 %. About 80-90% of fine needle aspirations are diagnostic and about 20% are suspicious. The procedure is very simple with low rates of complication and can be done without anesthesia in the office. A 25 gauge needle is used and the aspirated material is smeared on a glass slide and fixed in 95% ethyl alcohol and then Pap stained. The most important aspect of this is the interpretation by an experienced cytologist. The pathologist will then render the report in 3 categories: benign, malignant or suspicious. If malignant, this could represent metastasis rather than primary (papillary, medullary and anaplastic). Benign tumors include cysts, thyroiditis and colloid nodules. Suspicious tumors that give the cytologist difficulty are follicular and Hurthle tumors. If there is a paucity of cells recovered, then another biopsy may be needed. If the report returns as suspicious then surgical excision may be indicated or an ultrasound may be done. If a cold nodule is identified at US, then surgery is indicated. « Treatment of Malignant Nodules » Some surgeons will treat small papillary cancers < 1.5 to 2.0 cm isolated to one thyroid lobe with lobectomy and isthmectomy. Others would do a near total thyroidectomy. Large tumors or those that are multicentric, or metastatic to lymph nodes, should be treated with total or near total thyroidectomy. After the thyroidectomy the patient returns in about 2 months when the TSH should be above 35 mlU and the T4 around 1-2 ug/dl, and receives a radioiodine scan to ascertain if there is any residual thyroid tissue. If some is found then radioiodine ablation is carried out. If none is found then the patient has had a total thyroidectomy and the patient is placed on suppressive levothyroxine doses to suppress the TSH and a T4 in the high normal range. About 6 months following surgery the thyroid is discontinued, and when the patient is hypothyroid a whole body radioiodine scan is performed. If the scan is negative the levothyroxine is once again started for life. The TSH is kept at around 0.5 uU per milliliter (normal, .5-5). If the malignant tumor was metastatic or locally invasive, not completely removed or ablated by postoperative radioiodine, then the TSH should be kept in the subnormal range. « Treatment for Indeterminate Nodules » Surgery is probably the best approach, but the extent of removal is controversial. Total thyroidectomy isn't usually done. « Treatment for Cystic Nodules » 50% of cystic nodules will disappear permanently after one or more aspirations. However, those that recur are usually > 4 cm, and moreover, aspiration of these often yield blood and cannot be examined cytologically. These should be surgically removed. Thyroid therapy does nothing to suppress a cyst. « Treatment of Benign Nodules » Most of these are just followed by observation. Some would use thyroid suppressive therapy. In particular children who have had radiation for benign conditions might benefit, as there has been a 4.5 times higher incidence of recurrence when thyroid wasn't used. ■ HYPERCALCEMIA ■ This article will deal with the acute treatment of hypercalcemia (HC). HC is most commonly caused by cancer and primary hypoparathyroidism. In cancer patients the parathyroid hormone is low, and in primary hyperparathyroidism the parathyroid is high. Hypercalcemia in cancer patients and primary hyperparathyroidism is due to parathyroid-like hormone and parathyroid hormone, respectively ,which stimulates osteoclast reabsorption of bone. Also, these two hormones stimulate renal tubular reabsorption of calcium which further elevates the calcium. THe hypercalcemia itself interferes with reabsorption of sodium and water and this leads to polyuria and dehydration. Moreover, many cancer patients are immobilized which further increases the calcium. « Symptoms of Hypercalcemia » HC can be divided traditionally into Gastrointestinal (anorexia, nausea, vomiting, constipation and pancreatitis), Renal (polyuria, polydipsia and nephrocalcinosis), CNS (drowsiness, coma, apathy) and Cardiovascular (short QT interval on EKG, digitalis sensitivity, and hypertension depending on degree of hydration). « Other Causes of Hypercalcemia » Sarcoidosis, histoplasmosis, coccidioidomycosis, tuberculosis, leprosy, lithium, thiazide diuretics, estrogens and antiestrogens, multiple myeloma, Vitamin A and D toxicity, familial hypocalciuric hypercalcemia, milk alkali syndrome, immobilization, acute and chronic renal insufficiency, parenteral nutrition, pheochromocytoma, thyrotoxicosis, vasoactive intestinal polypeptide hormone- producing tumor and thyrotoxicosis. If the serum calcium after being corrected for albumin is 14 mg/dl, then immediate therapy is indicated. If the albumin is elevated then the calcium should be adjusted downward. If the albumin is low, then the calcium should be adjusted upward. « Treatment of Hypercalcemia » The decision to treat is usually clear-cut if the calcium is 14 or greater. However, calcium levels between 10.5 and 14 depend on several factors such as age, concomitant conditions, stage of cancer, and symptoms. There are four classes of treatment and include: hydration, enhance the renal excretion of calcium, inhibit bone resorption and treating the underlying condition. These will subsequently be discussed. Hydration with isotonic saline is usually the first step. Various amounts and time schedules have been used, but in general give 2.5 to 4 liters of saline daily with attention to the cardiovascular and renal status. When there has been restoration of intravascular volume then one could reasonably expect a diminution of 1.6 to 2.4 mg reduction of the calcium level. This occurs because of increased renal calcium clearance, decreased calcium absorption in the proximal renal tubule, and obligatory caluresis with increased presentation of sodium and water to the distal renal tubule. Furosemide is usually given along with isotonic saline in order to inhibit reabsorption of calcium in the thick ascending loop of Henle, and to protect the patient from saline overload. Thiazide diuretics should never be given as they increased the absorption in the distal tubule. Always precede loop diuretic agents as furosemide with saline hydration, because furosemide depends on the delivery of calcium to the loop. Depending on the degree of hypercalcemia and symptoms, the furosemide needs to be adjusted possibly from 20 mg every 6 hours to 80 mg every two hours. Careful attention must be given to electrolyte depletion. Etidronate works by inhibiting osteoclasts. The reduction in calcium begins at about 2 days and has a peak reduction at 7 days. The patient should be well hydrated as the etidronate works better under this situation. The dose is 7.5 mg/kg IV over a four hour period daily for 3-7 days. The length of treatment depends on the response. Etidronate is safe with transient increases in creatinine and phosphate. Pamidronate is more potent than etidronate. Giving a single 24 hour IV infusion of up to 90 mg will normalize the serum calcium in 70-100% of patients. Other schedules include giving a slow IV infusion of 15-45 mg daily for up to six days depending on the response. Pamidronate can also be given orally as 1200 mg daily for up to 5 days, but many hypercalcemic patients are unable to tolerate orally because of nausea and vomiting. Onset of action and peak action is about the same as Etidronate. Side effects are mild with transient increase of temperature which is usually less than 2 degrees C, transient hypophosphatemia and leukopenia. Plicamycin is given at 25 micrograms/kg over a 4-6 hour period and can be repeated at 1-2 day intervals depending on limiting side effects of the drug which include: hepatic and renal toxicity, thrombocytopenia, and cellulitis with extravasation of the drug. The onset of lowering the calcium starts at 12 hours and peaks at 48-72 hours. Calcitonin is usually given as salmon calcitonin at 4 units/kg every 12 hours and is the drug of choice if a rapid reduction of calcium is needed. The calcium starts to drop after a few hours and the peak drop is at 12-24 hours. The drawback is that calcitonin is fairly weak and doesn't lower the calcium to degrees that the bisphosphonates and plicamycin do. In spite of this, severe hypercalcemia can be treated with a combination of calcitonin which can be given for 1 to 2 doses and either plicamycin, bisphosphonate or gallium nitrate. Calcitonin also possesses pain relief properties that can relieve metastatic bone pain. Calcitonin is safe and causes mild nausea, flushing, abdominal cramps and allergic reactions to salmon. Skin testing with 1 unit of salmon calcitonin prior to therapy is recommended. Gallium nitrate is given as a continuous IV infusion at 200 mg/square meter of body surface in 1 liter of fluid daily for 5 days. Gallium appears to be more effective in lowering the calcium to normal and prolonging this effect than calcitonin. However, normal calcium levels are not obtained until the 5 days of therapy is completed and the lowest levels are at 3 days post infusion. Also, it appears that gallium is more effective than etidronate in normalizing the calcium by about 50%. The main side effect is nephrotoxicity and should not be given if renal insufficiency is present. Patients should not be given other renal toxic drugs as aminoglycosides and hydration should be maintained. Decreased hemoglobin and phosphates can also occur. Steroids are useful if the patient has multiple myeloma,lymphoma, vitamin D intoxication, or granulomatous disease and is given as 200-300 mg of hydrocortisone IV daily for 3-5 days. ■ CUSHING'S SYNDROME ■ When dealing with this topic, one must make the distinction between Cushing's SYNDROME and Cushing's DISEASE. Cushing's disease refers to a pituitary tumor producing excessive ACTH, where as Cushing's Syndrome may be caused by a pituitary tumor (such as a basophilic adenoma or chromophobe adenoma), adrenocortical tumor (such as adrenal cortical adenomas and carcinomas) or an ectopic ACTH producing tumor (such as a small cell carcinoma of the lung or a bronchial carcinoid). Cushing's syndrome may be fairly easy to diagnose, but Cushing's disease may be very difficult to distinguish from adrenocortical tumors and ectopic ACTH producing tumors. At first thought, you might think this differentiation is very simple. Just order a MRI- gandolinium enhanced scan of the pituitary, and a CT or MRI of the abdomen to evaluate the adrenals, and if a tumor is seen, then we have found the cause. However, this is not the case, because it has been shown by autopsy that about 1/3 of patients with no known endocrine syndromes during life have unsuspected, non-functional pituitary tumors, and 5-10% have unrecognized benign non functional adrenal tumors. With this in mind, a reasonable approach will be discussed in the following discussion of Cushing's syndrome. « Clinical » In 80% of cases of pituitary Cushing's disease, the adenoma is small enough that no visual field defect or abnormality on routine x rays of the sella turcica will be seen. There is a female predominance over males in a ratio of 4:1. Weakness occurs in about 90%, thin skin (84%), obesity which is centripetal with truncal obesity (79%), moonface, buffalo hump and supraclavicular fullness (51%, easy bruising and hypertension (77%), hirsutism (67%), edema and osteoporosis (48%), menstrual disorders and hirsutism (67&), impotence and striae (53%, psychiatric symptoms (31-70%) and proximal myopathy. Other findings that have been reported include: acne, pathologic fractures, poor wound healing, galactorrhea, renal stones and exophthalmos. Laboratory findings include: leukocytosis with a relative lymphopenia, occasionally polycythemia and hypercalcemia, hyperglycemia, and hypokalemic alkalosis seen with ectopic ACTH secretion. Ectopic ACTH producing tumors may include the following: small cell carcinoma of the lung (this is the most common cause occurring in only about 2%), islet cell tumor of the pancreas, bronchial carcinoid adenoma, hypernephroma, craniopharyngioma, neuroblastoma, seminoma, pheochromocytoma, medullary thyroid carcinoma, and carcinoma of the ovary, prostate, parotid, breast, colon and esophagus. These tumors often present with marked hypokalemic alkalosis, weakness and muscle wasting and hyperpigmentation due to production of Beta melanin stimulating hormone by the tumor. Adrenal carcinomas are rare, but adrenal adenomas account for approximately 10% of cases of Cushing's syndrome. Adrenal adenomas and carcinomas often present with virilization. Adrenal carcinoma patients usually survive for only 2-4 years, whereas adrenal adenomas have a good prognosis. These tumors are found more frequently on the left and can be bilateral. « Testing in Cushing's Syndrome » A screening test, the Dexamethasone test should be done by giving 1 mg of dexamethasone po at 11 to 12 PM with measurement of the plasma cortisol at 7-8 AM the following morning. If the patient is normal, there will be a plasma cortisol of less than 5 ug/dL. Most patients with non pituitary Cushing's syndrome will continue to secrete cortisol. By far, the most reliable test for Cushing's syndrome is the 24 hour urinary free cortisol measurement. Most all patients with Cushing's SYNDROME will have an elevated value above 100 ug. The normal value is < 90 ug or less. If the assay is done with high pressure liquid chromatography, the upper limit of normal is 50 ug. To distinguish a pituitary abnormality from the other 2 forms of Cushing's syndrome, the oral dexamethasone suppression test is done. In the low dose test, if 0.5 mg q 6h for 2 days is given to normal subjects there will be an inhibition of ACTH with urinary free cortisol decreasing to < 10 ng/24 hours on the second day. If the patient has Cushing's Disease, there is a relative resistance to suppression and the urinary free cortisol will not decrease. If the dose of dexamethasone is increased to 2 mg every 6 hours for 2 days there will be a 50% reduction in free urinary cortisol. If the patient has an adrenal adenoma or ectopic ACTH tumor there will be no change in the free urinary cortisol. To differentiate between an adrenal tumor and the ectopic ACTH syndrome, the plasma ACTH concentration should be done. The ACTH will be markedly elevated if the patient has an ectopic ACTH producing tumor, usually greater then 200 pg/mL, and too low to measure if there is an adrenal tumor. Patients with Cushing's disease usually have a moderately elevated ACTH level between 75 to 200 pg/mL. The CRH test is another test that may be used to differentiate between adrenal tumors and ACTH secreting tumors. « Treatment » If the pituitary is the problem, then transsphenoidal surgery should be done to excise the tumor. The surgery is successful in about 70% and the best results are obtained with microadenomas < 1 cm in diameter. If no tumor is found then pituitary irradiation is done delivering 4000-5000 rads. With irradiation the response time may require several months. If the patient does not respond to transphenoidal surgery or irradiation then bilateral adrenalectomy may be done. Following this procedure, Nelson's syndrome occurs in 5-10%, whereby there is growth of the pituitary gland with a large increase in ACTH and B melanocyte stimulating hormone which will result in hyperpigmentation. Hypophysectomy may be ultimately required. Adrenocortical tumors are removed surgically. If the patient has an ectopic ACTH secreting tumor, again, surgery may be needed. However, many of these tumors are metastatic and surgery cannot be done. Metyrapone and aminoglutethimide, ketoconazole and RU - 486 have all been tried. If the patient has a pancreatic islet cell tumor, octreotide, a long acting somatostatin analog, may be tried. ■ HIRSUTISM ■ Hirsutism is due to increased androgen production and can be defined as excessive coarse terminal hair accumulation on the face, abdomen, chest, lower back and thighs. Terminal hair on the lower abdomen, around the areolae and even on the face may be normal. This must be differentiated from hypertrichosis which is an excess of thin vellus hair, which depends on race and familial background. Androgens include testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS). In women, the ovaries and adrenal glands produce androgens. Circulating testosterone is derived from direct ovarian secretion (60%) and by peripheral conversion from androstenedione (40%. Androstenedione is secreted in equal amounts by the ovary and the adrenal. DHEAS is only secreted by the adrenals. DHEA, DHEA-sulfate and androstenedione are produced by the adrenal gland. Testosterone and androstenedione are secreted from the ovary, and androstenedione must be converted to testosterone in order to produce an androgenic effect. Testosterone is 98% bound. Only the free testosterone can exert an androgenic effect. Testosterone is converted to dihydrotestosterone (DHT) in the skin which can then stimulate the hair follicle. Cushing's syndrome is produced by excessive ACTH, either by the pituitary or ectopically, and usually is not a common cause of hirsutism. The dexamethasone screening test can be initially used, or the 24 hour urinary collection for free cortisol can be performed for diagnosis. Ovarian tumors such as Sertoli-Leydig cell tumors, dysgerminomas, hilar cell tumors and arrhenoblastomas may occasionally cause hirsutism. Most tumors of the ovary are palpable on the pelvic exam. Polycystic ovary syndrome may present with amenorrhea or oligomenorrhea, infertility, dysfunctional bleeding, obesity and anovulation. The obesity is only seen in about 50% of cases. Usually the polycystic ovaries are enlarged 2-5 times, with multiple follicular and atretic cysts, but not always. There may be a family history which is inherited as an autosomal dominant pattern. The testosterone is often elevated. The LH:FSH ration is > 2.0. By far, polycystic ovary syndrome and idiopathic hirsutism are the most common causes of hirsutism. The onset is at or near the time of puberty. If the DHEA-S is elevated, but below 700 ug/dl and the testosterone is elevated, but less than 200 ng/dl suspect PCO. Adrenal carcinoma can cause virilization which can be quite striking. DHEA-S values greater than 700 ug/dl are usually due to adrenal tumors. A CT should be done. If a tumor is not seen, adrenal hyperplasia can occasionally cause very high levels of DHEA-S. Some adrenal tumors are palpable. Congenital adrenal enzyme defects such as a 21-hydroxylase deficiency can cause ambiguous genitalia and hirsutism in female patients. The 21-hydroxylase deficiency is the most common, but there may be 11-hydroxylase and 3 beta hydroxysteroid dehydrogenase deficiency. About 1.2 - 6% of adult patients have a partial defect in adrenal 21-hydroxylase that can cause hirsutism. In these patients you should measure the early morning 17-hydroxyprogesterone level as it is usually elevated. Idiopathic hirsutism has no detectable hyperandrogenism. Most of these patients have regular menses but can be irregular. In this subset, there is increased hair follicle sensitivity to androgens with normal androgen levels. If the DHEA-S is elevated, but below 700 ug/dl, and the testosterone is elevated, but less than 200 ng/dl, suspect idiopathic hirsutism. About 25% of women with prolactinoma and the amenorrhea/galactorrhea syndrome have idiopathic hirsutism or polycystic ovarian syndrome. « Drugs Causing Hirsutism » The following drugs can cause hirsutism: Minoxidil, dilantin, diazoxide, androgens, steroids, cyclosporin, danazol, ACTH, metyrapone, anabolic steroids, and progestins. Prolactin elevation can cause hirsutism, and the following drugs can elevate the prolactin: Tranquilizers (thioxanthenes, butyrophenones), Narcotics (as morphine and heroin), Antidepressants (as MAO inhibitors), Antihypertensives (as aldomet, guanethidine and reserpine), Antiemetics (as metoclopramide), Antihistamines (as tagamet, meclizine and tripelennamine) and estrogens. Diseases capable of causing prolactin elevation are sarcoidosis, histiocytosis, hypothyroidism, renal failure and hepatic cirrhosis. « Laboratory » 1. Free Testosterone...may be elevated due to adrenal or ovarian overproduction, or increased peripheral conversion of androstenedione to testosterone. In women with idiopathic hirsutism or Polycystic ovarian syndrome the serum testosterone is often elevated. (70-80% in polycystic ovarian syndrome). Levels of total testosterone greater than 200 ng/dl are frequently present in patients with ovarian and adrenal tumors, but rarely above 200 with idiopathic or polycystic ovarian syndrome. If patients with polycystic syndrome are put on the "pill" (estrogen-progesterone) the testosterone will normalize, but will not normalize with ovarian tumor. 2. Prolactin...may be elevated. If elevated, then MRI of the pituitary may be in order. If there is galactorrhea or menstrual disturbance then this test should be ordered. If the level is twice normal then evaluation for a pituitary tumor should be done. Values less than this are commonly elevated in idiopathic hirsutism and polycystic ovary syndrome. 3. DHEAS-S...may be elevated in adrenal overproduction. Extremely high levels of DHEA-S greater than 700 ug/dl may be found in adrenal tumors. Lesser elevations between 450 and 700 ug/dl may be seen in idiopathic hirsutism and polycystic ovarian syndrome, congenital adrenal hyperplasia and some virilizing adrenal tumors. The DHEAS-S is not a good test for congenital adrenal hyperplasia as the levels are usually normal. 4. LH:FSH RATIO...is typically increased in polycystic ovary syndrome. 5. 17-OH progesterone...is typically elevated in congenital adrenal hyperplasia (21-OH deficiency). 6. ACTH stimulation test...Basal levels of 17 OH progesterone may be normal, but elevated 17 OH progesterone levels in late onset 21 OH deficiency may be seen after ACTH stimulation. 0.25 mg of synthetic ACTH is given IV and then the 17 OH progesterone level is measured in 1 hour. 7. 17-OH corticosteroids and free cortisol in 24 hour urine samples is done for diagnosis of Cushing's syndrome. The 24 hour urinary free cortisol is the method of choice. 8. 17-Ketosteroids...usually markedly elevated in adrenal cancer. 9. CT scan of adrenals may reveal an adrenal mass. Pelvic Ultrasound may show polycystic ovaries or ovarian mass. 10. Dexamethasone suppression test...If DHEA sulfate is increased to > 700 ug/dl, then do this test using .5 mg qid for 3 days, then repeat DHEA-S. If the DHEA-S is suppressed, this would indicate congenital adrenal hyperplasia. Tumors of the adrenal will not suppress. « Treatment » 1. Aldactone (Spironolactone) 100 to 200 mg daily in divided dosage may be beneficial. 2. Birth control pills are effective in only about 30%. 3. Flutamide (Eulexin) is being investigated for hirsutism. 4. Dexamethasone .5 mg at h.s. is effective for congenital adrenal hyperplasia. 5. Any drug that is causing the hirsutism should be discontinued. 6. All secondary diseases that have caused the hirsutism should be treated. 7. Shaving, waxing, depilatories, electrolysis and bleaching all can be used. ~gast.bin~ ■ HEMOCHROMATOSIS ■ Hemochromatosis was initially recognized in western Europeans over 100 years ago and was called bronze diabetes. It is a hereditary autosomal recessive genetic disorder, whereby the small intestine absorbs excessive amounts of iron. The cells of the duodenal mucosa regulate the dietary iron absorption. The gene frequency is such that 1 in 20 whites carry the gene and 1 in 400 are homozygotes. Hemochromatosis is HLA-related with linkage to HLA-A3 and HLA-B14 or HLA-A3 and HLA-B7. The excessive iron is deposited as hemosiderin in the liver (causing cirrhosis), adrenals, Leydig's cells of the testes (with resultant decreased testosterone production), pituitary (resulting in decreased production of gonadotropins), kidneys, synovium (producing arthritis), heart (cardiomyopathy) and islets of the pancreas (producing diabetes). Hemochromatosis can also be seen in sideroblastic anemia and beta-thalassemia. Excessive transfusions, iron injections and the presence of a portacaval shunt are additional causes. « Clinical » Clinical presentation is very often non-specific with weakness (83%), abdominal pain (58%), and arthralgia (43%). All of these symptoms are so common in the population that the diagnosis may be over looked if serum iron, transferrin saturation and ferritin are not done. It has been estimated that approximately 5 years elapse between initial presentation and treatment. Other signs and symptoms are loss of libido or impotence (38%), dyspnea on exertion (15%), diabetes mellitus, hepatomegaly (83%), skin pigmentation (75%), loss of body hair (20%), jaundice (10%), gynecomastia (8%), edema (12%), ascites (6%), and amenorrhea (22%). The disease is more common in males > 40 years of age, because it takes time for deposition of the hemosiderin and menstruation protects women, just as phlebotomy treats hemochromatosis. There can be a normal life expectancy if there is no cirrhosis, and the patient is treated with phlebotomies. Alcohol will increase the absorption of iron, and therefore, alcoholics are commonly affected. Hepatomas develops in 10%. « Laboratory » The serum ferritin is greater than 300 mcg/L for men and 120 mcg/L for women. However, there may be wide fluctuations in the ferritin. Also, the ferritin is an acute phase reactant, and may be elevated in other conditions. Probably the best test is the serum transferrin saturation. If greater than 50%, then further evaluation should ensue. If greater than 70% then a diagnosis of hemochromatosis is fairly secure. Serum iron is also elevated. The TIBC >60%. The transferrin saturation is calculated by dividing the total iron binding capacity into the serum iron concentration x 100. There is also increased urinary iron and urine hemosiderin. There is possible hyperglycemia, decreased FSH, LH, and testosterone. Liver biopsy should be the next step after the iron studies suggest hemochromatosis. There should be large amounts of Prussian blue stainable iron in the periportal areas. The hepatic iron index [the hepatic iron index is calculated by dividing the patient's age into the hepatic iron concentration (micromoles/gram of dry weight)] can differentiate homozygous hemochromatosis from other iron storage diseases. If the hepatic iron concentration is > than 400 umol/g dry weight then cirrhosis is almost certainly present. Alcoholic disease is particularly difficult to differentiate from hemochromatosis. However, in alcoholic liver disease, there is usually more iron in the Kupffer cells, increased fatty degeneration of the hepatocytes and an increase of portal inflammatory infiltrates. If there is evidence of cardiomyopathy, then an echocardiogram should be done. CT can estimate the liver iron load. Alpha fetoprotein may be increased in hepatoma. « Treatment » Phlebotomy of 500 ml of blood (about 250 mg of iron) once or twice weekly for about 2-3 years to achieve iron store depletion. The goal is a hematocrit of around 37-39%. When iron store depletion is achieved, maintenance phlebotomies every 2-4 months are continued. If phlebotomy is not feasible or there is severe heart disease then consider deferoxamine .5-1 g IM daily or subcutaneously via pump. Avoid alcohol, and family members should be screened. ■ DIABETIC DIARRHEA ■ Diabetic diarrhea usually occurs in patients with long standing history of insulin dependent diabetes mellitus. Peripheral neuropathy is usually present along with autonomic neuropathy (orthostatic hypotension, impotence, retrograde ejaculation, urinary bladder dysfunction, anhidrosis and abnormal pupillary responses). There may also be nausea and vomiting, fullness and impaired gastric emptying. The diarrhea is very often nocturnal and associated with anal incontinence, and can be very severe along with tenesmus. Males are slightly more affected than females. The overall prevalence varies between 8-22%. « Causes » Diabetic diarrhea may have multiple causes as the following: Bacterial overgrowth in the small bowel (there is greater than 10 to the fifth colony forming units/ml of bacterial in the small bowel aspirate), abnormal colonic motility (abnormal GI manometry and transit studies), exocrine pancreatic dysfunction, anorectal dysfunction (abnormal rectal sensation on anorectal manometry and decreased resting pressure. About 20% of long standing diabetics will have fecal incontinence), alterations in intestinal secretion, associated sprue (flat biopsy of the small bowel), bile acid malabsorption (increased stool bile acids), ingestion of sorbitol, lactose intolerance (abnormal results of lactose hydrogen breath test) and sorbital ingestion. OTHER CAUSES Of course, other causes may occur in diabetic patients and should be ruled out with analysis of stool for blood, leukocytes, ova and parasites, clostridium difficile, cultures and mucosal biopsies with sigmoidoscopy or colonoscopic exam to rule out inflammatory bowel disease, HIV, carcinomas and polyps etc. « Treatment » For patients that one can find no cause, treat with loperamide and diphenoxylate which can decrease diarrhea associated with a rapid intestinal transit. For patients that have intestinal motility or secretory disorder, clonidine may help by giving 0.1 to 0.6 mg bid. Be aware that clonidine may decrease gastric emptying and may cause orthostatic hypotension. Bacterial overgrowth can be treated with tetracycline, quinolones, metronidazole and cephalosporins for 14 days each month, rotating these so that resistance doesn't develop. A gluten free diet is given for celiac disease, and lactose free diet for lactose intolerance. Bile acid malabsorption is treated with cholestyramine in a dose of 4 to 12 g/day, or aluminum hydroxide. Octreotide acetate, a long acting somatostatin analogue may be given subcutaneously, 50 to 75 ug bid and can be given with the insulin. Be aware, however, that octreotide can inhibit exocrine pancreatic secretion. Patients that have pancreatic insufficiency can be given pancreatic replacement enzymes. ■ PRIMARY BILIARY CIRRHOSIS (PBC) ■ PBC should be suspected in any middle aged woman that complains of pruritus and has an elevated serum alkaline phosphatase. The disease is considered by some to be an immune mediated disease and perhaps an immune complex disease. The disease can recur in patients that have had liver transplants. The female:male ratio is about 10/1. All races can be involved and the incidence is about 10/1 million/year. « Clinical » Patients present insidiously with pruritus and fatigue. There may be diarrhea due to fat malabsorption, xanthomata(40%, hepatomegaly initially, and later a small liver. THe bilirubin has been used as an estimate of the progression of the disease. The disease has a range between 20-80 years, but mainly affects middle aged females. The cholesterol is elevated. Bone pain and osteomalacia may be present. Splenomegaly may even be detected in an asymptomatic patient early in the disease. Occasionally corneal Kayser Fleishcher rings are found due to accumulation of copper secondary to impaired copper excretion in bile. There may be wrist drop and foot drop due to an accumulation of lipids around the nerves. Late portal hypertension, ascites and bleeding esophagogastric varices may be seen. « Complications » Patients may develop scleroderma, Sjogren's syndrome and CREST. Primary hypothyroidism has been reported at 25%. Other associations have been made including polymyositis, polyarthritis, renal tubular acidosis, Hashimoto's thyroiditis, celiac disease, primary pulmonary hypertension, vasculitis and interstitial pneumonitis. It has been noted that non Hodgkin's lymphomas and even breast cancer are more frequent with PBC. « Laboratory » The diagnosis is established by finding a positive antimitochondrial antibody (AMA) in association with a compatible liver biopsy which shows a non-suppurative cholangitis associated with granulomas. The liver is enlarged and has a smooth surface. Lymphocytes and plasma cells predominate in the portal areas. Similarities between the lesions of PBC and graft versus host disease have been observed. The identification of granulomas on initial liver biopsy is associated with a more favorable prognosis. High titers of AMA > 1:160 are rarely seen in any other condition and are found in about 95% of patients. Make sure there is no evidence of any extrahepatic bile duct obstruction such as stone or stricture, carcinoma of the bile ducts, cholestatic liver disease associated with sarcoidosis, or inflammatory bowel disease. Ultrasonography should be done to exclude bile duct obstruction and endoscopic retrograde cholangiography may be indicated. Transhepatic cholangiography is used less often because the bile ducts are very small and few in number. A drug induced cholestasis has to be ruled out, especially that caused by phenothiazines as well as sclerosing cholangitis, chronic active hepatitis and bile duct carcinoma. Sarcoidosis may be clinically and histologically difficult to differentiate from PBC. The 5' nucleotidase and GGT can be increased to similar extents as the alkaline phosphatase. The bilirubin is normal or slightly elevated in early asymptomatic patients. A progressive rise in bilirubin is ominous. The cholesterol may get as high as 1000 mg/dl. There is an increase of HDL in mild to moderate cases. This tends to fall in the later stages of the disease. The IgG, IgA, and IgM may all be elevated, but the IgM is usually always elevated more than the IgG or the IgA, and the IgM is elevated in about 75% of the cases. The Antimitochondrial antibodies are usually performed using the ELISA analysis. AMAs are rarely found in patients with mechanical obstruction of the biliary tract, primary sclerosing cholangitis or in any other chronic forms of cholestatic liver disease such as drug induced disease and sarcoidosis. AMAs may be found in about 5-15% of patients with idiopathic chronic active hepatitis, but in general the titers are lower (1:40 to 1:80). The anticentromere antibody may be found in patients with primary biliary cirrhosis with the CREST variant. (calcinosis, raynauds, esophageal motility disorders, sclerodactyly and telangiectasia). This variant has been estimated to occur in about 3-17% of patients with PBC. Evidence of Raynauds or scleroderma may precede evidence of liver disease. The calcinosis is the least common part of the CREST syndrome when it occurs with PBC. Chronic destructive intrahepatic cholangitis would be a better descriptive name for the disease, as cirrhosis is usually not seen when the diagnosis is first made. There is progressive destruction and disappearance of the small interlobular hepatic bile ducts. « Treatment » Cholestyramine, 4-24 grams per day is useful for the pruritus if the bilirubin is only moderately increased. Cholestyramine may also help improve the serum lipid levels. Give the drug a few days to work. There may be mild constipation or diarrhea as side effects. The drug may be given with food, but other medications should be given 2 hours later to allow absorption. Colestipol is probably just as effective. Antihistamines and phenobarbital may help the pruritus. Rifampicin 10 mg/kg/day and phenobarbital 3 mg/kg/day given for 2 weeks with an interval of 30 days between treatments is often times useful. Plasmapheresis can help but is expensive and must be done frequently. Vitamin D replacement therapy can be given to prevent or treat osteomalacia. Give 1 gram of calcium/day to prevent osteoporosis, as fractures are common later in the disease. Azathioprine hasn't helped much. D-penicillamine is ineffective in improving survival or decreasing complications. Colchicine, 0.6 mg bid may be helpful, but dose related diarrhea may develop. With colchicine, the bilirubin, alkaline phosphatase and aminotransferase levels all decrease and survival might be improved. Ursodeoxycholic acid may be helpful using 13-15 mg/kg/day. There is usually an improvement in bilirubin, aminotransferases, alkaline phosphatase and GGT. The pruritus improves and the liver biopsies improve. Chlorambucil has not been used because of toxicities, and Cyclosporine A is of limited benefit because of its side effects of hypertension and increased creatinine. Liver transplantation in primary biliary cirrhosis is done as as a last resort. ■ MESENTERIC ISCHEMIA ■ Ischemia in the Superior mesenteric artery (SMA) may be due to occlusion or non-occlusion. In non-occlusion, the cause is usually due to low flow states as cardiogenic shock. Probably embolization from the heart is the most frequent occlusive cause, followed by thrombus and then non-occlusive. The heart as a source for the embolus should be assessed for valvular heart disease. Any patient with decompensated congestive heart failure, history of previous embolic disease, treatment with digitalis and vasopressors, recent myocardial infarction, burns, sepsis, bleeding and dialysis should be considered at risk for SMA ischemia. « Clinical » If embolus is the cause, the abdominal pain is sudden, and often times the pain is cramping and very poorly localized. Therefore, always remember that pain out of proportion to the abdominal findings is mesenteric ischemia until ruled out. Always check for atrial fibrillation as a cause of the embolization. The patient is usually over the age of 50 and may have a history of other atherosclerotic events as myocardial infarction, stroke, claudication, etc. There may be a history of intestinal ischemia preceding the mesenteric event, such as pain after eating. About 1/3 of patients will have this history. There may be a history of emboli to other organs as brain, kidney, etc. There may be nausea and vomiting in about half the cases, GI bleeding and diarrhea. Physical exam may show hyperactive peristalsis, mild non specific diffuse tenderness, and abdominal distention. Later, as the ischemia and infarction advances, there is fever, hypotension and tachycardia, transmural ischemia with rebound tenderness, and peristalsis which is now hypoactive. « Laboratory » Lab findings are non-specific and not helpful. The WBC is elevated in about 3/4 of patients and the phosphorus, CPK and LDH may be elevated. Abdominal x-rays may show thumbprinting, pneumatosis intestinalis, and demonstration of generalized dilatation of the small and large bowel. There may even be air in the portal venous system. Endoscopy may show submucosal hemorrhage, edema and superficial ulceration. CT and Sonography may show small amounts of ascites and bowel edema. Also CT can show air in the portal venous system and air in the bowel wall. ARTERIOGRAPHY is very important in the diagnosis and management of SMA ischemia. In the first place, if the exam is negative then another cause should be sought. Next, infusion of vasodilators can prevent or even reverse arterial spasm. Surgery alone results in mortality rates of about 80%. An initial flush arteriogram is usually done with the patient in the lateral position to assess the ostia of the celiac and SMA. If nothing is found, then selective angiograms are made to look for thrombus, embolus and spasm. If there is spasm, Tolazoline 25 mg can be given, and then a continuous drip using papaverine infused at 60 mg/minute. « Treatment » If the patient still has peritoneal signs with rebound tenderness after arteriography, the patient is taken to surgery. If the patient improves with the papaverine drip, then surgery may be deferred and a repeat arteriogram can be done in 24 hours. If EMBOLUS has been found via arteriography, embolectomy is done and necrotic bowel is resected. The papaverine is continued following surgery and at 48 hours after surgery heparin is started. If the arteriogram, prior to surgery, shows THROMBOSIS and the collateral circulation is good without spasm and vasoconstriction, the patient can be followed medically if there are no peritoneal signs. If there is poor collateral circulation, the patient is taken to surgery. Thrombosis usually occurs at the origin of the SMA and embolus more distally. At surgery revascularization is performed and infarcted bowel removed. Revascularization is done if the bowel appears ischemic, but not necrotic, or if the area of necrosis is limited. An antegrade bypass from the proximal aorta to an artery that is distal to the obstruction using a saphenous vein or Dacron graft can be used. Multiple bypasses may be needed. Alternatively, endarterectomy may be done. Bowel viability is checked following revascularization by arterial pulsations, color, and Doppler ultrasound and Fluorescein dye with Woods light. Again papaverine and heparin are used. In NON-OCCLUSIVE ischemia, arteriography is done for diagnosis, and papaverine may obviate the need for surgery if there are no peritoneal signs. If peritoneal signs are present, take the patient to surgery for necrotic bowel resection. Streptokinase infusion has been used to establish patency after an embolic event, but clot lysis is very slow. Angioplasty also has been used. After surgery, if the circulation is considered marginal, a second look surgery should be performed in about 24 hours. Routine measures as replacement of intravenous fluids, nasogastric suction and antibiotic therapy should be instituted. ■ ISCHEMIC COLITIS ■ Ischemic colitis is probably the most common of the intestinal ischemic syndromes. It is usually much milder than mesenteric artery insufficiency. There is mucosal hemorrhage and edema followed by mucosal ulcerations. Most patients will heal after these initial insults without scarring. A few, however, will go on to transmural infarction. Some will heal with stricture. Ischemic colitis has been associated with colon cancer and abdominal aortic aneurysm repair. Ischemic colitis is common following abdominal aortic aneurysm repair. Many will have post- operative diarrhea, but some will have signs of sepsis. The most frequent sites of involvement are the splenic flexure and the sigmoid colon. The rectum is a very rare site of involvement. « Clinical » The patient usually first notices a sudden mild to moderate abdominal pain and cramping in the lower abdominal area. Then there usually is a loose stool with some blood mixed in with it. There may be localized tenderness overlying the involved area. If the patient has transmural involvement the patient will develop hypotension, fever and peritonitis with rebound tenderness. « Laboratory » X-rays of the abdomen may show thumbprinting and bowel distention. If a barium enema is done, edema and submucosal hemorrhage may be seen as thumbprinting. If the patient has a repeat X-ray in a few weeks, the barium enema may show stricture or eccentric sacculation, or it may be entirely normal. If a colonoscopic exam is done, friable, edematous submucosal hemorrhage will be seen that alternates with blanched areas. There may be large and irregular ulcerations seen later in the course of the disease. The differential diagnosis would include inflammatory bowel disease and pseudomembranous colitis. « Treatment » No treatment is usually necessary, except in those rare cases that develop peritonitis. After a few weeks, a follow up colon X- ray may be done to rule out stricture. Other rare causes of intestinal ischemia will not be discussed in detail but would include mesenteric venous thrombosis (associated with abdominal malignancy, hypercoagulable states (due to antithrombin III deficiency, protein C and S deficiency, and Lupus anticoagulant), portal hypertension, splenectomy, and abdominal infections), inflammatory bowel disease, portal hypertension and sclerotherapy of esophageal varices. Mesenteric arteritis caused by polyarteritis nodosa, rheumatoid arthritis and SLE can cause intestinal ischemia. Cocaine, by causing vasoconstriction occasionally may lead to abdominal pain and diarrhea. Marathon runners commonly have diarrhea and abdominal cramping which often times can be attributed to ischemic colitis. ■ SPONTANEOUS BACTERIAL PERITONITIS ■ Spontaneous bacterial peritonitis (SBP) is a common complication of severe chronic liver disease with significant mortality. There is a 10-27% prevalence of SBP with routine paracentesis on hospital admission in patients with cirrhosis and ascites. There is an absence of a obvious cause. In this condition there is a spontaneous bacteremia with seeding of the ascites. Clinically, the patient presents with fever, abdominal pain and tenderness, encephalopathy, deteriorating hepatic and renal function, and worsening ascites, but none of these are pathognomonic . The initial diagnosis of SBP rests upon the combination of the clinical syndrome and an ascitic fluid polymorphonuclear leukocyte count of > 250 /cu mm. The diagnosis is confirmed with the finding of positive ascitic fluid cultures, generally for enteric organisms. Although organisms are seen on Gram stain of the ascitic fluid in about 60% of patients with SBP, the bacteria are not the same as the culture in all cases. Cultures should be obtained by inoculating 10 ml of ascitic fluid into each of two sets of aerobic and anaerobic blood culture bottles. If this is done, the sensitivity is greater than 90%. Cultures of the blood are done, but positive cultures are obtained in only about 50% of patients. SBP usually is caused by only one type of bacteria. About 1/3 of patients do not respond to antibiotic therapy and will die. A further 50% of patients will die during the hospitalization from complications of the severe chronic liver disease. « Clinical » About 54% will present with fever, abdominal pain (50%), abdominal tenderness (53%), encephalopathy (42%), no fever or abdominal pain (14%), and leukocytosis > 10,000 (54%). The clinical presentation is similar in patients with various cirrhotic liver disease which doesn't help with the diagnosis of SBP. Alcoholic cirrhosis is the most common cause of liver disease, but SBP has been reported as a complication of cryptogenic cirrhosis, hepatitis B cirrhosis, autoimmune or lupoid cirrhosis, alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease and in ascites complicating acute viral hepatitis. « Paracentesis » There is no association between a previous paracentesis and SBP. With SBP there is a single organism reported in 90%% of cases, whereas in peritonitis caused by perforation there are multiple organisms. Paracentesis can be done in patients with severe chronic liver disease without significant complications. The relatively avascular midline should be used to avoid hemorrhage, unless surgical scars are present. The lower quadrants are preferable to the upper quadrants. There is controversy regarding the "normal" values for WBCs and PMN leukocytes in sterile ascites of chronic liver disease. The generally accepted values are a WBC > 300/cu mm and PMN < 25%. However, higher values without evidence of infection are not uncommon. The glucose in SBP in peritoneal fluid is not lowered as in bacterial CSF and pleural fluid infection. Tuberculosis and bowel perforation, however, will lower the peritoneal fluid glucose. The most common gram negative bacteria in SBP is Escherichia coli which represents about 55% of total isolates, followed by Klebsiella pneumoniae. Other isolates that can be found include Salmonella sp., Enterobacter cloaci, Pseudomonas sp., Neisseria sp., Aeromonas sobria, Proteus sp., Citrobacter, Acinetobacter, Campylobacter sp. and Serratia. The most common gram positive bacteria is Enterococcus which represents only about 5% of total isolates. Other gram positive isolates include Streptococcus pneumoniae, and Staphylococcus aureus. Anaerobic bacteria include Bacteroides, which represents only 2% of total isolates. Other anaerobic isolates include Clostridium sp. and Lactobacillus. Candida albicans is present in less than 1 % of total isolates. « Diagnosis of SBP » Diagnosis is made by finding a positive ascitic fluid culture, ascitic fluid PMN > 250/cu mm, ascitic fluid pH <7.40, an arterial-ascitic fluid pH gradient, and an ascitic fluid lactate > 25 mg/dl. « Differential Diagnosis of SBP » The differential would include pancreatitis ascites, Tuberculous peritonitis, malignant ascites from a hepatoma, or other cancers, as ovarian. In particular, perforation should be ruled out. In GI perforation the total ascitic white cell count is usually > 10,000, whereas in SBP it is usually < 10,000. In perforation the ascitic fluid glucose is generally low, the protein is usually high, and the LDH is equal to the serum level. In contrast, in SBP the glucose of ascitic fluid is usually >50 mg/dl, the protein content <2.5 g/dl, and the LDH less than that of serum. The finding of pneumoperitoneum on KUB or chest x-ray is not pathognomonic for perforation, as cases of spontaneous bacterial peritonitis caused by Bacteroides fragiles and Clostridia species have been seen. However, these latter organisms are not common. ■ CHRONIC ACTIVE AUTOIMMUNE HEPATITIS ■ The diagnosis may be suggested by an acute and recurrent hepatitis pattern, OR an occult liver disease that is asymptomatic, but with extrahepatic signs and symptoms. Chronic active autoimmune hepatitis is usually a disease of young people with a female predominance. Common extrahepatic associations include skin rashes, polyarthritis and ulcerative colitis. Renal involvement and cerebritis are not common. « Clinical » ACUTE AND RECURRENT HEPATITIS PATTERN An acute attack of hepatitis presents as the initial presentation of this disease in about 25% of cases. There is malaise, fatigue, dark urine and icterus. There also may be arthralgias and skin rashes. There may be a striking fever which is unusual in viral hepatitis, unless the hepatitis presents as a fulminant hepatitis. The chemical profile of autoimmune hepatitis parallels viral hepatitis. The bilirubin is elevated in various degrees depending on the severity of the disease, and the presence or absence of an associated hemolytic anemia. 20% are anicteric. The AST is usually greater than 500 u/ml. The prothrombin time is usually normal, unless there is severe injury. There is a polyclonal hypergammaglobulinemia with values greater than 3 g/dl being common. The alkaline phosphatase is elevated, but not high. The patient usually does well initially, and seems to be recovering when there is a reoccurrence of symptoms and chemical liver abnormalities. This sequence of recurrent hepatitis may be repeated several times with varying time intervals of weeks to months. Sometimes, the chemical profile returns completely to normal. Finally, over time, a subacute and chronic course will follow. ASYMPTOMATIC LIVER PATTERN Clinically, the patient may be asymptomatic for liver disease, and this is the most common type of presentation. If the patient has no extrahepatic manifestations of chronic active autoimmune hepatitis, then the abnormal liver chemical profile may be found accidentally by routine blood work. Liver biopsy at this point may point to the disease. ARTHRITIS Usually the wrists, hands, knees and ankles are involved in about 20-30% of cases. The polyarthritis episodes may be associated with skin reactions and fever which may coincide with relapses of liver disease. The arthritis is usually non-erosive. SKIN DISEASE Many types of rashes have been described. There may be maculopapular rashes, erythema nodosum, ulcers around the ankles, alopecia, palpable purpura, pigmentation and photosensitivity. The malar rash of SLE does occur but is rare. It is interesting to note that the maculopapular rashes often coincide with exacerbations of liver disease. ULCERATIVE COLITIS Ulcerative colitis is associated with chronic active autoimmune hepatitis in about 10-20% of cases, but there is no relationship between flares of ulcerative colitis and flares of liver disease. Usually, the patients are asymptomatic as far as liver disease, and abnormal liver tests are only found with routine blood work performed for an ulcerative colitis workup HEMATOLOGIC DISEASE A coombs positive hemolytic anemia can be part of chronic autoimmune hepatitis. There also may be thrombocytopenia, leukopenia and anemia. There may be an iron deficiency anemia from the ulcerative colitis. RENAL DISEASE Renal disease is distinctly uncommon, but when present there may be two types of renal disease. The first group may have membranous or membrano-proliferative glomerulonephritis, which may present as the nephrotic syndrome or mild chronic renal insufficiency. The second type of renal disease is renal tubular acidosis and an interstitial nephritis. PULMONARY DISEASE Some patients may have pleuritis with pleural effusion. Others will develop interstitial pulmonary fibrosis which usually develops years after the onset of the liver disease. It is usually steroid resistant. Pulmonary function shows restrictive lung disease. X-rays commonly involve the lower lobes with a reticulo-nodular infiltrate. Pulmonary hypertension may follow. ENDOCRINE DISEASE Some young women will present with a picture not unlike that of Cushing's syndrome. There is amenorrhea, hirsutism, acne, purple abdominal striae and truncal obesity. This may be independent of steroid treatment for the liver disease. « Laboratory » There are several serological markers that may be associated with chronic active autoimmune hepatitis. A common finding is elevation of the gamma globulin. The levels may be as high as 6-7 grams. The elevation is polyclonal and the IgG is most affected. Most series report an elevation of ANA in about 50-90%. The pattern is usually speckled or diffuse. Anti double stranded DNA is almost always negative. There may be a positive anti-smooth muscle antibody which is usually present in about 20-30% of cases. This is a non-specific finding as this antibody is present in low titer in many liver diseases. The anti-mitochondrial antibody is usually associated with primary biliary cirrhosis where the antibody is present in greater than 90%. About 20-30% of chronic active autoimmune hepatitis patients will have a positive anti-mitochondrial antibody present. Other serological markers that may be present, but non-diagnostic, are the rheumatoid factor, positive Coombs test, depressed complement and circulating immune complexes. « Differential Diagnosis » SYSTEMIC LUPUS ERYTHEMATOSUS Significant liver disease usually doesn't occur with SLE and if a patient has elevated liver tests, then chronic autoimmune hepatitis is much more likely. Other symptoms, however, are shared between the two diseases as rashes, photosensitivity, non-erosive arthritis, serositis, proteinuria, seizures, thrombocytopenia, hemolytic anemia, leukopenia, anemia and positive ANA. The frequency of involvement does vary between the two diseases. Renal and neurologic symptoms are not prevalent in autoimmune hepatitis. About 50% of SLE patients have positive anti- double stranded DNA antibodies, as opposed to autoimmune hepatitis in which it is rare. SLE patients will have immunoglobulin deposition at the dermal-epidermal junction in about 50%, and only about 10-15% in chronic autoimmune hepatitis. Smooth muscle antibodies are not seen in SLE, but there is a fairly high incidence in autoimmune liver disease. CHRONIC DRUG INDUCED HEPATITIS Several drugs may be capable of causing liver changes and a patient's medications should all be checked when there is evidence of liver disease either, overtly, or accidentally found with blood work. Aldomet is notorious as an offender. CHRONIC VIRAL HEPATITIS The chemical, clinical, radiographic and histologic features of chronic active autoimmune disease may not be separated from chronic viral hepatitis due to Hepatitis B, (either alone or in combination with the Delta virus), or Hepatitis C (non-A, non-B type). The distinction between these may depend upon extrahepatic features, serological markers, as ANA and hepatitis serology. Chronic active autoimmune hepatitis is always progressive if not treated, whereas chronic viral hepatitis is usually more benign and doesn't progress as frequently to cirrhosis. WILSON'S DISEASE Any young person that has acute or chronic liver disease with a hemolytic component and neurologic features should arouse suspicion for Wilson's disease. PRIMARY BILIARY CIRRHOSIS This disease, if typical, should cause no confusion. Typically, there is pruritus and elevation of the alkaline phosphatase in a middle aged female. In addition, there may be a keratoconjunctivitis sicca, hyperpigmentation, steatorrhea or xanthomatosis. There is a high titer of anti-mitochondrial antibody and biopsy of the liver will show the destructive necrotizing interlobular cholangitic lesions. However, about 30% of patients with primary biliary cirrhosis will have a positive ANA, and a few will have a smooth muscle antibody. « Course and Prognosis » Chronic active autoimmune hepatitis is a progressive disease that will progress to cirrhosis within 2 years if treatment is not rendered. Death may be from several associated situations such as hemolytic anemia, ulcerative colitis, pulmonary hypertension, complications of drug treatment, liver failure as variceal hemorrhage, infections and ascites. If patients are treated early with steroids when they have acute hepatitis, the prognosis seems to be better. Many patients, however, have silent liver disease clinically which progresses without symptoms until significant damage occurs. « Treatment » Most cases of chronic active autoimmune hepatitis will respond to Prednisone 60 mg or less. It is rare to increase the Prednisone beyond 60 mg per day. The aim is to reduce the Prednisone to a level that will suppress liver activity and thus suppress collagenous repair, and to achieve the lowest possible dose to avert the well-known side affects of steroids. This may be impossible. If high doses of prednisone are needed, then Azathioprine may be added so the prednisone dose can be reduced. A common scheme that sometimes gives therapeutic efficacy with few side effects is Prednisone 10-15 mg per day and azathioprine 50 mg per day. ~gyne.bin~ ■ HEMATOLOGIC DISORDERS IN PREGNANCY ■ « Idiopathic Thrombocytopenic Purpura (ITP) » ITP is characterized by a platelet count < 100,000/mm3 and a normal CBC. ITP is an immunologic thrombocytopenic purpura with development of IgG immunoglobulin antibodies that have a propensity for adhering to the platelets, and subsequently cause sequestration in the reticuloendothelial system with destruction. Platelet survival ranges from a few minutes to 2-3 days. The bone marrow shows an increase of megakaryocytes which is a response to the destruction of the peripheral platelets. There is a prolonged bleeding time. Excessive surgical bleeding is rare unless the platelet count is < 50,000. Spontaneous bleeding starts at < 20,000/mm3 platelets. Medical therapy is started when the platelet count is below 100,000 with prednisone being used at a dose of 1-1.5 mg/kg of prednisone daily in divided doses. This will result in a 60% response. If the dose in increased to 2 mg/kg then an additional 10% will respond. An attempt is made to taper the dose to maintain the platelets at 50,000. If the patient is going to respond there will be a decrease of purpura usually within 2-3 days and and increase of the platelets in 7-10 days. If the platelet count hasn't,t increased to 50,000 by 3 weeks then the treatment is unsuccessful. Splenectomy is the second line of therapy with a significant response in about 70-90%. The platelets rise immediately following surgery and are normal with 2-4 weeks. Splenectomy should be considered during the second trimester if the patient doesn't respond to drugs. The surgery may be technically difficult due to the enlarged uterus and there may be excessive blood loss. If the pregnancy is advanced into the third trimester then a C-section may be required. Circulating antiplatelet antibodies remain elevated following splenectomy and there is a danger of neonatal thrombocytopenia with fetal intracranial hemorrhage during vaginal delivery. There is no maternal platelet count that would indicate danger to the fetus. A fetal scalp blood sampling during labor or by percutaneous umbilical cord just prior to labor should be done. If the fetal platelets are < 50,000 then C-section is recommended. Gamma globulin given at a dose of .4 gm/kg over 6-8 hours daily for 5 days may result in a rapid increase in platelets but unfortunately is transient. The therapy may have to be repeated weekly. Immunosuppressive agents as azathioprine appears to be relatively safe, but cyclophosphamide should not be used as it is teratogenic. « Von Willebrands's Disease » Von Willebrands's disease is an inherited disease affecting both males and females and is caused by a deficiency of factor VIII-related von Willebrands's factor (VIII:vWF). It is usually an autosomal dominant trait but a severe phenotypically recessive form is seen. The homozygous recessive patient generally has severe bleeding. The heterozygous forms have varying levels of factor VIII and the patient can be asymptomatic or have severe bleeding. Pregnancy may increase the factor VIII in the heterozygous form and cause a reduction of bleeding. Some patients may hemorrhage at delivery. If the patient has type I disease which is the most most common form, then desmopressin may be used at a dose of 0.3-.4 ug/kg in 50 cc of normal saline infused over 30 minutes. The bleeding time, factor VIII C, factor VWF:Ag and ristocetin cofactor should be done 30 minutes and 3-4 hours after desmopressin infusion is stopped. If the patient doesn't normalize the bleeding time or factor VIII C levels are < 50% by term, then cryoprecipitate may be given at 10 bags before delivery and 10 bags every 8-12 hours with a reduction in dose to daily for about 4-5 days. If the patient should need a C-section the factor VIII C should be 80% or greater and the bleeding time normal. If the patient is hemorrhaging, then cryoprecipitate should be given at 20 bags initially and then followed by 10-15 packs q 12 hours until stable. Factor VIII concentrates have less VIII:vWF than cryoprecipitate and are less effective in controlling hemorrhage. « Lupus Anticoagulant » Lupus anticoagulant (LA) is an antibody that is directed against phospholipid surfaces such as blood cells, platelets and vascular endothelium. This immunoglobulin on the phospholipid prevents the phospholipid from interacting with the coagulation factors to form fibrin. This leads to a prolonged PTT. LA causes thrombosis and not bleeding. Pregnant patients have a hypercoagulable state and LA augments this. If a pregnant patient has the lupus anticoagulant there is fetal growth retardation and death with recurrent abortion, placental infarction and decidual vasculopathy. Aspirin at 80 mg per day may be tried. « Antithrombin III Deficiency » This is a disease that produces venous thrombosis that is inherited as an autosomal dominant trait. The patient should be told that 50% of the offspring will inherit the disease. It is estimated that it occurs as 1 in 2000. Again, pregnant patients are at higher risk because of the hypercoagulability of pregnancy. The highest risk is in the immediate postpartum period when AT III levels fall to their lowest level. Patients with AT III deficiency have plasma levels 25-50% of normal. Low AT III levels can also be seen in fatty liver of pregnancy, DIC, heparin therapy and pre-eclampsia. The level of AT III in normal term infants is 50% of the adult and most affected infants have 25-30% activity. Diagnosis is made clinically with a history of recurrent thrombosis in family members as well as the patient, thrombosis resistant to heparin, and thrombosis in unusual places as cerebral and mesenteric veins. Therapy includes anticoagulation with heparin that may be given subcutaneously during pregnancy and IV or subcutaneously post partum. Heparin is required during the first trimester because of the associated embryopathy with warfarin during the first trimester. Following the first trimester warfarin may be used because heparin will further lower the AT III levels. Coumadin is used until 2 weeks prior to delivery when the warfarin should be stopped in order to prevent bleeding in the fetus and mother. AT III concentrates can be given at this point to maintain adequate levels of AT III. Following delivery, heparin should be resumed as the mother is at particular risk during this period. Coumadin can be started at the same time. The coumadin should be continued for at least 4 months, and for life if there is a history of thrombotic events. The heparin can be discontinued when the PT is in a satisfactory range. Also, AT III concentrate can be given at the time of highest risk around the delivery period. « Disseminated Intravascular Coagulation » DIC can be triggered by abruptio placentae, amniotic fluid embolus, dead-fetus syndrome, sepsis, and preeclampsia and eclampsia. Liberation of thromboplastin from injured or necrotic tissue activates the extrinsic system. Endothelial cell injury will also activate the Hageman factor and the intrinsic clotting system. The last mechanism producing DIC is injury to red cells or platelets which will then release phospholipid and this starts the intrinsic and extrinsic system. Thromboplastin activation causes release of tissue plasminogen activator which converts fibrin bound plasminogen to plasmin which in turn will lyse fibrin and fibrinogen with subsequent production of fibrin degradation products. These fibrin degradation products interfere with fibrin polymerization, and they also coat platelet membranes which makes the platelets unable to function. DIC is diagnosed with decreased platelets, prolongation of the PT, PTT, decreased fibrinogen and increased fibrin degradation products, shortened euglobulin clot lysis time and decreased antithrombin III. There is oozing at venipuncture sites, purpura, petechiae, thrombotic or embolic events, and minor or generalized bleeding. Treatment of DIC is directed at the underlying cause. This means treatment of sepsis and delivery of the infant. Fibrinogen should be kept at more than 100 mg/dL with fresh frozen plasma or cryoprecipitate. The platelet count should be kept > 50,000/ml and the hematocrit > 30%. Packed RBCs are deficient in several coagulation factors and fresh frozen plasma should be used to supply these factors in a ratio of 1 unit of fresh frozen plasma for every 4 units of packed RBCs given. Antithrombin III concentrates or fresh frozen plasma which contains some antithrombin III may be given for the depleted antithrombin III. « Abruptio Placentae » Abruptio placentae is the most common cause of DIC in pregnancy. Approximately 10% of abruptio placentae will develop DIC. If cesarean section is needed then fresh frozen plasma should be given prior to surgery to raise the fibrinogen above 100 mg/mL. However, vaginal delivery is better if there is no fetal distress and the fetus is dead as happens in about 38% of abruptio. « Fetal Death Syndrome » Thromboplastin from the dead fetus is released very slowly and causes DIC. The defibrinogenation is much slower than in abruptio placenta. A decreased fibrinogen level is seen 2-5 weeks following the intrauterine fetal death. Treatment should consist of induction of labor or D & C as soon as the diagnosis of fetal death is made. Within twin gestation, the release of thromboplastin may jeopardize the viable infant causing thrombotic events that could lead to renal or neurological damage and death. Therefore, if fetal maturity is present, then the viable twin should be delivered immediately. If there is still immaturity then the viable twin should be monitored with ultrasound for growth and any changes in the brain. The mother should also be followed closely for development of DIC. Heparin may be given if patient is not in labor giving 5000 units as an IV bolus followed by 1000 units per hours in order to keep the PTT between 1.5 and 2.5 times control. Induction of labor can start 6 hours after the heparin is discontinued. If patient is in labor given cryoprecipitate to keep the fibrinogen between 200- 300 mg/dL. « Amniotic Fluid Embolus » Amniotic fluid embolus is a rare disease but can be fatal to the mother in 80% of cases. The incidence is 1 per 8000 to 80,000 live births. Presentation is with shock, chest pain and dyspnea. It is more common in multigravid patients, tumultuous labor, first stage of labor and rupture of membranes. Death occurs in the first hour in 25%. Therapy includes cryoprecipitate and volume replacement with support by positive end expiratory pressure, pressor agents and possibly aminophylline and digoxin. « Sepsis » Can occur with septic abortion, pyelonephritis, infected amniotic fluid and endometritis. The bacterial endotoxins will decrease platelets and fibrinogen. Treatment consists of antibiotics, removal of infected material, restoration of platelets, volume and factors. Shock is monitored with Swan-Ganz and arterial lines. « Preeclampsia and Eclampsia » There can be a low grade DIC, but thrombocytopenia is the principal defect. The fibrinogen is usually normal, but fibrin degradation products are elevated and there is a reduction of antithrombin III. Treatment is delivery and replacement of deficient coagulation factors. ■ CONTRACEPTION (NEWER METHODS) ■ « Norplant » The Norplant subcutaneous implant was approved in December of 1990. Because there are menstrual irregularities associated with its use, about 50% will have the implant removed after about 3 years. About a third will complete the 5 year treatment, and of these, about 3/4 will request a renewal with the implant. In spite of this, it is convenient, and compliance is not an issue, and it is rapidly reversible, with immediate return to fertility. Six non-biodegradable silicone rubber capsules containing a total of 36 mg of levonorgestrel are buried in the subcutaneous tissue of the arm and these release about 30 ug per day. This will prevent contraception by suppressing ovulation and also by producing a thick cervical mucus which inhibits the sperm entry. The failure rate in the first year is 0.04% and 1.1 percent in the fifth year. If the patient is obese there has been shown to be a higher failure rate. In about one third of patients there will be irregular bleeding and prolonged bleeding and in some, particularly later, will have amenorrhea. The irregular bleeding improves with time and after about 1 year there may be regular bleeding that is timely. (at 2 years about 60% will have regular bleeding). If the patient does experience troublesome bleeding, and wants to remain with the system, then they may be treated with ethinyl estradiol .05 mg for 20 days (best for controlling irregular bleeding), OR conjugated estrogen 1.25 mg for 1-3 weeks, OR levonorgestrel, .03 mg bid for 20 days OR Ibuprofen 800 tid for five days. (Ibuprofen is best for reducing the length of bleeding). These are all started on the 8th day of the cycle. Of these, Levonorgestrel is the least effective. The best candidates for the Norplant system are those patients who have a contraindication to estrogen, women who can't comply with daily doses of oral contraceptives, those patients who smoke and are older than 35 and want contraception, and those that may want an immediate return to fertility. The absolute contraindications are undiagnosed vaginal bleeding, active liver disease, benign or malignant liver tumors, known or suspected breast cancer, active thrombophlebitis or thromboembolic disease, and pregnancy. If patients are concurrently taking drugs such as phenobarbital, anti-seizure drugs and rifampin, the serum levels of the levonorgestrel may dip to below therapeutic and protective levels with pregnancy resulting. The average cost for 5 years of treatment varies, but at the current time is $ 450.00 - 750.00. Some insurance carriers cover this type of contraceptive. « Depo-Provera » Depo-Provera (medroxyprogesterone acetate or DMPA) was approved in the USA in the late part of 1992. It is estimated that more than 9 million women world-wide are using this form of contraceptive. Its use equates with sterilization as far as efficacy. Of course, if the patient doesn't return to the doctors office at 3 month intervals, then the efficacy is diminished. This is the critical factor, for the patient will have to return 4 times a year to the physician's office for injection. The typical pregnancy rate for the first year is estimated to be .3% and, 0.9% for the five year cumulative rate. The cost varies, but in general at the current writing, is about 25-50 dollars for a 3 month period. DMPA will reduce the risk of ovarian and endometrial cancers and helps endometriosis. The overall risk for breast cancer is not increased. There may be a minor increase in cervical cancer and patients should be monitored with PAP smears. DMPA has a tendency to reduce sickle cell crises and seizures. Protection is afforded immediately after the 150 mg intramuscular dose is given. Patients should be told not to rub the injection site as this has been shown to shorten the efficacy. Like the Norplant system, DMPA works by thickening the cervical mucous and preventing ovulation. The dose is usually given during the first 5 days of menses so that pregnancy will be averted and no back up method of protection is required because of the instant protection. Menstrual cycles are going to change, just as with the Norplant. There will be spotting and bleeding and most will eventuate with amenorrhea which is different course than the Norplant. One cannot predict the menstrual irregularities. Minor side effects may occur as weight gain, nausea, headaches, dizziness mood changes, hair loss, depression and decreased libido. The lipids may change with minor decreases of the HDL and increase of the LDL. If the patient has hyperlipidemia, this may be a relative contraindication. For post partum protection, the drug should be given within five days of delivery for non-lactating women, and at six weeks for lactating women. It is probably safe for women who breast feed. DMPA is also useful for post-abortion. The usual absolute contraindications are essentially those associated with the Norplant system (see Norplant). One major drawback for the injectable DMPA is that the median period for return to fertility is about 9-10 months. This may not be agreeable for some women who may want to become pregnant sooner. About 70% of women will become pregnant within 1 year after stopping DMPA, and 85% will return to fertility by 2 years. « Post Coital Morning after Protection » Even though this is not a new method of treatment it is presented so that it can be compared with Mifepristone, which will probably be approved soon. Norgestrel .5 mg and ethinyl estradiol 50 ug (Ovral) has been used, giving two tablets within 72 hours after coitus when barrier methods fail, or there is unplanned intercourse. With this, the endometrium sloughs, which makes nidation unfavorable. Difficulties with this therapy is that the high dose may cause vomiting with poor absorption. Giving the medication with an anti-emetic will help. A better morning after drug that will probably soon be available will be Mifepristone (RU 486). This has been used in Great Britain for some time. The advantage to RU 486 is that this medication may be given past the 72 hour period. ~hema.bin~ ■ POLYCYTHEMIA VERA ■ Polycythemia vera (Vaquez-Osler disease is a myeloproliferative disease with monoclonal stem cell proliferation of all three hematopoietic cell lines (erythroid, myeloid and megakaryocytic elements of the bone marrow). There is no known genetic transmission and the incidence in the USA is .5 per 100,000. Males are affected slightly more than females. The usual age of presentation is around 60 years of age, but can range from 15-90. « Causes » Polycythemia vera always has to be differentiated from spurious polycythemia (increased Hb with a normal or high normal RBC mass and reduced plasma volume). This can be due to diuretic therapy and hypertension. Spurious polycythemia can result in thrombotic events. Treatment would be to decrease the diuretics and find out why the plasma volume is decreased. Secondary polycythemia would also have to be ruled out. This results in an increased RBC mass and Oxygen saturations of <90%. The hypoxia leads to increased erythropoietin levels and subsequent secondary polycythemia. Patients with this pattern should have renal ultrasonography or CT scan to rule out hepatoma, cerebellar hemangiomas, uterine fibromas, renal cysts and tumors which cause compression of intrarenal vessels and local hypoxia. Arteriography may be needed. In some patients with chronic lung disease there is a diurnal pattern and hypoxia only occurs at night. Therefore, night time oximeter studies or blood gases should be done. Pulmonary disease and right to left shunts would have to be ruled out, but the latter usually occurs during childhood. Hemoglobinopathies can also present with polycythemia because there is increased oxygen affinity and reduced unloading of oxygen. This results in a shift in the oxyhemoglobin dissociation curve and an increased O2 concentration at which 50% O2 delivery occurs. Hemoglobin electrophoresis should be done to rule out abnormal hemoglobins as Ranier, Chesapeake, Kempsey, and Yakima. Increased carboxyhemoglobin levels due to CO2 in cigarette smokers with a level greater than 6% can cause polycythemia. « Laboratory » The following findings may be present Polycythemia vera. Increased RBC mass in females > 32 mL/kg and in males > 36 mL/kg, Normal arterial oxygen saturation greater than 92%, Splenomegaly, Thrombocytosis with platelets > 400,000, Leukocytosis > 12,000, Leukocyte alkaline phosphatase, Increased serum B12 and increased unsaturated vitamin B12 binding capacity (transcobalamin), Elevated uric acid, cholesterol, histamine and basophils (greater than 40/mm3), Erythropoietin levels are low to normal (3-5 U/d in 24 hour urine. (In secondary anemic and secondary polycythemia these will increase to 30 U/d), Plasma volume is increased in 60% of polycythemia vera cases and reduced in stress polycythemia, Hemoglobin electrophoresis is normal in polycythemia vera but abnormal in hemoglobinopathies. CarboxyHgb levels are increased in smoking, Bone marrow biopsy will show RBC hyperplasia, absent iron stores and fibrosis during the spent phase of polycythemia vera. There is panmyelosis. There are larger megakaryocytes unlike chronic myeloblastic leukemia and secondary causes of elevated platelets. « Diagnosis » Increased RBC mass + normal oxygen saturation + splenomegaly OR Increased RBC mass + normal oxygen saturation + any two of the following: thrombocytosis, leukocytosis, leukocyte alkaline phosphatase, B12 or vitamin B12 binding capacity. « Symptoms and Signs » There may be headaches, fatigue, dizziness, pruritus after warm baths, conjunctivitis, plethora, tinnitus, blurred vision, epistaxis, spontaneous bruising, sweating, arterial and venous occlusive events, weight loss, upper GI bleeding with peptic ulcer disease, splenomegaly, hepatomegaly, bone pain and tenderness of ribs and sternum. « Complications » Budd-Chiari syndrome due to hepatic venous occlusion, mesenteric artery thrombosis, gout, vascular thrombosis as stroke and myocardial infarction, hemorrhage, peptic ulcer, leukemic transformation and increased risk for complications and mortality form surgery. Patients should not undergo surgery until the polycythemia has been corrected. « Treatment » Polycythemia vera is managed by phlebotomy, but when done alone there may be an increased incidence of thrombotic events in the early stages. Adding alkylating agents to phlebotomy will reduce the thrombotic events but there be increased transformation to leukemia. Hydroxyurea may not cause this increased rate of transformation. Allopurinol 300 mg/day is used for uric acid reduction, Cyproheptadine 4-16 mg can be used for pruritus and H2 receptor blockers for GI hyperacidity. Low dose aspirin to treat the potential proclivity toward thrombosis is controversial because of the associated bleeding. The goal of phlebotomy is to reduce the hematocrit to about 45%. Phlebotomy can be performed as often as every 2-3 days with 250- 500 cc removed unless the patient is elderly and has cardiovascular disease then reduce. ■ MULTIPLE MYELOMA ■ Multiple myeloma is an abnormal proliferation of transformed plasma cells in the bone marrow that are capable of secreting an M-protein that can replace the bone marrow with production of anemia, and also incite bone destruction with bone pain, osteoporosis, lytic lesions and pathologic fractures. The incidence of myeloma is estimated at 2 to 3 per 100,000 persons. Men and women are affected equally and the median age is 60 years of age. The incidence increases with age. There is a higher incidence in blacks. « Clinical » Any elderly anemic patient that complains of back pain or rib pain should be suspect for Multiple Myeloma. A normocytic normochromic anemia is present in almost all patients as a consequence of tumor related inhibition of erythropoiesis and bone marrow crowding. There may be a shortening of red cell survival, iron deficiency and blood loss. If the patient's multiple myeloma is treated the anemia will improve. Myeloma cells are capable of elaborating osteoclast activating factors which causes osteoclastic induced osteoporosis and lytic lesions. Pain can be the presenting symptom in over 70% of patients. The pain in the back and thoracic area is unlike the pain of metastatic carcinoma which is worse at night. The pain of myeloma is made worse by movement. If there is sustained pain this may indicate a pathologic fracture. Patients with multiple myeloma are susceptible to increased infections usually involving the lungs and kidneys. The most frequent bacteria causing pyelonephritis are Escherichia coli and gram negative organisms. Pneumonias are caused by Staphylococcus aureus, Streptococcus pneumoniae and Klebsiella pneumoniae. The presenting symptom may be recurrent pneumonias which is a tip off as to the etiology. Pneumococcal vaccine may be some benefit. Renal failure occurs in about 1/5 of patients and is due to to a combination of L chains, uric acid, infection, calcium and amyloid. Calcium nephropathy may be the most common cause but Bence Jones proteinuria is important. Hypercalcemia as a result of increased osteoclastic activity in bone can cause symptoms as confusion, etc. Hyperviscosity may cause mucosal bleeding, visual disturbances, mental alterations and vertigo. However, these symptoms are less common than in Waldenstrom's macroglobulinemia. Coagulopathies, by binding of factors I, II, V, VII, or VIII with the M-protein, may occur. Spinal cord compression may occur in conjunction with the lytic bone lesions producing typical symptomatology. « Laboratory » Patients almost always have a normochromic normocytic anemia. Patients suspected of myeloma should have both serum and urine protein electrophoresis (24 hour quantitative urine) and immunoelectrophoresis evaluated. Most patients (80%) will have a paraprotein M spike in the beta or gamma globulin region of the serum protein electrophoresis. If there is no evidence of the spike on serum then the urine protein and immunoelectrophoresis will demonstrate either a complete immunoglobulin or light chains, and the serum protein electrophoresis will demonstrate a hypogammaglobulinemia. Sixty percent of multiple myeloma patients will have an IgG paraprotein, 25% an IgA and 15% light chains only. Just finding a spike does not make a diagnosis of multiple myeloma as the spike may represent a benign monoclonal gammopathy (( monoclonal gammopathy of unknown significance (MGUS)), or a spike produced by malignant lymphoproliferative diseases as lymphomas, primary amyloidosis and Waldenstrom's macroglobulinemia. Most patients with MGUS have a monoclonal IgG spike of less than 2.5 g/dL and the height of the spike remains stable. Most patients that have an IgG spike greater than 3.5 g/dL have myeloma and an IgA spike of greater than 2 g/dL is usually due to multiple myeloma. Dipstick determinations of protein are useless in detecting the Bence Jones protein, but sulfosalicylic acid and toluene sulfonic acid can be used as screening tests. Bone marrow exam usually shows increased numbers of plasma cells at various stages of maturation numbering from 5% to 100%. Sheets or clusters of plasma cells may occur, but myeloma is a patchy disease. Bone scans are of no help as the lesions are osteolytic. The Westergren sedimentation rate is often elevated to levels above 100 mm/h. The BUN, and creatinine may be elevated if there is renal involvement. The uric acid may be elevated along with the calcium. There may be a low anion gap and the beta-2 microglobulin is usually elevated which may reflect the myelomatous burden. « Treatment » The patient may be treated with Melphalan given intermittently at 0.25 mg/kg/day for 4 days q 4-6 weeks or continuously, 0.09 to 0.14 mg/kg/day for 8-10 days followed by 0.03 mg/kg/day for maintenance. Prednisone is usually given with this, intermittently, at 1 mg/kg/day for 4 days q 6 weeks. This protocol will result in an objective response in about 60% of patients. The dose will have to be titrated as leukopenia and thrombocytopenia will develop. Bone marrow transplantation is experimental in young persons. If there is hypercalcemia between 10.5 and 12 mg/dl then hydration with IV saline and furosemide can be given. If renal function is normal and there is no hyperphosphatemia then oral bisphosphonates as etidronate may be used. Calcium levels greater than 12 usually need more aggressive treatment with hydration, IV etidronate or pamidronate or gallium nitrate and calcitonin. The patient should avoid immobilization as much as possible. For localized pain that does not respond to chemotherapy and is intractable, low dose palliative radiation may be given. Also, patients with impending or pathologic fractures should have these fractures stabilized and tumor removed. If there is back pain and tenderness, and neuropathies then the possibility of cord compression must be entertained. MRI and myelography will aid in the diagnosis. If cord compression is found, emergency radiation and steroids should be given. Patients may have permanent paralysis if there is a delay in the diagnosis greater than 12 hours. Plasmapheresis should be used for reducing the serum viscosity. This will rapidly reverse the bleeding and neurologic abnormalities. « Prognosis » With treatment, many patients will survive for greater than 5 years. Before chemotherapy was available patients survived for less than 1 year. For those that do relapse or do not respond to conventional chemotherapy a trial of VAD (vincristine, adriamycin and dexamethasone) or BCNU (cyclophosphamide, carmustine, vincristine and prednisone) may be given. ■ SICKLE CELL ANEMIA ■ Sickle cell anemia is a hemoglobinopathy transmitted as an autosomal recessive in blacks and characterized by a a chronic hemolytic anemia, episodes of painful crises and increased infections. The homozygous form is known as sickle cell disease and the heterozygous form is the sickle cell trait. In sickle cell disease there a functional asplenia and delayed physical and sexual maturation. Hemoglobin S is manufactured by a substitution of valine for glutamic acid in the sixth amino acid position of the beta chains of the hemoglobin molecule. If Hemoglobin S becomes deoxygenated, the characteristic sickling begins. The sickle cells are rigid and fragile and cause stasis and blockage of small arterioles and capillaries which causes ischemia and infarction. As a result, sickle cell complications can be divided into several types as: VASO-OCCLUSIVE Vaso-occlusive or painful crisis is the most common. One type of painful crisis is the Hand-foot syndrome which occurs only in infants and children. In children and adolescents, pain is common in the abdomen, chest and extremities. Adults will have pain in the low back and the extremities. The pain crises will usually last 2-6 days. HYPERHEMOLYTIC CRISIS In Hyperhemolytic crisis there is an increase in the intensity of hemolysis and this can be precipitated by bacterial infections. SEQUESTRATION CRISIS Sequestration crisis causes the abnormal cells to be trapped in the spleen. This condition occurs only in infants and young children. The condition usually occurs below the age of 2 and presents as a life threatening anemia which is extremely rapid with engorgement of the spleen and depletion of the red cell pool. Sequestration is frequently triggered by a viral infection. SUSCEPTIBILITY TO INFECTION Susceptibility to infection is increased because of a poorly functioning spleen and a defect in the alternate pathway of complement activation. Patients are particularly susceptible to Haemophilus influenzae and Streptococcus pneumonia because of autoinfarction of the spleen. Patients that are treated with deferoxamine for iron binding can be infected with Yersinia entercolitica and present as an acute abdomen. Salmonella typhimurium osteomyelits can occur also. APLASTIC CRISIS Aplastic crisis is frequently triggered by the parvovirus B19, the virus that causes erythema infectiosum. In this condition, there is a marked decrease of red cell precursors in the bone marrow with a severe diminution in the hemoglobin and reticulocyte count. This will last about 1-2 weeks. Many complications may results from Sickle cell anemia such as the following: The Acute chest syndrome which is caused by infarction and or infections and may be difficult to differentiate. The syndrome is characterized by chest pain, dyspnea, cough, fever and lung infiltrates. Patients may develop chronic leg ulcers, priapism, bone infarcts, aseptic necrosis of the femoral head, CVA's manifested by strokes in children and hemorrhage in adults, gall bladder stones, hematuria and hyposthenuria resulting from microvascular infarction of the renal medulla (can occur in Sickle cell disease or the trait), osteomyelitis, meningitis, pyelonephritis, hemosiderosis from multiple blood transfusions and cardiac enlargement and its sequelae. Any condition that leads to dehydration, acidosis, hypoxia, exposure to cold or strenuous physical exercise can induce sickling and subsequent crises. Pregnancy can be difficult and dangerous, especially the 3rd trimester and during delivery. There may be toxemia, phlebitis, pulmonary infarction and increase in infections and severity of the crisis. There is an increase of abortions and stillbirths with a fetal mortality that may approach 35-40%. Placental infarction can occur and result in low birthweight. « Laboratory » The Sickledex test is usually performed for screening. Following this a hemoglobin electrophoresis can be done which will show a predominance of Hemoglobin S, no Hemoglobin A, and varying amount of hemoglobin F. There is a reticulocytosis usually between 10-20% and leukocytosis. Band forms are normal in the absence of infection. The bilirubin is usually mildly elevated and the fecal and urinary urobilinogen high. There is a chronic anemia. « Treatment » INFECTION In a patient in whom you suspect infection the following should be obtained if appropriate in the clinical setting: blood cultures, CBC, reticulocyte counts, chest x-ray, lumbar puncture, and arterial blood gases. Antibiotics should be started such as cefuroxime which will cover S. pneumoniae and ampicillin resistant H. influenzae. Hydration should be maintained at 1.5 times daily maintenance fluid requirements. Penicillin prophylaxis (Penicillin V 125 mg bid beginning at the age 3 months; the dose is increased to 250 mg bid at 3 years of age. Erythromycin can be used if the patient is allergic to penicillin), Pneumococcal vaccine, hepatitis B vaccine, haemophilus b and meningococcal vaccines should all be given to children. A booster dose of pneumococcal vaccine may be needed at about 5 years of age. The risk of meningitis and septicemia is highest in the first decade of life but declines after this. LUNG DISEASE Infectious lung disease is often caused by Mycoplasma pneumoniae, S pneumoniae and H influenzae. Analgesics are needed but not in doses that will suppress breathing. Nerve blocks may be needed. Hydration and and oxygen are important. In 50% of the cases, an infectious cause cannot be found and the acute chest syndrome may be caused by pulmonary infarction or fat embolism. Bone marrow necrosis occurs which causes the fat embolism. Symptoms of fat embolism include lipemia retinalis, upper thorax and conjunctivae petechiae, confusion, dyspnea, thrombocytopenia, hypocalcemia, hyperuricemia and severe bone pain. Obtain a urine, sputum and biopsy of petechiae. These will show the lipid droplets. Treatment for fat embolism is early exchange transfusion. Ventilation/perfusion scan and pulmonary arteriograms may be necessary. Blood transfusion should be given to keep the hemoglobin S at less than 50%. SPLENIC SEQUESTRATION Splenic sequestration is seen in children mainly, but rarely can be seen in adults. Blood transfusion therapy to maintain the hemoglobin levels between 10 and 11 grams should be given. If the patient has repeated or life threatening sequestration then splenectomy may be needed. APLASTIC CRISIS Parvovirus usually precedes the aplastic crisis producing a severe anemia and reticulocytopenia. Blood transfusions are needed to maintain the hemoglobin until there is spontaneous resolution of the bone marrow which may occur at about 10 days. CENTRAL NERVOUS SYSTEM Cerebral infarction usually occurs in children under the age of 10. MRI should be done and the patient treated immediately with exchange transfusions followed by chronic transfusion and chelation for at least 3 years, maintaining the hemoglobin levels between 10 and 11 grams per dl and the hemoglobin S at less than 30%. If, in spite of this, there is continued infarction, the transfusion should be increased to keep the Hemoglobin S less than 15% and give ASA or dipyridamole. Cerebral hemorrhage (intracerebral and subarachnoid) occurs in older patients and should prompt an arteriogram, which should be preceded by an exchange transfusion, because the contrast load will increase the sickling. EYE DISEASE Sickle cell retinal proliferative disease can occur in sickle cell disease, but is more common in Hb SC or Hb S Thalassemia. Patients may develop hyphema after ocular trauma with increased intraocular pressure. Laser photocoagulation can prevent bleeding and retinal detachment. Vitrectomy or scleral buckling procedures may be needed. If these are done patients should have prior exchange transfusion, oxygenation, and hydration. RENAL DISEASE A painless type of hematuria occurs with sickle cell disease and trait. One must rule out other causes of hematuria such as renal calculi, AV malformation and infection. Papillary necrosis is common. Treatment includes alkalinization of the urine, hydration, and bed rest. If the bleeding is refractory, epsilon aminocaproic acid can be used at a dose of 2-8 grams per day. Be aware that Amicar can cause clot formation in the ureter and renal pelvis. Therefore, hydration should be maintained to keep urinary output at 3 ml per kg per hour. Erythropoietin appears to decrease the need for transfusion requirement in those with chronic renal disease. GALL BLADDER DISEASE Bilirubin levels may reach very high levels such as 40 mg/dl with cholestasis. These patients may be asymptomatic. The transaminases are usually less than 300 IU per liter. Only supportive care is needed as this benign form will resolve in about one month. If there is progressive cholestasis with fever and hepatic failure, exchange transfusion may be needed. The large load of bilirubin leads to gallstones. Surgery is recommended if there are common duct stones causing obstruction, cholecystitis associated with bacteremia or two or more episodes of cholecystitis. The cholecystectomy should be delayed for about 6 weeks if possible to decrease the risk of thrombosis. Pre- surgery exchange transfusions should be given to prevent thrombosis. PRIAPISM The priapism may be sustained for many hours or there may be minor episodes of stuttering priapism. The pain may be relieved somewhat with warm baths, and masturbation. Nifedipine 10 mg bid or tid may be of some benefit in minor episodes. For sustained episodes, hydration, analgesics, aspiration and exchange transfusion should be done. If there is no improvement after 36 hours, a more definitive surgical approach should be considered such as the Winter procedure, as impotence increases after 36 hours. ORTHOPEDIC Avascular necrosis of the femoral head can occur and should be suspected if a patient has a limp, pain in the hip and MRI is compatible. Replacement of the hip joint may be needed. The hand- foot syndrome is common in children and should be treated with analgesics and hydration. Any one with bone pain and fever should be suspect for osteomyelitis. Differentiation from bone infarction may be difficult. Aspiration for culture should be done. ■ CARCINOMA OF UNKNOWN PRIMARY SITE ■ Occasionally you will encounter a patient, that after all of the laboratory workup, and a complete history and physical, there will be no obvious primary site for cancer. The physical examination should involve a good testicular, pelvic, breast, rectal, lymph node and skin exam. The histo-pathologic exam is very important in leading one to a correct primary site, so that the patient may be treated with the appropriate medication. There should be an adequate specimen that may be subjected to electron microscopy, and histochemical and immunohistochemical staining. The specimen should be divided into three parts: One part is put in formalin for routine studies. The second portion should be frozen without fixation, and this is used for immunohistochemical studies. The last part should be placed in glutaraldehyde for electron microscopy. If the pathologist's report returns as a poorly differentiated or poorly differentiated adenocarcinoma, which occurs in about 35% of patients, it is incumbent on the physician to obtain further work-up as about 30-70% of this group will have a non-Hodgkin's lymphoma. Base line studies would include beta-hCG, alpha-fetoprotein, serum prostatic specific antigen, acid phosphatase and CT of chest, abdomen, pelvis and mammography. Immunoperoxidase staining should be done against the leukocyte common antigen (for lymphoma), cytokeratin (for carcinoma), prostate specific antigen (for prostate carcinoma), thyroblobulin (for follicular thyroid carcinoma), S-100 protein, HMB-45 antigen, vimentin, (for melanoma), chorionic gonadotropin, alpha-fetoprotein (for germ-cell tumors), neuron specific enolase, chromogranin (for neuroendocrine carcinoma), calcitonin (for medullary thyroid carcinoma), desmin (for rhabdomyosarcoma), and factor VIII antigen (for angiosarcoma). Any person that is less than 50 years of age, who has a poorly differentiated carcinoma involving the midline structures of the mediastinum and retroperitoneum, with or without bilateral pulmonary nodules, should be classified as the extra gonadal germ cell cancer syndrome. These patients will respond to a cisplatin based chemotherapy that is used in testicular cancer as VIP (VP-16, ifosfamide, cisplatin) OR a combination of bleomycin, etoposide, and cisplatin. Symptoms and signs should dictate which testing will be most suitable. If a patient has chest symptoms and x-ray mediastinal involvement, then fiberoptic bronchoscopy should be done. If a patient has an adenocarcinoma involving the axillary lymph nodes then they should receive mammography and measurement of estrogen and progesterone receptors. Modified radical mastectomy could be done in these patients as 40-70% of patients will harbor an occult tumor that is usually less than 2 cm in diameter. In general, the prognosis equates with that of a stage II breast cancer. Adjuvant therapy may also be carried out. Male patients that have osteoblastic metastasis should have a serum prostate specific antigen and immunoperoxidase PSA done. Any woman that has peritoneal metastasis should have cytoreduction by exploratory laparotomy as many will have carcinoma of the ovaries. Squamous cell carcinoma is found in 70% of patients from lymph nodes located high in the neck or midneck. Biopsy of these nodes is controversial because of presumed increase of local reoccurrence, wound necrosis and metastasis. Fine needle aspiration may be used as a substitute. The most common carcinomas in this group would include tonsil, base of tongue, nasopharynx and hypopharynx. These patients should be examined with pan-endoscopy and biopsy and MRI of the neck. If a primary site cannot be determined after this, the patient should be treated anyway, because those that have upper and mid-cervical involvement, and subsequently have neck dissection followed by radiotherapy, have a 5 year survival of 30-50%. Even unknown low-cervical nodes without a primary should be treated, but the results are not as good. If there is involvement of the lower neck and supraclavicular areas, then cancer of the lung would be suspected. Fiberoptic bronchoscopy should be done. Occasionally metastatic squamous carcinoma will metastasize to the inguinal areas. If after an exhaustive search for this subset of patients, no primary site can be determined, they should be treated with inguinal lymph node dissection with or without radiation because long term survival has been shown. Usually, however, lymph node involvement in the inguinal area would dictate an anoscopic and colposcopic exam. Many patients with carcinoma of the penis, vagina, anus, vulva and cervix can be cured. Occasionally, one finds only one solitary lymph node in the axillary, cervical or inguinal lymph nodes, and no primary site can be found. These patients should probably be treated, although the response and long term results are poor.There has been some response in 20-40 percent with a 6-8 week trial of combination therapy with fluorouracil, doxorubicin, mitomycin and cisplatin combinations. If there is a response, then continue therapy for 4-6 months. Some poorly differentiated cancers will present as neuroendocrine tumors that can be diagnosed by electron microscopy. These tumors are aggressive and should be treated, as many of these will be sensitive to Cisplatin regimes as cisplatin, etoposide, and bleomycin. ~infe.bin~ ■ HIV AND THE CNS ■ Patients that have HIV are prone to several opportunistic infections and to the HIV virus itself. By far the most common lesions producing focal neurologic deficits are CNS lymphoma and cerebral toxoplasmosis. Other possibilities include bacterial brain abscesses, tuberculomas, fungal abscesses and progressive multifocal leukoencephalopathy (PML). « Cryptococcal Meningitis » Cryptococcal meningitis usually presents with headache, and fever. Lab should include a serum cryptococcal antigen, and the cerebrospinal fluid may show a low glucose and positive India ink stain and cryptococcal antigen. The cryptococcal antigen titers are often very high (greater than 1:1000). However, CSF values may be deceivingly normal. There is usually a CSF pleocytosis of about 20 cells/ul, predominantly lymphocytes, and elevated protein. Cultures for Cryptococcus neoformans is usually positive, but may take several days. Treatment is with Amphotericin B 0.5-1 mg/kg/d until the patient is improved, and then followed by suppressive therapy with Fluconazole 200 mg PO qd OR Itraconazole 200 mg PO qd OR Amphotericin B, 1 mg/kg/wk IV. MRI is more sensitive than CT for detecting the punctate disseminated lesions of cerebral cryptococcosis. « Toxoplasmosis » Toxoplasmosis HIV patients with a low CD4+ cell count of less than 200/mm3 may present with a new headache, seizures or focal neurologic signs. MRI should be done as it is more sensitive for small lesions than CT with contrast. Multiple discrete lesions that have a ring shaped appearance with contrast enhancement, and located in the basal ganglia or deep in the cerebral hemispheres, is likely to be Toxoplasmosis. A Toxoplasmosis titer should be done as a negative titer indicates that Toxoplasmosis will be present in < 5%. Toxoplasmosis is usually due to reactivated infection. If titers are elevated and the patient has no symptoms, then no treatment is needed. Patients with typical brain lesions are usually empirically treated for at least 2 weeks to see if there is a favorable response. If there is no response to therapy within 2 weeks, or the patient develops toxicities from the therapy, then a brain biopsy is indicated. Treatment is with Pyrimethamine 100 mg/d PO + Folic acid 10 mg/d PO + Sulfadiazine 1 g PO qid for 6-8 weeks, followed by suppressive therapy with Pyrimethamine 25-50 mg/d + Folinic acid 10 mg/d + Sulfadiazine 2-4 g PO qd. An alternative approach would be to give Pyrimethamine 100 mg/d PO + Clindamycin 300-400 mg IV q6h or 600 mg PO q6h, followed by suppressive therapy with Pyrimethamine 25-50 mg/d + Clindamycin 300 mg PO q6h. If there is cerebral edema and increased intracranial pressure add IV steroids. Neutropenia is a major side effect of Pyrimethamine. Rash, fever and renal stones can occur with Sulfadiazine. Clindamycin may cause diarrhea, rash and fever. « CNS Syphilis » CNS Syphilis is characterized by a positive VDRL in the CSF. MRI of neurosyphilis is characterized as patchy areas of enhancement in the basal ganglia or middle cerebral artery territories. Treatment for neurosyphilis is with Aqueous penicillin G 12-24 million U/d IV giving 2-4 million U IV q4h for 10-14 days, followed by benzathine penicillin G 2.4 million U/wk IM for 3 weeks. If the patient is allergic to penicillin, desensitization to penicillin is recommended. Rash and fever are common side effects. « HIV Dementia » HIV Dementia presents early as acute aseptic meningitis and then later the patient develops cognitive slowing and diffuse cortical atrophy on CT. Treatment is with Zidovudine 200 mg PO 5-6 times per day. MRI may show large confluent patches similar to CMV lesions. « Cytomegalovirus Encephalitis » Cytomegalovirus Encephalitis is treated with Ganciclovir 5 mg/kg IV q 12h or Foscarnet 60 mg/kg IV q8h. Side effects of Ganciclovir include neutropenia, thrombocytopenia and anemia. Side effects of Foscarnet include nephrotoxicity, hypocalcemia and nausea. The MRI may show large confluent patches. « CNS Lymphoma » If a single lesion on MRI is seen as a bulky periventricular lesion, then lymphoma is likely. « Progressive Multifocal Leukoencephalopathy » Progressive Multifocal Leukoencephalopathy is due to a parvovirus and is characterized on the MRI as multiple discrete lesions with ill-defined borders, in contrast to the multiple discrete lesions of Toxoplasmosis which often times have well defined borders. PML is treated with Cytarabine in some cases. Bacterial meningitis is not more common among HIV infected patients but can occur. Herpes virus infections due to herpes can also occur. MRI is more sensitive than CT in demonstrating the early temporal lobe lesions of herpes simplex encephalitis. ■ LYME DISEASE ■ Lyme disease is a caused by the spirochete Borrelia burgdorferi, and transmitted mainly by the Ixodes dammini tick bite. This same tick also spreads babesiosis. Lyme disease occurs most commonly in children under 15 and the 25-44 year age group. The prevalence in the USA varies, but is more frequent in the Mid Atlantic area, followed by the New England area, North Central states, the Pacific states and the Southeast and Southwest. The mountain region has the lowest rate. The highest incidence is during the summer months from May to September. Typically, the disease is divided into 3 stages as follows: STAGE 1 Stage 1 is characterized by a an expanding painless, non- pruritic, erythematous annular rash that gives the appearance of a bull's eye. This rash is known as Erythema migrans. The rash occurs 3-30 days after the bite of the tick, and occurs in about 60-80% of patients. Arthralgias (98%), malaise (80%), headache (64%), fever (60%), and stiff neck also occur. Some patients rarely can be asymptomatic. STAGE 2 Stage 2 consists of cardiac and neurologic abnormalities. There can be a lymphocytic meningitis (15% and meningoencephalitis, peripheral sensory and motor neuropathies, facial nerve palsies (7%), myocarditis (8%), heart block, and pericarditis. STAGE 3 There is recurrent arthritis and chronic neurological symptoms manifested as memory loss, dementia, depression, sleep disorder, headache, confusion, fatigue, poor concentration, carpal tunnel syndrome, motor, sensory and autonomic neuropathies. There also may be iritis, optic neuritis, keratitis and retinal vasculitis. « Differential Diagnosis » HIV encephalopathy, various myopathies, Alzheimer's disease, amyotrophic lateral sclerosis, myositis, depressive and psychological disorders all must be ruled out. Ebstein-Barr disease may simulate Lyme disease. If the temperature is > 102 F, the diagnosis of EBV infectious mononucleosis must be entertained. Both diseases may produce rash. Lyme disease occasionally gives a malar rash like SLE in place of the typical erythema chronicum migrans rash. Bilateral posterior cervical adenopathy occurs with mononucleosis, but not in Lyme disease. Atypical lymphocytosis would favor mononucleosis. Viral meningitis can mimic Lyme meningitis. Both occur in the summer time. If the patient has photophobia, and diarrhea then a viral origin would be favored. Fatigue and intellectual impairment would point toward Lyme disease. The CSF in viral meningitis usually shows a lymphocytic predominance below 100, whereas in Lyme disease there usually is a higher cell count of around 200 cells per mm3. Septic arthritis in adults must be considered. Synovial glucose is decreased in septic arthritis and normal in Lyme disease. Cryoglobulins are increased in the synovial fluid in Lyme disease, and normal in septic arthritis. Also, Juvenile rheumatoid arthritis must be excluded in the differential. If there is not a high incidence of Lyme disease where you practice, and you suspect Lyme disease, recovering the tick for identification, and testing can be helpful. Tick bites are painless, and many patients are not aware of the presence of ticks on the their body. The sensitivity of lab tests is not presently good, especially early in the disease. However, there promises to be better, more sensitive and specific tests becoming available in the future. Presently, the ELISA IgG and IgM can be done. If you can get a culture of the advancing edge of the rash with a punch biopsy, then histology changes consistent with erythema migrans may be seen. If silver stains, such as a modified Dierterle or Bosma-Steiner stains are done, the pathologist may be able to see the spirochetes. The yield from biopsies, however, is low. « Treatment » Early treatment with antibiotics can shorten the duration of symptoms and prevent the later complications of the disease. Response to antibiotics in the later stages is variable. Because the spirochete can cross the placenta, pregnant patients with disease should be treated with IV antibiotics. Doxycycline is contraindicated during pregnancy. STAGE 1 TREATMENT Doxycycline 100 mg po bid is typically recommended but 100 mg tid may be more effective. Give at least for 3 weeks. Do not use in pregnancy or children under the age of 12. Do not take with milk or antacids. If patients are on warfarin, the warfarin may need to be adjusted downwards. Oral contraceptives may not be reliable, and photosensitivity is a problem. Amoxicillin is given at 1 gram tid for 21 days. In children give 25-100 mg/kg/day. Cefuroxime 500 mg bid, Cefadroxil 1 g daily, and Cefixime 400 mg daily also may be used for 3 weeks. Azithromycin 500 mg daily for at least 10 days appears to be effective also. STAGE 2 TREATMENT For recurrent or multiple Erythema migrans, Bell's palsy or peripheral neuritis use Doxycycline or Minocycline 100 mg bid for 30 days. For Meningoencephalitis or carditis, in order of preference, give oral or IV Minocycline 100-200 mg q 12 hours for 30 days OR Penicillin G 24 million units per day in 6 divided doses for 30 days OR Ceftriaxone 2 grams every 12 hours for 30 days OR Cefotaxime 3 grams every 4 hours for 30 days. A short course of steroids may be beneficial. STAGE 3 TREATMENT Can be treated with oral Amoxicillin 500 mg tid with probenicid 500 mg tid. If this fails then use IV ceftriaxone 2 grams qd or Cefotaxime 2 grams q 8 hours, both for 3 weeks. PREVENTION- Permethrin and DEET. ■ TOXIC SHOCK SYNDROME ■ Toxic shock syndrome is a multi-system disease that presents with hypotension, an erythroderma that resembles a sunburn, and fever. In particular, emphasis in the differential diagnosis should be placed on the hypotension as there are several diseases that can mimic TSS, but characteristically, don't have hypotension. The main contender that may present almost identically as TSS is the Toxic streptococcus syndrome. This syndrome is caused by an exotoxin producing species of group A beta hemolytic streptococcus. There is hypotension, rash and multiple organ failure, just as in TSS, but the source of infection is usually obvious. The differential will be discussed more fully later. TSS is caused by an exotoxin producing species of Staphylococcus aureus that produces TSST-1 exotoxin and staphylococcal enterotoxins A, B and C. However, no antibodies to the TSS toxin-1 (TSST-1) can be found. The patient can have nausea, vomiting, diarrhea, mental confusion, renal failure, hepatic failure and thrombocytopenia. There can also be meningismus, vaginitis with discharge, conjunctivitis, periorbital edema, myalgias, and arthralgias. TSS was initially reported in association with superabsorbent tampons in young menstruating females. Since then, however, cases have arisen in surgical and non-surgical wounds, abscesses, osteomyelitis, pneumonia, sinusitis and post partum infection. Vaginal diaphragms and contraceptive sponges have also been involved. Many of the cases of TSS are occult for an obvious source of infection. « Criteria for Diagnosis of TSS » The CDC has proposed the following, in order to make a diagnosis of TSS: MAJOR criteria are Temperature > 38.9 C, Systolic BP < 90 mm Hg, and a rash with subsequent desquamation, especially on the palms and soles about 1 week after the onset. MINOR criteria (must be 3 or more of the following): GI: (vomiting, profuse diarrhea), Muscular: (severe myalgias or > fivefold increase in creatinine kinase), Mucous membranes: (hyperemia of the vagina, conjunctivae or pharynx), Renal insufficiency: (BUN or creatinine at least twice the upper limit of normal, pyuria in the absence of urinary tract infection), Liver: (hepatitis with the bilirubin, SGOT, SGPT at least twice the upper limit of normal), Blood: (thrombocytopenia of less than 100,000/mm3), CNS: (disorientation without focal neurologic signs). There must be negative results of serologic tests for Rocky Mountain spotted fever, leptospirosis and measles. « Differential Diagnosis » MEASLES can occur at any age, but is more common in children and adolescents. There may be fever, malaise, conjunctivitis, photophobia, cough, Koplik spots, nasal discharge and rash that usually follows these prodromal signs and symptoms. The rash is maculopapular and starts on the face progressing to the trunk and extremities. The rash may coalesce, which would then simulate the rash of TSS. There is no hypotension. The skin rash usually fades in about 6 days starting with the face. ROCKY MOUNTAIN SPOTTED FEVER (RMSF) presents with an abrupt temperature elevation, headache, chills and a macular rash on the extremities that progresses to the trunk and extremities over 2-3 weeks. Hypotension would again be rare. RMSF is caused by Rickettsia rickettsiae and is transmitted by a tick bite. LEPTOSPIROSIS occurs in patients that come in contact with infected animal tissue and urine. Abattoir workers, farmers and trappers are susceptible to Leptospirosis. Onset is with sudden fever, headache, chills, myalgia, conjunctival and pharyngeal injection and rash on the trunk which can be macular, maculopapular or urticarial. Leptospirosis is caused by the spirochete Leptospira. Hypotension is not present. KAWASAKI'S DISEASE also needs to be ruled out. However, this disease typically occurs in children age 1-8. It is a mucocutaneous lymph node disease that presents with fever, nonpitting edema, desquamation of the skin and coronary artery aneurysms. Other diseases to rule out would include scarlet fever, drug reactions, staphylococcal scalded skin syndrome and septic syndromes. « Laboratory » There may be a positive culture for Staphylococcus aureus from the vagina or surgical wounds. There may be perineal or nasal carriage of Staphylococcus aureus. There may be increased SGOT, SGPT, CPK, BUN, creatinine, bilirubin, decreased calcium, magnesium and phosphate and pyuria. Blood cultures are almost always negative. Leptospirosis and RMSF serology should be performed if doubt exists as to the diagnosis. « Prognosis » In 1980 TSS had a mortality of about 5%. Now with additional acquaintance of the disease, the prognosis is considerably improved. There is a recurrence rate, however, of 10-15%. « Complications » Adult respiratory distress syndrome, and acute renal failure are the two main complications. Rarely, the patient may go on to disseminated intravascular coagulation, cardiomyopathy, sustained fatigue, memory loss and a toxic encephalopathy with ataxia. « Treatment » The main treatment is with IV fluids to reverse the hypotension, by giving normal saline .5 to 5 liters over 1-4 hours. If this is ineffective then Dopamine 4-20 ug/kg/min should be given IV. Nafcillin or Oxacillin 2 grams IV q 4 hours for 10 days (reduce Oxacillin if patient has renal insufficiency. This is not necessary with Nafcillin) OR Vancomycin (if allergic to penicillin) 500 mg IV q 6 hours, or 1 gram IV q 12 hours. May also require Methylprednisolone 10 mg/kg q 8 hours IV and Heparin 5000 U SQ q 12 hours. Betadyne vaginal douche also may be of help. ■ KAWASAKI SYNDROME (KD) ■ Kawasaki syndrome is a disease of unknown etiology that occurs in children usually less than 5 years of age and presents with a rash, mucocutaneous changes, lymphadenopathy and polyarteritis. The disease may last from 2-12 weeks or longer and there may be relapses.The syndrome was first described in Japan in the 1960s. Males are affected more so than females. The arteritis affects large and medium sized arteries with coronary aneurysms often times found in about 20% of cases. There is a seasonal incidence in the USA with more cases found in the winter and spring. Epidemics sometimes occur every 2-4 years. « Symptoms and Signs » The temperature is usually quite high around 103-104 F and persists for > 5 days. If the disease is not treated with ASA the temperature can last an average of 12 days or longer. If treated with ASA the temperature will resolve in 2- 3 days. There is conjunctival injection with limbal sparing around the iris. There is erythema, fissuring, crusting of the lips, diffuse oropharyngeal erythema and strawberry tongue. A non-pitting induration of the dorsum of the hands and feet is present. There are only two other diseases in the differential that are associated with peripheral edema. These are Rocky Mountain spotted fever and Toxic shock syndrome. Scarlet fever doesn't cause hand and feet swelling. The rash in KD starts within a day of the onset of the fever and is primarily truncal, but may extend to the face and hands. The rash is an erythematous deep red rash, often times with pruritic plaques or morbilliform erythematous papules. In a few cases the rash is a scarlatiniform erythroderma or rarely erythema marginatum. In some, it may present as an erythema multiforme and be urticarial. You should check especially for a peri-anal rash which is quite characteristic. There is an erythema or purplish red hue of the palms and soles, with subsequent desquamation of the fingertips and toetips appearing about 2 weeks after onset of disease. There may be pallor of the proximal part of the fingernails and toenails (leukonychia partialis) that develops during the first week of illness. Transverse grooves across the fingernails may develop about 2-3 months after the onset of the disease. Cervical lymphadenopathy develops in about 50% of patients and is usually unilateral. The nodes are > 1.5 cm. Inflammatory heart disease may develop in about 30% of cases. There may be pericardial effusions, myocardial and valvular dysfunction, arrhythmias and giant aneurysms > 8 mm. These can be very serious as they can thrombose. There can be transient mitral, aortic or tricuspid insufficiency. Tachycardia is common and CHF and cardiogenic shock may develop. Coronary aneurysms develop in about 20%. The mean time to first coronary artery aneurysmal development is 10 days post onset of illness, but can be as early as 5-6 days. CNS abnormalities develop in 90% of patients (aseptic meningitis (20%), irritability, emotional lability, lethargy and even a semi-comatose state may develop). Inflammation of the urethra with a sterile pyuria develops in 70% and boys may have a meatal ulcer that bleeds causing hematuria. Arthritis of the small or large joints can develop in 40%. Hepatic dysfunction and gallbladder hydrops may occur in 10% and and severe abdominal pain and diarrhea in 20%. « Laboratory » Leukocytosis with an intense release of bands is common. There may be a mild anemia, increased sedimentation rate and thrombocytosis in the second or third week. Ekg may show arrhythmias, left ventricular hypertrophy, and decreased voltage due to pericardial fluid. Echocardiogram should be done in all patients around the 5th week of illness in order to detect any aneurysm. « Differential Diagnosis » Stevens-Johnson syndrome, scarlet fever, leptospirosis, measles, RMSF, staphylococcal exfoliative syndromes, measles, toxoplasmosis, juvenile rheumatoid arthritis and infantile periarteritis nodosa. « Prognosis » A low mortality is associated with KD of about 1%. The deaths are not predictable. About 50% occur during the first month, 75% within 2 months and 95% within 6 months. Aneurysms tend to undergo resolution within one year accounting for the good prognosis after 6 months. Most fatalities are due to cardiac complications. In general, if no coronary artery aneurysm is found the prognosis is excellent. « Therapy » ASA 80-100 mg/kg/day in 4 divided doses until day 14 then after day 14 in afebrile patients give ASA 3-5 mg/kg/day in a single dose for 6-8 weeks after confirming the absence of coronary abnormalities. If coronary abnormalities are found then continue the ASA for several months. Follow serum salicylate levels and try to keep the level around 25 mg/dL. ASA has apparently no detectable effect on reversing the cardiovascular events but does help prevent thrombosis. Intravenous immunoglobulin at a dose of 400 mg/kg/day plus ASA for 4 days has demonstrated fewer coronary artery lesions than treating with ASA alone. An equivalent response has been found with one dose of 2 grams/kg of IV immunoglobulin. ■ SPOROTRICHOSIS ■ Sporotrichosis is caused by Sporothrix schenckii, and causes 3 different forms of disease and occurs world-wide. The 3 forms are the lymphocutaneous form, pulmonary, and disseminated form. The disease is most likely in horticulturists, miners, nursery workers, landscapers, florists, carpenters, farmers and gardeners. « Clinical » The lymphocutaneous form presents as movable subcutaneous nodules, ulcers and abscesses usually affecting the skin of the arms, hands and finger. The lesions are painless and non-tender, but they can progress to larger discolored fistulas and ulcers. There are no associated chills, fatigue or fever. Additional lesions appear along adjacent lymph node chains. Onset occurs from 20-90 days after the inoculation of Sporothrix schenckii. Sporothrix schenckii is found on thorny rosebushes, mulches, sphagnum moss, barberry bushes, hay and timber. If the fungus is inhaled it may cause pneumonia with infiltrates or cavities, hilar adenopathy, pleural effusion and pulmonary fibrosis. The disease is sometimes associated with Tuberculosis and Sarcoidosis. The pneumonic form is chronic and usually mild. The disseminated form occurs most often in people over the age of 60, chronic alcoholism, and drug or HIV immunocompromise, and affects bone, synovium and periosteum resulting in a suppurative arthritis and osteomyelitis in about 80%. Muscle and eye can also be involved.. Rarely, the CNS (chronic meningitis), spleen, liver, kidney and genitalia are affected. « Laboratory » The fungous is diphasic but the yeast form (cigar shaped), arranged in asteroid bodies is found in tissue. Culture of sputum, pus or bone drainage, done at 22 degrees, results in a leathery distinctive mycelian growth. Slide staining with PAS and Gomori stains from fixed tissue of skin results in a poor yield. There are no serologic tests available at the current time. « Treatment » Treatment of the cutaneous form is with a saturated solution of potassium iodide (SSKI) starting at 1 ml orally tid and increased by 1 ml/day to an optimal dose of about 4 ml tid. This should be added to a beverage because of the distinctive taste. The SSKI should be continued for 1-2 months after the lesions have healed. Iodism may develop with conjunctivitis, stomatitis, rashes, laryngitis, and bronchitis. If this does occur, discontinue the SSKI for 1-2 weeks and then restart at a low dose. Watch for hyperkalemia if SSKI is taken with amiloride, spironolactone or triamterene. Itraconazole has fewer side effects and can be used for the lymphocutaneous form in a dose of 100-200 mg daily for three to six months. For osseous or pulmonary sporotrichosis therapy is with IV Amphotericin B, 1.5-2.5 Grams being given for a total dose. Amphotericin B can cause chills, fever, nausea and vomiting Amphotericin B has been only modestly effective. SSKI is not effective at all and ketoconazole generally is not effective. In clinical trials, Itraconazole appears to be as good as Amphotericin B and has only a few side affects. Itraconazole may cause an increase in digoxin levels, and cyclosporine levels. Terfenadine and astemizole should not be given to patients taking itraconazole because of arrhythmias. Antacids, sucralfate and H2 receptor antagonists will decrease the absorption of itraconazole. Phenytoin, rifampin and carbamazepine increases the metabolism of itraconazole and may allow progression of the fungus. « Differential Diagnosis » Tularemia, sarcoidosis, Tuberculosis, Bacterial osteomyelitis, neoplasm, cat scratch disease and atypical mycobacterial infection should all be ruled out. ■ BLASTOMYCOSIS ■ Blastomycosis is caused by inhalation of spores of Blastomyces dermatitidis into the lung and is then spread by lympho- hematogenous dissemination to the lungs, bone, genitourinary and skin. Most patients with Blastomycosis are young or middle aged men. Adult respiratory distress syndrome has been reported in the elderly. The fungus is airborne in rotten wood dust and prevalent in the great Lakes area and the Southeast with high rates in states bordering the Mississippi and Ohio Rivers. The disease is rare in AID's patients. « Pulmonary Blastomycosis » Pulmonary Blastomycosis can be asymptomatic, acute or chronic. The acute form may start abruptly or slowly and may be asymptomatic and self limited. The patient may have fevers, myalgias, arthralgias, chills, sweats, cough (which may be dry and hacking early, followed by a productive cough later), hemoptysis, and can be associated with erythema nodosum. Weight loss is fairly common. The incubation period is 60-90 days. Chest x-ray may show upper lobe fibronodular infiltrates in 50% of cases and a mass lesion in 30%. There may be diffuse lung infiltrates, and cavitation occasionally occurs. Pleural thickening, pleural effusions (10%), with pleuritic chest pain and adult respiratory distress syndrome rarely occur. « Cutaneous Blastomycosis » Cutaneous blastomycosis may occur with or without pulmonary disease and represents the most common extrapulmonary presentation. The skin lesion is typically a wart-like verrucous lesion that may begin as a small papule or pustule. These may become crusted, and there may be central clearing with scar formation. There also may be skin ulcers with raised borders and a granulating base. Painless miliary microabscesses may develop along the borders of the lesions. Dermatologic involvement occurs in 40-80% of the extrapulmonary cases. « Osseous Blastomycosis » Osseous blastomycosis usually affects the ribs, vertebrae and long bones (tibia and femur are common). The lesions are well circumscribed osteolytic lesions. There may be adjacent paraspinous abscesses with vertebral involvement. The skeletal form occurs in 25-50% of extrapulmonary cases. « Genitourinary Blastomycosis » The prostate is most frequently involved followed by the epididymis and the testes. Prostate exam may reveal it to be tender and enlarged along with perineal discomfort, and the epididymis may be swollen and tender. « Laboratory » Sputum cytology will often reveal the characteristic large single budding thick walled yeast forms. Histopathologic examination of the skin lesions will reveal pseudoepitheliomatous hyperplasia. Tissue and body fluid should be cultured in Sabouraud's media and wet mounts should be done to demonstrate the yeast form which appear as a broad based budding structure with no capsule and refractile wall. They are about 5-15 micrometers in diameter. Special Gomori methenamine silver stains may be done on tissue and Periodic acid Schiff's stains will color the wall red. If there is a question of diagnosis, a mucicarmine stain will help to differentiate Cryptococcus (which has a capsule) from Blastomycosis dermatitidis (which has no capsule). For the disseminated forms, CT or MRI may be used with involvement of the brain and spine. Bone scan is helpful for detection of osseous involvement. Chest x-ray and chest CT are used for pulmonary involvement. « Treatment » Acute Blastomycosis may not need any treatment as it often times is self-limited. Amphotericin B is associated with too many adverse effects to be given routinely. However, with the introduction of the azole and imidazole drugs there is more of a tendency to treat because of less side effects with these newer oral drugs. Unless the patient is severely ill or has meningitis then oral therapy may be given for the acute form and the chronic form. Ketoconazole, fluconazole and itraconazole are the three drugs that can be used. With the introduction of itraconazole this drug could be used instead of ketoconazole. The dose of itraconazole is 200 mg once or twice a day. Itraconazole does not inhibit steroid and testosterone synthesis as does ketoconazole. Side effects of itraconazole consist of nausea, vomiting, hepatitis, hypertension, hypokalemia and edema. Treatment should be given for 6 months depending on the severity of the disease. Ketoconazole can be used for the milder forms at 400-800 mg PO daily for 6 months. Amphotericin B is used for the severe forms, giving 0.5-0.8 mg/kg IV over 4-6 hours daily for a total dose of 1.5 to 2 grams. A test dose of 1 mg in 200 ml of 5% in water should be given IV over a 2-4 hours period. The daily dose of Amphotericin B is increased by 10 mg daily until there is a maintenance dose of 0.5 to 0.8 mg /kg/day. If the patient develops fever with the infusion then treat with pre-infusion acetaminophen and diphenhydramine. If patient chills give merperidine. The patient should be monitored while receiving the amphotericin B with renal function, electrolytes (sodium, magnesium, potassium) and CBC twice a week. If the creatinine becomes greater than 1.6 mg/dl then change the Amphotericin infusions to every other day. The patient should also be monitored for development of hypotension and phlebitis. Avoid all nephrotoxic drugs while receiving amphotericin B. « Prognosis » If the patient is treated appropriately there should be a cure rate of over 90%. However, relapse does occur and may be more frequent when ketoconazole is used as anti-fungal therapy. ■ COCCIDIOIDOMYCOSIS ■ Coccidioidomycosis is caused by inhalation of the arthroconidia of Coccidioides immitis, a mold that is endemic in the soil in the southwestern USA, Mexico and in Central and South America and affects men aged 25-55 frequently. Suspect this disease in any one that lives or visits this area. Most natives that live in this endemic area acquire the disease in their youth. Dark skinned persons such as Filipinos, African-Americans, immunocompromised hosts, pregnant women and diabetics are at increased risk in acquiring this disease. It has principally two forms. The first involves the lungs and the second is progressive or disseminated. « The Pulmonary Form » The Pulmonary form is usually minor, subclinical and self-limiting in about 60%. In 40% there may be symptoms varying from a flu-like presentation with fever, chills pleuritic pain and predominantly dry cough. There may be swelling of the knees and ankles, conjunctivitis and erythema nodosum may appear 2-20 days after onset of symptoms. Pleural effusions may develop in 10% of cases with chest pain, sore throat and hemoptysis. Leukocytosis and eosinophilia may be present. Chest x-ray findings include small thin walled cavities, large cavities and infiltrates that may be diffuse or nodular. « The Disseminated Form » In this form the pulmonary findings become worse with mediastinal and hilar lymph node enlargement and lung abscesses may rupture into the pleural space with empyema. There may be a miliary dissemination to the lungs, bones, viscera, genitourinary tract, skin, pericardium, myocardium and meninges. The dissemination may occur weeks, months or occasionally years after the primary infection. There is loss of weight, anorexia, low grade fever and malaise. Of all of the complications meningitis is the most dreaded, because it is extremely difficult to eradicate. Coccidioidal meningitis is chronic with headache and confusion being common. The CSF shows increased protein, decreased glucose and lymphocytosis which is similar to Tuberculosis. Antibodies in the spinal fluid are found in over 90% of cases and are pathognomonic. « Laboratory » Cultures usually appear after a few days growth as a white mycelial growth. Laboratory workers should be extremely careful, as simply removing the top off a Petri dish containing the highly contagious C. immitis arthroconidia, may induce an infection. In coccidioidal meningitis, culture growth is very infrequent (30%), and the diagnosis is usually made by serologic tests. The tissue form of C. immitis is a very large thick walled, nonbudding spherule (sporangia). If the spherule containing multiple endospores is visualized in tissue the diagnosis of coccidioidomycosis is secure. The characteristic spherules of C. immitis are found in sputum, pleural fluid, CSF, pus from abscesses, exudate from skin lesions, gastric washings, biopsy specimens and on culture. The coccidioidin skin test which is a delayed cutaneous hypersensitivity reaction to coccidioidin or spherulin usually appears 10 to 21 days after infection and remains positive for years. In the disseminated progressive form the skin test is negative. A persistently rising complement fixation titer > 1:8 is very suspicious for dissemination. Complement fixation antibodies (IgG) rise at 1-3 months. However, if there is meningitis without further dissemination then the complement fixation titer may be low. There is a false negative rate of up to 30% in HIV related coccidioidomycosis. If patients have very mild symptoms they may never develop a positive serology. Blood cultures may be positive in about 30% of cases of the acutely disseminated forms. Serology precipitin antibodies (IgM) rise within 2 weeks and disappear after 2 months; « Treatment » For mild pulmonary symptoms no treatment is necessary. For progressive pulmonary or extrapulmonary dissemination, Amphotericin B IV can be used. Therapy should be given for a total of 2.5-3 grams and if meningitis is present this may have to be treated for life with Amphotericin B. Intrathecal Amphotericin B is generally given on a weekly basis until the disease comes under control, then monthly for several years. If meningitis is not treated the mortality is 100%. However, with the advent of Fluconazole and Itraconazole results are being obtained that are similar to Amphotericin, obviating the need for intrathecal therapy. If disease is limited to the chest Ketoconazole 200-800 mg daily 1 hour AC breakfast can be used for 6 months. If the patient develops giant infected or ruptured cavities then surgery may be needed. The progressive form can be fatal in 55-60% of cases. ■ HISTOPLASMOSIS ■ Histoplasmosis, caused by Histoplasma capsulatum, a soil saprophyte, is an oval budding cell found in the Ohio Valley and causes three type of infection: Acute primary pulmonary, Chronic pulmonary cavitary disease and the progressive, disseminated form. This organism has a propensity for affecting the elderly. Histoplasmosis capsulatum has a worldwide distribution. The fungus exists in mycelial form in nature and yeast phase when exposed to mammalian temperatures. The spores may remain active for up to ten years. Exposure to bat or bird excrement will promote growth of the fungus. Risk factors include: cleaning chicken coops, excavation in proximity to bird roosts, spelunking, exposure to decayed wood or dead trees, immunosuppression, and remodeling and demolition of old buildings. The occurrence in AIDS patient is about 2-5%. « The Acute Pulmonary Form » The acute pulmonary form is self limited and may cause mild pneumonic symptoms. Chest x-rays often times show calcification after the acute form. If the acute form is symptomatic there is a mild influenza like illness that lasts about 4 days. There may be fever, cough and mild chest pain. « Chronic Cavitary Form » Chronic cavitary pulmonary histoplasmosis occurs in the middle aged to elderly who have a significant smoking history. Having chronic obstructive lung disease seems to be an essential substrate for developing this form. The disease can present just as pulmonary tuberculosis with the same symptoms and chest findings. There is fever, weight loss, fatigue, night sweats, cough, hemoptysis, and sputum production. The chest x-ray will show the underlying chronic obstructive pulmonary disease as hyperlucency, flat diaphragms and maybe some bullous disease. Superimposed on this is the unilateral or bilateral multiple thick walled cavities in the upper lobes. In general, there is no disseminated disease concomitant with the pulmonary involvement. « Disseminated Form » Disseminated disease causes fever, cough, hepato-splenomegaly, lymphadenopathy, bone marrow invasion (with anemia, leukopenia and thrombocytopenia), chronic meningitis, diarrhea in children, ulcerative enteritis of the distal ileum and colon, endocarditis, fibrosing syndromes of the mediastinum (causing pulmonary hypertension, superior vena cava syndrome and bronchial obstruction), erythema nodosum, focal chorioretinitis, macular choroid inflammation and hemorrhage, skin and ulcerative mucous membrane involvement (the oral lesions are common and are found on the tongue, palate, buccal mucosa, and oro-pharynx), weight loss, and fatigue. The disease is uncommon (< .05% with about 1/3 affecting infants < 1 year of age and the remainder in the elderly) and affects the reticuloendothelial system with widespread involvement. The adrenal gland, in particular, is a target and can cause an acute adrenal insufficiency (50%). Other causes for an addisonian crisis would have to be ruled out as lymphoma, Hodgkin's disease, leukemia and sarcoidosis. The disease is fatal if not treated and may be difficult to diagnose. Liver involvement is seen on biopsy as a granulomatous intracellular fungus with calcification. « Laboratory » Culture should be done on specimens from sputum, lymph nodes, bone marrow, liver biopsy, blood, urine and oral ulcerations. Buffy coat samples may improve the yield. Obtain tissue for staining with Gomori's methenamine silver stain and periodic acid Schiff stain. In AID's patients one may see H. capsulatum in polymorphonuclear or mononuclear leukocytes in the peripheral blood on Wright or Giemsa stains. Histoplasmosis antigen assay has a sensitivity of greater then 90% for disseminated disease in AIDS patients. Complement fixation tests have a sensitivity of 95% in pulmonary disease, but only 70% in disseminated histoplasmosis in immunocompromised patients. Complement fixation antibodies at titers of 1:8 or 1:16 are presumptive for diagnosis. Titers of 1:32 is very suggestive as is a four fold increase. There may be a false positive complement fixation test if previous skin tests have been done. The skin test is not helpful in diagnosis, for reactivity stays for years following infection. Bronchoalveolar lavage and cerebrospinal fluid studies may be helpful in diagnosis in the progressive form. « Treatment » For self limited pulmonary disease, no treatment is usually needed. For disseminated disease Amphotericin B is indicated in a total dose of 1-2 grams. Relapses can be common especially in AIDs patients in which ketoconazole, fluconazole or itraconazole can be given after the initial IV amphotericin B therapy. Maintenance therapy with ketoconazole 400 mg daily, or Amphotericin B 50-100 mg IV weekly can be used with good results in AIDs patients. For chronic cavitary disease, Amphotericin B, 2-2.5 grams cumulative or ketoconazole 400 mg daily for 6-12 months might be used. Mediastinal granulomata may be treated with Amphotericin B. Mediastinal granuloma may mimic fibrosing mediastinitis (fibrosing mediastinitis does not respond to treatment). ■ HIV AND THE LUNG ■ Pneumocystis carinii (PCP) was first described in 1910 and has always been thought to be a protozoan until recent evidence indicates it may be a fungus. PCP has three forms: sporozoites, trophozoites and cysts. Trophozoites are the most plentiful form in lung tissue and bronchoalveolar lavage fluid. Most children will have antibodies to PCP by the age of 4 and Pneumocystis is probably dormant in lungs until immunosuppression occurs. Pneumocystis carinii in the past, before AIDS, was rare and occurred mainly in patients given immunotherapy for organ transplants and chemotherapy for cancer. Now, it is known that about 80% of patients with AIDS will have at least one episode of PCP and in about 64%, PCP pneumonia will be the initial manifestation. Opportunistic pneumonia is the most common respiratory complication in AIDS especially when the CD4+ lymphocytes (T helpers) reach 200 per cubic millimeter and below. Depletion of these lymphocytes occurs both peripherally and locally in the lungs. The total lymphocytes usually increase, but most of these are of the suppressor type. Patients that have a neutropenia don't appear to be at any further risk for development of PCP. « Clinical » The clinical onset of PCP pneumonia is characterized by fever, dyspnea, cough and pulmonary infiltrates. The presentation varies and may be very subtle with symptoms developing very slowly over weeks or months. On the other hand, the onset may be abrupt. The fever can be low grade or high. The cough is usually non-productive but can be a productive cough of whitish or clear sputum. There may be chest tightness, or sharp substernal pains along with dyspnea, tachypnea, and chills. « Laboratory » The typical chest x-ray consists of diffuse bilateral interstitial or alveolar infiltrates (48-86%) or both. However, chest x-ray findings may vary widely from a normal chest x-ray (6-23%) to asymmetric or unilateral infiltrates, localized homogeneous consolidation with air bronchograms, infiltrates located in the periphery or upper lobe, nodular infiltrates, cavities, pneumothoracies and cyst-like lucencies within areas of alveolar infiltrates. If patients are receiving aerosolized pentamidine for prophylaxis, infiltrates localized to the upper lung zones are seen. Measurement of carbon monoxide diffusing capacity (DLCO) by the single breath method is very sensitive for detecting PCP in AIDS. It is helpful if the chest x-ray and arterial blood gases are normal, in which there will be a low DLCO if PCP is present. Oximetry can be used during exercise. If exercise results in a decrease of 3 percentage points from resting oxygen saturation, the chances for PCP are high. The LDH is elevated but is non- specific. LDH can be elevated in other diseases that would be in the differential as TB, lymphoid interstitial pneumonia and lymphoma. Normal LDH may suggest another disease. Gallium may be used if the chest x-ray is normal, and the patient is unable to exercise. However, the specificity is low. If the gallium uptake in the lung is equal to or greater than the uptake in the liver then PCP may be present. Sputum induction with hypertonic saline inhalation or bronchoalveolar lavage (BAL) obtained by fiberoptic bronchoscopic exam is used to obtain samples for examination. Sputum induction will yield a diagnosis in 52-92%, and this is recommended as the initial step for diagnosis. The diagnostic sensitivity of BAL is between 90 and 100%. If the patient has been receiving aerosolized pentamidine when the pneumonia develops, then the yield for both BAL and induced sputum will decrease considerably (60-65%). It is recommended that transbronchial biopsy be added to BAL in these cases, as the sensitivity with both of these procedures performed in pentamidine treated patients approaches 100%. « Differential Diagnosis » Differential diagnosis would include: BACTERIAL PNEUMONIA (The most common are S. pneumoniae and H. influenzae). FUNGAL PNEUMONIA (The most common are cryptococci, histoplasma and coccidioides. Disseminated disease is usually seen with these 3 organisms. Cryptococcal infections can present as thoracic lymphadenopathy , parenchymal or pleural involvement). KAPOSI'S SARCOMA (usually follows the cutaneous involvement but not always. Occurs often with other visceral disease. Lung presentations are interstitial disease, pleural effusions, infiltrates, nodules, lymphadenopathy and endobronchial involvement. Gallium scan may be helpful in that it is negative in Kaposi's sarcoma). TUBERCULOSIS, MYCOBACTERIUM AVIUM INTRACELLULARE (occurs late in the disease of AIDS with CD4+ counts below 100 per cubic millimeter. Clarithromycin and Azithromycin may be effective.). VIRAL PNEUMONIAS (CMV is the most common but usually isn't important because antiviral therapy against it doesn't alter the course), and LYMPHOID INTERSTITIAL PNEUMONITIS in children. « Treatment » Trimethoprim-sulfamethoxazole (TMP-SMX) and Pentamidine are are the two principal drugs used to treat PCP. Trimethoprim-dapsone, clindamycin-primaquine and atovaquone also have been used. The success rate is about 75% with TMP-SMX, somewhat better than Pentamidine. TMP-SMX is preferred in patients with renal failure, and patients in whom you suspect other bacterial infections. If the patient has an allergy to sulfa drugs, or fluid restriction needs to be addressed, has an anemia, thrombocytopenia or neutropenia, then Pentamidine may be preferred. There is a high incidence of adverse reactions to TMP-SMX consisting of rash, elevated aminotransferase levels, nausea and vomiting, CBC depression, and fever. The rash and fever can be treated with acetaminophen and diphenhydramine unless the rash is severe and then the TMP-SMX needs to be discontinued. TMP-SMX treatment is given with TMP, 20 mg/kg/day and SMX at 100 mg/kg/day in 3 or 4 divided doses IV or orally for 21 days. If there is severe renal impairment (less than 30 mL/min creatinine clearance), reduce the TMP-SMX to 1/4 to 1/2 the usual dose after the sixth dose of medication. Pentamidine is given IV at 4 mg/kg in a single daily dose for 3 weeks. Watch for hypoglycemia which can occur anytime during the treatment, hepatic and nephrotoxicity, neutropenia and hypotension. When Dapsone is used with TMP the treatment is just as effective as TMP-SMX in mild to moderate initial episodes of PCP in HIV patients and is better tolerated. Give Dapsone 100 mg orally in a single daily dose and TMP at 20 mg/kg/day orally q 8 hours. Be alert to methemoglobinemia, rashes, elevation of liver enzymes, nausea and vomiting. The incidence of side effects is less than TMP-SMX.(50% lower). One disadvantage of using TMP and dapsone is that patients will have more opportunistic infections because TMP-SMX protects against H. influenza, Streptococcus pneumoniae, Nocardia, and possibly Toxoplasma and Isospora. Corticosteroids can decrease the incidence of respiratory failure and increase survival. Therefore, if the partial pressure of arterial oxygen is less than 70 mm Hg or an alveolar-arterial gradient of more than 35 mm Hg, steroids should be started as early as possible, preferably 72 hours of diagnosis. The first symptom to improve with effective treatment is decreased cough. The fever is reduced after a few days, but may take up to one week. Improvement in chest x-rays may take a month or more. « Prophylaxis » It is recommended that prophylaxis start when the CD4+ lymphocyte count drops to 200 or less. TMP-SMX is the drug of choice. Aerosolized Pentamidine, although less toxic, can be used, but is less effective and costs considerably more than TMP- SMX. Give 1 double strength tablet containing 160 mg of TMP and 800 mg of SMX once daily. If adverse effects occur, give every other day. If this isn't tolerated give pentamidine, 300 mg with a nebulizer once a month. Dilute 300 mg of pentamidine in 6 mL of sterile water and deliver with an airflow rate of 6 L/min from a 50 psi compressed air source until the reservoir is empty. If the patient is in the supine position and breathes deeply there may be better distribution of the drug to the apices of the lung. Bronchospasm and cough are side effects. If this happens give an inhaled Beta2 agonist and start the pentamidine 10 minutes after the Beta2 agonist. If the patient has TB, inhaled pentamidine should not be used because the pentamidine induced cough may spread the TB. Health care workers should always wear masks when giving the treatment and the pentamidine should be given in negative pressure ventilation rooms that have frequent air exchange to the outside. Pentamidine may be increasing the incidence of pneumothoracies. If a patient develops a pneumothorax while being treated with aerosolized pentamidine, he or she should be treated for PCP, because almost invariably they will be infected with Pneumocystis. If a patient is unable to tolerate either of the above drugs, then Dapsone alone at 100 mg daily, dapsone 100 mg/day + TMP 300 mg/day (in 3 divided doses), or Pyrimethamine 25 mg + sulfadoxine 500 mg every week can be given. ■ BABESIOSIS ■ If you see a patient that is complaining of chills, fevers, sweats, fatigue and possibly dark urine during the summer months, always ask about travel to the northeastern sector of the USA, and transfusions. Transfusions can transmit the organism. Babesiosis usually follows a tick bite (the northern deer tick, Ixodes dammini), that harbors the Babesia microti organism. The patient may not even remember the tick bite because the tick only measures about 3 mm fully engorged and usually about 2 mm. Human babesiosis is endemic in the northeastern USA especially the islands adjacent to the southern New England coast as Nantucket, Martha's Vineyard, Long Island, Block Island and Shelter Island. Southeastern Connecticut, Virginia, Georgia, Wisconsin, Indiana, Maryland, and the West coast have all reported the tick. Babesia microti infects the white footed mouse, and the Ixodes dammini tick lives on the white tailed deer. Epidemiologic studies on Nantucket have shown that about 60% of the white footed mice (Peromyscus leucopus) are infected with B. microti. The larval and nymphal stages of I. dammini usually feed off the white footed mice and the adults feed on deer. Following infection, Babesia microti invades the red blood cells and multiplies by binary fission to produce four merozoites (the tetrad form), which causes lysis of the cells liberating the merozoites to infect other erythrocytes. Thus, a chain reaction is set up producing a hemolytic anemia which may be mild or severe depending on the immunocompetency of the patient and whether the patient has a functioning intact spleen. If the patient has been splenectomized or has asplenia it has been shown that the severity of the disease increases dramatically. Ordinarily, in the normal person, the disease is self limited but may smoulder for months. « Clinical » The incubation usually ranges from 1 week to about 4 weeks after a tick bite, but after a transfusion may be six to nine weeks. If the patient has an intact spleen, the symptoms may be mild and gradual with malaise, arthralgias, nausea, vomiting, headache, myalgias, fatigue, weakness, chills, and drenching sweats. This onset is not unlike several other illness such as malaria. Malaria and Babesiosis can both cause splenomegaly, but no lymphadenopathy. Another co-existent feature further confuses the picture even more. The same tick Ixodes dammini can carry the Lyme vector of Borrelia burgdorferi and both of these diseases are endemic in the northeastern USA. So, the patient may present with symptomatology compatible with Lyme disease as rash, cardiac and neurologic symptoms. In fact, the first reported fatal case of Lyme disease occurred in a patient that harbored babesiosis. Ehrlichiosis, a rickettsia, that also occurs on the coast of New England, is another tick born infection that is similar to the clinical and laboratory findings of bebesiosis. In this disease there may be fever, myalgias, thrombocytopenia, abnormal liver tests, splenomegaly and rash. Also, you would have to rule out Rocky Mountain spotted fever and murine typhus. « Laboratory » Babesiosis produces a hemolytic anemia with reticulocytosis, decreased haptoglobin and excess urobilinogen in the urine. Liver enzymes may be elevated. Thick and thin blood smears should be made and examined, looking for the intraerythrocytic Babesia microti which may appear as trophozoite ring forms that resemble those of Plasmodium falciparum, but the pathognomonic merozoite tetrad or maltese cross is diagnostic. Other forms as the immature piriform bodies can be seen. Parasitemia can reach as high as 80 to 90 percent in asplenic patients which may require exchange transfusions. In general, patients with an intact spleen have a low grade parasitemia. Babesiosis differs from malaria due to P.falciparum by the absence of hemozoin (a by-product of hemoglobin digestion) and gametocytes on the blood smears. Thrombocytopenia may be present. Serologic testing with indirect immunofluorescence for IgM and IgG may be helpful, but there may be a low titer cross reactivity with malaria, other tick borne infections and other babesia species. An enzyme-linked immunosorbent assay using polyclonal IgM and IgG antiserum and antibody capture assay are also available for diagnosis. Inoculation of infected human blood intraperitoneally can be done for diagnosis, but is not used much. « Treatment » In patients who are immunocompetent and have a normal spleen there is spontaneous recovery from B. microti infection and possibly no treatment is needed. If patients are asplenic, infected with B. bovis or B. divergens, then those patients will need to be treated as the clinical course is fulminant. Clindamycin 300 mg IV or 600 mg po q 6 hours for seven days + quinine 650 mg orally q 6 hours for seven days has been successful. Folic acid 1 mg daily may be needed because of the hemolytic anemia. Exchange transfusions may be needed. ■ CAT SCRATCH DISEASE: (CSD) ■ « Clinical » Cat scratch disease is an infection caused by Afipia felis, a flagellated gram negative organism, that occurs world wide, usually affecting children and young adults that have been in contact with a cat. The cat often times is a kitten and appears healthy. The disease has been reported in AIDs, also. It is characterized by the development of a cutaneous lesion that is erythematous, may be crusty with a scabbed ulcer or a papule or rarely a pustule, measuring about 2-6 mm, and occurs about 3-10 days after the bite. These lesions will occur in about 60-90% of the cases. Following the lesion, about 1-3 weeks later, fever (usually less than 50%), headache (13%) and malaise (29%) may develop and the regional nodes enlarge. These nodes may be tender or non tender. They may be axillary, epitrochlear, cervical, submandibular or inguinal.There may be overlying skin inflammation. Suppuration occasionally occurs with fistula formation, but the pus is sterile. The lymphadenopathy and skin lesion usually disappear spontaneously within 2-5 months without any special treatment. Rarely, the patient may develop a conjunctivitis with palpable preauricular nodes (Parinaud's oculoglandular syndrome) (6%), Cat scratch encephalopathy (2%), osteolytic lesions, mesenteric adenitis, erythema nodosum, and thrombocytopenia. AID's patients have developed a disseminated form that resembles bacillary angiomatosis. Bacillary angiomatosis is caused by a rickettsial like organism which is treated with erythromycin or tetracycline which are ineffective in cat scratch disease. « Laboratory » Microscopic examination of the node shows hyperplasia, granuloma, microabscess and suppurative necrosis. The organism can be seen with the silver stain of Warthin-Starry or the Brown-Hopps tissue gram stain. The organisms are seen in the walls of the blood vessels. The ESR is elevated and eosinophils may be increased with a leukocytosis. The CSF protein is increased with occasional mononuclear cells. The skin test is not readily available. « Treatment » Treatment with antibiotics has not been good. However, there may be some response with ciprofloxacin 500 mg bid for 14 days. In vitro studies have shown susceptibility to cefotaxime, cefoxitin, mezlocillin and IV gentamicin 5 mg/kg/day has been used in the disseminated disease. ~neph.bin~ ■ BENIGN PROSTATIC HYPERPLASIA ■ This presentation will address the medical treatment of of BPH. Presently, within the United States there are two classes of drugs that are used. The first is the 5 alpha-Reductase inhibitors and this includes only finasteride. The second class of drugs are the alpha-Adrenergic antagonists and this class consists of the following drugs: prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura). Terazosin and doxazosin are both long acting and given once a day. Prazosin must be given given several times a day. « Finasteride » Finasteride (Proscar) inhibits the conversion of testosterone to the very potent androgen dyhydrotestosterone and as a result the prostatic size is reduced by about 25%. In some patients this will facilitate micturition by decreasing the mechanical obstruction of the prostatic urethra. One advantage of using finasteride is that it can be given once daily and the side effects are minimal. However, the monetary impact with this drug would negate its usage. It is estimated that a 1 month supply of finasteride would cost about $61.00 with an annual expense of $732.00. This is a high price to pay for only a 3 ml/s increase in peak urinary flow. Also, the alleviation of the symptoms may take 6-12 months to achieve maximal benefit. Furthermore, of major concern, is that finasteride consistently reduces the prostatic specific antigen (PSA) by about 50%. This is of concern in screening and following patients for prostatic cancer. On the basis of this, a new reference range of 0.0 to 2.0 ng/ml has been established for patients taking 5 mg of finasteride daily rather than the usual normal of 0.0 to 4.0 ng/ml. Also, the serum testosterone with both 1 mg and 5 mg will increased by about 10%. How significant this will be remains to be answered. By one year patients that were treated with 5 mg per day of finasteride had only a 14% decrease in prostatic volume. Other side effects consist of decreased libido (4.7) and decreased ejaculate volume (4.4%). THere also is a slightly higher incidence of impotence. « Terazosin » Terazosin (Hytrin) takes only 2-3 weeks to realize the beneficial effects. It works by decreasing the smooth muscle tone of the bladder neck, prostatic capsule and adenoma with resultant increase of flow through the prostatic urethra. There has been a 50% increase in peak urinary flow rates, a 46% increase in mean urinary flow rate, a 67% decrease in obstructive symptoms and a 35% decrease in irritative symptoms. There is no change in the PSA during treatment as with the 5 alpha-reductase inhibitors. Side effects are observed as follows: dizziness (14%), headaches (10%), weakness (7%), hypotension (4%),impotence (4%) and impotence (1%). Treatment plan: days 1-3 give 1 mg hs., days 4-14 give 2 mg hs, days 15-21 give 5 mg hs, days 22-29 give 10 mg hs. Check frequently for orthostatic hypotension and other side effects. The final dose of terazosin for treatment of BPH is 5-10 mg/day, as less than 5 mg/day is at placebo level. Giving the dose at bedtime may decrease the cardiac side effects. « Doxazosin » Doxazosin (Cardura) will decrease the irritative symptoms decreased by 80%, and obstructive symptoms by 63%. The peak urinary flow rates increase by 25%. Side effects are minimal with doxazosin, but can include syncope, dizziness, somnolence, fatigue, edema, rhinitis, polyuria, abnormal vision, orthostatic hypertension, sexual dysfunction, ataxia, leukopenia, neutropenia and arrhythmia.. Treatment is 4 mg per day, but starting low and building up to max of 16 mg per day would be prudent with monitoring of blood pressure and side effects. Doxazosin is available as 1, 2, 4, and 8 mg tablets. « Monitoring for Prostatic Cancer with Finasteride Usage » RECOMMENDATIONS FOR MONITORING FOR PROSTATIC CANCER IN PATIENTS RECEIVING FINASTERIDE Before a patient with symptomatic BPH is started on finasteride, the prostatic gland should be examined digitally and a basal PSA should be done. If both of these are normal then the patient may be started on finasteride. After 6 months of treatment, the PSA should be repeated. If the PSA has not decreased by 50% then the patient should be examined for cancer of the prostate. The PSA should be < 2.0 ng/ml. If the PSA is in this range then monitor the patient annually with digital exam and PSA. Be aware that patients may not comply with taking the medication and this will elevate the PSA. If compliance is an issue then obtain serum DHT which should be very low if patient is taking finasteride. « Transurethral Resection » TURP has been used for years in the treatment of BPH. Most patients will be benefited but the surgical procedure can have some morbidity. About 20% do not realize an improvement in voiding symptoms. Complications of TURP are as follows: Transfusions (6.5-10.5%), Urinary tract infection (2.3-20%), Impotence (3.5-10.2%), Epididymitis (1.2-4.8%), Incontinence (.4-3.3%) and Death of 0.2% in one series. ■ NEPHROTIC SYNDROME ■ Nephrotic syndrome affects children from ages 1.5 to 6 years. Adults can be affected at any age and males equal females in incidence. The basic lesion is increased glomerular permeability that allows protein to leak into the urine with proteinuria that is greater than 3.5 grams/24 hours or > 2gm/day/square meter. There also is hypoalbuminemia of less than 3 gm/dL, generalized edema, lipiduria and hyperlipidemia. « Signs and Symptoms » The clinical findings of nephrotic syndrome stem from the hypoalbuminemia which lowers the oncotic pressure which results in movement of intravascular fluid to the extravascular compartment. With the decreased volume, compensatory measures are activated with an increase of the renin-angiotensin- aldosterone system, increased antidiuretic hormone release and decreased atrial natriuretic peptide. This causes an increase in the sodium and water retention in an effort to offset the decreased intravascular volume. The patient may have edema, abdominal pain and distention, hypertension, puffy eyelids, scrotal swelling, and dyspnea. « Laboratory » Hyperlipidemia results from an increase in hepatic cholesterol and lipoprotein synthesis, decrease in peripheral and liver catabolism of lipoproteins and an increase in urinary excretion of HDL. There is an increase of the following in the serum: total cholesterol, LDL, VLDL and triglycerides. The HDL is decreased. This profile is important because the lipoprotein alteration can cause an accelerated coronary atherosclerosis and progression of renal disease. The serum calcium is often decreased also. The BUN and creatinine may be elevated and the urine usually will show fat bodies ( macrophages and renal tubular epithelial cells that are filled with fat droplets). The 24 hour total protein should exceed 3.5 g/day or the protein/creatinine ratio on a random urine is approximately 3.5 or greater in the nephrotic patient. (normal is < .2). These two tests will yield very accurate results. There may also be aminoaciduria. THere may be an increased serum IgM, beta-globulin and IgG. Biopsy results of the kidney may show thickened glomerular basement membrane, fused foot processes, focal sclerosis and renal tubular atrophy. « Special Laboratory Tests » Antinuclear antibody, rheumatoid factor, C3, C4, CH50, venereal disease serology including HIV, hepatitis B surface antigen, protein and urine electrophoresis, sedimentation rate and cryoglobulins. « Evaluation » The most important aspect in evaluation is a good history and physical. If the history and physical is largely negative then the patient has one of the primary forms, whereas if a secondary form is present then there may be symptoms of connective tissue disease, sexually transmitted disease, hepatitis, malignancy, HIV infection, ingestion of prescription or over the counter medicines and diabetes mellitus. Nephrotic syndrome can be divided into a primary group which have no know cause or secondary forms. « Primary Diseases » Minimal change disease, membranous glomerulonephritis, focal glomerulonephritis, focal glomerulosclerosis, membranoproliferative glomerulonephritis, IgA nephropathy, mesangial proliferative glomerulonephritis and rapidly progressive glomerulonephritis. « Secondary Diseases » Diabetes mellitus, Systemic lupus erythematosus, Allergens (snake venoms, insect stings, poison ivy and antitoxins), Amyloidosis, Erythema multiforme, Henoch- Schonlein purpura, Toxemia of pregnancy, Malignancy (lung, breast, stomach, kidney and colon), Heredofamilial (Alport's syndrome and fabry's disease), Familial mediterranean fever, Hodgkin's disease, Infections (bacterial, viral, helminthic and protozoal), Lymphomas and leukemias, Multiple myeloma, Melanoma, Drugs and toxins (mercury, gold, penicillamine, captopril, heroin, Sarcoidosis, Serum sickness, Polyarteritis nodosa and Sjogren's syndrome. « Renal Biopsy » Minimal change disease is likely in patients in whom the nephrotic syndrome develops rapidly and there is massive proteinuria of > 10 g/day. Most clinicians would probably not obtain a renal biopsy in this disease. Renal biopsy is probably not necessary in long standing diabetes mellitus. If the patient has small shrunken kidneys, a bleeding diathesis and uncontrolled hypertension, then renal biopsy is a relative contraindication. However, SLE has several subsets of renal histology and it is important to have this information to afford the best treatment plan. « Complications » If the patient develops hyperlipidemia there is premature atherosclerosis and all of its attendant complications. Hypercoagulability due to protein S deficiency is present and can cause pulmonary embolism, DVT and renal vein thrombosis. Dehydration can cause acute renal failure and hypotension. The potential of infection is always present because of the decreased protective immunoglobulin decrease. The patient may also develop anasarca, pleural effusion and ascites. There may be development of a factor IX deficiency. « Histology and Disease » Hodgkin's disease is associated with minimal change disease. Solid tumors and hepatitis B infection with membranous glomerulonephritis, and vesicoureteral reflux, HIV infection and heroin abuse are often associated with focal segmental glomerulosclerosis. SLE can be associated with several types of proliferative glomerulonephropathies. « Treatment (non-specific ) » Aggressive diuretic therapy should be tempered because of the decreased volume that may precipitate renal failure and initiate a hypercoagulable state. The patient's weight should be followed carefully. Lasix should be given initially and if the edema is resistant then metolazone can be added. The hypoalbuminemia is managed by using a high biologic value protein restriction daily diet of 0.8 g/kg of ideal body weight. Protein loading has been shown to increase urine protein excretion. Some patients, particularly in diabetes may benefit from angiotensin converting enzyme inhibitors or calcium channel blockers by decreasing proteinuria. The hyperlipidemia may be managed with a bile acid resin or one of the HMG CoA reductase inhibitors. These should be used with caution however as the inhibitors may cause rhabdomyolysis and worsen the renal failure. « Specific Therapy » Minimal change disease in adults can be treated with prednisone at 2 mg/kg of body weight daily for 1 week, then every other day for 7 weeks. This will bring about a remission in about 80% of adults. Up to 16 weeks of therapy may be required. If the patient doesn't respond then a second biopsy may reveal a focal segmental glomerulosclerosis that was not seen on the first specimen. Another schedule in adults would be to use prednisone at 1-1.5 mg/kg/day for 4-6 weeks. After response, continue the prednisone for another 2 weeks then change to maintenance of 2-3 mg/kg on alternate days for 4 weeks and taper to zero during the next 4 months. For children use prednisone 60 mg/square meter or 2 mg/kg/day orally for 4 weeks. After response, continue for another 2 weeks then change to maintenance of 2-3 mg/kg on alternate days for 4 weeks and taper to zero during the next 4 months. Membranous glomerulonephritis can be treated with month long prednisone alternating with month long courses of chlorambucil for 6 months. ■ ERECTILE DYSFUNCTION ■ Erectile dysfunction (ED) or impotence is the inability to obtain or sustain an erection that is satisfactory for intercourse and may feature a reduction in frequency of erection, detumescence during intercourse or complete lack of tumescence. Recent estimates are that there are about 20 million men with erectile dysfunction. Most of these men are > 65 years of age. However, erectile dysfunction can occur at any age and can be psychogenic, vasculogenic, medication induced, anatomic, surgery and trauma related, endocrine, or neurogenic. In some men the cause is multifactorial. « Endocrine Causes » Endocrine causes include diabetes mellitus with its associated renal disease, hypertension, vascular disease, high cholesterol, and low HDL. Primary testicular or hypothalamic-pituitary hypogonadism, hyperprolactinemia, hyper and hypothyroidism, Addison's disease and acromegaly can also be associated with ED. « Neuropathic Causes » Any alteration of the sacral cord center at S2-S4 and the thoracolumbar center of T12-L1, cerebrovascular, spinal, afferent, and autonomic systems can cause impotence. « Trauma and Surgery » Pelvic surgery and TURP can be associated with ED. « Medication Causes » This is a very important class, for indeed, something definitive can be done if the offending drug is removed. Many medications have been incriminated and include: alcohol, amphetamines, anticancer drugs, atropine sulfate, caffeine, chlordiazepoxide, chlorprothixene, cimetidine, digitalis, ismelin, imipramine, levodopa, lithium, marijuana, aldomet, MAO inhibitors, narcotics, nicotine, phenothiazines (particularly mellaril), reserpine, beta blockers, barbiturates, antihistamines, butyrophenones, clonidine, cocaine, ketoconazole, leuprolide, methadone, spironolactone, thiazides, tricyclic antidepressants, estrogens, and antiandrogens. « History and PHysical » The sexual history is needed to accurately define the patient's specific complaint and to refine what exactly the patient is trying to tell you. That is, does he mean erectile dysfunction, disturbance of orgasm or ejaculation, or sexual desire. He should be asked about the presence of nocturnal or morning erections, details of his sexual techniques, performance anxiety and what motivation he might have for rehabilitation and specific treatment. In the general, history risk factors should be ascertained such as hypertension, smoking, coronary artery disease, intermittent claudication, diabetes, peripheral vascular disease, pelvic trauma or surgery. If the patient has a decreased sexual desire then hypogonadism would be foremost in the diagnosis. Inquire about alcoholism, multiple sclerosis, strokes, spinal injury, radiation and any illicit drugs or medications that he might be taking as 25% of causes stem from medications. Ask about any symptoms from prostatitis, priapism, voiding dysfunction and peyronie's disease. Ask if there is any unusual depression or neurosis. Physical exam should include femoral and lower extremity pulses, a check on the secondary sexual characteristics and any evidence of Peyronie's disease, perianal sensation, bulbocavernosus reflex (elicited by squeezing the glans and checking for the anal wink) and sphincter tone. « Laboratory » An early morning testosterone and serum prolactin should be done. A low testosterone requires that the LH/FSH and prolactin be drawn. Inappropriately low LH/FSH levels with a low testosterone level mandates evaluation for hypogonadotrophic hypogonadism. Elevated LH/FSH with a consistently low testosterone indicates primary end organ (testes) failure and is treated by Depo-testosterone. In addition, check creatinine, BUN, FBS, UA, TSH, FT4 or FTI. To help differentiate organic impotence from psychogenic impotence use the 3 ring snap gauge. The DacoMed RigiScan is a small device that allows for the continuous monitoring of tumescence and rigidity and may be used on an outpatient basis.Three nights of data regarding the quality and quantity of erections are stored in the devices microcomputer. The device is then returned to the physician. The patient may be given a test for adequacy of arterial and veno occlusive function, and also to differentiate vascular from neuropathic causes, by injecting the intracavernous area with a vasodilating agent. Doppler ultrasound that compares the penile systolic blood pressure to the brachial systolic blood pressure with a resultant value of less than 0.7 is very suggestive of vasculogenic disease. Plethysmography will measure the flow across arteries of the penis and is more accurate than Doppler. CT of the pituitary is done if the prolactin is elevated. Other tests that can be done at a special medical or research center include: pharmacological pelvic-penile angiography, pharmacological duplex gray scale-color ultrasonography and pharmacological dynamic infusion cavernosometry-cavernosography. « Treatment » Treatment is unsatisfactory in a large proportion of men because of unwillingness to try a treatment and if started there is a high drop out rate with some of the devices. If the patient has psychogenic impotence then psychiatric care should be given. If medications are causing the ED then discontinue these. INTRACAVERNOUS SELF INJECTION THERAPY- with papaverine, prostaglandin E1 (alprostadil), vasoactive intestinal peptide and phentolamine can be tried. Combination therapy of these can be tried or monotherapy. Papaverine is being replaced by prostaglandin E1 as papaverine can cause hypotension, reflex tachycardia and reversible abnormalities on hepatic function tests, prolonged erection, and corporal fibrosis. Informed written consent should always be obtained with a prior discussion of the complications. The injections should be used only once in a 24 hour period and at the most 3 times per week. Patients should be examined every three months for injection nodules, corporal fibrosis or hematomata. Contraindications to the procedure include history of priapism, poor manual dexterity and visual acuity, sickle cell disease or any clotting disorder. VACUUM CONSTRICTIVE DEVICES- (ErecAid). These devices work by pumping blood into the penis by vacuum suction and a rubber constrictor prevents blood from flowing out. The drawbacks include obstruction of ejaculate and potential ischemic injury related to the wearing of the constriction rings (It is recommended that the constriction ring be used for less than 30 minutes). Patients and their partners are troubled by the lack of spontaneity in their sexual relationship and general discomfort of the device leads to a high drop out rate. VASCULAR SURGERY- For the penile venous leak, venous ligation can be done. However, currently the tests to determine a venous leak are incompletely validated. Arterial revascularization is usually restricted to large medical centers for congenital or traumatic vascular difficulties. PENILE PROSTHESES- In general there are three classes of prostheses: malleable, inflatable and semirigid. The main problems with these are mechanical failure, erosions and infection (particularly common in diabetics and spinal cord injuries). TESTOSTERONE- Should be reserved for the hypoandrogenic patient. Never use an oral dose because of hepatotoxicity and elevations in serum lipids. Give IM once q 3-4 weeks. Testosterone can improve libido without improving erectile function. All patients should have a baseline PSA and rectal exam because of the theoretical possibility of stimulating growth of an occult prostate cancer. Don't give testosterone if the prolactin is elevated. First normalize the prolactin by discontinuing drugs that cause the prolactin elevation, OR suppress prolactin with bromocriptine. Other side effects of testosterone include gynecomastia, rise in hematocrit, water retention, hypertension, and precipitation of CHF. YOHIMEX (Yohimbine) 5.4 mg tid can be tried. The patient should be treated for at least 10 weeks to determine the success or failure. Yohimex is contraindicated in renal disease. It is not recommended for females and during pregnancy. Side effects consist of antidiuresis with water retention, central excitement, elevation of BP and heart rate. Headache, skin flushing, tremor and irritability, and dizziness can also occur. If side effects occur reduce to 1/2 tab tid followed by gradual increase to 1 tab tid. VASODILAN (isuxuprine)- enhances the effectiveness of yohimbine and the two agents are often used in combination. ■ URINARY INCONTINENCE ■ Urinary incontinence is typically divided into 4 different classes: Urge, Stress, Overflow and Functional incontinence. There may be a combination of these that is operative in a particular patient. « Urge (Detrusor instability) » Urge incontinence is probably the most common of the four types and accounts for about 65% of cases. It is characterized by a leakage of urine caused by involuntary bladder contractions. Once a sensation to void occurs, the patient can't delay voiding. Causes would include cystitis, urethritis, bladder tumors and stones, diverticuli, stroke, dementia, and Parkinson's disease. Some elderly patient will have a sub-variety of urge incontinence known as detrusor hyperactivity with impaired contractility. In this entity there is incomplete emptying of the bladder with a residual urine greater than 50 ml. Normally, in urge incontinence the residual post voiding volume is normal. « Stress Incontinence » Stress incontinence occurs predominantly in elderly women, although it can occur in men following TURP and radiation therapy. It occurs when there is coughing, laughing sneezing or other activities that increase the intra-abdominal pressure. There is oftentimes a weakness of the pelvic floor with hypermobility of the urethra, weakness of the urethral sphincter or both of these. The post voiding residual is normal as in urge incontinence. « Overflow Incontinence » Overflow incontinence only accounts for about 10% in elderly patients. There is either an anatomical or neurogenic outflow obstruction, a hypocontractile bladder or use of certain medications. Causes include diabetic induced bladder neuropathy, urethral stricture, fecal impaction, anticholinergic medication, detrusor-sphincter dyssynergia and low spinal cord disease. Most patients will complain of a painful bladder distention except for those patients that have an impaired sense. There is increased post voiding residual urine found on catheterization. « Functional Incontinence » Functional incontinence occurs when the patient can't get to the toilet or is unable to get to the toilet. « Laboratory » A voiding record should be kept. Inquire into past surgical procedures and current medications (prescription and over the counter). Post voiding residual urine should be assessed. Check DTR's, perianal sensation, lower extremities sensory changes, and rectal sphincter tone. Palpate and percuss the abdomen for urinary bladder distention, check prostate and examine for fecal impaction. In women, pelvic exam should be done for atrophic changes, cystoceles or rectoceles. Have the patient cough while supine and standing to ascertain if there is any urine leakage. Urinalysis, cultures, calcium, BUN, glucose and serum electrolytes should be done to rule out diseases that produce polyuria. Ultrasound can help in searching for a distended bladder, enlarged kidneys, and prostate size. The voiding cystourethrogram can evaluate for the descent of the bladder and urethra at rest and when straining in the upright position. This latter test is useful in stress incontinence and men who have had a prostatectomy. « Medications Causing Incontinence » Diuretics, ephedrine, phenylpropanolamine, Minipress, Hytrin, Probanthine, antihistamines, calcium channel blockers, antidepressants, sedatives, analgesics, tranquilizers and antipsychotics. « Treatment » URGE Oxybutynin bid or tid is effective in 2/3 of cases of detrusor instability. It has a depressant effect on smooth muscle and moderate anticholinergic action. Propantheline 15-30 mg bid or tid is more effective if taken fasting. The side effects include blurred vision, constipation and dry mouth. It is contraindicated in patients with narrow angle glaucoma and bladder neck obstruction. Imipramine 25 mg qd to tid decreases bladder contractility and increases bladder outlet resistance. Side effects include those of anticholinergic medications, cardiac arrhythmias, postural hypotension, fatigue and malaise. Flavoxate 100-200 mg tid to qid comes in 100 mg tabs and there are side effects of nausea, vomiting, anticholinergic, vertigo, headache, drowsiness, urticaria, confusion, dysuria, tachycardia, hyperpyrexia, and blood dyscrasias. It is contraindicated in GI obstruction, obstructive uropathies and achalasia. Use precaution in glaucoma, elderly and cardiovascular disease. Transderm-Scop patch every 3 days and Dicyclomine 10-20 mg tid to qid can also be used. STRESS Pseudoephedrine 15-30 mg bid to tid, Imipramine 25 mg qd to tid, Estrogen (oral 0.625 mg daily or intravaginal 0.5-1 g 2 or 3 times a week or transdermal patch .05 mg every other day. May take up to 2 months before improvement is seen), and Phenylpropanolamine (use with caution in cardiovascular disease because of increased heart rate and blood pressure. It increases urethral resistance). OVERFLOW Prazosin 1 mg bid to tid, Terazosin 1 mg qd, Bethanechol 10 mg tid (this cholinergic agent increases the bladder pressure and stimulates bladder contractions. It should not be used with obstruction. Side effects are bronchoconstriction, abdominal cramps and diarrhea), and Finasteride 5 mg qd. MECHANICAL DEVICES Contraceptive diaphragm will help in stress incontinence, particularly with high impact aerobics. The vagina must be large enough to contain it. However, it may cause recurrent urinary tract infection. Weighted cones may be useful in about 30% of women with mild to moderate stress incontinence. The patient continually contracts the periurethral muscles to retain the cone. When the cone can be successfully retained it is replaced with progressively heavier cones. BEHAVIOR MODIFICATION Kegal exercises are effective for mild to moderate stress incontinence. Patients practice by stopping and starting urine flow. After this they contract the rectum about 5-80 times per day. By doing this, it is effective in about 60-90% of stress incontinent patients. Alternatively, the patient may insert a finger into the vagina and contract down on this. This procedure takes about 3-6 months before significant benefit is seen. Obese patients should lose weight and smokers with a chronic cough should stop smoking. Biofeedback is helpful in about 25% of cases. Bladder retraining drills are effective in patients with diminished sensory awareness. Patients are advised to urinate every 2 hours. As the patient improves the interval is increased by 30 minute increments. SURGERY Periurethral injection of polytef paste or glutaraldehyde cross linked collagen is injected into the periurethral tissue to provide increased resistance to the outflow of urine. More than 80% become continent after only two treatments. It is well tolerated by all ages. Only local anesthesia is needed. It is especially useful in elderly patients with incontinence caused by bladder outlet or urethral incompetence. For overflow incontinence caused by a large prostate, TURP, balloon dilatation, bladder neck incision and microwave tissue destruction may be used. ~neur.bin~ ■ STROKE IN THE YOUNG ■ When a young person presents with symptoms of a stroke, two key questions should be asked:. "Are you taking any drugs, either legal or illegal, and do you have any neck pain?". « Drugs Causing Strokes » Many young people are taking cocaine or other sympathomimetic drugs which can cause vascular constriction and inflammatory infiltrates in the vascular wall. Some illegal drugs have impurities that produce embolization or inflammation if used intravenously. Over-the-counter drugs such as diet pills and various stimulants have the potential of causing strokes. « Carotid Dissection » Neck pain is important information to elicit because carotid and vertebral dissection will cause this. Carotid dissection causes about 20% of strokes in the young person under 50 years of age. The average age is about 42, but there is a range from children up to the elderly. Females are involved more frequently than males. Approximately 50% will have a history of trauma to the neck. Trauma can be major as accidents, swimming and diving accidents, falls and gunshot wounds. Others are minor, and consist of minor neck strain as in lifting heavy objects, swimmers who constantly turn their heads in and out of water and wrestlers. The dissection typically begins at the base of the skull and dissects down the carotid artery. This pathway of extension is explained by the fact that the artery is fixed at the base of the skull, and the dissection takes the line of least resistance, dissecting the plane between the intima and the media. This will narrow the lumen, thrombosis will form, and then embolize to the brain. Adequacy of collateral circulation and other factors will dictate the degree of symptoms. This may be associated with Horner's syndrome ( miosis, ptosis, enopthalmos and decreased sweating), as the sympathetic fibers travel with the carotid from the superior cervical ganglion to the dilator muscle of the pupil. « Fibromuscular Dysplasia » Fibromuscular dysplasia is another disorder that may lead to stroke with or without dissection. Arteriograms will demonstrate the characteristic beading. Fibromuscular dysplasia can also involve the renal arteries. « Other Causes of Strokes » If occlusion or constriction of the cerebral vessels is seen on the arteriogram then one would rule out heart disease embolization, coagulation disorders and some systemic diseases. The angiogram may suggest premature atherosclerosis resulting from a metabolic abnormality of cholesterol with a family history of premature stroke or death. Hypercoagulable states would also have to be ruled out. It is important to obtain a CT to rule out hemorrhage, and possibly a MRI will be needed to rule out multiple sclerosis which can present as stroke at the onset in 20-25% of patients. If lesions are seen on the CT and MRI, then an arteriogram should be done within 5 days, as vascular events as embolus and thrombosis can lyse within a week and render the arteriogram normal. If the patient has a heart murmur and fever, then endocarditis would be a consideration. A transesophageal echocardiogram should be done in this case as chamber clots and valve vegetations can embolize. Systemic lupus erythematosus can present as a stroke rarely. Rash, pleuritis, arthralgia, renal failure, alopecia, etc would lead one to this diagnosis. ANA and antiphospholipid antibodies should be done as these are associated with venous thrombosis, abortion and strokes. Prothrombin time, partial thromboplastin time, sickle cell test, lumbar puncture, and blood cultures are other lab tests that might be done. Meningitis can cause thrombosis of the meningeal vessels, commonly in meningitis due to fungi, spirochetes, mycobacteria and neoplasm. Oral contraceptives can cause stroke. Migraine can present as a stroke-like onset. Most of these do not cause an overt stroke, but occasionally one does result from migraine. Other causes would include intracranial tumors, arteriovenous malformations and hypertension. ■ CERVICAL SPINE SYNDROMES ■ Most patients that you will see, will present with a non radiculopathy or a cervical radiculopathy. Both of these conditions will respond to conservative measures. How these respond will depend on many factors such as co-existing cervical findings, age, litigation and basic underlying personality of the patient. As one ages, degenerative changes take place that may be the cause of the radiculopathy or just be incidental when seen on investigative studies. As one ages, the gelatinous nucleus of the disk dries out and the annulus loses its elasticity and the facet joints take on osteoarthritic changes. The uncovertebral joints of Luschka produce spurs that can squeeze out the nerve roots. « Clinical » When a patient presents to you, your first task is to determine whether the pain is due to a radiculopathy, non-radicular neck pain, a cervical spondylotic myelopathy or instability. This can be done immediately by just putting together the patients symptoms. If there is neck pain that radiates to the arm or hand, then this may be a radiculopathy caused by nerve root compression from a bone spur or herniated disk. If there is only neck pain, this may just be a muscle spasm or disk degeneration and represent a non-radicular pattern. If the patient reports numbness, loss of bowel or bladder control, this may be a cervical spondylotic myelopathy due to cervical stenosis. Also, the situation in which the symptoms occur should also be taken into consideration. If this is a motor vehicular accident, then fracture or dislocation may be present. Open mouth views for C1 and C2 visualization, full lateral cervical spine including C7, and oblique views to check for fracture of the posterior processes should be done. If the patient has signs of infection, as fever, then sepsis with spinal abscess is a consideration. If there is any history of carcinoma, such as breast, kidney, lung, thyroid or prostate, metastasis to cervical spine is always a possibility. In any patient around 50 years of age, multiple myeloma also must be ruled out. « Cervical Radiculopathies » Cervical radiculopathies represent about 10% of cervical spine disease. If the patient is under the age of 45, then the radiculopathy may be due to herniation of the soft nuclear material from the disk and resolution is usual with conservative measures. If the patient is over 45 years of age then osteophytes and calcification of the annulus may compromise the nerve roots. The pain in this group usually never goes away completely, and there will be exacerbations and remissions. An MRI is probably the procedure of choice to identify the structure of the cervical spine. However, the specific nerve root that is involved cannot be ascertained with certainty. CT with intrathecal contrast is usually used if the MRI doesn't show the pathology. Myelography also is used to confirm a diagnosis of radiculopathy, and also to rule out infection or tumor. Myelography is less sensitive than MRI or CT with intrathecal contrast, and can miss central soft disk lesions. Patients also have pain with this procedure, and there can be false positives with myelography. Most cervical spine radiculopathies involve C6 and C7. If there is a C6 radiculopathy there will be pain in the lateral arm, radial forearm, thumb and index finger associated with weakness in the biceps, wrist and thumb extensors and a diminished biceps reflex. If there is a C7 radiculopathy the pain is in the posterior arm, radial forearm and the index and long fingers. There will be triceps and finger extensor weakness and the triceps reflex is diminished. C8 radiculopathies are fairly rare, but when present are usually more severe. There is pain in the medial forearm, ulnar palm and the 4th and 5th digits. There is weakness of the intrinsic muscles of the hand. In C5 radiculopathies there is shoulder and lateral arm pain and weakness of the deltoid and biceps muscles that is very severe. « Treatment of Cervical Radiculopathies » Most cervical disk herniations involving C6 and C7 can be managed conservatively. C5 radiculopathies may be so severe that early surgery must be done to save the motor function. Surgery consists of anterior diskectomy and interbody fusion or laminectomy-foraminotomy. The results or these two procedures are comparable. That is, if there is a one level procedure, the results for pain relief is 93 % and 85% for a 2 level procedure. However, like all other injuries that may be associated with workers compensation and or litigation, the results are poor until the litigation is settled. Also, any person that is dysfunctional with many somatic complaints and depression, will not respond optimally. Alcoholic and drug abuse is another subset of patients that do poorly. « Cervical Spondylotic Myelopathies » Patients may be older men with several levels of cord compression seen at C3-4, C4-5 and C5-6. There is lower extremity weakness, poor balance, difficulty with gait and paresthesia in the upper extremities. Ultimately, the patient may lose bladder and rectal control. The cause is usually due to multiple degenerative bone spurs at several levels. Men are affected more commonly than females, and the patient is usually over the age of 55. Large central disk ruptures, spinal cord or epidural tumors, multiple sclerosis, diabetic polyradiculopathy, and arteriovenous malformation all must be ruled out prior to surgery, which will be needed for stabilization. « Treatment of Cervical Spondylotic Myelopathies » The anterior approach with anterior diskectomy with or without interbody fusion is usually done if there are 1-2 sites of involvement. If multiple levels must be addressed, then laminectomy with wide decompression is usually a better approach. The latter may result in instability of the cervical spine because of the multiple wide laminectomies. If the patient has cervical kyphosis, then the posterior approach is contraindicated because the site of cord compression is usually anterior. Patients must be told that the surgery is done to prevent further cord compromise and that stabilization of the spine will not undo previous cord damage. « Instability of the Cervical Spine » Instability due to rheumatoid arthritis and trauma are major causes of instability. If there is subluxation greater than 4mm, then the probability of cord compression increases, and if there is any disturbance of upper motor function surgery may be indicated. Surgery usually comprises fusion and internal fixation to stabilize the spine and prevent cord compression. ~orth.bin~ ■ OSTEONECROSIS ■ Osteonecrosis is also known as avascular necrosis, Kienbock's disease, or subchondral fracture. « Causes » Causes are trauma, sepsis, stress or fatigue fractures, alcohol abuse, Gaucher's disease, Dysbarism, rheumatoid arthritis, SLE, vasculitis, hemoglobinopathy, coagulopathy, radiation, steroids (may occur in high short term doses, long term or intra-articular injections. Onset of symptoms is usually greater than 6 months, but may be more than 3 years), pregnancy, gout, aging, pancreatitis, Legg-Calve-Perthes, Sever's, Kohlers, Larsen's, Blount's, Panner's disease, Diabetes mellitus, and hyperlipidemia type 2 & 4. « Clinical » Presentation is pain, decreased range of motion, possible tenderness, and limp. May affect the shoulders, hips, and knees. « Laboratory » Bone scan shows a photon deficient area or doughnut sign early. Later, there is increased uptake. MRI shows a decreased signal with T1 & T2 weighting. Signal may vary over time. X-ray varies from mottled increased density in the femoral head to intense subchondral radiolucency (Crescent sign). « Treatment » In the Alcoholic: (abstinence), Transplant patients: (regulate the calcium & phosphorus & decrease steroids), Sickle cell: (hydration, exchange transfusion, oxygenation). Limit weight bearing & use crutches, NSAID's, and prosthetic joint replacement. ■ PAGET'S DISEASE OF THE BONE ■ Paget's disease (PD) is a bone disease that has no known cause, is often asymptomatic, but does cause bone pain, and is characterized by an increase of the alkaline phosphatase. About 3% of persons greater than 40 will have Paget's' disease, and males are more affected than females. The disease is more common in England, Australia, New Zealand, Eastern and Western Europe. There may be a family history in about 10-20% of patients. There is an increase in osteoclastic bone resorption and then remodeling with an increase in osteoblastic activity. The abnormal bone that is formed has increased numbers of arterioles and venous sinuses which causes arteriovenous shunting. « Clinical » The most common complaint, in about 50% of patients, is pain that is usually in the back, lower extremities, pelvis and hips. About 75% of all patients with Paget's disease have pelvic and sacral involvement. About 50% have some vertebral and/or femoral involvement, and about 1/3 have skull involvement. Disease in isolated long bones outside of joints responds best to treatment, whereas disease in the vertebrae or joint spaces never responds completely to treatment. About 45% have neuromuscular signs and symptoms, and cardiovascular findings occur in about 35%. Cardiac calcifications are not uncommon and have been reported to involve the aortic and mitral valves or the interventricular septum. There may be complete heart block with calcification in the bundle of His. Defective hearing, headaches and urinary tract complaints occur in 14%. Deafness is the most common neurologic complication and may be secondary to damage of the middle ear or the eighth nerve, and does not improve with treatment. Approximately 20-40% have skull or jaw enlargement and bowing of the lower extremities. Dyspnea and increasing head size may occur. There may be cranial nerve palsies involving the V and VII and VIII cranial nerves. Also, there may be hydrocephalus due to basilar invagination with obstruction of the CSF flow. Vertebral or brain stem involvement causes the greatest morbidity, but fortunately often reverses with therapy. Fractures, compression, and radicular symptomatology may be present. Physical examination reveals increased warmth overlying the involved bone, dilated scalp veins, and angioid streaks on funduscopy. High output heart failure may occur if there is more than 35% of the skeleton involved. Osteosarcomas may develop in long standing disease. « Laboratory » There is an elevated alkaline phosphatase. It is important to rule out other causes of elevated of alkaline phosphatase, such as liver disease, healing fracture, metastatic cancer, osteomalacia, and hyperparathyroidism. The serum calcium and phosphorus are usually normal. There is an increase in 24 hour urinary hydroxyproline. The bone scan is the most sensitive for picking up the early areas of Paget's disease. On x-ray, there may be cortical or trabecular coarsening, with or without enlargement of bone. The x-ray may also show areas of lysis, and osteoporosis circumscripta (the lytic phase that precedes sclerotic overgrowth) in the skull. In an occasional patient, bone biopsy may be needed to make the diagnosis, but in the majority, the entire picture is clear enough to make a diagnosis. « Treatment » CALCITONIN: For routine maintenance, 50 MRCU of calcitonin three times per week may be given. Many patients, however, will require higher doses of 100 MRCU three times per week. As preparation for orthopedic surgery, OR treatment of immobilization hypercalcemia, OR as initial treatment of patients with lytic disease in a weight bearing bone, 100 MRCU should be given daily. For neurologic complications, 100 MRCU bid will maximize the treatment response. Calcitonin is expensive and ranges from about $27.00 per week for 50 MRCU taken three times per week to $252.00 per month for 100 MRCU taken twice a day. Because this treatment is expensive and requires repeated injections, Didronel is often prescribed for most indications. Calcitonin is safe and effective with a rapid onset of action. About 80-90% of patients develop an acute clinical remission, and most patients demonstrate a 50% reduction in biochemical indicators of disease. Although sustained biochemical remissions are rare after 12 months, many patients experience prolonged clinical remissions. DIDRONEL (EHDP): Oral didronel is about as effective as calcitonin, but has a slower onset of action and may predispose to fracture in patients with lytic bone lesions. It can be administered at doses of 5 mg/kg/day po for no more than 6 months OR 20 mg/kg/day po for no more than one month. With either one of these regimens it is possible to achieve 50-70% suppression of biochemical indicators of disease, and to achieve a clinical response in up to 90% of patients. Since Didronel produces hypocellular bone, it should be avoided in patients requiring orthopedic surgery, or those with lytic disease in a weight bearing bone. For emergencies such as neurologic complications of Paget's disease, Didronel should be given at doses of 4.3 mg/kg/d IV for seven days. Since Didronel frequently produces long term remissions, it is reasonable to follow patients after one treatment cycle, and repeat treatment only when biochemical indicators rise or the patient again becomes symptomatic. Remissions lasting up to 24 months are fairly common. Didronel should be discontinued intermittently, even if long term remission is not achieved. It is common to treat with Didronel for 6 months and then follow with a six month drug free holiday. If symptoms become troublesome during the drug holiday, calcitonin can be used. Combination therapy with Didronel is not significantly better than maximal therapy with either agent alone. Didronel is safe and non-toxic if used properly, but onset of action is slow. Didronel is inexpensive and not associated with drug resistance. Almost 90% of patients improve clinically. Biochemical indicators of disease decrease by 50-70%. Long term biochemical and clinical remissions are common. Osteomalacia and possibly an increased risk of fracture are significant disadvantages. « Summary of Specific Treatment » 1...For bone pain prescribe calcitonin 50-100 MRCU 3 times per week or Didronel 5 mg/kg/d po for 6 months. 2...For bone pain with a lytic lesion prescribe calcitonin 100 MRCU/day until the lesion is healed. Then, use either calcitonin or didronel as described above. 3...For congestive heart failure find and treat the underlying cause. 4...For neurologic complications prescribe calcitonin 100 MRCU bid and/or Didronel 4.3 mg/kg/d IV times 7 days. 5...For orthopedic surgery prescribe calcitonin 100 MRCU qd for 3 months before and 6 months after surgery. 6...For active disease in a young patient prescribe calcitonin 50-100 MRCU 3 times per week or Didronel 20 mg/kg/day po for one month. Follow patient until relapse. ~pulm.bin~ ■ SARCOIDOSIS ■ Sarcoidosis is a multisystem granulomatous disease that has a predilection for the lungs, but can affect other systems such as the following seen in descending frequency: lungs, mediastinal lymph nodes, peripheral lymph nodes, skin, eyes, liver, spleen, bone, salivary and lacrimal glands, joints, heart, skeletal muscle, central nervous system, and kidneys. Since it is a noncaseating granulomatous disease that can proceed to hyalinization and fibrosis, other causes of non-caseous granulomata would have to be ruled out as: fungal, mycobacterial, infections, berylliosis, syphilis, Hodgkins's disease, brucellosis, Q fever, histiocytosis, tularemia, biliary cirrhosis, drug reactions as sulfonamides and phenylbutazone, leprosy, Wegener's granulomatosis and focal sarcoidal reactions in lymph nodes which drain a solid tumor. The cause of Sarcoidosis is unknown. Sarcoidosis is more common in blacks between the ages of 20 and 40 and they typically have a more aggressive prolonged course. The pulmonary disease is typically divided into 3 stages which also can serve as a prognostic guide. Stage I shows symmetric bilateral hilar adenopathy along with possible right paratracheal adenopathy. Prognosis for stage I is excellent especially if it is associated with erythema nodosum. Since this stage is usually associated with no symptoms it can sometimes be found on routine chest x-ray that is done for another reason. Stage II is bilateral hilar lymphadenopathy plus parenchymal infiltration and stage III is parenchymal infiltration in the absence of hilar lymphadenopathy. « Clinical » Symptoms would depend on the site of involvement. If the lung is involved there may cough, dyspnea, fatigue, fever and weight loss. If there are pulmonary fibrosis and cystic changes, there may be symptoms and signs compatible with cor pulmonale. Uveitis occurs in about 15% of patient. It is bilateral usually, and has to be treated as there may be loss of vision from the secondary glaucoma. Skin disease usually presents as subcutaneous nodules, papules and plaques. Myocardial involvement can cause conduction abnormalities, heart failure, and angina. CNS involvement occasionally shows cranial nerve palsies, in particular 7th nerve palsies. Diabetes insipidus can occur with involvement of the pituitary or hypothalamus. Polyarthritis may cause periarticular swelling and tenderness associated with changes in the phalanges. The knees and ankles are commonly involved. Hypercalcemia is caused by alveolar macrophage production of 1,25 dihydroxyvitamin D. The hypercalcemia may then cause damage to the kidneys by nephrocalcinosis, renal calculi and renal failure. Sometimes, Erythema nodosum occurs in conjunction with Stage I lung disease, and when this combination occurs, the diagnosis of sarcoidosis is secure, and the prognosis is good. Hepatic granulomas are found in 70%, even when the liver function tests are normal and the patient has no symptoms of liver disease. Hepatomegaly is only present in about 10% or less. « Laboratory » There is hypergammaglobulinemia, cutaneous anergy, positive Kveim test (the Kveim test is not used much because there is a lack of the antigen, a waiting period of 6 weeks until the test area can be biopsied, and false negative reactions that increase with the duration of the disease. There may also be hyperuricemia, hypercalcemia and hypercalciuria, low parathyroid hormone levels and elevated rheumatoid factor. The angiotensin converting enzyme (ACE) can be used to follow the activity of the disease, but isn't good for diagnosis as a false positive test may occur with other diseases as histoplasmosis, acute miliary TB, lymphoma and hepatitis. The alkaline phosphatase is elevated in liver disease. Biopsy sites include the mediastinal nodes via mediastinotomy or mediastinoscopy, intercostal lung biopsy, and liver biopsy. The most common procedure performed for diagnosis is transbronchial biopsy. THe biopsies will show non-caseating granulomas. Bronchoalveolar lavage and whole body gallium scans can also be done if diagnosis is obscure. The gallium scan will show symmetrical uptake in the hilar and mediastinal nodes, parotid, lacrimal and salivary glands. These areas may then be used for biopsy sites. A second use of gallium is to differentiate pulmonary fibrosis from reversible inflammation. Pulmonary function should be done which usually shows restrictive changes in Stage II and III. With advanced pulmonary disease there are obstructive findings. There is decreased diffusion capacity. Chest x-rays in advanced pulmonary sarcoidosis may show cystic, or bullous disease and cavities with aspergillus (fungus balls). « Treatment » If the patient has stage I lung disease, then baseline studies should be done as CBC, creatinine, calcium and serum ACE. The fundus should be examined as uveitis may be subclinical and asymtomatic. If there is painful erythema nodosum, this can be treated with NSAID's. No other treatment is needed as the prognosis is excellent. Stage one usually resolves in 1-2 years but is not predictable. Some have resolved after one month and as late as 15 years. The chest x-ray should be repeated in about 6 months. Once the chest x-ray does resolve there is very little chance for recurrence. Stage II or III should be followed for about 6 months. If there is no spontaneous resolution or there is progression, then probably steroids are indicated to suppress the inflammation with an attempt to prevent progression to fibrosis. Patients can be started on alternate day therapy with prednisone 40-60 mg per day. When there is evidence of decreased activity of the angiotensin converting enzyme, and the patient's clinical and laboratory parameters parallel this improvement, the prednisone can be tapered by about 10 mg every 3 months. If there is hypercalcemia or involvement of critical organs as heart, CNS, and eyes, prednisone should be used. Minor hemoptysis usually subsides depending on the etiology. In advanced sarcoid lung disease there may be massive hemoptysis and this is treated with gel foam bronchial artery embolization or resection of lung tissue. Fungous balls may require resection if not controlled with embolization, but the morbidity and mortality are high. Chloroquine has been effective in controlling cutaneous disease. ■ WEGENER'S GRANULOMATOSIS (WG) ■ WG is a fairly rare disease (large centers may see about 5 cases per year), predominantly affecting men (3:2) at a mean age onset in the 40's, and characteristically affects the upper airway, lung and kidney. However, it is a treatable disease with survivals of 75-90% at 5 years. Prior to prednisone and cyclophosphamide treatment, the disease was invariably fatal with a mean survival of about 5 months. There is no known cause, but it is an immune mediated hypersensitivity disorder that was first classified in 1936 by Wegener as a variant of polyarteritis. The diagnostic histologic lesion is a necrotizing granulomatous inflammation of small arteries and veins. There is a limited form of Wegener's disease that affects only the upper or lower respiratory tract. « Clinical » About 70% will present with pulmonary infiltrates that have a predilection for the upper lobes, and usually are multiple and bilateral nodules and cavities. The cavities may be fluid filled and there may be lobar atelectasis, and pleural effusion. (20%). Unusual findings would include paratracheal mass, mediastinal mass, calcified nodules, miliary pattern and a lower lobe interstitial disease. If high resolution, thin section CT is done feeding vessels into the cavities and nodules can be seen along with peripheral wedge shaped densities that probably represent ares of infarction. These changes cause a cough with some sputum production and occasionally minor hemoptysis. Sinusitis also is common (67%) with concomitant rhinorrhea, ulcers and erosions, epistaxis, pseudotumors, and saddle nose deformities. The kidney is also involved, usually later in the course of the illness. In most cases there is no associated hypertension. About 50% of patients with WG who are clinically asymptomatic will have evidence of disease activity on renal biopsy. Immune complex deposition is not common. Histology reveals basically 2 types; focal glomerulitis and crescentic glomerulonephritis (which is less common). A renal biopsy that is characteristic plus evidence of chronic destructive sinusitis and pulmonary nodules is presumtive evidence for WG. However, open lung biopsy is the best procedure for a definitive diagnosis. Diagnostic renal biopsies can be seen in SLE and Goodpasture's syndrome. Other symptoms, but less common, would include the following: arthralgias. (The arthralgias are polyarticular, symmetric and involve large and small joints. Arthritis is less common than arthralgia). Palpable purpura and ulcerative infarcts, granulomatous uveitis, (16%), orbital pseudotumor, otitis (25%), fever (34%), hemoptysis (18%), weight loss (16%), and epistaxis (11%) may also be present. Rare presentations would be pericarditis, coronary vasculitis, cranial neuritis (particularly involving the 1, 7 and 8th cranial nerves and mononeuritis multiplex. « Laboratory » Rheumatoid factor is found in 60% of patients. Circulating immune complexes are found in about 50%. The sedimentation rate is almost always elevated with mean values in the nineties. There is usually a leukocytosis and anemia of chronic disease. Thrombocytosis can be seen in 33% and Cryoglobulins are occasionally seen. The UA may reveal hematuria, with or without RBC casts and proteinuria. Often times the proteinuria is in the nephrotic range. Of importance is the fact that hepatitis B surface antigen, ANA and anti-DNA antibodies are usually negative. The antineutrophil cytoplasmic antibody test is positive in about 90%. There are two forms of this test. The cytoplasmic pattern of staining (c-ANCA) has a specificity of about 90% for Wegener's. The perinuclear staining (p-ANCA) is more non specific, but is seen in Wegener's and polyarteritis. « Differential Diagnosis » Differential diagnosis depends on the presentation but would include SLE, Churg-Strauss syndrome, Goodpasture's syndrome, bacterial endocarditis, uremic pneumonitis, sarcoidosis, systemic sclerosis, lymphomatoid granulomatosis and pneumonia complicated with glomerulonephritis. To diagnose Wegener's requires a biopsy revealing both necrotizing vasculitis and granulomatous inflammation. Biopsy of skin usually only shows a leukocytoclastic vasculitis. Ocular and upper airway biopsy may show inflammatory changes with or without granuloma or vasculitis but rarely both. Transbronchial biopsy is less effective than an open lung biopsy and shows inflammation with or without giant cells. « Treatment » Prednisone, 1 mg/kg/day is given with oral cyclophosphamide 2 mg/kg/day. The prednisone may be given for about 1 month and then tapered to alternate day treatment. This may be gradually be discontinued over 2-6 months depending on clinical response. The cyclophosphamide is usually continued for 1-2 years after the patient is in remission and tapered slowly. With this combination there has been a 70-93% complete remission rate. However, in 50% of these remissions there may be relapses even as long as 10 years after remission. About 13% will die from the disease or as complication from the treatment. Trimethoprim/sulfamethoxazole has been used alone with success in some patients with the limited form, and in those who cannot tolerate immunosuppressive drugs. ■ PNEUMONIA IN THE ELDERLY ■ It is estimated that by the year 2030, 17% of the population will be over the age of 65. There is an increasing population in nursing homes and in intensive care units. This subject will address the clinical aspects of bacterial pneumonia in the elderly as well as the treatment. Atypical pneumonia will not be addressed. « Clinical » Pneumonia in the elderly, more frequently presents with dyspnea. Most of the patients will have chills, cough, fever, chest pain and increased sputum production, but to a lesser extent than the young. Some may not even have a cough, sputum or chest pain. Tachycardia isn't common in the elderly and fever may not be present. Confusion is common in the elderly and this may be the only symptom. « Laboratory » There may be a leukocytosis, leukopenia or even a normal WBC. However, there is usually a consistent shift to increased numbers of band and polymorphonuclear leukocytes. On chest X-ray there is an increase of pleural effusions, incomplete consolidation and involvement of greater than one lobe in the elderly. Resolution typically takes greater than 14 weeks, as opposed to about 6 weeks for younger patients. In the elderly, there is greater progression of the infiltrates after appropriate antibiotic therapy has been started. « Types of Pneumonia in the Aged » Streptococcus pneumoniae is still prevalent in the aged and constitutes about 40-60% of community pneumonias. However, bacteremia is more common in the elderly. Haemophilus influenzae pneumonia occurs in about 15% of community acquired pneumonia. If the patient has chronic obstructive lung disease, Haemophilus influenzae is common, as the oropharynx is colonized in about 60%. The type B encapsulated strain is the one that usually causes bacteremia. In community pneumonia due to Haemophilus influenzae the organism are frequently non-typeable, unencapsulated Beta lactamase producers. Staphylococcus aureus pneumonia commonly occurs during influenza epidemics and constitutes about 10% of community pneumonia. Gram negative, community acquired pneumonia accounts for only a small percentage. Klebsiella pneumoniae is the most common. Next common would be Proteus mirabilis, Escherichia coli and Enterobacter which account for about 8%. Pseudomonas, Serratia marcescens, Citrobacter and Acinetobacter are rare. In hospital pneumonia, there is a decrease in Pneumococcal pneumonia with an increase of Haemophilus influenzae and a large increase in gram negative pneumonia. « Treatment of Community Acquired Pneumonia » Trimethoprim sulfamethoxazole has a good spectrum of coverage that would encompass the pneumococcus, beta lactamase producing Haemophilus influenzae and the gram negative organisms as Klebsiella pneumoniae, Escherichia coli and Enterobacter aerogenes. If the patient has a Staphylococcal pneumonia, then Nafcillin should be added, particularly during periods of influenza. Community acquired methicillin resistant staphylococcal pneumonia in the aged apparently has not been reported in the elderly. TMP/SMX can be given IV or taken orally, and is fairly cheap as compared to other antibiotics. What if the patient is allergic to sulfa? Then, the patient should be treated with a third generation cephalosporin which has good activity against beta lactamase producers. Either cefotaxime or ceftriaxone may be used as they provide good coverage similar to TMP/SMX. Cefixime would be an alternative oral 3rd generation drug that could be used. Two other antibiotics, Ampicillin/sulbactam, and Ticarcillin/clavulanate have a spectrum similar to the third generation cephalosporins and will treat Streptococcus pneumoniae, beta lactamase producing Haemophilus influenzae, Staphylococcus aureus (non methicillin resistant) and the usual gram negative pneumonia. Ticarcillin/clavulanate could be used if there is Pseudomonas aeruginosa or Serratia marcescens. « Treatment of Hospital and Nursing Home Acquired Pneumonia » Pseudomonas aeruginosa pneumonia may be increased up to 10% in this group. There also is an increase of gram negative bacillary pneumonia. Good choices would be an antipseudomonal penicillin as mezlocillin plus Gentamicin, or Ceftazidime plus Gentamicin. Gentamicin is usually preferred over Tobramycin as most strains of Pseudomonas aeruginosa are sensitive to gentamicin and the cost is usually better. (It is important to remember that in the elderly there is a reduction in the lean body mass and and total body water, and an increase in body fat. Therefore, blood and tissue concentrations of antibiotics may be higher than usual. The decreased muscle mass also means there would be a lower serum creatinine, and if the serum creatinine is used to calculate the dose of an aminoglycoside, you might get a higher than expected peak aminoglycoside level, which could lead to nephrotoxicity). If the patient has non-methicillin resistant Staphylococcal pneumonia, these two combinations will be effective. If a methicillin resistant Staphylococcal pneumonia is present, use vancomycin. « Specific Pneumonias in the Aged » Legionella pneumophilia pneumonia is not common, but occurs occasionally, particularly in smokers. The frequency varies geographically. Only about 2% of nursing home residents will have a significant antibody titer that is greater than 1:64. The onset is abrupt with headache, myalgias, weakness, fever, hemoptysis, bradycardia, watery diarrhea, abdominal pain and encephalopathy. Gram stain of the sputum shows leukocytes, but no organisms. The patient has alteration of liver function tests and hyponatremia is common. A direct fluorescent antibody test of the sputum should be done. This test has a high specificity of about 90%, but a low sensitivity varying between 25-80%. Legionella pneumophilia can be treated with erythromycin, rifampin or Trimethoprim sulfamethoxazole. Branhamella catarrhalis pneumonia occurs mainly in adults over the age of 65. Many of these patients have chronic obstructive pulmonary disease. Symptoms are usually uncommon. About 50% will be afebrile and have a normal WBC. Chest x-ray shows an incomplete consolidation. Positive blood cultures are rare, and pleural effusion and cavitation have not been reported. Most of the organisms are beta lactamase producers. Sputum exam would reveal gram negative diplococci in the WBCs. Acute and convalescent serology should be done. Treatment is with the same antibiotics that are used to treat community acquired pneumonia. ■ ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS ■ Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity pulmonary disorder that can complicate asthma, resulting in transient x-ray infiltrates, often in the upper lobes, and central bronchiectasis. « Clinical » All patients have asthma. The asthma may be new or old. Most patients are young adults who are 20-40 years of age. Most patients will have a cough with mucopurulent sputum. Some patients will expectorate sputum plugs, which are actually casts of bronchi. These have a brownish discoloration on one end which is due to Aspergillus hyphae. About 50% of the patients will have hemoptysis and elevated temperature associated with the radiographic infiltrates. A few patients will complain of chest pain described as pleuritic or chest wall pain. « Laboratory » There is an array of x-ray findings in ABPA. These will be discussed in the order of their frequency. INFILTRATES The infiltrates may appear as nodular alveolar infiltrates up to one cm in diameter and have either an ill defined or distinct margin. CONSOLIDATION The consolidation usually involves an entire segment or lobe without air bronchograms and is due to an eosinophilic involvement of the lung parenchyma. Several other types of pneumonia have been described as lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, lipid pneumonia and vasculitis. All of these will rapidly disappear when steroids are given. TRAM LINES Tram lines consist of two parallel lines near the hila that extend outward toward the bronchi, and represent the width of the normal bronchi. PARALLEL line shadows are similar, but represent a dilated bronchiectatic bronchus. Microscopically, the walls of the bronchi are infiltrated with a mixture of lymphocytes, plasma, eosinophils and sometimes neutrophils. There may or not be granulomata. THere is no Aspergillus invasion of the walls, but occasionally Aspergillus may be seen in the lumen of the bronchi. With steroid treatment, the normal width, inflamed bronchi will disappear, but the dilated bronchi will not, because these represent bronchiectasis. BAND (TOOTHPASTE) SHADOWS These shadows represent dilated bronchi that are filled with inspissated mucous containing Charcot-Leyden crystals, Curschmann's spirals, eosinophils, mononuclear cells, and fibrin. If the patient vigorously coughs these may disappear. PERIHILAR SHADOWS These shadows may simulate hilar adenopathy, but are central bronchi filled with fluid and surrounded by infiltrates. « Diagnosis » ASTHMA All patients must have asthma, but the degree of asthma may be quite variable, from mild to severe. Some patients will have a history of allergies and allergic rhinitis. RADIOGRAPHIC INFILTRATES The changes on x-ray will occur at some time during the course of ABPA, and may be absent at diagnosis, but if the course of ABPA is followed these changes will eventually be seen. PERIPHERAL EOSINOPHILIA This finding may not be too specific, because peripheral eosinophilia may be present in asthma without ABPA. However, the eosinophilia usually ranges from 8-40% in ABPA. If the patient has been on steroids, the eosinophilia may not be present. IMMEDIATE SKIN SKIN REACTIVITY TO ASPERGILLUS ANTIGEN All patients will show an immediate cutaneous reaction to Aspergillus fumigatus or mixed Aspergillus. The prick test is usually done for testing. ELEVATED TOTAL SERUM IgE Normal IgE is about 300 ng/ml. However, in ABPA the IgE level may be as high as 40,000. If the patient has been treated with steroids, or the patient is in remission, the IgE concentrations may not exceed 1000 ng/ml. The IgE may be used to indicate exacerbations of the disease. PRECIPITATING ANTIBODIES TO ASPERGILLUS This finding is non-specific because about 10% of patient who have asthma alone will have precipitating antibodies to Aspergillus. About 85% of patients with aspergillomas will also have precipitating antibodies. Furthermore, these antibodies may be suppressed by steroids. CENTRAL BRONCHIECTASIS This finding is considered diagnostic of ABPA. « Treatment » Prednisone 0.5 mg/kg daily for 14 days, then give this dose on alternate days for 3 months. Following this, the dose should gradually be tapered, and then discontinued. The total serum IgE should then be measured every 2 months for a year, as there may be exacerbations without clinical symptomatology. Also, chest x-rays should be obtained at 6 month intervals. These measures are done to prevent progression of the lung disease to stage five, which is the fibrotic stage characterized by irreversible obstructive and restrictive pulmonary abnormalities. ■ INVASIVE PULMONARY ASPERGILLOSIS ■ Invasive pulmonary aspergillosis usually invades the lung in about 90% of cases and may be the only site in about 70%. There are several predisposing factors that lead to the invasion, including hematopoietic malignancy, as acute lymphocytic and myelogenous leukemia and lymphoreticular malignancy. Patients that have had organ transplantation, especially bone marrow transplants during periods when rejection is being treated with immunosuppressive therapy. Any patient that is being treated with cytotoxic agents, corticosteroids and antimicrobials are subject to potential invasive aspergillosis. Granulocytopenia is especially fertile ground for invasion by Aspergilla. Aspergilla produce nodular lesions that usually are less than 3 cm in diameter with smooth or ragged margins. There is small artery invasion by the fungi. These lesions may be multiple and confluent with necrotic centers with a rim of hemorrhage. Hemorrhagic infarctions present as large pleural based, wedge shaped lesions, usually without cavitation. There may be major artery invasion with subsequent thrombosis. « Clinical » Most of these patients present with an unremitting fever, and in the right circumstances, such as granulocytopenia, immunosuppression, and underlying disease, invasive aspergillosis should be suspected. There may be pleuritic pain caused by the hemorrhagic infarctions and pulmonary embolic disease may be simulated. Aspergillus frequently colonizes the nasal and sinus cavities producing a nasal ulcer or epistaxis and sinusitis. The patient may develop skin lesions, DIC, and multiple organ failure with azotemia, acidosis, jaundice, delirium, hypoxic and death. CT may be helpful if one can find the halo sign which consists of a lung mass or nodule surrounded by a zone or halo of attenuation less than the center of the mass, but greater than air in the surrounding lung tissue. This sign is not pathognomonic as it may appear in patients with septic emboli due to aerobic bacteria. The typical evolution of a nodule is to cavitation in about 50%, or air crescents in 85%. The air crescent sign appears later in the course than the CT halo sign. There may be a ball in the cavitation, but this doesn't consist of a mass of hyphae as in aspergillomas. The ball is necrotic lung caused by arterial invasion and then infarction. Cultures of sputa are not reliable for diagnosis. In the first place, only 8-37% of patients with Aspergillus infection will culture out the organism. Even if it cultured, its presence may just signify colonization rather than invasion. Nasal cultures have been reported to be somewhat helpful in diagnosing lung invasion, because of its co-existence with invasive lung aspergillosis. However, if the nasal culture is negative, this doesn't mean that there is no lung aspergillus invasion. Probably the two best approaches for diagnosis are fiberoptic bronchoscopy and peripheral percutaneous needle aspiration. There is considerable debate as to whether open lung biopsy is appropriate as the initial diagnostic measure in diagnosis. Those that support open lung biopsy contend that an adequate sample of tissue is needed for histopathologic exam, stains and cultures. Those that oppose this view state that there are sampling errors, with erroneous diagnosis, and that even with a specific diagnosis there may not be any change in therapy. The reported survival rate has been estimated to be from 0-35% and the survival of treated patients is less than 30%. The diagnosis is only made in about 20-78% of cases. « Treatment » When invasive aspergillosis is suspected clinically, or is demonstrated on biopsy, there should be immediate institution of Amphotericin B after a test dose. The total daily dose is 0.8 -1 mg/kg/day IV for several weeks as tolerated. Thereafter, the dose is reduced to .6 mg/kg/d for a total dose of 2 grams. ~rheu.bin~ ■ LEUKOCYTOCLASTIC VASCULITIS ■ « Causes » This is also known as a hypersensitivity vasculitis or palpable purpura and can be associated with multiple etiologies. The disease is probably idiopathic in about 50 % of cases and is self limiting in about 2-3 weeks usually. However, drugs are a strong contender in causing the vasculitis; especially in the elderly. Most drug induced purpura does not involve autoantibodies and doesn't produce urticaria. Quinidine is one exception, in that it can induce antibodies that can destroy platelets that have quinidine on their surface, and this can result in thrombocytopenia. Diuretics and cardiac drugs are common offenders. One should not only question the patient about prescription drugs but over-the-counter medications. Also, ask about medications that are inhaled and rubbed on the skin. Ask about vitamins, food supplements, diet pills, sleeping pills, relaxants, birth control pills and medications that may have been taken belonging to another person. Interrogate for IV drug abuse that can cause an endocarditis with embolic purpura. Aspirin and non- steroidal anti-inflammatory agents can cause interference with platelet function and cause petechiae or ecchymoses. Systemic causes for purpura consist of mixed cryoglobulinemia syndrome, hepatitis, embolic disease and connective tissue disease as SLE, rheumatoid arthritis, and Henoch-Schonlein purpura (usually a pediatric disease). « Clinical » If SLE is being considered, ask about hair loss and sun sensitivity, fetal loss and hypertension during pregnancy. Physical exam may provide clues, as a malar rash, mouth sores and scalp lesions may point toward SLE. A heart murmur suggests endocarditis with embolism. Splinter hemorrhages can suggest endocarditis or a primary systemic vasculitis. Funduscopic exam may show emboli or vasculitis. Leukocytoclastic vasculitis produces a palpable purpura, usually of the lower extremities, that can be painful. Purpura due to platelet abnormalities, either quantitative or qualitative is not painful and is not palpable. Non-palpable purpura can be seen in senile, steroid or amyloidosis purpura. Thrombotic thrombocytopenic purpura TTP) would have to be ruled out as well as ITP. « Laboratory » UA may show hematuria, and proteinuria associated with a renal vasculitis. Sedimentation rate, platelets, bleeding time, creatinine, liver function tests and CPK should be done. If there is a history of sinusitis, then get sinus x-rays and chest x-ray to rule out Wegener's granulomatosis. EKG may show pericarditis with SLE or coronary vasculitis. ANA, rheumatoid factor, cryoglobulin and hepatitis serology should be done. Skin biopsy may show cholesterol crystals from an ulcerating atheromatous plaque or material from a cardiac myxoma. Transesophageal echocardiography can be done if the patient is very ill and embolism is high on the list. Transesophageal echo is the method of approach, as it is much more sensitive and can also show the aortic arch and descending aorta. Serum and urine electrophoresis and immunoelectrophoresis may be helpful. The immunoelectrophoresis may show a monoclonal paraprotein spike that isn't seen on the serum protein electrophoresis and point to a gammopathy of unknown significance that can progress in 10-30 % of cases to multiple myeloma or Waldenstrom's macroglobulinemia. An antineutrophil cytoplasmic antibody assay could be done that will help in the diagnosis of Wegener's granulomatosis and periarteritis nodosa. A bone marrow biopsy may reveal multiple myeloma. « Treatment » If idiopathic, no treatment is needed, unless the lesions are very painful. Then, a short course of prednisone might be indicated. Hepatitis B and C have been associated with mixed cryoglobulinemia with immune complex deposition. This may respond to alpha interferon with a disappearance of the hepatitis antigen and subsequent resolution of the cutaneous vasculitis. The underlying disease is treated depending upon the diagnosis. In general, steroids, cytotoxic agents and plasmapheresis are used. ■ VASCULITIS - AN OVERVIEW ■ Vasculitis tends to be a difficult diagnosis to make, mainly because some of the symptoms are so mundane and of the garden variety type, that the diagnosis is never even entertained. There is usually a long time gap before someone eventually makes the diagnosis. There have been many attempts to classify the vasculitides, but none is perfect because there is so much overlap between some of the diseases. Perhaps, one of the most simple and most helpful plans is dividing the syndromes into primary, in which the serum tests will show little evidence of an immune mechanism, and the secondary syndromes. The PRIMARY VASCULITIS SYNDROMES consist of the Churg-Strauss syndrome (allergic granulomatosis), Classic polyarteritis nodosa, Wegener's granulomatosis, Schonlein-Henoch purpura, giant cell or temporal arteritis and Takayasu's arteritis (aortic arch arteritis). The SECONDARY VASCULITIC SYNDROMES consist of RHEUMATIC diseases (rheumatoid arthritis, rheumatic fever, mixed connective tissue disease, dermatomyositis, SLE and dermatomyositis), INFECTIOUS diseases (bacterial endocarditis and hepatitis B), HYPERSENSITIVITY diseases (serum sickness, drug hypersensitivity, allopurinol vasculitis and amphetamine abuse), secondary CRYOGLOBULINEMIAS (essential mixed cryoglobulinemia, multiple myeloma and lymphoma). « Clinical » CONSTITUTIONAL SYMPTOMS consist of fever, weight loss, and night sweats and these occur in over 90%. ABDOMINAL PAIN is usually nonspecific, but some patients may have the typical postprandial pain of mesenteric insufficiency. ARTHRALGIA AND MYALGIA- Many will have severe pain in the extremities, but usually without synovitis. There may be some tenderness around the joints and a constant ache in the joints and extremities. SKIN LESIONS may present as petechiae, livedo reticularis with ulceration, palpable purpura, petechiae, splinter hemorrhages and gangrene of the digits. RENAL DISEASE occurs in about 50% of the patients with systemic necrotizing vasculitis. Urinalysis may show proteinuria, and hematuria. If a biopsy is done there usually is focal segmental necrotizing glomerulonephritis sometimes with crescents. Hypertension and uremia may develop. NEUROLOGIC LESIONS- This occurs in about 50% also. A specific form of neuropathy known as mononeuritis multiplex is sometimes present that involves both the motor and sensory nerves. These neuropathies develop either simultaneously in different nerves or within a few days of each other and involve the long nerves as the median, ulnar, and peroneal. The most common, but non-specific neurologic finding is a peripheral sensory neuropathy. Cranial neuropathies can occur also as well as strokes and transverse myelitis. The CNS vasculitis is a small vessel occlusion with perivascular inflammation, and not the necrotizing arteritis that is seen elsewhere. EYE DISEASE- Episcleritis is fairly common, and even though the lesions look terrible, the symptoms are usually minor. There may be some mild tenderness of the eye ball unless an iritis develops, which then will lead to pain, photophobia, decreased vision and a small pupil. Diplopia may develop with involvement of cranial nerves 3, 4 and 6. The optic nerve may be damaged by vasculitis and cause blindness that is sudden. Funduscopy will show a pale optic disc and some hemorrhages. If there is retinal vasculitis the vision is blurred and there are scattered hemorrhages. Temporal arteritis usually involves the optic nerve. DIAGNOSIS is made by laboratory testing, arteriography and biopsy. « Laboratory » Laboratory findings show an increased sedimentation rate in almost 100% of cases and in many there will be anemia and leukocytosis. Again, these are all non-specific findings, but when put together with other lab findings, will point toward the diagnosis. In the appropriate setting the following should be ordered: antinuclear antibodies, hepatitis B surface antigen, cryoglobulins, serum complement, antineutrophil cytoplasmic antibodies, eosinophil count and serum protein electrophoresis. The antineutrophil cytoplasmic antibody (ANCA) directed against proteinase 3 is very specific for Wegener's granulomatosis. ANCA perinuclear pattern directed against myeloperoxidase is also seen in Wegener's, idiopathic cresenteric glomerulonephritis and microscopic polyarteritis nodosa. Biopsy - Excisional biopsy is better than punch biopsy. Biopsy of palpable purpura may be very helpful, as is sural nerve and gastrocnemius muscle biopsy, if there is symptomatic neuropathy and nerve conduction studies show a delayed sural nerve conduction. Blind biopsies will yield varying degrees of diagnosis. Hepatitis B vasculitis is widespread and biopsy of the quadriceps or deltoid may be helpful. Arteriography may be useful in Takayasu's, arteritis involving the aortic arch, periarteritis involving the renal arteries with aneurysms and mesenteric aneurysms and occlusions. « Treatment » Steroids are used in temporal arteritis, aortic arch arteritis, leukocytoclastic cutaneous vasculitis, Churg-Strauss syndrome and hepatitis B. Corticosteroids are usually given in a starting dosage of prednisone of 1 mg/kg in divided doses. Steroids plus cytotoxic drugs: Wegener's granulomatosis responds extremely well to cyclophosphamide and prednisone. Steroids and cytotoxic drugs may also be used in Polyarteritis nodosa, fulminant cases of allergic granulomatosis and hepatitis B, and some cases of rheumatoid vasculitis. Plasmapheresis may be used in cryoglobulinemia. No therapy is given with Schonlein-Henoch purpura and serum sickness vasculitis from drugs. ■ CRYOGLOBULINEMIA (CG) ■ « Clinical » Any patient presenting with purpura, arthralgias and weakness should bring to mind cryoglobulinemia. The most common complaint is purpura and usually involves the lower extremities, but can extend to the lower abdomen and buttocks. Several triggering events have been noted, including medications as penicillin, salicylates, pulmonary infections and cold. There may be recurrent purpura that lasts for about 2 weeks and there may be some itching or burning associated with the purpura. Ulcerations, particularly around the malleolar area, and necrosis of the ears, fingers, toes and nose can occur. There also may be minor episodes of Raynaud's phenomenon. Arthralgias occur in about 72% of cases and involve the knees, ankles, hands and elbows in a symmetric and migratory fashion. Frank arthritis will develop in a few. RENAL disease develops in about 55% of cases of mixed cryoglobulinemia. Hypertension and edema are common with the glomerulonephritis of CG. Usually, renal disease is a late manifestation and presents as a subacute disease, or can be rapidly progressive. (Systemic diseases associated with rapidly progressive glomerulonephritis would include poststreptococcal glomerulonephritis, infective endocarditis, visceral sepsis, Hepatitis B infection, SLE, Goodpasture's syndrome, Henoch- Schonlein purpura, Necrotizing vasculitis, polyarteritis nodosa, Wegener's granulomatosis and Cryoglobulinemia). Renal biopsies show a diffuse proliferative glomerulonephritis or a focal involvement. Immunofluorescent studies usually reveal granular deposition of immunoglobulins which are the same as the serum cryoglobulins, such as monoclonal IgM and polyclonal IgG. Complement may also be present. Eosinophilic hyaline material may be seen in glomerular capillaries. Electron studies may show fibrillar glomerular deposits in the subendothelial region, and also occasionally in the intramembranous and intraluminal regions. These fibrillar deposits are considered to be a unique finding associated with cryoglobulinemia and when seen can solidify the diagnosis. LIVER disease is found in about 70% and is sometimes associated with hepatitis B infection. Several cases have demonstrated hepatitis B antigen and hepatitis B surface antibodies. Other cases are asymptomatic. The histology may range from mild triaditis to chronic active hepatitis and cirrhosis. LUNG disease is not commonly present, but occasionally there will be hemoptysis and pleural effusions. There may be interstitial lung involvement and cardiac involvement. « Laboratory » There are 3 types of cryoglobulins. Type I are monoclonal immunoglobulins and account for about 1/4 of the cryoglobulins. These are frequently present in amounts often greater than 5 mg per milliliter. Type I cryoglobulins are associated with multiple myeloma and Waldenstrom's macroglobulinemia. IgM is the most frequent type of immunoglobulin in Type I. Type II Cryoglobulins account for about 1/4 of the cryoglobulins and consist of a monoclonal immunoglobulin which is usually IgM and has a rheumatoid factor or anti-IgG activity mixed with at least one other type of polyclonal immunoglobulin which is usually IgG. This combination accounts for the most common Type II cryoglobulins. Type II cryoglobulins are associated with chronic lymphocytic leukemia and lymphocytic lymphomas, Sjogren's syndrome, rheumatoid arthritis, essential cryoglobulinemia and autoimmune hemolytic anemia. Type III cryoglobulins account for 50% and are composed entirely of polyclonal immunoglobulins. The IgM-IgG combination is the most frequent, and sometimes is in combination with complement components. Type III have less than 1 mg per milliliter in 80% of the cases. Type III is occasionally associated with chronic lymphocytic leukemia, lymphocytic lymphomas, idiopathic thrombocytopenic purpura, hemolytic anemia, Sjogren's syndrome, polyarteritis nodosa, rheumatoid arthritis, SLE and infections. The infections are Viral infections: (as Epstein-Barr virus, cytomegalovirus, and hepatitis B), Bacterial: (endocarditis, leprosy, lymphogranuloma), Fungal: (coccidioidomycosis), Parasitic: (toxoplasmosis, schistosomiasis and malaria). About 30% of patients with cryoglobulinemia will have no association with other diseases and the cryoglobulins are of the mixed variety. This is called essential mixed cryoglobulinemia, and occurs mostly in women around 50 years of age. These patients will have recurrent palpable purpura of the lower extremities for many years which may result in hyperpigmentation. Ulcers may be present, and if these ulcers are biopsied they show vasculitis. Other lab findings in mixed cryoglobulinemia are rheumatoid factor activity, which is usually present, and in 45% percent, the titers are greater than 1:640. Immunoglobulins are elevated in 60%. Serum complement levels are decreased. About 80% have a decrease in CH50. C3 and C4 are usually decreased with a striking depression of C4 in some series. Anemia and increased sedimentation rate are present in about 70%. Transient Coombs' positive anemia and speckled antinuclear antibodies are seen in some patients. « Treatment » Treatment is with Prednisone, Cytotoxic drugs and plasmapheresis. ■ SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) ■ SLE is a protean autoimmune disease with exacerbations and remissions that has a predilection for women aged 20-50. The incidence is higher in blacks. There are several interesting subsets of Lupus including Discoid lupus, subacute cutaneous lupus, systemic lupus erythematosus, ANA negative lupus, mixed connective tissue disease (MCTD), drug induced lupus, and lupus with antiphospholipid antibodies. Also, there are several associated serological markers that will be discussed. « Clinical » Many patients will present with arthralgias, arthritis, Raynaud's syndrome, fever and skin rash. The differential for this array of symptomatology is wide and would include gonococcal sepsis, rheumatoid arthritis, acute rheumatic fever, sarcoidosis, infectious mononucleosis, rubella, serum sickness and hepatitis. SLE can present just as thrombotic thrombocytopenia purpura with a hemolytic anemia, thrombocytopenia and CNS symptoms. Chest symptoms are common in SLE with pleurisy and pericarditis causing chest pain. Patients may complain about a receding hair line and alopecia, ulcers of the mouth and rashes about the malar area that are made worse by sunlight. Seizures and neuropsychiatric symptoms sometimes will occur. Renal disease with hematuria and proteinuria can be present and in some cases the renal disease is severe. « Laboratory » The patient may have a leukopenia of less than 4000 cells/mm3 in about 20%. Thrombocytopenia will develop in about 25%. The sedimentation rate is used to monitor the activity of the disease. There may be a Coombs' positive hemolytic anemia in 10% which is more common if the patient has a false positive VDRL. The anemia is usually a normocytic normochromic anemia of chronic disease. Hyperglobulinemia, circulating anticoagulants, rheumatoid factor, hypocomplementinemia, various antinuclear antibodies can all be present. The LE cell was discovered in 1948 and was used for years as a diagnostic test. This is no longer used. The immunofluorescent ANA is now used for screening diagnosis and is positive in about 95% of patients with active SLE. Many diseases may have a positive ANA. The double stranded DNA is very specific but suffers from sensitivity. If the patient has RBC casts and proteinuria then active renal disease should be suspected and the dsDNA may be positive. If there is prominent photosensitivity and dermal rashes then a positive Ro/La (SS-A/SS-B) would indicate the patient might have the subacute cutaneous lupus subset. Recurrent abortions, arterial and venous thrombosis, and migraines should trigger testing for the anti-cardiolipin antibody and lupus anticoagulant as found in the anti-cardiolipin antibody syndrome. If the patient has been taking drugs such as hydralazine, INH, phenytoin, procainamide, PAS, sulfonamides, penicillin, alpha methyldopa, tetracycline or propylthiouracil or the patient is elderly, and has cardiac arrhythmias and pulmonary symptoms, the Antihistone antibody may be positive. If the patient has Raynaud's syndrome, telangiectasia, calcinosis and skin involvement then you should get an anticentromere antibody as the patient has the Crest syndrome. If the patient is suspected of having mixed connective tissue disease (MCTD), consisting of muscle weakness from polymyositis, and scleroderma with tightening of the fingers and pleurisy, then a RNP (ENA) should be ordered. If polymyositis with proximal muscle weakness is suspected, then a jo-1 antibody should be done. If the patient complains of dry eyes and mouth the diagnosis may be primary or secondary Sjogren's syndrome. This would prompt Ro/La (SS-A/SS-B) antibody testing. « Subsets of Lupus » ANA NEGATIVE LUPUS This occurs in less than 5%, but can present with identical symptoms of Lupus erythematosus. It is a rather benign form with a low incidence of CNS and renal disease. Anti-Ro antibodies are present in about 60-70%. DISCOID LUPUS In Discoid lupus systemic symptoms are minimal or non existent in about 95% of patients. The ANA is only present in 20%. If the patient has extensive discoid disease, rather than local, there is a tendency for progression to SLE. The lesions usually affect the head and consist of erythematous plaques with scaling, scarring, atrophy, telangiectasia and hyperpigmentation. SUBACUTE CUTANEOUS LUPUS These patients have widespread papulosquamous or annular cutaneous lesions that tend to be symmetrical and involve exposed areas. These lesions usually do not scar or atrophy on healing as does discoid lupus. These patients may complain of arthralgias, malaise, fever and myalgias in about 50%. Kidney and CNS involvement is infrequent. Sjogren's syndrome may develop in about 10%. Anti-Ro antibodies are found in 40-60% and anti-La antibodies sometimes may be found. CARDIOPULMONARY Chest pain may be caused by pericarditis which is typically made worse by the prone position. There may be a pericardial rub or paradoxical pulse. Echocardiography should be done as there may be pericardial effusion, tamponade or constrictive pericarditis. Patients may have valvular disease which is seen more frequently if the patient has anti-cardiolipin antibodies. Pleurisy with or without effusion may be present. Examination of the pleural fluid typically shows a transudate, low WBC, normal glucose, decreased complement and positive ANA. The lung also may show infiltrates and interstitial disease. Pulmonary hypertension doesn't develop in SLE commonly, but does in mixed connective tissue disease and scleroderma. LUPUS AND ANTIPHOSPHOLIPID ANTIBODIES Antiphospholipid antibodies consist of positive tests for anti- cardiolipin antibody, lupus anticoagulant and false positive VDRL. These antibodies can cause recurrent venous and arterial thrombosis, thrombocytopenia, livedo reticularis, miscarriages, usually in the mid-trimester, migraines and cardiac valvular lesions. About 50% of the antiphospholipid syndrome will have SLE. THe other 50% that is not associated with SLE is known as the primary antiphospholipid antibody syndrome which may or not be significant. LUPUS AND RENAL DISEASE- There are about 4 major histologic subsets of renal disease that can be seen on biopsy. CLinical renal disease occurs in 50% of patients and can be the cause of death. If nephrotic syndrome develops in SLE suspect MEMBRANOUS NEPHRITIS. It develops slowly and has an indolent course. Absence of dsDNA antibodies, normal complement and resistance to high dose corticosteroids and immunosuppressive agents is typical of this subset. FOCAL PROLIFERATIVE NEPHRITIS has a good long term prognosis with most having only mild hematuria and proteinuria and failure to progress with renal insufficiency. A few in this subset will develop a more severe disease and high dose corticosteroids, or immunosuppressing agents, may suppress progression of this disease. DIFFUSE PROLIFERATIVE GLOMERULONEPHRITIS is the most severe form of all.There is proteinuria and hematuria and many develop renal insufficiency which will require high dose corticosteroid and immunosuppressive agents. There is usually depressed complement levels, positive anti-dsDNA and an increase in the systemic manifestations of SLE as well. MESANGIAL NEPHRITIS is the most benign form of renal involvement in which there is segmental or focal hypercellularity isolated to the mesangium. There may be immune complexes in these lesions. There is mild proteinuria and hematuria. There usually is no progression to renal insufficiency. Even though mesangial nephritis is mild it usually is associated with active systemic disease and treatment of this is done rather than the renal lesions. LUPUS AND THE CNS Lupus involvement of the CNS occurs in 50% of patients and is characterized by psychosis, depression, seizure disorders, strokes, movement disorders, peripheral and cranial neuropathies, and headaches. Patients with CNS involvement often times have a poor prognosis and must be treated with high dose corticosteroid agents and immunosuppressive agents. The difficulty is in associating the symptoms of the CNS with SLE. There is no one positive test that definitely confirms the diagnosis. MRI, and cerebral spinal fluid are both nonspecific. Antilymphocyte and antineuronal antibodies are present in some and there is an association between the presence of antiphospholipid antibodies and CNS lupus. « Treatment » SKIN Sun screens with a factor of at least 15 should be given because of the photosensitivity of patients with SLE. For facial cutaneous lesions, low dose topical 1% hydrocortisone should be given. Occasionally, high potency creams as clobetasol .05% bid may be needed as well as intralesional Triamcinalone injections. If all this fails, then hydroxychloroquine (Plaquenil) 200 mg bid will usually help. Patients should be seen by an eye specialist every 6 months because of occasional retinal toxicity associated with hydroxychloroquine. If the patient fails to respond adequately to Plaquenil then try chloroquine or quinacrine (Atabrine). As a last resort, systemic steroids may be tried. LUNG Start with a NSAID and then progress to prednisone if the NSAID fails. If acute lupus pneumonitis occurs this can be disastrous and should be treated with prednisone at 60 mg daily. If the patient has the antiphospholipid antibody, then there may be pulmonary emboli and the patient should anticoagulated. CENTRAL NERVOUS SYSTEM If patient has seizures they can be treated the same as if they didn't have SLE, utilizing the usual anticonvulsants. High dose corticosteroids are indicated for cerebritis and transverse myelitis. Cyclophosphamide may be used also. HEMATOLOGIC SYSTEM About 60% of SLE patients will have a positive direct Coombs' but only a few will develop hemolysis. If hemolysis does develop the patient may be treated with prednisone, 60 mg daily for 4-6 weeks and then taper slowly. If the patient doesn't respond then immunosuppressive agents or splenectomy may be done. If severe thrombocytopenia develops, prednisone can also be given at the same dosage given for hemolysis. If the patient doesn't respond to the prednisone, then IV pulse therapy with cyclophosphamide or azathioprine 2 mg/kg per day or danazol 200 mg qid or IV immunoglobulin 2 gram/kg given over 5 days. If the patient has antiphospholipid antibodies and associated recurrent thrombosis, start long term warfarin. RENAL DISEASE The worst prognosis is with diffuse proliferative or membranoproliferative nephritis as seen with renal biopsy. If the patient has mesangial nephritis no treatment is needed for the renal disease. Patients with focal and diffuse proliferative lupus nephritis may be treated with high dose oral prednisone 80 mg per day and taper after 1 month. When the tapering begins, give cyclophosphamide 1- 3 mg/kg/day OR azathioprine 1-3 mg/kg/day OR a combination of cyclophosphamide 1 mg/kg/day and azathioprine 1 mg/kg/day OR cyclophosphamide 500 mg per M2 of body surface in 250 ml of normal saline IV. (IV cyclophosphamide has been said to be less toxic than the oral form and more effective). The patient is then further hydrated with a liter or more or normal saline. The next month, the patient is given 750 mg/M2 and then 1000 mg/M2 the following month and maintained at this level for about 6 months of treatment. CBC should be followed with particular emphasis on the white count which should not be lower than 2000-3000 cells per mm3. Many chemotherapy programs and schedules have been devised and this is only one that may be tried. Hypertension should be treated to prevent progression and deterioration of renal function. If the patient has membranous lupus nephritis then a trial of prednisone of 120 mg every other day may be given for 8 weeks and then tapered over a 4 week period. ARTHRITIS Arthritis can be be treated with NSAIDs, Disalcid, low dose prednisone and Plaquenil.