                                  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.
      
      
