• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Differential diagnosis mnemonics
 

Differential diagnosis mnemonics

on

  • 7,816 views

 

Statistics

Views

Total Views
7,816
Views on SlideShare
7,816
Embed Views
0

Actions

Likes
3
Downloads
326
Comments
1

0 Embeds 0

No embeds

Accessibility

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel

11 of 1 previous next

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Differential diagnosis mnemonics Differential diagnosis mnemonics Presentation Transcript

    • - Differential Diagnosis � MnemonicsIJ
    • DifferentialDiagnosisMnemonicsThomas J. Donnelly, MDPulmonary and Critical Care ConsultantsDayton, OhioChristopher C. Giza, MDAssistant ResearcherDivision of NeurosurgeryUniversity of CaliforniaLos Angeles, CaliforniaHANLEY & BELFUS, INC. / Philadelphia
    • Publisher HANLEY & BELFUS, INC . Medical Publishers 2 1 0 South 1 3th Street Ph i ladelphia , PA 1 9 1 07 ( 2 1 5) 546-7293; 800-962- 1 892 FAX (2 1 5 ) 790-9 3 3 0 Web site: http : / www. han leya ndbelfus.com /Note to the reader: Although the i nformation in this book has been carefully re­viewed for correctness of dosage and ind ications, neither the authors nor the ed­itors nor the publ isher can accept any legal responsibil ity for any errors orom issions that may be made. Neither the publ isher nor the ed itors make anywarranty, expressed or i m pl ied , with respect to the material conta i ned here i n .Before prescribing a n y drug, the reader m ust review the manufacturers currentproduct i nformation (package i nserts) for accepted ind ications, absolute dosagerecom mendations, and other i nformation perti nent to the safe and effective useof the product described . library of Congress Cotolog ing-in-Publ icotion Dota Donnelly, T homos J, 1962- Differential Diognosis Mnemonics / Thomas J. Donnelly, Christopher C. Gizo. p. ; cm. Includes bibliographical references and index. ISBN 1-56053-31 1·0 lalk paper) 1. Diagnosis, Differential. 2. Mnemonics. I. Giza, Christopher c., 1965- II. Title. [DNlM: 1. Diagnosis, Differential-Term inology-English. 2. Association Learning-Terminology-English. WB 15 D685d 2000J RC71.5.D66 2001 616 075014-dc21 99-088120Differential Diagnosis Mnemonics ISBN 1-5605 3-3 1 1 -0© 200 1 by Hanley & Belfus, Inc. All rights reserved . No part of this book maybe reproduced , reused, republished , or transmitted in any form, or stored in adata base or retrieval system , without written permission of the publ isher.Last digit is the print n umber: 9 8 7 6 5 4 3 2 1
    • CO NTENTSI . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1How to Use This Book . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2General Approach to Differential Diagnosis . . . . . . . . . . . . . . : . . . . . 2Thi n king About Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . 4Presenting and Discussing Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . 8II. Pulmonary and Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1General Considerations General Approach to Pulmonary Med icine . . . . . . . . . . . . . . . . . 1 1 General Approach to Critical Care Med icine . . . . . . . . . . . . . . . 13 Chest X-Ray Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Clinical Symptoms and Sig ns Chronic Cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Clubbing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Dyspnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Hemoptysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 21 Stridor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Wheezing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Clinica l Conditions or Diagnoses ARDS - Diffuse Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . . . . . 27 Acute Respi ratory Failure . . . . . . . . . . . . . . . . . . . . . . . 29 Bronchiectasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Cavitary and Cystic Lung Disease . . . . . . . . . . . . . . . . . . . . . . . 31 Interstitial Lung Disease . . . . . . . . . . . . . . . . . . . . . 33 . Mediastinal Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Pleural Effusion . 38 Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 ; Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Pulmonary I nfiltrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 ! Pulmonary Nod ule . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Refractory Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52III. HematolOgy and Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 iGenera.l ConsiderationsClinical Symptoms and Signs Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Contents. v
    • Bleed ing Diatheses . . . . . . . 60 Splenomegaly . . . . . . . . . . . . 61Clinical Conditions or Diagnoses Eosinophilia . . . . . . . . 63 E ryth rocytosis . . . . . . . . . . . . 65 Hypercoagula ble States 66 Lymphopenia 68 Monocytosis . . . . . . . . . . . . . . . . . . . . . . 70 Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . 71 Neutrophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Pa ncytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Throm botic Thrombocytopenic Purpura 76 Throm bocytopenia . . . . . . . . . . . . . . . . . . . . . . . 77 Thrombocytosis .. . . . . . . . . . . . . . . . . . . . 80 Tra nsfusion Reactions 81IV. Infectious Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Clin ical Symptoms and Signs Fever of Un known Origin . . . . . . . .... . . 83 Infections Causing Splenomegaly . . . . . . . 85 Temperature/Pulse Dissociation . . 86Clinical Conditions or Diagnoses Acute Men ing itis . . . . . . . . . . . . . . . . . . . 87 AI DS/ Human I m m unodeficiency Virus . . . . . . . . 89 Immu nodeficiency States 91 Rheumatic Fever . . . . . . . . . . . . 92 Sexually Tra nsmitted Diseases 93V. Cardiology 97Clinical Symptoms and Signs Syncope . . . . . . . . . . . . . . . . . 97Clinical Conditions or Diagnoses Arrhyth mia 100 Atrial Fi bril lation . . 10 1 Congestive Heart Failure 1 02 Hypotension 1 04 Pericarditis . . . 1 05 Restrictive Cardiac Disease 1 07VI. Endocrinology . . . . . . . . 1 09General Considerations Pituitary/Hypotha lamus 109Cli nical Symptoms and Signs Amenorrhea . . . . . . . . . . . . 11 1 Gynecomastia 113 Hirsutism . . . . . . . . . . 114vi • Contents
    • -- Cli nica l Conditions or Diagnoses Adrenal I nsufficiency . . . . . . . . . . . . . . . . 1 16 Carcinoid Tumors . . . . . . . . . . . . . . . . . . 1 17 Hypercalcemia . . . . . . . . . . . . . . . . . . 1 19 Hyperphosphatemia 1 20 Hyperprolacti nemia . . . . .. . . . . . . . . . 1 21 Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . 1 22 Hypoca lcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 24 Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . 1 25 Hypophosphatemia . . . . . . . . . . . . . . . . . . . . . . . . . 1 27 Syndrome of I nappropriate Antidiuretic Hormone secretion 129 VI I . Nephrology . . . . . . . . . 131 General Considerations Cli nical Symptoms and Signs Edema . . . . . . . . . . . . . . . . . 1 33 Hematuria . . . . . . . . . 1 34 Hypertension . . . . . . . . . . . . . . . . . . . . . . . 136 Clinical Conditions or Diag noses Hyperka lemia . . . . . . . . . 1 38 Hypernatremia . 1 40 Hypoka lemia . . . . . . . . . . . . . 1 43 Hyponatremia . . . . . . . . . 1 46 Neph rotic Syndrome . 1 49 Renal Fa ilure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 50 Renal Stones 152 VI I I . Acid-Base 1 55 General Considerations Arterial Blood Gas Interpretation . . . . . . . . . . . . . . . . . . . 1 55 Clinical Conditions and Diagnoses Meta bolic Acidosis with a High Anioll Gap . . . 1 60 Meta bolic Acidosis with a Normal Anion Gap . . . . . . . 1 63 Low Anion Gap . . . . . . . . . . . . . . . . . . . . . . . 165 Meta bolic Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Respi ratory Acidosis 167 Respiratory Alkalosis 1 68 IX. Gastroenterology . 1 69 Clinical Symptoms and Signs Abdom inal Pa in . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ]69 Dia rrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 73 Dysphagia . . . . . . . . . . . . . . . . . . . . . 1 76 Hepatomega ly . . .. . . . . . . . . . . . . 178 Jaundice . . 179 Nausea and Vom iting . . . . . . . . 18 1 Contents • vii
    • Clinical Conditions or Diagnoses . Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 83X. Rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 87Clinical Symptoms and Signs Acute Monoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 87 Inflammatory Polyarth ritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 88 .Clinical Conditions or Diagnoses Calcium Pyrophosphate Di hydrate Deposition Disease . . . . . . . . . . 191 CREST Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 92 Osteoa rthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 93 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . 1 95 System ic Sclerosis (Scleroderma) . . . . . . . . . . . . . . . . . . . . . . . . 1 97 Systemic Lupus E rythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . 1 98 Vasculitis . . . . . . . . . . . . . . . . . . . 1 99 Wegeners Granulomatosis . . . . . . . . . . . . . . . . 20 1XI. Neurology . . . . . . . . . . . . . 203General Considerations How To Make a Broad Differential Diagnosis . . . . . . . 203 How To Make a "Working" Differential Diagnosis . . . . . . . . . . 204 How To Do a Good Neurologic Exam ination . . . . . . . 207 Neurologic Exam ination Summa ry . . . . . . . . . . . . . . . . . . 213Clinical Symptoms and Signs Altered Mental Status 215 Ataxia . . . . . . . . . . . . . . . . . . . . . 218 Autonomic Disorders . . . . . . . . 222 . Di plopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 . . . . . Dizziness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 226 . Headache . . . . . . . . . . . . . . . . . . . . . . . . . 229 . . . . . . Loss of Consciousness 233 . Monocular Visual Loss 237 Ptosis . . . . . . . . . . . . . . 239 Rig idity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 1. . . . . . Tremor . . . . . . . . . . . . . . . . . . . . . . . 243 . . . . . . Weakness . . . . . . . . . . 246Cl inical Conditions or Diagnoses Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Myelopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 1 Neuropathy . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . 253 Seizure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . 262Neurology Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267XII. Appendix . . . . . . . . . . . . . . . . . . . 271 Acronym Dictionaryviii • Contents
    • - PREFACE Generating a useful and complete differential diag nosis is a keystone of clinical medicine. Many texts exist which provide exhaustive lists of possible diagnoses for a particu lar com plaint. It is refining such lists into useful d ifferentials that is part of the "art" of med icine. Memorizi ng lists of diagnoses can be a daunting task, and a d ry one at that. By using mnemon ics as a framework, we wish to make learning differential d iagnoses more palatable and even enjoya ble. In ad- . dition, we present an organizational a pproach to differential d iag nosis that is practical and easily learned . The mnemon ics presented here range from concise lists that may be committed to memory aher the first read, to more lengthy, com­ prehensive listings that can be looked up when needed . In al most all cases, the mnemonics themselves spell out something that refers to the symptom or diagno­ sis, increasing the l i kelihood of remembering it. Throughout a students medical education, he or she receives countless little tips or "pearls" that a re of im mense practical worth but are ohen difficult to look up in the Iypical medical textbook . After each m nemon ic, we have i ncluded many pearls that refer to the symptom or condition descri bed . Some of these tips are j ust one-l i ners; others are small tables or outl i nes that help organ ize com­ monly referenced i nformation . We hope you find this to be a useful handbook that provides a sound organ­ i zational framework for a pproa c h i n g d i fferential d ia g noses. The m nemonic . format necessa rily led to some creative listi ngs, which should be easily remem­ bered as well as amusing . We welcome any suggestions or new m nemonics from our readers. Tom Don nelly Chris Giza Preface. ix
    • - a INTRODUCTION The purpose of this book is to help med ical students and clinicians form com pre­ hensive d ifferential d i a g noses for common i nternal med icine a nd neurology problems. It is an aid for organ izing diag nostic poss ibil ities qu ickly and effec­ tively in clinical situations. A number of excellent references provide comprehensive l ists of d ifferential diagnoses. This book was created with a similar pu rpose in mind, but we pre­ sent an a pproach based on mnemonics. The mnemonics are i ntended to pro­ vide simple fra meworks on which to construct differentia l diag noses . They a re not i ntended to be the sole source of i nformation, and pri mary texts should be read to fully understand d isease pathogenesis. It is doubtful that anyone can re­ mem ber every mnemonic i n this book. We hope that those for commonly en­ countered problems will be reta i ned ; the others can be referenced shou l d a particular problem a rise. Most students and residents are fa miliar with nu merous disease processes, but have difficu lty g iving an exhaustive d ifferential diagnosis from memory for a particular clinical entity. This problem often stems from the lack of a n organiza­ tiona l framework. Once d ifferential d iagnoses a re considered in terms of "cate­ gories" of i l l ness, they a re much easier to com plete . We have attem pted to identi fy a wide variety of clin ical scenarios and organize a d ifferential d iagno­ sis for each. Some entities a re common, such as anemia or renal failure, while others are more specialized, such as refractory hypotension. Having a complete list of possible diagnoses at the outset will lead to the correct diagnosis even in the most complex cases. Th is a pp roach encourages thorough ness i n eva l ua­ tions, so that d iag noses a re not missed . The mnemon ics range in length depending on the clin ical entity. Sometimes more than one has been included for brevity or organizational reasons. The best m nemon ics a re concise, perti nent words or ph rases constructed to reflect the pathogenesis of the problem. Others a re no more than sim ple words that help in remembering a list of possibilities . An explanatory section is included with each mnemonic to review pathogenesis or provide helpful i nformation . Some com­ monly used m nemon ics (a uthors generally u n known) are i ncl uded in deference to their history or for lack of a better replacement. F i nally, please forgive a ny "artistic" license taken in the creation of these m nemonics. Introduction • 1 i
    • H ow to Use This BookThe chapters are divided by organ system and presented with a common organi­zational theme. A "General Considerations" section starts some chapters to pro­vide an overview of differential diagnosis and clinical assessment pertinent to thatparticular system . Specific mnemonics, which are divided i nto two sections, follow.The first section , "Clinica l Symptoms and Sig ns, " l ists mnemon ics that refer tospecific clinical complaints by the patient (e. g . , cough, headache), or to particularclinical signs detectable on careful physical exami nation (e. g . , jaundice, ataxia) .The second mnemonic section, "Clinical Cond itions and Diagnoses," lists d iffer­ential diagnoses for clin icol conditions detected through the use of various d iag­nostic tests (such as thrombocytopenia, hypernatremia), general mnemonics forbroad diagnoses (e.g . , sexually transm itted disease, pneumothorax), and specificmnemonics that refer to a pa rticular d isorder (such as rheumatoid arthritis, AIDS). Thus, the first section is i ntended to help i n making a differential diagnosis listbased primarily on the chief complaint or a significant clinical sign, aher the initialhistory and physica l . The second section is a i med at generati ng more specificdifferentials based u pon initial diagnostic testi ng and careful consideration of theoverall clinical syndrome. Each section is listed alphabetically for ease of reference.G eneral Approach to Differential Diag nosesThe d ifferential diagnosis for any medical problem can be thought of i n terms ofcategories of d isegse. The mnemon ic "MEDICINE DOC" may be used as ageneral a pproach to a ny patient: Meta bolic disease (e. g . , nutritional deficiency, dysli pidemias, porphyria) Endocrine disease (thyroid disease, diabetes) Drugs/ med ici nes (iatrogenic, accidental, self-administered) I n fections (e . g . , bacteria l , viral, fu ngal, mycobacterial, protozoa l , hel mi nthic) Congen ital a bnormalities (inherited a natom ic, immunologic and metabol ic disorders) Immunologic disease (collagen vascular diseases, asthma, acqui red immuno- deficiency) Neoplasms (e. g . , primary, metastatic, paraneoplastic) Exotic ( "strange" diseases of unknown etiology such as sarcoid, histiocytosis X) Degenerative processes (e. g . , Alzheimers, a myotrophic lateral sclerosis) Occu pational!envi ronmental exposures (e.g . , asbestos, hypersensitivity, trauma) Cardiovascular d iseases (e.g . , arrhythmias, atherosclerosis, pulmonary em­ bolus, congestive heart failure)2 • Introduction
    • This list includes the primary etiologies for most medical problems. There is,of course, some overlap between categories: atherosclerosis i s both a cardio­vascular and metabolic disease; both i nfections and collagen vascular diseasesmay cause ca rdiovascular disease; many of the "exotic diseases" may have ani m m u nolog ic basis, a n d many i m m unologic di seases are exotic. The redun­dancy is necessary, however, si nce some entities a re difficult to classify or maybe forgotten if a framework based solely on pathogenesis is used. For exam ple;where does one classify arrhyth mias or pulmonary embolus? Both a re commonentities that have many causes. The cardiovascula� category helps you to re­member these com mon problems in u nusual presentations. When faced with any clinical problem, you can use either the MEDICINEDOC m nemonic or another, more specific m nemonic to develop a differentialdiagnosis. For exa m ple, if a patient has renal fa ilure, you can construct a differ­ential based on the categories in MEDICINE DOC or use the specific "I C HASEA RISING BUN," which lists specific ca uses of renal fa ilure: Pre-renal Intravascular vol ume depletion (dehydration, th ird spacing) Cardiac ca uses (CHF, MI, tamponade) Hepatorenal syndrome Arterial disease ( renal artery stenosis) Shock Eclampsia/obstetrical compl ications Pre-renal/Renal Acute tubular necrosis ( "ATN" in a sense, both " pre-" and "renal" in etiology) Renal Radiographic contrast and other toxi ns (drugs, rhabdomyolysis, hemolysis) I ntrarenal emboli (cholesterol, DIC) Scleroderma Interstitial nephritis Necrotizing vascul itis (polyarteritis nodosa , Wegeners) Glomerulonephritis Post-renal Bladder obstruction (usually prostatism, sometimes blood, pus, calcul i ) Ureteral obstruction (calcul i , retroperitoneal fi brosis, cancer) Necrosis of renal pa p i l lae (dia betes, sickle cell a nemia, NSAID a buse, i nfection) The two approaches provide fairly comprehensive lists of possibil ities, andthere a re strengths and weaknesses for both . MEDICIN E DOC a l lows broadclassification of disease processes, while I C HASE A RISING BUN l i sts spe­cific causes of rena l fa ilure a n d organ izes them in p re-rena l , ren a l , a n d post­renal categories . It is helpful to look at medical problems using both types ofapproach . Introduction • 3
    • � inking About Differential DiagnosesTwo thought processes are helpful in a pproaching differential d iag noses 1 . What is the most l i kely d iagnosis? This "gestalt" approach involves look­ing at the entire picture first and form ulati ng a hypothesis to explain it. After re­viewing a l l the data for a case, decide which d i agnosis is most l i kely. Theth inking process from this point focuses on proving or disproving the hypothesis.This a pproach is helpful for more simple cases, although most clin icians use it tosome extent i n all cases. Pay careful attention to a ny aspects that are i nconsis­tent with the presum ptive diagnosis and be able to account for them . Avoid be­coming fix,ated on a diagnosis and ignoring data that do not support it, 2 . What are the patients problems? This a pproach focuses on the "pa rts" orindividual aspects of the case. list all of the patients problems and consider a d if­ferential d iagnosis for each. Then, attempt to formulate a u nifying diag nosis thatexplains the data, creating a whole from the parts. This techn ique is helpful whenfaced with complex cases featuring multiple symptoms and large amounts of data. The m nemonic a pproach to differential diagnosis em phasizes sta rting witha com plete list of possibilities. Certain entities on the l ist wi l l be very uncommonand unl ikely in most circumstances, Common entities a re considered in the i n itiald ifferential diag nosis of a problem , but other aspects of a particu lar patientscase may di rect the work-up to more unusual entities. This approach is appropri­ate as long as you do not ignore features that may be i nconsistent with the pre­sumed diagnosis. Another a pproach to defi ning a long list of d iag nostic possibi l ities is to de­velop a second or perhaps even a third list based on a second sign or symptomof the patient. If you assu me that the man ifestations of the d isease in questionare secondary to one process, then you can limit the number of possibi lities byonly pursu ing diag noses that a re on both l ists. Be careful using this a pproach,because patients may have more than one disease process at work, and impor­tant diagnostic considerations may be eli m i nated prematurely. Aga i n , it is criti­cal to always refer back to the com plete list of differential d iagnostic possibilitieswhen all the features of a case do not add up to a coherent picture. Sources of Error in Differential Diagnosis Decision ana lysis is a process that attempts to classify errors in medical rea­soning, with the goal of i mproving the accuracy of differential diag nosis and en­suring that a critical diag nosis is not m i ssed , Althoug h controversy exists i na pplying decision analysis to clinical settings, i t i s worthwh ile to understa nd thesources of error. One a pproach focuses on fi rst outlin ing the basic steps in ar­riving at a presum ptive diag nosis a nd then classifyi ng errors accord i n g towhere they occur in those basic steps. The basic steps are: 1 , Triggering determ ining a d iagnostic possibil ity based on patient i nfor­ - mation .4 • Introduction
    • - 2. Framing-establish ing the context within which the problem will be solved . 3 . Gathering a n d processi ng - reviewi ng a n d i nterpreting d iag nostic data ; selecting and d iscarding possible diagnoses 4 . Verifi cation - reaching a final diagnosis, the one that best fits all of the data . Errors occur at each of these steps: Triggeri ng errors may result from a lack of knowledge and associations . Consider the exa mple of a renal fa i lu re patient in whom hypotension develops shortly after beginning dialysis. Some clinicians may consider sepsis or hemor­ rhage (which a re plausi ble) , but most neph rolog ists would i m med iately th i n k of a perica rd. ial effusion and tamponade as being m uch more likely Triggering is an associative process that comes with experience . Framing errors occur when you do not th ink broadly enough i n considering the cause of a patients problem . For exa mple, a patient with recurrent a bdomi­ nal pa in secondary to hyperca lcemia may undergo a n extensive gastroi ntesti nal work-up because the d ifferential d iag nosis of a bdominal discomfort was not framed broadly enough to i nclude metabolic or systemic disorders . This type of error demonstrates the importance of having a com plete list of diagnostic possibili­ ties prior to embarking on an extensive work-up. It also shows the value of framing the differential diagnosis i n two or more contexts (i e . , MEDIC I N E DOC and a mnemonic for a bdominal pa i n ) and then looking at the " i ntersection" of the sets . Broad framing and framing in mu ltiple contexts may decrease framing errors. Gathering and processing errors result from m isi nterpreting test results, not understanding the sensitivity or specificity of a test, or not knowing a particu lar disease preva lence or li kelihood i n a given patient. For exam ple, a slightly ele­ vated u rinary catechola m i ne in a 75-year-old patient with severe hypertension may lead a clinician to pursue a diagnosis of pheochromocytoma , even though this is a rare disease. It is much more l i kely that the catechola mine result is false positive, and the test probably should not have been ordered in the initial evalu­ ation of this patient. I ntrinsic renal d isease or renovascular d isease should be i n­ vestigated fi rst in this type of patient before looking for more un usual diag noses. (See "Other Sources of Diag nostic Error� on the next page for additional d iscus­ sion of proba bil istic thinking . ) Verifi cation errors occur when some data supporting a particular diag nosis are obtai ned , and the patient is then assumed to have that diagnosis, even when other, contradictory data subsequently become available. Failing to account for all aspects of a case and inappropriately adhering to a presum ptive diagnOSis re­ sults i n premature closure. Consider a woman with fever, rash , anem ia, renal i n­ sufficiency, and a positive antin uclea r anti body test suggesting the diagnosis of systemic l upus erythematosus (SLE) If this patient also had a heart murmur and a negative double-stranded DNA test, these features are less easily explained by a simple d iagnosis of SLE (although not impossible). Presumptive immunosuppressive therapy of this patient for a d iag nosis of SLE cou ld be hazardous if the patient rea lly has subacute bacterial endocard itis as the cause of her m ultiple problems. There also a re "no-fault" errors. These occur when the patients findings are highly atypical for the underlying disease, or the disease is extremely uncommon. Introduction • 5
    • An example of this type of error occurred when a young woman on birth con­trol pills presented with dyspnea, chest pa i n , and a h i g h-probability V /Qsca n . Most clin icians would proba bly i n itiate a nticoagulation , as was done i nthis case, given this constellation o f findings. Subsequently, however, the pa­tie nt develo ped card i ac ta m ponade d ue to hemorrh a g i c perica rd itis ( h e ractual problem) and h a d a prolonged i ntensive care course as a result o f thea n ticoagulation . An a rteriog ra m demonstrated a congenitally stenosed pul­monary a rtery su bseg ment, which expla i ned the h ig h-proba bility V/Q sca n .This type of error i s unfortunate but, i n some cases, u navoida ble . N o matterhow well we perform our duties, errors will occu r. This exa mple points to thefact that you must continue to be vigilant even when a diagnosis seems as­sured. Note that p remature closure, a lthoug h u ndersta nd a b le in this case,was to the patients detriment. The Importance of Probability in Differential Diagnosis When evaluating the data as they apply to a list of diagnostic possibilities,it is helpful to consider probabilities. Always question : 1. How common is the diseaseq 2 . How common is the d isease in the relevant population , i . e. in the par­ ticu lar patient being eval uated2 3 . How com mon is a pa rticular symptom, sign, or la boratory result in the disease bei ng consideredq As you prog ress in medical education and gain fa miliarity with different dis­eases, these questions become easier to answer. Bayes theorem is a mathemat­ical relationship that can be helpful in assessing the proba bil ity of one diseaseversus another, g iven a particular find ing. Probabil ities can be calculated basedon Bayes rule, which states that the l i keli hood of a disease in a patient with ag iven set of findings can be esti mated as the proportion of patients with thesame findi ngs who also have the d isease. For example, the likeli hood of pneu­monia in a person with fever, cough, and sputum is estimated by d ivid ing then umber of people with fever, coug h , sputum , and pneumonia by the num ber ofpeople with fever, coug h , and sputu m . The actual mathematica l calculation iscomplex, and there a re many criticisms of this type of ana lytical approach, buta few simple and useful poi nts can be offered : • Have a general idea of the prevalence a nd common symptoms of aparticular disease. For exa mple, a young woman with fever, sweating, anxiety,tachycard ia, and hypertension may have a pheochromocytoma , but hyperthy­roidism also is possible . The above symptoms are characteristic of both disorders;however, hyperthyroidism is much more likely to be the cause because it is morecommo n . The find ing of exophthal mos may be seen in Graves disease, butwould not be cha racteristic of pheoch romocytoma , aga in pointing toward hy­perthyroidism as the more likely cause. An evaluation a i med at hyperthyroidism,while keeping pheochromocytoma "on the back burner, " would be a ppropriate in this instance. Also, in the above setti ng, you should consider an anxiety disor­der (even more common) as a possible cause of the patients symptoms.6 • Introduction
    • • The more specific a find ing is, the more helpful it wi ll be in establ ishing al ist of l i kely diagnoses . Select one or two pivotal fi ndi ngs ( " pivots " ) of a pa­tients case for consideration of the differential diag nosis. Hypercalcemia, for ex­a m pl e , is a good pivot because it has a fa i rly we l l-defi ned list of causes .Clubbing also might be helpful as its list of diag nostic possibil ities is rather l i m­ited . Entities such as chest pa in or fatigue are more problematic because theyare nonspecific and can occur in a large number of diseases . • When considering diagnostic possibilities, it is perhaps best to compareone symptom or finding (pivot) across multiple diseases, instead of seekingseveral sym ptoms or findi ngs for a single d isease This step-wise l i m itation ofdata analysis keeps the proba bil ities of a specific find ing in a specific d iseasein the forefront. The difficu lty of this approach is the lack of specific data for theincidence and preva lence of signs and symptoms in specific d iseases. Also, themost proba ble d iagnosis based on one sym ptom may not be the most l i kelyafter all the data a re considered . The step-wise consideration of single pivots ismea nt to enhance, rather than replace, good cli nical judgment. Other Sources of Diagnostic Error • Giving equal weight to pdsitive and negative findings. Often we focuson a positive la boratory test result and pursue a diagnosis based on it. Beforegiving too much weight to a positive resu lt, pay attention to a bsent su pportive el­ements . This aspect of probabil istic reasoning often is neg lected . • Using the first informatian that comes to mind. This source of error hasbeen termed the "availability heuristic . " An example is the i m mediate considera­tion of myoca rdial infa rction as a possible diag nosis when a patient presentswith ·chest pai n to the emergency room; pericarditis or pulmonary embolism maynot come to mind as readily These latter d iag noses may not be considered ini­tia lly, and the evaluation and treatment may be misd irected . • Laoking for evidence that supports an early worki ng hypothesis andignoring contradictory data . An exam ple of this so-cal led confirmation bias isseeking ischem ic changes on the EKG of a patient with chest pa in, while ignor­ing more d iffuse cha nges which may be suggestive of perica rd itis. • Believing in the chosen course of action and favoring evidence thatsupports it. Physicians may become too invested in a d iag nosis and conti nuedown the wrong pathway in pursuit because of overconfidence. Summary ofTypes of Errors Triggering errors Not giving equal weight to Framing errors positive and negative findings Gathering and processing errors The availability heuristic Verification errors Confirmation bias No-fa ult errors Overconfidence/overreliance Premature closure on a method or dogma In troduction • 7
    • Ways to Avoid Errors 1. Carefully compile information 2. Pick one or two " pivots " 3 Have a complete differential diagnosis for each pivot. 4. Have at least a general sense of the prevalence of the disease in a g iven population and in the releva nt population for the patient being considered . 5 Have a general idea of the prevalence of a symptom in a particular disease. 6. Do not discard contradictory data when it becomes available. A careful accounting of unexplained aspects of the case is essentia l . 7 . Pay attention to what is not present, i . e , negative find ings . 8 . Know that differential d iag nosis is an im perfect science: You are fallible. The unexpected , unlikely, or atypical may occur.f?e senting and Discussing CasesA few words a re i n order regarding case presentation and discussion . Caseconferences a re inva lua ble teaching exercises. Lea rning to present cases in aconcise and orderly man ner teaches the princi ples of differential d iag nosis.Case presentation em phasizes organ ization of data . Case discussion employscritical th inking and organization of diagnostic possibilities. Case Presentation The key to case presentation is breVity. The traditional " H and P" (h istory andphysica l) format is the best framework for discussion. Begin with a chief complaint(why the patient came for medical attention) and then proceed with an orga nizedh istory and physica l exa m . The h istory should be d iscussed i n chronolog icalorder to avoid confusion. Patients who have been il l for a long time or havebeen transferred from another hospital typically have extensive and complex his­tories . It is the duty of the presenter to avoid overly long discussions of previouswork-ups or presum ptive diagnoses. Focus on the essential features of the case. Tips on Presentation • Be brief and be thorough You shou ld be able to present most cases com­ pletely in 5 minutes or less. Even the most complex cases can be sum ma­ rized effectively in a brief presentation. • Present the case in chronological order. • Avoid cl uttering the h istory with laboratory resu lts, previous work-ups, or other physicians presum ptive d iag noses. • Follow the trad itional "H and P" format a . Chief complaint b. History of present ill ness8 • In troduction
    • - c. Past med ical history d. Med ications e. Fam ily history 1. Social h istory g Review of systems (brief) h. Physical exam • Focus on pertinent positive and negative elements. It usually is best, for the sake of teach ing, to omit laboratory resu lts from the i n itial presentation . This om ission emphasizes the i m portance of a careful clini­ cal eva luation to guide the ordering of laboratory tests . Sometimes the incl usion of la boratory tests is unavoidable since it may be the reason for adm ission or re­ ferral (e . g . , anemia). I n most cases, however, it is best to fi rst consider diagnos­ tic possibil ities and then ana lyze appropriately focused diag nostic testi n g . Note that a thorough h istory a n d physical examination should be performed on every patient, and the presenter should be prepa red to prOVide any informa­ tion if it is requested . However, an exha ustive list of all negative findings is un­ necessary. Describing a Symptom When considering the differential diagnosis of a patients sym ptom or chief complaint, it is essential to obtain a thorough history and accurately describe the problem . Ma ny com plai nts , such as chest or abdom inal pa i n , have nu merous causes, and a more specific description is req u i red to d i rect the work-u p . Consider the m nemon ic "COMPLAINS" : Compla int-what is the problem? Onset -when did it begin? Magn itude- how severe is it? Pattern - episodic? crescendo, decrescendo? constant? Location -where is it? does it radiate? Associated symptoms - are any other symptoms tempora l ly related to the complai nt? Im provements - what makes it better? Negative sti mul i -what makes it worse2 Simila r episodes in the past - has it ever ha ppened before2 Obtain ing these descri ptive features may reveal the cause of a sympto m . Consider the complaint of chest pa in: Compla int- chest pa in Onset- began 2 hours ago Magn itude- 1O/ 1 0 Pattern -crescendo, crush ing Location -substernal location radiating to the jaw and left a rm Associated symptoms - shortness of breath, diaphoresis, anxiety Improvements - rest, nitroglycerin Negative sti m u l i - exertion Similar episodes in the past- 5 years ago before coronary artery bypass grah In troduction • 9
    • Chest pa in has myriad causes, but the above h istory strongly points to angina . Consider a different set of featu res for chest pain Compla int- chest pain Onset- began 6 hours ago Magnitude- 1 0/ 1 0 Pattern - constant, sharp Location - su bsterna I location, nonrad iati ng Associated symptoms - i nabil ity to take a deep breath Im provements -sitting-up, leaning forward Negative stimuli - lyi ng flat Similar episodes in the past- no prior history In this instance, the chest pa in features a re suggestive of pericardial pa i n , and a different l ist of diagnostic possibilities should be considered . Case Discussion 1. Beg i n with a summary statement. After l i stening to the case, g ive a one-sentence s u m m a ry of the case . For exa m ple: "The case concerns a 44- yea r-old male with a h i story of poorly control led d ia betes and i ntrave nous d rug a buse who presents with a 2-day h i story of fever, ras h , a nd decreasing u rine output . " The summary statement is a "gestalt, " or overa l l i m pression , of the case . It is helpful because a presentation often suggests a l i kely d iagno-. sis, and the d i scussion can focus on provi ng or dis proving this presu m ptive d iagnos is. 2. N ext, make a problem list of the major cu rrent and past problems. I n the above example, a problem l ist could include: Fever Rash Decreasing urine output History of dia betes History of intravenous drug abuse 3 . Construct the differential diagnosis framework based on the categories of disease or by using m nemonics for specific entities on the problem l ist. 4. Na rrow the d iagnostic possibilities based on the h istory and physical exa m . 5 . Request specific la boratory o r imaging tests t o further na rrow down the diag nostic possibilities. Specific m nemonics may be used to consider the differ­ ential d iag nosis for certain la boratory abnormal ities . When new data is not consistent with the diseases being considered, always return to the original, complete differential to reconsider diagnostic possibilities. 6. Summa rize the data and prioritize diagnostic possibil ities. 1 0 • In troduction
    • » III PULMONARY AND CRITICAL CARE General Considerations G eneral Approach to Pulmonary Disease Many d isorders have pulmona ry manifestations, and chest symptoms a re fre­ q uently the fi rst noticed by the patient (e . g . , cou g h , wheezi n g , shortness of breath) . The lung is a common "ta rget" organ for infection, drug toxicity, cardio­ vascular com promise, i m m u nologic disease, and neoplastic processes. I n ap­ proaching the patient with thoracic disease, think of the more common categories of illness, such as infection, neoplasm , toxic exposures, and cardiovascular dis­ ease. Also i m portant, but less common, a re the immunologic and "exotic" cate­ gories of disease, a mong which there is considerable overla p. Other categories of illness such as endocrine or metabolic diseases have less d i rect pul monary in­ volvement. We can apply the m nemonic "ME DICINE DOC": Metabolic (e.g . , a myloidosis, a lpha- l -antitrypsin deficiency) Endocrine (para neoplastic syndromes, neuroendocrine cell hyperplasia) Drugs/medici nes (e.g . , nitrofurantoi n , am iodarone, chemotherapy toxicity) Infection (e. g . , H IV-related , TB, bacterial pneumonia) Congenital (e . g . , bronchogenic cysts, Kartageners, cystic fibrosis) I m munologic (e . g . , Goodpastures, rheumatoid lung, asthma, BOOP, PIE) Neoplastic (primary lung, pleural and mediastinal tumors, metastatic disease) Exotic d i seases (e . g . , sarcoi d , eosi noph ilic g ra n u loma, LAM, interstitial d iseases) Degenerative (e.g . , COPD?, degenerative neuromuscular disease [ALS]) Occupational/environmental (e.g . , smoking, asbestosis, hypersensitivity) Cardiovascular (e . g . , PE, edema from CHF, VOD, pulmonary hypertension) Metabolic disorders cause multi-system disease, but the lung and chest usually a re not prominently i nvolved . Amyloidosis (also "exotic" and immunologic) may Pulmonary and Critical Care . 1 1
    • rarely present as parenchymal or vascular lung disease. Alpha- l -antitrypsin defi­ciency ohen leads to em physema, especia lly in young smokers, and also cou ldbe classified as an i nherited disorder. In addition, the lungs may be affected byongoing metabol ic processes, such as pu lmonary edema from u remia or tachyp­nea (Kussmaul breath ing) from diabetic ketoacidosis. The lung has little known endocrine function and so this category usually isnot helpful i n formu lati ng d ifferential diag noses for chest disease. Lung cancer,pa rticula rly small cel l carcinoma, can cause para neoplastic syndromes such asSIADH and Cush ings syndrome. Myxedema may be associated with pleural ef­fusions. The rare entity of neu roendocrine cell hyperplasia may present aschronic obstructive lung disease. Drugs can cause hypersensitivity reactions. Exa mples include nitrofu rantoinand phenytoin . Also, certa i n chemothera peutic agents have wel l-known pul­monary toxicities (methotrexate, cytoxa n , bleomyc i n , BC N U ) Amiodaroneca uses p u l monary fibrosis as well as other types of lung i n j u ry. I ntravenousd rug a b use and coca i n e a buse may ha ve a c ute a n d c h ron i c p u l m o n a rymanifestations . I n fectious processes of many types can involve the lungs - either prima rily,as in loba r bacterial pneumonia, or as part of a dissemi nated infection , such asasperg illosis in immunocomprom ised patients. Viruses, mycobacteria, hel minths,and other parasites ca n all cause pulmonary pathology. Certa i n infectiousagents may be specifica l ly associated with chronic diseases, such as PC P inAIDS, or Bu rkholderia in cystic fibrosis. The category of congen ital lung d isorders i nc l udes a natomic, i m m u no­logic, and metabolic abnormal ities. Anatomic disorders i nclude bronchogeniccysts, sequestration , and dysmotile cilia syndrome. Immu nodeficiency syndromessuch as immunog lobulin deficiency or functional neutrophil disorders characteris­tically present with recurrent si nopulmonary i nfections . Alpha-l-a ntitrypsin defi­ciency pred isposes patients to panlobu lar em physem a . Cystic fi brosis is acom mon i n herited disease with prominent pulmonary involvement i ncludingbronchiectasis, chronic i nfections, and fi brotic changes . Immunologic disease may affect the lu ngs specifical ly, as in asthma, or pul­mona ry i nvolvement may be only a part of a more widespread i m m u nologicprocess such as Goodpastures or Wegeners. Virtually all collagen vascular dis­eases can i nvolve the respiratory system. Exam ples include pulmonary fibrosis i nscleroderma, l u n g nodules in rheumatoid a rthritis, pleural effusions in SLE, a n dtracheal collapse in rela psing polychondritis. Neuroimmu nologic d isorders suchas myasthen ia g ravis and Gu illa in-Ba rre may lead to respiratory muscle fa ilure.Tropical eosinoph ilia represents an immunolog ic response to the i nfectious agentfilaria, and is treated with the a nti-fi larial agent d iethylca rbamazine. Allergicbronchopulmonary asperg il losis is another exa m ple of an infectious agent elicit­ing an i ntense i nfla m matory response . Treatment is primari ly d i rected at modify­ing the host response with steroids. Neoplastic disease may arise primarily in the lungs or metastasize from ad istant cancer. Neoplasms in other thoracic structures also can affect pulmonaryfunction (e. g . , pleura l tumors, compression of a irways from lym ph nodes).12 • Pulmonary and Critical Care
    • - N umerous exotic conditions affect the lungs, i ncluding h istiocytosis X, sar­ coidos is, Iymphang ioleiomyomatosis, and eosinophilic lung d isease. Many of these diseases are thought to have an immu nologic basis. Degenerative diseases may ca use pul monary symptomatology secondari ly, as is the case with neuromuscu lar d isorders such as ALS . These disorders can lead to swa l lowi ng dysfu nction and aspiration or respiratory fa i l u re . Severe kyphoscoliosis can lead to a restrictive ventilatory defect. Emphysema also could be considered degenerative. I n normal aging, lung function slowly decli nes and is thus degenerative. In the category of occupational and environmental exposures, smoki ng-re­ lated lung d isease is very common Other agents that can cause lung disease are leg ion and i n cl ude asbestos, s i l i ca, coa l d ust, and beryl l i u m . Hyper­ sensitivity reactions include farmers lung, bird-fa nciers lung, and nu merous other entities Tra uma may lead to hemorrhage, pneumothorax, lung contusion , o r ini ury to other i ntrathoracic structures. Cardiovascular diseases may i nvolve the lu ngs secondari ly, ca using pul­ monary infiltrates and pul monary hypertenSio n . Abnorma l ities of the heart and aorta are i m portant considerations i n thoracic d isease. The vascul itides (classi­ fied under i m m u nologic d isease) and pulmonary veno-occl usive d iseases a re more rare. Pul monary embolism is very com mon, u nderd iag nosed, and may be insidious. The presentations of pulmonary embolism are myriad, and the dis­ order should be considered in the d ifferential for most thoracic problems. G eneral Approach to Cri t i c al Care Medicine The care of critica lly i l l patients i s complex a n d requires a n organ ized a pproach for managing m u lti-system disease . Consider the m nemonic "MICUS LIFE GOALS " : Med ications/ prophylaxis Invasions Cardiovascular Uri ne/renal Ski n/decubitis care Lu ngs Infectious disease F l uids/electrolytes/ nutrition Endocrine Gastroi ntestina l/l iver Oncolog ic/hematolog ic Analgesia/ neurologic Long-term prognosis Social/family Pulmonary and Critical Care • 13
    • -- Many of these patients are on numerous medications which may cause sideeffects such os fever, rash, and cytopenias Carefully review the patients medi­ci nes dai ly, with an eye towa rd disconti nuing unnecessa ry agents. Consider allhospitalized patients for some type of DVT prophylaxis, especial ly ICU patients.Many patients should be considered for stress ulcer/gastritis prophylaxis, as wel l . I nvasive procedures and i n-dwel l i ng l i nes and catheters a re common i n theICU. These i nvasions, while often necessary, a re sou rces of iatrogenic compli­cations, especially i nfection, and should be discontinued as soon as possi ble. A systematic approach i s then used to add ress the patie nts problems :cardiac (e . g . , hemodyna m ics, d i u resis), u ri n a ry/renal (e . g . , fluid ba lance,BUN/c reati n i ne , dialysi s ) , skin (e . g . , ras h , decubitus care), l u ngs ( i ncludingventilator management! , infectious disease (active or suspected i nfections, a n­tibi otic thera py i n c l u d i n g treatment day!, fluids/electrolytes/nutrition ( IVFs,electrolyte disorders or replacement, enteral or parenteral nutrition!, endocrine(e . g . , diabetes, thyroid d isease, steroid thera py! , GI/liver (e.g . , gastroi ntestinalbleeding, d iarrhea/consti pation, ci rrhosis/hepatic dysfu nction , pancreatic dis­ease!, oncologic/hematologic (e . g . , m a l i g n a ncies, cytopenias, coag ulopa­thy! , and ana lgesia/anxiolysis/neurologic status (e . g . , pain ma nagement,coma, neurologic defiCits, psych iatric d isease). It is i m portant to reassess the long-term prognosis frequently so as to avoidfutile care . Careful attention often is g iven to a patients medical issues withoutconsideration of the l i keli hood of surviva l or chance of mea n i ngful recovery.Along the same l i nes , socia l/fa m i l i a l issues a re of para mount i m po rta nce .Family mem bers often a re upset and concerned . They req u i re regular meeti ngswith the ICU physician to discuss med ical problems, treatment decisions, prog­nosis, and end-of-life decisions.C hest X-Ray Interpretati o nReading a chest x-ray req u i res an organized a pproach and ca n be as easy asABCDE F . . Common methods used em phasize sta rti ng on the outside andworking in or starting i n the center and working out. The ABCDEF method * startswith a q u ick confi rmation of the fi l m s qual itative aspects a nd then outli nes achecklist for interpretation . Initial review: AP or PA Body position Confi rm name Date Exposure Films for comparison* This mnemonic was adapted from one proposed by Robert Crauseman, MD.1 4 • Pulmonary and Critical Care
    • • Interpretation . Ai rway/Adenopathy Bones/Breast shadows Cardiac silhouette/Costophrenic angles Diaphragm/Digestive tract Edges/Extra-thoracic tissues Fields/Fa ilure Initia l ly, the reader should look at the films projection (AP or PAl , then the body position (lordotic, rotated , etc ) , a nd then confirm the name of the pa­ tient, the date of the fi l m , and the type of exposure (over-penetrated or u nder­ penet rated) See if old films a re ava i la ble for a compa rison . Aga i n , using ABCDEF as your guide, review the releva nt structu res on the chest x-ray. Start by looking at the airway for width and focal narrowing . Then look for evidence of h i lar adenopathy or enlargement as m ight be seen with pulmonary artery hy­ pertension . Next, exa mine for breast shadows, which may affect the density in the lower lung fields, and ca refully review the bones for rib fractures or evi­ dence of lytic bone lesions. The cardiac silhouette as well as the costophrenic angles should be exam­ i ned for evidence of cardiac enlargement or pleu ra l effusions Look at the di­ aphragm to see if there is d iscrepancy in the height of the hemi-d iaphragms or evidence of free air under the diaphragm . The digestive tract then ca n be ana­ lyzed . With in the chest, look for evidence of esophageal enlargement or herni­ ation of the stomach as wel l as dilated loops of bowel below the diaphrag m . Look at the edges and extra-thoracic tissues. Particula rly, look a t the a pices for fibrosis or a pical d isease as wel l as pneumothoraces, which may occur a long the edges a pica lly, lateral ly, or at the base of the l u n g . Pleura l thickening or plaq ues may be present. Next, exa m i ne the extra-thoracic soft tissues on both the anterior and lateral projections. Final ly, assess the lung fields for evidence of a lveolar filling or interstitial processes. Evidence of cardiac fa i l u re may be seen i f there is a lveolar a i r space d isease with promi nent vascularity with o r without evidence o f pleural effusions. , Pulmonary and Critical Care • 15
    • .. C l inical Sym ptoms and Signs CHRONIC COUGH GASPS AND COU G H Gastroesophageal reflux disease Asthma Smoking/chronic bronchitis Post-infection Sinusitis/post-nasal drip Ace-inhibitor Neoplasm/l ower airway lesion Diverticulum (esophageal) Congestive heart failure Outer ear U pper airway obstruction G I - airway fistula Hypersensiti v ity/allergy N otes 1 . Cough is one of the most common complaints encountered by physicians. It is most often related to upper respiratory tract infections and/or smoki ng. A per­ sistent cough lasting longer than 2 weeks may ind icate a more serious disease. The above d ifferential for chronic cough refers to cases lasting severa l weeks i nI which chest radiographs a re norma l . 2 . I n a smoker, a chronic cough may i ndicate chron ic bronchitis o r i t may herald the development of ca ncer, particularly when it involves an ai rway. Any change i n the nature of a chronic cough i n a smoker warrants i nvestigation for pos­ sible neoplasm . 3 . Infections, the most common causes of cough , may be d ue to viral or bacte­ ria l pathogens; viral agents are the usual culprits . In addition, a post-infectiousI cough may a rise d ue to a cycle of i rritation and coughing, which further irritates 16 • Pulmonary and Critical CareI
    • the throat. A post-infectious cough may lost several weeks aher the resol ution ofthe acute infectious process . Treatment consists of cough su ppressa n ts , ipra­tropri um, and, occasionally, a course of inhaled steroids4. Both pulmonary parenchymal and pleural d isease may present as a coughwith or without dyspnea . A chest x-ray usua lly is the first test obtai ned after thehistory and physical in evaluating a chronic cough ( i .e . , a cough lasting longerthan 2 to 3 weeks) . If the chest x-roy is negative, consider a more l imited differ­ential diagnosis, as outlined by the GASPS AND COUGH mnemon ic.5. Certa in historica l featu res may poi nt to the etiology of a chronic cou g h .Symptoms of heart burn or worsening cough i n recu mbency (e. g . , night) may in­d icate gastroesophageal reflux. A cough that is worse in the evenings o r achildhood history of reactive airways disease may suggest asthma. Smoking-in­duced chronic bronch itis and post-infection coug h from chronic i rritation a revery common and should be suspected when there is a history of smoking or an­tecedent infection Nosal congestion or sensation of post-nasal drip may indi­cate sin usitis as the cause of a coug h . Ra rely, persistent clear rhi norrhea maybe secondary to a CSF leak, which should be considered if nasal drai nage andcough dont respond to treatment. ACE inhibitors, such as ca ptopri l , a re a common ca use of cough in pa­tients on anti hypertensive therapy. A neoplasm in the lower a irway, which is notvisible on x-ray, may be made manifest by cough. An esophageal diverticulum(e.g . , Zen kers d iverticulum) causes hal itosis, reg u rgitation , and cough associ­ated with eating. Patients with congestive heart failure may have an exacerba­ tion of reactive a i rways disease with coug h a nd/or wheeZi ng, often worse at nig ht. The presence of ear pain or ear disease should prompt an investigation ofthe outer ear canal and the ear dru m , as irritation in those a reas by hair, wax,or a foreign body may lead to sti m ulation of the vagus nerve and cough . Theea r canal should be exa m i ned in a l l patients presenting with coug h , as e(] r problems may be asymptomatic. The presence of stridor on physical exa m i nation or a palpable neck mass may indicate an upper airway problem as a cause of chron ic coug h . A gas­trOintestinal-a i rway fistula, usua l ly tracheoesophagea l , cha racteristicallycauses cough wh i le eati ng. And finally, the occurrence of the cough after workor worsen ing of the cough during the work week may suggest an occupationalcause leading to a hypersensitivity pneumonitis or an allergy. 6. Stud ies have shown that patients with cough lasti ng longer than 3 weekswho come to a pulmona ry special ist for evaluation almost i nvariably have oneof four ca uses of chronic cough : gastroesophageal reflux, asth ma, smoking-in­duced chronic bronch itis, or sinusitis/post-nasa l drip. The authors of these stud­ ies have suggested that a work-up for these four possible entities and/or empirictreatment of them will lead to resol ution of the cough in the g reat majority of cases. Adding the common entity of post-infectious cough to these four entitiescreates the mnemonic GASPS, which is a good start for d iagnosing the cause of chronic cough. Pulmonary and Critical Care • 1 7
    • 7 . Occasiona l ly, patients with pulmona ry fi brosis present with coug h and anegative x-ray. These patients usually have fine, "velcro" crackles on chest aus­cultation, and a CT scan will reveal the i nterstitial d isease.8 . Finally, for patients in whom all other causes of cough a re ruled out, a psy­chogenic etiol ogy is possi ble. This d iagnosis req u i res exclusion of the otheraforementioned etiolog ies. CLU B B I NGCLU BCancerLiver diseaseU lcerative colitisB ronchiectasis (especially cystic fibrosis)N oteClubbing has been observed in association with lung diseases si nce antiqu ity;however, its cause is unknown . It may be seen associated with cancers, particu­la rly pulmona ry neoplasms, and when such an association exists, there usuallyis evidence of hypertrophic pul mona ry osteoa rthropathy. Clubbing also is ob­served i n some cases of chronic l iver disease, as well as in inflam matory boweldisease, especially with ulcerative col itis. Clubbing is a very common symptomin patients with cystic fi brosis and in other patients with bronch iectasis. Otherl u ng d iseases that have been assoc iated with clubbing i nclude lung a bscessand asbestosis. Less commonly, it has been seen in association with sarcoidosisand eosi noph ilic g ra nu loma . Clubbing is less commonly associated with pul­monary fibrosis. It is not associated with COPD, the presence of clubbing shouldprompt an i nvestigation for other d iag noses . Clubbing may regress with treat­ment of the underlying disease. 18 • Pulmonary and Critical Care
    • - DYS P N EA S H E PANTS Stress/anxiety/deconditioning H eart disease Emboli Pulmonary disease A nemia Neuromuscular disease Trachea/upper airway obstruction Sleep disorder N otes 1 . Dyspnea is defined as an a bnorma l ly uncomforta ble awareness of breath­ ing and has diverse causes. Patients own descriptions of symptoms may include fatigue, heavy breath ing, weakness, chest tightness, wheezing, and other com­ plai nts . There a re four primary a natomic areas that i nfluence the sensation of breathing: Pulmonary/a irway stretch receptors, Aortic/carotid chemoreceptors, Neuromedullary chemoreceptors and Thoracic muscle stretch receptors ( " PANT" ) . I n put from these sites i nfluences the breathing pattern. For exa m ple, an acute exacerbation of COPD leads to lung hyperinflation and chest wall ex­ pansion, which i n tu rn sti mu lates pul monary and thoracic m uscle stretch recep­ tors, ulti mately leading to the sensation of dyspnea . Neuromuscular disease causes hypoventilation, al lowing CO2 to rise and O2 to fa l l . H igh pC02 and low p02 sti m u late aortic , carotid, and medullary chemoreceptors and ca use dyspnea . Alternatively, hypoxia from pul monary emboli sti m u lates aortic, carotid, and medulla ry chemoreceptors and causes dyspnea . 2 . The onset of dyspnea (acute, subacute, chron ic/progressive) as well as ex­ acerbants should be establ ished . Note that some patients with slowly prog res­ sive processes may g radually adapt by decreasing thei r physical activity, but compla i n of more acute symptoms at rest. Positional complai nts of dyspnea may be elicited, such as orthopnea (worsening i n the supine position - card iac d is­ ease, u pper airway obstruction, diaphragmatic paralysis! platypnea (shortness of breath when ass u m i ng an u pright position - ci rrhosis patients with intra pul­ monary shunts, pneumonectomy patients with i ntra-atrial shunts, patients with de­ ficient abdom inal m usculature!, trepopnea (dyspnea occurring in the right or left Pulmonary and Critical Care • 1 9
    • ..lateral decubitus position - heart disease , uni lateral pul monary d isease) , andparoxysmal nocturnal dyspnea ( most often related to left ventricular fa ilure, butmay be seen with obstructive lung disease or sleep-disordered breath ing).3 . I n addition to exertional and positional preci pita nts , q uestion the patienta bout occupational or environmental exposures, animal exposures, inhalationalagents, and seasonal worsening.4 . Stress, anxiety, and decond ition ing a re com mon causes of dyspnea ,but often req u i re a n extensive i nvestigation to rule out more l ife-th reateningetiolog ies.5 . Suspect heart disease or cardiac ischemia in patients at risk for or with a his­tory of cardiac disease. A history of exertional symptoms, orthopnea, paroxysmalnocturnal dyspnea, or chest pa in may be present, as well as physical exa m i na­tion findi ngs of edema , jugu lovenous distension , or card iac murmurs/gallops.I ntraca rdiac shunts also cause hypoxemia, CHF, and dyspnea .6. Pulmonary emboli may present with acute dyspnea , chest pai n , or wheez­ing . . Chronic, recurrent pulmonary emboli may be relatively "si lent" in itially andpresent as slowly progressive dyspnea . Evidence of lower extrem ity venous ob­struction may not be present.7. The category of primary pulmonary disease i ncl udes a i rway, interstitial andinfiltrative, pleura l , and pulmonary vascular diseases (embolic d isease is consid­ered separately a bove ) . Wheezing, coug h , and a worsening of symptoms inthe evening in a younger person suggest reactive ai rways disease, while g radu­ally prog ressive dyspnea and "velcro" crackles in an older patient suggest inter­stitial pul monary fibrosis. Pri mary pulmonary hypertenSion is often seen in youngwomen and may present as gradua lly progressive dyspnea with a paucity ofphysical find i ngs. 8. Anemia should be considered i n you n g , m enstruati ng women a n d i n pa­tients with gastrOintestinal disease, chronic renal disease, or maligna ncy. 9. Neuromuscular diseases include myopathies, neuropathies, and diaphrag­ matic dysfunction . 1 0. Obstruction of the trachea or upper airways, may be subtle, and wheez­ i n g may be attri buted incorrectly to asth ma or COPD. Tu mors of the uppera i rway and vocal cord dysfu nction a re poss i ble etiolog ies. The flow-volume loop may show a cha racteristic pattern of obstruction. 1 1 . Sleep-disordered breathing is com mon i n obese patients, the elderly, and Pl tients with chronic heart and lung d isease. Heavy snori ng, jerky l i m b move­ m� nts while asleep, morn ing headaches, daytime hypersom nolence, and sexualdysfunction a re clues to the diagnosis. It is important to obtain i nformation fromfa m i ly members and sleep partners as well as the patient . Sleep d istu rba ncecan cause fatigue, exercise intolerance, and complaints of dyspnea . 1 2 . One of the most common clinical conundru ms is the differentiation of car­diac from pulmonary dyspnea . Many patients have both hea rt and lung dis­ease, and the relative contribution of each may be d ifficult to d iscern . The i m portance of a careful physical exa mi nation can not be overstated . Look ca re­fully for the signs of C H F, including an S3 or S4 ga llop, rales, jugulovenous dis­tension UVD ) , and peri phera l edema . S i g ns of pulmonary l i m itation i n clude2 0 • Pulmonary a n d Critical Car£!
    • wheezing or reduced a i r entry, increased lung volumes, and hyperresonance topercuss ion . Note that JVD and pedal edema may be seen with cor pul monale,and they a re not always indicative of left-sided cardiac dysfunction . In additio n to the physical exa mination , a few simple measu rements may behel pful The peak expiratory flow (PEF) is an easily obtai ned measure of a i r flowlim itation . A reduction in PEF « 200 L/m in) i ndicates obstruction and a likely pul­monary etiology. The Pa02 also tends to be lower in pu lmonary dyspnea , a l­though there is considerable overlap One g roup of investigators has suggestedusing a combination of both measures, PEF X Pa02 / 1 000, to differentiate be­tween cardiac and pulmonary dyspnea . They have named this q uantity the dys­pnea d ifferentiation i ndex (DDI) and use a cut-off of 1 3 to disti nguish betweenpulmonary and cardiac etiologies. A DDI < 1 3 ind icates a probable pulmonaryetiology; values > 1 3 are suggestive of a cardiac etiology. Be careful to obta ina room air Pa02 and an accurate PEF (often tachypneic patients can not performthis test in itia lly) if these parameters a re being used . Another sim ple bedside parameter is the blood pressure response to theValsalva maneuver. The a rterial pressure response to the Va lsa lva maneuver isabnormal in either systolic or d iastol ic dysfunction (see Cha pter V, Cardiology) .Norma lly, there is a decrease in the pulse am plitude and a narrowing of pulsepressure in response to stra i ning. In CHF this response is blunted, prod ucing a"square wave response . " A normal arterial response to Va lsalva suggests a pul­monary etiology for dyspnea . H E M 0 PTYS I SCAV I TAT E SCongestive heart failureAirway disease/bronchiectasisVasculitis/vascular mal f ormationsI nfection (e.g., tracheobronchitis, anaerobes, fungi, T 8 )TraumaAnticoagulationTumo rEmb olismSto mach (G I or nasal source) Pulmonarv and Critical Care • 2 1
    • N otes 1 . When a patient complains of blood in the sputu m , fi rst determine if thesource is the lungs or ai rways (hemoptysis) and not the mouth , nose, pha rynx, orGI tract. The next steps are to q uantitate the a mount of blood and then considerpossi ble etiolog ies . The d isease processes caus i n g hemoptysis often causetissue necrosis, and the lung cavitates. Cavities, cystic cha nges, bronchiectasis,or alveolar ai rspace fi l l i ng on chest x-ray may ind icate a source of bleed i n g .Diffuse infiltrates suggest a more l i m ited d ifferential (e.g . , vascul itis with diffusea lveolar hemorrhage, coagulopa thy, m i tra l stenos is) . Although an a l a r m i n gsymptom, hemoptysis is often secondary to a benign etiology. Gross o r massivehemoptysis is most com monly caused by cancer, TB, or bronch iectasis.2. Congestive heart failure often causes pink, frothy sputum , but rarely fra n klybloody sputu m . Mitral stenosis is specifically associated with hemoptysis; ra rely,m itral regurg itation may cause expectoration of fra n k blood .3 . Diseases of the a irways often cause hemoptysis, with tracheobronchitis asthe most common cause of blood-ti nged sputum . Chronic a irway inflammationleads to bronchiectasis, which commonly causes hemoptysis.4. Vasculitides, such as Wegeners granulomatosis or Goodpastures d isease,are often characterized by fever, acute illness, and evidence of systemic involve­ment, often renal dysfu nction . Arteriovenous ma lformations may cause hemop­tysis and should be ruled out before biopsies a re ta ken .5 . Certa in infections, such as TB, fungi , and a naerobic lung a bscess, are morelikely to cause hemoptysis. Hemoptysis in these diseases is often seen in associ­ation with cystic or cavitary lung d isease. Staphylococcal infection following i n­fluenza characteristica l ly causes " rusty" or bloody sputu m . Rarely, Serratiamarcescens lung infection causes redd ish sputu m that appears bloody.6 . Trauma from thoracic injuries, in halations, pu l monary artery catheters, or en­dotracheal tubes may cause va ria ble a mounts of airway bleed i ng .7. Anticoagulation with coumad i n or heparin, or a bleed ing diathesis such asthrombocytopenia may precipitate bleed ing from the respiratory tract. Aga i n ,the presence of blood does not necessarily indicate a malignancy or specific in­fectious etiology, but be suspicious, si nce a nticoagu lation can " u n m ask" anoccult lesion .8 . Suspect tumors of the airway or parenchyma in smokers or patients with a known malignancy.9 . Pulmonary emboli may cause tissue infa rction and hemoptysis. Ra rely, pul­monary emboli cause cavitation. 1 0. Be careful to d iscri m i nate hemoptysis from stomach or other gastrointesti­nal bleed i n g . N asopharyngeal bleed i n g may cause cough and be m isi nter­ preted as hemoptysis. The pH of hemoptysis is usua lly a l kaline, while that fromthe stomach is acidic. 1 1 . The treatment of hemoptysis usually i nvolves observation and perhapsmaintaini ng the bleed ing source in the dependent position . If the hemoptysis is22 • Pulmonary and Critical Care
    • maSSive (arbitrarily defined as > 500 ml/24 hours) , i ntu bation with a double­lumen endotracheal tube is often required , with an attempt to isolate the hemor­rhaging lung and prevent "soi l i n g " of the non bleed ing lung . The sou rce ofmassive bleed ing is usually the bronch ial a rterial system , and hemostasis maybe obtained bronchoscopically, surgical ly, or by invasive radiologic procedure. 1 2 . A more comprehensive list of causes of hemoptysis is outlined below:TRAC H EALTracheobronchitis, Trauma, Tuberculosis, Thrombotic thrombocytopenic purpuraRupture of pulmonary artery (Swan-Ganz), Resin/paint production (trimeliitic anhydride), Rasmussen s aneurysmAspirated foreign body, A Ilergic bronchopulmonary aspergillosis, A naerobic/necrotic pneumoniaCancer, Cardiac (especiall y mitral stenosis) Crack coca i neHeparin, Hemosiderosis (idiopathic pulmonary), Helminths (paragonimus, echinococcus)E NT/esophagus (pseudo-hemoptysis), Embolism (pulmonary, septic), EndometriosisA rteriovenous malformation, A rteritis/vasculitis, AmyloidLung abscess, Left atrial myxoma, Lithiasis (broncholith), LymphangioleiomyomatosisAlso.· penicillamine and arterial bronchial fistula STR I DO RWE TRA C H O R TR EATWegener sE piglottitis/supraglottitis Pulmonary and Critical Care • 23
    • TracheobronchitisRelapsing pol y chrondritisAspirated foreign bodyCancer (endotracheal, metastatic, extrinsic compression)Hereditary (web, Ehlers-Danlos, Williams-Campbell, Mounier-Kuhn)Obstructive lung disease/"dynamic" compressionReidel s thyroiditis/Radiation (fibrosing mediastinitis)Trauma/T racheostomyR hinoscleromaE motion/anxiety (vocal cord dysfunction)AmyloidosisTracheopathia osteoplastica WH EEZI NGAST H MAAsthmaS mall airways diseaseTracheal obstruction/l a rge airways diseaseH eart failureMastocytosis/carcinoidA naphylaxis/A IlergyN otes1 . "All that wheezes is not asth ma" (Osler) . The mnemonic ASTHMA em pha­sizes the maior causes of wheezi ng . Wheezi ng is ca used by a i rway narrow­ing. The narrowing may be in the u pper a i rway (e . g . , laryngeal tumors, vocalcord dysfunction) , the large ai rways (e . g . , lung cancer, aspirated foreign body),or the small a i rways (e.g . , bronchiolitis, asth ma ) . When there is upper a i rwaycompromise, the wheezi ng sound is hea rd best over the trachea and is referred24 • Pulmonary and Critical Care
    • to as stridor. Extra-p u l monary d i sorders a lso may ca use bronchoc<) nstrictionan d wheezing E xa m ples i nclude edema from C H F, a n a p hylaxi � /al lergy,an d production of bronchoconstricti ng su bstances as occurs in the carcinoidsyn d rome and mastocytosis.2 . Asthma is a common cause of wheezing and should be suspec: ted whench a racteristic h istory, pul monary fu nction tests, and response to t he ra py aresee n . When unusual features a re encou ntered , consider other causes of wheez­ing Certa i n asthmatics may be at high risk for respi ratory fa ilure a n d death . Anum ber of factors suggest that asthma is severe and that closer foll()wup andperhaps more intensive therapy and education a re necessa ry: • Low socioeconomic status • More than two hospital izations per year • A history of intubation • High number of asthma medications • Sign ificant di urnal variations of > 30% change per day in airfl ow • Nocturnal asthma • High amount of beta-agon ist use ( more than two ca n isters per m onth) . • Associated psych iatric d isease.Other factors i ncluding age, degree of obstruction , and race also ca ll be signif­ icant ind icators of high-risk asth ma . 3 . Small airways diseases a re a group of poorly understood entiti es d i sti nct from asthm a . As the name indicates, they cause narrowing and ObStruction ofthe small a i rways and consequent wheeZing . A relatively com mon p hysical ex­ amination find ing is an end-inspi ratory "squeak, " which probably c O rrespondsto late opening of d istal airways. 4. Tracheal disease and large airway obstruction usually cause stritJ or, which may be d ifficult to differentiate from wheeZi n g . U pper airway lesions �an be de­ tected by physical examination (stridor over the upper ai rways) or Chl racteristicflow volume loops. A pa rticula rly common cause of upper ai rway W h eezi ng is vocal cord dysfu nction . These patients, often young women , typically h ave exer­ tiona I or emotionally ind uced wheeZing and shortness of breath whi� h may be severe. Characteristical ly, the wheeZing occurs with inspiration . The fI()w volume loop may show variabili ty in the i nspiratory phase. These patients oftE! n are mis­ diagnosed and treated im properly (often with steroids) as refractory Ci sth matics. Speech therapy and education are helpfu l . 5 . Extra-pulmonary disorders can cause bronchoconstriction . Heart f� i l u re may be made man ifest by wheezing or it may exacerbate normally q u i�scen t a i r­ ways hyperreactivity in certa in patients. A few un usual diseases (ma�tocytosis, carci noid syndrome) can produce h ista m i nic compounds that caus ras h , hy­ potension, and wheezi ng . Carcinoid tumors can cause wheeZi ng by two mech­ anisms: ( 1 ) airway obstruction by a bronchial carcinoid, and ( 2 ) prod ucti on of 5-H IAA, a bronchoconstrictor, which usually only causes wheeZing when the tumor i nvolves the liver (see Cha pter VI, Endocrinology, the Carcinoid secti on). 6. Anaphylaxis and allergy can cause bronchospasm and wheeZin g . It i s crit­ ical to identify environmenta l precipitants of wheeZing, as such knOW ledge can be life-savi ng. Avoidance of precipitants obviates the need for medic(:] tion s . Pulmonary and Critical t:are • 25
    • 7. Pulmonary function tests a re essential in the diagnos is of a i rway obstructionand assessing the response to therapy. Inspect the flow volume loop with both i n­spiratory and expiratory limbs for evidence of a large a i rway obstruction . Obtainlung vo,lume measurements: a n obstructive lung disease should show normal orincreased lung volumes. Then a n assessment of simple spi rometry IFEV I , FVC)determines if obstruction is present. Occasional ly, a provocative test for asthma; � needed ( i . e . , methacholine challenge test) when the d iagnosis is u ncerta i n .8 . Below i s a more comprehensive list of the causes o f wheezi ng:T H E AST H MATICSToxic fumesHypersensitivity pneumonitisEosinophilic diseaseAsthmaSmall airways diseaseTracheal obstruction/l a rge airways diseaseHeart failureMastocytosis/carcinoidA na phylaxis/AllergyThromboembolismI nfection/bronchitisCystic fibrosis/bronchiectasisSmoking/COPD26 • Pulmonary and Critical Care
    • C l inical Conditions or Diagnoses A C U T E R E S P I R AT O R Y D I ST R E S S SYN D R O M E­ D I F F U S E P U L M O N A RY I N F I LT R AT E SARDSAcute onsetRatio PaOiFi02 � 2 0 0Diffuse infiltrationSwan-Ganz wedge 1 8 mmHg <N otes 1 . The clinical definition of ARDS is: ( 1 ) acute onset, (2) ratio (Pa02/Fi02) of200 or less (regardless of PEEP level) , (3) diffuse, bilateral i nfiltrates on frontalchest x-ray, (4) Swan-Ganz wedge pressure � 1 8 m m H g or no c l i n i ca l evi-dence of leh atrial hypertension . /2 . The development of diffuse pulmonary i nfi ltrates may rapidly lead to respira­tory failure. Decide whether the etiology is secondary to congestive heart fa ilureor due to capillary leak. Capillary leak leads to the acute respi ratory d istresssynd rome. Diffuse pul monary infiltrates may be com posed of any of the previ­ously mentioned etiologies u nder pulmonary i nfiltrate (see previous section ) .3 . Both congestive heart failure a n d capillary leak syndromes cause fluid to accu­mulate in the a lveola r space, but the physiolog ic mecha n isms a re d ifferent Lehheart failure causes an increase in capillary hydrostatic pressure, and fluid is extrudedinto the alveol i , while ARDS occurs secondary to a capillary leak phenomenon ,in which fluid extra va sates i nto the alveol i . The physical exami nation in a patientin respiratory d istress or who is already on a ventilator may be lim ited, and otherdiagnostic tests may be needed to i ndicate the nature of the pulmonary i nfiltrates . Two useful tests are the echocardiogram, which can g ive an assessment ofoverall global card iac function as well as pulmonary pressures , and pulmonary Pulmonary and Critical Care • 2 7
    • artery catheterization (Swan-Ganz) . Although many paroa meters may be mea­sure d with the Swa n-Ganz catheter, the most i m portant i n d ifferentiating be­twee n card iogenic p u lmonary edema and noncardiogen i c pu l monary edemaa re the wedge pressu re and pulmonary d iastolic pressures . I n card i ogenic pul­monary edema, both the wedge and PA d iastolic are elevated typically > 20m m H g . I n nonca rd iogen ic pulmona ry edema, the pulmo m o ry capillary wedgepressure is usually < 20 mmHg.4 . The therapy of ARDS is supportive, with special emphCll s i s o n identifying andtreati ng the cause. There has been a great deal of intereslt i n steroid therapy forARDS, and current data suggests a role 1 -2 weeks aher onset, du ring the so­called fi broproliferative phase. Most stuQ ies have showm no sa luta ry effect ofsteroids when they were started early in the course of ARDS. F u rther studies areneeded to confirm benefit later i n the course.5. Here is a more comprehensive m nemonic for the causes of ARDS:CA R D S ? H O PE I T S N O T A R D Se N S disordersAspiration (especiall y gastric)RadiationDrugs (i.e., heroin, morphine, barbiturate-s, etc.)S moke/toxic gas inhalationHypotension/shockO2 ToxicityPancreatitisEmboli (i.e., pulmonary, fat, amniotic fluicrj)I nfection/sepsisTransfusion reactionS urgery (especiall y cardiac)Near drowningO bstetrical emergencies (e.g., eclampsia , HELLP)Thermal injury/burnsA Ititude sicknessRenal failureD iffuse intravascular coagulationSystemic lupus erythematosus28 • Pulmonary and Critical Care
    • A C U T E R E S P I R AT O R Y FA I L U R EA P E H I T I N T U BAT E DAspiration " White " X-Ra ysPusEdemaHemorrhageI mmunologicTumor " Black " X-Ra ysI nfarcted right ventricleNeurologic disease (drug overdose, botulism, CVA, Guillain BarreTension pneumothoraxU pper airway obstruction (anaphylaxis, foreign body aspiration)B ronchospasm (COPD exacerbation, asthma)ArrhythmiaTamponadeEmbolus (pulmonary, air, amniotic fluid, tumor)Diaphragmatic weakness (surgery/trauma, neurologic disease)N otes1 . This m nemonic i ndicates the ma ior causes of acute respi ratory fa ilure . Thefi rst part of the mnemonic, A P E H IT, ind icates the same processes causing pul­monary i nfi ltrates. These processes lead to opacifications on the chest x-ray. Thesecond half of the m nemonic, I NTU BATED, i n d icates etiolog ies in which thechest x-ray often d oes not show any i nfi ltrates. I n these entities, air space d is­ease is not the cause of respi ratory fa ilure, and you m ust consider other causesof hypoxemia (e . g . , neurologic i m pairment leading to hyperventilation , tension Pulmonary and Critical Care • 29
    • pneumothorax , upper and lower a i rway obstruct.on , a nd vascular obstruction ) .Therefore, a common way to d ivide u p the causes :Jf acute respiratory failure i s bythose that have "wh ite x-rays " (opacificaf ons) ane those that have "black x-rays"(clea r lung fields) .2 . There are six primary mechan isms of hy poxertia : • Low inspired fraction of oxyge n , • Hyooventi lation such as occurs at high a ltitude • DiFusion impairment • V/0 m ismatch • Low m ixed venous oxygen . • ShuntOf these ca uses , the m ost i m porta n t o n es a re V/0 m i sll atc h , s h u nt, a n dhypoventilation .3 . The indications for emergent endotrach eal intLbation are. • Hypoxem ic respi ratory failure ( p02 < 60 rrm H g on > 60% oxygen) • Hypercarbic respiratory failu re (res pi ratory acidosis with a pH < 7 . 3 ) • Airway protection • I ncreasing intracranial p ressure B R O N C H I E C TA S I SA SICK AI RWA YA irway/lesion/chronic obstructionS equestrationI mmunodeficiency syndrome (especiall y immunogl o bulin abnormalities)Cystic fibrosisKartagener s syndrome/dysmotile ciliary syndromesA lIergic bronchopulm onary aspergill osis (ABPA)I nfection/I nflammation (e.g., tuberculosis, post-viral, whooping cough, coll a gen-vascula r disease)R eflux (aspiration)/R ecurrent i njury (heroin, toxic gas inhalation)Williams-Campbell and other congenital diseases (e.g., Marfans, Mounier-K u n) hA Ipha-I antitrypsin deficiencyYellow nail syndrome, Young syndrome s30 • Pulmonary and Critical C.are
    • N otes1 . Bronchiectasis, a di lation of the ai rways, is usually a result of chronic endo­bronchial inflammation .2 . Hemoptysis may be a frequent feature of chronic bronchiectasis.3 . Bronch iectasis leads to d i lation of bronchial arteries and i ncreased bloodflow, which predisposes patients to bleed ing.4. "Dry" bronchiectasis refers to predom i nantly u pper lobe d isease ( i . e . , sec­ondary to TB or h i stoplasmosis). which usually dra i ns effectively. The ca rd i nalsym ptom is hemoptys is "Wet" bronchiectasis refers to lower lobe d isease ,which is characterized by chron ic cough and purulent sputum . Exceptions to thisrough classification include cystic fibrosis, which has prom i nent u pper lobe dis­ease and thick, tenacious secretions.5. A few diseases commonly cause bronchiectasis with an upper lobe predom­inance. These can be remem bered by the m nemonic " FACT" ( F u n g i , ABPA,Cystic fibroSiS, TBI6 . Ai rway lesions include tumors (benign and mal igna nt!. foreign body aspi ra­tion , and bronchol iths. These airway lesions may cause chronic atelectasis and,ultimately, bronch iectasis. C AV I TA R Y A N D C Y S T I C L U N G D I S EAS EWEIRD HOLESWegener sEmboli (pulmonary, septic)I nfection (e.g . , anaerobes, Pn eumocvs tis carin ii, T B )R heumatoid arthritis (necrobiotic nodules)Developmental cysts (bronchogenic, sequestration)Histiocytosis XOncologic (primary or metastatic cancer)Left atrial myxoma ( LA M )Environmental/occupational (silicosis, trauma)Sarcoidosis Pulmonary and Critical Care . 3 1
    • N otes1 . The presence of cavities or cystic cha nges on the chest x-ray may be causedby necrotizing processes such as i nfections, vasculitides, i nfarction from emboli,or maligna ncy. Also consider certain developmental a nomal ies, occupationalexposures, and u nusual primary l u ng diseases.2 . Pul monary cavities primarily result from six sections of the "MEDIC I N EDOC" m nemon i c : ( 1 ) I nfectious , ( 2 ) Congenita l , ( 3 ) I m m u nolog i c , ( 4 ) Neo­plastic, (5) Exotic, (6) Occupational/environmental exposures3 . Infectious etiologies i nclude mycobacterial disease, fungal disease, necro­tizi ng bacteria l i nfections, parasitic infections, and septic pulmonary embol i .Tuberculous cavities typica l ly occur i n the upper lobes, but can present i n a ny lo­cation . They a re part of a chron ic disease process, so prior fi lms are helpful i nanalyzing the progression of the disease. I n the a bsence o f superinfection , a i r­fluid levels are uncommon in tuberculous cavities. Sputum analysis often is posi­tive in active cavitary tubercu losis, as the organism load is relatively high with i nthe cavity. Fungal diseases, such a s coccidiomycosis, blastomycosis, a n d h isto­plasmosis, also can produce cavities Asperg illosis may couse on acute necrotizing pneumonia in i mmunocom pro­m ised patients, or it may colonize pre-existi ng cavities, producing a visible fungalboll on chest radiography. Because invasive aspergillosis characteristically i nvolvesblood vessels, thrombosis, i nfarction , and cavity formation often ensue. The char­acteristic "crescent" sign is produced by i nfa rcted tissue within the fu ngal cavity. Vi rtually all bacterial i nfections can cause a pneumonia that may producecavitary lung changes . Cavita ry cha nges a re more typical of a naerobes andg ra m-negative org a n i s m s . However, Staphylococcus aureus, Streptococcuspneumonia, and Legionella species all can produce cavitary l u ng changes. Ara re com pl ication of bacterial pneumon ia is pulmonary ga ngrene. The rad i o­logic a ppearance can be characteristic, with i nfa rcted lung tissue floati ng with i na parenchymal cavity. Surgery often is required for resolution. Pa rasitic i nfections should be suspected i n i n d ividuals with a pp ropriate travel and exposure history. Paragonim iasis is secondary to a l iver fluke and isendemic to Southeast Asia . Echi nococcus is associated with exposure to sheep,dogs, or wild hosts such as caribou or rei ndeer. A characteristic rad iologic a p­pearance, the "water-li ly" sign, is produced when the encysted organ isms mem­branes detach from the adventitia and float with i n a cavity. Finally, septic pulmonary emboli most commonly occur as a result of tricuspidendocard itis or a peri pheral source . Multiple cavita ry lesions may be present,often in the lower lung zones where the blood supply is greater. 4. Congenital anomalies i nclude developmental cysts (e . g . , bronchogen ic) aswell as pulmonary sequestration, and should be suspected in young adults pre­senti ng with asymptomatic cavitary lung lesions. 5. I m m u nolog ic processes i nclude the vasculid ities and rheumatoid a rthritis.Wegeners granulomatosis is the most common immunologic disease that presents32 • Pulmonary and Critical Care
    • ....I with pulmonary cavities. Rheumatoid arthritis ca n cause lung nodules that fea­ ture central necrosis a n d eventua l ly cavitate. Ankylosing spondylitis and polymyositis also may feature a pical bullous disease. 6. Oncolog ic processes can produce cavities by two mechanisms: ( 1 ) obstruc­ tion of a bronchus with d istal suppurative i nfection, or (2) cavitation of the tumor mass secondary to outgrowi ng of the blood supply. Squamous cell carci nomas have a particu lar propensity to outg row their blood su pply a n d cavitate . Angiocentric lymphoma (lymphomatoid granulo matosis) is a n u n usual mal ig­ nancy that can cause multi ple lung masses which may cavitate. 7. Exotic diseases causing cysts i nclude histiocytosis X, LAM, and sarcoidosis. Younger patients who present with multiple lung cysts should be suspected of haVing these diseases. Histiocytosis X, also called eosinophilic granuloma , is a disease of smokers. lANI is related to tuberous sclerosis and occurs in young females. 8. Envi ronmental or occupational exposures may lead to cystic lung d isease. A common occupational cause of cystic lung disease is sil icosis, which occurs in hard rock m i ners . Also, rarely, multiple trauma patients develop acute cavitary lung d i sease of uncerta i n etiology. Presumably, the trauma leads to vascular iniury, resulting in the cavitary changes on x-ray. 9 . As with most respiratory problems, emboli are a possible, albeit rare, cause of cystic or cavita ry changes . Both pulmonary and septic e m boli can cause necrosis, infarction, and subsequent cavitation . I N T E R ST I T I A L L U N G D I S EAS E IS IT I PF? I PF Sarcoidosis I nhalational (pneumoconioses) Treatment-related (e.g., medications, radiation, chemotherapy) I mmunologic (collagen-vascular diseases) Post-inflammatory (e.g., infection, A R D S ) Familial Pulmonary and Critical Care • 33
    • N otes 1 . The lung interstiti u m is the a rea between the gas-exchanging alveolar epithe­lium and the capi llary membra ne. Norma lly this space is very th i n and allowsfor effective gas exchange. When d iseases or toxins damage the in�-:: -titiu m , itmay become i nfi ltrated with inflammatory cells and, ultimately, scar tissue. Theseinterstitial lung d i seases produce an i m pa i rment in the d iffusion of oxygen andlead to respiratory sym ptomatology The chest rad iograph characteristicallyshows what is often called a reticular or li near pattern of i nfiltration . The term " d i ffuse pa renchym a l lung disease" m ay be more a ppropriatesince these d iseases may involve the a i rways and a i rspaces i n addition to theinterstiti u m . The m nemonic " I S IT IPF?" summarizes the pri mary causes of i nter­stitial d isease.2 . One of the m ost commonly encountered i n terstitial lung diseases is id io­pathic p u l m o n a r y fi brosis, I PF . Sarcoidosis is a lso very common and hasmyriad systemic manifestations . Immunologic/collagen-vascular diseases havewell-descri bed systemic features and pulmonary i nvolvement. Lung disease is oc­casion a l ly the i n i tial f i n d i n g i n patients with collagen-vascular d iseases .Treatment-related causes m ust be ca refully considered si nce removal of the of­fending agenr is critica l . A complete occupational and environmental histary ismandatory to exclude in halational lung d i sease . Avoidance of the i ncitingagent is mandatory for the patient, and other persons at risk may be identified .Pulmonary i nfections, ARDS, and other lung i njuries may result i n post-inflamma­tory fibrosis and permanent parenchymal changes. Finally, a number of unusualfamilial d iseases have associated interstitial lung d isease.3 . The history a n d clin ical exam i nation sometimes suggest an etiology for inter­stitial disease, such as a n exposure or an u nderlying disease. The chest rad io­g ra ph may show characteristic patterns which may also suggest a n etiology. Forexa m ple, certa i n diseases more commonly have predom inantly upper lobe i n­volvement, incl u d i n g Ankylosing spondyl itis, PIE (chronic eosi noph ilic pneumo­n i a ) , Infections (TB, h istoplasmosis), Coa l workers pneu mocon iosis/s i l icosis,Eosinophilic granuloma (h istiocytosis X), and Sarcoidosis/berylliosis ( "APICES").A predom i nantly lower lobe pattern of disease is seen i n asbestosis, alveolar pro­tei nosis, I PF, collagen-vascular diseases, and chronic hypersensitivity pneumonitis.Nodu les suggest sarcoidosis, Wegeners, inhalational exposures ( pneumoco­nioses). rheumatoid a rthritis, or lymphomatoid granulomatosis ("SWIRL"). The pres­ence of pleural disease is unusual in interstitial lung disease, but may be seen i nasbestosis, Iymphongitic carcinomatosis, a n d collagen vascular diseases. Normalor increased lung volumes and cystic changes are seen in only a few diseases.Finally, lymphadenopathy is also unusual in i nterstitial lung disease and may in­dicate sarcoidosis, amyloidosis, Iymphangitic carcinomatosis, or berylliosis.4. Diffuse pa renchymal lung d isease most often leads to i ncreased lung elastic­ ity and a reductio n in lung volumes. Pulmonary function tests usua lly reveal a re­strictive ventilatory defect. Occasionally i nterstitial disease is seen i n a patient34 • Pulmonary and Critical Care
    • with normal or i ncreased lung volumes, a n d this narrows the differential con­s i derably. The causes of I nterstitial lung d isease with normal or increased lungvolumes are summarized by the m nemonic LETS BRONC H : LAM, Eosinoph ilicg ranuloma ( h istiocytosis XL Talc injection ( i ntravenous drug a busel, Sarcoidosis,B ronchiectatic d iseases (e. g . , cystic fi brosis), Respi ratory bronch iol itis, Obliter­a tive bronch iolitis, Neurofibromatosis, COPD + ILD, Hypersensitivity pneumon itis.(This m nemonic is adapted from one i nvented by Robert Shpi ner, MD . ) I n con­trast to other causes of i nterstitial lung d isease, these diseases feature obstructionon pul monary function tests. Exceptions a re hypersensitivity pneumon itis andeosinoph i l ic g ra nuloma, which most often show restriction on pulmonary func­tion testing despite normal or i ncreased lung volumes .5 . There are a pproximately 1 80 known i nd ividual diseases that m a y b e associ­a ted with interstitial lung d isease . The most frequently encountered are I PF, sar­coidosis, and interstitial lung disease associated with collagen vascular diseases .The following m nemonic l ists many of the causes of i nterstitial lung d isease:I HAVE BRO N C H E D A N I NTERSTITIALLUNGI diopathic pulmonary fibrosis (I PF)H ermansky-Pudlak syndromeA R D S recoveryVeno-occlusive diseaseE nd-stage liver diseaseB ronchocentric granulomatosisR heumatoid arthritis and other collagen vascular diseasesO rganic and inorganic dusts (occupational/ environmental)N iemann-Pick and Gauchers diseasesCongestive heart failureH ypereosinophilic syndromeEosinophilic lung diseases (PIE syndromes)D rug exposures (e,g" amiodarone, gold, antibiotics, chemotherapy)AmyloidosisN eoplastic (Iymphangitic carcinomatosis, post-radiation therapy) Pulmonary and Critical Care • 35
    • Idiopa ltt--. ic p u lmonar y he m osNeuro f ib ro m atosis ider osisTuber (Q l..J S s c lerosisEosin P granuloRenal C::>f� h il ic /uremia ma/his ti ocytosis XSarcoi d �ilu re sisTrans b le nt a tion ( G V H D )I nfect i ll S esiduaToxic ioh em(ricals (ga seactfive infe ction of any type) par �cq ua t, rad iati or) ) s, um es , va pors, ae r os ols, ofIdiopaA Iveotail ic hyteinosi s nop h ilic synd rome ... pr o pereosiLymp� a. ng io leiomyo mat o si s ( LLympth a cy tic di so rd er s (e .g . , A M ) Iym ph oc ytic interstitia l p n pse udolymphoma,U I ce r � t i v e c oli tis an d ot he r geum onitis) .Nec r Q,ti :Z i n g va sculit i s (Weg e as tro intes tin al diseases Iy m p h o m atoid granulo m a ne r s, Ch u rg-S tra u ss ,Goo d � a. st ur es dis e as e an d tosi s) he fln a rrh ag e sy nd ro me s ot he r pu l m onary M E D I AST I N A L M AS SC H E ;g T A L A R MsCysts ( bro n chia l, pe ricar d ia l)H erni � � (B o chdalek , Mo rg ag ni)Es oplJ a ge al div ert i c ulu mSch w..a nTs (T lJ a noTm a/neuro ma , thtu mor s s: terato geni c Ym o n a, thy r oid , and ter ri. ble I Y � PtlO rn a) 436 • �u lrr, ona ry and Critical Car e
    • A neurysms (aortic and pulmonary)Lymph node enlargementAdipose tissueRenal (intrathoracic kidney)Metastatic diseaseS plenosis/extramedullary hematopoesisN otes 1 . One of the most common disorders of the mediastinum is a moss. The fi rststep in evaluation is to determ i ne the compartment of the med iastinum i n whichthe mass is located : a nterior, midd le, or posterior. The most common anteriormasses are the 4 Ts : thymona , thyroid moss, teratoma, terrible lymphoma . Themost common middle masses a re vascular mosses, lymph node enlargements,or cysts ( perica rd i a l , bronchogen ic) . Posterior masses i nclude neurogenictumors, hiatal hernias, or esophageal diverticu l i .2 . A CT scan , followed b y biopsy when appropriate, is the usual approach todiag nosis.3 . Ca uses of a med iastinal mass, by compartment, a re summa rized by them nemonic below. There is some overlap in the categories as some entities canbe found in more than one mediastinal compartment.N ERVES A N D CH EST PARTS Pos terior Media s tin umNeurogenic tumorsEsophageal enlargement or diverticulumRenal (intrathoracic kidney)Vascular (e.g., descending aortic aneurysm)Extramedullary hematopoesis/splenosisSkeletal /spinal (e.g., vertebral osteophyte, menin g ocel e ) Middle Media s tin umAdipose tissue ("fat pad")NodesDilated aortic root Pulmonary and Critical Care • 37
    • Cysts (pericardial, bronchogenic)Hematoma (e.g., after surgery or line placement)Enlarged pulmonary arteriesStomach (hiatal hernia)Tumor (metastatic, primary) A n terior Media s tinumParathyroid massAortic arch aneurysmR ight ventricular enlargementTs (teratoma, thymona, thyroid, terrible lymphoma)Subclavian catheter hematoma PLE U RAL E F FU S I O NP E H I T ? D E C U B , TA PPusEdemaH emorrhageI mmunologicTumorD ial ysis (peritoneal)Esophagus (Boerhaaves )ChyleU rineB ileTotal parenteral nutritionAscitesPancreatic38 • Pulmonary and Critical Care
    • - N otes 1 . There a re many d ifferent types of fluid that may enter the pleural space . Si m i lar to pulmonary i nfi ltrates, pleural fluid may consist of pus, edema, hemor­ rhage, i m munologic reactions, or tumor cells (PE H IT) These are the major causes of fluid i n the pleural space. However, other types also may gain access, such as dialysis fluid, i nflam matory fluid from a ruptured esophagus, chyle from i n j ury to the thoracic duct, urine, bile, total parenteral nutrition (TPN), ascitic fluid, or pancreatic fluid (DECUB TAP) There even have been cases of CSF ( pleuro-d u ro fistu la) and stool (fecothorax) in the pleu ra l space . As with pul­ monary i nfiltrates, pulmonary embolism must be considered i n the differential d i­ ag nosis of a pleural effusion . 2 . When a pleural effusion is discovered, decubitus films should be obtained to see if the fluid flows freely. Thoracentesis should then be performed without delay on freely flowing fluid. Thoracentesis is indicated i n virtually all newly d iagnosed , free-floWing pleural effusions. Exceptions to this rule are when the clinical diagnosis is certain (e.g . , CHF) or there is only a small amount of fluid in the pleural space. 3 . Pleura l effusions a re broadly cate g orized as tro nsudates or exudates . Tra nsudates occur when syste m ic factors that infl uence the formation and a b­ sorption of pleural fluid are altered . The most common causes are leN ventricular fai lure, pul monary embolus, and cirrhosis. Others i nclude nephrotic syndrome, peritoneal dialysis, myxedema, atelectasis, and uri nothorax. Urinothorax is the only cause of an acidic transudate. 4. Exudates occur when local factors that i nfluence the formation and absorp­ tion of pleural fluids are altered . The most com mon causes a re bacterial pneu­ monia, malignancy, viral i nfection, and pulmonary embolus. Pulmonary embolus may cause either a transudate or an exudate depending on whether i nfarction and hemorrhage occurs. Ca ncer and hypothyroidism also may cause either a transudate or exudate. 5 . Criteria for an exudate are: a. Pleural fluid protein/serum protein > 0.5 b. Pleural fluid LDH/serum LDH > 0 . 6 c . Pleural fluid LDH > 2/3 o f the normal upper limit for seru m . Transudates have none o f these features. 6. If the fluid is exudative, the follOWing tests should be ordered : glucose, amy­ lase, cell count and differential , cultures, cytology, gram sta i n , and pH. Two or three cytologi C samples will rule out a malignancy in most cases. 7. A possible para pneumonic effusion should be tapped i m med iately. It is said to be "compl icated" if any of the follOWing are present: a. Gross pus b. Organisms visi ble on gram stain c . Glucose < 50 d. pH < 7 . 0 Complicated effusions usually require chest tube drainage. Pulmonary and Critical Care • 39
    • � TB pleuritis usual ly requires a pleural biopsy for d iag nosis due to the scarcity of orgon isms in the fluid The flu id ohen ( but not always) lacks mesothelial cells. Ma king the d iagnosis of primary tu berculous pleuritis m ay be d i fficult, but i t should b e pursued agg ressively a s there i s a h igh i ncidence of progression to pulmonary parenchymal d isease. The diagnosis may be elusive: several new d i­ ag nostic stud ies a re ava i la ble. There is evidence that a n elevated adenosine dea m i nase level may be helpful i n establishing a d iagnosis of tuberculous pleu­ ritis . A second promising diag nostic test is a polymerase chain reaction assay specific for mycobacterial d isease. This test may be applied to sputum samples and has been used for ana lysis of pleural and other body flu ids. It has a high degree of sensitivity, with probably a lesser degree of specificity. 9. A low g lucose is characteristic of rheumatoid arthritis effusions. Other entities that may have a very low g lucose i nclude empyema, malignancy, tuberculosis, SLE , and esophageal rupture. 1 0 . B loody fl uid may be seen in many conditions, but an RBC count g reater than 1 00 , 000 suggests trauma, maligna ncy, pul monary embolism , post car­ d iac i n j u ry synd rome, or asbestos pleuritis ( I T B LE D - I ntravenous catheter, Tra u m a , BAPE [ benign asbestos pleural effusion ] , Lung ca ncer, E m bolism , Dresslers synd rome). 1 1 . A pleural fluid a mylase level occasiona l ly is helpfu l . The mnemonic AMY­ LASE UP (Adenocarci noma , Mycobacteria, Yorking (esophageal rupture), Liver disease, Acute pa ncreatitis, Serum hypera mylase m i a , Ectopic pregna ncy, U reteral obstruction, Pseudocyst) can help you remember related d isorders . Hydronephrosis and other d isease states that lead to an elevated serum a mylase also increase the pleural fluid a mylase level. The highest levels are seen in pan­ creatic d isease, and usua lly a re g reater than 2 0 . In other causes i ncluding cancer the pleu ral fl uid/serum a mylase level is usua l ly a bout 1 0 . Pancreatic pseudocysts typically have the h i g hest a mylase levels, often g reater than 1 00 , 000. Amylase isozyme ana lysis may be hel pfu l in pinpoi nting the cause of a h i g h pleural fl uid a mylase . A h i g h sal ivary i sozyme l evel indicates malig­ nancy, whereas a high pancreatic isozyme level ind icates pancreatic disease. The most common malignancies causing a high pleural fluid amylase are lung or ova rian carcinoma . This fact can be helpful i n differentiating lung carci noma from mesothelioma , because mesotheliomas do not make a mylase. 1 2 . A high percentage of eosinophils in the pleural space usually i ndicates the presence of air or blood . Eosi noph ils may accumulate aher a pneumothorax or hemorrhage into the pleural space. Other causes of pleural fluid eosinophilia in­ clude certa in d rugs such as dantrolene, pulmonary emboli , parasitic i nfections, funga l i nfections, and malignancies . Ben ign asbestos pleural effusion ( BAPE) is a compl ication of asbestos exposure that may occur 1 0- 1 5 years after the ini­ tial exposure. Because the pleural effusion is bloody, a high eosinophil cou nt may be seen with BAPE as wel l . The m nemonic BAPE ( B lood , Air, Parasites, Emboli) summarizes the primary causes of pleural fluid eosi nophilia 1 3 . Suspect the presence of lymphatic fluid i n the pleural space (chylothorax) when effusions re-accumu late ra pidly or have a m i l ky color. The fl uid is not always rrl ky however, and may be turbid or bloody Cond tions that c:ommonly 40 • Pulmonary and Cntlcal Care
    • lead to the accum u lation of lymphatic fluid (chyle) i nclude trauma, maligna ncy(especially lymphoma ), chest surgery, coughing, vomiting, or straining. A greatnumber of other cond itions may be associated with a chylothorax as wel l , in­cluding LAM; yel low nail synd rome; i nfections lead ing to thoracic lymphade­nopa thy, i ncluding tu bercu losis and fu ngal infections; filariasis; aortic a n dpul monary aneu rysms; and certa i n congen ital syndromes, for example Downssyndrome, Noonan s syndrome, and Turners syndrome. Some major etiologies of chylothorax a re summa rized by the m nemonicCHYLES - Cough/stra in/vom iting, Hereditary diseases, Yellow nail syndrome,Lymphoma/LAM/lymph node enlargement, Elephantiasis, Surgery/trauma . All ofthese cond itions lead to obstruction of lymphatics and/or i njury to the thoracicduct. A pleural fluid triglyceride level > 1 1 0 establishes the d iagnosiS of chylo­thorax. A level at 50-- 1 1 0 is intermediate and may be ind icative of chylothorax.When the level is i ntermed iate , the pleural fl uid should be subm itted for elec­trophoresis to look for the presence of chylomicrons. When a chylothorax is diag­nosed, establish NPO for the patient, and in itiate TPN . Do not attempt aggressivechest tube dra inage, as th is may lead to nutritional depletion. The thoracic ductmay then spontaneously hea l ; if it does not," surgical ligation may be ind icated . 1 4 . If the cause of a pleural effusion is not determi ned after thoracentesis, thenpleural biopsy is usually the next diagnostic step. If pleural biopsy fa ils to yield adiag nosis, then consider a n open surgical proced ure . Bronchoscopy may behelpful if there is another confirmed pulmonary lesion or hemoptySiS, but the yieldis qu ite low for an undiagnosed pleural effusion with an otherwise normal x-ray. 1 5 . A small n u m ber of exudative effusions elude d iag nosis even after openpleural biopsy. Experience shows that about two-thirds of these do not recur, andno d iagnosis is established . They are presumed to be a result of infection or otheri nfla m matory process that has resolved . The rema i n i ng one-third of cases a reeventually found to have a specific d iagnosis. Ma lignancy, usually lymphoma,is the most com mon cause . A few patients eventually a re diagnosed with colla­gen vascular diseases or other m iscella neous d iag noses . I n teresting ly, in thela rgest publi shed series, none of the patients with u nd iag nosed exudativepleural effusions who had surgical biopsy were ever found to have tuberculosis. 1 6 . Here is a longer list of the causes of pleura l effusions:U H , D O C I L L N E E D M Y T A P S TATU rinothoraxHypothyroidismo rugs (e.g., nitrofurantoin, amiodarone, procarbazine, dantrolene, methylsergide)Ovarian hyperstimulation syndromeCollagen vascular disease Pulmonary and Critical Care • 4 1
    • I nfection (pneumonia, parapneumonic effusion, emphysema, T B )Left ventricular failureLymphangioleiomyomatosisN ephrotic syndromeEsophageal ruptureE mbolism ( P E )Dial y sis (peritoneal)Malignancy (primary, metastatic, Meigs syndrome)Yellow nail syndromeTrauma (hemothorax)Ascites (hepatic or pancreatic)Post-surgicalSVC obstruction (or other great veins)Trapped lungAsbestos ( BA P E )T PN P N E U M OT H O R AXC H EST PAI NSCystic lung disease (e.g., cystic fibrosis, LA M , histiocytosis X, bullous emphysema)H ereditary connective tissue diseases (Marfans, Ehlers-Danlos, pseudoxanthoma elasticum)E ndometriosis (catamenial)S pontaneousTrauma42 • Pulmonary and Critical Care
    • -- Pneumonia, PCP A Ititude, A Iveolar microlithiasis Iatrogenic (thoracentesis, central line, ventilator, postoperati v e) Neoplasm (rare-osteogenic carcinoma metastases) Scleroderma, Sarcoidosis N otes 1 . Pri mary or "spontaneous" pneumothorax commonly occurs i n tall, thin i ndivid­ uals and is usua lly d ue to rupture of apica l blebs . Smokers a re at i ncreased risk. 2. Treatment of a large pneumothorax i n itially i nvolves aspiration , often fol­ lowed by chest tube re-expansion . Recurrent pneumothorax can be treated with sclerosing agents (tetracycline or bleomycin) or surgically. A small pneumothorax can be followed by serial chest x-rays, because it may resolve without medica­ tions or treatment. 3 . Tensian pneumothorax is life threatening and can lead to cardiac a rrest. It may be a compl ication of mechanical venti lation. It is treated emergently with a large-bore needle placed in the pleural space P U L M O N A RY H Y P E RTE N S I O N LV E D P Left-sided failure Vascular disease/obstruction Extrinsic compression D esatu ration/hypoxia Pulmonary parenchymal disease Pulmonary and Critical Care • 43
    • PA HTNSP ulmonary pare nchymal disease/primary pulmonary hypertensionA pnea/A noxiaH eart failureThromboembolismN euro m uscularlskeletal diseaseScleroderma/va sculitisN otes 1 . The differential diag nosis for pulmonary hypertension (PA HTNS) is a "plumb­i n g " problem. The h istory, physical examination , and chest x-roy guide you i ndeter m i n i n g where the " block" in the plumbing is located ( i . e . , aorta , aorticvalve, left ventricl e , m i tral valve, left atrium, large pul monary vei ns, pulmonaryvenules, pulmonary ca pi llaries, pul monary arterioles, pul monary arteries) . Alsoconsider pulmona ry valve disease, right ventricular dysfunction, tricuspid valvedisease, right atria l d isease, a nd subclavian vei n thrombosis.2. Left ventricular fa ilure is the most common couse of pulmonary hypertension . I nleft-sided fa ilure, t h e left ventricular end-d iastolic pressure (LVEDP) i s elevated . Thus,on i mporta nt first step is to assess left ventricular function to ru le-out a cardiaccouse of pulmonary hypertension . The physical exam ination may detect on S4 orpulmonary edema , suggesting left ventricular fa ilure . Physical findings ind icativeof pul monary hypertenSion of any couse i nclude jugulovenous distension, a rightventricular h eave, a loud P2, and a systolic pul monary murmur.3 . Ca uses of left-sided failure (post-pulmonary ca pillary) i nclude systolic anddiastol ic CHF, congeni tal heart disease, valvular heart disease, and atrial tumors .Vascular causes of pu l monary hypertenSion i nclude chronic thromboembol i , pri­mary pulmonary hypertenSion , intravenous drug a buse, collagen-vascular diseasessuch as scleroderma/CREST, schistosom iasis, diet/weight-loss pills, sickle cellanemia, and pulmonary hypertenSion associated with cirrhosis. Pulmonary venousd i sease is ra re and, a lthough vascular, it is a post-pulmonary capilla ry process that may look like C H F. Extrinsic processes causing pul monary hypertenSion i n­clude kyphoscoliosis, neuromuscular disease, a nd fibrosing med iasti n itis. Periodicoxygen desaturation caused by obstructive sleep a pnea or hypoventi lation syn­dromes eventually couse pulmonary hypertenSion . Chronic hypoxia of any cause leads to pulmonary vascu lar constriction a n d , u lti mately, hypertenSion . F i nal ly, pulmonary parenchymal diseases such as COPD and interstitial lung diseasedestroy the capillary bed, leading to pul monary hypertension .44 • Pulmonary and Critical Care
    • 4. An echocardiogram demonstrates both LV and RV function , valvular function,and an estimate of pulmonary a rtery pressures; it is a good i n itia l noni nvasivetest. Defin itive local ization of the "block" may require pul monary artery catheter­ization to measure the pul monary capillary wedge pressure ( PCWPl. a reflec­tion of left atrial pressure, and an ind icator of LVEDP. Pul mon()ry a ngiog ra phymay be necessary to rule out chronic pul mona ry embol i or other vascular ob­structions. The mnemonic below l ists the causes of pulmonary hypertension andi nd icates the helpful diag nostic i nformation provided by the PA catheter.I C H E C K PCWPS A N D LV E D PSI nterstitial lung diseaseChronic obstructive pulmonary diseaseHyperthyroidismEmboli (chronic pulmonary emboli, intravenous drug abuse)Collagen-vascular diseasesKyphoscoliosisPrimary pulmonary hypertension (including pulmonary capillary hemangiomatosis)Congenital heart diseaseWorms (e.g., schistosomiasis)Pulmonary veno-occlusive diseaseSleep apneaA trial diseaseNeuromuscular diseaseDiet pills (aminorex)Liver disease/cirrhosisVal v ular heart diseaseExtrinsic compression of pulmonary vasculature (e.g., fibrosing mediastinitis)Diastolic inhibition/equalization (tamponade, constrictive pericarditis)Primary cardiomyopathy (dilated, restrictive, infiltrative)Sickle cell anemia Pulmonary and Critical Care • 45
    • P U L M O N A R Y I N F I LT R AT EA PE H IT?AspirationPusEdemaHemorrhageI mmunologicTumorN otes 1 . A pulmonary i nfiltrate is a com mon med ical problem . Although the potentialetiologies are many, the composition of infiltrates is limited . A pulmonary i nfiltratemay be composed of: ( 1 ) aspirated food or oil, (2) pus ( infection ), ( 3 ) pulmonaryedema or vascular leak, (4) hemorrhage, (5) certa i n immunolog ic processesincluding collagen vascular diseases, eosi noph i l ic lung diseases, BOOP, andalveolar protei nosis, and (6) tumor i nfi ltration . As the m nemonic suggests, alwaysconsider pulmonary embolism in the differential diagnosis of a new i nfi ltrate,particularly when risk factors a re present or the cli nical picture is unclea r.2 . A patients specific presenting symptoms can indicate the nature of the infi ltrate.For exa mple, fever and productive coug h may i nd icate an infectious etiology.On the other hand, a patient with rales and a history of congestive heart fa iluremost likely has pul monary edema . Hemoptysis may indicate an underlying pul­monary hemorrhage syndrome, while the presence of certa i n systemic sym ptomsmay point toward an i m munologic cause of the lung disease. F i nally, risk of lungcancer or characteristic radiographs may lead to a consideration of neoplasm .Pulmonary neoplasms often block an a irway, leading to a post-obstructive pneu­mon ia, which may be recurrent ar fa i l to clear after appropriate thera py. Lesscommonly, neoplasms primarily i nvolve the a irspaces and cause an infiltrate (seebelow) Neoplasms can have the same effect by bleed ing i nto the a i rspaces.3 . Commun ity-acq u i red , bacterial pneumon ia (CAP) is the most common causeof a pulmonary i nfi ltrate. The typical presenting features a re fever, coug h withpurulent sputum , and a loba r i nfi ltrate. Multi-lobar disease is more serious andless common. With ti mely and effective antim icrobial therapy, clin ical and radio­graphic i mprovement a re evident. Of course, there are exceptions to these rulesdependi ng on host-specific factors (e . g . , the elderly) and the particular pathogen(e . g . , Legionella l , but they provide valuable g uidel i nes in assessing response.46 • Pulmonary and Critical Care
    • 4. A common cli nical problem is differentiating between CAP and other causesof ai r-space disease. When faced with a pulmonary i nfi ltrate, there are four pri­mary considerations: Cli nical presentation , Underlying d i seases/risks, Rad io­graphic a ppearance, and Expected response to thera py (CURE). The clin icalpresentation of CAP usua l ly includes acute onset of fever, cough, and purulentsputu m . The a bsence of these features ar the presence of less typical findings(e.g . , prolonged course, hemoptysis, lymphadenopathy, disproportionate hypox­emia) should prompt consideration of other entities. A particular patients under­lying diseases or risk factors (e . g . , AIDS, known mal ignancy, smoki ng/COPD,i mmobil ity/hypercoagulability, medications/drug use) pred ispose to speci ficpathogens or cond itions other than CAP. The radiographic pattern of the i nfil­trate may suggest a specific diagnosis (e. g . , volu me loss, peripheral pattern, re­cu rrence i n the sa me a rea) And, finally, has the patient had the expectedresponse to therapy, or has the i nfiltrate persisted or increased in size? An a lgorithm based on these principa l considerations beg i ns with empi rictherapy for CAP when the rad iograph and symptoms a re reasona bly sugges­tive. If the patient responds to treatment and radiographic clea ring occurs, thenno further investigation is needed. If atypiccil features a re present, progression orrecurrence occurs, or there is no i mprovement, then consider other etiologies.5. When a pulmonary infiltrate progresses or fa ils to resolve after specific ther­a pies, consider the causes of chronic pul monary infiltrates summarized by themnemonic ALVEOLAR LI ST: Alveolar cell carcinoma, Lym phoma, Vasculitis,Eosi noph i l ic pneumonia, Orga nizing pneu mon ia, li poid pneumon i a , Alveolarprotei nosis, Reflux/aspi ration, LIP/DIP (lymphocytic and desquamative i n tersti­ tial pneumonitis), Infection (e. g . , TB, fungi), Sarcoidosis, and Tracheobronchialobstruction. This m nemon ic refers to the fact that the ma iority of these entitiesshow an alveolar-fi lling pattern on chest x-rays A few other etiologies may rarely cause a chronic alveolar i nfi ltrate, including amyloidosis, alveolar m icro­ l ithiasis, and si lent m itral stenosis. 6 . The fol lowing mnemonic offers a more deta i led summary of the causes of pul monary infiltrates:CA N IT B E A PE?CHF (pulmonary edema)Aspiration (e.g., food, oil , G E R D )Neoplasm (airway obstruction, bronchoalveolar cell carcinoma, Iymphoproliferative disorders)I nfection (bacterial, fungal, viral, mycobacterial, protozoal, helminthic)T -cells/B-cells (LI P, sarcoidosis, hypersensitivity pneumonitis) Pulmonary and Critical Care . 4 7
    • BOOP (organizing pneumonia)Eosinophils (PIE syndromes)Alveolar hemorrhage (e.g., vasculitis, coagulopathy, focal processes)Protein (al v eolar proteinosis)Embolus (e.g., thromboemboli, tumor emboli, septic emboli) P U L M O N A RY N O D U L EA NODULEAgeN icotineO ld FilmsDoubling timeU nderlying diseasesLymph nodesExaminationsN otes1 . The find i ng of a solitary pulmonary nodule is cause for concern. The potentialetiologies are many, and same major causes a re summarized i n note number 1 1 .Even th is long l ist is not comprehensive, a nd so a more practical approach to thesolitary pulmonary nodule is outli ned by the m nemonic A NODULE.2. The most critical q uestions to answer a re whether or not the nodule repre­sents a malignancy and if su rgery is i nd icated . Severa l historical elements i n­crease the cha nce of a malignancy, and a stepwise approach also is outli nedby the m nemonic a bove.3 . A age g reater than 35 i ncreases the cha nce of malignancy. Therefore, a .J1more aggressive diag nostic strategy may be u ndertaken i n an older patient.4. N icotine addicts (smokers) have a g reatly i ncreased i ncidence of broncho­gen ic carcinoma . A smoking history mandates a more aggressive approach.4 8 • Pulmonary and Critical Care
    • 5 . One of the fi rst thi ngs to find out is whether or not old films a re available, todetermine if the nodule is a new find i n g . A lesion that was present on an oldfil m is much less likely to be malignant.6 . The doubling time of a nodule may indicate whether or not it is l i kely to bemalignant. Ma lignancies usually dou ble in size after 20 days but before 450days. Benign lesions may g reatly i ncrease i n size i n less than 20 days and oftenare due to i nfections. Also, a ny lesion that does not double i n 450 days is muchless likely to be malignant.7. Consider the patients underlying diseases. Is this patient a smoker with em­physema and at i ncreased risk for cancer2 Does the patient have a known ma­ligna ncy? Evidence of pneu monia a n d i n fecti o n ? Evidence of a collagenvascular disease or an i m munodeficiency syndrome? Ma ny h istorical featuresare ind icative of specific etiology for the nodule. 8 . Physical exam ination may reveal lymphadenopathy i ndicative of malignancyor i nfection . Also, if a lymph node is detected , th i s should be the fi rst site of biopsy. It will be easier to biopsy tha n the lung lesion and will esta bl ish stagi n g .9 . F i nally, diag nostic examinations should b e undertaken . T h e choice o f testsdepends, of course, on the patient and the a bove-mentioned risk factors, whichwill determine how aggressive the physician can be i n trying to identify whetheror not the lesion is malig nant. Exam i nations i nclude CT scans, fine needle aspi­ ration of the lesion , bronchoscopy with biopsy, thoracotomy with biopsy, or, i n some cases, mediasti noscopy. Recent evidence h a s shown that PET sca n n i n g may b e a ble t o differentiate mal ig nant from ben ign lesions. 1 0. The finding of multi ple nodules ind icates different types of disease. The cat­ egories of disease to be considered i nclude developmental a bnormalities, infec­ tious d i seases, i m m u nolog ic d i seases, m etastatic neoplasms, and tra u matic i n j u ry, as well as i d i opath ic causes . I n AIDS patients, m u ltiple nodu les may occur secondary to PCP, tuberculosis, cryptococosis, CMV, Kaposis sarcoma , lymphoma, and pyogenic organ isms (staph, strep) . 1 1 . Here is a partial list of causes of pulmonary nodules:LEAVE T H AT C H EST A LO N E P L EA S Elung cancerEmbolismAspirated foreign bodyVasculitisEchinococcusTumor metastasisHeart wormAmyloidomaTuberculosis Pulmollary and Critical Care • 49
    • Coccidioides and other fungal diseasesHamartomaEnlarged pulmonary arterySarcoidosisTeratomaArteriovenous mal f ormationLymphomaOrganizing pneumonia/BOOPNecrobiotic nodules (rheumatoid arthritis)Eosinophilic granulomaPseudotumorLocalized anthrosilicosisEnd ot h e l i a I tumor (hemangiopericytoma)A telectasis (round)SequestrationErythrocytes (hematoma) R E F R AC TO RY H Y P OT E N S I O NCRAS H I N GCardiovascularRespiratoryAddisons/AcidosisSepsis/toxicHypocalcemiaI naccurate readingNeurologicG I bleed/internal bleedingN otes1 . Although there o re many causes of hypotension , when refractory hypoten­sion is encountered, you must consider a very specific list of possible etiologies .50 • Pulmonary and Critical Care
    • Turn to this list when a patients blood pressure fa i ls to i ncrease despite use of i n­travenous fluids or pressor agents . Many of these causes of refractory hypoten­sion a re emergencies and require u rgent treatment.2 . A s i m ple system for remembering the causes of refractory hypotension issummarized by the m nemonic CRASH ING, or by the m nemonic TERMINAL­Toxic/drugs, E ndocri ne/electrolytes, Respi ratory, Myoca rd ial/vascular, Infec­tion/sepsis, Neurolog ic, Artifact, Losing blood .3 . Cardiovascular causes include right ventricular i nfarction , pul mona ry em­bol ism, cardiac ta m ponade, a rryth m i a , and massive leh ventricula r i nfarction .Respiratory causes ohen are seen in patients on the ventilator and i nclude ten­sion pneumothorax and auto-PEEP, which occurs when patients are over-venti­lated or have severe a i rway obstruction. E ndocrine causes i nclude Add isonsdisease, and systemic acidosis may cause hypotension. Sepsis/toxic causes i n­clude bacterial septic shock, toxic shock, a na phylaxis, a n d d ru g overdose .Hypocalcemia may cause hypotension si nce vascular tone and pressor agentsare ca lcium dependent. I naccurate blood pressure readings may result frompoor blood pressure cuff fit, peripheral vas.cular disease, and venous obstruction(e. g . , superior vena cava syndrome), leading to a false impression of refractoryhypotension . Neurologic causes i nclude CVA, spinal cord injury, and epiduralanesthesia. GI bleeding may be occult, or blood loss may occur i n the thorax,retroperitoneal area , or a bdomen .4. The following m nemonic lists specific causes o f refractory hypotension :ALAR M , B P THATS D R O P P I N GA rti f act (poor cuff fit, peripheral vascular disease, superior vena cava syndrome)Liver failureArrhythmiaRight ventricular infarctMassive left ventricular infarctB lood transfusionPulmonary embolismTamponadeHypocalcemiaAddisonsTension pneumothorax� epsis Pulmonary and Critical Care . 5 1
    • Drugs/toxins (anaphyl a xis, drug overdose, snake venom)Rewarming hypothermiaOccult blood l o ssPancreatitisP EEP/auto-PEEPI ntubation (usually transient)Neurogenic (spinal cord injury, epidural anesthesia, dysautonomia)Gastrointestinal bleeding SARCO I DO S I SH I LAR N O D E S *Hepatosplenomegal yI nterstitial fibrosis, pulmonaryLymphadenopathyA rth ra Ig ia/a rth ritisRenal·(calcium metabolism abnormalit i e s, nephrolithiasis)Neurologic involvement (unilateral facial paralysis, chronic meningitis, mass lesion)Ophthalmologic (uveitis, conjunctival granulomas, sicca syndrome)Diabetes insipidus/other pituitary deficiencyErythema nodosum/other skin lesionSali vary gland enlargement, bil a teral* Clinical characteristics52 • Pulmonary and Critical Care
    • - SARC O I D BLU ES * * S kin rash A rthropathy/arthralgias Respiratory Central nervous system O ptic (uveitis, iritis) I ncidental finding on chest x-ray Dysrhythmia/cardiac dysfunction Bone marrow/spleen Lofgrens syndrome (erythema nodosum, fever, malleolar, join pain, hilar adenopathy) Uveoparotid fever (e.g., Heerfordts syndrome) Ear, nose, and throat Syste m i c symptoms (fever, chills, myalgias, hypercalcemia) * * Possible presentations N otes 1 . Sarcoidosis is a m u ltisystem d i sease . Vi rtually any organ system may be i nvolved . • Pu lmonary i nterstitial i nvolvement (up to 1 00%) • Lymphadenopathy, hi lar/mediasti nal (75-90%) • Arthra lgia/arthritis ( 25-50%) • Bone ma rrow ( 1 5-40%), but rarely symptomatic beyond m i ld anem i a , neutropenia, a n d eosi noph ilia • Hepatomegaly/liver enzyme elevation ( 20-30%) • Ophthal molog iC (25%): uveitis (75-95% of eye cases) • Erythema nodosum (25%), skin lesions • Upper respi ratory tract (up to 20%) • Sal ivary gland, parotid enlargement, bi lateral ( 1 0%) • Splenomegaly (5- 1 0%) • Neurolog ic i nvolvement (5%): u n i lateral facial paralysis (most common ) , papi lledema , hearing a bnormal, hypotha lam ic/pitu itary lesion , chronic meningitiS , mass lesion , seizure • Cardiac disease (5%) arrhyth m ias, heart block , pericorditis, CHF • Renal ca bum meta bolism a bnormal , nephrolithiasIs (rare , < 5%) • Diobetes i nsipidus or other pituitary deficiency Pulmonarv and Cntical Care • 53
    • 2 . Pul mona ry, ocular, lym ph node, and ski n cha nges a re the m ost com mon,clinically important features.3 . Many cases are found inCidental ly on chest x-ray. In fact, this is one of onlya few diseases in which a patient may have a ma rkedly a bnormal chest x-ray,but a ppear q u ite healthy. .4 . The disease pathogenesis may be related to exaggerated helper T-cell activity.5 . Hyperca lcemia is d ue to an i ncrease in 1 , 2 5-hydroxylase activity i n theg ranulomas. It often responds to steroid thera py.6 . Certa in factors are associated with progressive d isease i n sarcoidosis, thepresence of which may be reason for more agg ressive i n itial thera py. Thesefactors i nclude c h ronic uveitis, chronic bone d isease, neph roca lci nosis, skinplaq ues, lupus pern io, and pulmonary i nfiltrates without nodu les ( "type 3 " pul­monary sarcoidosis) .54 • Pulmonary and Critical Care
    • -- IDI H EM ATO L O G Y General Considerati ons The d i fferential diagnosis for a hematolog ic disorder can be developed using the MEDICINE DOC categories: Metabolic (e.g . , a myloidosis, B 1 2 and folate deficiencies) E ndocrine (e.g . , para neoplastic synd romes, adrenal i nsufficiency, hypo- thyroidism) Drugs/med icines (e. g . , anti biotics, alcohol, chemotherapy toxicity) Infection (e.g . , HIV-related, TB, systemic i nfections) Conge n i ta l (e . g . , Fanco n i s, c h ronic granu lomatous d i sease, prote i n C deficiency) Immunologic ( e . g . , hemolytic anemia, ITP, autoimmune neutropenia) Neoplastic (e.g . , leukemia, lymphoma, metastatic disease) Exotic diseases (e. g . , sarcoid, porphyria, Wegeners) Degenerative (?myelodysplasia; also premalignantl Occupational/environmental (e. g . , radiation, hydrocarbons, heavy metal poisoning) Ca rd iovascular (e . g . , i ntracard iac shunt, hypercoagula ble states causing DVT/PE) Problems considered in the hematology section primari ly i nvolve the bone marrow and ohen a re made manifest by a decrease or i ncrease i n one of the primary blood cell types: RBCs, WBCs, and platelets. Also i ncluded are a bnor­ mal ities of the spleen and disorders of coagulation . Hematology • 55 ,
    • C l i n i ca l Sym ptoms and S i g ns AN E M IAM CVS pro blemM arrow ption/deCons um increasestruct ion (hemodilution)VolumeStool/m e nstrual / occult lossesN otes1 . Anem i a is defi ned as a d rop in the hemoglobi n conce ntration . The fou rbasic mech anisms a re l isted a bove. Exa m i nation o f the peri pheral smear andred cell indi ces ( i . e , mean cell volume [MCV] , RBC distribution width) is the firststep in eval uation of a nemia . The MCV is the most helpful vrde to guide the & �work-up . The m nemonic "MCVS" helps to na rrow down the ffer ntial by clas­sifyi ng an a nemia as microcytic, normocytic, or macrocytic .2 . Marrow problems are characterized by a decrease i n production of RBCs.There may be a defiCiency in com ponents needed for normal RBC synthesis; the ma rrow may be i nvaded and replaced by an i nfiltrative process such as a ma­ lignancy ( " myelophthisic process"); or there may be primary marrow dysfunction (" myelodysplasia" ) . Marrow problems may be m icrocytic ( i . e . , processes that per­ turb hemogl obin production, such as i ron deficiency), narmocytic ( i . e . , myelo­ dysplasia), or macrocytic (i . e . , processes that i n terfere with R BC maturation , such as B 1 2 deficiency). 3 . Consum ption/destruction of eryth rocytes occurs in patients with a utoi m­ m u n e or neoplastic d i seases (hemolytic anem i a ) , m ec h a n i ca l heart valves, severe systemic ill nesses such as sepsis (DIC), or thrombotic thrombocytopenic purpura (TI P) RBCs are destroyed either by antibodies (autoi m mune disorders) or a n i ntravascular cause ( mecha n ical heart valve or blood vessel process) . I ntravascul ar i n j u ry i s called " microangiopathic, " and the periphera l smear fea­ tures damaged RBCs called "schistocytes . " Consum ptive/destructive processes are accompan ied by increased bone marrow activity and more reticulocytes i n t h e peripheral smear. S i nce the reticulocyte is a you n g , la rge RBC , there is a n 56 • Hema tology
    • i ncrease i n the Mev. Thus these processes usually are macrocytic, u nless thereis concomitant marrow fa ilure l i . e . , iron deficiency from chronic hemolysis).4. Volume increase causes hemod i lution and a decrease in hemoglobi n con­centration . This situation is encountered when dehydrated patients receive i ntra­venous flu ids. Also, in acute blood loss, i ntravenous fluids may make the bloodloss man ifest si nce the i n itial hemog lobin may be norma l . The MeV is u naf­fected by volume increase and is usua lly normocytic.5. Stool/menstrual/occult blood losses frequently are accompan ied by irondeficiency and a re com mon causes of m icrocytic a nem i a . Young women areoften a nemic because of monthly menstrual blood loss. The other common causeof blood loss is occult GI bleed i n g lead i n g to hemoccult positive stools. Lesscommonly, occult blood loss occurs from an i nternal source, such as a retroperi­toneal bleed . Retroperitoneal bleeding may occur after an i nvasive procedure oras a compl ication of a nticoagulation. In add ition to a drop in the hemoglobin ,the BUN i ncreases from a bsorbed heme metabolites.6 . The m nemonic below d ivides the anem ias into categories accord ing to the .MeV: m icrocytic, normocytic, or macrocytic.ITS A N E M IAS B RA N D MicrocyticIron deficiencyThalassemiaS ideroblastic anemia Usually NormocyticAnemia of chronic diseaseNephrogenic anemia (uremia)E ndocrine disordersMyelophthisis (marrow infiltration)I V fluidsA plastic anemiaS ickle cell anemia Usually MacrocyticB 1 2 deficiencyReticulocytosis/hemolysisAlcohol/cirrhosisN utritional deficiency (folate)D rugs (D NA synthesis inhibitors, D ihydrofol a te reductase inhibitors) Hematology • 57
    • -- exfol iative ski n diseases, hemod ialysis), and malabsorption. Drugs that i n­ h i bit dihydrolate reductase (e. g . , methotrexate, triamterene) or DNA metab­ olism (e . g . , 5-FU, hydroxyu rea , azath iopri ne, AZT, acyclovir) a lso cause a macrocytic anem i a . 1 0. The work-up o f anemia i ncludes ruli ng out occult blood loss (usually stool or menstrua l!, exa m i nation of the peripheral smear, checking for deficiencies (iron, folate, or B 1 2! , a reticulocyte count to assess marrow activity, a hemolysis work­ up (bilirubin, LDH , ha ptoglobin, serum free hemoglobi n ! , and possibly a bone marrow biopsy. 1 1 . The reticu locyte count is a n i nd ication of the ma rrows capaci ty to make RBCs. Here is a slightly different mnemon ic for anemia [still based on MCV) that emphasizes the importance of the reticulocyte count: ITS A R ETICS D E F ECT Microc ytic I ron deficiency Thalassemia S ideroblastic anemia Usually Normocytic Aplastic anemia Renal failure Endocrine disorders Tumor/myelophthisis Illness/I nflammation (chronic disease) Cirrhosis (may cause macrocytosis or spur cell anemia) Sickle cell anemia Usually Ma crocytic D rugs (D NA synthesis inhibitors, D ihydrofolate reductase inhibitors) EtOH Fol a te Erythroleukemia (Di Guglielmos ) Cobalamin deficiency ( 8 1 2 ) TTP/hemol y sis Hematology • 59
    • 7. Microcyti c anemi as are due to a deficiency of one of the three ma jor con­stitue nts of hemoglobin : iron, globi n, and porphyrin . Hemoglobi n compri s s. 90% �of the protein in the RBC , so microcytic cells are small and pale. Iron deflc le �cyis seen in states of chronic- blood loss (stool , menstrual, occult) . RBC destruction( he m olysis) , or nutritiona l deficiency (vegetari an d iet) . The thalassemi� s are ad iver se group of d iseases re sulti ng i n defecti ve globi n cha i n prod uction . Theside robla stic a nemi as are characterized by " ringed sideroblasts" in the marrowand abnormal porphyrin syn theSi s . They may be hered itary ( rare, X-linked) . ac- �quire d (alcohol, isoniazi , lead). or idi opathic ( premali gnant) . . . ase states . The a nem i a of chron� c 8 : Normocytic anem i a IS seen in many d ise d i sea se is seen whenever th ere i s long-standi ng i nflamma tion or syste m i c d i S­ ea se . It is characteri zed by low serum iron and total iron-bind ing capa c i ty, but an e l evated or normal serum ferriti n . N ephrog eni c a nem i a is caused by re­ d U ce d erythropoetin levels a n d can b e ameliorated by erythro poeti n repla ce­ m e n t therapy. E ndocri ne di sorde rs ohen feature a normocytiC anemia because � an y hormones affect R BC proliferati on , inclu ng thyroxine, glucocorticoids, e stOsterone, a nd growth . � or mo di ne. Less commonly, hypot hyroidism .causes m a c ro cytosis . Myelophth i s I s i s m arrow i nfi ltration by neoplasm , i nfect i on , or m eta bolic isease ( neoplas m s can d ca use anemia by a variety of mechan isms, I n c l u di ng myelop hthisis, hem olyti C ane mia, occult blood loss, nutr itional defi­ C i e n cy, or the effects of che �atherapy)·. Myelophthisic processes cause a nor­ m Ocyti c anem ia, and the peri pheral smear may show immature eryth rOi d forms a n ? , o ccasion ally, ma rked n eutrophi l i a ( "leu kemoid reaction " ) . I ntravenous l f U i d s cause a d ilutional decrea se i n hemoglobin conce ntrat ion and may u n ma sk nemia after acute blood a loss . Apl a st i c a nem ia may be a primary � a r r o w failure or secondary to d rug tox icity. S kl e ce ll a nemi a , a hemoglo- ic I n o Pathy, features abnormally shaped cells, but the MCV i s usually normal . �. MacrocytiC anemi as are usually a result of an i m pai rment of DNA repl ica­ hon . Often the LDH level is very high due to accelerated turnover in the marrow or P �ri pherally. B 1 2 ( cobala m i n ) deficiency can occur in several settings, i �­ u d l n g gastroi ntestina l disea se, c �I h ron i C nitrou s ox ide use , and, rarely, nutn­ tl o n a l deficiency. Both B 1 2 and folate are important cofactors in DNA syntheSi S , a nd a deficiency in either r�sults i n large, abnormal R BCs . Macrocytosi S also occ u rs w ith R BC destrud on le .g . , h emolytic anemia, TIP) because of compen­ sato ry reticulocytosis (see above) . A l cohol depresses bone m a rrow R B C production, causi ng anem ia , often m ac r c O ytic . Alcoholics may ha ve pri ma ry macrocytosis (usua lly modest) o.r sec­ on d a r y macrocytosis from folate and /or B 1 2 defi Ciency. Anemia in cirrhoti C pa­ e nts lI may be mic rocytic, norm ocytic, or macrocytic beca use of thei r myriad p rob l e ms including blood loss, nutriti onal deficiency, and the effects of chron ic d l seo se . L ess commo nly, c i rr h oti cs have a hem ol ytic anem ia ca l led s pur cell �: m l a t hat is caused by the a bnorm al li poprotein balance present in advanced r d l s ase The d a gn s l s s IT de l � ,� � when a ci rrhotic patient has eVi d ence of he mo lys� l s w i th cha rac�er lSt l c spur cells i n the periphe ral smear. . N u t r i tional defic i ency of folate i s seen i n starvation , cond itions w i th I n­ cre a Se d requ irements ( pregna ncy, ma l i g n a n cy, ch ron ic hemolys i s , chron ic 58 . Hematology
    • B L E E D I N G D I AT H E S E SA PTTA natomic abnormality (e.g., AVM , peptic ulcer)Plasma protein abnormalityT hrombocytopenia/qualitative platelet abnormalityTraumaN otes 1 . A bleed ing problem is most commonly related to an anatomic abnormality.Congenital a bnormalities such as an arteriovenous malformation or acquired de­fects such as peptic ulcer disease a re com mon . Plasma protein abnorma litiesare less common and may be made manifest with unexpected hemorrhage asso­ciated with a m inor surgical procedu re . Thrombocytopenia has many causesand is relatively common, but qualitative platelet abnormalities a re rare. Finally,trauma is a common cause of hemorrhage and usually obvious, but excessivebleedi ng or bru ising aher minor trauma may i ndicate an occult bleedi ng diathesis.2. The APTI, PT, platelet count, and bleeding time a re the primary laboratorystudies obtained when i nvestigating a possible plasma protein abnormality or quali­tative platelet defect. Other tests i ncluding thrombin time, fibrinogen assay, clot solu­bility and lysis, and factor assays may be helpful in identifying specific deficiencies. Pri mary Hemostatic ( Platel et) D i so rd e rs Platelet adhesion defects: Von Willebrands disease Bernard-Soulier syndrome (absence, dysfunction of Gp l b/IX) Platelet aggregation defects Glanzmanns thrombasthenia (absence, dysfunction of Gp l l b/llla) Platelet release defects • Decreased cyclooxygenase • Granule storage pool defects activity Congenital Drugs-aspirin, nonsteroidal Acquired anti-inflammatory • Uremia agents • Platelet coating (e.g . , penicillin Congenital or para proteins) Platelet coagulant defect Scotts syndromeGp = glycoprotein.60 • Hematology
    • Relatio n s h i p Between Secondary Hemostatic Disorders and Coagu lation Test Abnormal ities Prolonged partial thromboplastin time (PTI) No clinical bleed ing - factors XII, HMWK, PK Mild or rare bleeding - factor XI Frequent, severe bleeding- factors VIII and IX Prolonged prothrombin time (PT) Factor VII deficiency Vitamin K deficiency -early Warfarin anticoagulant ingestion Prolonged PTI a nd PT Factor II, V, or X deficiency Vitamin K deficiency- late Warfarin anticoagulant ingestion Prolonged thrombin time (TI) Mild or rare bleed ing- afibrinogenemia Frequent, severe bleeding -dysfibrinogenemia Heparin-like inhibitors or heparin adm i nistration Prolonged PT and/or PTI not corrected with normal plasma Specific or nonspecific inhibitor syndromes Clot solubility in 5 M urea Factor XIII deficiency Inhibitors or defective cross-linking Rapid clot lysis Alpho2 plasmin inhibitorHMWK = high-molecular-weight kininogen; PK = prekallikrein .Both tables fram Handin R I : Bleeding and thrombosi s . I n Isselbacher KJ , et a l (eds) : HarrisonsPrinciples of Internal Medicine, 1 3th ed . New York, McGraw-Hi l l , Inc . , 1994 , pp 3 17-3 2 2 ;with permission. S P L E N O M E G A LYBA N T I SB lood flow problemAnemia/erythrocyte problemNeoplasm/infiltrative diseaseThyrotoxicosisI nfectionSarcoid/Systemic lupus erythematosus Hematology . 6 1
    • ,.. N otes 1 . Bantis syndrome is the eponym used to describe congestive splenomegaly with hypersplen ism . Using " BANTI S " as your g u ide, the ca uses of spleno· megaly can be classified in six categories . Blood flow problems cause spleno· megaly by increased splenic vei n pressures and consequent congestion . Splenic vei n thrombosis (often secondary to pancreatitis), portal vei n thrombosis or ex· tri nsic compression, ci rrhosis, hepatic vein thrombosis (Budd-C h i a ri synd rome), and CHF all cause congestive splenomegaly Anemias secondary to erythro­ cyte abnormalities (e . g . , thalassemias, sickle cell d isease, hereditary spherocy­ tosis) cause splenomegaly because there is hyperplasia of the reticuloendothelial system associated with the destruction of the a bnormal RBCs . These diseases also may cause splenic i nfarction (i e , sickle cell). Neoplasms and infiltrative diseases d i rectly involve the spleen and lead to its enlargement. I n myeloproliferative syndromes and myeloph thisic processes, because of marrow hypofu nction, there may be compensatory extra medu l la ry h e matopoiesis causing splenomega ly. Thyrotoxicosi s is associated with splenomega ly beca use of thyroid hormone-ind uced lym phoid hyperplasia . Numerous i n fections, usually chronic, may ca use splenomega ly. Disorders of i m m u ne reg u lation such as sarcoidosis and SLE may feature splen omega ly. Other examples i nclude rheumatoid arthritis ( Feltys syndrome), serum sickness, and immune hemolytic anemias. 2. The deg ree of splenomegaly va ries with the d isease entity. Massive splenomegaly occurs in chron ic myelocytic leukemia, myelofibrosis with myeloid meta plasia, ha i ry cell leuke m i a , Gauchers and N iema n n·Pick diseases , sa r· coidosis, thalassemia major, chronic malaria, congenital syphilis, leishmaniasis, and some cases of portal vein obstruction. These are chronic d iseases in which the spleen slowly enlarges. Rupture of the spleen may be seen in acute infec­ tious processes such as EBV mononucleosis, malaria , and typhoid fever. 3 . Here is a more com prehensive listi ng of the causes of splenomegaly: HIS BIG SPLENIC MASS Hepatic vein obstruction (Budd-Chiari) Infection S plenic vein thrombosis (e.g., pancreatitis) Berylliosis Infiltrative diseases (e.g., Gauchers , amyloid, eosinophilic granulomatosis) Graves diseas.e/hyperthyroidism 62 • Hematology
    • S LE/collagen vascular diseasesPortal vein obstructionLiver disease (cirrhosis)E rythrocyte abnormality (e.g., spherocytosis, sickle cell, thalassemia)Neoplasm (lymphoma, myeloproliferative disease, metastatic)I ron deficiencyC HF (congestive splenomegal y )Myeloproliferative diseaseA utoimmune-hemolytic anemiaSarcoidosisSerum sickness/drug reaction4 . Always consider an occult, i nfectious etiology for splenomegaly si nce thesediseases a re likely to respond to appropriate thera py. There a re numerous infec­tions associated with splenomegaly, many of which a re I �sted in Chapter IV (see" I nfections Causing Splenomegaly" ) . C linica l Conditions or Diagnoses EOSI NOPH I LIAALLERG I CAddisons (adrenal insufficiency)Lymphoma/malignancyL-tryptophanEczema/skin diseasesRespiratory diseases (asthma, allergic bronchopulmonary aspergillosis, P I E syndromes)GastroenteritisI nfections (helminths, coccidioides mycosis)Collagen vascular diseases Hematology • 63
    • N otes 1 . Eosi noph ilia is defi ned as > 500 eosinophils/m icroliter of blood . E osino­philia has d iverse disease associations, but "ALLERGIC" reactions are probablythe most com mon . Allergic reactions to drugs, pol lens, micro-organisms, andother antigens can sti m ulate eosi noph ilia.2 . Addisons disease frequently features a moderate eosinophi lia that resolveswith admin istration of corticosteroids . Lymphoma is the malig nancy most com·monly associated with eosi noph i l i a , although associations with m a ny sol idtumors have been described . Tumor-associated eosinoph ilia is probably a resultof i n terleu kin-5 secretion a n d often ind icates a widely d isse m i nated tu mor.Eosinophilic leukem ia is a rare hematolog ic neoplasm with dra matically h i g heosinophil counts. L-tryptophan preparations from a single source were i m pli­cated in the eosinoph il ia-mya lgia syndrome, a potentia lly fatal , m u ltisystem dis­ease. Eczema a nd several other skin diseases ( e . g . , pem ph igus , mycosisfungoides) may be associated with eosi noph ilia . Several respiratory diseases feature eosi noph ilia, i ncluding asthma and thePIE ( pu l monary infiltrates with eosi noph ilia) syndromes . The PIE syndromes i n­clude acute eosinoph i l ic pneumonia, chronic eosi noph ilic pneumon ia, Churg­Strauss vasculitis, parasitic infestation ( i . e . , "tropica l" pneumonia), and al lerg icbronchopulmonary asperg illosis (ABPA) The hypereosinophilic syndrome, a m ul­tisystem disease, may cause eosi noph i l ic i nfiltration of any organ including thelungs. Drugs also can cause eosi noph ilia with pulmonary i nfiltration . Eosinoph i l ic gastroenteritis is cha racterized by eosinophilic infiltration ofany portion of the gastrOintesti nal tract, peripheral eosi noph i l ia (75% of cases),and inflam matory d ia rrhea . I n fections with hel m i nths typically ca use eos i no­p h i l ia , and cocc idioides mycosis is u n i q ue a mong fungal i nfections in itspropensity to elicit eosinophilia . Collagen vascular diseases such as rheuma­toid arthritis, eosinoph ilic fasci itis, allerg ic angi itis, sarcoidosis, and Wegenersgranulomatosis also a re associated with eosi noph ilia.3. The eponym Loefflers has been a ppl ied to PIE syndromes, the id iopathic hy­pereosinoph i lic syndrome, and to eosinophilic endocard itis . Loeffler originallydescri bed tra nsient pulmonary i nfiltrates with eosinop h i l i a , which m ay havebeen related to ascariasis i nfestation . Although it has no specific definition, the name is sti l l u sed in cases of i d iopath ic, ben i g n pul monary i nfi ltrates witheosinophilia.4. The cytokine IL-5 is an i m portant sti m ulator of eosinoph ils and is probably i n­tegral in many or a l l causes of eosinoph i l i a . The folloWi ng mnemonic, empha­sizing the role of IL-5 , lists the causes of eosi noph ilia:64 • Hematology
    • P LASMA I L- F I V E RAG EParasitesL-tryptophanAddisonsSarcoidosisMalignancy (e.g., Hodgkins, CML, gastric, ovarian, lung, pancreatic cancers)A Ilergy/A topy (e.g., drugs, serum sickness, hay fever)Idiopathic hypereosinophilic syndromeLung diseases/LoefflersFungal (A B PA, coccidioides mycosis)I gE hypersecretion (Jobs syndrome)Vasculitis/collagen vascular diseaseEczema/skin diseasesRecovery from bone marrow transplantAngiogram/Atheromatous emboli ("cholesterol emboli")GastroenteritisE ndomyocardial E RYT H R O C YTO S I SH I RBCSH ypoxia/hypoventilationI nappropriate erythropoietinRelative polycythemia (stress, dehydration)Bone marrow disorderCarboxyhemoglobin/congenital hemoglobinopathies .Steroids/androgens Hematology • 65
    • N otes1 . Eryth rocytosis or polycythemia ind icates an i ncrease i n n u m ber of erythro­cytes i n a sample of blood, which may or may not be a reflection of total bodyred cells. It is i m portant to disti ngu ish between absolute erythrocytosis, a true i n­crease in total body red cell mass, and relative erythrocytosis, which occurs withdehydration (increase in RBC concentration ) and stress .2 . The basic mechanisms of erythrocytosis a re summarized by "HI RBCS . " H Y P E R C OAG U LA B L E S TAT E SPT I N R SP lateletsTrauma1 m m obo I ization/stasisNeoplasmRBCsSerum clotting factorsN otes 1 . Nu merous d isorders may predispose patients to thrombosis. Frequently, thehistory and physical examination reveal a likely etiology. Factors predisposing tothrombosis include obesity, varicose veins, trauma, general anesthesia, i mmobi­lization, maligna ncy, CHF, oral contraceptives, infection , preg nancy, neph roticsyndrome, and blood protein defects.2 . -Leiden factor 5, a mutation in which factor 5 is resistant to activated protein C,is the most common i n herited hypercoagulable condition known. Homozygousind ividuals are at high risk for recurrent thromboembolic events. The risk for het­erozygotes is less clear.66 • Hema tology
    • 3 . Protei n deficiencies may be difficult to identify. Current tests only identi fy 1 0-20% of the cases of familial thrombosis. Serum levels of proteins C and Swill be affected by large thrombi and warfarin a nticoagulation . Deficienciesmay be congenital or acquired . Antithrombin (ATI-1 II , protein C, and protein Sare the most common congenital conditions. The most common acquired defectsare AT-III and antiphospholipid antibodies.4. The "lupus anticoagulant" is an anti phospholipid antibody that prolongs thePTI by interfering with phosphol ipid in the laboratory assay. It does not causeclinical bleedi ng, but rather predisposes to thrombosis and mid-trimester abortion.5 . Urinary AT-I I I loss proba bly causes hypercoagulabi lily in patients with thenephrotic syndrome. These patients are pred isposed to renal vei n thrombosisand pulmonary embolism.6. High levels of homocystine predispose patients to arterial as well as venousthrombosis. Homocysti ne also may be an important factor in the development ofatherosclerosis.7. An important drug-related cause of hypercoagulabil ily is hepari n-associatedthrombocytopenia. The features are arterial thrombosis with falling platelet counts.Even low doses of subcutaneous heparin can cause this syndrome. A heparin-ag­gregation study is avai lable for laboratory confirmation in suspected cases .8 . Here is a more comprehensive list of hypercoagulable states:D VT , P E A N D C L O T SD rugs (e.g., tamoxifen, heparin)Venous catheter (central)Trauma (endothelial in j ury)Prosthetic valvesErythrocytosis (polycythemia)A nticardiolipin/A ntiphospholipid antibodiesNephrotic syndrome/N eoplasmDysfunctional platelets/DysfibrogenemiaCHF/Collagen vascular disease (e.g., 8eh<;ets , S L E )Leiden factor V/Low protein C and So bstetrics/O ral contracepti v esTTP/Th ro m boa ng i itis obliteransSmoking/StasisAlso: hyperviscosity (Waldenstrom 5), homocystinuria, AT-III, a/pha- l antiplas­min, heparin cofactor II, plasminogen, plasminogen activator, and factor XIIdeficiencies. Hematology • 67
    • LY M P H O P E N I AN OT A T C E L LNormal variant/no diseaseOccult carcinomaT B/infectionsA I DSThoracic duct drainage/chylothoraxCytotoxic drugs/chemotherapyEating disorder/malnutritionLymphomaLupus/collagen vascular diseaseN otes1 . Absolute lymphopenia is defined as < 1 000 Iymphocytes/ m l . Relative lym­phopenia is present when < 1 5% of leukocytes are lym phocytes. Absolute lym­phopenia is most often secondary to steroid therapy or cytotoxic drugs, but theliterature suggests n umerous d isease associations. I n truth , any severe systemicill ness may feature lymphopen ia .2 . Although the disease associations a re myriad, the finding of lymphopenia i simportant because it is relatively rare. I n one, pre-AIDS era study o f patients at amajor referral center, the i ncidence of either a bsolute or relative lym phopen iawas only 2 . 4%, and it was significantly associated with malig nancy. Given theincreased severity of i llness i n this referral group of patients, it is probable thatthe incidence of lymphopenia in the general population is much less.3. The consequences of lymphopenia i nclude life-threatening i nfections, espe­cially those caused by vi ruses, fungi, and mycobacteria . Since lym phocytes areim portant in i m m u ne su rveillance and preventing neoplastic prol iferation, lym­phopenia also may predispose patients to malignancies. As mentioned above,there is an association between lymphopenia and maligna ncy, but cause andeffect are not certa i n .4 . Lym phopenia may b e a clue t o a n u nderlying systemic d i sease such a sAIDS,-Iupus, o r lymphoma . Consider the possibility of AIDS i n any patient withu nexplai ned lym phopen i a . In addition to the d i seases l isted below, lym pho­pen i a has been seen i n patients with COPD, d ru g al lergy, adva nced age,68 • Hematology
    • hyperparathyroidism, trigeminal neuralgia, myasthenia gravis (without thymec­tomy), periodic paralysis, a myotrophic lateral sclerosis, and hypothyroid ism.IM H E LPLESS WITHOUTT AND B CELLSI rradiationMalariaHeart failureE lectrocution/burnsLymphocyte antiglobulin therapyPancreatitisLupusExhaustionSteroidsStarvation (pyridoxine deficiency)Whipples diseaseI nfection/sepsisTBHereditary immunodeficienciesOccult carcinomaU remiaThymectomyThoracic duct drainageA I DSNormal variant/no diseaseD iabetesBone marrow failure (agranulocytosis)Chemotherapy/cytotoxic drugsExtracorporeal blood irradiationLymphomaLiver failureSarcoidosis Hematology • 69
    • M O N O C YTO S I SMONOMycobacteriaOther odd infectionsNeoplasm (metastatic)Other inflammatory conditionsN otes 1 . Monocytes are circulating cells with a half-life of 1 2-24 hours . They leavethe blood stream a nd enter tissues, differentiati ng i nto m acrophages ( " bigeaters" ) specific for the pa rticular organ (e . g . , alveolar macrophages, splenicmacrophages, l iver Ku pffer cells, bra i n m icrog l ial celis, dendritic cel ls). Theyhave diverse functions, such as phagocytosis, lymphocyte activation, a nd othercytokine-mediated activities. Many disorders affecting PMNs, i ncluding toxinsand infections, also affect monocytes . A significant i ncrease in monocytes, how­ever, should prompt consideration of certai n specific conditions .2 . In the presence of monocytosis, examine for malignancy, tuberculosis, and afew other odd i nfections.3. Here is a more specific differential for monocytosis, emphasizing the evolu­tion of a peripheral blood monocyte into a tissue-specific macrophage:I L L B E A MACROP HAG EI nflammatory bowel diseaseLeukemiaLeishmaniasis (ka)a azar)B rucellosisEndocarditisA rteritis (polyarteritis nodosa, temporal arteritis)70 • Hematology
    • Myeloproliferati ve disordersAcid-fast bacilli (T 8 , other mycobacteria)CytomegalovirusRocky Mountain spotted feverOncologic/Occult malignancy (usually metastatic disease)Plasmodium infections (malaria)Hemol ytic anemiaAcquired neutrophil disorders (e.g., chronic granulomatous disease, Chediak-Higashi)G ranulomatous diseases (sarcoid, berylliosis)Evans syndrome N E UT RO P E N IAANCSA utoimmune/A ntibodiesNeoplasm/infiltrative/toxicCardiopulmonary bypass/hemodialysisSepsis/overwhelming infectionN otes 1 . The normal concentration of neutroph ils is approximately 3 650/ml ( range 1 8 30-7250). The a bsolute neutrophi l count (nANC) is determined by multi ply­ing the percent neutrophils by the tota l white blood cell count. When the ANCis less than 1 000, infectious complications increase sign ificantly, and the i nflam­matory process is essentia lly a bsent when the ANC is less than 200. Neutro­penia may resu lt from four basic mecha nisms: autoimmune or antibody-med iatedperipheral destruction; neoplastic, infiltrative, or toxic depression of the marrow;cardiopulmonary bypass and hemodialysis; or sepsis/overwhel m i ng infection.2 . Autoimmune processes may feature antineutrophil anti bodies and/or hy­persplenism, causing neutrope n i a . Examples include SLE , rheumatoid a rthritis,Feltys syndrome, ond Wegeners granu lomatosis. Drugs such as d i u retics, Hematology • 71
    • alpha-methyl dopa , a nd some phenothiazines also may act as ha ptens, promot­ing peripheral destruction of neutroph ils.3. Processes that i m pair ma rrow production of neutrophils i nclude neoplasticinvasion, infiltrative/infectious i nvolvement of the marrow, and the cytotoxiceffects of drugs. Neutropenia is common in patients treated with high doses ofchemotherapy. The duration and severity of neutropenia can be a meliorated byadministration of G-CSF.4. Cardiopulmonary bypass and hemodialysis cause peripheral pool ing anda tra nsient neutropenia . Sepsis/overwhelming infections a lso may cause atransient neutropenia, which may be an effect of endotoxin release. Be carefulnot to m i ss sepsis, especially in elderly patients, who may have a paucity ofother signs of infection .5 . Neutropenic patients a re predisposed to infections with bacteria and fungi(especiolly Candida a nd Aspergillus) . Some conditions occurring predominantlyin neutropenic patients i nclude skin lesions from fungal infection , ecthyma gan­g renosu m (often a result of Pseudomonas i nfection) . Sweets syndrome ( neu­trophi l ic dermatosis), typh litis ( i nflammation of the cecu m ) , peri rectal i nfections,and opportunistic pneumonias.6. Here is a more complete differential for neutropenia:M I N I MAL Wh ite B l ood C e l i SMedications/toxins (especially chemotherapy)Idiopa.t hic (benign cyclic neutropenia)N utritional ( 8 1 2 , folate)I nfection (e.g., sepsis, mononucleosis, typhoid)Myelophthisis/invasion of marrowA plastic anemiaLeukemiaWegenersBenign cyclic neutropeniaChediak-Higashi/Congenital neutropeniasSplenomegaly72 • Hematologv
    • N E UT R O P H I L IAPMNSPeripheral demarginationMarrow releaseNew synthesisSystemic disease/miscellaneousN otes1 . Neutrophilia, an increase in " PMNS" (polymorphonuclear neutroph ils!, re­su lts from four primary processes : peripheral dema rg ination of existi ng PMNs,ma rrow release of an ex isting pool of PMNs, newly synthesized PMNs, andsti mulation by miscella neous systemic diseases (probably by a combi nation ofrelated processes) .2 . Peripheral demargi nation occurs when neutroph ils outside the bonema rrow are released from their sites of adherence along blood vessels ( manya long vessels i n the spleen a nd lung) . Th is process can rapidly double thenumber of neutrophils seen on the peripheral smear. Demargination occurs withphysiologic stress, exercise, exogenous epinephrine administration, steroid ther­apy, and nonsteroidal anti-inflam matory agents. The deficiency of the leukocytead hesion protein CR3 causes neutroph ils to ad here poorly to endothelial cellsa nd margination is i n h i bited . Patients with this defect have prom i nent neu­trophilia and recu rrent infections .3 . Marrow release of a n existing pool of neutroph ils occurs with steroid ther­apy, acute infections, and inflam mation (e . g . , thermal iniury) .4 . New synthesis of PMNs occurs i n response to i n fections, necrosi s oftissue (e.g . , gangrene, pul mona ry or myocardial infarction, thermal i n i uryl, i n­flammatory states (e . g . , vascul itis, hypersensitivity reactions!, steroid thera py,a nd myeloproliferative d i sorders ( e . g . , polycythemia vera , AML, myeloidmetaplasia ) .5 . Va rious systemic disorders, includ ing d i a betic ketoacidosis, uremia fromac ute renal fa i l u re, metastatic cancers, acute hemorrhage, hemolYSiS, a ndeclampsia, can sti mulate neutrophilia . Toxic exposures such as poisoning a ndl ithium admin istration a lso may be assoc iated with neutroph i l i a . The mecha­n i s m of neutroph i l ia in these d isorders may be a combi nation of the a boveprocesses.6. Persistent neutroph i l i a of 3 0 ,000 to 5 0 , 000 cells/ml is cal led a leuke­moid reaction (to distinguish from leukemia) and may be the result of malignant Hematology • 73
    • i nvasion of bone marrow, extensive inflammation, or severe i nfection . The neu­trophils seen in the circulation are usually mature .7. Two more specific differentials for neutrophilia are given below:HI PMNSH emorrhageI nfectionPhysiologic (stress)Myeloproliferative disorderN ecrosis of tissueSteroidsNote: This mnemonic emphasizes the most common etiologies o f neutrophilia.MAD N E UTROP H I LSMyeloproliferative disorderAdhesion protein deficiency (leukocyte C R3 receptor)D iabetic ketoacidosisNecrosis of tissueEclampsiaU remia (acute renal failure)Toxin ingestionR heumatologic disorders/vasculitisOncologic (usually metastatic)P hysiologic (stress)H emorrhage/H emolysisI nfectionLithiumSteroidsNote: This mnemonic lists most o f the causes o f neutrophilia.74 • Hematologv
    • PA N C Y T O P E N I AAIDS?Aplastic marrowI nvaded marrowDysplastic marrowS plenomegalyN otes 1 . There a re fou r primary mechan isms of pancytope n i a : aplastic ma rrow( hypocel lular), i nvaded ma rrow ( neoplasm, storage d iseases), dysplasticmarrow (normo or hypercellular), and splenomega ly. As the mnemonic suggests,H IV infection should be considered in any patient with pancytopen ia .2 . Causes of apla stic anemia include congenita l d isorders (e . g . , Fa ncon i sa nemia), chemical and other toxic exposures (e. g . , benzene, alkylating agents,a rsen icals, rad iation), i m munolog ically mediated aplasia (e . g . , SLE), infections(e . g . , hepatitis, pa rvovi rus), other m iscellaneous associations (e. g . , pregnancy,transfusion-associated graft versus host d isease), a nd id iopath ic a plastica nem i a . Marrow i nvasion and replacement occurs with hematologic malignan­cies, metastatic cancers, storage cell d isorders, osteopetrosis, a nd myelofibro­sis. Dysplastic disorders feature a normal or hypercellular marrow a nd includeB 1 2 deficiency, folate defic iency, AIDS, and primary myelodysplasia .Splenomegaly a nd consequent hypersplen ism promote accelerated remova l ofcells from circulation, and marrow cellularity is usual ly normal .3 . In a pproaching pa ncytopenia, first rule out drugs, toxins, i nfections (e.g . ,AIDS), a nd nutritional deficiencies a s causes . Exa m i nation of the peri phera lsmear may provide clues to the d iag nosis, but bone ma rrow aspi ration andbiopsy are the defin itive tests.4 . The following mnemonic lists the primary causes of pancytopenia:LO P M N S A N D RBCSLeukemiaOsteopetrosis Hematology • 75
    • ,... Paroxysmal nocturnal hemoglobinuria Myelodysplastic syndrome Neoplastic invasion of bone marrow Sarcoidosis Aplastic anemic N utritional deficiency ( B 1 2 , folate) Drugs/toxins R heumatologic diseases B ig spleen Congenital disease (Falconis , Gauchers ) Sepsis/infections T H R O M B OT I C T H R O M B O CYTO P E N I C PU R PU RA R ET I C Renal dysfunction Elevated temperature Thrombocytopenia I ntravascular hemolysis Central nervous system N otes 1 . TIP is a disease of un known etiology, The diagnosis is based on the pentad of: ( 1 ) renal dysfunction, (2) elevated body temperature, ( 3 ) th rombocytopenia, (4) intravascular hemolysis (" microangiopathic"), a nd (5) central nervous system dysfunction ( i . e " altered mental status, seizures). 2 . TIP may be the result of endothel ial release of abnormal Von Willebrand factor multimers. These multi mers precipitate the formation of fibrin m icrothrombi 76 • Hematology
    • that occlude blood vessels and da mage R BCs and platelets . There is also evi­dence that an inhibition or deficiency of a critical Von Willebrand cleaving factoris responsible for the microthrombi . The result is a m icroangiopathic process withsevere thrombocytopenia and anemia. The primary end-organ damage is seenin renal and neurologic dysfunction. The peripheral smear is the key to making aprompt diag nosis and i n itiating treatment. The smear shows schistocytes, cellsda maged by the m icroang iopath ic process, a nd a ma rked reticu locytosis( " RETIC ) . The reticulocytosis is evidence that the marrow is functioning normallyin response to peripheral destruction of RBCs. The MCV (see Anem ia section) iselevated because of the increase i n these large, i mmature erythrocytes.3 . Coagula tion tests a re norma l in TIP, whereas i n DIC a bnormalities of PT,PTI, fi brinogen, fi brin split products, and W i mer are the rule.4. Treatment of TIP involves prompt plasma pheresis and plasma exchange.Intravenous immunoglobul i n , vincristi ne, and glucocorticoids may be beneficial,but controlled studies are lacki n g . Splenectomy may have a role in refractorycases. Platelet transfusions are not ind icated .5 . Hemolytic urem ic syndrome, a syndrome closely related to TIP, is seen pre­dominantly i n chi ldren and has more prom i nent renal i nvolvement. It may occu rafter gastroenteritis caused by E . coli 0 1 57: H7 T H R O M B O CYTO P E N I AP LT SPeripheral destructionLab errorTrapping (hypersplenism)Synthesis problem (marrow failure)N otes 1 . Thrombocytopenia is a result of one of four problems: peripheral destruction,laboratory error, trapping i n the spleen , a nd synthetic problems. Peripheral de­struction of platelets occurs with ITP, DIC TIP, PTP, prosthetic valves, pregnancy­associated disorders, certa i n drugs, systemic i nfections, and collagen vasculard iseases. Laboratory error may occur with automated d ifferentials. Be certa i nto look at the peripheral smear to rule out platelet clumping, which will g ive a Hematology . 77
    • fa lsely low count. Trapping i n the spleen (seq uestration) reduces c i rculatingplatelets and is seen i n a ny of the processes that cause splenomega ly ( seeSplenomegaly section) . Synthesis problems are primary bone marrow produc­tion a bnorma l i ties that occu r with i nvasion of m a rrow, drugs (those ca usingmarrow suppression), and some i nfections. Synthesis problems a lso may featuredecreased numbers of other cells (see Pancytopenia section) .2 . Acute thrombocytopenia i s an emergency, and " ITPS" lists the most importantetiologies. A prompt d iagnosis is critica l, because bleed ing can be life-th reaten­ing, and the treatments differ.ITPSIdiopathic thrombocytopenic purpura ( ITP)Thrombotic thrombocytopenic purpura (TT P)Pregnancy/Post-transfusion purpura ( PTP)Sepsis/disseminated intravascular coagulation (Ole)3 . ITP or immune thrombocytopenia may occur as an isolated phenomenon orin association with maligna ncies, collagen vascular diseases, or administrationof certa i n drugs. Anti body-med iated destruction of platelets may req u i re i m­munosuppressive therapy. A careful search for a causative d rug is critical , assmall a mounts of the offending agent can trigger the reaction . Prolonged throm­bocytopenia occurs with d rugs that are cleared slowly from the body, such asgold and phenytoi n . Heparin causes a specific a nd potentially catastrophic syn­drome of th rom bocytopen i a and arterial thro m bosis ca l led hepari n-ind ucedthrombocytopenia. The hepari n-induced platelet a ntibody test is diagnostic. Allheparin, i ncluding IV flushes, must be d iscontinued .4. TIP a nd the closely related hemolytic u remic syndrome a re treated withplasma exchange (see TIP section).5. PTP a nd pregnancy-ossociated syndromes should be suspected in womenwith acute throm bocytopenia. PTP is a rare phenomenon that occurs 1 weekafter transfusion in i nd ividuals (almost a lways women) lacki ng certa i n plateletantigens (the most common is PlA 1 ) . Most patients have had a prior exposure toPlA 1 antigens during pregnancy or a prior transfusion . Intravenous immunoglob­ulin or steroids may facil itate recovery i n 4-5 days. The related pregnancy-as­sociated syndromes of eclampsia, acute fatty liver, and H E LLP ( hemolysis withelevated l iver enzymes and low platelets) a re life-threatening . Microangiopathicdestruction lowers platelets preci pitously, a nd ti mely delivery of the fetus is theonly cure.6. Ser:>si s/DIC is a syndrome of anemia, thrombocytopenia, and coagulopa­thy often occurring in association with a severe, system ic infection . It a lso occursin association with malignancies and infla � matory conditions such as pancreatitis.78 • Hematology
    • Patients have ra pidly fa l l i n g hemoglobins and platelet cou nts , with a n ele­vated partial throm boplastin time. B leed ing and ischemia from clotting maybe present. There is a bigh morta l ity rate, and i m provements occur with treat­ment of the u nderlying i l l ness . There may be some benefit i n trying to treatsevere bleed ing (platelet, R BC, a nd plasma transfusions) or ischemia ( hepa rin)i n certa i n patients, but such treatment is i nd ividualized . Treatment of acutepromyelocytic leukem ia may precipitate DIC, and prophylactic hepa rin is ofbenefit .7 . The approach to thrombocytopenia includes a complete history with a care­fu l search for possi ble causative drugs, infections, or infla m matory cond itions,and a physical exa m i nation focusing on the spleen and l i ver. The peripheralblood smear is examined for evidence of clumping, m icroang iopathic changes,or other a bnormal ities. If the cause is not certa i n , then a prompt bone marrowbiopsy should be performed . Patients with ITP, TIP, PTP, a nd other causes of pe­ri pheral destruction will have normal or increased numbers of megakaryocytes .A primary marrow disorder may show decreased megakaryocytes o r an infi ltra- .� �OC�.8 . Here is a more complete differential for thrombocytopenia:H ELP M E, ITS O l e !H emo) ytic uremic syndrome(TTPEclampsia/HEELP/acute fatty liverLiver disease/portal hypertensionProsthetic valveMalignancy/Marrow failureE rror (laboratory artifact)Idiopathic thrombocytopenic purpuraTransfusion (PTP)Storage diseases/hypersplenismD rugs (e.g., heparin, antibiotics)I nfections/sepsisCollagen vascular disease (especially lupus) Hematology . 79
    • T H R O M B O CYTO S I SP LAT E L ET C R I S I SPolycythemia veraLeukemiaAcute hemorrhageTumorsEssential thrombocytosisLymphomaEpine p hrineToxinsC rohns diseaseR heumatoid arthritisI nfectionSarcoidosisI ron deficiencySplenectomyN otes1 . Platelets increase in response to systemic processes ("acute phase reacta nt") .Mast cases of th rombocytosis a re a reflection of an i nflam matory cond ition .When the platelet count exceeds one m illion, suspect a primary myeloprolifera­tive disorder such as essential throm bocythem i a , polycythem i a vera , or leu­kemia. Bone marrow biopsy is indicated .2 . The four " I " s of throm bocytosis are i nfection, i nflam mation , i ron deficiency,a nd increased production.8 0 • Hematology
    • T R A N S F U S I O N R E ACT I O N SGOT A BAD U N ITG raft versus host diseaseOverload (iron, volume)Thrombocytopenia ( PTP)A IloimmunizationB lood pressure instability (anaphylactic)Acute hemolytic reactionDelayed hemolytic reactionU rticaria (allergic cutaneous)Neutrophilic (febrile)Infection (H I V, hepatitis, C M V, bacterial sepsis)Transfusion-associated lung injury (T R A L I )N otes 1 . Blood product transfusion is an i m portant and frequently life-saving therapy.Adverse reactions to transfusions a re com mon, however, a nd thus parsimonioususe of this i ntervention is needed . Transfusion reactions are broadly classified asi m m u ne and non i m m u ne . I m m u n e causes i nclude g raft versus host d i sease,post-transfusion throm bocytopen ia, a l loimmunization , blood pressure i nstabilityfrom anaphylaxis, acute a nd delayed hemolysis, urticaria, neutrophilic febrile re­actions, and TRAU , a neutrophil-induced lung i n j u ry. Nonimmune complica­tions of transfusion i nclude overload (either acute volume expansion or chron ici ron overload) and i nfections.2. Graft versus host disease (GVHD) is a rare complication of transfusion re­su lti ng from tra nsfusion of Viable, donor lymphocytes. Tra nsfusion-associatedGVH D usually occu rs when a patient receives blood from a closely relateddonor. The donors lymphocytes have common a ntigens a nd a re not recogn izedas foreign by the reC i pient. These lym phocytes, however, see the reci pient asforeign a nd proliferate, leading to fulmi nant multiorgan system fa ilure and death.3 . Overload states, either volume or i ron, a re common non i mmune complica­tions of tra nsfusion . In older patients a nd patients with card iac d i sease, thevolume of the transfusion may cause pulmonary edema . This com pl ication can Hematology . 8 1
    • be avoided by slow i nfusion or a d m i n istering a d i u reti c . I ron overload mayoccu r in patients requiring chronic transfusions. This potentia lly fatal com plica­tion can be prevented with chelation therapy.4. Thrombocytopenia is a rare consequence of transfusion . It is usually seen inwomen with a specific platelet antigen-type, who have had a prior pregnancy. Thetypical presentation is marked thrombocytopenia occurring several days after atransfusion . Patients spontaneously recover, but steroid therapy or IV immunoglob­ulin may be of benefit.5. Alloimmunization to blood cell a ntigens or HLA a ntigens is com mon andcomplicates subsequent transfusions and organ transplantation . ObViously, mini­mizing exposu re to blood products is desirable.6 . Blood pressure instab i lity and shock occur in patients with antibod ies toIgA. These individuals require IgA-deficient blood products from relatives or raredonor lists.7. Ac�te hemolytic reactions are rare and ohen a result of ABO incompatibilityor a few other antigens . The cause frequently is clerical error, and the result israpid intravascular hemolysis. Patients may have flush ing, chest and back pa in,nausea, d iarrhea, dark urine, fever, chi lls, and shock. Hemoglobinuria, renal fail­ure, DIC, and death may ensue. An important clue to a transfusion reaction is thatthe hemoglobin does not rise to the expected level aher the transfusion . Otherhelpful la boratory stud ies i nclude ha ptog lobin, u nconjugated bilirubin , serumand urine free hemog lobins, and a d i rect Coom bs test. The indirect Coombstest may not be positive si nce a g reat number of antibodies a re bound to RBCs .8 . Delayed hemolytic reactions are a result of extravascular hemolysis and havea more g radual onset. These reactions most ohen are caused by antibodies to theRh system, but others (e.g . , Kell, Duffy, Kidd) a re common . Malaise, jaundice, andfever occur 5- 1 0 days aher tra nsfusion , but more severe compl ications are rare.9. Urticaria from a cutaneous a l lerg ic reaction is a common and ben ign re­sponse to transfusion. It can usua l ly be ma naged by slowing the i nfusion andadmin istering antihista mi nes . 1 0 . Neutrophilic reactions usually cause fever and a re a result of immune de­struction of transfused leukocytes . These reactions a re usually mild and treatedwith antipyretics. 1 1 . Infections from transfusion may be caused by vi ruses, bacteria, or proto­zoa ns. The risk of i nfection is low, but sti ll present. Sterilization is possible forsome plasma components, but not for cellular products. Careful donor screeningand standard laboratory assays are the most important preventive measures. 1 2 . Transfusion-associated lung injury is a rare type of neutroph ilic reaction .An allerg ic pul monary edema results from lung sequestration of antibody-coatedneutrophils. Patients with this more severe reaction have a high titer of antibod­ies that react with donor leukocytes. With supportive care, most patients have agood recovery.82 • Hematology
    • II INF ECTIOUS DIS EAS E Clinical Sym ptoms and Signs F EV E R O F U N K N OW N ORIGINI GOT THE FEVER*Inflammatory bowel diseaseG ranulomatous disease (mycobacteria, fungus, "granulomatous" hepatitis)Other infections (multiple)Tumor (especially l y mphoma, renal cell carcinoma/hepatoma)Toxins/medications (" drug fever")Hypothalamic disease/strokeEndocarditisFactitiousEmboli (multiple pulmonary)VasculitisETOH-induced liver diseaseR heumatologic disease* differential diagnosis Infectious Disease • 83
    • N otes 1 . The classic fever of u n known ori g i n ( F UO) was defined as: fevers higherthan 3 8 . 3°C on several occasions, duration of illness > 3 weeks, a nd fa ilure toreach a diagnosis aMer 1 week of i nhospital i nvestigation. This has been modi­fied somewhat as many patients are not hospitalized, and special considerationis g iven to neutropenic, nosocomial, and H IV-associated F UOs.2 . Infections now cause a smaller a mount of FUOs because microbiology stud­ies have improved detectio n . TB; prolonged mononucleos is syndromes withEBV, CMV, and HIV; i n tra-abdom i nal a bscesses; osteomyelitis; infected pros­thetic devices; and endocard itis are considerations. Culture-negative endocardi­tis is ra re, a lthough prior treatment with anti biotics a nd fastidious org a n isms -("HACEK" Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans,Cardiobacterium, Eikenella corrodens, Kingella kingae) should be considered.3. Tumars a re less frequent causes due to improved imaging modalities.4. Factitious fevers are important considerations. Many have occurred i n youngwomen in the health professions.5 . In many classic FUOs, there has been an error in the initial work-up . It is im­perative to carefully review all previous diagnostic studies (i maging, pathologicspecimens, and microbiology) and not sim ply rely on reports. The patient shouldbe off a l l medications, if possi ble, a nd m u ltiple blood cultures (th ree to six)should be obta i ned a nd be kept for at least 2 weeks to ensure growth of fastidi­ous ( i . e . , HACEK) organisms. Other specialized culture techn iques may be indi­cated for fungi /atypical mycobacteria , or n utritional va r i a nt bacteri a . Theremainder of the work-up is dictated by the particular case. ESR, febrile agglu­tin i ns, and titers for various infectious causes oMen are obta i ned , but are proba­bly of low yield. liver and bone ma rrow biopsies are routine in FUO work-up,as are i maging studies (usually chest a nd abdom inal CTs). Periodic review a ndreassessment is critica l . AMer 6 months, a significant portion of FUOs may be u n­diagnosed (> 20%).84 • Infectious Disease
    • I N F E CTI O N S CAU S I N G S P L E N O M E G A LYT H E T R EATA B L E S P L E N I C M A S STularemiaH istoplasmosisE BV (infectious mononucleosis)Trypanosomiasis, AfricanRelapsing fever (borelliosis)E ndocarditisA IDSToxicariasisAcid-fast bacilli (T B and other mycobacteria)B rucellosisLeishmaniasis (kala-azar)E rlichiosisSalmonella (typhoid fever)PsittacosisLyme diseaseEchinococcal cystN ecrotizing lymphadenitis (Kikuchis disease)I nfectious hepatitis (viral)C MVMalariaAbscess (bacterial)SyphilisSchistosomiasisN oteAlways consider an occult, infectious etiology for splenomegaly si nce these dis­eases are likely to respond to appropriate therapy. listed above is a d ifferentialof the numerous i nfections associated with splenomega ly. Infectious Disease • 85
    • T E M P E R AT U R E P U L S E - D I S S O C I AT I O NBAD T E M PS , LO H RB rucellaAtypical pneumonia (mycoplasma, legionella)Dengue feverTularemiaE BVMycobacteriaPsittacosisSalmonellaLeptospirosiso rbivirus (Colorado tick fever)H epatitisRickettsial IllnessAlso: yellow fever, "factitious" feverN oteThe clinical finding of a low heart rate with a high temperature may i ndicate i n­fection with a n i ntracellular pathogen . Older patients with cardiac conductionsystem disease or on beta-blockers also may have a lower than-expected heartrate with fever.86 • Infectious Disease
    • Clinica l Conditions or Diagnoses AC U T E M E N I N G I T I SI N F E CTS A LOT*Iatrogenic/post-neurosurgicalNeisseria m eningitidisFungalEs cherichia coliCongenital defect/dermal tractTuberculousStrep tococcus pneumonia eAseptic meningitis (viral)Lis teria monocvtogenesOtitis/mastoiditis/sinusitisTraumatic bony defectAlso: subarachnoid hemorrhage* differential diagnosisN otesAcute meningitis is the abrupt onset of meni ngeal i nfla mmation, typically associ­ated with infection .1 . Classic symptoms of acute men i ng itis i nclude fever, headache, stiff neck,a nd alteration in menta l status . In addition , seizures, photophobia, vom iting ,and focal neurologic deficits may occur.2 . Work-up of suspected men ing itis must i nclude exa m i nation of CSF: Infectious Disease • 8 7
    • Aseptic Bacterial Herpes Simplex Meningitis (Viral) Meningitis Encephalitis TB Mening itisW BC 1 0-2000 1 000- 1 00,000 0- 1 000 1 00- 1 000Differential Early PMNs Mostly PMNs Mostly lymphs Early: PMNs Later lymphs Later: lymphsGlucose Normal May be low Normal May be lowProtem Normal May be high Normal May be highIn add ition , check C BC and d ifferential for evidence of systemic infectio n .Check electrolytes, glucose, a n d BUN /creati nine, a n d obta i n blood cu ltures.Cranial CT scan is ind icated in cases with focal neurologic deficits or evidenceof increased i ntracranial pressure, or if subarachnoid hemorrhage is suspected .Chest and sinus x-rays are helpful in identifying potential sources of infection .3 . Bacteria l meni ngitis is a med ical emergency, and diagnosis and treatmentmust be in itiated in a timely fashion. Idea lly, CSF should be obtained promptlyand antibiotics started as soon as the LP is com pleted . However, antibioticsshould not be delayed while awa iting neuroimaging or if there a re difficulties i nobtaini ng CSF.4. Suspected etiologic agents differ with patients age a. Neonates/I nfants: E. coli, other gra m negatives, Group B streptococcus,L. monocytogenes, rarely 5 pneumoniae b Children : N. meningitidis, 5 pneumoniae. Haemophilus influenzae as acause of child hood mening itis has decreased d ue to widespread use of H. in­fluenzae immun ization . c . Adu lt 5 pneumoniae, N. meningitidis. In older populations, E. coli, othergram negatives, and L. monocytogenes occur with increasing frequency.5 . Other risk factors/cl inical findings that may help to determine likely organ­Isms include: a. Recent neurosurgical procedure - Staphylococcus aureus, S. epidermidis,anaerobes, gram negatives b. Bra i n /epidural abscess, head trauma - a naerobes, g ra m negatives, S.pneumoniae c. Endocarditis/IV drug use - So aureus d . Splenectomy, sickle cell disease - So pneumoniae e. Immu nocompromised secondary to chemotherapy, steroids- So pneumo­ niae, L. monocytogenes, fungi, Mycobacterium tuberculosis, cytomegalovi rus,herpes f. HIV/AIDS- Toxoplasma gondii Cryptococcus neoformans, M tuberculosis,cytomegalovirus, herpes g . Chronic alcoholis m - S. pneumonaie, L. monocytogenes h Congenital defect/dermal tract - So aureus, S. epidermidis, E. co/i, gra m negatives i . Otitis/mastoid itis/sin usitis- S. pneumoniae, H. influenzae i . Rash/purpura N. meningitidis -88 • Infectious Disease
    • 6. Men i ngismus (stiff neck, nuchal rigid ity) is rarely seen i n neonates and i n­fants. likewise, it may not be prom i nent in elderly, debi litated patients.7. Subarachnoid hemorrhage may present with alteration in mental status, stiffneck, headache, and even fever.8 . Treatment is di rected at likely u nderlying organisms. E mpiric treatment shouldbe i n itiated as soon as possible and may be changed later as CSF and cultureresu lts become ava i lable . In neonates , empiric therapy generally consi sts ofampicillin and gentamici n . I n children, cefotaxime or ceftriaxone are used ini­tially; in adu lts, pen icillin G . A I D S/H u MAN 1 M M U N O 0 E F I C l E N CY VIRUSS T O P CATC H I N G I T *S a l m o n e l l a (se p s i s , d i a r r h e a )T h ro m bocyto p e n i aO n c o l og i c d i se a s e ( Ka p o s i s , l y m p h o m a )Pneumocys tis cariniiC yt o m e g a l ov l ru ::; , � ryptococco s i s , C a n d i d i a s i s , C ryptos p o r i d i u mA vium in trace llulare, m ycobacteriumT oxo p l a s m o s i sC o n st i tu t i o n a l sym pto m sH e rp e s s i m p l ex/zosterI at rog e n i cN o d e e n l a rg e m e nt/lym p h a d e n o pathyG u i l l a i n Ba rre sy n d ro m e/n e u ro pathyI so s p o raT u be rc u l o s i sAlso: dementia* clinical manifestations/opportunistic infections Infectious Disease • 89
    • N otes 1 . Opportunistic infections may be classified accord ing to the organ system(s)i nvolved . a . Agents associated with pneumonia/pneumonitis include: Pneumocystiscarinii cytomegalovirus, Mycobacterium tuberculosis, herpes simplex. b. Disseminated infections are seen with Mycobacterium avium introcel/u­lore, Mycobacterium tuberculosis, cryptococcosis, herpes simplex. c. Neurologic i nfections such as encephalitis and meningitis are caused bycytomega lovi rus, M . tuberculosis, cryptococcosis, toxoplasmosis, and d i rectCNS infection by H IV d . Ocular infections usua lly a re associated with cytomega lovirus or toxo­plasmosis. e . Gastroi n testinal (esophag itis, d ia rrhea) manifestations are seen with :cytomegalovirus (esophag i tis), cand idiasis (esophag itis, oral thrush), herpessimplex (esophagitis), cryptosporid ium (diarrhea ) , isospora (diarrhea), a nd sal­monella (diarrhea ) . f. Cutaneous i n fections a re usually due t o : herpes s i m plex a nd herpeszoster.2 . Oncologic manifestations of AIDS are pri marily due to Kapos i s sarcomaand lymphoid malignancies.3 . There a re a myriad of neurolog ic manifestations of AIDS which correlatetemporally with the stage of the underlying disease. • Asymptomatic • Aseptic mening itis, usually early in course • Acute demyel inating polyneuropathy (Guillain Barre) usually early • Chronic polyneuropathy, later • Myelopathy, later • Meningitis/encephalitis, opportunistic i nfection late in course • Cerebral neoplasm ( pri mary cerebral lymphoma), late in course • Seizures, variable • Stroke/ischem ia, variable • Dementia, late in course4 . Hematolog ic manifestations of AIDS/HIV a. Thrombocytopenia b. Anemia c. Decreased T4 lymphocyte count5. Constitutional/system i c symptoms are very common and may be nonspe­cifiC, particula rly i n the early stages of the d i sease. However, they a lso mayherald the onset of an opportunistic i nfection, and thus must be taken seriously.These signs and symptoms i nclude fevers, a rthralgia, rigors, myalgias, rash,diarrhea, abdominal pain, headache, fatigue, and weight loss.90 • Infectious Disease
    • I M M U N O D E F I C I E N CY S TAT E SSCANT D I S EASE B LOCKSS ki n d i seaseC o m p l e m e n t d e f i c i e n cyA n t i body d e f i c i e ncyN e u tro p h i l d i sorde rs/n e utro pe n iaT-c e l l a b n o r m a l i t i e sD i a betesI n t rave n o u s d ru g a b u s e rsS p l e n ecto m i zed pat i e n tsE l d e r lyA I DSS te ro i d s a n d ot h e r i m m u n o s u p p re s s ive d ru g sE TO H a b u se rsB abiesL i ver fa i l u reO rg a n t ra n s p l a n tC a n ce rK i d n ey fa i l u reS ta rva t i o n/ma I n u t r i t i o nN otes 1 . The "SCANT" port of this mnemonic emphasizes the five major componentsof the i mmune system : cutaneous and mucus membrane barriers, complement,anti body, phagocytes, and cell-mediated immunity2 . Patients with anti body deficiencies have recurrent or chronic sinopul monoryinfection, men ing itis, and bacterem ia, all of which ore most commonly causedby pyogenic bacteria .3 . Patients with complement deficiencies are pred isposed to pyogenic bacter­ial i nfection, and those with ter m i na l complement component deficiencies(C5-C9) may have recurrent Neisseria infections. Infectious Disease • 9 1
    • 4. Abnormal ities of T-cells pred ispose to d isseminated viral i nfections as well asfungi and other opportunistic organ isms .5 . Neutropenic patients are predisposed to bacterial and fu ngal infections.6. Splenectom ized patients a re at high risk for severe infections by enca psu­lated organisms due to S. pneumoniae, H. influenzae, and N. meningitidis . TheDF-2 bac i l lus ( Capnocytophaga canimorsusj is a fastid ious g ra m-negative or­ganism that may cause fulminant infection after a dog bite . Splenectomized pa­tients a lso may have more severe i l l nesses from protozoa such as Plasmodiummalariae and Babesia. R H E U M AT I C F E V E RJ O N ES *J o i n t s ( p o l y a rt h r i t i s )O ve r l oa d/o p e n i n g s n a p ( c a r d i t i s , va lve d i s e a se)N e u ro l og i c (ch orea)E ryth e m a m a r g i n a t u mS u b c u ta n e o u s n o d u l es* maior manifestationsN otes 1 . Rheumatic fever is an inflam matory d isease that occurs as a delayed se­quela to g roup A streptococcal pharyngeal i nfection. The diagnosis is made byspecific maior and m i nor man ifestations of the d iseases. The maior manifesta­tions of rheumatic fever are summa rized by the mnemonic JONES, which refersto the Jones criteria .2 . The joint i nvolvement of rheumatic fever is an acute migratory polya rthritismost com monly affecti ng the large ioi nts of the extrem ities, but it may affectalmost any iOint in the body.3 . Overload/open i n g snap refers to the card iac i nvolvement of rheumaticfever. This is the most important manifestation because it may be fata l in the acutestages or lead to permanent valve damage and long-term ca rdiac dysfunction .4 . The neurologic manifestations of rheumatic fever have been called Syden­hams chorea or SI. Vitus dance, a nd these na mes refer to the cha racteristic92 • Infectious Disease
    • sudden , a i m less, i rreg ular mavements which may be accom pa n ied by m uscleweakness and emotional insta bil ity. The chorea is often a delayed manifestationof rheu matic fever.5 . Erythema marg i natum is an evanescent pink rash that is cha racteristic ofrheumatic fever. The erythema is tra nsient, migratory, and may be brought on bythe appl ication of heat6. Subcutaneous nodules are small, pea-sized , pain less swell i ngs that accurover bony promi nences and tendans.7. Mi nor man ifesta tians that can be used in esta b l i s h i n g the d iag nosis ofrheumatic fever include the clin ical fi ndings af a rthralgia and fever as well as thela boratory findi ngs of an elevated eryth rocyte sed i mentation rate, an elevatedC-reactive protein level , and a prolonged PR interval on the EKG .8 . Evidence su pporting an antecedent group A streptococcal i nfection i ncludesa positive throat culture, a positive rapid streptococcal antigen test, or an ele­vated or rising streptococcal anti body titer. The d iagnosis of rheumatic fever i smade by major a n d m i nor man ifestations, as well as su pporting evidence o f ag roup A streptococcal infecti on . If there is evidence of a preced i n g g roup AstreptoGoccal i nfection and two ma jor manifestations, or one major and twom i nor manifestations, then there is a high proba bil ity that the patient has acuterheumatic fever.9 . Other fi ndi ngs that may be present in a patient with rheumatic fever i ncludeabdom inal pa i n , tachycard ia, and epistaxis, but these findi ngs a re nonspecificand of m i nor diag nostic va lue. S E X U A L LY T R A N S M I T T E D D I S EAS E SN O W R A P , U G E TS C LA P *N O n g o n ococca l u re t h r i t i sW a rt s , g e n it a lR e ite r s syn d ro m eA I DSP roctiti s , i nfect i o u s U l ce ra t i ve g e n i t a l l e s i o n s ( h e rp e s s i m p l ex) Infectious Disease • 93
    • G o n o rrheaE p i d i dy m i t i sT richomonasS yp h i l i sC ytom e g a l ov i ru s , C e rv i ca l ca n c e rL i ceA rth r i t i sP e lv i c i n f l a m matory d i s e a s e* differential diagnosisN otes 1 . Clinical sym ptoms that bring sexua lly transmitted d iseases (STDs) to a physi­cians attention include genital discha rge, pa in/ d iscomfort, or visible lesionsMany patients with STDs are asymptomatic and do not seek med ical care .2 . Proper ma nagement of a patient with an STD m ust i nclude identification andtreatment of the infected partner.3 . It is helpful to classify STDs into com mon clin ical presentations or syndromes: a. U reth ritis ( males) f. Proctitis/lower GI i nfections b. Epididymitis g. Acute a rthritis c. Ureth ritis/cystitis (females) h. Warts d . Vulvovagin itis i . Pelvic infla m matory d isease (females) e. Ulcerative lesions4. U rethritis typically presents as a urethral d ischarge and/or dysuria in a sexu­a l ly active male The most likely agents are N gonorrheae, Chlamydia tracho­matis, Ureaplasma urealyticum, and herpes simplex virus. Alternate d iag nosesto be considered include bacterial cystitis or prostatitis5. Epid idym itis may present as unilatera l testicular pa i n . The differential d iag-nosis includes testicular torsion, trauma, testicular cancer, or infection . As in ure- thritis, N gonorrheae and C trachomatis a re the predom i na nt agents. Gra mnegatives may cause epid idymitis in older men or aher urinary tract procedures.6. Lower gen itourinary infections in females present with vaginal d ischarge, dy-suria, painful intercourse, and/or gen ital d iscomfort. U rethritis/cystitis genera llycauses dysuria and is due to N gonorrheae, C trachomatis, or bacterial cystitis .Vulvovagin itis typically manifests with vag inal d ischarge, vag i nal pain/discom-fort, and "dysuria" due to contact of urine with inflamed labia . Primary etiologicagents are yeasts ( Candida albicansl , Trichomonas vaginalis, and bacteria( Gardnerella vaginalis, mycoplasma, etc ) .7 . Genital ulcers a re caused by the following orga n isms : a . Treponema pallidum (syphil is)94 • Infectious Disease
    • i . Les ion (chancre ) : u lcerated , pa in less, firm, indurated pa pule. I ncu­ bation 1 0-90 days. i i . Adenopathy: firm , discrete, mova ble, pa inless, occurring 1 week after chancre. b. Herpes genitalis i . Lesion : multiple, painfu l , erythematous vesicles. Incubation 2-7 days. i i . Adenopathy: tender, soft; not prom inent with recurrent lesions. c. Haemophilus ducreyi (chancroid) i. Lesion : soft, not i n d u rated , very pa i nful ves icle/pa pule to ulcer. Incubation 3-5 days . i i . Adenopathy: painfu l , unilatera l , suppurative, occurring 1 week after pri mary. d. Chlamydia trachomatis (lym phog ranuloma venereu m) i. Lesion : pa i n less, often u n n oticed papule/u lcer. I ncubation 5-2 1 days. i i . Adenopathy: tender, bi lateral ( 3 3%), matted , suppu rative, occurring 5-2 1 days after. e. Calymmatobacterium granulomatis (gran uloma inguina le) i . Les ion pa in less, irreg u lar, th ickened papule/u lcer. Incubation 9-50 days. i i . Adenopathy: none . May develop groin abscesses, however.8 . Acute arthritis is most commonly caused by N. gonorrheae in young adults.Reiters syndrome is second . Differential d iagnosis i ncludes other infectious a rthri­tides ( meningococcus, Yersinia, syph ilis), crysta l-i nduced a rthritis, RA, SLE, andsarcoid. See the differential for acute monoarthritis in the Rheumatology cha pterfor more information .9. Genital warts (condyloma acum inata) are caused by human papi llomavi rusand a re associated with cervical dysplasia . The differential d iag nosis of wartsincl udes condyloma lata (secondary syphilis) and molluscum contagiosum . 1 0 . Pelvic inflam matory disease is typically caused by N. gonorrheae or Ctrachomatis. Symptomatology includes lower abdomina l/pelvic pa in, often duringmenses, and sometimes cervical d ischarge, pelvic mass, and/or leukocytosis. Infectious Disease • 95
    • II CARDIOLOG Y C l i n ica l Sym ptoms a nd Signs SYN C O P E ACLS A nx i ety C a rd i ova s c u l a r c a u s e s L os s o f vo l u m e/o rt h o s t a s i s S e i z u re/n e u ro l og i c ca u s e s Also: see "Loss of consciousness " in the Neurology chapter. N otes 1 . Syncope is a generalized weakness of muscles with loss of postural tone, in­ ability to stand upright, and a loss of consciousness. There are many causes of syncope, and it must be differentiated from feelings of dizziness or faintness as well as seizures. Si nce patients often present with a loss of consciousness with­ out a clear history 0; a ntecedent events, we i nclude seizu res in the d ifferential d iagnosis of syncope even though strictly speaking they do not cause syncope. 2 . The mnemonic ACLS g ives a s i m ple g rou ping for the ca uses of a pparent · syncope. Anxiety or emotional stress may cause a loss of consciousness and subsequent syncope. Cardiovascular causes include congestive heart fa ilure, valvular heart d isease, i m pa i red venous return, a nd a rrhythm ias. Loss of volume causes hypotension and subsequent orthostasis. Exa m ples include blood loss from gastrointestindl hemorrhage, dehydration, and Addisons disease. Seizures Cardiology • 97tr
    • or neurologic disorders also can cause a loss of consciousness. Aga in, the dif­ferentiation between seizu res and the true causes of syncope is a critical aspectof the eva l uation . A more com prehensive a n d m echan istic a pproach to theproblem of syncope is summarized by the following mnemon ic:VA S O V A G A L SV o l u me lossA n x i ety attackS e i z u re/eVAO bstru c t i o n of ve n o u s retu rn ( m i ctu r i t i o n , Va l s a l va , c o u-g h , myxo m a )V a so d e p r e s s o r/V a s oco n strictor d efectA rrhyt h m i aG l u co s e d ro pA o rt i c d i s s e cti o nL ow ca rd i a c o u t p u tS hy- D ra g e r/S ym pa t h e t i c dysf u n ct i o n3 . VASOVAGALS outlines the causes o f syncope accord ing t o the physiologicmechanisms. Volume loss, anxiety attacks, and seizures/CVA a re aga in i m por­ta nt considerations. Obstruction of venous return may occur with m icturition ,Valsa lva maneuvers, cough, or, rarely, a bal l-valve effect of an atria l myxoma . Vasodepressor/vasoconstrictor defects may precipitate neurocardiogenicsyncope . Syncope in this setting typica l ly occurs when there is a d i m i n ishedvenous return to the heart upon standing. This diminished venous return leads to areduction in stroke volume and a reflex increase in sympathetic activity. In suscep­tible ind ividuals, the increased sympathetic activity causes a complex interactionbetween the heart and the autonomic nervous system. The net result is inappropri­ate peripheral vasod ilation and bradycard ia, which precipitate hypotension andsyncope The d iagnosis is made by tilt-table testing, ohen using isoproterenol i n­fusion . Neurocardiogenic syncope ohen responds well to beta-blocker therapy. Cardiac arrhythmias, either tachyarrhyth m ias or bradyarrhythm ias, are i m­porta nt in potentially life-threatening causes of syncope Arrhyth mias often indi­cate the presence of ischemic or mechanica l card iac disease.4. A blood glucose drop also can ca use fa i ntness and a syncopal event. I nsevere cases, low glucose levels m a y induce seizures. I nsulin-dependent dia bet­ics and elderly patients on oral hypoglycemic agents are at risk.5. Aortic dissection is a less common cause of syncope, and the d iagnosis isoften unsuspected . Aortic d issection can be ra pidly fata l , and the sym ptomsmay be relatively nonspecific. The dissection may cause a loss of blood volumeor perica rdial tamponade and resulting syncope. A low cardiac output may be98 • Cardiology
    • secondary to congestive heart fa il ure; valvu lar heart disease, especially aorticstenosis; massive pul mona ry embolism; or card iac ta mponade A high level ofsuspicion and prompt d iagnosis may be lifesavi ng .6. Finally, Shy-Drager/sympathetic dysfunction refers to peripheral autonomicdysfu nction that causes a vasoconstrictor defect. Shy-Dra ger syndrome is anid iopathic autonomic disorder. Surgical sympathectomy or pha rmacologic sym­pathectomy due to anti hypertensive med ications can cause inadequate vaso­constriction when assuming an upright postu re . Dia betic neuropathy or infi ltrativediseases such as amyloidosis are common causes . Cerebral hypoperfusion re­sults with a subsequent syncopal episode.7. Differentiating syncope from seizure is critical. Seizure patients more oftenhave no memory of the events preced ing the event and demonstrate post-event(postictal) confusion . Also, severe iniury from fa lling, tongue biti ng, and inconti­nence are ind icative of a seizure.8 . A com prehens ive l ist of the individual entities causing syncope is summa­rized by the m nemonic THIS MADE ME DAMN VAGALTHIS MAD E M E DAM N VAGALT a m po n a d eH y p e rt e n s i v e crtstsI nt ra c ra n i a l h e m o rr h a g e/CVAS e i z u reM yocard i a l i n fa rcti o nA o rt i c d i ss e ct i o nD ru g sE m o t i o n/a n x i ety a ttackM i ct u r i t i o n/tu s s iveE m bo l u s ( P E)D ys rhyt h m i aA d d i s o n sM i g ra i n e ( ba s i l a r)N e u roca r d i og e n i cV o l u m e l os sA o rt i c ste n o s i s/ob stru c t i o nG l u cose d ro pA utonom i c dysf u n c t i o nL ow ca rd i a c o u t p ut ( C H F) Cardiology • 99
    • Clinical Conditions or Diag noses A R R H YT H M I A AICD ME? A d re n e rg i c sti m u l i I sch e m ia C o n d u c t i o n syste m d i s e a s e D ru g s M e cha n i ca l sti m u l i (e . g . , st retch , PA cath ete r) E l e ct ro lytes N otes 1 . Cardiac a rrhyth mia can be subdivided into tachyarrhyth mias or brady­ arrhyth m i a s . Although the electrophysiolog ic mechanisms of a rrhyth m ia a re complex, a few basic etiologies should be considered in every patient with an a rrhyth mia . These mechan isms a re sum ma rized by the m nemonic "AICD ME2" The mnemonic also asks the clin ical question of whether an a utomatic i m pla nt­ able card iac defi bri llator (AI CD) is ind icated . This form of therapy is becoming increasingly com mon , particula rly for patients with ventricular a rrhythmias and congestive heart fa ilure . 2 . Adrenergic stimuli may prec i pitate card iac tachyarrhythm ias. Exam ples in­ clude excessive caffeine i nta ke, beta-adrenerg i c agonists, a nd pheoch romo­ cytoma . Cardiac ischemia a lso is an i m porta nt consideration in a rrhyth m i a . Ischemic damage to the conduction system may set u p the substrate for arrhyth­ mia, or resultant congestive heart fa ilure may couse myoca rd ial stretch and also precipitate a rrhythmias. Conduction system disease can be congenital or sec­ ondary to ischemia or mechanical sti m u l i . Drugs a re a common preci pita nt of cardiac arrhythm ias . In add ition to adrenergic stimuli, agents such as cisapride and terfenadine in combination with macrolide anti biotics have been i mpl icated as etiologies of card iac a rrhyth mia. Many agents used to treat cardiac arrhyth­ m i a s may have proa rrhyth m i c effects . Mec h a n ical sti m u l i can prec i pi ta te 100 • Cardiology.",
    • card iac a rrhythmia. Finally, electrolyte a bnormalities, especially perturbations inpotassium, magnesi u m , and calc i u m , a re i m portant considerations i n a patientwith card iac arrhythm ias. AT R I A L F I B R I L L AT I O NI HAVE A F I BI sch e m i aH yp e rthyro i d i s mA c ute p e r i c a r d i t i sV a l v u l a r h e a rt d i se a s e ( e s p ec i a l l y m it ra l ste n o s i s )E m bol us ( P E)A t r i a l septa l d efectF a i l u re (CH F)I nfect i o nB oozeN otes 1 . Atrial fibril lation is a common arrhyth mia that can be intermittent ( pa roxys­m a l ) or persistent. It is characterized by d i sorga n ized atri al activity with a n"irregularly irregu lar" ventricular response. The major morbid ities of atrial fibrilla­tion are : a . Tachyca rd ia that m a y precipitate hypotensio n , syncope , p u l monaryedema, or angina b. Loss of "atrial kick" that facil itates left ventricular filling and output c. Systemic emboli most often causing stroke. Most patients with c h ronicatrial fibri llation should be considered for warfarin anticoagulation (target INR of2 . 0-3 0) to reduce the risk of cerebrovascular accident.2. After initial rate control of symptomatic atrial fibril lation, search for an etiol­ogy. Most often , u n derlyi ng card iopulmonary d isease such as pericard itis,valvular heart disease, atrial septal defect, or failure (left sided or right sided)is present. Myoca rdial infarction is a rare cause of isolated atria l fibrillation, butpatients with ischemic heart d isease may develop atrial fibrillation over time. Cardiology . 1 0 1
    • 3 . Investigate other primary causes or factors that may unmask atrial fibri llationin a susceptible ind ividua l . Atrial fibri l lation may be the first sign of hyperthy­roidism or pulmonary embolism. Systemic disorders such as infection also canprecipitate atrial fibril lation Booze i ngestion may preci pitate a va riety of a r­rhythm ias, i ncluding atrial fibrillation The so-ca lled hol iday heart Iypically occursafter a binge d rinking episode on a weekend .4 . Ra rely, atrial fibril lation occurs without associated hea rt d isease or theabove-listed preci pitants. This "lone" atrial fibril lation generally has a good long­term prognosis and may be a manifestation of underlyi ng tachycard ia-bradycar­dia syndrome. C O N G E ST I V E H EA RT FA I L U R EI S C H E M IA ? PA CAT H S L o w o u tp u tI sch e m i aS u ba cute b a cte r i a l e n d oca rd i t i sC a rd i o myopathyH yp e rte n s i o nE ff u s i o n/ta m po n a d eM it ra l va l ve d i se a s eI n fect i o u s myoca r d i t i sA o rt i c va l ve d i se a s e High o u tp u tP ag et/mye l o m aA -V fistu l aC a rd i a c s h u ntA nemiaT h i a m i n e d e f i c i e ncy ( be ri-be r i )H yp e rthyro i d i s mS ep s i s1 02 • CardiologV
    • N otes 1 . Congestive heart fa ilure (CHF) is a clinical diagnosis. If a careful physicalexa mination revea ls the findings of CHF (edema, iugular venous distention, a rightor leh-sided heave, an auscultatory S3 or S4, rales, pleural effusions), then regard­less of other diagnostic testing results, the patient is in cli nical CHF. The im portanceof the physica l exa m i nation findi ngs cannot be over-e mphasized there a remany forms of C H F in which ca rd iac function may appear normal on imagingstud ies. Once a careful clin ical exa mi nation is done, and the patient has beendetermined to be clinically in C H F, clin ical imaging studies such as an echocar­diogram may be used to confirm the diag nosis and to elucidate the etiology.2. The mnemonic "ISCHEMIA? PA CATHS" divides congestive heart fa i lure i ntotwo main types : those associated with low cardiac output, and those associatedwith high cardiac output When a careful exa m i nation revea ls the clin ical fea­tures of CHF, but the echoca rdiogra m shows a normal eiection fractio n , con­sider one of three possibilities: a. The echoca rdiogram is subopti mal. b . High-output CHF is present c. A diastol ic, restrictive or constrictive defect is present3 . Low-output states are the most common causes of C H F. Ischemia with subse­quent leh ventricular dysfunction is the most common cause of CHF and potentiallyreversible. Subacute bacterial endocarditis may cause tachyca rdia and vasodi­lation, stressing the heart. It also can cause valvular iniury and subsequent stenosisor regurgitation . Idiopathic cardiomyopathy, also called dilated cardiomyopathy,causes CHF in the absence of coronary a rtery d isease. Long-sta nding hyperten­sion may cause cardiac dysfu nction in a low-output state . Hypertension also cancause a restrictive cardiomyopathy. Perica rdial effusion or tamponade may causesymptoms of C H F, and should be detected by echoco rd iog ra phy. Mitral andaortic valvular diseases a re less common today, but still important causes of CHFAga i n , echoco rd iography is useful to rule out these entities. F i nally, infection,usually vira l , may cause myocard itis and a subsequent d ilated cardiomyopathy.4. H igh-output fa ilure is less com mon than the low-output states. " PA CATHS"summarizes the causes of high-output failure . It also ind icates the most importanttest to perform when a patient is in C H F, but the echocardiogram suggests normalsystolic function : pulmonary artery catheterization . The abnormal physiology of theh ig h-output state may be secondary to a systemic shunt, as occurs with Pagetsdisease and multiple myeloma . In these diseases there a re bony, intramed ullaryshunts. There is increased blood flow through these shunts without tissue oxygendelivery. The result is an increase in SV02 and increased demand on the heart tomai ntain a higher cardiac output to meet the oxygen demands of the other tissuesin the body. A large arteriovenous fistula or cardiac shunt may have the sameeffect. Severe anemia reduces the oxygen carrying capacity of the blood, forcingthe heart to maintain a higher cardiac output Thiamine deficiency causes diffusevasodilatation which in turn leads to an increased volume of circulation that the Cardiology . 1 03
    • heart m ust mainta i n . A characteristic hyperdyna mic c i rculation is see n . Hyper­ thyroidism , with its heig htened metabolic demands, also can cause a high-output state. Sepsis leads to a hig h-output state with systemic vasod ilatation . Again, in these conditions the heart is u n der stress, a nd fa i l u re may ensue . Sepsis also may have a d i rect card iac depressa nt effect, and this can exacerbate ci rcula­ tory failure . I n restrictive diseases, the cardiac output may be normal or high 5. I n a pati ent with known C H F, decom pensation may occ u r, lead i n g to an edematous state with pedal edema , or "edema toes . " The following m nemonic summarizes the i m porta nt considerations in decom pensated CHF. All of these entities should be considered when determining the cause of C H F exacerbation . EDEMA TOES E mbolus D ys rhyth m i a E c l a m p s i a/p re g n a n cy M yoca rd i a l i nfa rct i o n A nemia T hyro i d d i s e a s e O ve rexe rt i o n/exc e s s ive f l u i d o r s a l t E l eva ted b l oo d p res s u re S e p s i s/i n fect i o n 6 . Although most C H F is due to systol ic dysfu nction , certa i n conditions may i m pede the hea rts abil ity to relax. This "diastolic dysfu nction" impedes card iac f i l l i ng and leads to the c l i n i cal state of C H F The d i sti ngu ishing fea tu re is a normal left ventricular ejection fraction on an echocardiogram or other imaging test. Remember that the left ventricular ejection fraction is a measure of systolic function, but does not assess the hearts diastolic function . H Y P OT E N S I O N B P D EC LI N E D B lood loss P oo r P O i nt a ke 1 04 • Cardiology--
    • D ia rrh ea/D e hyd rat i o nE n d o c r i n e ( e . g . , Ad d i s o n s)C a rd i a c d i se a s eL ive r fa i l u reI nfect i o n/s e p s i sN e u ropathy ( a u to n o m i c)E m b o l u s ( p u l m o n a ry)D ru g sN otes 1 . This differential shares many of the features of syncope.2. Addisons d isease may look very much like sepsis with fever, altered mentalstatus, a nd refractory hypotension . It is rapidly i m proved ( m i n utes) with intra­venous gl ucocorticoids. P E R I CAR D IT I SPR D I P, ST U PP ost -pe r i ca rd i oto myR h e u m a t i c feve rD ru g sI nfect i o n (T B , v i ra l , pyog e n i c)P u l m o n a ry e m b o l u sS LET hyro i d d i s e a s eU re m i aP o st-M I ( a c u t e , D re s s l e r) Cardiology . 1 05
    • N otes 1 . Pericarditis is a syndrome caused by inflam mation of the pericard i u m . The results of this i nflam mation include chest pa in, a pericardial friction rub, pericar­ d ial effusion, and cha racteristic EKG changes. 2. Chest pa in loften severe) is a com mon symptom of acute pericard itis. It may be a bsent in more subacute d i sease, such as tuberculosis or myxedema Cha racte ristica l ly, the pain is relieved by sitti ng up and lean i n g fo rward Swallowing may exacerbate the pa i n . 3 . Perica rd i a l friction r u b i s the most i m porta nt physical s i g n . It i s a h i g h­ pitched , scratching sou nd a nd may have th ree components correspond i n g to the cardiac cycle. 4. "PR DIP, ST up" describes the cha racteristic E KG changes in paricarditis de­ pression of the PR intervals and Widespread elevation of ST segments. T wave inversion a lso may be seen . Differentiation of these E KG cha nges from those of acute myoca rd ial ischemia is important. 5 . Here is a mnemonic for the d ifferential diagnosis of perica rditis: IT CA U S E D P E R I CA R D IT I S I nfect i o n (vi ra l , bacte r i a l , myc o b a ct e ri a l , f u n g a l , parasitic) T u m o r ( p r i m a ry, m eta stat i c ) C o l l a g e n-va s c u l a r d i seases (e . g . , S L E , RA, s c l e ro d e r m a ) A c ute MI U re m i a S a rco i d o s i s E m bo l u s D res s l e r s P o st-p e rica rd i otomy E xt e r n a l tra u m a R h e u m a t i c feve r I n h e rited (fa m i l i a l , FM F) C h o l e stero l/C h y l o p e ri ca rd i u m A tri-a l septa l d efe ct R u ptu red a o rt i c a n e u rysm D ru g s ( p roca i n a m i d e , hyd ra l a z i n e , and oth e rs) I d i o pa t h i c 7 06 • CardiologV--
    • T hy ro i d d i se a s e ( myxe d e m a )I rra d i a t i o nS evere, ch ro n i c a n e m ia6. Inflam mation of the perica rd i u m may be secondary to an infection, usua llyvira l , but bacteri a l , mycobacterial, and other etiolog ies a re possi ble . I nfla m­mation also may occu r as a resu lt of d i rect i n j u ry to the pericard i u m , such aspost-cardiac surgery, or from chest trauma . Adjacent infla mmation of the lung,as occu rs with pul monary embolism, or the hea rt, as occu rs with acute my­ocardial i nfarctio n , a lso can cause pericard itis. Myoca rd ial i n fa rction maycause an acute pericardial effusion or a later, autoimmune phenomenon cal ledDresslers syndro,rn e . Dresslers syndrome also can occur after card iac su rgery.Other collagen-vascular diseases such as rheumatoid arthritis or systemic lupuserythematosus com monly cause perica rd ial d isease. Perica rd i tis is a lso one ofthe card iac manifestations of rheumatic fever. Systemic illnesses such as uremiaand hypothyroidism can cause pericardial inflam mation and effusion . Finally,certa i n drugs may cause pericardia I d isease a nd/or effusion i ncluding hy­dralazine, proca inam ide, and m i noxid i l . R E S T R I C T I V E C A R D I AC D I S EAS EA STI FFER C H FA my l o i dS a rc o i d o s i sT u m o r i n f i l t rat i o nI d i opat h i cF i b ros i s ( e n d o myocard i a l )F a b r y sE os i n o p h i l i cRadiationC o n st r i ct ive p e rica rd iti sH yp e rte n s i o n/H y p e rt r o p hyF e ove r l o a d ( h e moch ro m otos i s ) Cardiology . 1 0 7
    • N ote This m nemonic lists those infi ltrative and fibrotic diseases that lead to d iastolic dysfu nction . Also i ncluded in this l ist is the entity of constrictive pericard itis, which may be difficult to distinguish from restrictive d isease even after echocar­ diography and pul monary a rtery catheterization . The differentiation of constric­ tive perica rd itis from restrictive disease is critica l , beca use constri ctive pericarditis is surgically correcta ble. 1 08 • Cardiologyb
    • II E NDOCRINOLOGY Genera l Considerations Endocrine disorders present i n myriad ways and a re a category in the MEDI­ CINE DOC mnemonic. Critical to the understanding of these disorders is the con­ cept of a sti mulatory signal ("trophic" hormone) from a remote source and a target gland that produces the "effector" hormone. Feedback from the target organ or from a metabolic product further downstream is oHen responsible for the subsequent inhi bition of the trophic hormone. Because of this regulatory system , endocrine d isorders may result from dysfunction of the stimulatory o r the effector organs. When considering endocrine d isease, think a bout the consequences of hyper- and hypo-function of each effector gland and its sti mulatory gland . Note that sta ndard endocrinologic testing is best done in an out-patient setting when the patient is in a stable state of health. Acute illnesses in hospitalized patients can unpred ictably alter hormonal testing and make test interpretation u n reliable. Rtui t arY/Hypothalamus The pituitary i s the master, o r "TOP GLAND," (see next page) because i t produces six major hormones (TSH, prolacti n, g rowth hormone, the gonadotropins LH and FSH, and ACTH), and stores two others (ADH and oxytocin). The pituita ry-hypo­ thala mic axis is a tri partite system consisting of the anterior pitu itary ("TOP GLA" ) , the posterior pituitary or neu rohypophysis ("N") and the hypothalamus ("D"). The posterior pitu itary is essentially an extension of an a rea of the hypotha lamus. The optic chiasm lies anterior and superior to the pituitary gland and is compressed by anterior pituitary neoplasms causing visual field defects. Visual symptoms may be the fi rst sign of a pituitary tumor. The anterior pituitary is a major producer of en­ dogenous opiates, including endorph ins, enkepha l ins, and dynorphins. TSH Optic chiasm/Opioids Prolactin Endocrinology . 109•
    • Growth hormone LH/FSH ACTH Neurohypophysis (ADH, oxytocin) Dopa mi ne/hypothalamic releasing factors Anterior Pituitary: H ypo- a n d H yper- Fu n ction TSH . Symptoms of hypofunction a re those of hypothyroidism, including fa­tigue, letha rgy, constipation, cold intolerance, muscle cramps, carpal tunnel syn­d rome, menorrhag ia, edema, weight loss, slowing of i ntellectual function, d ryskin a nd hair, deepening of the voice, and com a . Signs of hyperfu nction a rethose of hyperthyroidism (see Hyperthyroidism section) . Optic chiasm. Although not a hormone-secreting entity, anterior pituita rytumors . impinge upon this structure and cause visual field d isturbances. Prolactin . H igh levels of prolactin may cause hypogonad ism and galactor­rhea , while low levels are cha racterized by the inability to lactate. Growth · h ormone. Excess g rowth hormone ca uses acromega ly, a syn­drome that may include fatigue, increased sweati ng, heat intolerance, enlarg­ ing hands and feet, coa rse n i n g of facial featu res, headache, vision loss,macroglossia, C H F, impotence, kidney stones, hypersomnolence, and obstruc­tive sleep a pnea . LH and FSH. Deficiency of the gonadotropins results in hypogonadism andi nferti l i ty. Gonadotropin excess is usually d iag nosed in men with decreasedl ibido, and may be m isd iag nosed as primary hypogonadism if a pituitary tumoris not suspected . ACTH . ACTH excess resu lts i n Cush i n g s syndrome, cha racterized bymuscle weakness, hypertension , a menorrhea , glucose intolerance, osteoporo­sis, striae, and central distribution of fat. ACTH deficiency causes secondaryadrenal i nsufficiency (see Adrenal I nsufficiency section) N e u rohypophys i s ( Posterior Pitu ita ry) : Hypo- a n d Hyper-Fu n ction ADH . ADH excess is reviewed i n the SIADH section . Loss of ADH causesdiabetes inSipidus (see Hypernatremia section in the Nephrology chapter) . Oxytoci n . Oxytoci n sti m u lates uterine contraction and contraction of my­oepithelial cells of the breast, causing m i l k ejection . Oxytoci n has an ADH-l ikeeffect, which may be c l i n i cally sign ificant when it is g iven i n large doses forobstetrical uses. It a lso has a vasod i latory effect, which may cause hypoten­sion and card iovascular comprom ise, pa rticula rly in patients with heart diseasea nd when anesthetics are coadmin istered . H ypotha l a m u s : Hypo- a n d H yper-Fu n ction Dopa mine ( prolacti n-releasing factor) and the hypophysiotropic hormones(TR H , C R H , LH R H , G H R H , a n d G I H [somatosta t i n ] ) a re prod u ced by the1 1 0 • Endocrinology
    • hypothalamus and regulate prolactin release, thyroid function, the adrenal axis, gonadotropi ns, and growth hormone release .. Injury to the hypothalamus or pitu­ itary stalk results in a reduction in levels of GH, LH, FSH, TSH , and ACTH , with a rise in prolactin, which is norma lly i n h i bited by ton ic release of dopa m i ne . Argin ine vasopressin a n d oxytocin levels fall i f the neurohypophysis is injured . C l i n i cal Sym ptoms and Signs AM E N O R R H EA WHAT S EX ? * W e i g h t l os s H ypot h a l a m i c ( p i t u i t a r y dysf u n ct i o n ) A n a to m i c a n o m a l i es o f t h e va g i n a a n d u t e ru s T e sti c u l a r fe m i n i za t i o n S t ress (syste m i c i l l n es s ) E xe r c i s e X O (Tu rn e r s ) Also: Gonadal dysgenesis, Kallman s syndrome, physiologic delay * primary amenorrhea PERIOD GAP* P o lycys t i c ova ry d i sea s e/i n s u l i n res ista n ce E n d o m et r i a l fa i l u re (As h e rm a n s) R es i sta n t ova ry syn d ro m e I l l n e s s ( s evere syste m i c d i s e a s e ) O var i a n fa i l u re ( a u to i m m u n e , e a r l y m e n o pa u s e ) D i eti n g/exe rc i s e Endocrinologv . 111e
    • G ravid A d re n a l dysf u n ct i o n (co n g e n it a l a d re n a l h y p e rp l a s i a , Ad d i s o n s ) P itu ita ry d i se a s e * secondary amenorrhea N otes 1 . Amenorrhea is divided i nto primary (no i n itiation of menses) and secondary (cessation of esta bl ished menses) categories 2. Preg na ncy m ust be ruled out first in any patient with a menorrhea F u rther evaluation is generally undertaken in the following i nstances: a. No menses have occurred by age 1 4 , and development of secondary sex characteristics is absent or reta rded . b. No menses have occurred by age 1 6 . c . A woman with establ ished menses has no bleed ing for th ree cycles or 6 months. 3. The basic categories of problems a re outflow problems (anatomic block), ovarian disorders, anterior pituitary disorders, and CNS disorder (hypothalamus) . 4. Evaluation after pregnancy is ruled out includes a history and physical exam, with a clinical assessment of estrogen status. On pelvic examination, normal es­ trogen-stimulated vag inal mucosa is moist and rugated . Normal cervical m ucus stretches and demonstrates fern ing when placed on a slide. 5. If clin ica l exa mi nation is norma l, a TSH and prolactin are obta ined, and the patient is given a progestational cha llenge to check for withdrawal menses . If withdrawa l bleed ing occurs and prolactin and TSH are normal, then the d iag­ nosis is anovulatory bleed i n g ( polycystic ovarian d i sease) If no withd rawa l bleed ing occurs, then evaluation depends u pon the prolactin level. If prolactin is elevated and/or galactorrhea is present, then pituita ry imaging is ind icated . If prolactin is low or norma l, then LH and FSH should be measured. If LH and FSH a re elevated, then the diag nosis is ova rian fa i lu re If gonadotropins a re low or normal, then the diagnosis is a hypothalamic-pitu ita ry disorder or an anatomic uterine defect (e. g . , Asherma n s) . Cyclic estrogen a nd progesterone should cause menstruation if the uterus is norma l . 1 1 2 • Endocrinologyb
    • G Y N E C O M AST I ATEST M ET e stoste r o n e d ef i c i e n cyE strog e n excessS e n i l ityT e e n a g e rs/i nfa ntsM ed icationsE ti o l ogy u n k n ow nN otes 1 . Gynecomastia does not i n d i cate a bsolute hormone levels, but rather achange in the ratio of male to female sex hormones. Gynecomastia may be i n­d icative of u n derlyi ng endocrin opathy or may be the resu lt of obesity or anormal physiologic phenomenon (newborn , adolescence, aging).2. Ca uses of gynecomastia can be classified as either patholog ic or physio­log ic. Pathologic causes may be d ivided i nto those which lead to a decrease intestosterone leve l , a n i ncrease i n estrogen leve l , or a re secondary t o t h eeffect of a medication . A decreased testosterone level m a y b e t h e result o f acongen ital disorder or testicular fa i l u re secondary to renal fa ilure, trauma, ororchitis. I ncreased estrogen effect may be secondary to a primary increase inestrogen , such as occu rs with tu mors of the testes, true hermaphrod i tes, orhCG-prod ucing tumors. An increased estrogen effect also may be seen whenthere is i ncreased substrate ava ilable for extra-g landular a romatase, such asoccurs in adrenal disease, liver d i sease, mal nutrition , or hyperthyroidism . A pri­mary i ncrease in extraglandular a romatase also can lead to increased estro­gen effect. Physiologic ca uses are those changes that occur during the normal human lifetime such as in newborns, teenagers, and the elderly. Most casesa re id iopath ic (etiology unknown) . A defi nitive diag nosis can be reached i nless than one-half of patients.3 . Physi cal exa m i nation should incl ude testicu lar exa m i nation . If testes a resma l l , obta in a ka ryotype . If testes are asymmetric, a tu mor may be present.4. J n itial laboratory tests include liver and renal function tests . Endocrine evalua­tion incl udes measurements of serum and rostenedione or 24-hour uri nary 1 7-ketosteroids, plasma estradiol, hCG, LH, and testosterone.5 . Drugs may ca use gynecomastia by pro-estrogenic or anti-testosterone mechanisms. They may act d i rectly as estrogens, enha nce estrogen secretion , Endocrinology . 1 1 3
    • - i n h ibit testosterone action or synthesis, or act by an u n known mecha n i s m . A ca reful drug history is essential . Drugs that cause gynecomastia include estro­ gens, ketoconazole, metron idazole, various chemotherapeutic agents, spi rono­ lactone, ci metidine, fluta mide, isoniazid, methyl dopa, tricycl ic antidepressants, omeprazole, AC E i n h ibitors, calcium-chan nel blockers, mari juana, and heroin . 6 . Men with Kli nefelters syndrome have a h i g h i ncidence of breast ca ncer. Screening mammography is essential. 7. Here is a more comprehensive list of the causes of gynecomastia : N U D E T E S TA M E N T N ewbo rn/te e n a g e r U re m ia/re n a l fa i l u re D ru g s E st ro g e n s T e stoste ro n e i n h i b itors E lderly S ta rva t i o n/n u t r i t i o n a l d e f i c i e n c y T est i c u l a r fa i l u re A d renal di sease M o r b i d o b e s i ty ( h i g h a ro m a t a s e ) E n d-st a g e l ive r d i se a s e N eo p l a s m (test i c u l a r o r o t h e r H C G-prod u c i n g t u m o r) T hy r o i d d i s e a s e H I RS UTI S M peO D HAIRS P ro l a cti n o m a C o n g e n it a l a d re n a l hype r p l a s i a O va r i a n tu m o rs ( a r r h e n o b l a sto m a , h i l u s c e l l tu m o r) D ru g s 1 1 4 • Endocrinologyb
    • H i l u s ce l l hype rp l a s i aA d re n a l t u m o rsId i o path i c (fa m i l ia l )R es i sta n c e to i n s u l i n (syndrome X, polycystic ova ry d i sease)S te ro i d s (exog e n o u s , C u s h i n g s)Also: idiopathic (familial)N otes1 . H i rsutism is defined as male-pattern hair g rowth in women, i n contrast to hy­pertrichosis, which is excessive ha i r g rowth i n a normal body distribution .H i rsutism is due to a hormonal imbala nce (i .e. , excessive androgen production! ,while hypertrichosis results from stimulation of existing hair, often by medications(e.g . , cyclosporin or m i noxid il). There is considerable va riabil ity in hair g rowthin normal men and women; thus abnormal hair g rowth is difficult to defi ne.2. The clin ica l scenario dictates the diag nostic eva luation of h i rsutism Poly­cystic ovary disease ( " PCOD") is one of the most common causes of pathologich i rsutism and is subacute in onset. Rapid onset and frank viril ization a re cha rac­teristic of malignancies and mandate com plete evaluation .3 . The h istory should focus on d rug ingestion, fam i ly h istory, and menstrual h is­tory. Physical examination signs of viril ization i nclude deepening of voice (laryn­geal enlargement), tem poral b a l d i n g , cl itoromega ly, male escutcheon, a ndi ncreased m uscle mass. Signs of Cushings syndrome (stria , moon face, truncalobesity, and " buffa lo hump") should be sought.4. Obta in plasma testosterone, prolacti n , and DH EAS levels, possibly followedby adrenal and ova rian imag i ng .5 . Most patients on steroid therapy do not have hirsutism, because steroids suppressadrenal androgen production . Androgen production is sti mulated by ACTH, soonly conditions featu ring excessive ACTH secretion typically cause hirsutism .6 . Drugs (and polycystic ovary disease or Stei n-Leventhal syndrome) a re themost common ca uses of nonfa m ilial h i rsutism . True d rug-ind uced h i rsutism ( i ncontrast to hypertrichosis) results from a d i rect androgenic effect o r sti m ulation of .androgen secretion. 7. Congen ita l adrenal hyperplasia (late 2 1 -hyd roxylase deficiency) may beclin ically indisti nguishable from PCOD. Patients with this disorder have a defect in cortisol synthesis lead ing to elevated ACTH levels, which in turn cause exces­sive androgen prod uction . E levated DH EAS and dexamethesone-su ppressi ble hyperandrogenism are strong supports for this d iagnosis. 8 . Patients with Cushings syndrome may not always have hirsutism. Glucocorticoidssuppress adrenal androgen production. ACTH stim ulates androgen production . Endocrinology . 1 15
    • - Clinical Conditions o r D iagnoses AD R E NAL I N S U F F I C I E N CY LACKS A D R ENAL* L ow s od i u m Acidosis C a l c i u m e l eva t i o n K + e l evat i o n S ki n hype r p i g m e n t a t i o n A I t e r e d m e nta l sta t u s D e p re s s i o n R ef ractory hypote n s i o n E os i n o p h i l i a N a u s ea/a b d o m i n a l pa i n/a n o rexia A st h e n i a L o s s o f we i g h t * characteristics of adrenal insufficiency N otes 1 . Pri mary ad renocortical deficiency is rare, but secondary (due to steroid ther­ apy) is relatively com mon . Adrenal insufficiency may be unmasked by stress due to, for example, systemic illness or infection . 2 . Causes of adrenal insufficiency include anatomic destruction of the adren­ als (autoi m m une destructio n , surgical remova l , i nfectio n , hemorrhage, o r metastatic invasio n ) , metabolic fa i l u re (congen ita l adrenal hyperplasia o r enzyme i n h i bitors such as meta pyrone o r ketoconazole), ACTH-blocking anti­ bod ies, suppression of the hypothalam ic-pitu itary axis due to steroid therapy, and hypopituita rism secondary to hypothalam ic-pituitary d isease. 3 . Pri mary adrenal insufficiency may be pa rt of a polyglandular autoi m m une syndrome. Associated conditions i nclude lym phocytic thyroiditis, premature ovar­ ian fa i l u re, diabetes, and hyperthyroidism Add itional d isorders include perni­ cious anemia, vitiligo, alopecia, sprue, and myasthenia gravis. 1 1 6 • Endocrinology
    • 4 . Laboratory diagnosis of adrenal insuffici ency requi res ACTH sti m u lationtesting to assess adrenal reserve capacity for steroid production. Serum and uri­nary steroid levels may be in the normal range in mild adrenal insufficiency, andtherefore are not reliable for diagnosis Basal levels of cortisol and aldosteronemay be subnorm a l , but defi n itive d iag nosis is obta i ned when they fa i l to i n­crease after ACTH sti mu lation .5 . Consider adrenal insufficiency in any patient on steroid thera py, si nce dura­tion of therapy can not rel iably predict which patients wi ll have suppression ofthe adrenal axis. Patients on steroid therapy who have significant intercu rrent il l­ness should be given stress-dose sterOids empi rica lly while acutely ill6 . Solumed rol and pred n isone i n terfere with the ACTH sti m u lation test.Hydrocortisone therapy makes i nterpretation of the test difficult, as wel l . In a pa­tient with suspected adrenal insufficiency, dexamethasone may be given acutely,as it will not interfere with the ACTH sti mulation test. Both solumedrol and pred­n isone are ulti mately converted to pred n isolone, which d i rectly i nterferes withthe cortisol assay. Hydrocortisone also di rectly interferes with the cortisol assayDexa methasone does not interfere, but if it is g iven over several days it can sup­press the adrenal axis. Dexa methasone a lso has very l ittle mi neralocorticoideffect and may not improve hypotension as d ra matica lly as hydrocortisone.7. I n critica l ly ill patients, interpretation of the ACTH sti mulation test is difficult,and free cortisol levels vary g reatly. At this time, there is no convi ncing evidencethat steroid supplementation is benefi cial in these patients in the a bsence ofclearly demonstrable adrenal insufficiency. CARCI N O I D TU M O RS5-H IAASH ea rtI n test i n eA i r wayA st h m aS ki nN otes - 1 . Carcinoid tumors a re thought to arise from neu roendocrine cel ls. They syn­thesize a variety of hormones a nd biogenic a m ines; the mast prominent of these Endocrinology . 1 1 7
    • - substances is serotoni n . Serotonin is meta bol ized in the body to 5-hydroxyin­ doleacetic acid (5-H IAAl, which is then excreted in the urine. Serotonin is the ma jor med iator responsi ble for ca rd i n a l manifestations of the carcinoid syn­ d rome, and these five manifestations are conveniently outlined by the mnemonic "5-H IAAS . " 2 . Carcinoid tumors can be found i n a number of locations. The lungs, bronchi, and trachea a re the most common sites for a carci noid . Other sites i nclude the stomach , d uodenum, jej u n u m , ileum, a ppendix, cecu m , colon, and rectum . I n genera l , the carcinoid synd rome, with all its systemic manifestations, is seen i n patients with metastatic disease to the liver. This i s thought to occur because the enteropathic circu lation normally meta bol izes the prod ucts of the carci noid tumor, thus preventing systemic symptoms. Once hepatic metastases are present, the products produced by the ca rci noid tumor are released freely i nto the circu­ lation, avoiding hepatic clearance. 3. Carcinoid heart disease occurs in two-th i rds of patients who have the car­ cinoid syndrome. Tricuspid reg u rg i tation and tricuspid stenosis a re the most common manifestations, but also pul monary stenosis may occur. Left-sided heart disease occurs i nfrequently - i n less than 1 0% of patients. The preponderance of lesions on the right side of the heart suggests that the heart disease is related to factors secreted into the hepatic vei n by liver metastases. This concept is sup­ ported by the fact that the anorectic d rugs fenfl u ramine and dexfenfl u ra m i ne a ppear to interfere with normal serotonin metabolism and have been associated with similar cardiac va lvular lesions. A second man ifestation of the carcinoid syndrome is hypotension . 4 . Intesti nal manifestations include gastrOintestinal bleed i n g , obstruction , or, with the carci noid syndrome, patients may develop d iarrhea. The most common type of dia rrhea is mixed secretory and hypermoti lity-induced, prod ucing watery stools un responsive to fasting . 5 . Airway obstruction from a carcinoid tumor with local ized wheezing is one of the more common presentations of this tumor. These a i rway tumors are very vascular and may present with hemoptysis in addition to local ized wheezi ng . 6. Asthma, with sign ificant wheezing, is another manifestation of high levels of serotonin release. In addition to the a bove-mentioned loca lized wheezing from an a i rway lesion, d iffuse wheezing may occur due to bronchial hyperreactivity sti mu lated by the biogenic amines produced by the carcinoid tumor. 7. Skin manifestations are part of the classic man ifestations of the carcinoid tumor. Patients have intense cutaneous flushing lasting up to several hours. This involves most prom inently the face and u pper portions of the body. A rare skin man ifestation of a carci noid tumor i nvolving the pancreas or g a l l bladder is necrolytic erythema. Effective treatment of carcinoid tumors depends on their lo­ cation and symptoms. Loca lized disease and ai rway may respond to surgical resectio n . Metastatic d isease, however, prima rily involves treatment of severe symptoms associated with the carcinoid syndrome. Octreotide is a potent in­ h ibitor of hormone secretion by carci noid cel ls, and this agent can provide ef­ fective control of d i a rrhea , flus h i n g , and wheezing i n as m a ny as 75% of cases . 1 1 8 • Endocrinology
    • HYPE RCALC E M IA H y p e rCALC E M IAS H y p e r pa rathyro i d i s m C a ncer A c ute re n a l fa i l u re L it h i u m C o n g e n i t a l (fa m i l i a l hypoca l c i u r i c hype rca l c e m i a ) E n d o c r i n e d i se a s e s (Ad d i s o n s , p h eoch ro m ocyto m a , thyrotoxi c o s i s ) M i l k a l ka l a i syn d ro m e I m m ob i l iz a t i o n (exa cerbates a n o t h e r u n d e rlyi n g d i s o r d e r) A a n d D hypervita m i n o s i s S a rc o i d a n d oth e r g ra n u l o m a t o u s d i s e a s e s A/50. thiazide diuretics N otes 1 . Signs and symptoms of hyperca lcemia include neuromuscu lar weakness, ab- dominal pa i n , psych iatric d isturbance, renal stones , and fractures ( " bones, g roa ns, stones, and psychic moans"). 2. When hyperca lcemia is confi rmed ( usua l ly by ionized ca lcium measu re­ ment) , then a defin ite diagnosis must be established . 3 . Primary hyperparathyroidism is the most common cause of asymptomatic hy­ percalcem ia in an adult. Therapy for this entity depends upon the age of the pa­ tient and the presence of compl ications . Patients under 50 years old routinely undergo surgery. Other ind ications include: a. Elevation of serum ca lcium more than 0 . 25-0 .40 mmol/L over the upper limit of norma l b. H istory of a life-threatening episode such as dehydration c. DecreaSing renal function d. Renal stones e. Elevation of urliJ ary ca lcium > 400 mg/24 hours f. Sign ificant reduction of bone mass by noni nvasive measurements. 4. Ma lig nancy-associated hypercalcemia may be due to severa l mecha nisms: a . Bony invasion (e . g . , prostate, breast) Endocrinologv . 1 1 9
    • - b . Secretion of PTH-related prote i n ( i . e . , squa mous cel l a n d u roepithel ial cancers) c. Production of osteoclast activating factor, which is probably interleu kin- l (i e , myeloma) 5. Thiazide d i u retics i ncrease calci u m reu pta ke, whereas loop d i u retics (fu rosemide), after proper rehydration, promote ca lcium excretion . 6. Immobil ization does not cause hyperca lcemia alone, but may make an occult cause manifest, such as Pagets disease, hyperparathyroidism, or malignancy. H Y P E R P H O S P H AT E M I A H I G H P04 PARAS H ypopa rathyro i d i s m I ntest i n a l a b so r p t i o n (vita m i n D ) G rave s d i s e a s e H e molysis P a re n te ra l P04 O n co l og i c/o r g a n i n fa rction P a ra p rote i n A d d i so ns R e n a l fa i l u re A cidosis S a rc o i d o s i s/g ra n u l o m at o u s d i s e a s e N otes 1 . Hyperphosphatemia has many causes, which are outl i ned by the mnemonic "HIGH P04 PARAS . " Characterized by a high level of phosphorus ( H IGH P04), one of the primary causes is hypoparathyroidism . 2" Since parathyroid hormone is phosphaturic, hyperphosphatemia is a card inal feature of hypoparathyroidism . A second i m portant mediator in phosphorus homeostasis is vitamin D. Vitam i"n D enha nces intestinal absorption of phospho­ rus, and hyperphosphatemia may be seen with over-medication of vitamin D or in granulomatous diseases, in which there is enhanced conversion of vitamin D to its 120 • Endocrinology
    • active form . Si nce steroids enha nce the excretion of phosphorus into the urine,pa rticula rly mi neralocorticoids, Addisons d isease with its deficiency of steroidscan result in hyperphosphatemia Graves disease and other causes of hyperthy­roidism also act to decrease renal excretion of phosphorus. Enhanced cellular re­lease of phosphorus may occur with tumor lysis syndrome, organ infarction, orhemolysis. Hyperthyroidism also may act to increase cellular release of phospho­rus . An acute meta bolic or respiratory acidosis causes a cellular shift of phospho­rus out of cells, lead ing to hyperphosphatemia . Parenteral administration ofintravenous phosphate salts or phospholi pid i nfusions can increase serum phos­phorus levels . Abnormal, positively cha rged serum proteins, which may occurwith multiple myeloma, may cause a ma rked elevation of phosphorus. These pro­teins seem to have a very high-bi nding affinity for phosphorus. Finally, renal fail­ure is perhaps the most com mon and importa nt cause of hyperphosphatemia.This is commonly managed with intesti nal phosphate-binding resins and dietaryrestrictions. Phosphorus can be removed by dialysis only to a lim ited extent. H Y P E R P R O LAC T I N E M I APRO LACTI N SP re g n a n cyR e n a l fa i l u reO ra l c o nt ra ce pt ives a n d oth e r m e d i c at i o n sL i ver fa i l u reA d e n o m a ( p ro l a ct i n-s e c ret i n g tu m o r)C h est wa l l d i se a s e ( i n c l u d i n g h e rp e s zoste r, s u rg e ry)T hy ro i d a l d i se a s e ( hypothyro i d i s m )I n f i ltrative d i s e a s e o f t h e p itu ita ry ( s a r c o i d o s i s , X) h i st i ocyt o s isN u rs i n g/n i p p l e s t i m u l a t i o nS t a l k effectN otes1 . Normally, prolactin secretion by the pitu itary is restra i ned by hypotha lamicdopa m ine secretion . Thus, a ny process that d isrupts hypothalamic secretion ofdopamine or blocks its activity can cause hyperprolactinem ia. Endocrinology . 121
    • - 2 . Hyperprolacti nemia causes hypogonadism in men and, rarely, gynecomas­ tia and ga lactorrhea . It commonly causes hypogonadism , a menorrhea , and galactorrhea in women; h i rsutism is rare. 3 . Obtain a careful drug history. Drugs that block dopamine synthesis, release, and action include phenoth iazines, butyrophenones, metoclopra mide, methyl­ dopa , and reserpine. Estrogen sti mulation overcomes normal dopaminerg ic in hi­ bition . This effect is only seen in hig h-dose estrogen prepa rations. Estrogen a lso blocks prolactin action at the breast, preventing lactation . 4. In add ition to serum prolactin levels, la boratory evaluation includes thyroid function tests and, in the appropriate setting , renal and liver function tests . Most patients requi re cranial imag ing (MRI) 5 . Any process that affects the pitu ita ry sta lk ("stalk effect") blocks dopamine se­ cretion , releasing the pituita ry from dopa m i nerg ic inhibition and resulting i n hy­ perprolacti nem ia. H Y P E RTHYRO I D I S M T H E TS H T S H excess H a m b u rg e r thyrotox i c o s i s (occ u l t h o rm o n e i n ta ke) E ct o p i c thyro i d t i s s u e T hy r o i d g l a n d hyperf u n ct i o n S t i m u l a t o r of t h e thyro i d g l a n d H a s h i m otos ( r e l e a s e o f p refo r m ed h o r m o n e ) N otes 1 . "THE TSH " refers to the first test to order when eva luating thyroid function There a re six major mechanisms of hyperthyroidism ( 1 ) TSH excess, ( 2 ) "ha m­ burger" thyrotoxicosis/occu lt sou rce of hormone, ( 3 ) ectopic functioning thyroid tissue, (4) thyroid gland hyperfunction, (5) unregulated sti m ulators of the thyroid g land, and (6) Hashi motos/release of preformed hormone. Of these mechanisms, the latter th ree, "TS H , " a re the most com mon. TSH is elevated in the first case and suppressed in the other five In addition to TSH, assays for T3 and T4 func­ tion , auto-a nti body titers, and possibly scintillation scann ing a re often indicated . 122 • Endocrinologv
    • In acutely ill, hospitalized patients, TSH levels may not reflect thyroid function ac­cu rately and cannot be relied on .2 . TSH excess is quite rare and is caused by TSH-secreting tumors and scenarios in which the pituitary is resistant to feedback i n h i bition . Hamburger thyrotoxi­cosis ( ingestion of ani mal thyroid tissue) and surreptitious use of thyroid hormone(thyrotoxicosis factitia) a re secondary to an exogenous sou rce of thyroid hor­mone. Ectopic thyroid tissue is a rare condition in which ovarian tissue (strumaova rii) or a metastatic follicular thyroid carcinoma produces excess thyroid hor­mone . Thyroid gland hyperfunction occurs with a hyperfunctioning adenomaand in toxic multinodular goiter. Stimulators of the thyroid gland act l i ke TSH ,and the most common is the long-acting thyroid sti mu lator ( lATS) of Graves d is­ease. Trophoblastic tu mors may a lso produce a n a bnormal thyroid sti m ulator.Hashimotos thyroiditis as well as irrad iation, subacute, and chronic thyroiditiscause hyperthyroidism by excessive leakage of preformed thyroid hormone intothe circulation. Thyroid suppressive therapy is useless in these patients, and treat­ment is ai med at amel iorating the symptoms of thyrotoxicosis.3 . Manifestations of hyperthyroidism include nervousness, emotional labil ity, in­abi lity to sleep, tremors, frequent bowel movements, sweati ng , weight loss, andheat i ntolerance. Proximal muscle weakness, tremor, hyperreflexia, tachycard ia,hypertension with widened pulse pressure, and other signs of sympathetic over­sti m u lation a re cha racteristic . Graves d isease patients may a lso demonstrated isti nctive infiltrative ophthalmopathy and dermopathy. In a few (usually older)patients, a clin ical picture of apathy, weight loss, and hypermeta bolism possi blycom pl icated by heart fa ilure and atrial a rrhyth mias ("a pathetic thyrotoxicosis" )may be present. A rare syndrome of hypokalemic periodic paralysis may occur in thyrotoxic patients, especially Asian and Latin American men.4 . The following m nemonic l ists most of the causes of hyperthyroidismI G ET A T S HI rrad i a t i o nG rave s d i se a s eE xo g e n o u s h y p e rthyro i d i s m ( i od i n e , i a t rog e n i c , fact i t i o u s )T ox i c m u lt i n od u l a r g o ite rA denomaT S H - p rod u c i n g t u m o rS u ba cute thyro i d i t i sH a s h i m otosAlso: "TSH" (Trophoblastic disease, Struma ovarii, Heparin -all very rare) Endocrinology . 123
    • H YP O CALC E M I AIS PTH OK?I atrog e n i cS epsisP a rathyro i d ectomy/P s e u d o hy p o pa rathyro i d i s mT u m o r lys i s/T ra u m aH ypopa rathyro i d i s m/H ypo m a g n e s e m i ao stf; o m a l a c i a ( r i ckets)K i d n ey d i s e a s eN otes 1 . Hypocalcemia may be a tra n sient phenomena or a c h ronic conditi on .C ritical to determ i n ing the cause of a low measured serum calc i u m is under.standing the functional state of parathyroid hormone ( PTH; "IS PTH OK2 ") PTHacts to increase serum calcium, and in hypocalcemic states may be present, buttransiently dysregulated ; a bsent; present and ineffective; or overwhelmed .2 . When interpreting the serum ca lcium, remember that a low serum a lbuminresults in a low measurement of serum calc i u m . An ionized ca lcium measure­ment will be norma l .3 . Iatrogenic causes include tra nsfusions o f citrated blood products, plasmaexchange therapy, and medications such as heparin, prota m i ne, and g lucagonThese effects a re usually tra nsient and may not require treatment.4. Sepsis and critical ill ness often a re accompan ied by a low serum calciu m ,but often have normal ion ized calcium levels . Pa ncreatitis ca uses a persistentlow calciu m level during the acute stage for unclear reasons. Treatment is prob­a bly not ind icated in most patients, si nce the signs and symptoms of hypocal­cemia a re a bsent. Remember that IV calcium a n d hyperca lce m ic states mayprecipitate pancreatitis.5. Parathyroidectomy, either intentionally or as a result of thyroid surgery, re­sults in the a bsence of PTH . The im mediate postoperative period presents pa rtic­ular p roblems if severe bone d isease is p resent. Osteitis fi bros is results fromlong-stand ing hyperparathyroidism, and bone m i nera l deficits a re large, result­ing in the inability to respond to low serum calcium levels6. Pseudohypoparathyroidism is a hereditary d isease cha racterized by end.organ un responsiveness to PTH . PTH is present ( i n increased a mounts) and inef­fective. Parathyroid g land hypertrophy is present.124 • Endocrinology
    • 7. Tumor lysis syndrome and trauma causing rhabdomyolysis a re acute causes of hyperphosphatemia, and calci um levels fall precipitously. Concomitant renal fa i l u re exacerbates the hyperphosphatemia , and PTH is overwhel med . Treatment is di rected toward loweri ng phosphorous and im proving renal function 8. Hypoparathyroidism con occur as on isolated congenital defect or in asso­ ciation with other anomalies . Acq u i red hypoparathyroidism may occur after surgery (d iscussed above) or as on autoimmune phenomenon. PTH is absent or in insufficient amou nts. 9. Hypomagnesemia, when severe, is associated with hypoca lcemia due to i m paired PTH release. PTH is a bsent or inappropriately low. 1 0 . Osteomalacia (rickets) occurs when vita m i n D is absent (dieta ry, lock of sunl ight, i ntesti nal malabsorption!, defectively metabolized (a nticonvu lsa nt ther­ a py, vita m i n D-dependent rickets type I) or i neffective ( l iver disease, renal d is­ ease, vitamin D-dependent rickets type I I ) Without vitamin D, PTH is ineffective. 1 1 . Kidney disease results in phosphate retention, which lowers calci u m and interferes with conversion of 25-0H vita m i n D to its active 1 , 25 OH form . In a sense, it overwhel ms PTH and ma kes it ineffective . Reduci ng dietary phosphate a n d using phosphate binders a n d calcitriol thera py a re the cornerstones of treatment. H Y P O G LY C E M I A I NS U L I N O MAS I ns u l i noma N eo p l a s m ( e . g . , l a rg e retro p e rito n e a l t u m o rs ) S u lfony l u re a s U re m i a/re n a l fa i l u re L ive r fa i l u re I n s u l i n a nt i body syn d ro m e N ut r i t i o n ( " rea ctive hypog l yce m i a " ) O th e r d ru g s ( e t h a n o l , p r o p ra n o l o l , a s p i r i n ) M u n ch a u s e n s s y n d r o m e ( s e lf-a d m i n i stered i n s u l i n ) A d re n a l i n s uff i c i e n c y ( i n c l u d i n g pa n hypo p i tu i t a r i s m ) S ta rva t i o n Also: rare hereditary enzymatic defects Endocrinologv . 125lL
    • N otes 1 . I nsulin and sulfonylurea therapy cause the great ma jority of hypoglycemic episodes. A careful assessment of medications is essentia l, as mistakes i n med­ ications may cause hypoglycem ia (e.g , acetyl hexa mide su bstitution for aceta­ zola mide) Other medications can cause symptomatic hypoglycemia such as intravenous pentamadine in AIDS patients. Some drugs may have activity similar to sulfonyl u rea l agents (e.g . , Bactri m l , causing hypog lycemia i n elderly or mal­ nourished patients. 2. Symptoms of hypoglycemia are related to epinephrine secretion and CNS g lucose deprivation . A ra pid drop in g lucose level leads to symptoms associ­ ated with excess epinephrine secretion such as tachycardia, sweati ng, tremor, anxiety, and hu nger. With more g radual drops, CNS symptoms predom inate, such as dizziness, headache, clouding of vision, confusion, and seizures. 3 . Insulinoma is a rare tumor. Levels of i nsul i n , proi nsul in and C-peptide should be obta ined duri ng hypog lycemia Demonstration of low-g lucose and h i g h-in­ sul i n levels during the hypoglycemic episode is not sufficient evidence for the di­ ag nosis of i n s u l i noma . Factitious hypog lycemia from insulin i n jection or sulfonylurea d rugs is probably the most com mon cause of hypog lycemia in non­ diabetics. Insulin injection causes a rise in insulin levels, but low C-peptide and proinsu l i n levels. Most patients with insul inomas have elevated proinsu lin frac­ tions (> 25% of the total serum insulin) Chronic insulin in jection a lso may induce the development of anti-i nsulin antibodies . 4 . Pseudohy poglycemia is a term g iven to patients who have symptoms 2 to 5 hours after meals, but dont have an associated low gl ucose level . These pa­ tients may be referred for evaluation because of a spuriously low measurement. It should be remembered that a pproximately 25% of normal ind ividuals have a low serum g l ucose level 2 to 5 hours after a meal, so this alone is insufficient to diag nose true hypoglycemia . True hypog lycemia should cause symptoms and elicit a hypothalamic-pituitary response of increasing serum cortisol. 5 . I n the insulin antibody syndrome, insulin is bound by the antibodies after a mea l . Several hours later, the i nsulin is released and a hypoglycemic episode occurs. 6. Reactive hypoglycemia may be difficult to diag nose, and oral gl ucose toler­ ance testi ng is not helpfu l . A high percentage of normal people demonstrate a decrease in serum glucose, si nce insulin levels normally rise after a meal . 7. Tu mors a re a rare ca use of hypog lyce m i a , and i nsuli noma is the most com mon . Non-islet cell tumors ca use hypoglycemia by several mecha nisms: ( 1 ) release of insuli n-like growth factor I I ( IGF-I I ) or its high molecu lar weight precur­ sor ( " b ig " IGFI, ( 2 ) massive tumor burden with high g lucose utilization , ( 3 ) he­ patic infi ltration by tumor, and (4) production of autoa nti bod ies to insulin or its receptor. 126 • Endocrinology-
    • H Y P O P H O S P H AT E M I A PHOSPHORS P a rathyro i d e ctomy H yp e rve n t i l a t i o n O n cog e n i c S ta rva t i o n -refe e d i n g P h o s p hate b i n d e rs H y p e rt h e r m i a O st e o m a l a c i a R ecove ry f r o m d i a beti c ketoa c i d o s i s S te ro i d s P H O S FAT E P a rathyro i d ectomy H ype rpa rathyro i d i s m O n cog e n i c S te ro i d s F ee d i n g A l ka l o s i s T h e r m a l i nj u ry/hype rt h e r m i a E nt e r i c ( P04 b i n d e rs , d i et a ry d ef i c i e n cy) 1 . Hypophosphatemia can be moderate or severe . Severe hypophosphatemia is defined as phosphorus levels in the seru m below 0 . 3 mM/L The effects of phosphorus depletion include rha bdomyolysis, cardiomyopathy, respiratory fail­ ure, eryth rocyte dysfu nction, leu kocyte dysfu nction , skeleta l deminera l ization and bone disease, nervous system dysfunction , and metabolic acidosis. 2 . Hyperparathyroidism is associated with phosphorus depletion; however, after parathyroidectomy for long-standing hyperparathyroidism, " h ungry bone syn­ drome" may occur, and large a mounts of phosphorus may go ra pidly into the bone, producing clinical hypophosphatemia. Hyperventilation results in a res­ piratory alkalosis. The elevation in pH increases the rate of g lycolysis and sub­ sequent phosphorylation of glucose. This results in an i m med iate cellular uptake of phosphorus and hypophosphatemia. So-called oncogenic osteomalacia is a Endocrinology . 127D
    • renal phosphate wasting syndrome ossociated with certa i n mesenchymaltumors. It is thoug ht that an as yet u nidentified mediator promotes excessive u ri­nary phosphorus loss. Starvation with subsequent re-feeding also may result i nsignificant hypophosphatemia in the initial days o f calorie repletion . T h e sameeffect can be seen with hyperali mentation. I n chronic alcohol ics, phosphorus content is reduced i n skeletal muscles,probably because of renal phosphate losses. When chron ic alcoholics go i ntowithdrawal from alcohol, phosphorus may be ra pidly taken up into the skeleton,muscle, or liver, resulting in severe hypophosphatemia, wh ich may i n turn pre­cipitate acute rha bdomyolysis. Phosphate-binding a ntacids may decrease in­testi nal absorption of phosphorus and lead to hypophosphatemia if overused . In cases of hyperthermia, particularly the neuroleptic mal ignant syndrome,phosphate levels may fall acutely. A similar phenomenon can be seen in the re­covery from exhausted exercise or with severe thermal burns. Osteomalacia orrenal ·rickets results in renal tubular losses of phosphorus. This results from a defi­ciency of vita m i n D, which norma l ly promotes phosphorus absorption . I n pa­tients with d i a betic ketoacidosis, metabolic acidosis a n d i ns u l i n-deficiencymobil ize intracellular phosphate stores and lead to their excretion in the urine.These patients a lso may have had poor nutritional i nta ke, leading to a lowerlevel of phosphate stores. When insu l i n is then administered a n d there is in­creased g lucose entry in the cells, phosphorus also enters the cells, and serumhypophosphatemia may result. Finally, steroid therapy, particularly aldosterone,but also glucocorticoids, tends to promote phosphate excretion into the urineand may lead to a depletion of total body phosphorus.3 . Treatment of hypophosphatemia depends on the clin ical scenario. In acutesymptomatic hypophosphatemia , phosphorus salts may be g iven by i ntravenousiniection . In cases with coexistent hypokalemia, potassium salt may be adminis­tered . In treating alcoholics -who often are phosphate-, potassi um-, and mag­nesium-deficient- potassium salt and magnesium su lfate may be coad ministeredalong with glucose.128 • Endocrinology
    • SY N D R O M E O F I N A P P R O P R I AT E A N T I D I U R ET I C H O R M O N E S E C R ET I O NSIADHS m a l l ce l l c a rc i n o m a a n d o t h e r ca n c e rs ( p a n c re a t i c , H od g k i n s d i s e a s e , thyro i d , d u o d e n a l )I nfe ct i o n s ( t u b e rc u l o s i s , p n e u m o n i a , l u n g a b s c e s s )A R D S/m echa n i c a l ve n t i l a t i o n/p u l m o n a ry d i s e a s eD ru g sH ea d t ra u m a/n e u ro l o g i c d i s e a s eN otes1 . SIADH is the term applied to excessive vasopressin release associated withhyponatremia without edema . U r i ne is i na ppropriately concentrated (usua l ly> 300 m mol/L) despite a low plasma osmolal ity a n d seru m sod i u m con­centration . Sod i u m excretion in the urine is mai nta i ned ( usua lly > 20 m mol/L)by hypervolem ia, suppression of the reni n-ang iotensin-aldosterone system, andincreased levels of atrial naturietic peptide. BUN and creati n i ne may decreasedue to di lution .2 . SIADH may be secondary to malignancies, pulmonary diseases, d rugs, andcentral nervous system disorders. Mal ig nancies causing S IADH include smallcell carcinoma, pancreatic carcinoma, Hodg ki ns disease, thyroid carci noma ,and duodenal carcinoma . Pulmonary diseases causing S IADH include tubercu­losis, pneu monia, and lung a bscess, as wel l as chron ic obstructive pul monarydisease, ARDS, and mecha nical ventilation . Drugs that may cause SIADH i n­clude hypoglycem i c agents, psychotropics, na rcotics, and chemothera peuticagents . Central nervous system disorders ca using S IADH incl ude headtrauma, hemorrhage, encephalitis, men ingitis, Guillain-Barre, and porphyria .Other causes o f euvolemic hyponatremia i nclude psychogenic polyd i psia, hy­pothyroidism, adrenal insufficiency, pa in, surgery, and anesthesia .3 . SIADH should be suspected when patients have hyponatremia and a con­centrated u rine (> 300 m mol /kg) in the a bsence of dehyd ratio n . I m portant Endocrinology . 129
    • - conditions to rule out include dilutional hyponatremia (such as occurs in adreno­ corticosteroid insufficiency), edematous states (CHF, hypothyroid ism) , hyperten­ sive states (renal a rtery stenosis), diuretic use, "pseudohyponatremia" (excessive plasma trig lycerides or proteins), and primary polyd i psia (a lways associated with a dilute urine, osmolal ity < 1 50 m mol/kg ) . 4 . A water load test a s well a s urinary or plasma AVP levels a re useful i n the eva l uation . In the water load test, a patient drinks a la rge volume of fluid and then urine is col lected in hou rly sa mples. Normal ly, at least 65% of the water should be excreted by 4 hours, or 80% by 5 hours, and the lowest urine osmo­ lal ity (usually reached in the second hour) should be less than 1 00 mmol/kg . Plasma AVP is i m m easura ble i n hyponatremic states, but i n SIADH it is de­ tecta ble even after a water load. 5 . Treatment of SIADH involves relieving the underlying cause a nd fluid restriction . The drug demeclocycline inhibits ADH and may be a useful treatment. Some pa­ tients with chronic SIADH can be treated with a high sa lt and protein diet. The high osmolarity will increase free water excretion . 130 • Endocrinologv
    • mD N E P HROLOGY Genera l ConsiderationsThere a re two ways of approaching renal disease : 1 1 ) based on etiology, asoutli ned in the MEDICINE DOC mnemonic, and 1 2 ) based on pathology from arenal biopsy. It is i m po rta nt to recog n ize that the sa m e disease process cancause different pathological processes in the kidney Ifor exa mple , systemic lupuserythematosus may cause a variety of renal lesions) . Metabol ic-e. g . , amyloidosis, hyperuricemia E ndocrine - e . g . , hyperca lcemia, hyper and hypothyroidism, SIADH and diabetes insipidus Drugs/medicines - e . g . , chemotherapeutic agents, anti biotics, rad iocon- trast dye I nfection - e .g . , H IV-related , tuberculosis, pyelonephritis Congenita l - polycystic kidney disease, Alports syndrome, reflux nephropathy I m munologic- e . g . , Goodpastures, Wegeners g ranulomatOSiS, SLE Neoplastic - e . g . , renal cell carci noma , transitional cell carcinoma, tumor lysis syndrome Exotic diseases -e. g . , sarcoidosis, ITP, cryog lobulinemia Degenerative - ag i ng, ?hypertension Occupational!environmental - trauma Card iovascu la r - e . g , atherosclerOSiS, hypertensive nephropathy, choles­ terol emboli A multitude of metabolic disorders may cause renal d isease. These includeamyloidosis, hypercalcemia, and other diseases that lead to abnormal i ncreasesin metabolic products in the blood stream . Hyperlipidemia leading to atheroscle­rosis a lso could be considered a metabolic disease leading to renal insufficiency. Endocrine diseases may be made man ifest by renal insufficiency. Aga i n ,hypercalcemia, secondary t o hyperpa rathyroidism, c a n lead t o renal fa i l u reand/or nephrolithiasis. Dia betes can cause proteinu ria or progressive renal in­sufficiency and, ulti mately, renal fa ilure . Other endocri ne syndromes i nvolVingthe kidney i nclude SIADH and hypo- and hyperthyroidism . In addition, renal cellcarcinoma may have several associated para neoplastic syndromes. Nephrology . 1 3 1
    • ..... . Drugs are a frequent cause of renal insufficiency, and virtual ly any drug can cause renal disease. A common problem is renal insufficiency ind uced by anti­ hypertensive a gents, especi a l ly ACE-i n h i bitors. Other forms of d rug-i nduced renal disease i nclude interstitial nephritis and forms secondary to chemothera­ peutic agents, intravenous radiocontrast, or i ntravenous d rug a buse . Many types of infections ca use renal d isease . H I V d i sease ca n lead to severe protei nuria and renal fa i l u re . Tu berculosis may prima rily involve the kid­ neys and the u rinary tract. Pyeloneph ritis is also a common i nfectious disease in­ volving the kidneys. Congenital diseases can cause renal man ifestations. Anomalies of the uri­ nary tract and chronic reflux nephropathy may lead to renal fa i l ure. Polycystic kidney disease and medulla ry sponge kidney disease are fa milial causes of renal fai lure. Other inherited metabolic diseases such as Fabrys d isease and various storage diseases can lead to renal insufficiency. A va riety of congenital disor­ ders may cause renal stones, including cystinosis and Lesch-Nyhan syndrome. Immunologic diseases often affect the kid neys, and renal d isease may be the first man ifestation of an i m m u nolog ic disease . Virtua lly a l l of the collagen­ vascular d iseases (e.g . , SLE) have renal man ifestations. The vasculitides, includ­ ing Wegeners , Goodpastures, and polya rteritis nodosa , may lead to rena l fa ilure. Neoplastic disease may a rise primarily i n the kidneys or involve the kidneys secondari ly. Renal cel l ca rcinoma can be widely metastatic and often has asso­ ciated para neoplastic syndromes. Metastatic tumors or loca lly invasive tumors, often gynecolog ic, may cause com press ion of the u reters and renal fa i l u re . Hyperca lcemia secondary to malig nant disease c a n lead to renal fa i l u re, a s can mu ltiple myeloma . Numerous exotic diseases affect the kid neys, i ncluding sarcoidosis, fam i l ial Mediterranean fever, and ITP. Some of these d iseases a re thoug ht to have an im­ mu nologic basis. Perhaps the most i m portant aspect of degenerative disease to consider is the effect of aging on renal functio n . The glomerular fi ltration rate decreases steadily with age, and a low serum creati n i ne may not reflect actual renal func­ tion in an elderly patient. Occupational and environmenta l exposures may lead to renal dysfu nc­ tion . Extrinsic trauma can cause kidney damage, hematuria , or fra nk bleed ing. Hydrocarbon exposure may cause Goodpastures syndrome. Cardiovascular diseases may i nvolve the kidneys secondarily. C hronic hy­ perte nsion can lead to renal i nsuffi ciency a n d , u lti mately, re nal fa i l u re . Cholesterol emboli m a y occur with severe atherosclerotic disease after a rad i­ ogra phic dye procedu re . Also, congestive heart fa ilure is a very com mon cause of pre-renal azotemia . 132 • Nephrology b
    • Clin ical Sym ptoms and Signs EDEMAT H E L E A K O F V E I N S o r VA L V E SV e n o u s d i s e a s e (o bstru c t i o n , i n s u ff i c i e n cy)A l b u m i n u ri a/a l b u m i n l o s s i n sto o lL y m p h a t i c obstruct i o n ( c o n g e n it a l , a cq u i re d )V o l u m e ove r l o a dE l ectro l yte/n u t ri t i o n a l d e f i c i e n cyS e p s i s/ca p i l l a ry l e a korTumorH ea rt fa i l u reE n teropathy ( p rote i n- l o s i n g )L ive r fa i l u reE n d o c r i n e ( hypothyro i d i s m , a l d o s t e ro n i s m , d i a betes)A I t i t u d e s i ck n e s sK i d n ey d i se a s e ( re n a l fa i l u re , n e p h ro t i c syn d ro m e )O bstruct i o n o f l y m p h a t i c sF i lariasisV e n o u s th ro m bo s i sE c l a m p s i a/preg n a n cyI a t rog e n i cN u t r it i o n a l d ef i c i e n cyS e p s i s/ca p i l l a ry l e a kN ote"VALVES" refers to the loss of venous va lvu lar com petence with a g i n g , acommon cause of edema Edema may result from venous disease (thrombosis, Nephrologv . 133
    • extrinsic com pressi on, tra u m a , venous va lvu lar i nsuffi ciency) , loss of a l b u m i nInephrosis, protein-losing enteropathy) , lymphatic obstruction Icongenita l , malig­nant, filariasis) , volume overload ICHF, renal fa ilure, ci rrhosis), electrolyte/nutri­tional deficiencies that cause a loss of venous integrity, and sepsis a nd othersystemic conditions causing capillary leak . H E M AT U R I AUA RBCSU ret h raA rt i fa ctua l (e . g . , d a r k u r i n e , m e n s e s , m e d icat i o n s )R e n a l (e . g . , t ra u ma , cys t s , pye l o n e p h r i t i s )B ladderC o l l e ct i n g syste mS yste m i c d i s o rd e r (e . g . , vasc u l i t i s , coa g u l o pa t hy)N otes1 . Hematuria is defined as the presence of g ross blood or RBCs I> 1 -2 perh pf) i n the spun u ri na ry sed iment. It is important i n itially to look at the sed i ment torule out false hematu ria . Certa i n med ications Irifa m p i n , phenazopyrid ine) anddiseases Iporphyria) may alter u rine color. Nso, both myog lobinuria and hemo­globinu ria cause a pos itive d i pstick test with a n egative u ri na ry sed i ment.Menstruation also con be mistaken for hematuria.2 . Hematuria may origi nate at any site from glomerulus to the u rethra . The pres­ence of "crenated" RBCs, RBC casts, proteinuria , or elevated BUN and creatininesu pport a glomerular source. Isolated hematuria IWithout casts or prote i n u ria)suggests bleed i n g from a site i n the col lecti ng syste m , bladder, or u reth ra .Poss ibil ities i nclude neoplasms, TB, renal stones, tra u m a , pa p i l l a ry necros is,ana lgesic neopathy, prostatitis, cystitis, or u reth ritis.3 . I n itially, exclude UTI , coagu lation disorders, and TB. The patients age andpresentation determine the d i rection of the work-u p . For exa m ple, a you n gfemale with dysuria would most likely b e treated with a trial o f anti biotics, whilea n older man with recent onset of g ross hematuria may be i nvestigated withrenal i maging a nd/or cystoscopy. In younger patients without evidence of i n­fection, an IVP is often the first imaging test ordered .134 • Nephrology
    • 4 . A common rena l disease that features hematuria is IgA neph ropathy. IgAnephropathy is cha racterized by gross or microscopic hematuria without othersym ptoms. The prognosis is va riable, but disease progression Iypica lly is slow,with approximately 50% of patients developing renal fa ilure within 23 years ofdiag nosis. Self-l imited acute renal fa ilure may develop folloWing on upper respi­ratory infection. There is no known effective treatment for IgA neph ropathy, andthe role of renal biopsy in this disorder is controversia l .5 . Some of- the more common causes of hematu ria are summarized by the fol­lowing m nemon ic:I PEE RBCSI nfecti o nP s e u d o h e m a t u r i a ( m e n se s , d a r k u r i n e )E xe rc i s eE xt e r n a l t ra u m aR e n a l d i se a s e ( g l o m e ru l a r s o u rce)B e n i g n p rostat i c h y p e rt r o p hyC a n cerS to n e s6 . Here i s a more complete differential for hematuria:I D PASS H E MATU RIAI gA n e p h ro pathyo r u g s/da rk u ri n e ( p s e u d o h e m atu r i a ) _P o lycysti c k i d n ey d i s e a s eA n a l g e s i c n e p h ro pathyS ickle cellStones Nephrology . 1 35
    • H e m og l o b i n u ri a , myog l o b i n u ri a , p o rp h y r i aE xe rc i s eM a l i g n a n cyA c ute g l o m e ru l o n e p h r i t i sT ra u m aU re t h r i t i sR e n a l i n fa rct i o nI n fect i o nA I po rt s syn d ro m e a n d o t h e r i n h e ri t e d d i s ea s e s ( e . g . , s i ck l e ce l l , p o l ycys t i c k i d n ey d i s e a s e ) H YP E RTE N S I O NI C H ECK A BPI d i o pa t h i c ( e s s e n t i a l )C N S d i s o r d e rsH i g h o u t p u t statesE ndocri ne d iseasesC oa rctat i o nK i d n ey d i s e a s eA cu t e stressB i rt h c o n t r o l p i l l s a n d other d ru g sP re g n a n cyN oteEssential hypertension accou nts for g reater than 90% of hypertension cases .The primary causes of a n elevated blood pressure a re outli ned by " 1 C H EC KA B P. "136 • Nephrology
    • S E C O N DA RY H Y P E RT E N S I O NR E NALSRenalE ndocri neN e u ro l og i cA o rt i c coarct a t i o nL i c o ri ce g l u ttonyS c l e ro d e r m aN otes 1 . Hypertension is idiopathic, "essentia l , " or secondary to one of the causesoutli ned by "RENALS " 2 . Renal diseases that cause hypertension incl ude many types of re nal parenchymal d isease as well as renovascu lar hypertension.3 . Endocrine causes of secondary hypertension are acromegaly, aldosteronism,j-G cel l tumor, Cushings synd rome, pheochromocytoma, and hyperca lcemia . Pheochromocytomas are characterized by pa roxysmal or sustai ned episodes of severe hypertension . Headache, pal pitations, and/or profuse diaphoresis a realmost a lways associated with the hypertension . The tumors may secrete epi neph­ rine, norepinephrine, serotoni n , or nothing. The "ten percent rule" refers to the ob­servation that 1 0% a re malignant, 1 0% are bi latera l , and 1 0% are extra-adrenal . Extra-adrenal sites include sympathetic ganglia (organ of Zuckerkandel) and thebladder (m icturition-ossociated symptoms). A J-G cell tumor produces ren in leadingto hypertension . It may resemble Conns syndrome (primary hyperaldosteron ism ) ,except that renin levels are decreased in Conns synd rome. Ora l contraceptives could be considered an exogenous endocrine cause of secondary hypertension. Estrogens sti mulate ang iotensinogen production by the liver, thereby increasingang iotensin I I and aldosterone levels. Steroid therapy also raises blood pressure .4 . Neurologic disorders caus ing hypertension include increased intracranial pressure, acute spinal cord injury, dysautonom ia, polyneuritis (acute porphyria, lead poisoning), and psychogenic factors .5 . Aortic coarctation may be diagnosed by a blood pressure and pulse differ­ential between upper and lower extremities and characteristic rib-notching (from increased flow through intercosta l a rteries) seen on x-ray. 6. Licorice contains glycyrrhizic acid , which increases the m i neralocorticoid ef­ fects of endogenous cortisol.7 . Scleroderma renal crisis is a d ramatic and l ife-threatening manifestation ofthe disease. ACE inhi bitors are the treatment of choice. Nephrology . 137
    • C linical Conditions or Diagnoses H Y P E R KA L E M I A A HI K A cidosis H ypoa l d oste ro n i s m I a trog e n i c/ I n a cc u rate m e a s u re m e n t ( LA B e rror, d r u g s , I V p ota s s i u m ) K i d n ey d i se a s e ( re n a l fa i l u re , r e n a l t u b u l a r d i s e a s e ) N otes 1 . The primary causes of a high seru m potassium a re summa rized by "A H I K . " Acidosis causes potassi u m to sh ift out o f cells. Hypoaldosteronism causes hy­ perkalemia because aldosterone normally promotes renal potassi u m excretion. Iatrogen ic causes of hyperka lemia include drug therapy ( h epari n , potassi um­ sparing d i u retics) and IV solutions containing potassi u m . I naccurate measure­ ments may be obtai ned when hemolysis of the speci men occurs or from poor blood d rawi ng tech nique (overi nflation of blood pressure cuff) Fi nally, kidney disease inh ibits normal potassium excretion and leads to hyperka lem ia. 2 . True hyperkalemia occurs by one of three mechanisms: inadequate excretion ( renal d isease, hypovolemia, hypoaldosteronism, potassiu m-spa ring diuretics), potassium shift from tissues (tissue damage, d rugs, acidosis, hyperosmolality, i n­ sulin deficiency, hyperka lemic periodic paralysis), or excessive i ntake. Pseudo­ hyperkalemia occurs with thrombocytosis, leukocytOSiS, or in vitro hemolysis. 3 . Renal mecha nisms of hyperka lemia i nvolve a decrease in fi ltered blood or tubular d isease. Acute renal fa ilure is more l i kely to cause severe hyperka lemia than chron ic renal insufficiency, un less oligu ria supervenes. Hyporen inemic hy­ poaldosteronism may be seen in patients with moderate renal dysfunction . Type IV renal tubular acidosis, freq uently seen in diabetics as well as other interstitial nephritides, is assoc iated with a hyperchloremic meta bo l i c acidosis. Non­ steroidal anti-inflam matory d rugs, converting enzyme inhi bitors, and beta-block­ ers may induce hypoperinemic hypoaldosteron ism . 138 • NephrologV•
    • 4 . Drugs that may induce hyperkalemia incl ude hepa rin ( i n h i bits aldosteronesecretion), potassiu m-spa ring diuretics, succinylcholine, d igita l is, and a rg i n ine,as well as NSAIDs, ACE inh ibitors, and beta-blockers.5. Artifactual elevationof potassi u m may occur if blood is drown after repeatedclenching of the fist and tourniq uet application . For this reason , a lways i m medi­ately recheck on elevated potassium level .6. Ma nagement should involve o n i mmediate E KG to look for hig h-peaked Twaves, prolongation of the PR interval , or com plete heart block. Progressive hy­perka lemia leads to a "sinewave" E KG configuration, ventricular fibrillation, andstandsti l l . Acute interventions include administration of IV ca lcium (which is car­dioprotective) as well as IV insul i n , glucose, bicarbonate, and possibly epi neph­rine, a l l of which sh ift potass i u m i ntracellula rly. Potass i u m-bi nding resins,diuretics, and/or dialysis may be i nd icated to remove potassium from the body.7. Here is a more complete list of the causes of hyperka lem i a :A BAD K PLI G HTA I d ostero n e d e f i c i e ncy (Ad d i s o n s co n g e n i t a l a d re n a l hype r p l a s i a , hypore n i n e m i a , h e p a r i n )B l ood d i se a s e s (th ro m b ocytos i s , l e u kocytos i s , l e u ke m i a )A cidosisD ru g sK i d n ey d i se a s e ( re n a l fa i l u re , re n a l tu b u l a r d i s e a s e )P e r i o d i c p a r a l ys i s ( hype rka l e m ic)L a b o ratory e rrorI n trave n o u s pota s s i u m a d m i n i st rat i o n , a nt i b i ot i c sG eo p h a g i a/excess ive i n ta keH yp e r os m o l a l ityT i s s u e n ec ros i s Nephrology . 139
    • H Y P E R N AT R E M I A AVP A l tered m e n t a l statu s/a b n o rm a l t h i rst/a c c e s s to wate r i m pa i re d V o l u m e l o s s ( re n a l , ext ra-re n a l ) P r i m a ry s od i u m g a i n ( r a r e , i a t rog e n i c ) N otes Arg i n i n e vasopressi n IAVP) is a lso cal led antidiuretic hormone, and its major action is to conserve water by concentrating the urine. AVP release is primarily regulated by changes in concentration of plasma solutes. As plasma osmolality rises, so do the levels of AVP. To a lesser extent, decreases in plasma vol ume also stimulate the release of AVP. Water deprivation causes both hyperosmolality a nd vol ume depleti on, and thus is a potent sti m u l us to AVP release. AVP then acts to maxi mally concentrate the urine, thus defending vol u me . The loss of ef­ fective AVP leads to volume loss and hypernatremia. 1 . Hypernatremia is defined as a serum sod i u m of g reater tha n 1 45 mM/L. Si nce sodi u m and its accompanying anions are the major effective osmols of the extracellular fluid, hypernatremia is by defin ition a state of hyperosmolalily . The three major mechan isms of hypernatremia are outlined by the AVP m nemon ic: 1 1 ) altered mental status or impaired access to free water; 12) volume loss; 13) pri­ mary sod i u m ga i n . In the strictest sense, either free water is lost, which is the most common scenario, or, more rarely, tota l sod i u m is gai ned . The appropriate re­ sponse to hypovolem ia and hypernatremia is i ncreasing water intake Isti mu lated by th irst) and excreting a maximally concentrated u rine Icontrolled by AVP release) . 2 . Most cases o f hypernatrem i a a re secondary to a net l oss o f free water. Altered mental status in acutely ill or post-operative patients, l i m ited access in i nfants, hand icapped patients and mecha nically ventilated patients, and abnor­ mal thi rst mechanism in patients with a hypothalamic in jury all cause a net loss of free water. Hypothalamic i m pai rment may be d ue to granulomatous disease, tumors, cerebrovascular accident, or, ra rely, "essential hypernatrem ia . " Essential hypernatremia represents an osmo-receptor defect in AVP release. It is character­ ized by a lack of response to fOrced water intake. 3. Volume depletion from free water losses may be either renal or extra-rena l . Rena l free water losses a re most com monly secondary to drugs, such a s loop 140 • Nephrology .»
    • diu retics, which interfere with counter-cu rrent reabsorption. An osmotic diuresis also may result i n net-free water loss. Hyperglycemia from uncontrolled diabetes is the most common cause; however, Ma n n itol a d m i n istration has the sa me result. I ncreased urea levels from a hig h-protein d iet or steroid therapy can result in an osmotic d iuresis and net-free water loss. When there is a loss of AVP function, the syndrome of diabetes insipidus re­ sults . There a re two primary categories of dia betes i nsipidus: central dia betes i n­ sipidus, which resu lts from destruction of the neurohypophysis and thus the neurons which secrete AVP, and nephrogenic diabetes, which enta ils a lack of responsiveness of the kid ney to AVP. This may be either a primary congen ital defect or secondary to l ithium a d m i n i stration , hyperca lcem ia, hypoka l e m i a , papillary necrosis, o r pregnancy. Pregnancy is an interesti ng physiolog ical state, in that the placenta secretes a vasopressi nase, which decreases the effective ac­ tivity of AVP. 4 . Lastly, primary sodium gain may lead to hypernatremia . However, this is rare and iatrogenic. Most com mon ly, this results from administration of hyper­ tonic saline or sod ium bica rbonate solutions in hospitalized patients. 5. like hyponatremia, patients with hypernatremia can be d ivided i nto hypo­ volemic, euvolemic, and hypervolemic categories . Hypavolemic hyperna­ tremia occurs in the very you n g and very old, and is seen i n situations of extreme extracellular fluid losses and/or an inabil ity to take in free water ade­ quately (febrile i l lnesses, vom iting, dia rrhea, and severe renal losses) . Euvolemic hypernatremia a lso can be due to extracellular fluid loss without adeq uate access to water, or from the loss of control of water homeostasis Diabetes i n­ sipidus, either centra l or nephrogenic, causes an inability to reabsorb fi ltered water, resu lting in system i c hyperton icity but a hyperos molar u r i n e . Hyper­ volemic hypernatremia, a lthough u ncom mon, is iatrogen ic , and it may occur after sod ium bica rbonate in jection or administration of hypertonic saline. 6 . For the g reat majority of patients, the treatment of hypernatremia i n itially i n­ volves volume repletion with hypotonic fluids Normal saline is relatively hypo­ tonic, but shou ld only be used to establish Circulatory stability. Once Circulatory sta b i l i ty is atta i ned , patients can then be rehyd rated either i ntravenously or (preferably) orally with more hypotoniC fluids Be carefu l to slowly correct the water deficit - no more than 1 2 m Eq/L over 24 hours . Cerebra l edema may result from too rapid correction. 7. I n choosing the appropriate fluids for correction, it is critical to know the pa­ tients urina ry concentrati ng capacity. Some patients, especia lly those with d ia­ betes insi pidus, have uri nary osmolalities as low as 40 to 60 m mol/L. An infusion of half-normal saline (osmolality 1 54 m mol/L) will result in a further rise in serum sodium, and so more hypotonic fluids (5% dextrose in water) should be adminis­ tered . In some cases of central d iabetes insi pidus, a synthetic analog of antidi­ uretic hormone, DDAVP, can be admin istered either intravenously or intra nasal ly. 8 . H el pfu l formu las for correct i ng total body sod i u m and water deficits a re ava ilable in the New EnglandJournal of Medicine, Vol . 342(20): 1 497, 2000. To estimate the effect of 1 L of any i nfusate on the serum osmolal ity, use the fol­ lowing formula : Nephrology . 1 4 1h
    • . + [i nfusate Na+ - seru m Na+] Cha nge I n seru m Na = [tota l body water (l iters) + 1 ] Total body water is usua lly estimated as 40-60% of the body weight (0 4-0 6 x wI. in kg ) . This formula allows you to predict the effect of 1 L of a particular in­ travenous fluid on the serum sod i u m . To decide how m uch fluid to g ive, sim ply d ivide the desired correction (e . g . , 1 2 m Eq/24 h rs) by the change in serum Na+ calculated by the eq uation . Also add to this amount extra volume for ongo­ ing losses during the i nfusion time. This approach works well for most causes of free water loss as long as the change in electrolyte concentrations and ongoing free water a re ca refu lly monitored . As mentioned a bove, the individual patients urinary concentrating abil ity must be known (urine osmolal ity) . 9. AVP conserves water by concentrating the u rine. It increases the permeability of the d ista l collecting d uct, thereby facil i tating free water reu pta ke i nto the medullary interstiti u m . In the a bsence of AVP, free water is lost and hype rna­ tremia ensues . The ca uses of hypernatremia a re organ ized by the fol lowing m nemonic. "TIGHT COLLECTOR" refers to a n i m permeable collecting d uct (lack of effective AVP activity) and subsequent free water losses, and "A STU PID MD" refers to the often iatrogenic causes of primary sodium gain. T I G H T C O L L E CTOR V S . A S T U P I D M D L o w A VP 2 ° to eNS disease T ra u m a In fect i o n ( m e n i n g i t i s , e n c e p h a l it i s , etc . ) G u i l l a i n- B a rre H e m orrh a g e T u m o r/ma s s In e ffe c tive A VP 2 ° to rena l impairmen t C o n g e n ita l n e p h ro g e n i c d ia betes i n s i p i d u s O s m ot i c d i u re s i s L ith i u m/d r u g s L oo p d i u re t i c s E a rl y p h a s e of ATN ( p o l y u ric) C a l c i u m e l evat i o n T u b u l a r defect ( e s p ec i a l ly m e d u l l a ry cys t i c k i d n ey) O t h e r i nt r i n s i c re n a l d i se a s e s R e l i e f o f u ri n a ry obstru ct i o n Nonrenal fre e wa ter losses V o m iti n g/d ia rrhea/NG s u ct i o n S ki n/sweat i n g 142 • Nephrology-
    • Inadequa te in takeA Ite red m e n ta l status/a l t e re d t h i rst/a c c e s s i m p a i rm e nt Primary sodium gainS a l i n e i nf u s i o n ( hypert o n i c r e l a t i ve to c o n c e n t ra t i n g a b i l i ty)T PNU te r i n e i nj e ct i o n with hype rto n i c sa l i n eP O saltI V b i ca rbon ateD ia lysate ( hy p e rt o n i c)M i n e ra l oc o rt i c o i d s (C u s h i n g s , C o n n s)D rown i n g , d r i n k i n g s e a water H Y P O KA L E M I ALESS KL a s i x/d i u ret i c sE nt e r i c l os s e s ( e . g . , d i a rr h e a , f i st u l a s)S te r o i d s ( C u s h i n g s , a l d ostero n i s m , exo g e n o u s stero i d s )S h i ft (a l ka l o s i s , treatm e n t o f D KA, p e ri o d i c pa ra l ys i s )K i d n ey d i se a s e ( re n a l t u b u l a r a c i d o s i s [ RTAI , L i d d l e s syndrome)A M EGA K DROPA l ka l o s i sM ag n e s i u m d e p l e t i o nE nt e r i c l o s s e s ( d i a rr h e a )G l u c o c o rt i c o i d exc e s s ( C u s h i n g s , exo g e n o u s s t e ro i d s , e cto p i c ACTH )A l d o s t e ro n i s m Nephrology . 143
    • K etoa c i d o s i s D i u re t i cs (th i a z i d e s , f u r os e m i d e , e t h a c ry n i c a c i d ) R e nta l tu b u l a r d i s e a s e s ( RTA, L i d d l e s , l e u ke m i a , a nt i b i ot i cs ) O s m o t i c d i u re s i s P eriodic paralysis N otes 1 . The principle mechanisms of hypokalemia a re a . E nteric losses b. Kid ney losses ( RTA, d i u retics, osmotic d i u resis, m i n e ra locorticoids and g l ucocorticoid excess, mag nesiu m deficiency) c. S h ift of cel lular potassi u m (alka los is, period ic paralysis, i n s u l i n effect, catecholami nes) 2. Enteric losses are usually due to diarrhea , although vomiting, vil lous adeno­ mas, fistulas, and u retosigmoi dostomy may lead to excessive potassium loss. With vomiting, loss of gastric acid leads to metabolic alkalosis, which increases tu bular bicarbonate concentration . Increases in bicarbonate a n ions eventuate in i ncreased tu bular potassium concentration and su bsequent excretion . I n addi­ tion, secondary hyperaldosteronism from volume depletion contri butes to potas­ sium losses. 3 . Kidney losses can occur with volume concentration and m etabolic alkalosis, d i u retic use and osmotic d i u resis, excess m i neralocorticoid activity, or in renal tu bular d isease. Diuretics aug ment sod ium and fluid del ivery to the distal tubule potassium secretory site, thereby enhancing potassium losses. I n osmotic diure­ sis, such as in diabetic ketoacidosis, excessive potassium losses occur d ue to u ri­ n a ry l osses of negatively cha rged keto acids. The serum potassium may be normal i n itia lly due to cel lular sh ift, but it fa lls precipitously with correction of the acidosis. Excessive m i neralocorticoid activity can be seen with pri mary a ldostero­ nism, or with secondary aldosteronism in conjunction with malignant hyperten­ s i o n , Ba rtters syn d rome, a n d j uxtaglomerular cel l tumo rs . Licorice conta i ns g lycerrhizic a c i d , which i n h i bits 1 l -B-hyd roxysteroid dehydrogenase. This enzyme converts cortisol to o n inactive form with no mi neralocorticoid activity. I n h ibition of the enzyme increases the m i neralocorticoid activity of endogenous cortisol . Glucocorticoids st i m u l a te ren a l potass i u m secreti o n , lead i n g to hypo­ ka lemia and a l ka losis. Renal tubular potassfum wasting occu rs in types I and I I renal tubular acidosis, lidd les syn d rome, leuke m ia-associated renal tubular d i sease , a n d in tubular dysfunction secondary to d ru g the ra py ( pe n i c i l l i n s , a m photericin B ) . 144 • Nephrology- JJ
    • 4. Hypokalemia a lso is seen in conditions that cause an intracellular shift ofpotass i u m , such as alka losis, periodic paralysis, i nsulin a d m i n i stration , ar i n­creased beta-adren erg ic activity. This shift is the premise for treating hyper­kalemia with insulin, glucose, bicarbonate, and beta-adrenerg ic agents.5. Iatrogenic causes such as lasix-diuretic administration and steroid therapya re common in renal potassium loss .6. The presence of hypertension suggests hypera ldosteronism or g l u cocorti­coid excess. In Ba rtters syndrome, there is seconda ry hypera ldoste ro n i s m ,but normal bl ood pressu re A h i g h ren i n level su p ports the d i agnos i s of are n i n-secreti ng tu mo r. I n norm ote n sive patients, u ri na ry potass i u m levelsshould be assessed . Low u ri n a ry potassi u m excretion suggests GI losses arprior d i u retic use. High u rinary potassi u m I> 2 5 m mol/L) suggests rena l tubu­lar acidosis, diabetic ketoacidosis, vom i ti n g , cu rrent d i u retic use, or Bartterssyndrome. Hypokalemio Consider ce() shifts (a(kaiosis, insulin, fJadrenergic aganists, periodic paralysis) Blood Pressurelower Gl losses Diuretics Renal tubular Vomiting Malignant Hyperaldoster­ Glucocorticoid Deficient (prior use) acidosis Diuretics hypertension onism excess intake Diabetic (current use) Renin-secreting licorice acidosis 8orffers fumorFlow chart for hypokalemia evaluation . IFrom LeVi nsky NG: Fluids and electrolytes.In Issel bacher, Brau nwald, Wi lsen, et 01 leds): Harrisons Princi ples of InternalMedicine, 1 3th ed New York, McGraw-Hili, 1 994; with permission . ) Nephrology . 145
    • H Y P O N AT R E M I A OSM O s m o t i ca l ly a ct ive s o l ute S o d i u m d i sorder M ea s u re m e n t e r r o r N otes 1 . The serum osmolality and the patients volume status are the two key elements in evaluating the cause of a low serum sod i u m . Hyponatremia (sod ium < 1 3 5 m Eq/L) does not simply indicate a state of low tota l body sod i u m . Total body sod i u m may be red uced, norm a l , or i ncreased . The measu red serum sod i u m concentration is dependent o n the seru m osmolal ity ("OSM ) , which determi nes whether a pathologic sod ium disorder is present. A serum osmola lity differenti­ ates between the th ree categories of hyponatremia : ( 1 ) Osmotica l ly active solutes, ( 2 ) Sodium d isorders, and ( 3 ) Measurement errors. 2 . A high serum osmolality (> 285) ind icates the presence of osmotically active �.olutes such as ma n n itol or g l ucose . Glucose a nd m a n n itol a re osmotically :lctive solutes, which cause water movement out of cells and a d i lution of the plasma. Hyponatremia ensues but, si nce plasma osmolality is i ncreased, clinical manifestations of hypotonicity a re absent. The low serum sod ium is, in a sense, appropriate, si nce a normal sodium level would lead to an even h igher osmo­ lal ity. Th is scena rio is com monly encountered in patients with hyperglycemia, in whom correction of the high glucose levels with insulin is accompanied by a rise in serum sod i u m . An osmotic diuresis causes free water loss, and hypernatremia may result after clea ring the osmotica lly active solute. 3. A pathologic sod i u m disorder is defi ned by a low serum osmolal ity « 2 80), the causes of which may be d ivided i nto hypovolem ic, euvolem ic, and hypervolemic etiologies as listed on pages 1 48- 1 49. 4 . A normal serum osmola lity ( 2 80-2 85) suggests pseudohyponatremia d ue to a measurement error, which can occur i n severe hyperlipidemia or hyperpro­ tei nemia . Th is type of error is less com mon with newer laboratory techniques . 5 . Once pseudohyponatremia from measurement errors a nd accu mu lation of osmotically active solutes is ruled out, then a true, patholog ic sodium disorder is present. The patients volume status is then used to elucidate the cause . Edematous states and profound volume depletion a re usua l ly obVious, but i n some cases it may be difficult to distinguish between moderate volume depletion, normovolemia , and modest volume expansion by physical exam ination a lone. 146 • Nephrologyb
    • 6. Hypovolemic hyponatremia indicates salt losses in excess of water losses Ifa hyponatremic patient appears to be clin ically volume depleted, then it shouldbe determi ned whether the losses are extra-renal (sequestration or skin ) or renal(osmotically active solutes, diuretic therapy, urina ry salt wasti ng , dopamine infu­sion or m i neralocorticoid deficiency) . Measurement of the urinary sodium estab­l ishes the cause, with a h i g h u ri ne sod i u m (> 20 m mol/L) i nd icati ng renallosses, and a low urine sodium « 1 0 m mol/L) i ndicati ng renal sod ium conser­vation and extra-renal losses.7. Euvolemic hyponatremia is essential ly a result of excessive free water i ntake(with inadequate solute intake), or excessive ADH activity. Excessive, surreptitious,free water intake occurs with psychiatric illnesses. This condition may be d ifficult tod istinguish from SIADH, si nce patients do not acknowledge the problem . Otherforms of th is i ntake imbala nce are "beer potomania," an excessive intake of hypo­tonic fluids with little d ietary solute, and the "tea and toast" syndrome, in whichelderly patients i nadvertently have a similar d ietary imbalance. The latter problemmay be made man ifest when a d iuretic is prescribed to an elderly patient with apoor d iet. E levated ADH levels i n hibit the kid ney from excreting free water. Theresult is modest volume expansion (ohen clin ically inappa rent) and hyponatremia. The key feature of SIADH is a n i na ppropriately concentrated u ri n e i n theface of serum hypo-osmolal ity a n d normovolem i a . There a re many causes ofSIADH, i ncluding drugs, neoplasms, and C N S d isorders . Some other statessuch as pai n , emotion , and the postoperative state may also temporarily i mpa i rwater excretion , probably a s a result of an ADH-mediated mechanism . ADH i sproba bly i m po rta nt i n endoc r i n e causes o f hyponatremia such a s hypothy­roidism and pure cortisol deficiency (Addisons disease usua lly results in hypov­olemia and features salt-wasting). In SIADH , urine sod i u m usual ly exceeds 20m mol/L un less fluid i ntake has been restricted .8 . An i m portant d istinction to make in neurosurgical patients is between SIADHand cerebra l salt wasting (a hypovolemic state ) . Cerebral salt wasting is rela­tively rare a nd may be re lated to elevated levels of atrial natr i u retic peptide(AN P). The diagnosis depends on establishing a reduction i n blood vol ume andina ppropriate natriuresis. Volume restriction (as is appropriate in SIADH) may behazardous in cerebral salt wasting si nce it can lead to cerebral ischem ia fromvasospasm . The proper treatment is to mai ntain i ntravascular volume and correcthyponatremia with norma l sa line i nfusion . Dopa m i ne a lso sti m u lates ANP re­lease and promotes natriuresis.9 . A less well understood euvolemic state is "essential" hyponatremia or the "sickcell" syndrome. It is hypothesized that these patients have a reset serum "osmostat"« 2 8 0 m mol/L) and mai ntain a lower serum sodium due to reesta blishing the"normal" range of osmolality. Alternatively, it may also represent a state of elevatedADH activity secondary to an un known nonosmotic sti mulus. When osmolal ity islowered sufficiently, osmotic inh ibition of ADH overcomes the nonosmotic stimulus. 1 0 . Hypervolem i c hyponatre m i a occurs with edematous states . Mec h a n i s­tically, these conditions a re similar to the hypovolemic states in that the effectivec i rculating volume is reduced and the kid ney conserves sod i u m ( u ri ne sod i u m< 1 0 m mol/L) . CHF is the most common cause o f hypervolemic hyponatremia, Nephrology . 1 4 7
    • and hyponatremia is associated with a poor prognosis Loss of plasma proteins (albuminuria , protei n-losing enteropathy) causes th i rd spacing of fluids, intravas­ cular depletion, and hyponatremia End-stage l iver disease impa i rs circu lation and plasma protein synthesis with consequent edema and hyponatremia . Renal fa ilure impairs the abil ity to excrete a normal volume of dilute u rine and results in hyponatremia and edema . Early in the course of renal failure, the volume expan­ sion may be modest, and patients may a ppear to have euvolemic hyponatremia . 1 1 . Treatment: In genera l , only severe , symptomatic hyponatremia and hypo­ natremia developing over 24 hours or less ( e . g . , patients with psychogenic polyd i psia, surgical and obstetric patients) should be treated with hypertonic so­ lution and more prompt correction . In the majority of patients, rapid correction of hyponatremia i s hazardous and may lead to centra l nervous system damage (i . e . , centra l ponti ne myel i nolysis) A sta nda rd ru le is that the serum sodium should not be raised by more than 0.5 to 1 . 0 m mol/L per hour and no more than 1 2 mmol/L over 2 4 hours . Another maxim of hyponatremia treat­ ment is that the time for correction should approxi mate the ti m e course of devel­ opment ( i . e , ra pidly occurring hyponatremia should be corrected ra pidly, and more chronic conditions should be corrected gradually) . 1 2 . The following m nemonic separates hyponatremic conditions i nto four cate­ gories: pseudohyponatremia, and hypovolemic, euvolemic, and hypervolemic (edematous) states: A S O D I U M WAT E R CA P E R Ps eudoh ypona tremia A rtifactu a l Hypovolemic S eq u estra t i o n , S k i n l o s s e s ( b u rn s a n d sweat i n g ) O s motic d i u re s i s D i u re t i c s I ntest i n a l l os s e s ( d i a rr h e a , vo m it i n g ) U ri n a ry s a l t wast i n g M i n e ra l ocort i c o i d d ef i c i e n cy Euvolemic W at e r i n toxi c a t i o n A D H exce ss ( S I A D H ) T e m porary i m pa i rm e n t of water exc r e t i o n ( pa i n , e mot i o n , d ru g s , post-o p e rat ive ) E n d o c ri n e ( hypothyro i d i s m , p u re c o rt i c o l d ef i c i e n cy) R es et o s m ostat ( " s i ck ce l l " ) 148 • Nephrologyb
    • Hypervo/emic C o n g est i ve h e a rt fa i l u re A l b u m i n u ria P rote i n- l o s i n g e n te ro p a t hy E n d-st a g e l ive r d i s e a s e ( c i rr h o s i s ) R e n a l fa i l u re N E P H R OT I C SY N D R O M E MAD NEPH ROTICS M ed i cat i o n s/tox i n s/d r u g s A my l o i d o s i s D i a betes N eo p l a s m E n d oca rd i t i s/i nfect i o n s P ri m a ry g l o m e ru l a r d i s e a s e H e re d ita ry d i se a s e s R e n a l ve i n t h ro m bos i s O be s ity ( m o rb i d ) T hy ro i d d i s e a s e ( myxe d e m a a n d thyro i d it i s ) I nterstitia I neph ritis C h ron i c ref l u x/o b s t ruct i o n S L E , c o l l a g e n va s c u l a r d i s e a s e s N otes 1 . Neph rotic synd rome is cha racterized by a l bu m i n u ria (> 3 . 5 g/d ) , hypo­ album inemia, and edema . Urinary loss of critical plasma proteins predisposes patients to thromboembolic events ( renal vein thrombosis, pul monary embolus), hyperlipidemia and accelerated atherosclerosis, vitamin D deficiency, and pro­ tein mal nutrition , as well as drug toxicity from decreased plasma protein binding . 2 . The majority of cases a re due to glomerular d isease (75%), including mem­ bra nous (40%), m i n imal change d isease, focal g lomeru losclerosis, membrane proliferative glumeruloneph ritis (GN), and mesang ioproliferative GN. Nephrology . 149lL
    • 3 . Systemic diseases, including diabetes mellitus, SLE, amyloidosis, drug reac­tions, thyrOid disease, infections, and maligna ncy, as wel l as obesity, accountfor about 25% of cases.4. Ma l i g n a nci es that may be assoc iated with nephrosis i nclude myelom a ,Hodgkins a n d non-Hodgkins lymphomas, leukemia, a n d breast a n d GI tractcarcinomas.5. Drugs that cause the nephrotic synd rome i ncl ude gold, herO i n , penicil­lamine, proben icid , captopril, and N SAIDs.6 . Infections associated with the nephrotic syndrome include endocard itis, hepa­titis B, shunt i nfections, syph ilis, and mala ria .7. Evaluation of nephrotic syndrome includes 24-hour urine for protein and cre­atine, serum albu m i n , cholesterol, and com plement. Rule out dia betes and SLE ,as well as d rug exposure, u nderlyi ng maligna ncy, and infection If no systemicdisease or exposure can be discovered , then a renal biopsy is ind icated . R E N A L FA I L U R EBIG BUNSB l ood f l ow p ro b l e m ( p re-re n a l )I n t r i n s i c re n a l d i s e a s e ( re n a l )G I/i n te r n a l b l ee d i n g ( m eta b o l i s m o f h e m e )B l a d d e r o u t l et o b s t r u ct i o n ( post-re n a l )U retera l/c o l l ect i n g syst e m obstruct i o n ( p o st-re n a l )N e p h rotox i n s (e . g . , d ru g s , r h a b d o myo lys i s , u ri c a c i d )S te ro i d s (cata b o l i c states)N otes 1 . An elevated blood urea nitrogen (BUN) level may indicate renal insufficiency(reduced GFR) or may occur secondary to increased catabolism of proteins (e.g . ,steroid therapy) o r with i ncreased metabolism of heme products (e.g . , GI or otherinternal bleed ing). " BIG BUNS" prOVides a quick list of causes of a rising B U N .When renal i nsufficiency i s the cause o f a rising B U N , it is helpful to categorizeetiolog ies as pre-rena l , renal, or post-rena l . Pre-renal azotemia occurs whenrenal blood is reduced and, as a consequence, renal fi ltration (GFR). Prerenalcauses include volume depletion , heart failure, vascular disease, and shock. Renal150 • Nephrology
    • causes of low urine output result from damage or disease of the renal parenchyma,including the g lomeru l i , i n terstitiu m , and tubules. Toxins, vasculitides, i nterstitialdiseases, and primary g lomerulonephritides a re a mong the causes . Post-renalconditions that lead to low urine output a re characterized by on anatomic obstruc­tion to u ri ne output. The most com mon of these is prostate enlargement, a lthoughpapillary necrosis, bilateral ureteral obstruction, and bladder outlet obstruction arepossible causes. There is, of cou rse, overlap in etiologies (e. g . , CHF may pre­cipitate ATNl , but this classification is useful in organ izing diagnostic possibil ities.2. The following m nemonic l ists most of the causes of renal fa ilure accord ing topre-rena l , renal, and post-renal mechanisms:I CHASE A RISING B U N Pre-renalI n t rava s c u l a r vo l u m e d e p l e t i o n ( d e hyd rat i o n , t h i rd spacing)C a rd i a c ca u s e s ( C H F, M I , t a m p o n a d e )H epatore n a l syn d ro m eA rte r i a l d i s e a s e ( r e n a l a rtery ste n o s i s )S h ockE cl a m ps i a/obstetri ca l c o m p l i cat i o n s Pre-renallRenalA cute tubular necrosis RenalR a d i o g ra p h i c c o n t ra st a n d oth e r toxi n s ( d r u g s , r h a bd o myo l ys i s , h e m o l ys i s )I n t ra re n a l e m bo l i (ch o l e s t e ro l , D I C)S c l e ro d e r m aI n t e rst i t i a l n e p h ri t i sN ec roti z i n g vas c u l i t i s ( po lya rte r i t i s , n od o s a , Weg e n e r s)G l o m e ru l o n e p h ri t i s Pos t-renalB l a d d e r obstruct i o n ( u s u a l ly p rostat i s m , s o m et i m e s b l oo d , p u s , ca l c u l i )U rete ra l obstruct i o n (ca l c u l i , retro p e ri to n e a l fi b ros i s , ca n c e r)N ec r o s i s of re n a l p a p i l l a e ( d i a bete s, s i c k l e ce l l a n e m i a , N SA I D a b u se , i nfect i o n ) Nephrology . 151
    • 3 . The usual approach again depends on the history and physical evaluation . Frequently, prerenal causes a re obvious, such as C H F and ci rrhosis. Post-renal causes can be excluded in a ppropriate patients by placement of a Foley catheter. BUN and creati nine may further help to identify the pathogenesis I n pre-renal causes, BUN rises d isproportionately t o creati n i ne (often in a ratio of 2 0 : 1 or g reater) , while i n renal causes, creatine elevation usually is more pro­ nounced . Pre-existi ng renal disease may confound these para meters and is a common factor in low urine output. 4. When the etiology is sti ll in question, a renal u ltrasound is helpful to evaluate the collecting system for presence of obstruction and to assess renal size. Small, shrunken kidneys indicate long-standing d isease that is unlikely to be reversible. Normal or large kidneys may be ind icative of more acute disease. Certa i n sero­ logic tests and renal biopsy may be appropriate. Prompt renal biopsy is espeCially i m portant in cases of prog ressive renal i nsufficiency when i m m u nosuppressive therapy may preserve renal function (e. g . , vasculitis) . 5 . Hypocom plementemic renal failu re : "COMPS" Cryoglobulinemia Occult infection (endocarditis, "sh unt" nephritis) Membranoproliferative glomerulonephritis Post-streptococcal g lomerulonephritis Systemic lupus erythematosus Low complement levels a re occasionally helpful in the d ifferential diag nosis of glomerulonephritis, sign ificantly na rrowi ng the list of diag nostic possibil ities . The role of complement in glomerular i n jury and progression of renal insufficiency is not clear. In id iopath ic mem branoproliferative g lomeruloneph ritis, an antibody cal led C 3. nephritic factor is capable of inducing C 3 cleavage and proba bly causes the persistent depression of C 3 levels. This entity often is seen in associa­ . tion with hepatitis B infection. R E N A L S TO N E S OUCHS O xa l ate U rate C yst i n e H yp e rca l c e m i a S t ruvite 1 52 • Nephrologybr
    • N otes 1 . Kidney stones are among the most pa inful of afflictions, hence the mnemonicOUCHS.2. Oxa late is a common com ponent of kid ney stones . Hyperoxa l u ria canoccur i n mala bsorptive gastroi ntesti nal disorders, such as Crohns disease andulcerative colitis. Normally, free oxalate is bound by calci u m i n the gut and isnot absorbed . Mala bsorbed fat binds calci u m , lead ing to free luminal oxa late.Free oxa late is read ily a bsorbed and then excreted in the urine. H igh levels ofoxalate in the u rine precipitate calcium oXGJlate stone formation .3 . Uric acid stones occu r with low pH a n d su persatu ration o f the urine withund issoc iated u ric aci d . Myeloprol iferative disease, chemotherapy, and Lesch­Nyhan syndrome couse massive production and excretion of uric acid . In gout,dehydration, and id iopathic u ric acid l ithiasis, urine pH is usually low. U ric acidfac i l i tates heterogenous n ucleation of ca lci u m oxa late; th us, hyperuricosuriacauses calciu m oxalate stones.4. Cystine stones a re rare and a re seen in patients with hereditary cystinosis.5. Hypercalcemia (e . g . , hyperparathyroidism, neoplastic hyperca lcemia) in­creases urinary calci um concentration and precipitates calci u m stone formation.Hyperca lciuria may be id iopath ic or result from renal tubular d isease. I n distalrenal tu bular acidosis, on al kaline urine and low uri nary citrate levels favor for­mation of calcium phosphate stones.6. Struvite stones (Mg N H4P04) occur mai nly in women and result from u rinarytract infections with u rease-prod ucing organisms (usually Proteus) . Struvite stonesmay grow quite large and fill the renal pelvis ("staghorn calculus"). Nephrology . 1 53
    • mID ACID- BASE Genera l ConsiderationsA rte ria l B lood G a s I nte rpretationThe interpretation of on a rterial blood gas can be sim pl ified by the steps out­l i ned in the m nemonic "ABG READ" : Accurate ABG? ( Henderson-Hassel balch) Basic or acidic? (primary disorder) Go p/delta gop (onion gop) Respi ratory or metabol ic? Extreme disturbance? Appropriate compensation? Double or triple d isorder?F i rst, determine if the gas is accurate by determining the hydrogen ion concen­tration [H+] using the Henderson-Hasselbolch equation : A sim ple way to recall this relationship is to remember that [H+] increases asthe pC02 increases or [HC03-] decreases The [H+] for a given pH can be de­termined by either of the following methods: ( 1 ) Remember that at pH 7. 2-7 . 5 ,every 0 1 u n i t change in pH changes [H+] concentration by . 1 0 m Eq/L i n theopposite direction . So, if [H+] for pH 7.4 is 40 m Eq/L, then [H+] for pH 7.5 is30 mEq/L and [H+] for pH 7 . 3 is 50 mEq/L (2) With every 0 1 unit rise i np H , multiply the preced ing [ H + ] b y 0 . 8 (e. g . , for a change i n pH from 7 . 4 to =7 . 5 , 40 mEq/L x 0 . 8 3 2 m Eq/L) . Conversely, for every 0 . 1 unit fa ll i n pH,mu ltiply the preced ing [H+] by 1 . 25 (e . g . , for a cha nge in pH from 7.4 to 7. 3 ,40 mEq/L x 1 . 25 50).= The second method is slig htly more accurate, but either m ethod is usu­a l ly sufficient for con f i r m i n g a ccu racy The follow i n g l i sts the [ H + ] for ag iven p H : Acid-Base • 1 55 (
    • = pH 7. 8 , [H+] 1 6 .4 = pH 7 . 7, [H+] 20 5. = pH 7.6, [H+] 2 5 . 6 = pH 7.5, [ H + ] 3 2 = pH 7 . 4 , [ H+] 4 0 = pH 7 . 3 , [ H + ] 5 0 = pH 7 . 2 , [ H + ] 6 2 . 5 = p H 7. 1 , [ H+] 78 5 = pH 7.0, [ H+] 97.7 = pH 6.9, [ H+] 1 2 2 . 1 The com ponents of the bica rbonate/ca rbon ic acid system a re always i nequ i librium i n the blood, a n d so pH, pC02, and [ HC0 3-] measured by venousblood chemistry should adhere to the constra ints of Henderson-Hasselba lch . Ifthere is disagreement, then a la boratory or col lection error has occurred andrepeat determination should be obtained . To assess the accuracy of oxygenation , add the p02 a n d pC02 . I f the tota lis g reater than 1 40 TORR (at sea level), then the patient was on su pplementa loxygen or a la boratory error was made. The oxygen level decreases with age,which can be estimated by subtracting 1 TOR R from 80 for every yea r of agea bove 60 . So, an 80-yea r-old patient should have a p02 no less than 60 atsea level. After establishing the consistency of the values for pH, pC02, and [HC0 3-],look at the pH to establ ish if the primary or dominant d i sorder is basic oracidic. Si nce there is no over-com pensation for an acid-base d isorder, t h e pri­mary disturbance is determi ned by the pH . Occasional ly, a chronic respi ratoryacidosis or alka losis may have a normal pH in the a bsence of a m ixed disorder. Next, the serum anion gap, [Na+] - ([CI-] + HC0 3-1, is calculated to lookfor the p resence of u n m easu red a n ions, as occ u rs with the add ition of a nystrong acid to body fluids The anion gap can be altered i n the a bsence of a nacid-base disorder. A low seru m albumin or an i ncrease in u nmeasured cation,such as occurs with lithium ingestion or when certa i n paraproteins a re present i nm u ltiple myeloma, m a y decrease the g a p (see Low Anion G a p section) . On theother hand, meta bolic al ka losis may modestly i ncrease the a n i on gap. An i n­crease in the a n ion gap usually ind icates the presence of a metabolic acidosis,but the normal a n ion gap va ries widely, with an averag e va lue of 1 0- 1 2m Eq/L. Given the large number of factors that can affect the a n ion gap, previouselectrolytes measurements from the patient may be helpful for comparison . With a high anion gap metabolic acidosis, there should be a close reci pro­cal relationsh i p between the rise i n a n ion g a p a n d the decrease of serum[ HC03-] , cal led the delta gap. The delta gap is defined as (an ion gap - 1 2 ) .I n simple gap acidosis, a red uction i n serum [HC0 3-] by 1 0 i s associated withan i ncrease in anion gap of 1 0 . Addition of the va lue for delta gap to the mea­sured [ HC0 3-] allows you to determ i ne the [HC0 3-] level that existed prior tothe development of the gap acidosis. Thus, if delta gap + [ H C0 3-] is in thenormal ra nge for serum [ HC0 3 -], then a simple an ion gap acidosis is present156 • Acid-Base
    • ( i e . , the added acid has caused the expected drop in [ HC03-]) . If the value is outside the normal range, then another d isorder must have been present prior to the development of the gap acidosis. The following rules su mmarize the use of delta gap after a high anion gap is detected : 28 � delta gap + [ HC03-] � 2 3 , sim ple high gap acidosis Delta gap + [HC03-] < 2 3 , a non-anion gap acidosis also is present. Delta gap + [HC03-] � 2 8 , a metabolic alkalosis also is present. Next, determ ine the specific type of acidic or basic disorder. Acid-base dis­ orders can be classified as either respiratory or metabolic. Respi ratory d isor­ ders are i n itiated by a change in PaC02 while metabolic disorders a re i n itiated by a change in [HC03-] . These primary d isturbances initiate predictable com­ pensatory changes (see below). Look to see if there is an extreme cha nge i n pH, pC02, or [ HC03-], as this often ind icates an acute process or two processes that cause the pH to change in the same d i rection (e. g . , a m etabolic al ka losis and respi ratory a l ka losis as occu rs in a preg nant patient who has severe vom iting from hypereme � is. g ravida, or COPD with CO2 retention and hypoxia ca using lactic acidosis) Acid-base disturbances in which the response to a primary d isturbance is obvi­ ously inappropriate (e . g . , increase pC02 with meta bolic ac idosis) a re mixed and do not require the use of predictive formulas. Extreme disturbances require rapid therapy. If the cha nges i n pH, pC02, and [ HC03-] are not extreme and do not rep­ resent on inappropriate d i rection of compensation, then assess whether appro­ priate compensation has occurred by usi ng specific predictive formulae. These formulae are useful in pred icti ng the appropriate degree of response, but keep in m i nd that an a ppropriate venti latory response for a metabolic d istu rbance may toke 1 2 hours to occur, and adequate renal compensation for a respi ratory d isorder may take several days to occur. It is also im porta nt to u nderstand that the compensatory responses do not normalize the pH . Exception : occasionally, chronic respi ratory acidosis or alkalosis may have a normal pH. S u m m a ry o f t h e Pri m a ry D i sturba nces and Compen satory Responses for Acid-Base D i sorders Compen- Appropriate Primary satory Response for a Disorder Disturbance Response Type Single Disorder Comments Respiratory Increased Increased Acute For each change pH is lower acidosis pC02 HC03 in pC02 of than chronic 1 0 TORR Ifrom acidosis normal pC02 Uncompl icated of 40 TORR), acute respi- expected change ratory acidosis Table continued on next page. Acid-Base • 1 57
    • �� S u m ma ry of the Pri mary Disturbances and Compe nsatory Responses for Acid-Base D isorders (Con tinued) Compen- Appropriate Primary sa tory Response for a . Disorder Disturbance Response Type Single Disorder Respiratory Increased Increased Acute in pH is 0 . 08 will not elevate acidosis pC02 HC03 {cont i units (patient with [HC03-] over (conti {cant } {cont.} pC02 of 60 32 unless should have pH superimposed of 20/ 1 0 x metabolic = 0.08 0 1 6, so alkalosis is predicted pH is present - 7.4 0. 1 6 7 24)= HC03 increases 1 mmal/L for each 1 0 mmHg in- crease in pC02 Chronic For each change in pH less than pC02 of 1 0 TORR normal, but from normal pC02 may be normal . of 4 0 TORR, ex- Unusual for pa- pected change in tients with pH is 0.03 un its pC02 > 60 (patient with pC02 TORR to have of 60 should have normal pH. pH of 20/ 1 0 x . ,= 0 0 3 0 .06 so , predicted pH is 7 . 4 - 0 . 06 7 34) = HC03 increases 3- 3.5 mmol/L for each 1 0 mmHg increase in pC02. Respiratory Decreased Decreased Acute Same rule as acute pH is higher alkalosis pC02 HC03 respiratory acidosis than chronic (patient with pC02 alkalosis of 20 should have pH of 7 56) HC03 decreases 2 mmal/L for each 1 0 mmHg decrease in pC02. Chronic Same rule as chronic Unusual for respiratory acidosis HC03- to fall (patient with pC02 to less than of 20 should have 1 5 mEq/L in pH of 7 46) absence of Table continued on next page. 1 58 • Acid-Base
    • S u m ma ry of the Pri mary Disturbances and Compensatory Responses for Acid-Base D i sorders (Con tinued) Compen- Appropriate Primary satory Response for aDisorder Disturbance Response Type Single DisorderRespiratory Decreased Decreased Chronic HC03 decreases accompanying alkalosis pC02 HC03 lcont.) 4-5 mmol/L for metabolic Icont ) lcont.) Icont.) each 1 0 mmHg acidosis. decrease in pC02. The pH is often normal .Metabolic Decreased Decreased = pC02 [ 1 5(HC03) Full compensation acidosis HC03 pC02 + 8) ± 2 (patient (hyperventila- with metabolic tion) may take acidosis and HC03 1 2-24 hours of 1 0 should have pC02 of [ 1 .5( 1 0) + 8) ± 2 23 ± 2= = 2 1 -25 TORR. = pC02 last 2 digits of pH x 1 00.Metabolic Increased Increased = pC02 0.9* Compensation alkalosis HC03 pC02 (HC03) + 9 less consistent (patient with meta- than for meta- bolic alkalosis and bolic acidosis. HC03 of 40 pC02 > 45 should have pC02 occurs in 25% of 0 . 9 * (40) + of cases. Rare = 9 45 TORR) to see pC02 > 55 TORR = * range 0.6-0.9 except in severe alkalosis or superimposed respiratory alkalosis. After checking for a ppropriate compensation , decide if the d i sorder issimple or if a double or triple d isturba nce is present. Types of m ixed d isordersand clues to their presence QTe as follows: 1 . Metabolic a lkalosis + respi ratory alkalosi s - Both processes i n­crease the pH . A decreased pC02 is seen with i n c reased HC0 3 A veryhigh pH is possible because the a l kaloses sum mate. There is a m i ld elevationof a nion gap. Hypokalemia freq uently is p resent. Exa m ple preg nancy withvom iti ng . 2 . Respiratory acidosis + metabolic alkalosis- Both processes increasethe HC03. Often there is a normal pH and a very high HC0 3 pC02 is h ig hertha n predicted on the basis of metabolic alkalosis alone. Example: COPD + d i­uretic therapy. Acid-Base • 1 59
    • 3 . Metabolic acidosis + respiratory acidosis- Both processes decrease the pH . pH is very low because the acidoses sum mate. Example: decom pen­ sated COPD + lactic acidosis 4. Metabolic acidosis + metabolic alkalosis- The two processes change the HC03 and the pC02 in opposite directions. The pH may be increased, de­ creased , or norma l , depending on the relative severity of the two processes . Consider this d iagnosis when the anion gap is increased, but the HC03 is not decreased. Example: DKA + vomiti ng . - 5 . Metabolic acidosis + respiratory alka losis Both processes decrease the HC03 . Consider this diag nosis when a metabolic acidosis is accompanied by a pC02 that is lower than predicted, or when respiratory alkalosis is associated with an HC03 measurement lower than predicted . Example: sal icylate overdose . 6. Triple acid-base disturbance- triple distu rbances occur when a m ixed metabolic acidosis + meta bolic alkalosis is compl icated by either a respiratory acidosis or a respiratory a l kalosis. While m ixtu res of meta bol i c distu rba nces may occur, m ixed respiratory disturbances ca nnot occur by definition, because a person can never concu rrently over- and u nder-excrete CO2. The d iagnosis of a triple d isturbance is generally made in a patient with metabolic alkalosis and res­ pi ratory acidosis or alkalosis i n whom the anion gap is found to be sign ificantly increased (> 1 6) . Example: DKA + vomiting + obtundation/hypoventilation . Cl inica l Conditions and Diagnoses M E TA B O L I C A C I D O S I S WITH A H IG H AN ION GAP KLU ES I K et o a c i d o s e s Lactic acidoses U re m ia ( o rg a n i c a c i d s ) E thyl e n e g lyco l a n d t h e a l co h o l s S a l icylates 160 • Acid-Base-
    • N otes 1 . This m nemonic lists the primary conditions i n which the anion gap, {[Na+] ­( [CI] + [ HC03])}, i ncreases . Because of electroneutrality, unmeasured anionsm ust i ncrease as bicarbonate fa lls, lead ing to a widen i n g of the an ion gap." KLUES" to the cause of an i ncreased an ion gap come from the history and lab­oratory tests, i ncluding BUN, creati n i ne, glucose, lactate, seru m ketones, serumosmolality, and a toxin screen.2. Ketoacidosis occu rs i n three settings: d iabetes, alcoholism, and malnutri­tion ("DAM ! " ) . In diabetic ketoacidosis, acetoacetic and beta-hydroxybutyricacids are produced more ra pidly than they can be metabolized . They accumu­late, causing a d rop i n plasma bicarbonate a n d a rise i n the a n ion g a p .Alcoholics m a y have poor food i ntake and vom iting associated with h i g hethanol intake, causing ketoacidosis and an elevated an ion gap. T h e ketoaci­dosis may be missed because the n. itroprusside test for ketones only detects ace­toacetic acid and not beta-hyd roxybutyric acid, which tends to pr·edomi nate.Ma ln utrition alone may cause a modest ketoacidosis. Red uced ca rbohydratelevels cause low i nsul i n and high gl ucagon . These hormonal changes (also rele­vant to DKA and alcoholic ketosis) favor glycolysis and ketogenesis.3. Uremia is characterized by the accumulation of organic acids, which normallyare excreted by the kidney. In acute renal failure, plasma bicarbonate falls by 1 to2 mmol/L per day if impaired renal acid excretion is the sole cause of metabolic aci­dosis. Greater rates of decline suggest the presence of an additional cause ofacid production. In chronic renal failure, the bicarbonate tends to stabilize at levels of 1 2- 1 8 mmol/L and rarely falls below 1 0 m mol/L unless another disorder is present.4. Lactic acidosis occurs when there is an i m balance between lactate produc­tion and el i m i nation ("LACTIC") . During a naerobic conditions, glycolysis is ac­celerated and pyruvate i ncreases . Pyruvate is in eq u i l ibrium with lactate; thus,lactate levels i ncrease. Si nce one proton is generated for each lactate moleculeproduced, acidosis is the result of lactate production . Because the l iver is the ma jor organ for meta bolizing lactate, severe liverd isease causes lactic acidosis. Lactate production is norma l , but meta bol ism isi mpa i red . With significant l iver dysfunction , the normal lactate load producedby the body is not metabolized , lactate accum ulates, and acidosis ensues . Selective dysfunction of m itochondria (e . g . , congenital disease, biguan idetoxicity) causes lactic acidosis i n the a bsence of other evidence of liver dysfunc­tion. Lactate overproduction results from c;.i rcu latory fa i l u re . Tissue hypoxia, asoccurs with cardiopulmonary grrest, �arbon monoxide poison ing and severeanem ia, leads to lactic acidosis. Vigorous exercise or muscular tetany as occurswith seizures may cause a tra n sient rise in lactate. System ic infection/sepsi scauses circulatory shock, org an hypoperfusion, a n d subsequent lactate produc­tion . Lactic acidosis may complicate �ancers, such as leukemia and lymphoma,when tissue hypoxia is not i n evidence. Overproduction of lactate by the mal ig­ nant tissue may be a factor. Acid-Base . 1 6 1
    • Note that lactic acidosis a lso may contri bute to the severe acidosis seen with salicylate, methanol, or ethylene glycol poison ings. 5. Ethylene glycol and methanol a re converted to acidic m etabolites, which accumu late i n the bloe>d . An increase i n osmola r gap is characteristic, and prompt intervention is critical . Isopropyl alcohol causes a more modest increase in anion gap and serum osmolal ity. 6. Salicylates cause a characteristic in itial respiratory alkalosis by stimulating cen­ tral respi ration . The presence of respiratory alkalosis combined with an increased anion gap frequently occurs with sal icylate intoxication and should not be m issed . 7. Certain gastrOi ntestinal disorders have been reported to cause a gap acidosis secondary to accum ulation of D-Iactate. It is thought that certa in bacteria pro­ duce D-Iactate in the gut that is systemically a bsorbed . A special serum assay for D-Iactate is ava i lable, as it is not detected by the conventional assay. 8. Other drugs have been associated with a gap acidosis. Isoniazid causes re­ fractory seizu res and a subsequent lactic acidosis. Paraldehyde is rarely used , a nd its role i n ca using gap acidosis is not well documented , but it is remem­ bered beca use of the fa m i l i a r "MUD PILES" m nemonic ( m etha n oJ , u rem i a , DKA, paraldehyde, isopropyl a lcohol , lactic acid, ethylene g lycol , sal icylates). Propylene glycol, a d i luent used i n some intravenous medications (e. g . , nitro­ glyceri ne) , may rarely cause a secondary lactic acidosis. 9. When measured plasma osmolal ity exceeds the calculated osmolality [(2 x plasma No) + glucose/ 1 8 + BUN/2 .81, suspect ethylene g lycol or methanol toxicity. Ethanol intoxication and some cases of lactic acidosis or alcoholic keto­ sis also may feature a small "osmolal gap" (up to 1 0- 1 5 mOsm/kg ) . DAM U LACT I C GAPS Ke toacidoses D i a betic ketoa c i d o s e s A l c o h o l i c keto s i s M a l n utriti o n Organ ic acids U re m ia Lactic a cidoses L ive r d i se a s e A rrest C a rbon m o n o x i d e p o i so n i n g T eta ny/s e i z u res ( rh a b d o myo l ys i s) I nfect i o n/s e p s i s C a ncer 1 62 • Acid-Baseb
    • O ther unmeas ured anionsG a stroi ntest i n a l d i s e a s e ( D- I a ctate)A l c o h o l s/a n t i-f reezeP ro py l e n e g lyco l/pa ra l d e hydeS a l icylates M E TA B O L I C A C I D O S E S WITH A N O R MAL AN ION GAPGUTG a stroi ntesti n a l l o s s e s ( d i a r r h e a , pa n c re a t i c f i stu l a )U ri n a ry l o s s e sT ota l p a r e n t e ra l n utrit i o nN otes1 . N ormal anion gap or hyperchloremic acidoses almost a lways result fromHC03 loss from the GI tract or from the kidney. As the a bove m nemon ic sug­gests, GUT losses from d i a rrhea a re the most common cause. Uri nary lossesfrom renal tubular disease a re less com mon .2 . In both GI and renal disorders, sod i u m bica rbonate stores a re low, a ndsod ium chloride is reta i ned in excessive a mounts to preserve volume status. Theurine net charge or u rinary anion gap, { ([Na] + [K] - [CI] }, is useful in d iffer­entiating between renal and gastrointestinal causes of HC03 loss. Urinary acid­ification results from the excretion of a m m o n i u m , N H4 + The p resence of thepositive ion, N H4+, ind icates that other maior cations, [Na] + [K] , a re present inlower amounts when compa red to the maior anion, [Cl] . A negative u rine an iongap i m pl ies the presence of N H4+ in the urine, ind icati ng appropriate rena lacid ification in response t o acidosis ( a s in GI losses) . A positive va lue ind icatesa renal acidification defect (no N H4+ in the uri ne) . If the cause appears to berenal dysfu nction (positive urinary a n ion gap), then the serum potassium is help­ful. Low potassium suggests an H+ secretion defect, whereas high values areconsistent with deficient aldosterone action (Type IV renal tubular acido�i� rRTA] ) . Acid-Base • 1 63
    • 3 . I n rare cases, iatrogenic normal gap acidosis results fro m i ntravenous ad­ m i n i stration of TPN or acidic a m i no acid solutions, a m mon i u m ch loride or hy­ d rochloric acid . An apparent, normal gap acidosis is occasionally seen when a gap acidosis is accompanied by a pre-existing condition that lowers the anion gap, such as hypoalbuminemia or a cationic para protein (see Low Anion Gap section) 4. Respiratory alkalosis with reduced pC02 levels leads to a loss of bicar­ bonate. With rapid correction ( i . e , decreased respiratory rate), pC02 returns to norma l , but bica rbonate conservation and reclamation by the kidney takes 24 to 48 hours to return levels to norma l . A tra nsient non-gap acidosis occurs . 5 . In DKA, it is common to see a n incidental hyperchloremic acidosis i n the recovery phase. This phenomenon occurs because sodium ch loride is reta ined with vol u me repletion . The ketones (a source for regenerating bica rbonate) are lost i n the urine, and bicarbonate regeneration is slowed S i m i la rly, vigorous volume replacement in a dehyd rated patient suppresses aldosterone secretion . S i nce a ldosterone i ncreases bica rbonate regeneration a n d a bsorpti o n , the lower levels tend to mainta i n the hyperch loremic state. This "expa nsion acido­ sis" is the converse of the "contraction alkalosis" seen with vol ume depletion; the latter i s a h i g h a ldosterone state. The acidosis from vol u me replacement is rarely of cli nical sign ificance. 6 . A more comprehensive listing of causes of non-gap acidoses is listed below. The mnemonic em phasizes the i m portance of calculating the urine gap when the cause is u ncerta i n . U R I N E G A P : N A + K-C L U retero s i g m o i do stomy R TA I ntest i n a l d i s e a s e ( d i a rr h e a ) N H 4+/T P N E a rl y re n a l fa i l u re G l u e s n i ff i n g (to l u e n e ) A I d osterone defi c i e n cy P a n c rea t i c f i stu l a N a C I i nf u s i o n ( "expa n s i o n " a c i do s i s ) A ft e r D KA o r res p i ratory a l ka l o s i s K+�s p a r i n g d i u reti cs C a rbon i c a n hyd ra s e i n h i bitors ( i m pa i rs u r i n e acid i f i cati o n ) L axative a b u se ( G I l o s s e s ) 1 64 • Acid-Basebn
    • L ow A N I O N G A PALB U M I NA lb u m i n lossL ithiumB ro m i n eU n m e a s u red cati o n s ( K, M g , C a lM ye l o m a (cati o n i c pa ra p rote i n )I od i d eN a + u n d e resti m a t i o n/a rtifactN otes1 . A low seru m a l bu m i n is the most com mon cause of low a n ion gap Thenormal an ion gap is a pproximately 5- 1 2 . Because of this wide ra nge of normaland the many factors affecting the an ion gap, the clin ical usefulness of a lowmeasured an ion gap has been questioned . Knowing the factors that affect thean ion gap is perhaps most useful when tryi ng to determine the sign ificance ofmodest changes in the anion gap (e.g . , an an ion gap of 1 6 may be sig nificantin a patient with a very low album i n ) . A reduction in the anion gap may also bedue to laboratory error.2 . A lower serum a n ion gap may be observed in conditions with an i ncreasein unmeasured cations, such as occurs with hyperkalem ia , hypercalcem ia , orhypermagnesemia . It may also be seen when there is an increase in unmeasuredcations that are not normally present, such as with multiple myeloma, polyclonalg a m mopathy, or lith i u m . A l ow gap is seen with a decrease i n un measuredanions (usually hypoalbuminemia). Sodium underestimation is much less likely tooccur g iven new d i rect ion-selective techniques (a low gap was more commonpreviously i n cases of hyperviscosity and severe hypernatremia). Chloride overes­timation was formally seen i n cases of hypertriglyceridemia, but this also is less ofa problem now. However, bromine and iodide may lead to ch loride overesti­mation and thus reduce the anion gap. Bromine and iodide have slightly lowerrenal clearances than chloride. Electrolyte measurements do not disti nguish be­tween brom ine or iodide and chloride, so a rise in brom ine or iodide is falselymeasured as an ever g reater rise in ch loride. Other rarely reported causes of alow serum anion gap include renal transplantation and hyponatremia .3 . Clea rly, there are many considerations i n calculating the a nion gap- partic­ularly in a patient with m ultiple med ical problems. Take all of these factors intoaccount when interpreting the a n ion gap. Acid-Base • 1 65
    • M E TA B O L I C A L K A L O S I SALOOSA l d oste ro n eLasixD e hyd rati o nO ve r-ve n ti l a t i o nS t 6 m a c h l os s e sN otes1 . Metabolic alkalosis is not a specific d isease; it is usually a response to NaCIand K+ deficit. Understanding the hormone aldosterone is the key to understandingmost cases of meta bolic a l kalosis; hence, the m nemonic ALDOS . Aldosteronepromotes renal acidification and concom itant bicarbonate regeneration and a b­sorption . Pri mary hyperaldosteronism and other hypermi nera locorticoid statescause metabolic alkalosis. Simi larly, volume depletion causes a secondary i n­crease in aldosterone, a lso promoting metabol ic al kalosis. With volu m e con­traction, there is an increase in sod i um avidity due to aldosterone activity.Because of electroneutrality, anions must be reabsorbed with sodium; therefore,chloride is maximally reabsorbed , leaving very little chloride in the urine . For thisreason, the measurement of urine chloride (see mnemonic next page) is helpfulin determining the cause of metabolic alkalosis.2 . The majority of m etabolic a lkalosis cases a re due to extracel lular fluidvolume contraction and respond to saline admin istration . These so-called sali ne­sensitive types com monly result from vom iting and d i u retic use. I n these i n­stances, volume loss leads to renal sod ium conservation, necessitating maximalreabsorption of ch loride as an obligate an ion . Urine chloride is usua lly less than 1 0 mmoles/L in sali ne-sensitive metabolic alkalosis. Replacement of the volumedeficit corrects the alkalosis.3. Hyperminera locorticoidism (primary, Cush ings syndrome, renal artery stenosis,malignant hypertension, J-G cell tumor, Bartters syndrome, and licorice gluttony) isthe other major mechan ism that can mai ntain metabolic alka losis. These condi­tions a re sa l i ne-sensitive and typically have a urine ch loride concentration > 20m moles/L. The patients volume status helps to differentiate between a sa line-sen­s itive cause (low volu me) and a saline-i nsensitive cause ( normal or increasedvol u me) . Rarely, patients with extracellular fluid vol ume depletion have othercauses for metabolic alkalosis ( mag nesium depletion, Bartters syndrome). liddlessyndrome is a rare disorder in which patients appear to have hyperaldosteronism,1 66 • Acid-Base JI
    • but aldosterone levels are low. It is probably due to an i ntri nsic tubular defectand can be treated with trai mterene or amiloride, but not spi ronolactone.4. The following m nemonic lists the specific causes of metabolic alkalosis :R E N A L C L- E VA LR e covery from hype rca p n i a , orga n i c a c i d o s i sE mesisN a s o g a s t r i c s u ct i o nA l d oste ro n i s mL a s i x/ l o o p d i u re t i csC ys t i c f i b r o s i sL ow K + , M g + +E xsa n g u i n a t i o n/m a s s ive t ra n sf u s io n ( c i t rate)V o l u m e d e p l et i o nA l ka l a i i n t a ke ( I V b i ca rb, m i l k-a l ka l a i )L i d d l es syn d ro m e R E S P I R AT O R Y A C I D O S I SCOPOSC a rd i a c a rresto btu n dati o nP u l m o n a ry d i se a s e/a i r way obstruct i o nD ru g s/ove r d o s eS ke l eta l/n e u ro m u s c u l a r d i s e a s eN otes1 . Respi ratory acidosis represents a fa il u re of venti lation. Obstructive lung dis­ease is the most common cause of both acute and chronic respi ratory acidosis,hence the mnemonic COPDS . Acid-Base • 1 67
    • 2 . Common causes of hypoventi lation and subsequent respiratory acidosis in­clude card iac arrest, obtu ndation, pul monary d isease or la rge a i rway obstruc­tion, C N S-depress ing d rugs/overdose, and skeleta l /neuromuscular disease(e.g , ALS, myasthenia g ravis, advanced kyphoscoliosis). R E S P I R AT O R Y A L K A L O S I Speo2 V E N TSP re g n a n cy V e nt i l a t o rC i rr h o s i s E mbolusO 2 d ef i c i t N e u ro l og i c d i s e a s e T e m p e ratu re (fev e r, h ea t ) S a l i cylates/d ru g sN otes 1 . I n contrast to respiratory acidosis, respi ratory alka losis is seconda ry t o hy­perventi lation . Over-excretion of carbon d ioxide, PC02 V E NTS, accounts forthe alkalosis.2. Respi ratory center sti m u lation in pregnancy is due to increased productionof progesterone, while in cirrhosis there probably is decreased meta bolism ofsubstances that stim ulate the respiratory center. Hypoxia (02 deficit) also causeshyperventilation. Patients on mecha nical ventilators may have respiratory alka­losis when the minute ventilation is i nappropriately high. Tachypnea and respira­tory alkalosis is a very sensitive albeit nonspecific sign of pulmonary embolus.CNS injury or neurologic diseases also may cause hyperventilation . Temper­ature elevations with fever or heat exhaustion sti mulate breath ing, and respira­tory alkalosis is the initial acid-base a bnormality in salicylate overdose.1 68 • Acid-Base
    • 113 G ASTRO ENT EROLOGY Clinica l Sy m ptoms and Signs A B D O M I N A L PA I NM EAN G U TM eta b o l i cE n d o c ri n eA bd o m i n a lN e u ro g e n i cG yn e c o l o g i c/g e n ita l iaU ri n a ry/r e n a l systemT h o ra c i cN otes 1 . "MEAN GUT" provides a simple outline for a pproaching abdomi nal pa i n .The most i m portant in itial decision i s whether u rgent surgical intervention o r d i­ag nostic testi ng is ind icated . The history and physical exa m i nation and a fewsimple tests gUide the decision-making . It is essential to exclude extra-abdominalcauses of pa i n ( i . e . , meta bolic, endocri nolog ic, neurolog ic, gynecolog ic, uro­log ic, and thoracic) before embarking on expensive and invasive testi ng .2 . Metabolic causes of a bdom inal pain include u remia , porphyria, C 1 esterasedeficiency, Fami lial Mediterra nea n Fever, and poisons (e g . , heavy metals, en­venomation, chemotherapy) . Endocrine causes include adrenal insufficiency, hy­percalcemia , and diabetic ketoacidosis. Most of the i ntra-abdo m i na l etiologies Gastroenterology . 1 69
    • of pa i n a re listed i n the "PREP FOR SURGICAL APPE NDECTOMY?" m nemonicon page 1 72 . Neurogenic ca uses of pa i n incl ude herpes zoster, tabes dor­salis, psychogenic pa i n , functional bowel d isease, a n d spinal rad i c u l itis.Gynecologic causes of pa i n - i mportant i n any female patient and especia llythose of menstruating age - a nd urologic causes of pai n , such as renal stones,pyelonephritis, and u rinary retention, also a re i ncluded in the differential for ap­pend icitis . Finally, pa i n may be referred from thoracic problems such as pneu­monia and myoca rd ial ischemia . Esophagea l d i sease usually causes chestd iscomfort, although patients may complain of a bdom inal symptoms.3 . The in itial d iag nostic eva luation of a patient with acute a bdominal pa i noften includes CBC, urinalysis, a mylase a nd/or lipase, liver enzymes, a n d a b­dominal x-rays, taken with the patient in the u pright position to eva luate for d i­lated loops of bowel or free a i r. Other tests may be appropriate i n selectedpatients, such as serum electrolytes, BUN, creati n i ne, calcium, cosyntropin stim­u lation testing for adrenal i nsufficiency, or a chest radiograph.4 . Important tips for internists: a. Be careful to exclude meta bolic derangements, systemic d i seases a n dextra-a bdominal processes, which m a y present with a bdom i nal pa i n . b. Rule out ectopic pregnancy i n a n y female o f menstruating age. Pelvic ex­a m ination should be performed on virtually a l l women with acute a bdom i na lpa i n . Every woman o f reproductive a g e must have a pregnancy test. c. E lderly patients with acute a bdom i na l processes may have atypical pre­sentations and should be ma naged with g reater caution. Mesenteric ischem ia,for example, may present with severe pai n and an unimpressive physical exam­i nation ( i . e . , pa i n out of proportion to the clinical findi ngs) . Also, patients on cor­ticosteroid therapy may have atypical presentations, as steroids may mask (clinical findings .5 . The location , d u ration, progression, and onset of pa i n (see ta ble) can behelpful in d ifferentiating between causes of a bdom inal pai n . There is consider­a ble overlap, but a general time cou rse is often helpful in d iscerning the causeof abdom inal pai n . Relieving and aggravating factors a re helpful in local izingthe source. For exa m ple, pa in relieved by the passage of bowel movementssuggests the colon as a l i kely source. Pa i n i n itiated by swallowing implicates theesophagus, wh i le pain aggravated by a ny action that moves the abdomen sug­gests periton itis (the patient usually prefers ta lie sti l l ) . On the other hand, withobstruction of a hollow viscus, patients usually move about in an attempt to seekrelief, and movement does not make the pain worse.1 70 • Gastroenterology
    • Pa i n Accordi n g to the Acuity of Onset Abrupt-Gnset Pain ( instant)Gastrointestinal Causes Nongastrointestinal CausesPerforated ulcer Ruptured or dissecti ng aneurysmRuptured abscess or hematoma Ruptured ectopic pregnancyIntestinal infarct PneumothoraxRuptured esophagus Myocardial infarction Pulmonary infarction Dissecting aneurysm Rapid-Onset Pa in (minutes)Gastrointestinal Causes Nongastrointestinal CausesPerforated viscus Ureteral colicStrangulated viscus Renal colicVolvulus EctopiC pregnancyPancreatitisBiliary colicMesenteric infarctDiverticulitisPenetrating peptic ulcerH igh intesti nal obstructionAppendicitis (gradual onset more common) Gradual-Gnset Pain (hours)Gastrointestinal Causes Nongastrointestinal CausesAppendicitis CystitisStrangulated hernia PyelitisLow intesti nal obstruction SalpingitisCholecystitis ProstatitisPancreatitis Threatened abortionGastritis U rinary retentionPeptic ulcer PneumonitisColonic d iverticulitisMeckels diverticulitisCrohns diseaseUlcerative colitisMesenteric lymphadenitisAbscessIntestinal infarctMesenteric cyst Gastroenterology . 1 7 1
    • 6. Here is a m nemonic delineating the d ifferential diag nosis for a ppendicitis: P R E P F O R S U R G I CA L A P P E N D ECTOMY? P ye l o n e p h r i t i s R e n a l sto n e E ctop i c p re g n a n cy P e lv i c i nf l a m matory d i s e a s e F o l l i c l e ru ptu re ( m i tt e l s ch m e rz ) O va r. i a n cyst t o rs i o n R u pt u re of c o r p u s l ut e a l cyst S p l e n i c ru ptu re U ri n a ry rete n t i o n R u ptu red a n e u rysm G a st r o e n t e r i t i s I nfarcted/i sch e m i c g ut Cro h n s/u l c e rat ive co l i t i s A bs c e s s L ive r c a ps u l e d i st e n s i o n/i rrita t i o n A ppendicitis P a n creatit i s P e rforated u l c e r E s o p h a g e a I ru ptu re N o disease D i vert i c u l it i s E ndometriosis C h o l ecys t i t i s T wi sted bow e l O bs t ru cted bowel M ecke l s d ive rt i c u l u m Y e rs i n ia/lym p h a d e n it i s 1 72 • Gastroenterologyb
    • D IA R R H EA SOILING S ec retory O s m ot i c I n f l a m matory L a xa t i ves (fact i t i o u s ) I sch e m i c N e u ro g e n i c G a st ro i ntesti n a l b l e e d i n g N otes 1 . The pri mary mechan isms of d iarrhea (or apparent d iarrhea ) a re summa rized by the m nemonic SOI LING. Dia rrhea is defined as an i ncrease in daily stool weight above 200 grams per day. Si nce this is not a very easily obta ined mea­ sure, dia rrhea is here defined from the patients perspective : an i ncrease in stool frequency and/or liqu idity. This defi nition includes hyperdefecation, which is an increase i n frequency without a n increase i n stool weig ht as occurs i n i rritable bowel syndrome, hyperthyroidism, and fecal i nconti nence. Also i ncluded is gas­ trointesti nal bleeding causing melena, which patients may describe as d ia rrhea . 2 . Secretory (watery) diarrhea is characterized by volu m i nous feca l output not necessa rily related to food inta ke, which fa i ls to i mprove with fasting. There is perturbation of normal fluid and electrolyte transport in the gut, and the result is watery stools with normal electrolyte concentrations and no increase in stool os­ molal ity. The classic exa m ples of secretory d ia rrheas are hormona l , including ca rci noid syndrome, Zol l i n ger-E l l ison , VIPoma, medullary thyroid carcinoma, and systemic mastocytosis. An exception is somatistati noma , in which the diar­ rhea is osmotic with steatorrhea secondary to inhi bition of pancreatic secretions and gall bladder motil ity. Bile salts stimulate colonic secretion, and processes that i ncrease bile salt delivery to the colon also cause secretory d iarrhea . Examples include: ileal bypass or resection ( reduced reabsorption), tru nca l vagotomy (ab­ normal transit), and after cholecystectomy (reduced storage capacity ) . 3 . Osmotic dia rrheas (such as pa ncreatitis, sprue, bacterial overgrowth , and Whi pples d isease) a re cha racterized by bulky, g reasy, foul-smel l i n g stools, weight loss, and i mprovement i n diarrhea with fasti ng . This form of diarrhea re­ sults from an ingested solute that is not a bsorbed by the sma ll intestine /The un­ absorbed solute exerts an osmotic force and draws fluid i nto the i ntestinal lumen . The resultant i ncreased stool volume exceeds the colons reabsorptive capacity, Gastroenterolog . y 1 73tb
    • po; a nd dia rrhea ensues. Stool analysis shows a gap between electrolyte concen­ trations and total stool osmolal ity d ue to the unabsorbed solute. 4. Inflammatory causes (infla m matory bowel disease, rad iation enterocolitis, eosinophilic gastroentereitis and certai n AI DS-associated infections) a re charac­ terized by fever, a bdominal pa i n , and blood and/or leukocytes in the stool. In these d i sorders there is i nfla mmation and i n j u ry to the i ntesti nal mucosa . The mechanism of dia rrhea may include mala bsorption or secretion due to disrup­ tion of normal mucosal functions. 5. Factitious dia rrhea from laxative abuse is osmotic and should be suspected in women with chronic dia rrhea , hypokalemia, and a h istory of psychiatric i l l­ ness . Certa i n prescri bed medications also can cause d i a rrhea , such as antacids, theophyl li ne, colch icine, digita lis, and antibiotics. 6 . Ischemia is not a common cause of d iarrhea , and the clin ical picture de­ pends on the deg ree of vascular comprom ise. Acute, fulminant ischemic colitis is due to complete vessel occlusion and features severe abdominal pa i n , bloody d ia rrhea , and rapid decompensation . Nonocclusive ischemia has a less severe course and usua lly resolves without intervention . Patients with nonocclusive is­ chemia have lesser deg rees of pain and bleed i ng , occ u rring over a longer period of time. Anorexia, vomiting, and diarrhea may be the primary complaints. 7. Neurogenic d isorders a re d isturbances of intestinal motility that often cause hyperdefecation or i nconti nence as o pposed to true d i a rrhea . The i rrita ble bowel syndrome (IBS) is a common a nd increasingly recog nized form of neuro­ genic diarrhea . IBS is characterized by alternating constipation and d iarrhea , as wel l as d iffuse a bdom inal pai n . I B S beg ins by early adulthood a n d should not be accepted as a diagnosis in a n older patient with recent-onset diarrhea . Other neurologic diseases (diabetes, cauda-equina syndrome, Shy-Drager) also can cause altered intestinal moti lity a nd diarrhea . 8. Gastrointestinal bleeding, when subacute, may cause frequent loose, black stools. Although not strictly d i a rrhea , patients may interpret it as such . Also, some of the other mechanisms of diarrhea may feature bleed ing, especially the infla mmatory etiologies and ischemia . 9 . The majority of cases of acute diarrhea « 7- 1 4 days in d u ration) a re i n­ fectious, the d iagnosis of which ca n be suspected by a history of recent travel, ingestion of unusual food (raw seafood or undercooked poultry products or ham- . burgeri, or recent contact with people who have been sick. Infections by inva­ sive bacteria ( Campylobacter, Shigella, Salmonella, Aeromonas, certa i n Escherichia coli) a re often associated with bloody diarrhea . It is i m portant to ex­ clude other causes of bloody dia rrhea such as mesenteric ischemia and inflam­ matory bowel disease. Infections by noninvasive bacteria a nd protozoa ( Vibrio cholerae, enterotoxigenic E. coli, Klebsiella, Giardia, Cryptosporidia) typically produce watery diarrhea without blood . C. difficile rarely causes bloody diar­ rhea . Yersinia, which commonly infects the term inal i leum and cecum, often pre­ sents with watery d i a rrhea and right lower quadrant pa i n , which ca n m i m ic a ppend icitis and Crohn s d isease. 1 0. A more comprehensive list of the causes of chronic diarrhea, organ ized pathophysiolog ically, follows: 1 74 • Gastroenterology b d
    • I RACE TO PASS LOTS O F WI LD 8 M ,FI N D A CURE ! Isch emiaI sch e m i a Secre toryR ecta l v i l l o u s a d e n o m aA fte r c h o l ecystectomy (ch o l e rr h e i c )C o l l a g e n o u s c o l i t i s ( l y m p h ocyt i c o r m i c ro s c o pi c co l it i s )E n d oc r i n e (Zo l l i n g e r- E l l i s o n , V I Po m a , ca rc i n o i d , m e d u l l a ry t h y r o i d ca rc i n o m a , m a s tocyto s i s )T ru n ca l va g otomyO be s i ty s u rg e ry ( i l e a l bypa s s o r resect i o n ) Osmo ticP a n crea t i t i s (ch ro n i c p a n c r e a t i t i s w i t h steato r r h e a )A beta l i p o p rote i n e m i aS o m atostati n o m aS h o rt-bowe l syn d ro m eL y m p h a n g i ecta s i aO ve rg rowth o f bacte r i aT ro p i c a l s p r u eS p r u e ( g l u te n -se n s itive)o l es t ra/d i etet i c foodsF ru its/ca n d y (fru ctos e , s o r b i ta l )W h i p p l e s d i s e a s eI nfect i o n s ca u s i n g stea t o r r h e a ( I s o s p o ra , G i a rd i a , S t ro n g y l o i de s )L a ctose i nt o l e r a n c eo r u g s ca u s i n g steato r r h e a (e . g . , c o l ch i c i n e , n eomyc i n ) Factitious o r "pseudo " diarrh eaB leeding (melena)M u n ch a u s e n s/ma l i n g e r i n g ( l a xa tive a b u s e ) Gastroenterology . 1 75
    • Ne urogenic or altered m o tilityF eca l i n c o n t i n e n c e o r i m pacti o n ( o b st i pati o n )I rrita b l e bowe lN e u ro l og i c d i se a s e s (e . g . , a uto n o m i c n e u ropat h i es , . ca u d a e q u i n a syn d ro m e )D i a betes m e l l it u s In flammatoryA I DS-a s so c i a t e d i nfect i o n s (ch ro n i c i nfecti o n s )C ro h n s d i s e a s eU l ce ra tive co l it i sR a d i a t i o n e nteroco l i t i sE os i n o p h i l i c g a stroente r i t i s DYS P H AG I ABITESB l ocked e s o p h a g e a l l u m e nI n t r i n s i c n a rrow i n g o f t h e e s o p h a g u sT h roat/m o u t h d i se a s e ( o ro p h a ry n g e a l dys p h a g i a)E xt r i n s i c c o m p res s i o n of t h e e s o p h a g u sS m o ot h/S t r i a t e d m u s c l e d i s o rd e rsN otes1 . There are five primary mechanisms of dysphagia. Blockage of the esopha­geal lumen results from i m pacted foreign bod ies and swa l lowing too large afood bolus. Processes that cause i ntrinsic narrowing of the esophagus i ncludeherpes virus and other opportu n istic i nfections, esophageal webs and rings,peptic strictures and caustic burns, ben ign and malignant tumors, and Croh n sdisease. Abnormal ities of the throat and mouth cause oropharyngeal dysphagiaand i nclude pharyngeal weakness from stroke, lack of saliva from Sjogrens syn­d rome and lesions affecting the tongue. Extrinsic compression of the esophagusmay be caused by a thyroid mass, Zenkers diverticu lum, vascular a nomal ies, or 7 76 • Gastroenterology
    • mediasti nal tumors. Hiatal hernias predispose patients to both i ntrinsic narrow­ i n g (strictures from G E RD) a n d extri nsic com pression ( i ncarceration of a paraesophageal or sliding hernia). Disorders of smooth muscle (scleroderm a , achalasia, Chagas disease, diffuse esophageal spasm o r " n utcracker" esopha­ gus) and striated muscle (neurom uscular d iseases, rabies, teta nus) cause motor dysphagia. 2. The symptom of dysphagia may be oropha ryngeal or esophagea l . Oro­ pharyngeal dysphag ia (throat and mouth etiologies) is suggested by a history of other oropharyngeal symptoms including nasal regurgitation , coughing on at­ tempting to swallow and concomitant speech d isturbances Patients with recent stroke are particularly likely to have oropharyngeal dysphagia . 3 . Esophageal dysphag ia is caused by the other fou r etiolog ica l g roups ( blockage, i ntri nsic, extri nsic, and smooth/striated m uscle) Blockage of the esophagea l l u me n , intrinsic narrowi ng, and extri nsic com pression cause me­ chanical obstruction, while diseases of smooth and striated muscle cause neuro­ muscular dysphag i a . Mecha nical and neuromuscular types of dysphagia can usually be d isti ngUished by a brief, but ca refu l , h istory focusing on the type of food i nd ucing dysphagia (solids, liquids) , the pattern of dysphagia ( i nterm ittent, constant and/or progressive), and whether heartburn is present 3 . Dysphagia for solid foods only: This sym ptom sug gests mecha n ical ob­ struction, as fluids a re a ble to traverse the partial ly obstructed esophagus more easily than solids If dysphagia for solid food is i nterm ittent, it may be due to a n esophageal (Schatzki) ring . With esophageal rings, the obstruction is m i l d , and only la rge food bol uses a re obstructed ; hence the intermittent nature of sym p­ toms. Prog ressive dysphagia with a h istory of heartburn suggests peptic esophag itis with or without a peptic stricture. ProgreSSive dysphagia for sol ids without a history of heartburn is characteristic of esophageal tumors. 5. Dysphagia for both solids and liquids: This symptom is cha racteristic of neu rom usc u l a r dys phagia ( m oti l i ty d i sorder), o r adva nced mecha nical ob­ struction preventing fluids from passi ng . ProgreSSive moti lity-type dysphagia is usua lly due to achalasia . Pseudoachalasia , due to tumor i nfi ltrating the myen­ teric plexus, is a rare cause of this symptom . I ntermittent, episodic moti lity-type dysphagia w i th a ssoc i a ted c h est pa i n may i n d i ca te d i ffuse esophageal spasm . In patients from South America , chagasic achalasia should be consid­ ered . Progressive dysphagia with severe associated hea rtburn is seen with scleroderm a . 6 . Physical examination should i nclude a search for cervical a n d supraclaVicu­ lar lym ph nodes and features of con nective tissue d isease . A barium esopha­ gram typically is the fi rst diagnostic test obta i ned . If a motil ity disorder is l i kely, esophageal manometry is obtained and, possi bly, an upper GI endoscopy to rule out pseudoachalasia . If mechan ical obstruction is seen on the barium study, an upper GI endoscopy with biopsy is ind icated . Thoracic CT is useful for d iag­ nosi ng the cause of extri nsic compression of the esophagus.7>. Here is a comprehensive list of the causes of dysphagia : Gastroenterology . 1 77
    • -- O H WH E N EATI N G BITES O ro p h a ry n g e a l dys p h a g i a (stroke, Sjog re ns, to n g u e p a r a l y s i s/i nj u ry) H e rp e s s i m p l ex/o p p o rt u n i st i c i nfect i o n s ( C M V, Ca n d i d a ) Web H i a t a l h e r n i a ( i n c a rc e rated) E so p h a g e a l s p a s m N ut c ra cke r e s o p h a g u s E xt r i n s i c co m p re s s i o n (thyro i d m a s s , Z e n ke r s d ive rti c u l u m , a n e u ry s m ) A ch a l a s i a T rypa n a s o m i a s i s ( C h a g a s d i se a s e ) I n f l a m m a t o ry bowel d i s e a s e ( C ro h n s) N e u ro m u sc u l a r d i se a s e s ( myasth e n ia g ra v i s , p o l i o mye l i t i s , A LS, p o l y myo s i t i s ) G E R D /p e pt i c s t r i ct u re B u rn (ca u st i c i n g e s t i o n ) I m pa ct e d fore i g n body T u mo r E so p h a g e a l r i n g S c l e ro d e r m a H E PAT O M E G A LY B I G H E PA T I C M A S S B u dd-C h i a ri syn d ro m e I nfect i o n s ( v i r a l h e p a t i t i s , E BV, We i l s d i se a s e , T B , a m e b i c a bs c e s s , hyd a t i d cyst) G a u c h e r s d i s e a s e/G I ycog e n stora g e d i s e a s e s 1 78 • Gastroenterology ,M
    • H epatic cysts ( p o l ycys t i c d i se a s e ) E xt ra m ed u l l a ry h e mato p o i e s i s ( i . e . , mye l o p ro l ife rative d iseases) P ri m a ry b i l i a ry c i rr h o s i s A my l o i d o s i s T oxi n s I ron ove r l o a d ( e . g . , h e m och romatos i s ) C o n g estive h e a rt fa i l u re M a l i g n a n cy (e . g . , h e pato m a , m etastat i c tu m o rs , I y m p h o p ro l i fe rat ive d i se a s e s , a d e n o m a ) A l co h o l S a rc o i d o s i s/g ra n u l o m at o u s h e p a t i t i s S ch i stoso m i a s i s (va s c u la r o bstru cti o n ) N otes 1 . A palpable l i ver, hepatomega ly, may i nd icate acute i nfection, toxic damage, infiltration , metabolic d isease, obstruction to bile d ra i nage, or vascu­ lar congestion/obstruction. A pa lpa ble liver may also be detected in patients with COPD where there is downwa rd d i splacement of the l iver and , rarely, when there is an a natomic anomaly (Riedels lobe). 2. The evaluation of hepatomegaly depends upon the rapidity of enlargement and presenting historicol and clin ical features. In general, assess l iver enzymes, bilirubin, a nd hepatic synthetic function (prothrombin time, albumin), and follow up with i maging studies. J�U N D I C E BILE B i l i a ry obstruct i o n I n h e rited d i so rd e rs o f b i l e meta b o l i s m L iver pa r e n c h ym a l d a m a g e ( i nfect i o n , tox i n s) E ryth ro cyte destruct i o n Gastroenterology . 1 79&
    • N otes 1 . The pathophysiologic mechanisms of hyperbilirubinemia a re outli ned by the B I LE mnemonic ( 1 ) biliary obstruction (i e . , cholel ithiasis), ( 2 ) inherited disor­ ders of bile con i ugation or excretion ( i e , Gil berts, Dubi n-Johnson , Crig ler­ Naiiar and Rotor syndrome), ( 3 ) liver parenchymal damage ( i nfection, toxins), and (4) erythrocyte destruction (hemolysis, ineffective erythropoiesis) . 2 . Jau nd ice results from hyperbi l i rubinemia and a ppears as yellowi ng of the skin and sclera . Other conditions may cause yellowing (carotenemia) or darken­ ing (Add isons) of the ski n , but do not ca use scleral icterus. After obta i n i n g a serum bilirubin level and confi rming that skin pigmentation changes are due to iaund ice, the next step is to fractionate the bilirubin i n to unconi ugated ( " i ndi­ rect" ) and con iugated ("direct") fractions. 3. Uncon;ugafed hyperbilirubinemia rarely causes bilirubin levels g reater than 5 mg/d l ; order hemolysis labs (ha ptog lobi n , reticulocyte count, d i rect and indi­ rect a nti-globulin tests, etc . ) if a n other cause is not a pparent. Disorders that cause a predomi nantly unconi ugated hyperbil i rubinemia include eryth rocyte a b­ normalities, sepsis (decreased hepatic u ptake), C H F, and certain in herited con­ ditions (Gilberts, Crigler-Naiiar types I and I I ) . 4. If t h e patient h a s a predomina ntly con;ugafed hyperbilirubinemia, the next step is to differentiate between liver parenchymal da mage and biliary obstruc­ tion . liver parenchymal i n i u ry ca uses very h i g h levels of tra nsa m i nases : AST (SGOT) and ALT (SGPT) Biliary obstruction has a lesser i ncrease iri transa m i­ nases and a more rema rka ble elevation of a l ka l i ne phosphatase (and 5 nu­ cleotidase, if obta i ned) If bil iary obstruction is suspected , then d ifferentiate between intra-hepatic and extra-hepatic biliary obstruction by i maging studies, often ultrasonography. Disorders that cause a predominantly coniugated hyper­ biliru binemia incl ude hepatocellular destruction ( i nfection , d rugs), bil iary obstruc­ tion (stones, anomal ies of the bile d uct, cancer, sclerosing cholangitis), and a few i nherited disorders of bile excretion (Dubinjohnson , Rotor) . 5 . Here is a more complete list of etiologies of iaundice : I M P A G I N G M R S W H I P P L E S TA T I n fe c t i o n ( e . g . , v i ra l h e patit i s , s e p s i s , l e ptos p i ro s i s , Clonorchis, Ascariasis) M ed i ca t i o n s/d r u g s P osto p e rat ive c h o l esta s i s A l p h a - 1 a n ti-tryps i n defi c i e n cy G a l l st o n e s 180 • Gastroenterologyb
    • I nj u ry/tra u m a ( h e m o b i l i a )N eo p l a s m s ( e . g . , ch o l a n g i o c a rc i n o m a , p e r i a m p u l l a r y c a rc i n o m a , carc i n o m a h e a d o f pa n c r e a s )G ra n u l o m a t o u s/i n f i l t ra t i ve d i s e a s e (e . g . , s a rc o i d o s i s )M a l fo rm a t i o n o f t h e b i l ia r y t r e e (atre s i a , s t r i ct u re , c h o l e d o ch a l cyst, etc . )R eyes syn d r o m eS c l e ros i n g ch o l a n g it i sW i l s o n s d i s e a s eH e red i t a ry d i se a s e s ( G i l be rt s , D u b i n-Jo h n s o n , R oto r syn d ro m e , C r i g l e r- N aj j a r)I ro n ove r l o a dP re g n a n cy-re l ated ( ch o l esta s i s of p reg n a n cy, p re-ec l a m ps i a , a c u te fatty l iver of preg n a n cy)P ri m a ry b i l ia ry c i rr h o s i sL a e n n e c s c i r rh o s i s (a l co h o l i c ) .E ryth rocyte d e st r u ct i o nS ta rva t i o n/fa s t i n gTPNA u to i m m u n e h e patitisT oxi n s N AU S EA A N D VO M I T I N GI VO M ITI n c re a s e d i nt r a c ra n ia l p r e s s u re/C N S d i se a s eVascularO bstructiveM et a b o l i c/tox i cI nfect i o u sT ra u m a t i c Gastroenterology . 181
    • N otes 1 . Nausea and vom iting a re very common symptoms and may be associatedwith any of the causes of a bdominal pa in (see Abdominal Pa i n section ) . In fact,these symptoms often occu r together. When na usea and vom iting are the pri­mary symptoms, however, a different prioritization of diag nostic possibil ities­summa rized by the m nemonic I VOMIT (see a lso Pa n c reatitis section ) - isa ppropriate. Increased intracranial pressure, as occurs with intracerebral hem­orrhage, can cause nausea and vom iting . Vascular etiolog ies i nclude mesen­teric ischemia, myoca rd ial ischem i a , and m igraine headache. Obstruction ofthe GI tract (e.g . , adhesions, volvu lus, intussusception) and pseudo-obstruction(e. g . , scleroderma, gastroparesis) a re com mon causes of nausea and vom iti ng .Metabolic/toxic causes i n clude pregnancy, hyperca lce m i a , adrenal i nsuffi­ciency, kid ney fai lure, d rugs, and diabetic ketoacidosis. Infectious etiologies in­cl ude gastroenteritis, a ppendicitis, a bscess, Helicobacter pylori, sepsis, andmening itis. Finally, trauma to the abdomen, either extrinsic or related to surgery,a re easily recognized causes of nausea and vom iting .2 . Seek a history of headaches or nE:uroiogical symptoms, as these may poi nttoward a eNS cause of nausea and vom iti n g . Abdom inal pa i n preceding thevom iting may help localize an i ntra-abdom inal i nflam matory process (e. g . , epi­gastric pa i n with pancreatitis, right upper q uadrant pa i n with cholecystitis, rightlower quadrant pain with append icitis). Undigested food in the vom itus mayhelp localize the etiology to the stomach, but ca nnot d istinguish m echan ica lobstruction from gastroparesis. Fecu lent vom itus suggests bowel obstruction orfistula .3 . In addition to perform ing a general physical examination, measure orthosta­tic changes in pulse and blood pressure to estimate the degree of dehydration.Orthostatic changes may also be due to autonomic dysfunction in diabetic pa­tients, or due to d rug therapy.4 . Abdominal exam i nation should esta bl ish the presence or a bsence of d isten­sion . An absence of bowel sounds on a uscultation may indicate an i leus or ani nfla mmatory condition with peritonitis. Pa l pation of the a bdomen helps d istin­guish the two, as localized tenderness with guarding is present in i nflammatorycond itions. The local ization of pa i n a n d tenderness may i nd icate the organsystem i nvolved .OH GOD AM I SICKO bstet r i c a l ( p re g n a n cy, h y p e re m es i s g ra v i d a )H yp e rca l ce m i a1 82 • Gastroenterology
    • G a st r o e n t e r i t i s ( b a ct e ri a l a n d v i ra l )O bstruct i o n ( a d h e s i o n s , vo l v u l u s , i nt u s s u scepti o n , peptic s t r i ct u r e s , tu m o rs )D i a betes ( D KA, g a stropa res i s )A d re n a l i n s uff i c i e n cyM ed i cati o n s ( o p i ates, a nt i b i ot i c s , N SA I D s , ch e m o t h e ra pe u t i c a g e n t s , a n t i a rrhyt h m i cs )I n t ra-a b do m i n a l i n f l a m m a t o ry co n d it i o n s ( p a n crea t i t i s , ch o l ecysti t i s , a p p e n d i c i t i s , t ra u m a )S c l e ro d e rma ( a n d oth e r p s e u d o-obst ru ct ive states)I sch e m i a ( m es e n t e r i c , myoca rd i a l )e N S d i se a s e ( m i g ra i n e s , i n creased i nt r a c ra n i a l p re ss u re , m e n i n g i t i s , stroke)K id n ey fa i l u re C l inica l Conditions or Diagnoses P A N C R E AT I T I SVOMITVascularO bst ru ct iveM et a bo l i c/toxi cI nfect i o u sT ra u ma t i cN otes1 . The VOMIT m nemonic (see Nausea and Vomiting section) can be used toclassify the causes of pancreatitis. Vosculor causes of pancreatitis include necrotizing Gastroen terologv . 1 83
    • - vascul itis, atheroemboli, and TIP. Obstructive causes of pancreatitis incl ude bil­ iary disease/cholelithiasis, pancreas divisu m , ampullary malig na ncies . Crohn s d isease, sphi ncter of Oddi dysfunction , Ascariasis infestation , duodenal divertic­ ulum and ( probably) cystic fibrosis. Metabolic/toxic processes causing pancre­ atitis include a lcohol, d rugs, renal fa ilure, acute fatty liver, scorpion sting, Reyes syndrome, hyperca lcemia, and hypertriglyceridem ia. Infectious causes of pan­ creatitis i nclude m u mps, other viral i nfections, Reyes syndrome (a lso a toxic/metabolic process) , Mycoplasma and Ascariasis (obstructs pancreatic out­ flow). Traumatic caus�s of pancreatitis include external trauma, ERCP, surgery, erosion of duodenal ulcer, and after renal transplantation (the latter a lso may be considered toxic/metabolic) . 2. The most com mon causes of acute pa ncreatitis a re ( 1 ) bil iary obstruction by gall stones, ( 2 ) alcohol toxicity (these fi rst two account for approximately 90% of cases), and ( 3 ) drugs, which account for a bout 5% of cases ( "BAD") . Other ia­ trogenic causes ( e . g . , ERCP, post-operative, and ca lcium a d m i n i stration) a re being increasingly recogn ized . 3 . An i m portant d iag nostic test is the a mylase level, a lthough a normal level does not rule out pancreatitis. The lipase level may have somewhat g reater sen­ sitivity and specificity in the diag nosis of acute pancreatitis. 4. Other non-pancreatic conditions wh ich cause an elevation of serum amylase include renal insufficiency, salivary gland disease, macroamylasemia, DKA, cer­ ta in tumors ( l u n g , esophagus, ova ri a n ) , bu rns, ectopic pregna ncy, and other intra-a bdominal disorders (perforated viscus, penetrati ng ulcer, peritonitis). 5. Serial measu res of serum amylase a re not helpful , and patients are best fol­ lowed clinical ly. Urine amylase esti mation is only helpful for making the diagno­ sis of macroamylasemia. In this cond ition , the a mylase com plex is too large to be filtered into the urine, and u rine levels a re low i n contrast to elevated serum levels. 6 . Ra nsons criteria for pa ncreatitis may be used for p rognosis. " H E LLO RANSON" lists these factors : On Admission Within 48 Hours Hyperglycemia Renal fa ilure (BUN i ncrease (Glucose > 200 mg/ dl) > 5 mg/dl) Elevated AST > 250 u/I Anemia ( hematocrit d rop > 1 0 mg/dl) Leu kocytosis No calciu m « 8 mg/dl) (WBC > 1 6, 000/m m 3 ) Sequestration (> 4 L fluid) LDH > 350 u/I Oxygen d rop ( P02 < 60 mmHg) Older patients (Age > 55 years) No albumin « 3 . 2 g/d l) Patients with only one of these factors have an i ncreased risk of complications; those with two risk factors may have a mortality rate as high as 2 0-30%; and those with six to seven risk factors have a nearly 1 00% morta lity rate. I n patients with gal lstone-assoc iated pancreatitis, the prog nosis is genera l ly better, a n d modified criteria have been proposed . Other ind icators o f poor prog nosis in­ cl ude acidosis (base deficit > 4 m mol/L), hypotension (BP < 90 mmHg), tachy­ cardia ( heart rate > 1 30), oliguria « 50 cc/hr) and hemorrhagic peritoneal fluid ("toxic broth"). An APACHE II score > 1 2 is a lso predictive of more severe disease, 184 • Gastroenterology
    • a lthough it is a com plex and seldom used calculation . The i m portance of risk stratification is that high-risk patients should be mon itored more closely and a re candidates for earlier interventional therapy (surgica l , radiolog ic, endoscopic) . 7. The treatment for pancreatitis is largely supportive , with fl u id resuscitation. and ana lgesia . The pancreas is rested by eli minating oral intake. Monitoring for complications ( i nfection , hemorrhage, hemodynamic collapse, respi ratory fa il­ ure, hypoca lcem ia, hyperglycem ia ) is critica l . There are no proven benefits for routine nasogastric suction, peritoneal lavage, administration of antibiotics, or therapy with other medications. In cases of gal lstone pancreatitis, i m med iate re­ mova l of stones in severely ill patients may improve outcome. Other invasive therapies a re reserved for severely ill patients with specific com plications (e . g . , a bscess, pseudocyst, phlegmon ) . 8 . The fo l lowi n g m n e m o n i c l i sts m o s t of t h e causes a n d a ssociations for pa ncreatiti s : B A D PA N C R EATI T I S C RAS H ES H A R D B i l i a ry d i s e a s e (ch o l ed o ch o l it h i a s i s ) A lcohol D ru g s/tox i n s P a n c re a s d i vi s u m A m p u l l a ry m a l i g n a n cy ( a d e noca rc i n o m a o f t h e pa n c rea s , p r i m a ry a m p u l l a ry, etc . ) N ecrotiz i n g va s c u l it i s ( l u p u s , p o lya rte r i t i s n od o s a ) C ys t i c f i b ro s i s R eyes syn d r o m e E RC P A t h e ro e m b o l i T ra u ma I nfect i o n (vi ra l , p a r a s i t e s , bacte ria l ) TTP I d i o p at h i c/i n h e rited S u rg e ry ( posto p e rative pa n creati t i s , e s p e c i a l l y post card i o p u l m o n a ry bypa s s ) Gastroenterology . 1 85
    • -- C ro h n s d i s e a s e R e n a l fa i l u re A c ute fatty l ive r of p re g n a n cy S co r p i o n st i n g H yp e rca l c e m i a E ros i o n o f d u o d e n a l u l c e r S p h i n ct e r of O d d i dysf u n c t i o n H y p e rt r i g lyce r i d e m i a A sca r i a s i s R e n a l t ra n s p l a n t D u o d e n a l d iv e rt i c u l u m 1 86 • Gastroenterology
    • 13 R H EUMATOLOGY Clinical Sym ptoms and Signs AC U T E M O N OA R T H R I T I SHIS G O UT FIT*H e m a rt h ro s i s ( c oa g u l o pathy, e . g . , h e m o p h i l i a )I n fect i o n ( b a cteri a , [e . g . , g o n ococc u s ] , myc o b a cte r i a l , f u n g a l , Lym e d i s e a s e , v i ra l )S ystem i c i l l n e s s ( R e i t e r s , S L E , r h e u m a t o i d a rt h ri t i s , p s o ri a s i s , s a rc o i d , B e h ge t s )G o u t/ps e u do g o u tO steoa rt h r i t i sU l c e rative c o l i t i s/C ro h nsT ra u m a/fo re i g n body s y n ov i t i sF i b r i n d e p o s i t i o n ( pa l i n d ro m i c a rt h r i t i s )I sch e m i c n ec ros i sT u m o r ( m et a s t a t i c , pri m a ry)* Differential diagnosisN otes1 . Acute pa in and swelling i n a joint req u i res i m med iate eva l uation a n d , inalmost all cases, im mediate arthrocentesis to rule out infection . Rheumatology . 1 87 .
    • 2 . The age of the patient, history of other d isease or symptoms (gastroenteritis), fa m i ly h istory, and sexual h istory m ust be carefully evaluated . Physical exa m i na­ tion is performed to look for signs of infection (skin cha nges) o r evidence of other systemic ill ness. Consider cu lture of the throat, u rethra, and rectu m in indi­ viduals suspected of gonococcal infection 3. Examine joint fluid by g ram sta i n and polarized light i n itia lly, and send for a culture and cell count. Normal synovial fluid contains fewer than 1 1 0 cells/mm 3 , most of which a re mononuclea r. F l u id is cOhsidered " n o n i nflam matory" if i t conta ins less than 3000 cells/mm 3 As the cel l count increases, s o does the sus­ picion of i nfectio n . Effusions with more than 1 00 , 000 WBC/mm 3 a re con­ sidered septic, but there is a wide range of possible va lues . Careful exam i nation of fluid for crystals may esta blish a d iagnosis early and obviate the need for hos­ pital ization . The presence of crystals, however, does not exclude infection, and if there is sti ll a q uestion of infection , the patient should be adm itted for a ntibi­ otics until cu lture results a re ava i lable. (See ta ble i n I nfla m matory Polya rthritis section . ) 4 . A freq uent diag nostic dilemma i nvolves d ifferentiati ng i nfections from other acute i nfla m matory a rthritides . Patients should be admitted for i ntravenous anti bi­ otics while awa iting cu lture results. N SAIDs should be withheld initially to j udge the response to antibiotics alone. I N F L A M M AT O R Y P O LYA R T H R I T I S A G G RAVAT E D S Y N OV I A L J T S * A d u lt Sti l l s d i s e a s e G o u t/ps e u d o g o u t G o n ococce m i a R h e u m a t o i d a rt h ri t i s A c u t e r h e u m a t i c feve r Vascu litis A my l o i d o s i s T u be rc u l o s i s E n d oca rd i t i s D e rmatomyo s i t i s/polymyo s i t i s 1 88 • Rheumatologvb
    • S yste m i c l u p u s e ryt h e ma t o s u sY e rs i n ia , Ca m py l o b a ct e r, S h i g e l l a ( Re i t e r s)N o n-g o n ococca l u reth ritis ( R e ite r s)O ve r l a p syn d ro m e s (e . g . , m i xed c o n n ective t i s s u e d i sease)V i ra l i nfe ct i o n s ( reactive)I n f l a m m a t o r y bowe l d i s e a s eA I DSLyme d iseaseJ uve n i l e r h e u m a t o i d a rt h r i t i sT re p o n e m a l i n fect i o n (syp h i l i s )S a rc o i d o s i sAlso: scleroderma, polymyalgia rheumatica, psoriasis, intestinal bypass surgery,hemochromatosis* This m nemonic provides the differential diagnosis.N otes 1 . A q U ick and easy etiolog ic way to look at i nfla m matory polyarthritis is asfollows a . Infection - d irect infection of joint ( bacteria, syphilis, TB, etc . ) b. Crysta l-ind uced (gout, pseudogout) c. Immunologic ( RA, SLE, vasculitis, etc) d . Reactive - i n response to infection elsewhere in body (Reiters synd rome,AIDS, etc . ) e . Id iopathic (ankylosing spondylitis)2. Work-up of inflammatory polyarth ritis includes: a. Laboratory studies: CBC, E S R , C R P may help distinguish i nfla m ma toryfrom noninfla m matory conditions. b . Synovial fluid aspiration is a lways ind icated when either an i nfectious orcrysta l-i nduced i nfla m matory a rthritis is being considered . Normal viscosi ty issuch that when expressed from a syri nge, each d rop has a long ta i l or stringattached . R BCs a re not generally seen i n synovial fl u id except i n a settinq ofhemarthrosis or trauma. Rheumatology . 1 89
    • Synovial F l u i d Characteristics Noninflammatory Crystal-Induced Infectious Arthritis Arthritis ArthritisAppearance Clear Tu rbid, yel low Turbid, opaqueW BC < 3000 cells/ ml 3000-50,000 > 50,000 cells/ml cells/mlDifferential Mostly mono- Mostly PMNs Mostly PMNs nuclear cellsGlucose Normal (within Normal or low Low 1 0- 1 5 mg/dl of serum values)Protein Normal Normal or high HighViscosity Good , stri nging Poor, no stri ng ing Poor, no stringing of fluidCrysta ls No Yes NoGram stain/ Negative Negative Positive culture c. Specific serologic tests seek RF, ANA, com plement levels, ASO titers, etc.only when a specific diag nosis is suggested ; these tests are not useful as screen­ing tools. d. Rad iograph ic tests i nclude • X-rays are ind icated with history of trauma, suspected chronic i nfection, monoa rticular i nvolvement, or progressive disabi l i ty. For i nfla m matory disorders, findings i nclude primarily soft tissue swell i ng and periarticular dem i neral ization. I n chronic disease, ioint space na rrowi ng, calcifica­ tion , osteophyte formation, and subchondral cysts may be seen. • Radionucl ide scans may show increased uptake i n synovitis, i nfection, or maligna ncy. Osteonecrosis may be seen as decreased uptake .. 1 90 • Rheuma tology d
    • C linica l Conditions or Diagnoses C A L C I U M P Y R O P H O S P H AT E D I H Y D R AT E D E P O S I T I O N D I S EAS E H OW I GOT BA D CPPD H yperparathyro i d i s m O steoa rt h ri t i s W i l so ns d i se a s e I ron ove r l o a d G out O ch ro n o s i s T hyro i d d i s e a s e ( hypoth y ro i d i s m ) B owe l d i se a s e ( C r o h ns, u l c e ra tive c o l i t i s ) A c ro m eg a l y D i a betes C o n g e n it a l hypoca l c i u r i c hyperca l c e m i a P a g et s d i s e a s e P ost-tra u ma t i c D i s e a s e rese m b l i n g r h e u m ato i d a rt h r i t i s Also. amyloidosis, hypophosphatemia, hereditary calcium pyrophosphate dihy­ drate deposition (CPPD) N otes 1 . There are numerous reported disease associations of CPPD (or pseudogoutl, but the importance of some is debatable, as rigorous, controlled studies are not Rheumatology . 1 9 1s
    • ava i la ble. However, i n patients with CPPD, consideration must be g iven to the possibi lity of an u nderlyi ng disease process. 2 . One characteristic feature of this disease is patellofemoral joint disease with a normal femoral/tibial joint. 3. Screening work-u p usual ly i ncludes TSH , calciu m , and gl ucose levels. Also consider ferritin and ceruloplasmin . C R E ST SY N D R O M E CREST* C a l c i n o s i s c ut i s R ay n a u d s s y n d r o m e E so p h a g e a l dys m ot i l ity S c l e rodactyly T e l a n g i e ct a s i a * The mnemonic presents clinicol characteristics. N otes 1 . Anti-centromere antibodies are seen in a high percentage of patients with CREST, but few patients with scleroderma/systemic sclerosis. 2. Calci nosis cutis descri bes i rreg ular cuta neous papu les that a re f i rm a nd white . 3 . Raynauds phenomenon involves episodic vasoconstriction o f the small ar­ teries and arterioles of the digits. Triggers i ncl ude cold , vibration, and stress . An i n itial vasoconstrictive event leads to whitish pallor i n affected areas associ­ ated with the sensation of coldness, ti ngling, or pa i n . A cyanotic ( blue) phase may occur, and the episode eventually ·resolves with a period of reactive hyper­ emia ( red) . 4. Esophageal dysmotility may man ifest as dysphag ia, heartbu rn, regurg ita­ tion, and/or a sensation of epigastric fullness. 5. Sclerodactyly i nvolves ta ut, thinned skin over the d ig its, which may often have a tapered appea rance. It eventually leads to dimin ished joint movement. 6. Telangiectasia features superficial cutaneous ca pillary malformations. 1 92 • Rheumatologyb d
    • O ST E OA R T H R I T I SI G OT M R . PAI N , DOC*I d io pa t h i c p r i m a ry osteoa rt h r i t i sG o utO cc u p a t i o n a l/s p o rtsT ra u m a , a c u te/f ra ctu reM et a bo l i c ( h e m o ch ro ma tos i s , W i l so ns , G a u c h e r s , och ro n o s i s )R h e u ma t o i d a rt h r i t i sP so r i a t i c a rt h r i t i sA c r o m e g a l y/e n d o c r i n e (hype rpa rathyro i d i s m , D M , o b e s ity, hypothyro i d )I nfect i o nN e u ropat h i cD eve l o p m e n t a l ( Leg g-Ca l ve-Pert h e s , co n g e n it a l h i p d i s l ocati o n , etc . )O steopetro s i s/osteoc h o n d ri t i sC a lc i u m deposition d i sease* Differential diagnosisN otesOsteoa rth ritis (OA) is a disease or pathology of movable, synovial joi nts. It issynonymous with degenerative joint d iseaseHeberdens nodes a re bony enla rgements of the d istal interphalangeal joints .They are the most common form o f id iopathic osteoa rthritis.Bouchards nodes a re bony enlargements of the proximal interphala ngea ljoi nts. ,1 . OA may be classified as primary or secondary. Prima ry OA occurs in theabsence of an identifiable underlying etiology. Secondary OA is due to an u n­derlying condition or d isease. Rheumatologv . 193
    • ... 2 . Locations of OA: a. Interphalangeal ioi nts: Heberdens and Bouchards nodes b. H i p : most cases are secondary and d ue to congenital or developmenta l defects. c. Knee : • Varus deformity (bow-legged) due to medial comportment OA • Valgus deformity (knock-kneed) due to lateral compartment OA • Chondroma lacia, a syndrome of knee pa in, usually occurs in younger patients and is not generally prog ressive to true OA . d . Spine • Spondylosis- degenerative disk disease • Diffuse id iopath ic skeletal hyperostosis-calcification and ossification of paraspinous ligaments • Osteoarth ritis of the spine - degeneration of mova ble, synovial-li ned spinal ioints 3 . Clinical signs and symptoms a. Pa i n has gradual onset, dull aching. joint tenderness and pa in occur with range of motion . b. Morn ing stiffness is not prom inent, as in infla mmatory rheumatic disease. c. Crepitus is a g rinding sound or sensation hea rd or felt as ioint is moved . d . joint enlargement may be due to soh tissue swelling/effusion or osteophytes. e. joint deformity, such as Heberdens and Bouchard s nodes, varus or valgus angulation 4. Work-up of OA a . X-rays of affected ioi nts - may be normal, or show ioint space na rrowi ng, subchrondral sclerosis, subchondral cysts, and marginal osteophytes. b. Ro utine la boratory tests help identify causes of secondary OA, including ESR, CBC, seru m chem istries, u rina lysis. c. Synovial fl u i d : m i ld leukocytosis « 2 000 WBC/ml, < 25% PMNs), no crysta ls, good mucin clot. 5. Charcot ioi nts - secondary OA d ue to underlying neurologic disease. R H E U M AT O I D A R T H R I T I S RF RISES R h e u m a t o i d facto r e l evated F i n g e r/ha n d j o i nts i nvo lved 1 94 • Rheumatology
    • R h e u m a t o i d n od u l e sI nvo lve m e n t of t h ree o r m o re j o i ntsS tiff n e s s , m o r n i n gE ro s i o n s/d eca l c i f i cati o n s o n X-raysS y m m et r i c ( b i l a t e ra l ) a rt h r i t i sN otesRheumatoid a rthritis (RA) is a chronic multi-system disorder characterized by in­flammatory joint disease, usua lly symmetric.1 . Diag nostic criteria a. Four of the seven criteria a bove are needed to d iag nose RA. b. Patients with two or more other clinical d iagnoses a re not excluded .2 . Elevation of serum rheumatoid factor can be determ i ned by any methodthat has < 5% false positive rate .3 . Finger/hand joint involvement incl udes arthritic changes in the wrist andthe metacarpophalangeal (MCP) or proximal i nterphalangeal (PIP) joints.4. Rheumatoid nodules a re fir m , round, subcutaneous nodules over the joints,extensor surfaces, or bony prominences. They a re seen i n 20-25% of patients.5 . Multiple joint i nvolvement (of three or more) refers to soft tissue swelling orjoint effUSions, not j ust osteophytes. Fourteen possi ble areas a re descri bed : rightor left proxi mal i nterphalangea l , metacarpopha langea l , wrist, el bow, knee,ankle, and metatarsophalangeal joi nts.6. Morning stiffness is defined as a joint stiffness upon awakening that persists 1 hour before maximal i mprovement.7 . Radiographic findi ngs in hand and wrist x-rays must i nclude erosions orbony decalcification in or ad jacent to affected joi nts. 8. Symmetry means simultaneous involvement of the sa me joint bilatera lly.9. Signs and symptoms: a. Joint man ifestations • Generalized : pa i n , joint swelling, effUSion, wa rmth , and lim ited range of motion . • Cervical spine: most serious is atla ntoaxial su bl uxatio n . May cause nerve root impi ngement, spinal cord symptoms, or even lower bra i n­ stem problems. • Cricoarytenoid joint: i m pairs voca l cord mobil ity, cause hoarseness. • Shoulder: synovitis and rotator cuff injury. • Elbow: rheumatoid nodules on extensor surface of forea rm lead to ole­ cranon bursitis. • Ha nd/wrist: typ ically d ista l interphala ngeal (DIP) joi nts a re spa red . Swan neck deformity is flexion at the DIP and MCP joints and hyper­ extension at the PIP joi nts . Boutonniere deformity is DIP hyperextension Rheumatology . 195
    • --- with PIP flexion . Carpal tunnel syndrome is not uncom mon . Ulnar drift is a deformity characterized by PIP flexion and deviation of the fi nger­ tips toward the ulna • Hip: may manifest with g roin pa i n . Severe involvement is rare (5%) • Knee: very com mon . Bokers cyst is a posterior hern iation of synoviu m a n d fluid from the knee into the popliteal fossa . • Ankle/foot Common i n both a n kle a nd foot. Cock-up toe deform ity occurs at the metata rsophala ngea l l oint. b. Systemic man ifestations include weight loss, fatigue, achi ness, anorexia , malaise. c . Other organ involvement i . Rheumatoid nodu les: see number 4, previous page i i . Eye manifestations: Sicca complex is burning, gritty eye sensation; d ry mouth; and sal ivary gland enlargement. Episcleritis and scleritis may a lso occur. i i i . Card iac: rarely clinically sign ifica nt, but include pericard itis and in­ fla mmatory g ranulomas. iv. Pul monary: pleuritis, pleural effusions, i nterstitial fi b rosis and nodules. Coplons syndrome consists of i nterstitial fi brosis and multiple nodules . v. Neu rologic: entra pment neuropath ies (carpal tunnel) , occasional vas­ cul itic com plications. vi . Hematolog ic: anemia, throm bocytosis (500-700 KI, m i ld leu kocyto­ sis. Feltys syndrome is a com bi nation of RA, throm bocytopenia, leukopenia, and splenomegaly. vi i . Vasculitis: cutaneous, neuropath ic, or visceral i nvolvement with is­ chemic com plications. 1 0 . Diag nostic work-up a . CBC - normochromic, normocytic anem ia. Also throm bocytosis, elevated ESR, i ncreased IgG, and even eosi noph ilia. b . Rheumatoid factor- pOSitive i n 70-8 0% . N onspecifi c . ANA positive ( 2 5% of patients) and VDRL false positive (5- 1 0%) c. Synovia l fluid - WBC 5000-2 5 , 000, mostly PMNs. Glucose low and complement levels low. No crystals. d. X-rays - approximate symmetric i nvolvement, osteopenia/deca lcification , soft tissue swelling, bony erosions, joint space na rrowi n g . 1 96 • Rheumatologyb
    • SYST E M I C S C L E R O S I S (SCLE RO D E R MA) SCLERODERMA* S kin changes C a rd i a c i nvolve m e nt L u n g i nvo l ve m e n t E so p h a g e a l dysfu ncti o n R ay n a u d s p h e n o m e n o n O bstruct i o n , p s e u d o­ D ry eyes/ m o u t h E n d o c r i n e ( hypothyro i d i s m ) R e n a l fa i l u re M yo p a thy/myos i t i s A rt h r i t i s * Clinical characteristics N otes 1 . Skin changes include early swel ling, particula rly of the fingers and hands. Later, skin becomes firm and thickened . Chron ical ly, skin becomes th in and at­ roph ic. Skin over the fi ngers become taut, and contractu res l i m i t movement. Other cutaneous man ifestations include telang iectasia, subcutaneous calcifica­ tions, sa lt-and-pepper pigmentary changes, abnormal nail bed capilla ries, and skin ulcers . 2 . Cardiac involvement i ncludes perica rditis, pericard ial effusion, hea rt fa il­ ure, and heart block!a rrhyth m i a . Myocard ial fibrosis ca using cardiomyopathy Occurs in < 1 0%. 3 . Lung involvement occurs in two-th i rds of patients and is often manifested by exertional dyspnea and d ry, nonproductive cough. Additional com pl ications in­ clude pulmonary fibrosis, aspiration pneu mon ia, decreased vital capacity, and decreased lung com pliance. Pulmonary hypertension in the a bsence of fibrosis can occur in < 1 0%. 4 . Gastrointestinal dysmotility is related to neuromuscu la r dysfu nction This may manifest as hea rtbu rn , dysphag i a , reflux/reg u rg itation , delayed gastric Rheumatology . 197th
    • --- emptying, bloati n g , a bdom inal pa i n , and pseudo-obstruction . Bacterial over­ growth can lead to mala bsorption syndrome. 5. Hypothyroidism may occur a nd is due to either antithyroid a nti bod ies or fibrosis. 6. Renal failure may occur i nsid iously or as a renal crisis . Renal crisis is char­ acterized by m a l i gnant hypertension, hypertensive encepha lopathy, severe headache, retinopathy, seizures and left ventricular fa ilure. This occurs due to overactivation of the ren in-angiotensin system. Renal fa ilure is the leading cause of death in systemic sclerosis. 7. Muscular effects of scleroderma include d isuse atrophy, myopathy without enzyme a bnormalities, and, rarely, a polymyositis-like syndrome. 8. Polya rthritis is manifested by pai n , swelling, and stiffness - particularly i n the hands, fingers, and knees in more than 50% of patients. Tendon sheath fibrosis may become a problem, and can lead to carpal tun nel syndrome when it occurs in the wrist. SYST E M I C L u p u s E R Y T H E M AT O S U S ORDER H IS ANA O ra l u l c e rs R as h ( m a l a r) D i.s c o i d ras h E xa g g e rated p h otose n s itivity R e n a l d i se a s e H e m a to l o g i c a b n o rma l it i e s Im m u n o l og i c a b n o r m a l i t i e s S e ro s i t i s A rth ra l g i a s/a rth r i t i s ( n o n e ro s i ve) N e u ro l og i c d i se a s e A nti-n u c l e a r a n t i body 198 • Rheumatologyb
    • N otes 1 . The d iag nosis of SLE depends u pon the presence of fou r or more of theabove 1 1 criteria . The d isease, however, may involve a ny organ syste m .2. The findi ngs o f oral ulcers, m a l a r rash, d iscoid rash, exaggerated photosen­sitivity, and a rthritis are obta i ned by history and physical exa m i nation . Neu ro­log ic criteria include seizures and psychosis ( i n the a bsence of other d rugs orpreCi pitants). Renal disease is defined as persistent proteinuria or cellular casts.Serositis may be manifested as pleuritis or pericard itis. Immunolog ic criteria fordiag nosis include a positive LE cell prepa ration, anti-DNA antibodies, a nti-SMantibodies, or a false-positive serologic test for syph ilis. Hematologic criteria i n­clude hemolytiC anemia, leukopenia, lym phopenia , or thrombocytopen ia .3 . Other manifestations of SLE include fever, pancreatitis, hepatitis, retinal d isease,myocardial disease (myocarditis, endocarditis), gastrOintestinal disease, pulmonarydisease (diffuse infi ltrates, vascul itis), and coagulopathy (lupus a nticoagulant) . VA S C U L I T I SWHAM ! A N G I ITIS *W e g e n e r s g ra n u l o ma to s i sH yp e rs e n s i tivity vasc u l it i s ( H e n och-Sch b n l e i n )A ss o c iated with syste m i c d i s e a s e , r h e u m a t i c d i s e a s e , neoplasmM u cocuta n e o u s l y m p h n o d e syn d ro m e ( Kawa s a k i s )A l l e rg i c a n g i i t i s ( C h u rg-Stra u s s d i se a s e )N od o s a , p o l ya rt e r i sG ia nt c e l l a rt e r i t i s (te m po ra l a rt e r i t i s )I atro g e n i c/d rug-i n d u c e dI nfecti o nT a kaya s u s a rt e r i t i sI so l ated C N S va s c u l it i sS erum s ickness* Differential diagnosis Rheumatology . 1 99
    • N otes Vascul itis is a disorder characterized by inflam mation and damage to blood ves­ sels, often resulting in ischemia to tissues supplied by affected vessels. It may occu r as a primary manifestation of disease or in combi nation with other patho­ logic processes, and may be limited to one organ or affect multiple organs. 1 . Wegeners g ranulomatosis vascu l itis usually affects small vessels and is classically associated with u pper and lower respiratory tract involvement and glomerulonephritis (see Wegeners section ) . 2 . Hypersensitivity vasculitis is a broad group of d isorders believed to b e d ue to a. reaction to a particu lar (endogenous or exogenous) a ntigen and involving small vessels. a. Henoch-Schon lein purpura - palpable purpura (usually on buttocks and lower extre m ities) , arthralgias, GI sym ptoms, and g lomerulonephriti s . More com mon in children. b. Associated with other primary diseases - often con nective tissue diseases (SLE, RA, S iogrens syndrome), malignancies ( lymphoid or reticuloendothelia l , hairy cell leukem ia), o r other ill nesses (cryoglobulinemia, pri mary biliary cirrhosis, alpha l antitrypsin deficiency, ulcerative colitis, and intesti nal bypass surgery) . c. latrogenic/drug-induced - penicillin and sulfa may ind uce a serum sick­ ness-like reaction. - d. Infection subacute bacterial endoca rd itis, E pstein-Barr virus, hepatitis e. Serum sickness - fever, u rtica ria, a rth ra lg ias, a n d lym phadenopa thy 7- 1 0 days after primary exposure or 2-4 days after secondary exposure to for­ eign protein. 3 . Mucocutaneous lymph node syndrome ( Kawasaki s) �acute; fever, cervi­ cal adenitis, con i u nctiva l edema , orol ingual a nd pa lmar erythemia , fingertip desq uamation; occu rs in c h i ld re n . Da nger is later development of coronary artery aneurysms. Treat with IV i m munoglobulin and aspiri n . 4 . Allergic angiitis (Churg-Strauss) i s characterized by hypereosi nophilia, aller­ gic rhinitis/asthma, and small-medium vessel vasculitis involVi ng two or more extra­ pulmonary sites . 5 . Polyarteritis nodosa ( PAN ) - small-medium vessel arteritis involving m ultiple organ systems, i ncluding renal (60%), m uscu loskeletal (64%), peripheral nervous system (5 1 %), GI tract (44%), skin (43%), card iac ( 36%�, gen itourinary ( 2 5%), and CNS (2 3%) .. 6. Giant cell arteritis (temporal a rteritis) - large vessel a rteritis associated with fever, anemia, headache, and elevated ESR. Usua lly in elderly patient. Da ngeri is development of ama urosis fugax and retinal ischemia . Diagnosed clin ica l ly and confirmed by temporal a rtery biopsy. Treated with prednisone.· 7. Takayasus arte r itis - medium-Ia rge vessel arteritis, more prevalent i n East Asia, and more l i kely in the aortic a rch or its d i rect branches. Manifestations are I I usually ischemia in distribution of affected a rteries (i nclud ing cerebral infarction).i1 200 • Rheumatology
    • 8 . Isolated eNS vasculitis- usually or/erioli/is, but any size vessel may be af­fected Diag nosed by ang iogra phy and bra i n/meni ngeal biopsy. Associatedwith CMV, syph ilis, bacteria, varicel la-zoster virus, Hodgki n s disease, and am­phetam ine abuse. WEGENERS G R A N U L O M AT O S I SL U N G H EA O *L u n g/p u l m o n a ry va sc u l it i sU p p e r re s p i rato ry t ract d i s e a s e , s i n u s i t i sN e u ro p a thy, c ra n i a l o r p � r i p h e ra lG l o m e r u l o n e p h r i t i s/re n a l d i s e a s eH ea rt i nvo lve m e ntE ye i nvo l ve m e n tA rth r a I g i a s/a r t h r i t i sD e rmato l og i c l e s i o n s* Clin ical characteristicsN otes1 . Classic clin ical presentation: a. U pper respi ratory tract i nvolvement-si nusitis, nasa l d rai nage b. Lower res p i ra to ry tract/ p u l monary i nvolvement- coug h , hemoptys is,dyspnea c. Renal i nvolvement- g lomerulonephritis, proteinuria, hematuria2. Neurologic sig ns/symptoms occur in 22% of patients. Granu lomatous in­volvement of cranial nerves or mononeuritis multi plex due to vascul itis may occur.Less likely is CNS vasculitis or cerebral granulom a .3 . Cardiac manifestations ( 1 2% o f patients) include pericarditis, coronary vas­culitis, or, rarely, cardiomyopathy. Rheumatology . 201
    • - 4. Ophthalmologic involvement is fairly common (60%) conjunctivitis, episcleri­ tis, scleritis, uveitis, vascul itis, and/or retro-orbital mass resulting in proptosis. 5. joi nt-related symptoms i nclude arth ralgias/joint pa i n (up to 50%) True syn­ ovitis is rare. 6. Cutaneous man ifestations of Wegeners a re seen in 45% of cases and i n­ clude papules, vesicles, purpura, ulcers, or subcutaneous nodules . 7. An i m porta nt d iag nostic d istinction is that between Wegeners and lym­ phomatous g ranulomatosis. Wh ile the former is a multisystem infla m matory vas­ cul itis, the latter is a diffuse infiltration of atypical Iymphocytoid cells which is seen in the lung, ski n , CNS, and kidney. Lymphomatosis evolves into malignant lym phoma in 50% of cases, while Wegeners does not. 202 • Rheumatologyb J
    • EU NE UROLOGYThe key to a good d ifferential d i agnosis is to start with a b road , a l l-inclusivedifferential based on the major points of the case and narrow it down logica llyto a smal ler, "worki ng" differential based on the specifics of the case. If the pa­tients signs/symptoms become atypica l , or new information becomes ava i l­able, you can go back to the broad d ifferential; in this way, you will not missu n usual presentations of disease . Consider a 50-year-old man with hyperten­sion, diabetes, and hyperlipidemia presenti ng with stroke: the expanded differ­ential should i nclude all causes of stroke, but the working d ifferential featuresatheroth rombotic d isease, hemorrhage, a nd embol ism as l i kely etiolog ies. Ifthe CT scan shows a mass lesion, then youd better return to the broad d iffer­ential to include tumor and bra i n a bscess. If the patient develops a fever and isfound to have a sed i mentation rate of 1 00 , then you should return to the ex­panded differential and retrieve vasculitis and infection to add to you r worki ngdifferentia l . Without a com plete i n itial differential diagnosis, o r a return to . the in itial dif­ferential when a typical case becomes atypica l, you wil l miss diagnoses. General ConsiderationsH ow to M a ke a B road D ifferential DiagnosisDespite t h e stereotype o f neurology as a mysterious and a rcane " black box , "there a re severa l effective methods to help any physician make a complete dif­ferential diagnosis for neurological d isease. Differential by Etiology The M E D IC I N E DOC mnemonic is a useful sta rting place to develop acomplete neurolog ic differential diag nosis. To review: Neurology • 203
    • Meta bol ic d i sease (e . g . , metabolic e ncepha lopa thy, leu kodystrophy, Wilsons disease) E ndocrine d isease ( e . g . , d i a betic neu ropathy, myxedema como, hypo- glycemic seizures) Drugs/medicines (e.g . , iatrogenic, occidenta l , self-admin istered) Infections (e.g . , meningitis, herpes encephalitis, H IV dementia, neurosyph ilis) Congen ital abnormal ities (e.g . , spino bifida, Chiari ma lformations, muscu- lar dystrophy) Immunologic disease (e . g . , vascul itis, myasthenia g ravis) Neoplasms (e.g , primary tumors, metastatic disease) Exotic ( "stra nge" d i seases of u ncerta i n etiology, e . g . , m u ltiple scleros is, Guillain-Barre) Degenerative processes (e. g . , Alzheimers, Pa rki nsons) Occupational exposures (e.g . , environmental or occupational toxins, trauma) Cardiovascular (e . g . , infarction, hemorrhage, embol ism, aneurysm, a rterio- venous malformation) Diffe re n ti a l by Anatomy A deta iled understanding of neuroa notomy, although useful in precisely lo­ calizing lesions, pinpointing d iag noses, a n d i m press i n g/bori ng col leag ues during rounds, is not required to make basic differentials. The sim plest method is to sta rt at the m uscle and work bock anatom ica l ly to the cerebral cortex. Exam ples of on anatomic d ifferential for "weakness" are i n parentheses: 1 . Muscle ( polymyositis) 2 . Neurom uscular j unction ( myasthenia g ravis) 3 . Peripheral nerve (Guilla i n-Barre) 4. Nerve plexus (brachial amyotrophy) 5 . N erve root (d isc herniation) 6. Meninges/subarachnoid space (arachnoid itis) 7 . Spinal cord (spinal cord tumor) 8. Brainstem ( pontine i nfarction) 9 . Subcortical structures - basal ganglia, thalamus ( lacunar infa rction - in­ ternal capsule) 1 0 . Cortica l structu res - cerebr u m , cerebe l l u m ( m i d d l e cerebral a rtery i nfarction) H ow to M a ke a " Worki n g " D iffe rential D i a gn os i s Essential i n the development of a useful working d ifferential d iagnosis is ta ki ng clinical characteristics from the case in point and using them to narrow down the broad differentia l . Here i n l ies the a rt of d iagnosis: how do you know when a history of a lcohol a buse is helpful in making the d iagnosis of alcohol withdrawal 204 . Neurologyb
    • seizure, or simply a " red herring" distracti ng you from the correct diag nosis ofmening itis? If things dont fit, go bock to the brood differential Make sure noth­ing has been overlooked . Differential by Time Course In many diseases, and pa rticula rly in neurologic diseases, the time cou rse ofsymptomatology is critical to intelligently narrowing down the differential. Differentetiolog ies a re suggested by d ifferent time cou rses . I ntermittent sym ptoms withcomplete resolution between epi sodes invoke a different set of diag noses tha nchronic, g radually progressive sym ptoms. A history of headache with nauseaand vom iting might be due to migraine in a patient with the first time course, butthe second cou rse is more consistent with a bra in tumor. It a lso is possi ble for ahistory of episod ic symptoms to be g radually progressive (such as crescendotransient ischemic attacks). Take a careful history of the ti m i ng of the symptoms. A good history of the time cou rse incl udes not only whether the symptomsare i ntermittent or conti nuous, but a lso the fol lowi ng i nformatio n : whether thesymptoms were maxi mal at onset, ra pidly progressive, or prog ressing in a step­wise fashion; what factors exacerbate/precipitate symptoms and what factorsameliorate symptoms; if episod ic, the duration and frequency of the episodes;and if and in what order associated symptoms occur. Here is a general overview of the relationship between time cou rse and theonset of i n itial symptoms and etiology. HYPERACUTE ACUTE SUBACUTE CHRONIC (seconds-minutes) (min utes-hours) (days-weeks) (weeks-months)Hemorrhage f-----------------------------------------------------------�Ischemia * f-------------------------------------------------------------�Seizure* f-------------------------� - - - - - - - - - - - - - - -- )Trauma f-------------------------� - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - -) -Infa rction f--------------------------------------------------------� - - - - - - - - - - - - - - - ) (- - - - - - - - - - -)Migrainous* - - - - - - - - - - - - - - - f-----------------------� - - - - - -Toxin (- - - - - - - - - - - - - - - - - f-------------------------------------------------------� - - - - - - - - - - - - - )Metabolic (- - - - - - - - - - - - - - - - - f------------------------------------------------� - - - - - - - - - - - - - )Infection f------------------------------------------------------------------------------ �Inflammatory (- - - - - - - - - - - - - - -f--------------------------------------------------- �Neoplastic 1- - - - - - - - - - - - - - f--------------------�Compression Inontraumatic) (- - - - - - - - - - - - - - f---------------------�Degenerative f-------------------�* Denotes etiologies that are particularly l i kely to cause intermittent symptoms with complete resolution of symptoms between episodes Differential by Age of Patient It is helpful and important to narrow the differential d iag nosis based on theage of the patient. An acute n eu rologic deficit has an entirely d ifferent list oflikely etiologies in a 90-yea r-old than it does i n a 20-year-old . I n genera l , con­genita l , tra u matic, m i g ra i nous, and infectious etiolog ies a re more frequent i n Neurology • 205
    • younger patients. Older patients are more likely to have symptoms related to is­chem ic, neoplastic, chronic com pression; or degenerative d iseases. D ifferential by N e u ro a n ato m i c Loca l izat i o n The most basic d istinction i n neuroanatomy is whether a lesion is located i nthe central nervous system (the bra i n a n d spinal cord) o r the peripheral nervoussystem ( peri pheral nerves, nerve roots, neuromusc u l a r j u nction and muscle) .Some clin ical exa m i nation fi ndings a re useful i n making this distinctio n . In theexample below d iagnoses suggested by a given combination of exam findi ngsand neurologic localization a re i n parentheses. Factors Disting u i s h i n g Location of I nj u ry CNS PNSExam Finding (brain/spinal cord) (nerves/ roots/NMJ/ muscle)• Cranial Nerve ExamVisual loss Field cut (occipital infarct) Monocular loss (retinal artery occlusion)Optic disc Normal or bilateral May be abnormal on one side abnormality (increased only (optic neuritis) intracran ial pressure)Facial weakness Forehead spared (frontal Forehead weak ( Bells palsy) infarct)• Motor ExamMuscle tone Acutely decreased , later Decreased increasedAtrophy Absent Acutely absent, later presentFasciculations Absent Acutely absent , later presentDeep tendon reflexes Acutely hypoactive , later Hypoactive hyperactiveBobinski May be present AbsentClonus May be present Absent (multiple sclerosis, cere- (radiculopathy, neuropathy, bral infarct, intracranial myopathy, myasthenia) bleed , brain tumor, spinal cord injury)Both upper and lower (amytrophic lateral sclerosis motor neuron signs [ALS], cervical stenosis) D ifferential by R i s k Factors a n d Coexist i n g M ed i ca l C o n d itions Ma king d differentia l d ia g nosis solely on the basis of risk factors is fool­hardy, to say the least. However, risk factors such as environmental exposures,medications, d rugs/a lcohol, and coexisting medical cond itions are helpful i n206 • Neurology
    • narrowing down to a good working differential . For example, diabetes, hyper­tension , atrial fibril lation , and smoking are all risk factors associated with cere­bra l infa rction. Pre-existi ng cancer m ight suggest severa l risk factors, includingmetastatic d isease, i m m u nosu ppress ion , a nd exposu re to chemothera peuticdrugs and/or rad iation, each of which will mold the d ifferential i n a slightly dif­ferent way. Immunosuppressed status by itself suggests a whole host of infectionswhich would not norma l ly be considered in an i m m u nocom petent patient.I ntravenous drug abuse i ncreases the possibil ity of bacterial endocarditis, spinalepidura l a bscess, and bra i n a bscess, as wel l as H I V U re m i a can l ead toencephalopathy, seizures, myoclonus, and neu ropathy. Organ tra nspla ntationhas a whole host of d isorders associated with dysfu nction of the transplantedorgan, immunosuppression, and side effects of m ultiple med ications. Use these factors as h i nts and suggestions, but do not rely on them to makethe d iag nosis. For example, the a lcoholic who iust seized and now has a hem i­paresis may have had an a lcohol withdrawa l seizure with a post-ictal Todd sparalysis, but dont m iss the subdural hematoma he got falling down the stairs,which is the real reason he seized and is hem i paretic. If you i u m p to the conclu­sion that he has had " i ust" an alcohol withdrawa l seizure, then you may findyourself u nhappily awakened to see him herniating in the m iddle of the night.H ow to Do a G ood N e u ro l o g i c Exa m i nationThere a re several aspects of the neurological work-up that are unique and mustbe considered when evaluating a patient with neurological disease. The historyis critical . The h istory is where you w i l l get i n formation regarding the exactsymptoms the patient experiences or experienced and the time course of thesesymptoms. In many cases, the history ma kes the diagnosis, and the exam i nationserves merely as a confirmation of your historical d iagnosis. Rea l ize, however, that the sym ptoms the pati ent reports can sometimes(often?) be vague and difficult to interpret: It is in these cases that the exa m i na­tion plays a key role. A patient may com pla i n of visual loss in the len eye, but onexa m i nation , it becomes clear that the patient actually has a left homonymoushemianopia . This d isti nction is of g reat value, for monocular visual loss ind icatesd isease in the eye or the blood supply to the reti na (from the ca rotid a rtery),while a left visual field cut suggests pathology i n the right OCCi pital lobe or itsblood supply (from the vertebral-basilar arteries) The work-up and treatment thusa re significantly altered by the exa m findings, which help to clarify the patientsinterpretation of h is/her neurologic deficit. If something is found on exam that is inconsistent with the patients h istory,this does not necessa rily i mply mali ngeri ng, but rather a d ifficu lty in accu ratelydescribing symptoms. Always be sure you understand what the patient is tryi ngto describe. Some patients compla in of weakness, when they rea lly mean numb­ness, and vice versa . A patient may compla i n of an acute or subacute onset of Neurology • 207
    • wea kness , but exa m i nation shows severe atrophy. Atrophy is a sign of lower. motor neuron disease, but it is not present acutely. In this case, further question­ ing would be necessary to try to elicit a more chronic (and perhaps subtle) h is­ tory of weakness (a nother possibility is a pre-existi ng chronic weakness with a superim posed new, acute insult) . From these exa mples you can see that the neurologic history and exa mina­ tion are interrelated and that, while the history ohen suggests the diagnosis, it is im­ portant to synthesize the information from both to come up with the correct answer. In addition , rea lize that if a basic neurologic function is impa i red , it is not easy to rel ia bly test higher neurologic functions; i . e . , if a patients arm is paralyzed or paretic, then fine motor coordination is difficult to assess; likewise, it would be unfair to label a patient as having severely impaired memory if the patient is aphasic. The M e ntal Statu s Exa m i nation A good mental status exa mi nation leaves no doubt about the patients level of arousal for the next exa m i ner. Terms l i ke "sleepy, " " leth a rg i c , " "stuporous" may mean slig htly different thi ngs to different examiners . The best mental status exam Simply states what the patient can or ca nnot do. For exa m ple, "The pa­ tient was awake, watching television , and spea king normal ly, " or "The patient was asleep, arousa ble to tacti le sti m ulation" but would fa ll back to sleep if u n­ stimulated . " Remember to check basic a n d objective information . I s the patient oriented to person, place , and time? Assess the patients attention . This is most easily done by having the patient repeat a series of ra ndom n u m bers, starti ng with th ree numbers in 3 seconds and working up until the patient is no longer able to correctly repeat them (normal is five to seven numbers in as many seconds) . This is known as the digit span. If a patients attention is impaired, as demonstrated by a digit span of less tha n 5 , then more com plicated menta l status testing may be difficult to interpret. For instance, a patient with a digit span of 3 is not likely to be a ble to remember three objects in 5 minutes, but this does not necessa rily i m ply a pri mary memory problem and may just represent poor attention to the exa m i ner. I mpa i red attention may mean Simply that the patient is preoccupied or anxious or may signi fy an acute confusional state or encephalopathy. Speech is i m porta nt to assess for both fluency ( language output) and com­ prehension (language i n put) . An i m pa i rment of smooth a n d fluent output sug­ gests dysfunction of the dominant ( usually left) frontal lobe ( Brocas a real, while fluent output with an inability to understa nd spoken language indicates damage to the dominant parietal-tem poral a rea (Wernickes area ) . Difficulty with both flu­ ency and comprehension is usua lly the result of a more extensive dominant hemi­ sphere lesion (such as a m iddle cerebral artery infarct) . C ra n i a l N e rve Exa m i nation Objective assessment of many of the cranial nerves (eNs) is possible, and thus brainstem function may be assessed even in comatose or otherwise uncooperative 208 • Neurologv
    • patients . Abnormalities i n the cranial nerve exa m usually suggest u n derlyi ngbrainstem pathology. eN I : Sense of smell usua lly is not tested , but may be by asking the patientto identify a characteristic a roma with eyes closed (e.g . , coffee, flowers). eN I I : Check visual fields to confrontation (Can patient see movement in allfields? Can patient count fingers in all fields?) and look for consensual pupil/aryreactivity. eN III, IV, VI: Have the patient follow the movement of l ight in all directions . Dol/s eye maneuver (oculocepha l ic ) - This is most useful i n patients whoseconsciousness is impaired . A normal or positive response occurs when vigorouslyrotating the patients head to one side, a nd the eyes deviate to the oppositeside. An a bnormal or negative response is when the eyes do not move in theorbits regardless of head position - the dolls eyes are absent. A fully consciouspatient may be a ble to voluntarily override th is reflex, resulting in a "false" nega­tive result. Cold calorics (ocu lovesti bula r) - ea r canals a re inspected for a clear viewof the eardrums, the patients head is hyperextended a bout 30°, a nd ice-coldwater is i rrigated i nto one ear canal .. A normal or positive response in an awake patient is deviation of the eyes toward the irrigated ea r and nystagmus beatingaway from the i rrigated ear. (Si nce awake patients ca n volu ntarily move thei reyes, and since cold calorics can be qu ite nauseati ng, calorics are seldom indi­cated in awake patients . ) A normal or positive response in a comatose patient isdeviation of the eyes toward the irrigated ea r, with no nystagmus. An a bnormalor negative response shows no eye deviatio n . After 5 m i n utes, repeat the testwith the opposite ear. eN V: Ask the patient to close his/her eyes, touch (or use a pin to prick) the patients face on the forehead, cheek, and chin on either side, and have the pa­tient identify specifically or point to the place touched . eN VII : Ask the patient to close his/her eyes tightly and look for the abilityto "bury the eyelashes" symmetrical ly. Look for a symmetric smile. Ask the patientto "puff out his/her cheeks" and try to gently push the air out of the cheeks withyour fingers. Ask the patient to clench his/her teeth together and look for sym­ metric contraction of the platysma m uscle (stretches from the ch i n/jaw to the clavicles) eN V/VII : Corneal test-A light wisp of cotton or tissue is brushed gently agai nst the cornea, approaching from the side ( not from the front). A positive re­ sponse is eye closure/bl inking. This should be done on one eye, then the other. Cornea Is may be a bsent in patients with a history of contact lens use . This test is not routinely performed in awake patients. eN VII I : Whisper numbers (or letters) into the patients ear from a distance of about 1 foot and note if the patient ca n repeat the numbers . eN IX/X: Gog test- Using a Q-tip or tongue depressor, touch the back of the oropharynx on one side, then the other, and look for a gag with symmetric palate elevation . If the patient is intubated, a Q-tip can sti ll be used . Pulling on the endotrachea l tube is n ot recom mended as a method for testing the gag reflex. A decreased or a bsent gag someti mes can be fou n d i n otherwise Neurology • 209
    • ... normal patients , but a n asym metric gag usua l ly is i nd ica tive of b ra i nstem pathology. . C N X I : Aga i nst resistance, have the patient shrug h is/her shoulders u p (trapezius) a n d turn h is/her head to one side (sternocleidomastoid). Remember, difficulty turn ing the head to the right i ndicates a weak left sternocleidomastoid, and vice versa . CN XII: Ask the patient to stick out h is/her tongue. The tongue will deviate toward the weak side. M otor Exa m i nation Although the motor exa m i nation as typically discussed relies significantly on patient cooperation, there is a lot of obiective i nformation that can be elicited by a skilled exa m i ner. . Muscle bulk is very obiective, and focal atrophy or fasciculations a re a sign of chron ic lower motor neuron disease (ALS, neu ropathy, rad iculopathy, some­ ti mes myopathy) . Muscle tone can be assessed by passively moving a ioint throu g h its full ra nge of motion . Flaccid tone offers little or no resista nce, and the movement will seem limp. This demonstrates either an acute upper motor neuron lesion or a lower motor neuron lesion . Spastic tone offers more resista nce the faster the movement. Spasticity is seen with subacute or chronic upper motor neuron i n iury (spinal cord iniury, cerebral i nfarct, bra i n tumor, multi ple sclerosis, ALS) . Rigidity shows equal resistance throughout the entire range, regardless of the velocity of the movement. Occasionally rigidity has a ratchety qual ity, which is referred to as cogwheeling ( Pa rkinsonism, other basal ganglia d isease) . Experience aids greatly i n the accurate evaluation of m uscle tone. Pronator drift is an excellent m ethod of testi ng for su btle corticos p i n a l wea kness . The patient is asked t o h o l d both a rms fu lly extended i n front of h i m/herself with the pa lms u p . The palms should be level a n d not touch i n g each other. The patient must then mai nta i n this position with the eyes closed . A positive drift (and hence, evidence of corticospinal weakness) is cha racterized by not only a downward movement of the affected side, but also pronation of that extremity. Su btle lower extrem i ty weakness is suggested by external rotation of the hip at rest. Di rect strength testi ng of i nd ividual m uscles is g raded on the fol lowi ng scale: o No movement 1 Twitch or fa int movement 2 Movement but not against g ravity 3 Full movement against g ravity but not against resistance 4 Movement agai nst partial resistance 5 Movement agai nst full resistance I A "+" or "_,, sign often is used to denote smaller va riations of strength ( e . g . , I slight weakness against full resistance would be 5-. Paralysis or plegia means 210 • Neurology
    • that there is no observa ble movement. Paresis mea ns there is weakness but stillobserva ble movement. Another part of the motor exam that assesses strength without d i rect one­on-one m uscle testing is functional testing . Can the patient easily rise from asitting position to a standing position without push ing up with the a rms? An i n­ability to do this suggests proxi mal lower extrem ity weakness. Can the patientwa l k up steps? Sta nd on one leg? Hop on one leg? Bei ng able to sta nd onones tip toes i m pl ies at least 4 to 4+ power i n the gastrocnemius. Being a bleto sta nd on ones heels suggests at least the same degree of power in the a n­terior tibialis. Does the patient have a resting tremor ( Pa rkinsonism)? Does the patienthave a tremor when forced to m a i nta i n posture, such as when the hands a reoutstretched? This is cal led a postural tremor and is ohen physiologic, but maybe fa milial (essential tremor) . C e re b e l l a r Exa m i nation Ca n the patient ra pidly a n d alternately pat the pa l m of the hand and thedorsum of the hand on a surface? This is the rapid alternating movement test,which assesses the cerebellum s abi lity to coord inate agonists and antagonists.Impa irment of this is termed dysdiadochokinesis. An intention tremor is a tremor that worsens with motion toward a particularpoi nt. It is checked for by havi ng the patient ra pidly a l ternate po inting (andtouching) the exa miners outstretched finger and the patients nose (finger-nose­fi nger test). The heel-knee-shin test involves touching one heel to the opposite knee andsmoothly moving the heel down the opposite shin to the ankle and back up tothe knee. Normally this is a steady movement, but patients with ataxia wobblethe moving leg from side to side. An inabil ity to perform any of these tests (in the absence of sig nificant motorweakness) suggests i psi lateral cerebellar dysfunction. Gait and Stance Exa m i nation Ga it and stance may be observed casually when the patient is wa lking tothe exa m i n ing area . Normal gait has a narrow sta nce, fluid movement, andsymmetric arm swi nging. Normal stance is steady with feet side by side and noswaying . Specific ma neuvers can be tested later in the exa m . Tandem g a i t i s tested by haVing the patient wa l k heel to toe in a stra i g htl i ne, and a d ifficulty with this (ataxic -ga it) suggests m id l i ne cerebellar dysfunc­tion. Obese and elderly patients may have some difficulty with tandem gait with­out specific cerebellar disease. Ataxic g a it is cha racterized by u nstead i ness, swaying, wa lking with thefeet widely apa rt, and an inability to perform tandem gait. Hemiparetic gait demonstrates decreased movement of the weak side, with he patient having to lea n away from the paretic leg and swing it back to front Neurology . 2 1 1
    • (circumduction ) . The arm swi ng usually is decreased on the affected side, andthe arm may be held i n a flexed posture. Parkinsonian gait classically has a stooped forward posture with smallsh uffl ing steps and a tendency to fa ll over backward ( retropu lsion ) . Tu rns a renot made with a smooth rotation , but usually consist of a series of small steps(en-bloc turn i n g ) . Parki nsonian patients may have difficu lty getting started wa lk­ing, but once sta rted may actually walk faster and faster and be unable to stop(festi nation ) . Steppage gait is associated with a foot d rop, and this involves simply step­ping h igher with the affected leg so that the foot, which is hanging down, canclea r the g round. These patients often g ive a history of stu mbli ng/tri pping overtheir toes on the weak side. Scissor gait is seen in patients with a spastic paraparesis (spinal cord injury,cerebral palsy) and shows increased tone in the thigh adductors, such that when­ever a step forward is attem pted , the legs actually cross ( hence the name scissor) . S e ns o ry Exa m i nation It is not necessary to memorize every poss ible com bination of peripheralnerve or dermatomal sensory loss; however, some general guidelines a re help­ful . A pin (or a toothpick) is more accurate than a finger at mapping out a reas ofsensory loss. Dermatomes to Remember Root Sensory Distribution C6 Thumb C7 Middle finger C8 Pinky T4 Nipple T1 0 Umbil icus L5 Big toe Sl Sole of foot Peripheral Nerves to Remember Nerve Sensory Distribution Radial Dorsum of hand Ulnar Pinky side of hand Median Pajm of hand Lateral femoral cutaneous Lateral aspect of thigh Peroneal Lateral aspect of leg and dorsum of foot If spinal cord compression is suspected, be certa i n to check for a sensorylevel on the trunk. Perianal sensation is i m portant to check in patients with sus­pected cauda equ i na lesions.212 • Neurology
    • Dissociated sensory loss, i . e . , loss of pain and temperature on � ne side ofthe body and loss of vibration and proprioception on the other, is characteristicof a hem i-spi nal lesion i psi latera l to the vibratory/proprioceptive loss ( B rown­Sequard syndrome) . D e e p Te ndon Reflexes An easy way to remember roughly which nerve roots serve which tendon re­flexes is to start at the a nkles and move up: Count Reflex Root 1 -2 Ankle S l -S2 3-4 Knee L3-L4 5-6 B iceps C5-C6 7-8 Triceps C7-C8Grading of reflexes is as follows: o Absent trace Fl icker of muscle contraction 1+ Hypoactive (moy be normal, especiolly in muscular or obese patients) 2+ Normal 3+ Hyperactive, usually shows spread of reflex (may be normo l , especially i n th i n or anxious potients) 4+ Hyperactive, clonus (always abnormal) Spread of a reflex refers to when one reflex is bei ng checked and musclecontraction occurs in another reflex. Clonus refers to repetitive reflex contractionsafter a single stimulus (usually elicited by abrupt dorsiflexion of the a n kle by theexaminer) . Plantar response is elicited by a qu ick, noxious sti mulus (scratching with akey or other i m plement) to the latera l planta r aspect of the foot. A flexor re­sponse is when the great toe flexes and is the normal response of adu lts a ndolder children . An extensor response (positive Babinski) is when the g reat toe ex­tends (dorsiflexes) and the other toes spread apa rt. This is usually a sign of uppermotor neuron disease (cerebral i nfarct, spinal cord com pression, tu mor), but ca nbe normal in i nfants.N e u rolOgiC Exa m i nation S u m ma ryMental Status • Level of a rousa l : description • Orientation: to self, place, time, situation r Attention : digit spa n (normal 5-7) • Speech: fluent? comprehension? Neurology . 2 1 3
    • Cranial Nerves • I I - visual fields; consensual pupillary response • III, IV, VI - pupillary reactivity/an isocoria ; extraocular movements. dolls eyes - positive=eyes deviate in opposite di rection of head turn . cold ca lorics- pos itive=eyes deviate ton ically toward i rrigated ea r ; with or without nystagmus away from i rrigated ear. • V - facial sensation ; cornea l reflex (sensory) - eyebl i n k when cornea touched with cotton wisp. • VI I - facial expression - if forehead movement is spared , lesion is above the facial nucleus (central); if forehead is weak, lesion is peripheral (Bells palsy) . • VIII - hearing • IX, X - palate symmetry, gag • XI - head turn (sternocleidomastoid); shoulder shrug (trapezius) • XII - tongue protrusion - deviates toward weak sideMotor Exam • Bulk: check for symmetry; atrophy, fasciculations • Tone: check for symmetry; is tone flaccid, spastic, rig id (cogwheeling)? • Strength/power: 0 No movement 1 Trace/flicker of movement 2 Movement but not against g ravity 3 Movement agai nst g ravity but not against resistance 4 Movement agai nst partial resistance 5 Movement against fu ll resistance • F u nctional tests: Pronator drift - arms outstretched with pa lms u p . Also, can patient rise from cha i r without pushing u p with arms? stand on tip­ toeS"? stand on heels? hop? hop on one foot? • Tremor: resting tremor, postural or essential tremorCerebellar Examination • Rapid alternation movements (dysdiadochokinesis) • F i nger-nose-finger ( i ntention tremor) • Heel-knee-shin.Gait and Stance Examination • Casual gait: observe as patient wa lks i nto room and during formal neuro exam • Tandem gait: walk stra ight line heel to toe. • Specific Ga its : ataxic - lurching, u nsteady, swaying, wide stance; hemi­ paretic - decreased movement on weak side, circumduction of leg , de­ creased arm swi n g ; parki nson i a n - stooped , sh u ffl i n g , retropu lsion , en-bloc turns, festi nation ; steppage - foot d rop, wa l ks with high step on weak foot; scissor- legs cross when stepping forward .Sensory Examination • Modalities to test: l ig h t touch, pi nprick, temperature; vi bration , proprio­ ception . • Sensory leve l : check with p i n up a n d down trunk when suspicious of spinal cord lesion .2 14 • Neurology
    • • Perianal sensation : check with suspicion of lower cord or cauda equina lesionDeep Tendon Reflexes • Root • Reflex • Grading of Reflexes S 1 -S2 Ankle o Absent L3-L4 Knee trace Flicker of muscle contraction C5-C6 Biceps 1+ Hypoactive C7-C8 Triceps 2+ Normal 3+ Hyperactive; may show spread 4+ Hyperactive; pathologic; clonus Clinical Sym ptoms a nd Sig ns A LT E R E D M E � TA L S TAT U SI WA T C H D E A T HI nfect i o nW it h d rawa lA c ute m et a bo l i c d e ra n g e m e ntT ra u m ae N S p a t h o l ogyH ypoxiaD ef i c i e n cyE ndocri neA c ute va sc u l a rT oxi n s/d r u g sH eavy meta l s Neurology . 2 1 5
    • CT, LP, A N D E E G H I MC e re b rova sc u l a r a c c i d e n t ( b ra i n st e m i s ch e m ia/i nfa rct)T ra u m aL ow b l o o d p re s s u re/hypote n s i o nP sych i a t r i cA n ox i a/hypoxiaN eo p l a s mD ru g s/tox i n s/wi t h d rawa lE p i l e psy ( n o n convu l s i ve stat u s , post-ict a l )E l evated b l oo d press u re ( h y p e rte n s ive e n ce p h a l op a t hy)G l u co s e l a ck/hypog lyce m i aH emorrhage/bleed (i ntracra n i a l , especi a l ly posterior fossa)I nfect i o n ( m e n i n g i t i s/e n c e p h a l i t i s/s e p s i s )M et a b o l i c/e n d o c r i n e The fi rst m nemonic i s shorter but less comprehensive. The second m nemonicis more com plete, and it pokes fun at a nonspecific a pproach to these patients.The CT, LP, and EEG a re not requi red for all patients. The following describes o norgan ized approach to this common problem .N otesAltered mental status refers to any acute or su bacute change i n the level of con­sciousness, ra nging from m ild confusion to deep com o . Chronic problems suchas dementia or mental retardation a re not considered in this d iscussion . 1 . Initial treatment of como or unconsciousness is ai med at rapidly identifyi ngand treating any reversi ble process . Protocol : a . ABCs (Ai rway, Breath i n g , C i rculation), vital signs, s u pplemental O2 ifnecessary, pulse oximetry and ABG, ECG. b. IV l i ne with normal sa l i n e . Send blood for CBC with d ifferential a n dplatelets, electrolytes, BUN, creatine, glucose, Co, Mg , PT, PH Other tests tobe considered i nclude toxicology screen, liver enzymes, a m monia, blood cul­tures, urinalysis. • F i ngerstick glucose, then 1 00 mg th iamine, then 5 0 m l 50% dextrose . solution IV • Rapid assessment of clinical situation , exami nation . Consider head CT sca n . Emergent treatments i nclude the following :2 1 6 • Neurology
    • If opiate overdose suspected , Naloxone 0 0 1 mg/kg IV If seizure activity noted , Larazepam 2 mg IV If infection suspected , begin IV anti biotics, then proceed qU ickly with CT and LP. If herniation detected , i ntubate, hyperventilate, mann itol 1 g/kg IV, CT, ca ll neu rosurgery. • Defin itive treatment will depend on the cause of the coma.2 . The exami nation of the comatose patient can be both q U ick and hel pful indetermining the etiology of the coma (see " H ow To Do a Good Neurolog icExami nation , " page 207) . a . Mental status: Use specific descri ptive terms; avoid vag ue terms l i ke"sleepy" or " letharg i c . " To what level of sti m u l u s does the patient respond?verba l, touch, pain? b . Cranial nerves: C heck pupils, eye movements (dol l s eyes) , cornea Is,facial symmetry, and gag (see page 209 for specifics on how to perform thesetests). Cranial nerve abnormalities suggest brainstem dysfunction. c . Motor/sensory: Observe the patients movements . Note any obviousasym metries . Passively m ove the patien ts l i m bs to assess for asym metry ofmuscle tone. Does the patient move spontaneously? Is the movement pu rpose­ful? Does the patient move to command? Does the patient move to noxioussti muli? When assessing the patients reaction to noxious sti muli, note what sortof motor response is obta i ned . Purposeful withdrawal mea ns movi ng the l i m baway from t h e sti m ulus and i m pl ies integrity o f t h e cerebral cortex. Decorticateposturing is described as a flexion response i n the u pper extremity and exten­sion in the lower, and suggests cortical dysfuf)ction . Decerebrate posturing i n­volves extension of both upper a nd lower extremities i n response to a noxious -sti mulus, and this i m pl ies bra instem dysfu nction . No motor response suggestssevere bra instem dysfunction or peri pheral paralysis (Guillain-Ba rre synd rome,iatrogenic paralysis ) . d . Reflexes: Look for asym metry o f deep tendon reflexes. Check for clonusand Babinski responses. 3. There a re three mecha nisms of coma/depressed mental status. a. Bi lateral cerebral hemisphere dysfunction (e . g . , bilatera l infarcts, bi lateralsubdu rals, hydrocephalus, men i n g itis, subarach noid hemorrhage, general izedseizure activity) b. Bra i nstem dysfunction only • Direct bra instem i n j ury ( bra instem infarction, tumors or bleeds) • Bra i nstem compression/displacement by su pratentorial lesion ( hern ia­ tion secondary to supratentorial tumor, edema or bleed) c . Diffuse cerebral and brainstem dysfunction (e.g . , hypoxia , hypoglycemia,drug intoxications, uremia, hepatic encepha lopathy, meningitis, suba rachnoidhemorrhage) Unilateral cerebral dysfunction alone does not cause coma ( i . e . , a uni lateral i n­farct or tumor does not explain com a , u n less herniation a n d com pression ofbrainstem structures has occurred . Neurology • 2 1 7
    • 4. Approach to the differential diagnosis of coma:Be aware that brainstem lesions do not a lways show up clearly on CT scans, soif bra instem pathology is strongly suspected and the CT scan is "normal , " con­sider neurologic consultation and MRI scanning. COMATOSE PATIENT t ABCs, Como PROTOCOL t Broinstem exomination/reflexes � r- Intact Abnormal I I r--- CT r--- CT ------, Abnormal Normal Abnormal Normal t t t tBilateral subdurals Meningitis/encephalitis Brainstem hemorrhage Acute brainstem imarctHydrocephalus Toxic encephalopothy Brainstem neoplasm Toxic encephalopothyBilateral infarcts Metabalic encepha· Brainstem infarction MetaboliC encepha-Multiple contusions Iopathy Subarachnoid bleed lopathySubarachnoid bleed Drug-induced Supratentorial mass Meningitis/encephalitisMeningitis/encepha- Hypoxic/anoxic with herniation Drug-induced litis Acute bilateral infarct Brainstem/cerebellar Hypoxic/anoxicCerebral edema/Reyes Seizure abscess Basilar migraineEpidural bleed Hypotension/shockNeoplasm(s) Hypertensive encepha-Abscess(es) lopothyVasculitis (infarcts) Sinus thrombosisSinus thrombasisMetabolic insult superimposed on old focal lesion ATA X I AC a n t Sta n d V e ry W e l lC e re b e l l a r a t a x i aS e n so r y a t a x i aV esti b u l a r a t a x i aWeakness2 1 8 • Neurologv
    • A C U T E ATA X I AU N A B L E T O S TA N DU n d e rlyi n g wea kn ess ( may m i m i c a t a x i a )N ut r i t i o n a l n e u ropathy (vita m i n B 1 2 defi c i e n cy)A rte ri t i s/va s c u l it i sB a s i l a r m i g ra i n eL a by r i n t h i t i s/vesti b u l a r n e u ro n i t i sE n c e p h a l i t i s/i nfect i o nT ra u ma ( postco n c u s s ive)O th e r ( ra re meta bo l i c or g e n e t i c d i s e a s e s )S tro ke ( i s ch e m i a o r h e m o r r h a g e )T ox i n s ( d r u g s , to l u e n e , m e rc u ry)A I c o h o l i ntox i ca t i o nN e o p l a s m/pa ra n eo p l a s t i c syn q ro m e sD e mye l i na t i o n ( M i l l e r F i s h e r, G u i l l a i n B a rre, M S) C H R O N I C ATA X I ACA N T STA N DC on g e n it a l m a l fo rm a t i o n/C h i a riA utosom a l recess ive a t a x i a sN ut r it i o n a l (vita m i n B 1 2 defi c i e n cy)T ra u ma ( postcon c u s s i ve )S t roke s e q u e l a eT ox i n s ( d r u g s , to l u e n e , a l co h o l )A utoso m a l d o m i n a n t a t a x i a sN eo p l a s m/pa ra n eo p l a s t i c syn d ro m e sD e mye l i n a t i o n ( M S) Neurology Ii 219
    • -- N otes Ataxia is the subjective com pla int or objective finding of i m paired coord ination, usua lly manifested as an impa i rment of gait or dexterity in the absence of sign if­ icant muscular weakness. Dysdiadochokinesis is an i mpairment of the ability to perform ra pid alter­ nating movements . Dysmetria is i m pa i rment in the normal acceleration and deceleration of di­ rected movements. Usua lly eva luated by finger-nose-fi nger and heel-knee-shin tests . Intention tremor is an exaggerated oscillation of a limb, most pronounced as it is approaching a target, and essentially absent at rest or at the beg i n n ing of a movement. Intention tremor is a man ifestation of dysmetria . Titubation is a moderate frequency head tremor, usually anteroposterior. 1 . The time course ot ataxia helps narrow the d ifferential d iag nosis. Acute ataxias usually are due to acute bra i n i n j ury (trauma, i nfarct, bleed ) , i n toxica­ tion, infection, inflam mation/a utoi m mune reactions (vascul itis, para neoplastic), or migraine. Ch ronic ataxias usua l ly are caused by congen ita l ma lformations, sequelae of bra i n i njury ( post-stroke, cerebral palsy, trauma!, multi ple sclerosis, bra i n tumors, or genetic diseases ( Friedreichs, ataxia-telangiectasia). 2. Evaluation of ataxia includes coordi nation testing and sensory testi ng. a. F i nger-nose-finger: The patient is asked to use the i ndex finger to alter­ nately touch his/her nose and the exa m i ners outstretched fi nger� b . Heel- knee-s h i n : The patient is asked to touch one heel to the opposite knee and then move the heel down the shin to the foot. c. Rapid a lternating movements : The patient is to a lternately pronate and supinate either hand, usually patting on the thigh or another horizontal surface. In the lower extrem ities, this may be tested by having the patient tap either foot on the floor. d . Proprioceptio n : Position sense is tested by havi ng the patient identify whether a digit is being moved up or down at a joint (usua l ly interphalangeal finger or toe) with the eyes closed . At least one joint on each limb is tested sev­ eral ti mes . If a deficit is detected d istally, continue testi ng proximally u ntil the pa­ tient is able to identify movements correctly ( i . e . , if position sense is i m paired i n t h e fingers, follow with testing at the wrist, elbow or even shoulder to determi ne the extent of the deficit) . e. Romberg sig n : This is tested by havi ng the patient assume a comfortable stance with the eyes open and the feet as close as possible, then closing his/her eyes . Conti n ued sta bi l i ty is a negative Romberg , a n d i ns tabil ity/fa l l i ng with eyes closed is a positive Romberg . A positive Romberg is i ndicative of i mpai red proprioceptive i n put. Romberg testing is not useful in patients unable to stand steadily with their eyes open . 220 • Neurologvb
    • 3 . Ataxia may be divided into four categories that often can be disti nguished by careful h i story and exa m i na tion . Some d i sorders may be associated with more than one type o� ataxia ( i n particular, cerebellar a n d vestibular ataxia often occur together) . a . Cerebellar ataxia is c h a racte rized by dysmetria , dysd iadochokine· sis, hypoto n i a , a n d u nsteady g a i t i n the a bsence of s i g n ificant motor wea k­ ness, na usea , o r vom iti n g . Nysta g m us may be p resent. Cerebellar ataxia may be u n i latera l or bi latera l . U n i lateral cerebellar ataxia suggests a focal lesion ( tumor, infarct, bleed, multiple sclerosis) , while b i late ra l cerebe l l a r a t a x i a i s m o re l i kely d u e t o d i ffuse c a u ses ( a lcohol, drug intoxication, paraneoplastic) . b. Sensory ataxia is caused by impaired position sense and not by cerebel­ lar pathology. Findings consistent with sensory ataxia i nclude i m pa i red sensa­ tion, particularly p ropriocepti on and vi brati o n . Na usea , vom iting, a n d nysta g m us a re not seen with sensory ataxia . Etiolog ies i nclude neu ropath i es and spinal cord dorsa l col u m n pathology (e. g . , vitamin 8 / 2 deficiency, neu- . rosyphilis/tabes dorsalis) . c . Vestibular ataxia typically is associated with vertigo, nausea and vom it­ ing. Impa i red coordination , d i m i n ished hearing, nystagmus, and gait i nstabil ity also may occur. Vestibular causes of ataxia include labyrinthitis/vestibular neu­ ronitis, brainstem ischemia, and multiple sclerosis, among others. d. Weakness due to hemiparesis may man ifest by falling or gait d isturbance and is not true ataxia. In the setting of sign ificant motor weakness, it is d ifficult to assess coordi nation separately. Sig nificant focal weak.ness should raise the pos­ sibility of a foca l cerebral lesion ( tumor, infarct, bleed, abscess) . 4 . Intoxication is a common cause of acute ataxia . Offendi ng agents include many anticonvulsants (e . g . , phenytoin, carbamazepine) and alcohol . 5 . A good family history is essential in the evaluation of chron ic or recu rrent ataxia . Migra i nes often occur in persons with a positive fa m i ly history of m i­ g ra ine headaches (aura , photophobia, nausea, vom iti ng). Metabol ic diseases presenting with recurrent or progressive ataxia often have a utosomal recessive i nheritance ( maple syrup urine d isease, ataxia telangiectasia, Friedreich ataxia ) . Autosomal dominant forms o f ataxia i nclude von H i ppel-lindau disease (cere­ bellar hema ngioblastoma) , oIivopontocerebeliar atrophy, and Machadojoseph disease. 6. Work-up for ataxia depends on the d ifferential diagnosis. Neuroi mag i ng (CT acutely, but MRI is better for chronic symptoms) is necessary if a foca l lesion is suspected . Acute, nonfocal ataxia warrants testi ng for alcohol and d rug intox­ kation . I n patients with known malignancy, work-up for metastases (CT/MRI) and paraneoplastic syndromes (autoanti bodies) should be considered . Lum bar puncture should be performed i n cases where C N S i n fection is l i kely (fever, meningismus). Patients with primarily sensory ataxia should be eva l uated for ca uses of sensory neu ropathy a n d d orsa l col u m n pathology by checking VDRL/RPR, g lucose, and vita m i n 8 1 2 . Neurology . 22 1"
    • ..... A U TO N O M I C D I S O R D E R S A BP DROP, I G U ESS A my l o i d o s i s B otu l i s m P a rk i n so n s d i se a s e D i a betes R i l ey-Day syn d ro m e/fa m i l i a l dysa uto n o m ia o n c o l o g i c/pa ra n eo p l a st i c P o rphyria I d i o pa t h i c/I a t rog e n i c G u i l l a i n- B a rre syn d ro m e U re m i a E t h a n o l/a l co h o l i s m S hy-D ra g e r sy n d ro m e S p i n a l c o r d d i s o rd e rs N otes Autonomic d isorders constitute a wide range of neu rolog ic derangements, which man ifest prima rily through symptoms of a utonomic dysfunction, including but not l i mited to orthostatic hypotension/syncope, cardiac arrhyth m ias, altered lacrimation, i m pa i red temperature reg u lation, dia phoresis/anhidrosis, sexua l dysfunction, and bowel/bladder problems. 1 . Autonomic dysfunction can occur d ue to impairment of the a utonomic nervous , system in the bra i n (Shy-Drager syndrome, hypothalamic tumor, Parkinson s dis­ ease) , spinal cord ( tumor, myelitis, multiple sclerosis) , a utonomic nerves ( dia­ be/es, Gull/ain-Barre syndrome, amyloidosis) or neuromuscular j unction (botulism) . Systemic diseases (peripheral vascular disease, connective tissue disease, prosta- : tism) may manifest with autonomic symptoms. Autonomic impairment becomes more i pronounced with advancing age, prolonged bed rest, and various medications. 2 . Autonomic symptoms are rarely the sole manifestation of an u nderlying i l � i ness, a n d the diagnosis often i s made based on the combinatio� of autonomic 1 222 I • Neurology
    • impairment and other cardinal signs/symptoms. For exa m ple, the followingdiag noses feature autonomic sym ptoms in combi nation with others: a. Parkinson s, Shy-Drager- bradykinesia, rigid ity, postura l instabil ity ( restingtremor in Parkinsons) b Guillain Barre - su bacute onset, ascending pa ralysis, a reflexia, auto­nomic instabil ity c. Peripheral vascular disease, diabetes - orthostatic hypotension, i m paireddi sta l circulation, poor wound h eo l i n g i n extremities (hyperg lycemia i n dia­betes) .3 . Management of autonomic disorders ahen is symptomotic, once the underly­ing condition has been diagnosed and is being treated. a . Orthostatic hypotension - mai ntain good hydration and sodium, g radualpostura l changes, disconti nue hypotension medications, avoid prolonged inac­tivity. Fluorohydrocortisone may be helpful in patients with d ifficult to control or­thostasis. b . Bladder dysfu nction - flaccid bladders may respond to bethanechol .Spastic bladders may be relaxed using propa nthe l i ne a nd/or oxybutyn i n .Intermittent self-catheterization often i s helpful i n preventing urinary incontinencein certa in patients ( multiple sclerosis, spinal cord disease) . c. Sexua l dysfu nction - pe n i l e i m pla nt, medication , endocrine a n d u ro­logic/gynecologic evaluation . DI PLOPIAH I N T : I S CT D O N E? Cen tralH e m o r r h a g e , c e reb e l l a rI nfa rct/T I AN e o p l a s m ( b ra i n st e m t u m o r)T ox i c/meta bo l i c Periph eralI nfe ct i o u s/me n i n g i t i sS u ba rach n o i d h e m o rr h a g e/a n e u rys mC a n c e r (ca rc i n o m a t o u s m e n i n g i t i s , cave r n o u s tu m o r)T hy r o i d o p h t h a l mopathy Neurology • 223
    • D ia betes O rb i t a l p rocess ( o rbita l f ra ctu re/ma ss) N e u ro m u s c u l a r j u n c t i o n d i se a s e ( myasth e n ia ) E ye p ro b l e m ( l e n s s u b l uxat i o n ) CT W H O M ? M O S T CT I M A G E D Cen tral C VA/i sch e m i a , b ra i n st e m T ox i n s/d r u g s W e r n i ckes H e m orrh a g e , c e re b e l l a r O n co l og i c ( b ra i n st e m tu m o r) M u l t i p l e s c l e ro s i s Peripheral M yast h e n i a g ra v i s O rb i t a l p rocess ( o r b i t a l f ractu re/ma ss) 5 u b a ra ch n o i d h e m o rr h a g e T ra u m a ( s h ea r i ng I nj u ry to c ra n i a l n e rve) C ave r n o u s s i n u s p ro c e s s T hy r o i d o p ht h a l m opathy I nfect i o n s ( h e rp e s zoste r o p h th a l m i c u s ) M a l i g n a n cy (ca rci n om a t o u s m e n i n g it i s ) A n e u l ys m a l co m p re s s i o n G ra n u l o m a to u s (sa rc o i d , To l o s a- H u nt) E ye p ro b l e m ( l e n s s u b l uxati o n ) D i a betes Also under Peripheral: increased intracranial pressure (as i n pseudotumor cere­ bri) can cause cranial nerve (eN) VI palsy with resultant diplopia.. N otes Diplopia is the subjective symptom of double vision . Dysconj ugate gaze is the objectiv,e exa m i nation find i ng of eye rtlisalign­I ment; which may or may not be associated with symptoms of diplopia. 224 • Neurology
    • 1 . Exa m i nation i ncludes d i rect observation of eye move ments i n a l l axes of movement. Does the patient report resolution of diplopia if one eye is covered ? Is the visual acu ity in both eyes eq ual? 2. Drugs and toxins a re a co m mon cause of d i plopia . Offending agents i n­ clude carbamazepine, phenytoin, and alcohol . 3 . Congenita l strabism us, if not corrected , leads to suppression of the visual i mage from one eye. Thus, it is possi ble for a patient with obViously dysconiu, gate gaze not to complain of d iplopia 4. Monocular d i plopia (di plopia with one eye covered) al most always is sec­ ondary to intraocu lar disease. 5 . A CN I I I palsy may be a cause of d i plopia . A com plete CN III pa lsy causes ptosis; inabil ity to move the eye up, down , or i nward; and a d ilated, un reactive pupi l . Many are incomplete. Compressive lesions of CN I I I (aneurysms, tumors) are most likely to cause pupillary i nvolvement and should be i maged . A patient with a ppropriate i m pa i rment of eye movement a nd no pupillary involvement most likely has a medical CN III palsy ( presumed to be a microi nfarction of the nerve fibers), especially if the patient has diabetes . Generally these patients do not need a brain CT, and palsy resolves over a few weeks . They should be fol­ lowed closely, however, to ensure that the pupil does not become i nvolved . 6. Diplopia can be a man ifestation of cavernous sinus disease. The cavernous sinus is an i ntracranial compartment located beh i nd the orbit and lateral to the pitu ita ry. The carotid artery, CNs I I I , IV, and VI, and the V 1 bra nch of V pass throug h this area . The V2 branch of CN V occupies the most inferior portion of the cavernous sinus. Whenever a combination of CN deficits i nvolVing I I I , IV, V l , V2, and/or VI is detected , a structural lesion in the cavernous sinus should be ruled out with an imaging study, preferentially a gadolinium-enhanced MRI. 7. Herniation is a condition where a supratentorial mass causes latera l dis­ placement of the b ra i n stem a nd can ca use a n i psilateral palsy i nvolving the pupi l . Patients who a re herniating have altered menta l status, and thus are not likely to be compla ining of anyth ing, let alone diplopia. The typical clin ica l pic­ ture i n which herniation is a concern is the comatose patient with a "blown" ( i . e . , fixed and di lated) pupil. Hern iation requ i res i mmediate treatment to reduce intracra n ia l pressure (hyperventi lation , man nitol) and prompt CT scann ing to de­ termine the ca use of the problem . Patients with a dilated pupil and a normal mental status are not herniating.,8 , Central causes of diplopia l isted above involve primarily the bra instem and cerebellum . There may be other evidence of bra instem or cerebellar dysfunction (other CN palsies, ataxia, hyperreflexia , u pgoing toes, hemipa resis). Imaging studies are indicated in patients with other focal nevrologic findings. 9, Peripheral causes of diplopia listed a bove involve the eye itself and cranial nerves ( I I I , IV, VI). A careful ophthalmolog ic exam i nation is warranted, particLl­ larly in cases of monocular d i plopia . Imaging studies of the brain generally are not needed for intraocular causes of diplopia, medical eN III palsy, or myas­ thenia gravis. However, when u n certa i n a bout exa m find i ngs, imag i ng may help to eliminate the more omi nous possibil ities. Neurology • 225
    • D I ZZ I N ESSSo Very D i zzy N owS y n cope/presyncopeV e rti g oD i se q u i l i b ri u mN o n s pe c i f i cOLD SPI N NING MAMAO to l i t h ( be n i g n p o s it i o n a l ve rt i g o )L ow b l ood s u g a rD e mye l i n a t i o n ( m u lt i p l e s c l e ro s i s )S t ro ke/T I A/b l ee dP ost-tra u m a t i cI n t rava s c u l a r vo l u m e d e p l et i o n/hypot e n s i o nN e u ro m a/n e o p l a s mN e u ro n i t i s/l a byri n t h i t i sI ntox i ca t i o n ( Et O H , d ru g s , m e d i c a t i o n s )N e u ropathy/mye l o pathyG I b l e ed/a n e m i aM u l tifacto r i a l/m i g ra i n eA m i n o g lyc o s i d e s/ototoxi c m e d i ca t i o n sM e n i eres d i se a s eA nx i ety/h y p e rve n t i la t i o n226 • Neurology
    • A HOBBLED MAN SPINSA n e m iaH ype rve nti l a t i o n/psych i a t r i cO th e r ( m u l tifacto r i a l , m i g ra i n e )B e n i g n pos i t i o n a l ve rt i g oB l e e d/h e m o r r h a g eL a byri n t h i t i s/vesti b u l a r n e u ro n i t i sE n d ocri n e/met a bo l i c ( hypog l yc e m i a )D e mye l i n a t i o n ( m u l t i p l e s c l e ro s i s )M e n i e res d i s e a s eA m i n o g lyco s i d e tox i c i tyN e u ropathy/mye l o pa t h yS yn cope/hypote n s i o nP ost-tra u ma t i cI ntox i ca t i o n ( Et O H , d ru g s , m e d i ca t i o n )N e u ro m aln e o p l a s mS t ro ke/T I AN otes 1 . A complaint of d izzi ness may mea n d ifferent things to different people. Tryto historically determine which category 0f symptoms the patient has (these cate­gories can be remembered by the m nemonic "So Very Dizzy Now. " a . Syncope/presyncope: lig htheaded ness, fa intness, postu ra l . DDx morel i kely to i nclude a rrhythm i a , decreased cardiac output, orthostasis, autonomicneuropathy, vasovagal reflex. b. Vertigo: I l lusion of movement of patient or surrou nd i ngs, often w ithna usea , vom i ti n g . DDx more l i kely to i nclude benign positional vertigo,labyrinth itis, Menieres, MS, post-trau matic, vesti bular nerve neu roma . c . Disequilibiru m : u n steadi ness, feel ing "drunk, " clumsi ness, wobbly. DDxmore l i kely to i ncl ude d rug i ntoxication , E tO H , a m inog lycoside ototoxicity,severe peripheral neuropathy, m ultifactorial. d . Nonspecific: Anxiety, weakness, vague, d ifficult to describe. DDx morel i kely to incl ude hyperventi lation, systemic disease (anemia, meta bolic!, m u lti­factorial. Neurology • 227
    • 2 . When exa m i n i ng a patient with d izzi ness, try to reprod uce the patientssymptoms with a variety of ma neuvers. a. C heck for orthostasis by blood pressure and pulse (su pine and standing)and note any subiective com plai nts the patient has. b. Perform the Hall-Pi ke (Barany) maneuver (see 6 a ) to d iag nose benignpositional vertigo. c. Hyperventilation may reproduce symptoms of d izziness associated withanxiety or pan ic attacks. d . Va lsalva maneuver may reproduce symptoms related to decreased car­d iac output.A patient may compla in of some form of d izziness with more tha n one of thesema neuvers. It is most helpful if the patient can determine which ma neuver actu­al ly reproduces the symptoms comprising the ch ief com plaint.3. Vertebrobasilar ischem i a rarely causes isolated vertigo. I nvestigate thor­oug hly for other evi dence of bra instem/ cerebellar dysfu nction (other c ra n i a lnerve palsies, ataxia, hyperreflexia , upgoing toes, hemiparesis) .4. Meniere s disease is associated with hearing loss. Benign positional vertigoand labyrinthitis/vestibular neuronitis are not.5. In many cases of dizziness, no single foetor stands out as the causative one.A com bi nation of factors may conspire to make the patient more symptomaticthan any one factor would alone. For exa mple, a patient may have m i ld dia­betic neuropathy, cataracts, and a history of alcohol abuse. The combination ofperipheral neu ropathy, decreased visual acuity, and diminished cerebel lar func­tion , plus the possibil ity of a diabetic autonomic neuropathy, put this patient inthe multifactorial category of this differential diagnosis.6 . Benign positional vertigo (BPV) is cha racterized by attacks of vertigo follow­ing a change in head position , most com monly rol ling over in bed or lookingup It is most common in the elderly and is thought to be caused by free-floatingcalcifications (otoliths) in the posterior sem icircular conal . a . The Hallpike maneuver is used to diag nose this cond ition . The sta rti ngposition is with the patient sitti ng, the exam i ner standing to the side, and faCingthe patient, with the exa miners hands supporting the patients head . The patientmay hold onto the exa miners elbow. The final position is with the patient supine,eyes open, the neck extended 30° below the plane of the bed , and the headrotated 30° laterally toward the side being tested (the side the exam iner is on).The ma neuver involves ra pidly moving the patient from the first position to thesecond . The test is considered positive (diag nostic for benign positional vertigo)if, after a brief latency of 3-30 seconds, the patient develops a torsional nys­tagmus in the direction of the side being tested . Upon sitting up, there often is atorsional nystagmus in the opposite d i rection. Each side is tested to determinewhich side is involved . Occasional ly, both sides a re affected . b . .Torsional nystagmus is the hallma rk of BPV The eye on the side of the af­fected labyri nth demonstrates a mostly lateral nystagmus toward the affectedside, while the opposite eye shows a more rotatory component, with the top ofthe globe rotating toward the affected side.228 • Neurology
    • c . A va riation of the Hallpike known as Epleys maneuver may be used tod islodge the offending calcificati on . The Hallpike is performed to the sym pto­matic side, then , without allowing the patient to sit up, the patient is rolled to theasymptomatic side into a lateral decubitus position . Fina lly, from this lateral decu­bitus position , the patient is allowed to sit up. The patient should feel vertigi nousthroughout the maneuver, burt aher it is completed , the vertigo should resolve . d . If Epleys maneuver is unsuccessful , the patient can be instructed in vesti bu­lar exercises to desensitize the vesti bular apparatus . These consist of self-admin­istered Hall pike maneuvers done two to three times a day, with five repetitionseach time. e. Vestibular suppressants such as meclizine prolong the period of vesti bulardesensitization and a re general ly less helpful , except in severe cases involvingdehydration risk from nausea and vomiting. H E A DAC H ECT S CA N M E ?C l u st e rTensionS i n u s i t i s/ot i t i s/m a sto i d i t i sC ravi n g ( d rug-s e e k i n g v s . rebo u n d )A n e u rys m/a rte r i t i sN e u ra l g i a , t r i g e m i n a lM i g ra i n eE l evated i nt r a c ra n i a l p re s s u re ( s u bd u ra l h e m a t o m a , h e m o rr h a g e , AVM , t u m o r, p s e u dotu m o r, h y p e rte n s i o n , hyd roce p h a l u s )Also: infection (meningitis/meningoencephalitis), metabolic, psychiatriC, post-LP,osteoarthritis, post-concussive, sinus thrombosis Neurology • 229
    • l CA N T STOP H EA D PA I N S C l u st e r/m i g ra i n e A rteritis (te m po ra l , l u p u s ) N e u ra l g ia (tri g e m i n a l ) T e n s i o n h ea d a ch e S i n u s t h ro m bos i s (ve n o u s) T ra u m a ( p ost-co n c u s s ive) o steoa rth r i t i s/m u s c u l o s ke l eta II P ost- L P,. H yd roce p h a l u s E l evated b l ood p r e s s u reI A n e u rysm/s u ba ra ch n ai d h e m o rr h a g e o ru g s ( o piate rebo u n d h ea d a c h e , ste ro i d wit h d rawa l , oral conva c e ptives) P se u d ot u m o r c e r e b ri A rt e r i ove n o u s m a lform a t i o n Infect i o n s ( m e n i n g it i s/m e n i n g o e n c e p h a l i t i s ) N eo p l a s m S i n u s it i s/oti t i s/ma stoi d it i s Also: psychiatric, metabolic (hyperthyroid, Cushing s, chronic lung disease with hypercapnia) N otes Headache is a general term used to describe a ny pa i nful sensation i nvolving the structures of the cranium, face, and/or neck. 1 . H istory is all-important in the diagnosis of heaQache. Questions to ask i n­ clude the following: a. Precipitating factors - stress, trauma, certa i n foods, caffeine, alcohol, time of day, d rug use b. Prodromal symptoms -visual scotoma, focal weakness/numbness, aphasia c. Rapidity of onset-seconds, m i nutes, hours d. Lecation (uni- or bi latera l, tem pora l, OCCi pital, cervical) and nature (fh rob­ birig, stabbing, pressu re-l ike, lancinating) of pa i n e. Associated symptoms - n ausea, d i plopia, vertigo, vom iting, lacrimation , 230 • Neurology
    • fever, gait d isturbance, a ltered menta l status, seizures, photophobia , exacer­bated by sta nd ing f. Duration - seconds, minutes, hours, days, dai ly/ch ronic g. Alleviating factors - qu iet, sleep, ana lgesics, darkness, prescription med­ications h . Other pertinent med ica l history - cancer, hypertension, preg nancy, h istoryof similar headaches, fam ily history of m ig ra i ne, medications, trauma2. To scan or not to sca n? Worrisome complai nts such as new-onset severeheadache, seizures, recent change in pattern of a c h ronic headache,and/or focal neurologic deficits may ind icate the need for a n imaging study.However, routine scanning of patients with symptoms of classic mig ra ine and anonfocal neurologic exam has a very low yield of revea ling a treata ble intracra­nial abnormal ity. Routi ne sca nning of patients with chronic headache com pla ints(migra i ne or nonmigra i ne) and a nonfocal neurologic exam a lso tends to have alow yield of demonstrating treatable i ntracranial disease.3. Approach to diag nosis of chronic headache: see ta ble. Be aware of typesof chronic headaches that dont fit well into these categories, i ncluding temporala rteritis, l u pus, some pituitary tu mors, cluster headaches, hypercapnea sec­onda ry to pulmona ry d isease, and some endocrinopath ies. Approach to D i a g nosis of C h ro n i c Headache Headache TypeCharacteristics Migraine Tension Elevated fepOnset Minutes Hours-days Days-weeksTime course of Maximal in 1 5-60 Moderate, waxing Gradually worsen­ pain minutes, and waning, ing over time normal between may be headaches persistentDurationHours-(days) Hours-weeks- (Days)-weeks- (months) monthsLocation Unilateral, but can B ilateral, esp. Unilateral if focal be on either side frontal, OCCipital lesion, other- wise bilateralQuality of pain Throbbing, pulsatrle Achey, pressure-like, Pressure-like, dull muscle tensionNausea, Common with No Nocturnal , early vomiting headache morninglight and noise Common No No sensitivity (Table continued on next page.) Neurology • 231
    • Approach to Diagnosis of C h ro n i c H eadache (Con tinued) Headache TypeCharacteristics Migraine Tension Elevated fepFocal neurologic Stereotyped and No Gradual onset and signs transient, often progressive, visual (scotoma) sometimes di plopiaSeizures Very rare No OccasionalPapilledema No No Yes4 . S u m m a ry of specific headache types: . Type SymptomsCluster Uni lateral stabbing peri/retro-orbital pai n ; i psi lateral lacrimation, rhinorrhea Occurs i n "clusters" of daily attacks over a period of weeks, between clusters may be asymptomatic for weeks/months/years Duration usua l ly 1 5-30 m i n utes, may last 2-3 hours Unl ike migraine patients, may be agitated, generally do not sit sti llMigra i ne, Episodic, recurrent, throbbing , u ni- or bilateral pai n common Associated with light and noise sensitivity, nausea a nd vomiting Duration usua l ly 2-4 hours, may last u p to 2-4 days Patients seek quiet, dark a reas and try to sleep a nd be stil lMigra i ne, S i m i l a r to common migraine but preceded b y focal neurologic classic disturbance (visual scotoma, n u m bness, a phasia, vertigo) and lasting a few m i nutes to an hourTem poral Throbbing temporal or bitemporal pai n in elderly patient arteritis Associated with monocular visual loss, jaw claudication, tender temporal a rtery( ies) to pal pationI ncreased Wakens from sleep intracra nial Associated with early morning vomiting pressure May have papilledema on funduscopic exami nation With • Tumor - focal neurologic deficit, seizures, h/o systemic cancer focal • Abscess - focal neurologic deficit, seizures, may have fever, lesion evidence of systemic emboli (check fund i , nailbeds, cardiac murmur) • AVM- focal neurologic deficit, seizures, head bruit Without • Pseudotumor cerebri -.may have visua l loss (decreased visual focal fields and/or decreased visual acuity), sixth nerve palsy/diplopia lesion • Hydrocephalus- may have gait disturbance, decreased upgaze, i ncontinencePost-LP Often positional, better when lying down Duration may last up to a week (Table continued on next page. )232 • Neurology
    • Type SymptomsSubarachnoid Abrupt onset, may have initial loss of consciousness hemorrhage "Worst headache of my life" May have fever, stiff neck, altered mental statusMeningitis/ Associated with fever, stiff neck, altered mental status encephalitis May have seizures (especially herpes encephalitis)Tension "Pressure-like" or " hat-ba nd" bifrontal or bioccipital pai n May b e associated with neck/shoulder/back pa in Often c h ronicRebound Associated with worsening of headache as analgesics/na rcotics wear off Diagnosis of excl usion5. Therapy for headache is dependent on the d iagnosis. Treatment with anal­gesics/ na rcotics may tem pora r i ly a lleviate d iscomfort, but does not treat thecause of the headache. In general , beware of treating pain while leaving theunderlying etiology untreated (e . g . , meningitis, hemorrhage) . Loss OF CONSCIOUSNESSVA G A L S Y N C O P EV o l u m e l o s s/b l e ed i n gA o rt i c d i ss e ct i o nG l u cose d ropA uto n o m i c dysf u n ct i o nL ow ca rd i a c o ut p u tS e i z u reY o u r m a m a s v i s i t i n g/a n x i ety/psych o g e n i cN e u roca rd i og e n i c/ref l exe VA/s u b a rach n o i d h e m o r r h a g eO rt h o s t a t i c hypote n s i o nP u l m o n a ry e m bo l i s m/pe r i p h e ra l va s c u l a r d i s e a s eE l evated b l ood p re s s u reAlso� basilar migraine Neurology • 233
    • A C LS ! I H A V E TO PA S S O U TA o rtic a n e u rysm/d i s s e c t i o nC o u g h/ m i ctu r i t i o n/re f l ex s y n c o p eL ow g l u co s eS i n u s hyperse n s i tivity, ca roti dI at rog e n i c/d ru g/m e d i ca t i o nH e m o rr h a g e , s u ba ra ch n o i dA uto n o m i c n e u ropathyV a sova g a l s y n c o p eE t h a n o l i n toxica t i o nT ra n s i e nt i s ch e m i c attackO rt h os t a t i c hypote n s i o n ( hypovo l e m i a , poor va s c u l a r tone)P sych og e n i cA systo l e/h e a rt b l ockS e i z u reS u bc l a v i a n stea lO ut f l ow obstru cti o nU n d e rp owe red h ea rt/ca r d i o myop a t hyT a chya r rhyt h m i aAlso: basilar migraineT H I S M A D E M E VA G A LT l A/c e r e b ra l i s ch e m i aH yp e rte n s i o nI n t ra c ra n ia l h e m o r r h a g e ( s u ba ra ch n o i d )S e i z u reM yo ca r d i a l i nfa rct i o nA o rt i c d i ssecti o nD ru g s/a l co h o lE m oti o n s/psych i a t r i c234 • Neurology
    • M i g ra i n eE m b o l i s m , p u l m o n a ryV o l u me lossA rrhyt h m i aG l u co s e d ropA uto n o m i cL ow ca rd i a c o ut p u t ( c o n gest ive h e a rt fa i l u re , a o rt i c ste n o s i s , p u l m o n a ry hype rt e n s i o nAlso: neurocardiogenic/reflex syncopeN otesSyncope ( i e , fa inting) is defined as a transient loss of consciousness and pos­tura l tone d ue to impaired cerebral blood flow.1 . A description of the spell is crucial tQ appropriate worku p and d iagnosis.The patient as well as any eyewitnesses should be q uestioned . I mportant histori­cal i nformation can be d ivided into three time periods: a. Prior to the event- postural cha nges (e . g . , patient stands up), precipitat­ing factors (ski pped meals, physical exertion, severe stress, cough, m ictu rition ) ,symptoms (headache, dizziness, chest pa in, shortness o f breath, heart pa lpita­tion, fa intness, focal neurologic symptoms, nausea ) , and eyewitness descriptions(altered behavior/mentation, pa llor, excessive sweating) . b . During the event (usually from the eyewitness) - rapid ity of onset, durationof episode/unresponsiveness, involuntary motor activity, a pnea , overt seizu reactivity, inj ury to the patient, loss of continence. c. After the event- orientation/responsiveness, a m nesia, rapidity of recov­ery to baseline mental state, recurrent episodes.In addition, pertinent information about pre-existing med ical cond itions, cu rrentmedications, recent a lcohol!d rug i ngestion, a nd fa m i ly h istory of fa inting orseizures should be sought.2. Cond itions that may mimic syncope incl ude seizure, drug/alcohol intoxica­tion, subarachnoid hemorrhage and basilar migraine. Conditions associatedwith faintness but in which complete loss of consciousness is rare i nclude hypo­glycemia, anemia, hyperventilation, panic disorder, and hysteria.3 . The differential for syncope can be thoug ht of in four major categories: a. Neurocardiogenic- reflex inhi bition of heart via autonomic nervous system • I ncl udes vasovagal attock, carotid sinus syndrome, m ictu rition, cough, valsalva, emotional stress. • Disti nguished by the presence of preci pitating event and a bsence of cardiac and peripheral vascular pathology. Usually in younger persons. Neurology • 235
    • b. Orthosta ti c - drop in blood pressure due to inability to mai ntain vasculartone • Med ications, postu ral change, neu ropath ies (especially a utono m i c ) , neurodegenerative disease, peripheral vascula r d isease, hypovolemia . • Disti ngu ished by orthostatic tachycardia/hypotension oll exa m , a n d history o f spells correlating with postura l change. c. Card i oge n i c - di rect card iac pathology • Cardiomyopathy, aortic valve disease, tachyarrhyth m i a , bradyarrhyth­ mia/asystole. • Disti ngu ished by ca rd iac sym ptomatology ( e . g . , chest pa i n , pa lpita­ tions), known cardiac d isease, and ECG abnormal i ties during spell. d . Other- miscellaneous • Hypog lyce m i a , cerebral ischemia/i nfa rct, i ntracra nial hemorrhage, basilar m ig raine, drug/a lcohol intoxication , pulmonary embolism (PEl, . aortic dissection . • SystemiC metabolic causes (hypoglycemia, intoxication) associated with "woozi ness , " more g radual onset . Vascu lar causes usually due to a sudden mechan ical obstruction of cerebral vasculature (infa rct, d issec­ tion ) . Catastrophic causes i nclude PE and intracranial bleed .4. Reflex syncope is due to excessive vagal sti m ulation , which slows the heartrate a n d decreases cerebral blood flow, causing u nconsc i ousness . Carotidsinus syndrome is due to excessive pressure sensitivity of the carotid sinus. Tightcollars o r other extel nal pressure on the neck can provoke syncope . Otherknown provocateurs of reflex syncope include m ictu rition , valsa lva maneuver,a n d cou g h i ng . Vasovagal syncope is a type of reflex syncope triggered bypa i n , fear, or other sudden emotional stress . It typica l ly occu rs in adolescentsand young adu lts and may be more likely in the setting of prolonged standing,fatigue, and/or fasti ng.5 . Med ications commonly i m plicated in orthostatic hypotension i nclude anti hy­pertensive d rugs, diuretiCS, nitroglyceri n and other a rterial vasodi lators, tricyclica ntidepressants, phenothiazines, lith i u m , calcium channel blockers , a nd betablockers. 6. Cardiac causes of syncope can be revealed by physical exam and ECG. Itmay be necessary to monitor patients with card iac telemetry or a Holter monitorto detect a tra nsient a rrhyth m i a . Ec hocard iogra phy may demonstrate aorticvalve disease or cardiomyopathy.7. Initial workup for a transient loss of consciousness is fa i rly stra ightforwa rd : a . ABCs; if episode over, then proceed with further evaluation i ncluding h is-tory and exa m . b . ECG a n d blood pressure monitors. c. Accucheck, pulse oxi metry. d . Laboratory studies to be considered electrolytes, g l ucose, BUN/C r,CBC, etha nol , tox screen. 8. F u rther workup (and treatment) depends on the suspected cause of theepisode. a. Seizure CT/MRI, EEG.236 • Neurology
    • b . Card i a c cardiac telemetry/Holter mon itor, echocard iogra m , cardiacenzymes Pul monary embol ism -VQ scan , pulmonary ang iogra m c. Orthostatic some cases may need provocative testing such as tilt table d Neuroca rdiogenic if i n itia l workup negative a nd history suggestive ofreflex syncope, general ly no further workup is requ ired . e. Cerebrovascular: Aortic d issection/aneurysm - chest x-ray/CT, ang iogra m S u ba rachnoid hemorrh age/cerebral a neu rys m - head CT MRI, Angiogra m , lumbar pu ncture Tra nsient ischem ic a ttack - head CT/MR I , ca rotic/vertebral doppler, a ng iogra m , coagulation lab studies f. Metabolic Hypoglycemia- check serum glucose, admin ister IV glucose I ntoxication - blood ethanol, seru m or urine tox screen M O N O C U LA R V I S U A L L o s sBLI N DB l o o d vess e l s ( a rteriti s , h e m o r r h a g e , e m b o l i s m )L e n s (cata ract)I nfect i o nN e rve (tu m o r, o p t i c n e u ri t i s , g la u c o ma-v i a p r e s s u re o n n e rve)D et a c h e d reti n a/ot h e r reti n a l d i se a s eG RAVE V I S I O N E DG la ucomaR et i n a l/oc u l a r m i g ra i n eA rte r i t i s , te m po ra lV e n o u s t h ro m bo s i s ( c e n t ra l reti n a l ve i n o c c l u s i o n )E m bo l i s m (ce n t ra l reti n a l a rt e r y o c c l u s i o n ) Neurologv • 237
    • paz V a sc u l a r occ l u s io n (ca ro t i d ) I nfect i o n s ( C M V ret i n it i s ) S e n i l e cata ract I n t ra oc u l a r b l e e d O pt i c n e u ri t i s N eo p l a s m ( o p t i c n e rve g l i o m a ) E l evated s e r u m v i co s ity ( s i c k l e c e l l , po lycyt h e m i a ) D et a ch e d ret i n a M O N O -VI S I O N E D M ig ra i n e , o c u l a r/reti n a l O cc l u s i o n , c e n t r a l ret i n a l a rtery N eo p l a s m O cc l u s i o n , ce n t ra l ret i n a l ve i n V a s c u l i t i s , t e m p o ra l ( g i a nt c e l l ) I nfect i o n S e n i l e cata racts I n t ra o c u l a r b l e e d O pt i c n e u ri t i s N ot m o n o c u l a r v i s u a l l o s s E l evated s e r u m v is c o s ity D et a ch e d reti n a Also: glaucoma N otes Monocular visual loss is either a subjective report of tra nsient visual loss in one eye (as opposed to Ofle visual field) or a n objective finding of decreased visual acu ity in one eye. Pseudotumor cerebri and other causes of increased intracra­ nial pressure generally produce bi lateral signs/symptoms 1 . It is critical to distinguish between monocular visual loss and a visual field cut. With monocular visual loss, yisual acuity is diminished in one eye, a nd the lesion is in the eye o� optic nerve. With a visual field cut, vision is i mpaired in a particular a rea of tbe visual field in both eyes, and the lesion is in the optit: tract 238 • Neurology
    • or the bra i n . This distinction ca n be made clear by testing visual acuity andvisual fields one eye at a time. Sometimes, patients mistake a visual field cut formonocular visual loss on the same side ( " Doc, I ca n t see out of my left eye. " I .On exam , however, the patient demonstrates a left visual field cut in both eyes .2 . True monocular visual loss is ca used by a lesion i n the eye or optic nerve(anterior to the optic chiasm), a n d thus may be d ue to problems in the lens,retina , blood vessels, or the optic nerve itself.3 . Amaurosis fugax is the sub iective compla i nt of tra nsient visual loss in oneeye, often described as a veil or shade com ing over the eye. Th is is essentiallya transie(lt ischemic attack of the reti na, and may be caused by emboli from theheart to the central reti nal a rtery, an ulcerated carotid plaque causing emboli orocclusion, or temporal mteritis i nvolvi ng the carotid a rtery.4. It is critical not to miss the d iag nosis of tem poral arteritis because prompttreatment could prevent com plete infarction of the reti na. The classic clin ical pic­ture is a person > age 65 , with uni lateral or bi lateral severe headache, tendertemporal a rteries, low-g rade fever, a nemia , and elevated ESR. Amaurosis fugax,polymya lgia rheu matica , and iaw claudication may occu r. Treatment is withpred n isone 60- 1 00 mg/d and should not be delayed to obta i n tem pora lartery biopsy, but biopsy should be performed bilaterally within 3 days of initi­ating steroids. ESR should be monitored and used to g uide therapy. In cases ofacute retinal ischemia, IV methylprednisolone has been used .5 . Ophthal moscopic exa m i nation is also of g reat i m porta n ce i n eva l uati ngmonocular visual loss, since central reti nal a rtery occlusion , central retinal vei nocclusion , retinal detach ment, cataracts, infections/reti nitis, hemorrhage, a n doptic disc edema can b e detected . P TO S I SLID DROPL i d i nf i l t ra t i o n ( by tu m o r o r i nf l a m m a t o r y t i s s u e )I nfe c t i o n (zoster, botu l i s m )D ia betes/thyro i dD ru g s .R eceptor q nt i b o d i e s ( myast h e n i a )O cu losym patn e t i c p a l s y/oc u l o motor p a l syP ropto s i s Neurologv • 239
    • T E N S I LO N M E, DOC T h i rd n e rve pa l sy E ye d ro p s (ste ro i d ) N e u ro m u sc u l a r j u n c t i o n d i se a s e ( mya sth e n i a ) S u rgery I n fect i o n ( h e rp e s zoste r o p h t h a l m i c u s) L i d i n f i l t ra t i o n ( by t u m o r o r i nf l a m matory t i ss u e) O c u l o sy m p a t h e t i c pa l sy ( H o r n e r s syn d ro m e) N e u rotox i n s ( botu l i s m ) M yopathy ( m u s c u l a r dystrop hy, myoto n i c dystrop hy) E n o p h th a l m os ( eyeba l l retra c t i o n i nto o r b i t) D i a betes/thyro i d d i s e a s e O p p o s i te l i d retra cti o n C l u s t e r h e a d a ch e Also: congenital ptosis!iI N otesI Ptosis is a physical finding of one pa lpebral fissu re being sma ller than the other, i e , a d rooping eyel id . 1 . Ptosis may be the result of a partia l or complete thi rd nerve palsy (with asso­ ciated ophtha l moplegia and pupi llary dilation/unreactivity) . For a full descrip­ tion of third nerve palsy, see notes 5-9 under the heading Diplopia, page 225 . 2 . Ptosis is part of the oculosympathetic palsy or Horners syndrome, which con­ sists of unilateral ptosis, m iosis (small pupil), and anhidrosis of the face (de­ creased sweating) . The sympathetic pathways go down the spinal cord to the thoracic level, where they exit the cord and ascend the neck as the sympathetic trunk to the su­ perior cervical ganglion, then follow the i nternal carotid a rtery and, ultimately, the V l d ivision of cranial nerve V to the eye. Any lesion that interru pts the oculosym pathetic pathways can result i n Horners syndrome, i ncluding tumor (lung, mediastinal, thyroid, pharyngeal , lym­ phoma, spinal cord ) , tra u m a , a nd congen ital causes, as well as ( less l i kely) carotid dissection/occlusion, cervical d isc or rib, mening itis, bra i nstem infarct, syrinx, polio, pneumothorax, and ALS . A significant proportion of Horners cases are id iopath ic, with a high frequently of diabetes and hypertension in this idio­ pathic group 240 • Neurology
    • 3 . Neuromuscular d isease , speci fica l ly myasthen ia g ravis, may present asptosis (often bilateral but asym metric) . This often is associated with fluctuati ngocular palsies (diplopic:L facial weakness, weakness of speech and swa llow­ing, and neck and shoulder g i rdle weakness. Not infrequently, the weakness af­fects the m uscles of respiration . Characteristica l ly, muscles a re fati g uable ifsubjected to susta ined contractio n . Pupillary muscles, smooth m uscle, cardiacmuscle, and sensation are unaffected The Tensilon (edrophonium) test is helpful in the diagnosis of myastheni a .Myasthenia i s caused by a utoa ntibod ies to the acetylchol ine (ACh) receptor.Norma lly, ACh crosses the synapse, binds to the receptor, and eventually is me­tabol ized by acethylcholine esterase (ACh E ) In myasthenia, the ACh receptor ispa rtia lly blocked, and ACh is m eta bolized by ACh E betore it can bind the re­ceptor. Edrophonium is an AChE inhi bitor, delaying the meta bolism of ACh andincreasing the likeli hood of ACh binding to the partially blocked receptor. Thus,a d m i n i stration of ed rophon i u m to a myasthenic patient should i n crease thestrength of involved muscles.4. An eyelid may appear ptotic even when it is normal, if compared to a re­tracted eyelid (e.g , proptosis) on the opposite side. likewise, a normal lid maylook ptotic if the eyeball itself is retracted into the orbit due to loss of orbital tissue. R I G I D I TYD O PAM I N ED ysto n i ao l ivo po ntoce r e be l l a r a t ro p hy ( O PCA)P a rk i n so nsA n ky l os i n g s p o n d y l i t i sM e n i n g i s m u s ( m e n i n g i t i s , s u ba ra ch n o i d h e m o r r h a g e )I n c re a s e d t o n e/s p a s t i c i tyN e u ro l e pt i c m a l i g n a n t syn d ro m eE l evated i ntracra n ia l p r es s u reN otesRig idity is a conti nuous or intermittent i ncrease i n muscle tone throughout the full . .range of passive movement. Neurology • 24 1
    • p • Cogwheeling is a form of rigid ity charaGterized by rhythm ic, rachet-l i ke resistance throughout the range of motion . • Lead-p i pe is a form of rigid ity cha racterized by u n iform resi sta nce throughout the ra"nge of motion . Spasticity i s a n i ncrease i n m uscle tone that i s m i ld with slow movement and more pronounced with rapid movement. Classical ly, rapid passive movement is met with i ncreasing resistance until a point at wh ich the resistance breaks ( "clasp knife phenomenon " ) . 1 . Rigid ity m a y be caused by: a . Neurolog ic pathology • Extrapyra m idal/basal ganglia disorders (dystonia, oIivopontocerebel­ lar atrophy, Parkinsons, drug effects) • Corticospinal i nvolvement (spasticity, elevated intracranial pressure/her­ · n iation) . b. Men ingeal i rritation (men ingitis, suba rachnoid hemorrhage) c. Skeletal i m mobi lity (ankylosing spondylitis, severe spinal osteoarthritis) 2 . In genera l , i ncreases in m uscle tone may be due to corticospinal or ex­ trapyramidal pathology. The term rigid ity may be used to refer to hypertonus of extrapyra m ida l orig i n , and spasticity refers to i ncreased tone of corticospinal orig i n . Disti nguishing characteristics of" each a re summa rized i n the table. Extra­ pyra m idal syndromes of rigid ity a re not usually associated with hyperreflexia, Ba binski signs, or pa ra lysis, and are more often associated with other move­ ment disorders such as tremor, choreoathetosis, ataxia, and/or dystonia . Rigidity Spasticity Cogwheel or lead-pipe Clasp-knife I i Associated abnormal movements Yes No Associated weakness/paralysis No Yes Deep tendon reflex/plantar Normal Increased/ upgoing response 3. Acute general ized rigidity is often an emergent sign. I n itial treatment a i ms at maintain ing vital functions while rapidly determi n i ng the etiology. a . ABCs, vital signs, monitors, O2 b. Work-up by suspected d iagnosis: • Increased ICP/herniation: EMERGENCY. May requ i re i ntubation, hy­ perventilation, and/or mannitol . Diagnostic tests i nclude head CT /MR I . Diagnostic considerations i nclude mass lesion, i ntracranial bleed, C N S i nfection, head trauma. • Meni ngitis: EMERGENCY. Check CBC and differenti a l , electrolytes, B U N /C r, g l ucose, cu�ures, l u m ba r punctu re ( i f no evidence of i n- . creased i ntracran ial pressure) . , . Subarachnoid hemorrhage: EMERGENCY. Check C BC , platelets, PT/PTI ( I NRI. electrolytes, BUN/Cr, glucose, head CT. 242 • Neurology
    • • Neuroleptic malignant syndrome: EMERGENCY. Rule out other causes of acute rigidity, obta i n medication h istory, check tox scree n , CBC, electrolytes, glucose, BUN/Cr. • Dystonia: U RGE NT. Rule out other causes of acute rigid ity, obta i n med­ ication h istory. c. Treatment is di rected toward the underlying process.4. Chronic rigidity is more l i kely a permanent sequelae of neurolog i c in i u ry(spasticity) or a neu rodegenerative condition ( Pa rki nson s , OPCAI, or due toskeletal lim itations (ankylosing spondylitis, severe spinal osteoa rthritiS)5. Acute iatrogenic dystoniC reactions may occur in response to therapy withphenothiazines, haloperidol, an tiemetics, and other related drugs. Treatmentwith di phenhydra mine relieves the dystonia in most cases. TREMORS HAKE IT U PS ta g e f r i g h t/e moti o n a lH yp e rt hyro i d/hypo g l yc e m iaA l co h o l w i t h d rawa lK i n e s og e n i cE ss e n t i a l/fa m i l ia lI nt e n t i o nT ox i n s/d r u g s/m e d icat i o n sU n d e rl y i n g m eta b o l i c c o n d i t i o n s ( u re m ia , h e p a t i c e n c e p h a l o pat hy, W i l so n s)P a rk i n s o nsH ELP, I M SHAKINGH yp o g l yce m iaE ss e n t i a lL it h i u m/va l p roate/o t h e r m e d i c a t i o n sP a r k i n so n s NeurologV • 243
    • I ntox i c a t i o n (e . g . , sti m u l a nts)M eta b o l i c/a ste r i x i sS ta g e f r i g h t/e m oti o n a lH yp e rt hy ro i dA l c o h o l wit h d rawa lK i n e s og e n i cI nt e n t i o nN o r m a l/phys i o l o g i cG e n et i c (e . g . , W i l so n s , H u nt i ngto n s d i s e a s e )N otesTremor is defined as an involu ntary rhythm ic oscillatory movement. Asterixis is a condition cha racterized by nonrhyth m ic, episod ic loss ofm uscle tone . Max.; be confused with tremor.1 . Tremor can be d isti nguished into th ree main types based on clin ica l featu res. a. Resting tremor is typica lly a coarse, relatively slow ( 3-5 hertz) tremor thatis maxi mal when the affected area is at rest. Usually associated with forms ofparkinsonism . b. Intention tremor is a rhyth mic oscillation that becomes more pronouncedas the affected a rea approaches a target, and is a bsent or m i n i mal at rest andat the beginn ing of motion . Etiologies include all forms of cerebellar d isease. c. Postural/action tremor is a rhyth m i c tremor present when the affecteda reO is actively mainta i ned in a particular posture or during active movement,but a bsent at rest. Physiologic tremor, alcohol withd rawal, hyperthyroidism, andfamil ial essential tremor a re all good exa mples.2. Six cardinal signs of parkinsonism: resting tremor, rigid ity, bradyki nesia ,flexed postu re, loss of postural reflexes, and "freezi ng . " For a defin ite diagnosisof pa rkinsonism , at least 2 of the 6 features must be present, and at least 1 ofthe 2 must be either resting tremor or bradyki nesia.3. Pa rki nsonism may be d ivided into four maior syndromes. a. Idiopath ic: No known etiology- Pa rkinsons d isease. b. Symptomatic: Due to an identifiable insult- drug-i nduced ( phenoth iazine,ha loperidol), hyd rocephalus, hypoxic, postencepha litic, pa rathyroid dysfunc­tio n , toxic ( manga nese, ca rbon monoxide, "designer" d rugs -MPTP, cya n ide),posttraumatic, tumor, infarction . c . Parki nson-plus< Pa rki nson i a n with additional sign ifica n t sym ptoms ­Alzheimers disease, multi ple system atrophy, progressive su pran uclear pa lsy. d . Genetic: I nherited forms of parkinsonism - Hallervorden-Spatz, H u nting­tons disease, Wi lsons disease.244 • Neurology
    • 4 . I ntention tremor is characterized by i m pa i red finger-nose-fi nger and heel­ knee-shin ma neuvers. These patients often have other evidence of cerebellar dys­ fu nction , such as nystagmus a nd gait i nstabil ity U n i lateral intention tremor is suggestive of focal cerebellar disease such as i nfa rct, bleed , or tumor, and should be evaluated with MRI (CT if acute) .. 5 . Postural or action tremor is not present at rest, and, although it is brought out by motor activity, is not greatly a m plified u pon approach to a target like i nten­ tion tremor. Postural tremor may be obvious s i m ply by hold ing the arms out­ stretched . 6. Two major types of action tremor i nclude the following : a . Physiolog ic: This tremor is simply an exaggeration of a normal phenome­ non ( usually 8- 1 4 hertz) . I t is precipitated by many sti m u l i , i ncluding anxiety/fear, hyperthyroidism, caffeine, l ith i u m , va lproic acid, alcohol/drug withd rawa l , exerci se, and e n ha nced adrenergic sti m ulation ( i n c l u d i n g pheochromocytoma) . b . Familial or essential tremor: Usua l ly 4-8 hertz shaking of the hands or head, often a ble to be suppressed by a lcohol , va riable in i ntensity. If there is a fa m i ly history ( usually a utosomal dom i nant), it is considered familial tremor; if fam ily history is not evident, it is termed essential tremor; and if it man ifests only late in l ife, it is called senile tremor. 7. Drugs associated with tremor i nclude adrenerg ic d rugs (al buterol, meta pro­ terenol ) , sti m u lants ( methylphen idate , coca ine, caffei ne, a m pheta m i ne), theo­ phyl line, pred nisone, va lproic acid , and lith i u m . 8. Management of tremor depends upon the type of tremor. a . Id iopath ic parki nson ian tremor may respond to ca rbidopa/levodopa , dopa m i ne agonists ( bromocri ptine, pergolide), or anticholi nerg i cs (tri­ hexyphenidyl, benztropine) . b. SymptomatiC parkinsonism also should be managed by treating the cause ( i . e . , discontinuing offending d ru g , identifying and e l i m inating toxi n exposure, relief of hydrocephalus, etc . ) c. Severely d isabl ing d rug-resistant parkinsonian and essential tremors have been successfully treated with stereotactic thalamotomy. d . Cerebellar tremor also may be treated depending on the cause ( i . e . , re­ moval of hemorrhage, excision of tumor, etc . ) e . Essential tremor i s effectively treated with either propranolol o r prim idone. Neurology • 245
    • WEAKN ESS *M ISS GIMPM ye l opathy ( a c ute)/myo pathyI nfect i o nS tr o keS yste m i c i l l n e s sG u i l l a i n- Ba rre s y n d r o m eI atrog e n i c/d r u g sM ya st h e n iaP a ra lyt i c tox i n s/p e r i o d i c p a r a l ys i sNote: MISS GIMP emphasizes the acute causes of motor weakness.G , I M L I M P , CA N T S TA N DG u i l l a i n- B a rre syn d ro m eI atrog e n i c ( p a ra lyti c a g e n t s , a m i n og l yco s i de s , stero i d s )M yo pa thy/myos i t i sL o u G e h ri g s d i s e a s e (ALS, m ot o r n e u ro n d i s e a s e- u s u a l l y g ra d u a l )I nfect i o n ( p o l i o, botu l i s m ).M ye l o pathy ( a c u te )P e ri o d i c pa ra l ys i s , p o r p h y ri a , pa ra p rote i n e m iaC u s h i n g sA rt e r i t i s/va s c u l it i s/st ro keN eo p l a st i c ( m e n i n g it i s , p a ra n eo p l a s t i c)T ox i n s ( l e a d , a rse n i c, p u ffe rf i s h , t i ck pa ra l y s i s )* Acute/subacute, bi lateral with minimal sensory involvement246 • Neurology
    • S yste m i c i l l n e s s ( a n e m i a )T hy r o i dA dd i s o n sN e u ro m u sc u l a r j u n c t i o n d i s e a s e ( myast h e n i a ., La m b e rt-Eaton syn d ro m e )D ia betic a myotrop hyN otesWeakness is the reported symptom or demonstrable sign of decreased strengthof m uscular contractio n . The cause of wea kness m ay be at any level of themotor u n it (bra i n , spinal cord, nerve root, peripheral nerve, neuromuscular j unc­tion , or muscle). It a lso may occu r secondary to systemic or psychiatric illness.1 . Localization of weakness can be determined from only a few qual ities ofthe patients com plai nts/physical signs: sym metry, sensory i nvolve ment, a n ddeep tendon reflexes/planta r responses.Lesion Usually ProminentLocation Symmetric Sensory Loss DTRs Toes Up?Central Brain No Often ipSilateral Increased Yes to weakness (decreased acutely) Spinal Cord Maybe Yes, usually have Increased Yes sensory level (decreased acutely)Peripheral Peripheral nerve Maybe Yes Decreased No Neuromuscular Yes No Decreased No junction Muscle Yes No Decreased NoBoth Motor neuron Maybe No Increased Yes disease =DTRs deep tendon reflexesMuscle weakness due to brain lesions is discussed under "Stroke." Muscle weakness due tospinal cord lesions is discussed under "Myelopathy. " Muscle weakness due to peripheral nervelesions is discussed under "Neuropathy. "2 . Amyotrophic lateral sclerosis (ALS; also called Lou Geh rigs d isease, motorneuron d isease) is unique in that it presents with chronic, progressive weakness, Neurologv • 247
    • and on exam i nation has mixed u pper (increased tone, increased DTRs, u pgoingtoes) and lower (atrophy, fasciculations) motor neuron signs.3 . Acute/subacute weakness can be o n emergency, especially if the integ rityof the a i rway and respi ratory m uscles is comprom ised . Diag noses that meritcareful mon itoring of respi ratory function i nclude: Guillain-Barre, periodic paral­ysis, acute myelopathy (high cervical ) , and myasthen i a . Serial vital capacitiesare critical in the ma nagement of these patients.4. In general, neuropathic causes of weakness will be weaker dista lly and willhave some sensory involvement, and neurom uscu lar j u n ction and m uscularca uses of weakness will be weaker proximally a nd have no sensory i nvolve­ment. In addition, muscular causes of weakness may show elevated m uscle en­zymes (CPK, aldolase).5 . Guillain-Borre syndrome is a sing ular neuropathic couse of acute/subacuteweakness in which sensory com pla ints are not often promi nent. It is cha racter­ized by symmetric, d ista l-to-proximal, progressive motor paralysis with areflexia .Diagnosis is often mode clinically, but can be supported by delayed nerve con­duction studies. Lumbar puncture may reveal elevated CSF protein without pleo­cytosis Treatment is either plasmapheresis or i ntravenous i m m u noglobu l i n . Careful monitoring of respiratory function (by vital capacity) and autonomic function ( byvital signs) is necessary to determine when i nterventions such as i ntubation maybe req uired . Other supportive care includes aspiration precautions ( if not i ntu­bated ) , prophylaxis for deep venous thrombosis, decu bitus prophylaxis, bowel and bladder care, n utritional supplementation, and range of motion exercises to prevent contractures. 6. Myasthenia gravis can present with acute/subacute weakness and respi ra­ tory insufficiency. Typical clin ical cha racteristics i nclude waxing and wa n i n gsymmetric proximal extremity a n d bulbar (cranial nerve) weakness with n o sen­ sory loss. Diagnosis is suggested by the clinical picture, and can be supported by a positive Tensilon test (see the Ptosis section) EMG also shows a cha racter­ istic decremental response to repetitive sti mu lation . Chest i maging may demon­strate an associated thymoma . Acetylcholine receptor a ntibod ies may be detected in the seru m . Treatment acu tely i nvolves su pportive care m uch as outli ned a bove (for GUillain-Barre) with careful monitoring of vital capacity and i ntubation when nec­ essary. Plasma pheresis and a nticholi nesterase d rugs ( pyridostig m i ne , neostig­ m i ne) a re useful acutely. Thymectomy is indicated in all cases of thymic tumor, and may help i n many other cases because of non-neoplastic thymic hyperpla­ sia . Corticosteroids and other i m m u nosuppressants (azath iopri ne, cyclophos­ phamide) are used for long-term therapy. 7. Patients who undergo iatrogenic paralysis for management of a venti lator have been reported to remain para lyzed for a prolonged period of time (days to weeks) after disconti nuation of the paralytic agent, in spite of the (normally) short half-lives of these agents. The likeli hood of prolonged post-treatment paral­ ysis appears to increase with longer duration of therapeutic paralysis and with the severity of other systemic i l lnesses (especially renal fa ilure ) .248 • Neurology
    • 8 . Endocrinologic causes of weakness include the folloWing: Thyroid Thyrotoxic-grodually progressive, especially in thig hs/pelvic m uscles, normal CPK Thyrotoxic periodic paralysis - attacks of symmetric wea kness, usually with low K Thyroid ophth a l mopathy - exophtha l m os a n d wea kness of extraocu lar muscles Myasthenia gravis-associated with dysthyroidism (either hyper­ or hypo·) Hypothyroidism - diffuse myalgias, stiffness, slowed contraction, and relaxation of muscles Adrenal Addisons - genera lized weakness, fatigability, associated with electrolyte i m bala nce Cush ings - proximal weakness, also may be seen aher cortico- steroid treatment9. Systemic causes of nonspecific weakness may be secondary to a nemia,congestive heart fa ilure, malnutrition, deconditioning, cancer, etc.1 0. Several paralytic i ntoxications may lead to acute weakness and even res­pi ratory collapse. These i nclude botu lism, tick paralysis, pufferfish i ngestion, andparalytic shellfish poisoning. C l inical Conditions or Diagnoses D E M ENTIADEMENTIAD eg e n e rat iveE t h a n o l/tox i n s/d r u g s (ch ro n i c)M u I t i -i nfa rctE n d o c ri n e/m et a b o l i cN o rma l p re s s u re hyd roc e p h a l u sT u m o r/t ra u m aI nfect i o nA l z h e i m e r s Neurologv • 249
    • D E M E N TIA M I N D D egenerative ( Pa r k i n sons, P i cks) E th a n o l M u lti-i nfa rct E n docri ne (thyro i d d i sease, C u s h i n g s , Ad d iso ns) N o rmal pre s s u re hyd roce p h a l u s T u m or I nfecti on ( H I V, n e u rosyp h i l i s) A l z h e i m e r s M eta l s a n d oth e r ch ro n i c i ntoxications I nj u ry (co ntu s i o n s , chro n i c s u b d u ra l s ) N utritiona l/m eta bol i c ( 8 1 2 def i c i e n cy, Korsa koffs) D ep ress ion/psych iatric (pseudode mentia) N otes Dementia is an acquired condition characterized by chronic deterioration of i n­ tellectual function and associated with i m pa irment i n at least three of the follow­ ing areas: language, memory, visuospatial skills, personality, and cog nition . It is not associated with an acute confusional state. 1 . By defi n ition , it is not possible to make a clear diagnosis of dementia in a patient with an acute encephalopathy. Only after the encepha lopathy clears can the diagnosis of dementia be enterta ined . 2 . Sta ndard work-up for revers i ble causes of dementia i n cludes CT /MRI ( normal pressure hydrocephalus, neoplasm, m ulti-infarct), TSH ( dysthy­ roidism), VDRL/RPR ( neurosyph ilis) , B 1 2 , and folate. If the onset is su bacute or ra pidly p rog ress ive, an LP (subacute a n d chronic infections) should be strongly cons idered . 3 . Dementia must be d isti nguished from a num ber of other cond itions. a. Aphasia: This is purely an a bnormal ity of language expression/compre­ hension . With aphasia , it may be d ifficult to determine that the patient has intact memory and intellectual function. Aphasia may be a part of dementia, but by itself is suggestive of focal cerebral pathology. b. Depression/pseudodementia : Severe depression may man ifest as ex­ tremELpsychomotor retardation . Patients with pseudodementia have a primary psych iatric disorder, and the symptoms resolve upon successful treatment of this disorder. They tend to answer " I dont know" to di rect questions, and show no evidence of cortical dysfunction l i ke a phasia . This i s u s u a l ly a diag nosis of 250 • Neurology", s1
    • exclusion . It is important to realize that depression can accompany many de­ menting illnesses without being the cause of the dementia . . c . Acute confusional state/deliriu m : This is the most important disorder to distinguish from a dementia, because delirium requires urgent diagnosis and treatment of its underlying cause. Clinical features associated with delirium in-;; �Jude a waxing and waning course, abrupt onset, underlying medical disease, and hallucinations. It is possible for a demented patient to become delirious (i.e . , a patient with Alzheimers d isease develops a cystitis or pneumonia and becomes more confused), but the diagnosis of dementia cannot be made for the first time in a delirious patient. M Y E L O PAT H Y BAD STRA I N B leed/hemorrhage/a rteriovenous ma lformation A bscess, e p i d u ra l D e my� l i nating d i sease ( m u lt i p l e sclerosis) S pond ylosis/ste nosis T ra u m a R adiation A rteriat occ l u s i on/vascu l i t i s/i nfa rction I nfection N eoplasm ITS S A V I N G T H E C O R D � diopath ic roxie/iatrogenic ( i nt r athecal ch emothera py) System i c l upus e ryth ematosus Neurology • 251•
    • S po n dy l o s i s/ste n o s i s ( d e g e n e rative s p i n e d i se a s e ) A ra ch n o i d i t i s V a sc u l a r/i sch e m i a I nfe c t i o n (tra n sverse mye l it i s , syp h i l i s , Potts d i sea se/t u b e rc u l o s i s ) N utriti o n a l ( B 1 2 d ef i c i e n cy) G e n etic ( Fr i e d r e i chs a t a x i a ) T ra u ma H e m o r r h a g e/a rte r i ove n o u s m a l f o r m a t i o n E p i d u ra l a bs c e s s C o n g e n i t a l (tet h e re d c o r d , C h ia ri m a lfo r m a t i o n , s y r i n x ) O nco l o g i c ( p ri m a ry s p i n a l t u m o rs , e p i d u ra l a n d b o n y m etasta s e s , c a rc i n o m a t o u s m e n i n g it i s ) R a d i at i o n D e mye l i n a t i o n ( m u lt i p l e s c l e ro s i s ) N otes Myelopathy is any pathologic process lead ing to spinal cord dysfunction . 1 . Clinical signs of a myelopathy i nclude weakness and sensory loss below the level of spinal cord injury. 2 . Although the classic motor findings of a myelopathy are upper motor neuron signs (spasticity, hyperreflexia, upgoi ng toes), upper motor neuron signs may be absent acutely; that is, acute motor find i ngs of a myelopathy a re often a flaccid paralysis. 3 . A classic sensory finding of spi nal cord dysfunction is a sensory level, i .e . , numbness or sensory loss o n the tru n k below a certai n dermatome. This is i n­ valuable in loca l izing the segment of cord i nvolved . 4 . Remember that the spinal cord ends at L H2. If the lower extremities show upper motor neuron signs, and the u pper extrem ities a re norma l, i mage the tho­ racic and u pper lumbar spine. If all four extremities a re i nvolved , i mage the cer­ vical spine. 5 . Acute myelopathy is a neurologic emergency. I ma g i n g is u rgent in a l l cases, a n d I V methylpred n isolone should b e administered i n cases o f myelopa­ thy resulting from trauma or neoplasm . Definitive acute therapy may i nclude sur­ g ical decompression/spine stabilization and, for neoplastic disease, rad iation. 6 . It is i m porta nt to obta i n any history of trauma, back/neck pai n , pre-existing cancer, multiple sclerosis, bowel/bladder dysfunction , and previous radiation to the spine. 252 • Neurologyb
    • N E U R O PAT H Y P R I M A R I LY M O T O R A TA D L I M P A myot ro p h i c l a t e ra l s c l e ro s i s T oxi n ( h exa n e , d a p s o n e ) A nti-G M 1 a n t i b od i e s D e mye l i n a t i o n ( G u i l l a i n- B a rre, ch ro n i c i nf l a m m a t o ry d e mye l i n a t i o n p o l y n e u ropathy [ e I D P ] ) Lymphoma I nfect i o n ( po l i o , d i p h t h e r i a , h e pat i t i s , H IV) M eta l , h eavy ( l ea d ) P orphyria P R I M A R I LY S E N S O R Y G ET PAI N OR N U M B G e n et i c E n doc r i n e T ox i c P o l yc l o n a l/m o n o c l o n a l a n t i b o d i e s A my l o i d I nfect i o n N ut r i t i o n a l O cc u pati o n a l (ca r p a l t u n n e l ) Radiation Neurology • 253•
    • N e o p l a s m/pa ra n eo p l a st i c U re m i a M ed i c a t i o n B rach i a l n e u ri t i s M I X E D S E N S O R I M OT O R W EA K A N D T I N G L E W o r k-re l a te d/t ra u m a E l evated I g G ( p a r a p rote i n e m i a ) A uto i m m u n e vasc u l i t i s ( p o lya rte r i t i s , l u p u s ) K i d n ey fa i l u re/u r e m i a A l co h o l N utriti o n a l D e mye l i n a t i o n (C I D P) T ox i n ( m e rc u ry) I nfect i o n (H I V, Lym e d i s e a s e ) N e o p l a s m/pa ra n e o p la st i c G enetic L ive r d i s e a s e E n d o c r i n e ( d i a bete s , thyro i d ) N otes Neuropathy is any disorder that affects primarily peripheral nerves and is mani­ fested by symptoms of weakness or sensory d i stu rba nce or both . Some d i sor­ ders ca n mimic neuropathies by causing sim i lar symptoms, and are i ncluded i n the differential diagnoses a bove, even thoug h they involve more than just the pe­ ri pheral nerves (ALS, brachial neuritis). Paresthesia is a sensation of num bness or ting l i ng . Dysesthesia i s on uncomfortable sensation o f ti ngling, prickl i ng o r burn ing, often elicited by light ( normally nonpainful) touch . Hypesthesia/hypoesthesia is a sensation of n umbness; diminished sensation . 254 • Neurologyb ""
    • 1 . Clin ically, the diagnosis of neuropathy can be a ided greatly by categorizing the symptoms i n two ways. Fi rst, by type of neuropathic d isturbance; that is, pri­ marily sensory, m ixed sensori motor, or primarily motor. Second, categorize the neuropathy by its onset/duratio n : acute (hours/days), subacute (weeks/months), or chronic ( months/years). Categorizing N e u ropathy Sym ptoms Onset/ Type of Disturbance Duration Primarily Motor Mixed Sensorimotor Primarily Sensory Acute Guillain-Barre syndrome Arsenic Herpes zoster Poliomyelitis AI DS (Guillain-Barre-like) Neuromuscular blockade (myasthenia, drug·induced) Myopathy (periodic paralysisl Subacute Chronic inflammatory Diabetes Amyloid demyelinating AIDS Herpes zoster neuropathy Uremia Lyme disease Toxins (hexanes , lead) Alcohol-related Medication Paraproteinemia Nutritional deficiency Nutritional defi- Neuromuscular disease (e. g . , B 1 , B 1 2 , B6 ) ciency (e. g . , (myasthenia) Toxins (hexanes , arsenic) B 1 2 , B6 , E) Myopathy (polymyositis) Medications Para neoplastic Motor neuron disease Rheumatolog ic Post-radiation (ALS) Sarcoid therapy Vascular Vitamin B6 Para neoplastic toxicity Paraproteinemia Hypothyroidism Leprosy Critical illness polyneu ropathy Chronic Paraproteinemia Diabetes Amyloid Hereditary motor sensory AIDS Hereditary neuropathy Uremia sensory Neuromuscular disease Alcohol-related neuropathy (myasthenia) Nutritional deficiency Herpes zoster Myopathy (muscular (e .g. , B 1 , B 1 2 , B6) Lyme disease dystrophy) Toxins (hexanes, arsenic) Medications Motor neuron disease Medications Nutritional defi- (ALS , post-polio Rheumatolog ic ciency (e.g. , syndrome) Sarcoid B 1 2 , B6 , E) Vascular Post-radiation Para neoplastic therapy (Table continued on next page.1 Neurology . 255....
    • Categorizing Neu ropathy Sym ptoms (Con tinued)Onset/ Type of DisturbanceDuration Primarily Motor Mixed Sensorimotor Primarily SensoryCnronic Paraproteinemia (cont ) Hypothyroid ism Leprosy Hereditary motor sensory neuropathy Critical illness polyneuropathy2 . The d ifferentia l diag nosis for a primarily motor neuro pathy includes otherconditions such as motor neuron disease, neuromuscular j unction ( NMJ ) dysfunc­tion, and myopathies. Neu roanatomic local ization can be difhcult. Genera lly,the motor neuropathies cause decreased reflexes, while motor neuron d isease(ALS) has increased reflexes and u pgoing toes. Neuropathies and ALS tend tocause d ista l weakness, wh i le in NMJ diseases and myopathies, the weakness ismore proximal. C l ues for the Differe ntial Diagnosis Disorder Myopathy/NMJ Motor NeuronSigns Neuropathy Disease Disease/ALSAtrophy Yes, if chronic Yes, if chronic Yes, always chronicReflexes Hypoactive Variable HyperactivePlantar response Down Down UpDistribution of Distal Proximal, bulbar Distal, bulbar weaknessFasciculations Yes, if chronic No Yes, always chronicSensory loss Yes, sometimes No - No small3 . Acute weakness may be due to cerebral, neuropathic, neuromuscular, andmuscular d i sorders. For d i fferentia l diagnosis of genera l ized acute/subacutewea kness see Wea kness, page 246. For acute focal wea kness see Stroke,page 262 .4. Chronic weakness i n the absence of sensory complaints merits workup forNMJ d i sease, ALS, and myopathy, in add i tion to the few primary motor neu­ropath ies. Using the a bove chart, try to d isti nguish clin ica l ly where the pathol­ogy is. Workup depends on the neuroanatomic loca lization and may i ncludeEMG/NCV, cervical MRI, tensilon test, CPK, a ldolase, ESR, vita min B 1 2, and .uri ne/serum protei n electrophoresis.5 . Most nonacute neuropathies fa ll i nto the category of sensori motor or pri­marily sensory. There is a massive d iffe�ential d iagnosis for th is, and workup256 • Neurology
    • should be a i med at the most common and the most treata ble neuropathies (notnecessa rily the same) .Diagnostic Tests DiagnosisSerum gl ucose, gl ucose tolerance test Diabetic neuropathyBUN, Cr U remic neuropathyTSH Hypothyroidism , hyperthyroidismliver enzymes Hepatic diseaseVitamin B l 2 B l 2 deficiencyH IV AIDSESR, ANA, RF Polyarteritis nodosa, lupus,Urine/serum protein electrophoresis RA, etc .Anti-Hu , -Ri, -Yo; gu iac, CXR, Paraproteinemia mammogram Paraneoplastic neuropathyRPR, VDRL SyphilisLyme titers Lyme diseaseVitamin E Level Vitamin E deficiencyGrowth hormone, pituita ry CT/MRI Acromegalic neuropathy Be careful with the shotgun a pproach ! Dont order every test at once! Decideclinically which diagnoses are likely and test for those first. If no diagnosis is madeand symptoms persist or worsen , conti nue the workup methodically. Also, don tforget to look for risk factors for neuropathies (e. g . , alcohol, toxin exposure, familyhistory, known malignancy, medications, known medical condition, IV drug use) .6. Specific treatment of neuropathies is a imed at the underlying cause. I n addi­tion , symptomatic ,elief may be helpful in cases of painful neuropathy. Here a resome suggested medications and their uses: Amitri ptyl ine, other TCAs Chronic pa i nful neu ropathies ( low-medium dose) Gabapentin Pai nful neuropathies, diabetic, post-zoster Capsa icin (topical) Diabetic, post-zoster Phenytoin, carbamazepine Trigem inal neuralgia Aspirin, ibuprofen, naproxen General nonnarcotic anti-inflam matories Codeine, oxycodone General na rcotic analgesics7. In add ition to pharmacologic i ntervention, general supportive care may bebeneficial, includ i n g : physica l thera py, range of motion exerc ises, padd i n g ,skin care, orthotics, safety awareness.8. Med ications known to cause neuropathy include:Drug Type of Neuropathy CommentsIsoniazid Initially sensory, then m ixed Treat concomitantly with B6Eth ionam ide Similar to isoniazidHydralazine Simila r to isoniazidN itrofu rantoin I n itially sensory, then mixed Especially in urem icsDisulfiram I n itia lly sensory, then mixedVincristine I n itia lly sensory or m ixed Dose relatedC i:,platin Primarily sensory Especially proprio­ ception/vibration (Table continued an next page) Neurology • 257
    • Drug Type of Neuropathy CommentsChloramphenicol Mild sensory Associated with optic neuropathyPhenytoin Mild m ixed sensorimotor Associated with chronic (years) useMetron idazole Similar to phenytoin Associated with chronic (years) useAmitriptyline Similar to phenytoin Associated with chronic (years) useDapsone Primarily motorAmiodarone Mixed sensori motor 5% of patients aher monthsNeuromuscular Primarily motor Prolonged ventilation/ICU blockersL-tryptophan Mixed sensorimotor Associated with impurities, results in eosinophi lia- myalgia syndrome9. Focal neuropath ies, rather tha n a general problem with a l l peri phera lnerves, i nvolve individual peripheral nerves a nd ohen are caused by local com­pression . Common syndromes include: a. Carpal tunnel syndrome Clinical : pa in/numbness in digits 1 -4, worseat n ight, ra re weakness, positive Tinels a nd/or Phalens sign. Location: wrist.Diagnosis: NCY slow through carpa l tunnel; risk factors are repetitive motion,rheumatoid arthritis, acromega ly, hypothyroidism, a myloid. Treat: anti-inflamma­tory drugs, wrist spli nts, proper adi ustment of workstation/posture. Surgery issometi mes necessary. b . Ulnar neuropathy Clinica l : pai n/numbness in digits 4-5, hand weak­ness, claw-ha nd deformity. Diagnosis: NCY slOw along course of ulnar.Locations: several, especially elbow. Treat: symptomatic, surgery to relievecompression. c . Radial neuropathy Clinical : wrist drop, i mpa ired sensation on back ofhand . Location: axilla or upper arm. Diagnosis: NCY; causes include crutch inaxi lla, arm over back of chair or edge of bed ("Saturday N ight Pals/I, humeralfracture, lead toxicity. Treat: underlying cause. d . Meralgia paresthetica C l inical lateral thigh pa in/num bness, purelysensory. Location : i nguinal ligament. Diagnosis: clinica l; risk factors are obe­sity, pregnancy, diabetes, tig ht/heavy workbelt/ha rness, backpacking. Treat:relieve compression . Benign. e. Peroneal palsy Cli n ica l : weak dorsiflexion of foot, top of foot n u m b­ness, often weak fool--eversion . Location: head of fibula. Diagnosis : clin ica l ,NCY; risk factors a re plaster cast, prolonged leg crossing while seated, tightknee boots, emaciation, fibula fracture, diabetes. Treat: underlying cause.258 • Neurology J
    • SEIZURE BITE TO N G U E B l eed/h e m o rr h a g e I nfect i o n T ra u m a E t h a n o l/d rug s/toxi n s T u mor O xyge n l ack/i sch e m i a/hypoxia N o n c o m p l i a n ce ( s u bt h e ra p e u t i c m ed s ) G l u cose l ack/hypog lyc e m ia U re m i a/meta b o l i c E c l a m ps i a I CO NVU LS E B I G TI M E I nfec t i o n C oca i n e/d ru g s O xyg e n l a ck/i s ch e m i a/hypox i a N eoplasm Vascular ma lformatio n U re m ia L ytes (hypo N a , hypo M g , hypoCa) S i n u s t h ro m b o s i s E th a n o l w i t h d rawa l B l eed/h e m o r r h a g e I d i opath i c G l u cose l a ck/hypo g l yce m i a T ra u m a I n bo r n e rro r o f m eta b o l i s m M ed i cat i o n s (too m u ch , too l i tt l e ) E c l a m ps i a Neurology • 2591
    • N otes A seizure is a clin ical man ifestation of excessive, a bnormal synchronous activity of neu rons in the cerebral cortex. It is usua l ly transient, and man ifestations in­ clude alterations of consciousness, involuntary movements, sudden loss of motor tone, and sensory disturba nces (especially olfactory or g ustatory) . Epilepsy is a term reserved for chronic, recurrent seizures . A single seizure does not make a diagnosis of epilepsy. 1 . The description of the seizure is helpful in diagnosis and treatment. A good description of a seizure includes any premonitory symptoms reported by the pa­ tient, any foca l motor activity noted during the seizure, whether the motor activity was rhyth mic and synchronous, the presence and d i rection of eye deviation, res­ pi ratory pattern, whether the patient was a ble to respond to verbal sti m u l us, whether the patient bit h is/her tongue or experienced i ncontinence, and the presence and duration of post-ictal confusion . 2 . Major types of seizures: a. Absence - sta ring, blinking, very brief, preci pitated by hyperventilation , onset in chi ldhood , no post-ictal confusion . b . General ized ton ic-clon ic - a l l fou r extremities stiffen i n itially (ton ic!, then undergo rhyth m i c contraction and relaxation (clon ic); post-ictal confusion is a lways present (to some degree) ; may be assoc iated with cya nosis, tongue biti ng, and incontinence. May often start as a focal/partial seizure and be sec­ ondarily generalized, particularly in adults. c. Simple partial- may be motor (focal motor twitching) or sensory (foca l sen­ sory disturbance!, with no alteration i n level of consciousness during episode, no post-ictal confusion . May secondarily become generalized tonic-clonic. d. Complex partial - a lteration in consciousness, automatisms (lip-smacki ng, eye blinking, swallowi ng, picking at clothes!, preceded by aura (unusual smell, taste). May secondarily become generalized tonic-clonic. 3 . Treatment by seizure type a . Treatment of a bsence seizure is primarily with ethosuximide or valproic acid . b. Treatment of primarily generalized seizures is usually with valproic acid . c . Treai ment of seconda rily general ized seizures is pri m a ri ly with ca rba­, mazepine, phenytoin, or valproic acid . d . Treatment of partial seizures (simple or complex) is pri mari ly with carba­ . mazepine, phenytoin , or valproic acid .I Other med ications used to treat epilepsy i nclude ch lorazepate, clon- azepa m , felbamate, gaba penti n , phenoba rbita l , prim idone, tiagabine, topira­ mate, and lamotrigine. 4 . It is i m porta nt to d i stinguish between seizure, syncope, and psychogenic seizure/ pseudoseizures. a. Syncope is typically preceded by a lightheadedness, p recipitated by pos­I I tural change, results in a fa ll/colla pse with loss of consciousness lasti ng only1 260 • Neurology
    • seconds, and has no post-ictal confusion . Occasionally, a few myoclonic twilches may accompany syncope. Syncope is usually preci pitated by a vasovagal re­action, but is also associated with arrhyth mia, orthostatic hypotension, low car­diac output, and aortic valve disease. See the Loss of Consciousness section . b. A generalized tonic-clonic seizure may also present with a fal l/collapse,but is associated with grunting or apnea, occasional cyanosis, tonic then clon icmotor activity, sometimes tongue-biting and inconti nence, and a lways post-ictalconfusion (usually lasti ng 5 m i n utes or longer) . The d uration of a general izedseizure is usua lly longer than a syncopal event, lasting seconds to minutes. c . Pseudoseizures may be d ifficult to d isti ngu ish from epi lepti c seizures;indeed , the two disorders frequently overlap. I n genera l , pseudoseizures occurin the presence of observers, are not stereotypic, have no post-ictal confusion ,a n d a re not associated with self-in j u rious activity l i ke fa l l i n g or tongue-biting.Motor activity incl udes com pletely asynchronous limb movements, strugglingagai nst restra ints or resisting eye open ing, and repeated side-to-side head m ove­ments . None of these is d iagnostic, but carefu l observation helps avoid placingthese patients on anticonvulsants or increasing dosages unnecessarily. 5 . The most common couse of a seizure in a patient with a known seizure dis­order is subtheropeutic medication. This may be d ue to noncompliance (due toside effects or lack of understanding) or increased dosing requ i rements.6, I ndications for neuroimaging studies: a. New focal-onset seizure or seizure with residual focal neurologic deficit b. Status epilepticus of unknown etiology c. New-onset seizure ( uncerta i n focalityJ without known precipitant d. Any second seizure (except typical a bsence) not preViously i maged .I t is not necessary to re-i mage a patient with a known seizure disorder after atypical seizure (see number 5 above). It is not necessary to i mage a child withtypical a bsence seizures.7. Indications for lumbar puncture: a . Status epilepticus of unknown etiology b. Patients u nder suspicion for suba rachnoid hemorrhage c. Patients u nder suspicion for CNS infection ( mening itis, encephalitis) 8. For seizures secondary to alcohol withdrawal and meta bolic abnormalities,a nticonvulsants are always second-l i ne treatment; first-l ine treatment is d irectedat the u nderlying process ( i .e. , treat withdrawa l , correct electrolyte a bnormal i­ties, correct hypoglycemia , etc . ) 9. Generalized convulsive status epilepticus means contin uous general ized convulsions or repeated generalized convulsions without full recovery of mental status between seizures for a period lasti ng g reater than 30 minutes. Protocol for treatment (Note: Items 1 -4 are generally done nearly simultaneously) 1 . Carefully observe seizure activity. ABCs. Supplemental O2 if necessary. 2 . IV l i n e with norma l sal i ne. Send blood for CBC, electrolytes , BUN , Ca , Mg , glucose, anticonvulsant levels. .Send ABG. Send U/ A, con- sider tox screen . ECG monitoring. 3 . Accucheck, then 1 00 mg thiamine , then 50 ml of 50% dextrose solu­ tion if ind icated. Neurology . 26 1
    • 4. Lorazepam 2 mg IV. Do not exceed 2 mg/m i n . May repeat up to 0 . 1 mg/kg . Call neurologist. 5. Phenytoin (Fosphenytoin) 20 mg(pEl/kg IV. When using phenytoin, do not exceed 5 0 mg/m i n . When using Fosphenyto i n , do not exceed 1 50 PE (phenytoi n-equivalents)/m i n . Monitor ECG, respi ra­ tion and blood pressu re. 6. Phenytoin ( Fosphenyto i n ) 5- 1 0 mg(PE)/kg IV. Max i m u m rates per minute as descri bed a bove . Maximum dose 30 mg(PE)/kg . 7. Consider intubation if not already i ntubated . 8 . Phenobarbital 20 mg/kg IV. Do not exceed 1 00 mg/m in. 9. Consider barbiturate coma (in consultation with neurologist) . 1 0. Common drugs having interactions with anticonvulsants include erythromycin, H2 blockers, isoniazid, methylphenidate, phenoth iazines, warfarin, oral contra­ ceptives, and other anticonvulsants. Drug interactions may result in increased or decr.eased a nticonvulsant levels or altered efficacy of the concomitantly adminis­ tered drug . In general, newer anticonvulsants have fewer drug-drug interactions. 1 1 . A rough clinica l gU ide to phenytoin levels: 0- 1 0 No nystagmus Above 1 0: Gaze-evoked nystagmus . Above 20: Ga it ataxia Above 30: limb ataxia Above 40: Stupor/confusion STR O KE SAV E D B RA I N 5 u bsta n c e a b u se/d r u g s/m e d i ca t i o n s A lte red c oa g u l a t i o n/hype rc oa g u l a b i l ity V a sc u l i t i s E mboli i D i ss e ct i o n : B l ee d/h e m o rr h a g e/AVM R a re c a u ses ( e . g . , m ig ra i n e , i a t ro g e n i c ) A t h e roth rom b o s i s I nfect i o n s N eo p l a s m 262 • Neurologyb
    • D EA D H EA D S D ru gs/m e d i c a t i o n s E l evated b l ood p res s u re A rt e r i t i s/va s c u l it i s D ecreased p e rf u s i o n ( c a rd i a c a rrest, hypote n s i o n ) H e m o rrha g e o r H ypercoag u l a b i l ity E mbolism A t h e ro sc l e ro s i s D i s s e ct i o n S pa s m ( m i g ra i n e) Note: "DEAD HEADS" emphasizes the vascular causes o f stroke. C VA S , D O I C T T H E M ? C oca i n e/d rugs V a s c u l i t i s/c o l l a g e n va s c u l a r d is e a s e A t h e roth ro m bos i s S yp h i l i s , t e rt i a ry/m e n i n g ova s c u l a r D is s ecti o n/dys p l a s i a (fi b ro m u s c u l a r) O ra l c o ntraceptives I ntra c ra n i a l b l e e d ( a n e u rys m , AVM ) C a ncer T h ro m b o s i s , s i n u s T ra u m a/h e r n i a t i o n H e ma to l og i c * /hyp e rcoa g u la b l e * * E m b o l i c ( i n c l u d i n g pa ra doxi ca l ) M ig ra i n e Neurology • 263•
    • DO SAVE T H E M B RA I N SD i s s e ct i o n/dys p l a s i a (fi b ro m u s c u l a r)O ra l c o n t ra c e pt ivesS i n u s t h ro m b o s i s , ve n o u sA t h e roth r o m b o s i sV a s c u l i t i s/co l l a g e n va s c u l a r d i s e a s eE m b o l i s m ( i n c l u d i n g pa ra d ox i ca l )T ra u m a/h e r n i a t i o nH e m a to l o g i c * /hypercoa g u l a b l e * *E xog e n o u s toxi n s/d r u g s ( e . g . , coca i n e )M igraineB l e e d/AVM/a n e u rysmR a diationA ng i og ra p hyI nfect i o n s ( n e u rosyp h i l i s , m e n i n g i t i s )N eo p l a s t i c ( b l e e d , m e n i n g it i s )S yst e m i c hypote n s i o n/s h ock *Thrombocytosis, polycythemio, sickle cell anemia* * Protein C deficiency or resistance, protein S deficiency, ontithrombin III deficiency, malig­nancy, onticordolipin antibody syndrome, factor V deficiency, homocystinuriaN otesStroke refers to the sudden onset of a focal neurologic deficit that does not re­solve. The etiology of a stroke is generally vascular, either hemorrhagic or is­chemic. The vascular event may be precipitated by a d ifferent underlying cause( infection, tumor, hereditary condition) . Transient ischemic attack (TIA) refers to the sudden onset o f a focal neuro­logic deficit that resolves in 24 hours or less. Reversible ischemic neurolog ic deficit (RIND) is a neurolog ic deficit thatlasts longer than 1 day and less than 3 weeks; essentially, a mild stroke . Hemiparesis refers to a weakness on one side of the body. Hemiplegiarefers to paralysis of one side of the body. Astereognosis is the inability to identify obiects by touch only. Agraphesthesio is the inabil ity to identify letters/numbers traced on the skinwithout visual cues.264 • Neurology cd
    • 1 . Types of stroke a . Hemorrhagic- refers to focal bleed i n g , usually i nto bra i n parenchyma .Associated with acute hypertens ion , coagu lopathy, amyloid angiopathy, occa­sionally trauma. b . T h romboti c - refers to g radual occl usion of cerebral a rteries by localplaques/thrombi Associated with longstanding hypertension, diabetes, athero­sclerosis. • Small vessel/ l acu n a r - occ lusion of m icrovessels, typica l ly in deep gray matter and/or brai nstem . - • Large vessel throm b osi s m ay not hea r carotid bruit with a low-g rade or a very high-grade stenosis. c. Embolic- refers to a sudden occlusion of cerebral arteries by blood clotsthat origi nate elsewhere in the vascular system May be a rtery-to-artery (carotidto middle cerebra l , aortic to carotid or vertebrobasilar), cardiogen ic ( heart tobra i n ) , or pa radoxical (venous system through atri a l septa l defect to a rterialsystem to bra i n ) . Associated with cardiac arrhyth m ias (especially atrial fibril la­tion) , right to left shunts, valvular heart d isease.2 . Hemorrhagic strokes can effectively be diag nosed by a noncontrast headCT. Presentation is usually that of a very a brupt onset of neurologic deficit whichmay not fit wel l i nto the vascular patterns descri bed below. Very la rge hemor­rhagic strokes in the cerebrum could result in decreased mental status secondaryto herniation; posterior fossa hemorrhages may lead to a very rapid decrease inlevel of consciousness. Etiology is most often hypertension . Treatment consists of gentle control ofextreme hypertension, su pportive care, and occasionally (especially in posteriorfossa/cerebel lar bleeds) surgical evacuation . Anticoagu lation is contra i ndi­cated . Prognosis for functional recovery after hemorrhagic strokes is usua l lybetter than after ischemic ( i e , th rombotic or embolic) infarcts.3 . Several stroke syndromes have been descri bed as lacu nar/small vesselthrombosis; that is, i nvolving small i nfa rcts as a result of occlusion of tiny pene­trating vessels . These presentations i nclude the following clin ical syndromes: a. Pure hemisensory deficit (contralateral to a thalamic infarct) b. Pure hemiparesis (contralateral to an i nternal capsule infarct) c. Clumsy hand-dysarthria (multiple localizations) d. Ataxia/hemiparesis (both contralateral to a pontine infarct)Onset of symptoms may be stuttering, stepwise deterioration or may be one ofg radually worsening TIAs . The typical d istri bution of a hem isensory deficit i n­volves the face, arm.., and leg equally, because the sensory fi bers a re closelycompact in the tha lamus, so even a small ischemic lesion will l i kely affect a l l . likewise for pure hemiparesis, which shou ld · be relatively equal i n the face,a rm , and leg, as the corticospinal fi bers a re crowded closely in the i nterna lcapsule Etiology is most likely chron ic hypertensive damage to small penetrating ves­sels. Treatment acutely consi sts of avoiding hypotensio n , using a nti plateletagents, and supportive care. Long-term treatment i nvolves dimi n ishing risk factors such as smoki ng, hypertension , hyperli pidemia, and diabetes. Anticoagulation Neurology • 265
    • is unproven . Tissue plasmi nogen activator (TPA) may be beneficial within the first3 hours.4. Large vessel thrombosis may present with gradua lly worsening (crescendo)TIAs or an a brupt onset of symptoms Usually symptoms occur in a vascular d istri­bution as descri bed below. Carotid occlusion may presen t with o n ly m iddlecerebral a rtery infarction (due to collateral flow to the i psilateral anterior cere­bral from the anterior com m u n icating a rtery ) . Etiology is usually an atheroscle­rotic plaque with loca l t h rom bus formation. Treatment acutely i ncludes TPA,avoiding hypotension , and supportive care . Ca rotid enda rterectomy is i nd i­cated for symptomatic stenosis of 70% or g reater, often i n the setting of TIAs .E mergent carotid enda rterectomy is u n proven . Anticoagulation is u n p roven .Ca rotid endarterectomy in the setting of com plete carotid occlusion is genera l lynat ind icated .5 . Embolism classically presents with an a brupt neurolog ical deficit that is max­imal at onset. Symptoms occur in a vascu lar d istribution as described below.The hemipa resis of m iddle cerebral artery (MCA) occlusion d iffers from that oflacuna r d isease in that MCA infarction causes hemiparesis that is greater inthe face and arm than the leg a n d is usually associated with hemisensory lossin a s i m i lar d istribution . Etiology is by occlusion of an a rtery by a blood clotfrom either another artery (e . g . , carotid to middle cerebra l ) , the heart (ca rd io­genic), or the venous system via a right to left shunt ( pa radoxica l ) . Treatmentacutely may involve TPA, followed by a nticoagulation , especially in cases ofatrial fibri llation and small cerebral infarcts. Acute anticoagulation in the settingof a very large cerebral infarction has an i ncreased risk of precipitating hemor­rhagic transformation .6 . Local ization of large vessel disease (thrombotic or embolic) a. Specific signs/symptoms • Anterior ( i . e . , carotid Monocular visual loss Hemi neglect artery) Agraphesthesia Aphasia Visua l-spatial deficits Astereognosis • Posterior ( i . e . , vertebral Di plopia Nystagmus basi lar arteries) Ataxia Bi lateral sig ns/ Vertigo symptoms Face signs/symptoms Vom iting opposite arm/leg signs/symptoms • Either Hemiparesis Hemisensory loss . Dysa rthria Visual field cut (u sually PCA, but may be present with large MCA i nfarctions) b. Vascular syndromes • Anterior cerebral artery Contralateral Leg weakness > face/ar� I ncontinence266 • Neurology
    • .. • Middle cerebral artery Contralateral Face/ arm weakness > leg Hem isensory deficit Hemia nopsia • Posterior cerebral artery Contralateral Hemianopsia Mild hemiparesis Hemisensory deficit • Vertebral basilar arteries Contralateral Hemi pa resis Ipsi lateral Hemisensory deficit May be bi lateral C ranial nerve palsy Possibly hemiataxia 7. Standard workup for stroke includes a head CT (hemorrhage!, CBC (throm­ bocytosis, polycythemia!, glucose (diabetes!, and lipids (hyperlipidem ia). Other blood tests which may be usefu l include PT/PTI (coagulopathy, inadequate a n­ ticoag u lation ! , ESR (vascul itis), and VDRL/RPR ( neu rosyph ilis). Carotid d uplex should be done in cases of anterior circu lation strokes and TIAs . Tra nscranial Doppler is helpful in eva l uation of posterior circulation (vertebrobasi la r insuffi­ ciency). Echocardiography is performed to rule out valvular lesions and atrial or ventricular thrombi in patients suspected of having an embolic infa rct. Magnetic resonance angiography is a noni nvasive method of visua lizing all of the cranial vasculature (a nterior and poste rior circulation!, and the resolution of MRA has greatly improved over the last few years. 8 . In young patients « 45 years old) or patients with no clear etiology, the work-u p for stroke/cerebral infarction can be m uch more extensive and may in­ clude protein C, protein S, anticard iol i pin a nti body, antithrom bin I I I , factor V, and homocysteine (hypercoagulable states!, angiography (arterial dissection, fi­ bromuscular dysplasia, aneurysm!, MRI (tumor, AVM!, u rine drug screen (coca ine, amphetamines!, LP (i nfection, inflammation/vasculitis!, and transesophageal echo with bubble study (atrial septal defect with paradoxical embolism). 9 . Recently, the use of TPA has been recommended i n acute stroke . Consider it in patients who present to med ical care within 3 hours of onset of neurological sym ptoms, have sign ificant n eu rologic deficits, and have no evidence of in­ tracranial hemorrhage. Neu ro logy G lossary Agraphesthesia is the inability to identify letters/numbers traced on the skin with­ out visual cues Akathisia descri bes an involuntary restlessness a nd inability to sit still. Altered mental status refers to any acute or subacute change in the level of con­ sciousness, ra n g i ng from m i ld confusion to deep coma . Synonymous with Neurology • 267+
    • 1 delirium . Chronic problems such as dementia or menta l retardation a re not considered in th is category.Amaurosis fugax is the subjective com plaint of transient visua l loss in one eye, oMen descri bed as a veil or shade coming over the eyeAstereognosis is the inabil ity to identify objects by touch only.Asterixis is a cond ition cha racterized by nonrhythmic, episodic loss of m uscle tone. May be confused with tremor.Ataxia is the subjective complaint or objective find ing of impaired coord ination, usua lly manifested as an i m pa irment of gait or dexterity in the a bsence of sig­ n ificant muscular weakness.Autonomic disorgers constitute a wide range of neurologic derangements which may man ifest prima rily through symptoms of autonomic dysfu nction, including but not l i mited to orthostatic hypotension/syncope, card iac arrhythmias, a l­ tered lacri mation , i m pa i red temperature regulation , dia phoresis/a nhidrosis, sexual dysfunction, and bowel/bladder problems.AVM is the acronym for a rteriovenous ma lformation ; on a bnormal ta ngle of blood vessels that can develop in the central nervous system.Choreoathetosis is an i nvolu ntary movement disorder characterized by ra pid, jerky, dancing-l i ke movements (cho rea ) associated with or superi m posed upon writhing, flowing, continuous movements (athetosis).Clonus is an a brupt, unidirectional series of muscular contractions i n response to a sudden stretch . Also used to describe repetitive, rhyth m i c muscle contrac­ . tions seen i n some types of seizures.Cogwheeling is a form of rigidity cha racterized by rhyth m i c , rachet-l ike resis­ tance throughout the range of motion.CT is the acronym for computed tomography, a diagnostic neuroimaging test.CVA is the acronym for cerebrovascu lar accident; refers to any acute cere­ brovascular pathology, generally ischemia or hemorrhage .Dementia is an acquired condition characterized by chronic deterioration of i n­ tellectual function and associated with i m pairment in at least three of the fol­ lowing a reas : language, memory, visuospatial ski lls, personality, and cogn ition . I t is not associated with on acute confusional state.Diplopia is the subjective symptom of double vision .Dizziness is a symptom with many meani ngs, but particularly used by patients to refer to feelings of fa intness/lig htheadedness, vertigo, a nd/or unsteadi­ ness/d isequili bri u m .Dysconjugate gaze i s the objective exa m i nation finding of eye misalign ment, which may or may not be associated with symptoms of d i plopia .Dysdiadochokinesis is on i m pai rment of the ability to perform rapid alternating movements.Dysesthesia is an uncomforta ble sensation of ting l i n g , prickling, or burn i n g , often elicited by l ight (normally nonpa inful) touch .Dyskinesia is o n a bnorm a l i ty o f movement. T h i s usua l ly refers t o excessive motor activity ( L-dopa- i nd uced dyskinesias, tard ive dysk i nesia ) , but a lso may reflect a severe general ized slowing of move ment ( pa rki nson i a n bradykinesia).268 • Neurology ".
    • T ..I Dysmetria is impa i rment i n the normal acceleration and deceleration of d irected movements. Usually eva luated by finger-nose-finger and heel-knee-shin tests . Dystonia is a condition of i m pa i red muscle tone, which usua l ly is i ncreased , persistent, and at an extreme of the range of motion for the affected area . EMG is the acronym for electromyogra m , a d iagnostic test that exa m i nes the electrical properties of m uscle tissue (analogous to the electrocard iog ram for the heart) Epilepsy is a term reserved for chronic recurrent seizures. A single seizure does not make a diagnosis of epilepsy. Gegenhalten descri bes an inability to relax muscles subjected to passive move­ ment. On exa m i nation, it feels as if patient is resisting the exam iners motions. Headache is a genera l term used to describe any pai nful sensation i nvolvi ng the structu res of the cranium-, face, and/or neck. Hemiparesis refers to wea kness/pa rtial paralysis on one side of the body. Hemiplegia refers to com plete paralysis of one side of the body. Hypesthesia is a sensation of n u m bness; d i m i n ished sensation . Synonymous with hypoesthesia I n}ention tremor is an exaggerated oscil lation of a l i m b most pronounced as it is approaching a target, and essentially absent at rest or at the beginning of a movement. I ntention tremor is a man ifestation of dysmetria . . Lead-pipe is a form of rigidity characterized by uniform resistance throughout the range of motion . LP refers to lumba r puncture; also known as a spinal ta p. Monocular visuai loss is either a subjective report of transient visual loss i n one eye (as opposed to one visual field) or an objective find ing of decreased visual acu ity in one eye MRI is the acronym for mag netic resonance i maging, Q diag nostic neuroi mag­ ing test with higher resolution than CT, but which takes longer and is gener­ al ly more expensive Myelopathy is any pathologic process lead ing to spinal cord dysfunction. Myoclonus refers to a sudden, nonrhyth mic contraction or spasm of a m uscle or g roup of muscles . Contractions genera lly a re u n i d i rectional, asynchronous, and asymmetric. Nerve conduction study is a diag nostic test that looks at the electrical function of peripheral nerves and roots . Neuropathy is any d isorder which affects primarily peri phera l nerves a nd is manifested by symptoms of weakness or sensory d isturbance or both . Paresthesia is a sensation of n u mbness or ti ngling. Ptosis is a physical finding of one palpebral fissure being smaller than the other, i e , a drooping eyel id . Reversible ischemic neurolog ic deficit (RIND) is a neurologic deficit that lasts longer than 1 day and less than 3 weeks; essential ly, a m i ld stroke. Rigidity is a continuous or i nterm ittent increase in muscle tone throughout the full -ra nge of passive movement. Seizure is a clinical manifestation of excessive, abnormal , synchronous activity of neurons in the cerebra l cortex . It usually is transient, and manifestations Neurologv • 269
    • i nclude alterations of consciousness, i nvolu ntary movements, sudden loss of motor tone, and sensory disturbances (especially olfactory or gustatory) .Spasticity is an increase in m uscle tone that is m i ld with slow movement and more pronounced with rapid movement. Classically, rapid passive movement is met with i ncreasing resistance u ntil a point at which the resistance breaks (clasp knife phenomenon).Stroke refers to the sudden onset of a focal neurolog ic deficit that does not re­ solve. The etiology of a stroke generally is vascular, either hemorrhagic or is­ chem ic. The vascular event may be precipitated by a d i fferent underlying cause (e . g . , infection, tumor, hereditary condition).Syncope is defined as a tra nsient loss of consciousness and postural tone due to i m pai red cerebral blood flow. Synonymous with fa inting.Tics a re stereotypic, invol unta ry, repetitive spasmod ic muscular contractions. Typically a ble to be suppressed briefly, o n ly to brea k out with increased severity. Often a ppear purposeful or sem i purposeful .Titubation i s a moderate-frequency head tremor, usua lly antero-posterior.Torticollis is a form of focal dystonia involving persistent contraction of cervical muscles, leading to a head . tilt.Transient ischemic attack (TIA) refers to the sudden onset of a focal neurologic deficit that resolves in 24 hours or less.Tremor is defined as an i nvolunta ry, rhythmic, oscillatory movement.Weakness is the reported symptom or demonstrable sign of decreased strength - of m uscular contraction.270 • Neurology
    • Em A p PENDIX Ac ronym Dictiona ryABG Arterial blood gasALS Amyotrophic lateral sclerosisANA Anti n uclear antibodyARDS Ad ult respi ratory d istress syndromeATN Acute tubular necrosisAVM Arteriovenous ma lformationAVP Arg i n i ne vasopressi n BOOP Bronchiol itis obl itera ns-org a n izing pneumon iaBUN B lood u rea nitrogenClDP C h ronic id iopath ic polyradiculopathyCOPD C h ronic obstructive pulmonary d i seaseCPK Creati ne phosphoki naseCVA Cerebrovascu lar accidentCXR Chest x-rayDDX Differential d iagnosisDKA Diabetic ketoacidosisDVT Deep vei n throm bos isECG Electroca rd iogramEEG E lectroencepha log ra mESR E ryth rocyte sed i mentation rateGERD Gastroesophageal reflux d iseaseGVH D Graft versus host d i seaseITP Id iopath ic th rom bocytopen ic purpuraIVF I ntervertebral fora menLAM Left atrial myxomaLP Lumbar punctureMCA Middle cerebral arteryMCV Mean cell volume Appendix . 2 7 1
    • MI Myocard i a l i n fa rctionMS Multiple sclerosisNCV Nerve cond uction velocityPCA Posterior cerebra l a rteryPIE Postinfectious encepha lomyel itisPT Prothrombin timePTI Pa rtia l thromboplastin timeRDW Red blood cell d i stribution width i ndexRPR Rapid plasma rea g i nSIADH Syndrome o f i n a ppropriate secretion o f anti d i u retic hormoneSLE System ic lupus erythematosusTIA Tra nsient ischem ic attackTPN Tota l pa renteral n utritionTSH Thyroid-sti m u lati ng hormoneVDRL Venera l disease research la boratoryVOD Veno-occlusive d isease272 • Appendix
    • DI FFERENTIAL D IAG NOS I S M N EM O N ICS is a memory aidto help you form comprehensive d ifferential d iagnoses forcommon i nternal medicine and neu rology problems. Clever,often witty m nemon ics allow you to organize diagnosticpossibilities quickly and effectively for a wide va riety of clinicalscenarios. The method succeeds because each m nemonicprovides you with a framework on which to construct thed ifferential .This book assures that you r eva l uations w i l l b e thorough , andd iagnoses will not be m issed!For More Memory Aids . . . ® The SECRETS SER I ES has been extraordi na ri ly popular,and the distinctive approach has given birth to a wide rangeof books i n the major medical specialties and subspecia lties.Questions and short a nswers as wel l as an i nformal tone a reemployed to make the text enjoya ble as well as usefu l . Thel ist is constantly changi ng and expan d i ng. H ere a re a few ofthe more than 50 titles: CARD I O LOGY SECRETS, 2/e CRITICAL CAR E SECRETS, 2/e EN DOCR I N E SEC R ETS, 2/e GI/LiVER SECRETS HEMATOLO /ON CO LOG SECR ET , 2/e GY Y S I N FECTIOUS DISEAS E S EC R ETS N EP H RO LOGY SECR ETS N E U ROLOGY SECRETS N E U ROSCI ENCE SECR ETS P ULMONARY/RES P I RATO RY CAR E S ECRETS R H EU MATOLOGY SECR ETS S U RGICAL SECRETS , 4/e Hanley & Belfus, Inc. , Medical Publishers 2 1 0 South 1 3th Street Philadelphia , Pennsylvan i a www.hanleyand belfu$.com