NMS Medicine

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ABC Ambe r CHM Conve rte r Tria l ve rsion, http://w w w .proce sste x t.com/a bcchm.html

Editors: Wolfsthal, Susan T itle: NMS Medicine, 6th Edition Copyri ght Â©2008 Li ppi ncot t W i l l i ams & W i l ki ns > Front of Book > Edit ors

Editor

Susan Wolfsthal MD Cel es t e L. W oodward Profes s or i n Humani t ari an and Et hi cal Medi cal Pract i ce; As s oci at e Chai r for Educat i on; Res i dency Program Di rect or, Int ernal Medi ci ne Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and

Contributors to the Sixth Edition Pamela J. Amelung MD As s i s t ant Profes s or Depart ment of Medi c i ne, Di vi s i on of Pul monary and Cri t i c al Care Medi c i ne, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Yanis Bellil MD Chi ef Res i dent 2007â€“2008; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and R. Michael Benitez MD As s oci at e Profes s or Depart ment of Medi c i ne, Di vi s i on of Cardi ol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Sonia E. Blome MD Chi ef Res i dent 2007â€“2008; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Mary E. Bollinger DO As s oci at e Profes s or Depart ment of Pedi at ri c s , Di vi s i on of Pedi at ri c Pul monol ogy and Al l ergy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Marc F. Brazie MD Res i dent Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er,

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Bal t i more, Maryl and Jennifer Zahn Cooper MD As s i s t ant Profes s or Depart ment of Dermat ol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Raymond H. Flores MD As s oci at e Profes s or Depart ment of Medi c i ne, Di vi s i on of Rheumat ol ogy and Cl i ni c al I mmunol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Evonne G. Fontanilla MD Chi ef Res i dent 2006â€“2007; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Bruce D. Greenwald MD As s oci at e Profes s or Depart ment of Medi c i ne, Di vi s i on of Gas t roent erol ogy and Hepat ol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Donna S. Hanes MD, FACP As s oci at e Profes s or Depart ment of Medi c i ne, Di vi s i on of Nephrol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Kerri Kissell MD Res i dent Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Janaki C. Kuruppu MD As s i s t ant Profes s or Depart ment of Medi c i ne, Di vi s i on of I nfec t i ous Di s eas es , Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Jefferson H. Lee MD Chi ef Res i dent 2007â€“2008; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Dan Lender MD

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As s oci at e Profes s or Depart ment of Medi c i ne, Di vi s i on of Endoc ri nol ogy, Di abet es , and Nut ri t i on, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Jeffrey C. Liu MD Chi ef Res i dent 2007â€“2008; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Rebecca L. Manno MD Chi ef Res i dent 2006â€“2007; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Devang M. Patel MD Chi ef Res i dent i n Medi ci ne-Pedi at ri cs 2006â€“2007 Depart ment of Medi c i ne and Depart ment of Pedi at ri c s , Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Neil C. Porter MD As s i s t ant Profes s or Depart ment of Neurol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Darryn R. Potosky MD Chi ef Res i dent 2006â€“2007; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Alexandra K. Pratt MD Chi ef Res i dent 2007â€“2008; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Jennifer A. T aylor MD Chi ef Res i dent 2006â€“2007; Cl i ni cal Ins t ruct or Depart ment of Medi c i ne, Uni vers i t y of Maryl and Medi c al Cent er, Bal t i more, Maryl and Katherine H. Rak T kaczuk MD As s oci at e Profes s or Depart ment of Medi c i ne, Di vi s i on of Hemat ol ogy/Onc ol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and

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Ann B. Zimrin MD As s i s t ant Profes s or Depart ment of Medi c i ne, Di vi s i on of Hemat ol ogy/Onc ol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and

Fifth Edition Editor-in-Chief Allen R. Myers MD Profes s or of Medi ci ne Sec t i on of Rheumat ol ogy, Depart ment of Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne, Phi l adel phi a, Penns yl vani a

Contributors to the Fifth Edition E. Victor Adlin MD As s oci at e Profes s or of Medi ci ne Emeri t us Endoc ri nol ogy and Met abol i s m Sec t i on, Depart ment of Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne; At t endi ng Phys i c i an, T empl e Uni vers i t y Hos pi t al , Phi l adel phi a, Penns yl vani a Jack M. Becker MD As s oci at e Profes s or of Pedi at ri cs Drexel Uni vers i t y Col l ege of Medi c i ne; Chi ef, Sec t i on of Al l ergy, Sai nt Chri s t opher's Hos pi t al for Chi l dren, Phi l adel phi a, Penns yl vani a Hossein Borghaei DO, MS As s i s t ant Member Depart ment of Medi c al Onc ol ogy, Fox Chas e Canc er Cent er, Phi l adel phi a, Penns yl vani a Blase A. Carabello MD Profes s or of Medi ci ne Bayl or Col l ege of Medi c i ne; Chi ef, Depart ment of Medi c i ne, Hous t on Vet erans Affai rs Medi c al Cent er, Hous t on, T exas Gerard J. Criner MD Profes s or of Medi ci ne; Di rect or Pul monary and Cri t i c al Care Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne, Phi l adel phi a, Penns yl vani a Anthony J. DiMarino Jr. MD W i l l i am Rorer Profes s or of Medi ci ne T homas Jeffers on Medi c al Col l ege; Chi ef, Di vi s i on of Gas t roent erol ogy, T homas Jeffers on Uni vers i t y Hos pi t al ,

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Phi l adel phi a, Penns yl vani a T homas Fekete MD Profes s or of Medi ci ne I nfec t i ous Di s eas es Sec t i on, Depart ment of Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne; At t endi ng Phys i c i an, T empl e Uni vers i t y Hos pi t al , Phi l adel phi a, Penns yl vani a Stanley Goldfarb MD As s oci at e Dean for Cl i ni cal Educat i on Uni vers i t y of Penns yl vani a Sc hool of Medi c i ne, Phi l adel phi a, Penns yl vani a Donald P. Goldsmith MD Profes s or of Pedi at ri cs Drexel Uni vers i t y Col l ege of Medi c i ne; Chi ef, Sec t i on of Rheumat ol ogy, St . Chri s t opher's Hos pi t al for Chi l dren, Phi l adel phi a, Penns yl vani a S. Christine Kovacs MD, MPH Di vi s i on of Rheumat ol ogy, Lahey Cl i ni c , Burl i ngt on, Mas s ac hus et t s Stuart R. Lessin MD Seni or Member and Di rect or of Dermat ol ogy Fox Chas e Canc er Cent er; Profes s or of Medi c i ne (Dermat ol ogy), Chi ef, Di vi s i on of Dermat ol ogy, Depart ment of Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne, Phi l adel phi a, Penns yl vani a Allen R. Myers MD Profes s or of Medi ci ne Sec t i on of Rheumat ol ogy, Depart ment of Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne, Phi l adel phi a, Penns yl vani a Ronald N. Rubin MD Profes s or of Medi ci ne Sec t i on of Hemat ol ogy, Depart ment of Medi c i ne, T empl e Uni vers i t y Sc hool of Medi c i ne; Chi ef, Cl i ni c al Hemat ol ogy, T empl e Uni vers i t y Hos pi t al , Phi l adel phi a, Penns yl vani a Barney J. Stern MD Profes s or of Neurol ogy Depart ment of Neurol ogy, Uni vers i t y of Maryl and Sc hool of Medi c i ne, Bal t i more, Maryl and Louis M. Weiner MD

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Profes s or of Medi ci ne T empl e Uni vers i t y Sc hool of Medi c i ne; Chai rman, Depart ment of Medi c al Onc ol ogy; Seni or Member, Di vi s i on of Medi c al Sc i enc e, Fox Chas e Canc er Cent er, Phi l adel phi a, Penns yl vani a Fuad N. Ziyadeh MD Profes s or of Medi ci ne Di vi s i on of Renal , El ec t rol yt e, and Hypert ens i on, Depart ment of Medi c i ne, Uni vers i t y of Penns yl vani a Sc hool of Medi c i ne; At t endi ng Phys i c i an, Hos pi t al of t he Uni vers i t y of Penns yl vani a, Vet erans Affai rs Medi c al Cent er, Phi l adel phi a, Penns yl vani a

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Editors: Wolfsthal, Susan T itle: NMS Medicine, 6th Edition Copyri ght Â©2008 Li ppi ncot t W i l l i ams & W i l ki ns > Front of Book > Dedic at ion

Dedication

To my l ovi ng hus band, Bi l l , my daught ers , Rebecca and Jenni fer, and my ment ors who have s upport ed and encouraged my career i n medi cal educat i on at t he Uni vers i t y of Maryl and.

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Editors: Wolfsthal, Susan T itle: NMS Medicine, 6th Edition Copyri ght Â©2008 Li ppi ncot t W i l l i ams & W i l ki ns > Front of Book > Prefac e

Preface

â€œOnc e s t udent s have t he opport uni t y t o get t hei r hands on a w arm pat i ent , t hey bei ng t o unders t and w hat i t 's al l about .â€• T heodore E. Woodw ard, MD, MACP (1914â€“2005), Profes s or and Chai rman, Depart ment of Medi c i ne (1954â€“1981) On t he oc c as i on of hi s ret i rement , Uni vers i t y of Maryl and Sc hool of Medi c i ne, 1981. He c ont i nued t eac hi ng s t udent s at t he Uni vers i t y of Maryl and for t he next 23 years . The fi rs t expos ure t o cl i ni cal medi ci ne duri ng medi cal s chool i s an e ye-openi ng experi enceâ€”a t i me when t he s t udent bri ngs t oget her t he vas t amount of i nformat i on l earned i n t he bas i c s ci ences and merges t hat wi t h act ual pat i ent care. It i s a gl ori ous t i me for l earni ng and t he amount t hat needs t o be abs orbed grows exponen t i al l y wi t h t i me. It i s wi t h t hes e fi rs t s t eps i nt o cl i ni cal medi ci ne t hat t he young s t udent begi ns t o comprehend t he i mport ance of bei ng a l i fel ong l earner. W e abs orb bas i c concept s and bui l d upon t hem, modi fy what we know as new advances are di s covered, and cont i nual l y add t o our knowl edge for t he res t of our l i ves . Thi s al l t oo s hort revi ew t ext of i nt ernal medi ci ne i s our at t empt t o capt ure t he es s ent i al concept s and key el ement s of our s peci al t y at t hi s poi nt i n t i me. Al t hough i nt ernal medi ci ne i s cons t ant l y evol vi ng, t here are bas i c pri nci pl es and t hought proces s es t hat remai n t he es s ence of our s peci al t y. Learni ng t he fact s i s onl y t he begi nni ng. Medi cal s t udent s mus t devel op t hei r s ki l l s i n deduct i ve reas oni ng and s ynt hes i ze t hes e fact s , wei ghi ng t he pros and cons of t he eval uat i on and management choi ces for t hei r pat i ent s . Thi s newes t edi t i on of NMS-Medi c i ne was not onl y wri t t en by s peci al i s t s i n t he fi el d but , for t he fi rs t t i me, coaut hored by chi ef res i dent s and s eni or i nt ernal medi ci ne res i dent s at t he Uni vers i t y of Maryl and. The chi efs and s eni or res i dent s are much cl os er t o t he medi cal s t udent s i n t erms of t hei r t rai ni ng and experi ence, and hence, bri ng a fres h and rel evant approach t o t hi s mat eri al . W e

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wel come t hem as aut hors of t hi s t ext not onl y for t hei r i nput , but al s o becaus e we enjoy ment ori ng our young col l eagues and provi di ng t hem wi t h an opport uni t y t o advance t hei r academi c careers . Thi s edi t i on has been compl et el y updat ed, i ncl udi ng t he chapt ers , ques t i ons , and probl em s ol vi ng exerci s es . W e have al s o pl aced a s i gni fi cant amount of mat eri al onl i ne, i ncl udi ng addi t i onal chapt er cont ent , t abl es , and i l l us t rat i ons . A

i con s i gnal s t o t he reader

where t o fi nd t hes e s uppl ement al onl i ne res ources . Al s o avai l abl e onl i ne i s a comprehens i ve exam cons i s t i ng of approxi mat el y 150 board-s t yl e revi ew ques t i ons wi t h ans wers and expl anat i ons . Al t hough t hi s book i s geared t oward medi cal s t udent s and res i dent s l earni ng i nt ernal medi ci ne, we ant i ci pat e t hat i t i s al s o us eful for ot hers l earni ng t he es s ent i al pri nci pl es , concept s , and i nformat i on i n our s peci al t y. As a reader of t hi s t ext , we encourage you t o us e t he mat eri al pres ent ed as merel y t he fi rs t s t ep t o readi ng about t hes e t opi cs i n more dept h, ei t her i n t he l arger and more cl as s i c t ext books of i nt ernal medi ci ne or, more i mport ant l y, i n t he pri mary s ource l i t erat ure. The proces s of bei ng a l i fel ong l earner begi ns here. W e hope you accept t hi s chal l enge, are exci t ed by t he fi el d of i nt ernal medi ci ne, and s hare i n our ent hus i as m for our chos en profes s i on. Sus an D. W ol fs t hal MD

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Editors: Wolfsthal, Susan T itle: NMS Medicine, 6th Edition Copyri ght Â©2008 Li ppi ncot t W i l l i ams & W i l ki ns > T able of Cont ent s > Chapt er 1 - Cardiovasc ular Diseases

Chapter 1

Cardiovascular Diseases Jennifer A. T aylor Michael Benitez

I. Congestive Heart Failure (CHF) A. Definition Conges t i ve heart fai l ure (CHF) i s t he i nabi l i t y of t he heart , worki ng at normal or el evat ed fi l l i ng pres s ure, t o pump enough bl ood t o meet t he oxygen requi rement s of t he body t i s s ues . CHF s houl d never be cons i dered a di agnos i s . Rat her, i t i s a s yndrome res ul t i ng from many di s eas es t hat i nt erfere wi t h cardi ac funct i on. In act i ng as a mus cul ar pump, t he heart does onl y t wo t hi ngs : i t cont ract s (s ys t ol e) and i t rel axes (di as t ol e). Therefore, heart fai l ure can res ul t from onl y t wo broad abnormal i t i es â€”s ys t ol i c dys funct i on and di as t ol i c dys funct i on.

B. Etiology 

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1. Systolic dysfunction. Sys t ol e i s governed by t hree cardi ac propert i es : contractilityâ€”t he abi l i t y of myocardi um t o generat e force, afterloadâ€”t he force agai ns t whi ch t he heart mus t cont ract , and preload â€”t he s arcomere s t ret ch before cont ract i on. o

o

a. Decreased contractility. Mos t cas es of CHF occur when an i ns ul t t o t he myocardi um reduces i t s abi l i t y t o generat e force, t hereby reduci ng i t s cont ract i l i t y. 

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(1) Myocardial infarction (MI). In MI, a port i on of t he myocardi um undergoes necros i s and can no l onger generat e force, res ul t i ng i n weakeni ng of t he vent ri cl e. If ext ens i ve areas of t he myocardi um are i nfarct ed, CHF res ul t s .

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(2) Valvular heart disease res ul t s i n s t enos i s or regurgi t at i on of t he cardi ac val ves , whi ch pl aces a pressure or volume overload, res pect i vel y, on t he vent ri cl es . Ini t i al l y, compens at ory mechani s ms [s ee I B 1 c] accommodat e t hes e overl oads and mai nt ai n normal cardi ac out put at accept abl e fi l l i ng pres s ures . However, event ual l y t hes e mechani s ms fai l and heart fai l ure ens ues .

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(3) Hypertension. Hypert ens i on may cont ri but e t o ei t her s ys t ol i c or di as t ol i c dys funct i on.

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(4) Cardiomyopathies are di s eas es t hat di rect l y i njure t he myocardi um. 

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(a) T oxic. Subs t ances di rect l y t oxi c t o t he myocardi um (e.g., et hanol and cat echol ami nes ) may damage i t s force-generat i ng abi l i t y. Prol onged expos ure t o t hes e agent s may l ead t o t he devel opment of CHF.

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(b) Idiopathic. W hen t he cont ract i l e

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funct i on of t he myocardi um fai l s i n t he abs ence of a known et i ol ogy, a vi ral caus e oft en i s i mpl i ed but frequent l y cannot be proven. Ot her cl i ni cal pres ent at i ons , i ncl udi ng peri part um cardi omyopat hy, are of unknown et i ol ogy. 

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(c) Infiltrative. Infi l t rat i on of t he myocardi um by a vari et y of s ubs t ances (e.g., amyl oi d) may reduce cont ract i l i t y.

o

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b. Increased afterload. Increas i ng t he aft erl oad makes i t harder for t he vent ri cul ar mus cl e fi bers t o s hort en, t hereby reduci ng cardi ac out put . Aft erl oad can be quant i fi ed by cal cul at i ng t he s ys t ol i c force on t he myocardi um us i ng t he Lapl ace equat i on for s t res s : St res s = (pres s ure Ã— radi us )/(2 Ã— t hi cknes s ) Thus , di s eas e s t at es t hat i ncreas e ei t her t he s ys t ol i c pres s ure (hypert ens i on, aort i c s t enos i s ) or chamber radi us (di l at ed cardi omyopat hy, val vul ar regurgi t at i on) i ncreas e aft erl oad unl es s t he wal l t hi cknes s i ncreas es proport i onat el y.

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c. Compensatory mechanisms devel op i n res pons e t o t he vent ri cul ar pres s ure and vol ume overl oad t hat accompany decreas ed cont ract i l i t y. 

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(1) T he Frank-Starling mechanism i s act i vat ed when reduced vent ri cul ar empt yi ng res ul t s i n more vol ume ret ai ned i n t he vent ri cl es at t he end of s ys t ol e, whi ch l eads t o a great er vol ume at t he end of di as t ol e. Increas ed end-di as t ol i c vol ume i ncreas es s arcomere s t ret ch (prel oad), whi ch i ncreas es t he number of s ys t ol i c act i nâ€“myos i n cros s -bri dges t hat devel op. The great er number of cros s -bri dges i ncreas es t he s t rengt h of cont ract i on.

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(2) Cardiac hypertrophy provi des addi t i onal mus cl e mas s t o bear t he burden of vari ous overl oads .

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(3) Adrenergic stimulation by endogenous cat echol ami nes i ncreas es t he i not ropi c s t at e.

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2. Diastolic dysfunction. Di as t ol e i s governed by active and passive propert i es . Act i ve rel axat i on occurs earl y i n di as t ol e as cal ci um i s pumped out of t he myocardi um, res ul t i ng i n t he near ces s at i on of act i nâ€“myos i n cros s -bri dge i nt eract i on. Pas s i ve fi l l i ng occurs as t he mi t ral val ve opens , al l owi ng t he bl ood s t ored i n t he at ri a t o fi l l t he vent ri cl es . o

o

a. Abnormalities in active relaxation. Act i ve rel axat i on i s i mpai red when t here i s del ay i n cal ci um reupt ake at t he begi nni ng of di as t ol e.

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ABC Ambe r CHM Conve rte r Tria l ve rsion, http://w w w .proce sste x t.com/a bcchm.html o

b. Abnormalities of passive filling. Pas s i ve rel axat i on i s i mpai red when t he myocardi um i s s t i ffer t han normal . St i ffnes s i s defi ned as a change i n pres s ure (Î”P) per uni t change i n vol ume (Î”V), or Î”P/Î”V. W hen s t i ffnes s i s i ncreas ed, any change i n vol ume requi res or caus es a great er i ncreas e i n pres s ure. Thus , t o fi l l t he heart t o an adequat e vol ume, hi gh fi l l i ng pres s ure occurs , whi ch i n t urn l eads t o pul monary and s ys t emi c conges t i on. Increas ed pas s i ve s t i ffnes s of t he vent ri cl es occurs when concent ri c hypert rophy caus es t he chamber wal l t o be t hi cker t han normal , as mi ght occur i n hypert ens i on or when t he myocardi um i s i nfi l t rat ed by abnormal s ubs t ances s uch as amyl oi d.

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3. T he neurohumoral hypothesis of heart failure. Heart fai l ure l eads t o t he pers i s t ent act i vat i on of many neurohumoral s ys t ems and hormones , i ncl udi ng t he reni n-angi ot ens i n-al dos t erone s ys t em, t he adrenergi c nervous s ys t em, i nfl ammat ory cyt oki nes , endot hel i n, and vas opres s i n. Al t hough once t hought of as compens at ory, pers i s t ent overact i vat i on of t hes e agent s i s cardi ot oxi c, i n t urn l eadi ng t o a progres s i ve decl i ne i n cardi ac funct i on. Thus , bl ockade of t hes e s ys t ems s houl d be benefi ci al i n t reat i ng CHF.

C. Types of Heart Failure 

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1. High-output failure i s charact eri zed by cardi ac out put t hat may be s everal t i mes hi gher t han normal but s t i l l i s not adequat e t o mai nt ai n t i s s ue perfus i on needs or, i f adequat e, i s mai nt ai ned wi t h a hi gher-t han-normal fi l l i ng pres s ure. A cl as s i c exampl e of hi gh-out put fai l ure

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i s chronic severe anemia, whi ch caus es reduced oxygen-carryi ng capaci t y. In chroni c s evere anemi a, t he fol l owi ng occurs : o

o

a. Compens at i on i s provi ded by i ncreas ed forward cardi ac out put , whi ch i s faci l i t at ed by cardi ac enl argement , decreas ed t ot al peri pheral res i s t ance, and i ncreas ed venous ret urn t o t he heart . Thi s caus es a vol ume overl oad of vent ri cl es .

o

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b. Event ual l y t he demands on t he heart l ead t o cardi ac fai l ure; cardi ac out put , al t hough hi gh, s t i l l i s not adequat e t o meet t he ci rcul at ory demands pl aced on t he heart by t he anemi a. Some ot her caus es of hi gh-out put fai l ure i ncl ude art eri ovenous fi s t ul a, beri beri , and t hyrot oxi cos i s .

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2. Left-sided failure i ndi cat es t hat t he l eft vent ri cl e i s t he fai l i ng chamber. A di s eas e t hat pri mari l y affect s t he l eft vent ri cl e (e.g., MI) may reduce i t s cont ract i l e force, whereas t he ri ght vent ri cl e cont i nues t o pump normal l y. Thus , l eft vent ri cul ar fai l ure can occur wi t hout ri ght vent ri cul ar fai l ure.

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3. Right-sided failure i ndi cat es t hat t he ri ght vent ri cl e has fai l ed, ei t her as a res ul t of l eft vent ri cul ar fai l ure or i n i s ol at i on from t he l eft vent ri cl e. o

o

a. The most common cause of ri ght vent ri cul ar fai l ure i s left ventricular failure. W hen l eft vent ri cul ar fai l ure occurs , t he fi l l i ng pres s ure i n t he l eft vent ri cl e becomes el evat ed, i ncreas i ng t he

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workl oad of t he ri ght vent ri cl e (t he chamber res pons i bl e for fi l l i ng t he l eft vent ri cl e). Thus overt axed, t he ri ght vent ri cl e event ual l y fai l s al s o. P.3

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b. The ri ght vent ri cl e al s o may fai l i n i s ol at i on from t he l eft vent ri cl e. In t he pres ence of chronic obstructive pulmonary disease (COPD), i ncreas ed pul monary vas cul ar res i s t ance devel ops as a res ul t of archi t ect ural changes i n t he l ungs . The hi gher pul monary vas cul ar res i s t ance produces a pres s ure overl oad on t he ri ght vent ri cl e, whi ch l eads t o i ncreas ed ri ght vent ri cul ar work and event ual fai l ure. Pul monary embol i s m and pri mary pul monary hypert ens i on are s ome ot her caus es of ri ght -s i ded fai l ure.

D. Clinical features 

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1. Symptoms o

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a. Dyspnea i s t he mos t frequent l y encount ered s ympt om of CHF. 

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(1) The feel i ng of breat hl es s nes s i s caus ed by vascular congestion, whi ch reduces pul monary oxygenat i on. In addi t i on, t he vas cul ar conges t i on di mi ni s hes l ung compl i ance, i ncreas i ng t he work of breat hi ng, t hus addi ng t o t he feel i ng of breat hl es s nes s .

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ABC Ambe r CHM Conve rte r Tria l ve rsion, http://w w w .proce sste x t.com/a bcchm.html 

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(2) Dys pnea al s o res ul t s from reduced cardiac output to the periphery, whi ch t ri ggers t he s ympt om t hrough neurohumoral mechani s ms . In t he earl y s t ages of CHF, dys pnea occurs onl y wi t h exert i on. As heart fai l ure progres s es , t he amount of exert i on requi red t o produce dys pnea becomes progres s i vel y l es s unt i l dys pnea may occur at res t .

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b. Orthopnea refers t o dys pnea t hat occurs i n t he recumbent pos i t i on and i s rel i eved by el evat i on of t he head. Ort hopnea res ul t s from vol ume pool i ng i n t he cent ral vas cul at ure duri ng recumbency, whi ch l eads t o i ncreas ed cardi ac vol ume and, i n t urn, t o i ncreas ed l eft vent ri cul ar fi l l i ng pres s ure, pul monary conges t i on, and t he feel i ng of dys pnea. The phys i ci an may gauge t he degree of ort hopnea by not i ng t he number of pi l l ows t he pat i ent us es t o s l eep. However, i t s houl d be recogni zed t hat many pat i ent s s l eep on more t han one pi l l ow out of habi t , not becaus e of breat hl es s nes s . Nocturnal cough, whi ch has t he s ame pat hophys i ol ogy as ort hopnea, may occur t oget her wi t h, or i ns t ead of, noct urnal dys pnea.

o

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c. Paroxysmal nocturnal dyspnea i s t he occurrence of s udden dys pnea t hat awakens t he pat i ent from s l eep. Li ke ort hopnea, i t occurs duri ng recumbency as a res ul t of pool i ng i n t he cent ral vas cul at ure, whi ch i ncreas es l eft vent ri cul ar fi l l i ng pres s ure. Paroxys mal noct urnal dys pnea may occur

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i n t he ort hopnei c pat i ent who i nadvert ent l y s l i ps off t he pi l l ows us ed t o el evat e t he upper body. Us ual l y, t he pat i ent awakens from s l eep and feel s t he need t o s i t upri ght or t o go t o an open wi ndow for i ncreas ed vent i l at i on. The s ympt om us ual l y s ubs i des aft er t he pat i ent has been i n t he upri ght pos i t i on for 5â€“20 mi nut es . o

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d. Nocturia devel ops i n CHF as a res ul t of i ncreas ed renal bl ood fl ow when t he pat i ent i s recumbent and as l eep. 

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(1) During the day, when t he s kel et al mus cl es are act i ve, l i mi t ed cardi ac out put i s s hi ft ed away from t he ki dney t oward t he s kel et al mus cul at ure. The ki dney i nt erpret s t hi s reduct i on i n bl ood fl ow as hypovolemia and becomes s odi um avi d vi a act i vat i on of t he reninâ€“angiotensin system.

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(2) At night, when t he pat i ent i s at res t , cardi ac out put i s s hi ft ed t oward t he ki dney, and di ures i s ens ues .

o

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e. Edema. There are many caus es of peri pheral edema, s everal of whi ch are noncardi ac. Cardiac edema occurs when t he s ys t emi c hydros t at i c venous pres s ure i s great er t han t he s ys t emi c oncot i c venous pres s ure. Thus , cardi ac edema i s a s i gn of right-sided failure; i t occurs becaus e of t he i ncreas ed s ys t emi c venous pres s ure t hat res ul t s from ri ght vent ri cul ar dys funct i on.

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2. Physical signs o

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a. T achycardia. Increas ed heart rat e occurs i n heart fai l ure due t o i ncreas ed rel eas e of cat echol ami nes as a compens at ory mechani s m for mai nt ai ni ng cardi ac out put i n t he pres ence of decreas ed s t roke vol ume. Cat echol ami nes i ncreas e bot h t he force and t he rat e of cardi ac cont ract i on. However, i n chroni c heart fai l ure, adrenergi c downregul at i on occurs , and heart rat es over 100 bpm i n t he abs ence of arrhyt hmi a are di s t i nct l y unus ual .

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b. Pulmonary rales. The i ncreas ed l eft -vent ri cul ar fi l l i ng pres s ure as s oci at ed wi t h CHF i s referred t o t he l eft at ri um and t he pul monary vei ns . The i ncreas ed hydros t at i c pres s ure produces t rans udat i on of fl ui d i nt o t he al veol i . As ai r ci rcul at es t hrough t he al veol i , crackl i ng s ounds (ral es ) are produced. Not e t hat t here are mul t i pl e caus es of pul monary ral es ; t he mere pres ence of ral es does not neces s ari l y i ndi cat e CHF. P.4

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c. Cardiac enlargement. As t he fai l i ng heart rel i es more and more on t he Frank-St arl i ng mechani s m, i t di l at es and may devel op eccent ri c hypert rophy. In t he pres ence of cardi ac enl argement , t he poi nt of maxi mal i mpul s e (PMI) of t he l eft vent ri cl e i s s hi ft ed downward and t o t he l eft . Thi s s hi ft i s

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det ect ed duri ng a phys i cal exami nat i on wi t h t he pat i ent l yi ng s upi ne. o

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d. Fourth heart sound (S 4 ). Pat i ent s i n s i nus rhyt hm and heart fai l ure oft en have an S 4 (at ri al gal l op). The S 4 i s produced as l eft at ri al s ys t ol e propel s vol ume i nt o t he l eft vent ri cl e. In CHF, t he l eft vent ri cl e i s noncompl i ant and t he S 4 probabl y res ul t s from t he reverberat i on of t he bl ood eject ed i nt o t he l eft vent ri cl e. In el derl y pat i ent s , however, an S 4 may i ndi cat e reduced compl i ance of a s t i ff l eft vent ri cl e as a res ul t of agi ng rat her t han heart fai l ure. The S 4 al s o may be heard over t he ri ght vent ri cl e i n ri ght vent ri cul ar fai l ure.

o

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e. T hird heart sound (S 3 ). An S 3 (ventricular gallop), whi ch occurs earl y i n di as t ol e, probabl y i s t he s i ngl e mos t reliable sign of left heart failure reveal ed duri ng phys i cal exami nat i on. The S 3 occurs duri ng rapi d fi l l i ng of t he l eft vent ri cl e. Increas ed l eft at ri al pres s ure (whi ch propel s t he bl ood forward wi t h i ncreas ed force) and noncompl i ance of t he l eft vent ri cl e are t wo i mport ant fact ors i n t he product i on of t hi s ext ra s ound. Al t hough an S 3 i s a rel i abl e s i gn of heart fai l ure i n i ndi vi dual s ol der t han age 40, a s i mi l ar s ound i s a normal fi ndi ng i n young, heal t hy at hl et es .

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f. Neck vein distention. The neck vei ns can be cons i dered manomet ers at t ached t o t he ri ght at ri um and, as s uch, refl ect ri ght at ri al pres s ure [

det ect i on of cent ral venous pres s ure i s

des cri bed onl i ne (Onl i ne Fi gure 1-1)]. o

To es t i mat e cent ral venous pres s ure i n cm H 2 O, t he pat i ent 's back i s el evat ed or l owered s o t he poi nt

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demarcat i ng t he di s t ended from t he nondi s t ended port i on of t he neck vei n can be di s cerned cl earl y. The vert i cal hei ght i s meas ured from t hi s poi nt t o t he manubri um. The average dept h of t he ri ght at ri um i ns i de t he ches t cavi t y (5 cm) i s added t o t he hei ght of t he neck vei n. Thi s s um approxi mat es t he ri ght at ri al pres s ure.

Online Figure 1-1 As s es s ment of jugul ar venous pres s ure s houl d be done wi t h t he head of t he bed at an angl e of 30 degrees . The hi ghes t l evel of jugul ar venous pul s at i on s houl d be not ed and a l i ne or rect angul ar object ext ended from t hi s poi nt paral l el t o t he ches t wal l . Meas ure t he hei ght above t he ches t wal l at t he s t ernal angl e and add 5 cm t o account for t he di s t ance bet ween t he ri ght at ri um and t he ches t wal l . o

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g. Hepatic enlargement. El evat ed cent ral venous pres s ure can l ead t o hepat i c conges t i on, i n t urn caus i ng hepat omegal y. On occas i on, rapi d hepat i c enl argement may al s o caus e l i ver t endernes s .

o

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h. Edema. Lower ext remi t y and pres acral edema occur i n ri ght -s i ded fai l ure as i ncreas ed venous

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pres s ure res ul t s i n t rans udat i on of fl ui d i nt o t hes e areas . For edema t o be at t ri but abl e t o CHF, di s t ended neck vei ns i ndi cat i ve of el evat ed ri ght -s i ded fi l l i ng pres s ure al s o s houl d be pres ent . o

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i. Ascites. Trans udat i on of fl ui d i nt o t he peritoneal space al s o may occur as a res ul t of i ncreas ed s ys t emi c venous pres s ure. W hen as ci t es i s caus ed by CHF, t he neck vei ns t ypi cal l y are el evat ed and t he l i ver i s di s t ended from pas s i ve conges t i on.

E. Diagnosis Management of CHF mus t focus on t he caus e of t he heart fai l ure, not s i mpl y on rel i evi ng t he s ympt oms . Al t hough a careful hi s t ory and phys i cal exami nat i on are t he mos t i mport ant t ool s avai l abl e i n arri vi ng at a di agnos i s , i n many cas es a di agnos i s may not be reached. In t hes e i ns t ances , t he fol l owi ng s t udi es oft en are hel pful : 

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1. The electrocardiogram (ECG) frequent l y i s nons peci fi c. However, t he pres ence of Q waves hel ps confi rm t hat MI has been t he caus e of t he CHF.

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2. The chest radiograph i s us eful i n demons t rat i ng cardi ac chamber enl argement and i n document i ng conges t i on i n t he l ungs .

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3. The echocardiogram i s es s ent i al i n i dent i fyi ng chamber enl argement and i n quant i fyi ng l eft vent ri cul ar funct i on and val vul ar funct i on. The mos t commonl y us ed des cri pt or of vent ri cul ar funct i on i s t he ejection fraction. Eject i on fract i ons bet ween 55% and 76% are normal .

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ABC Ambe r CHM Conve rte r Tria l ve rsion, http://w w w .proce sste x t.com/a bcchm.html 

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4. Doppler interrogation meas ures t he di rect i on and vel oci t y of bl ood fl ow. Thi s t echni que i s us eful for det ect i ng bl ood fl ow movi ng i n an abnormal di rect i on, whi ch i s charact eri s t i c of val vul ar regurgi t at i on and i nt racardi ac s hunt s . In addi t i on, Doppl er i nt errogat i on can det ect and quant i fy val vul ar s t enos es by meas uri ng how much vel oci t y i s neces s ary t o mai nt ai n cons t ant bl ood fl ow t hrough a s t enot i c val ve.

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5. Radionuclide ventriculography i s us ed t o meas ure ri ght and l eft vent ri cul ar eject i on fract i on. It i s an excel l ent noni nvas i ve procedure t o us e when i t i s neces s ary t o quant i fy preci s el y t he degree of s ys t ol i c cardi ac dys funct i on.

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6. Duri ng cardiac catheterization, i nt racardi ac pres s ures , chamber s i ze, val vul ar s t enos i s , val vul ar regurgi t at i on, and coronary anat omy can be eval uat ed. Gi ven t he current accuracy of echocardi ography, cat het eri zat i on i s performed pri nci pal l y for t he eval uat i on of i s chemi a.

F. Therapy 

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1. Etiologic therapy. It i s i mport ant , when pos s i bl e, t o di rect t reat ment at t he et i ol ogi c agent of CHF. For exampl e, i f aort i c s t enos i s i s t he caus e, aort i c val ve repl acement i s t he mos t effect i ve t herapy. P.5

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2. Systolic heart failure o

o

a. Therapy s hown t o enhance s urvi val and del ay progres s i on of t he di s eas e. Compens at i on for devel opment of heart fai l ure by i ncreas i ng t he neurohormones res pons i bl e for i ncreas i ng cardi ac cont ract i l i t y and heart rat e can i mprove s ympt oms of heart fai l ure i n t he s hort t erm. However, chroni c s t i mul at i on l eads t o cardi ac remodel i ng and decompens at i on (s ee I B 3). Bl ockade of t hes e agent s have been s hown t o revers e remodel i ng, i mprove mort al i t y, and del ay t he progres s i on of heart fai l ure. 

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(1) Renin-angiotensin system blockade. Angi ot ens i n-convert i ng enzyme (ACE) i nhi bi t ors have been s hown t o have a mort al i t y benefi t . Becaus e many vas odi l at ors have fai l ed t o i mprove s urvi val des pi t e reduci ng aft erl oad, propert i es of ACE i nhi bi t ors ot her t han vas odi l at i on are t hought t o be operat i ve, namel y revers al of remodel i ng. In pat i ent s who devel op coughi ng due t o ACE i nhi bi t ors , angi ot ens i n recept or bl ockers (ARBs ) may be s ubs t i t ut ed wi t h s i mi l ar effi cacy. Addi t i onal bl ockade of t he reni n-angi ot ens i n s ys t em, us i ng s pi ronol act one or epl erenone t o bl ock t he fi nal product of t hi s s ys t em, al dos t erone, i s al s o benefi ci al i n s el ect ed pat i ent s .

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(2) Î²-Blocking agents. Becaus e s t i mul at i on of t he Î²-recept or i ncreas es t he force of

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cardi ac cont ract i on, Î²-agoni s t s have been us ed i n t he t herapy of end-s t age CHF. [See 2 b (3) (b)]. Paradoxi cal l y, caut i ous us e of Î²-recept or ant agoni s t s has al s o been effect i ve i n revers i ng t he s ame s yndrome. The mechani s m of act i on for t hi s cl as s of agent s i n t he t reat ment of heart fai l ure s t ems from prot ect i on of t he heart from t he t oxi c effect s of prol onged expos ure t o t he hi gh l evel s of ci rcul at i ng cat echol ami nes . 

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(3) Hydralazine and nitrates. The combi nat i on of hydral azi ne and ni t rat es us ed i n cl as s II and III heart fai l ure has al s o been s hown t o i mprove mort al i t y by decreas i ng prel oad and aft erl oad and i mprovi ng cardi ac out put . However, t he mort al i t y benefi t wi t h ACE-i nhi bi t ors i s great er.

o

o

b. Symptomatic therapy. Al t hough not s hown t o i mprove mort al i t y, many drugs can i mprove t he s ympt oms and morbi di t y of heart fai l ure. 

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(1) Reducing afterload. Agent s t hat caus e art eri ol ar di l at i on reduce i mpedance of t he out fl ow of bl ood from t he l eft vent ri cl e. By di mi ni s hi ng res i s t ance t o eject i on, t hes e agent s caus e cardi ac out put t o ri s e becaus e t he l eft vent ri cl e can eject more compl et el y agai ns t a l ower aft erl oad. The net effect i s i ncreas ed cardi ac out put wi t hout a s eri ous fal l i n bl ood pres s ure l eadi ng t o s ympt omat i c i mprovement . Several vas odi l at ors are us ed i n

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t he t reat ment of CHF t o reduce aft erl oad, i ncl udi ng ACE i nhi bi t ors , ni t rat es , and hydral azi ne. 

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(2) Reducing preload and left ventricular filling pressure. The i ncreas ed prel oad res ul t i ng from vol ume ret ent i on i n t he vent ri cl es i s a compens at ory mechani s m t hat hel ps i ncreas e forward cardi ac out put by us e of t he Frank-St arl i ng mechani s m; however, an exces s i ve i ncreas e i n prel oad i s as s oci at ed wi t h i ncreas ed l eft vent ri cul ar and ri ght vent ri cul ar fi l l i ng pres s ures , whi ch i s res pons i bl e for s ympt oms of pul monary and s ys t emi c conges t i on. Judi ci ous reduct i on i n fi l l i ng pres s ures wi t hout exces s i ve reduct i on i n prel oad i s i ndi cat ed i n t he t herapy of CHF. 

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(a) Di uret i cs reduce renal t ubul ar abs orpt i on of s odi um and wat er and i ncreas e t he cl earance of t hes e s ubs t ances from t he body. The res ul t i s a reduct i on i n cent ral vol ume and i n cardi ac fi l l i ng pres s ure.

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(b) Vas odi l at ors , whi ch i ncreas e t he capaci t y of t he s ys t emi c venous s ys t em, t rans fer cent ral vol ume t o t he peri phery, t hus reduci ng cent ral prel oad and fi l l i ng pres s ure. Ni t rat es and ACE i nhi bi t ors are effect i ve prel oad-reduci ng vas odi l at ors .

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(3) Increasing the contractile state.

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Cont ract i l e dys funct i on i s t he mos t common mechani s m t hat produces heart fai l ure; t herefore, i ncreas i ng t he cont ract i l e s t at e may res ul t i n s ympt omat i c i mprovement . 

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(a) Cardi ac gl ycos i des (e.g., di goxi n) i ncreas e t he cont ract i l e s t at e by +

+

i mpedi ng t he Na /K -ATPas e-cont rol l ed i nt racel l ul ar pump. Thi s res ul t s i n t he net i nfl ux of cal ci um i nt o t he myocardi um, whi ch i ncreas es cont ract i l e s t rengt h. 

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(b) Î²-Adrenergi c agoni s t s (cat echol ami nes , e.g., dobut ami ne) i ncre as e cont ract i l e funct i on by i ncreas i ng t he product i on of cycl i c adenos i ne monophos phat e (cAMP), whi ch res ul t s i n great er myocardi al cal ci um rel eas e. They are admi ni s t ered as a cont i nuous i nfus i on i n end-s t age heart fai l ure as a t empori zi ng meas ure. P.6

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(c) Phos phodi es t eras e i nhi bi t ors (e.g., mi l ri none) i ncreas e cont ract i l e funct i on by i nhi bi t i ng t he breakdown of cAMP. Si mi l ar t o Î²-adrenergi c agoni s t s , t hey are al s o admi ni s t ered as a cont i nuous i nt ravenous i nfus i on i n end-s t age heart fai l ure for s hort -t erm us e.

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3. Diastolic heart failure. Unl i ke s ys t ol i c heart fai l ure, no medi cal t reat ment i s avai l abl e t hat reduces mort al i t y i n di as t ol i c heart fai l ure. Treat ment i s ai med at s ympt omat i c rel i ef. o

o

a. Diuretics. Di uret i cs are t he mai ns t ay of t reat ment . By reduci ng vent ri cul ar vol ume t hey l ower vent ri cul ar pres s ure and reduce t he s ympt oms of conges t i on. The dos i ng mus t be careful l y regul at ed, however, as reduced vent ri cul ar vol ume al s o l owers s t roke vol ume and cardi ac out put . The opt i mum range woul d be one t hat prevent s exces s dys pnea and hepat i c conges t i on but al l ows for adequat e cardi ac out put .

o

o

b. Induction of bradycardia. Sl owi ng t he heart rat e i ncreas es t he t i me avai l abl e for vent ri cul ar fi l l i ng. Î²-bl ockers and nondi hydropyri di ne cal ci um channel bl ockers (verapami l and di l t i azem) are us ed t o caus e rel at i ve bradycardi a.

o

o

c. Relief of ischemia. In pat i ent s wi t h coronary di s eas e, i s chemi a i mpai rs t he act i ve rel axat i on phas e of di as t ol e by i mpai ri ng cal ci um reupt ake by t he s arcopl as mi c ret i cul um. Thus , s t andard t herapy for angi na i s al s o effect i ve i n i mprovi ng di as t ol i c dys funct i on. [See III A 5 a (4)].

o

o

d. Maintenance of sinus rhythm. The normal at ri al â€œki ckâ€• afforded by at ri al cont ract i on i mproves t he effi ci ency of vent ri cul ar fi l l i ng t hat i s l os t i n

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at ri al fi bri l l at i on. Thus , every effort s houl d be made t o mai nt ai n s i nus rhyt hm (s ee II). 

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4. Nonpharmacologic therapy o

o

a. Cardiac resynchronization. Many pat i ent s wi t h advanced heart fai l ure devel op el ect ri cal conduct i on di s t urbances , i ncl udi ng l eft bundl e branch bl ock, whi ch del ays t he i mpul s e s i gnal i ng cont ract i on from get t i ng t o t he l eft vent ri cl e. Thi s del ay di s coordi nat es cont ract i on, i n t urn caus i ng furt her reduct i on i n cardi ac out put . Ins ert i on of a pacemaker t o res ynchroni ze cont ract i on i n pat i ent s wi t h conduct i on del ays i mproves funct i onal capaci t y and qual i t y of l i fe and decreas es mort al i t y.

o

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b. Physical conditioning. An i mport ant adjunct t o t he medi cal t reat ment of CHF, phys i cal condi t i oni ng permi t s t he peri pheral t i s s ues t o us e cardi ac out put more effi ci ent l y. Thus , t he pat i ent experi ences an i ncreas e i n t ol erance t o phys i cal act i vi t y wi t hout an i ncreas e i n cardi ac out put .

o

o

c. Cardiac transplantation may offer an i mproved qual i t y of l i fe t o s el ect ed pat i ent s i n whom cont rol of CHF i s not pos s i bl e and prognos i s i s poor. Current l y, approxi mat el y 75% of pat i ent s undergoi ng cardi ac t rans pl ant at i on achi eve a 5-year s urvi val rat e. The pauci t y of cardi ac donors i s t he pri mary fact or l i mi t i ng t he us e of t hi s t herapy. Left vent ri cul ar as s i s t devi ces (LVADs ) may provi de a bri dge t o t rans pl ant at i on.

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5. Pulmonary edema i s t he mos t ext reme exampl e of CHF i n whi ch profound t rans udat i on of fl ui d i nt o t he pul monary al veol i occurs becaus e of a hi gh l eft vent ri cul ar fi l l i ng pres s ure. The res ul t i s i mpai red oxygenat i on and, i f unt reat ed, deat h. The goal of t herapy i s t o i mprove oxygenat i on, t o reduce l eft vent ri cul ar fi l l i ng pres s ure, and t o i ncreas e forward cardi ac out put . o

o

a. Oxygen s houl d be admi ni s t ered by facemas k becaus e pat i ent s i n pul monary edema are s o dys pnei c t hat t hey breat he pri mari l y t hrough t hei r mout hs .

o

o

b. Diuretics. Furos emi de i s l i kel y t he s i ngl e mos t commonl y us ed medi cat i on i n t he t reat ment of acut e pul monary edema. Thi s rapi d-act i ng l oop di uret i c promot es an i mmedi at e di ures i s i n mos t cas es .

o

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c. Morphine sulfate. Thi s opi oi d reduces pat i ent anxi et y, whi ch may hel p rel i eve t he art eri al vas ocons t ri ct i on oft en pres ent i n acut e pul monary edema. Thi s , i n t urn, hel ps i ncreas e forward cardi ac out put . Morphi ne i s al s o a venodi l at or; t herefore, i t reduces cent ral vol ume and l eft vent ri cul ar fi l l i ng pres s ure.

o

o

d. Other vasodilators. Ni t rogl yceri ne (admi ni s t ered s ubl i ngual l y or i nt ravenous l y) or ni t roprus s i de (admi ni s t ered i nt ravenous l y) i s oft en effect i ve i n

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t reat i ng pul monary edema when ot her t herapi es fai l . Nes i ri t i de, an anal og of B-t ype nat ri uret i c hormone t hat caus es venous and art eri ol ar vas odi l at i on may al s o be benefi ci al . However, t he pot ent vas odi l at i ng abi l i t y of t hes e drugs requi res t hat bl ood pres s ure be moni t ored cons t ant l y duri ng admi ni s t rat i on t o avoi d hypot ens i on. P.7

o

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e. Intravenous positive inotropic agents (dobut ami ne, mi l ri none) may be us ed i f peri pheral perfus i on i s compromi s ed. They wi l l hel p t o i ncreas e cont ract i l i t y and i mprove cardi ac out put and al s o have s ome aft erl oad reduct i on propert i es t hat wi l l al l ow i ncreas ed forward fl ow i n acut e decompens at i on.

o

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f. Intubation and positive-pressure ventilation. If t he pat i ent 's oxygenat i on does not i mprove rapi dl y wi t h t he previ ous l y not ed t herapi es , i nt ubat i on or pos i t i ve-pres s ure vent i l at i on may be neces s ary t o provi de mechani cal vent i l at i on and i mprove oxygenat i on.

o

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g. Invasive hemodynamic monitoring. Mos t cas es of pul monary edema res ol ve qui ckl y, maki ng hemodynami c moni t ori ng unneces s ary. However, i n cas es of refract ory pul monary edema wi t h s evere cardi ac compromi s e, exact knowl edge of i nt racardi ac fi l l i ng pres s ure may be us eful i n gui di ng t herapy. Hemodynami c moni t ori ng vi a

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Swan-Ganz cat het eri zat i on provi des t hi s i nformat i on s o t hat opt i mal fi l l i ng pres s ure and cardi ac out put may be obt ai ned.

II. Cardiac Arrhythmias A. Introduction Bradyarrhyt hmi as res ul t from i nadequat e s i nus nodal i mpul s e product i on or from bl ocked i mpul s e propagat i on, and us ual l y are not caus e for concern unl es s s yncope or pres yncope devel ops . Sus t ai ned at ri al t achyarrhyt hmi as us ual l y permi t adequat e cardi ac out put and are l es s dangerous t han s us t ai ned vent ri cul ar arrhyt hmi as , whi ch oft en caus e col l aps e or deat h.

B. Atrial tachyarrhythmias The at ri al t achyarrhyt hmi as can be cl as s i fi ed i nt o t wo s ubcat egori es : t hos e t hat produce a regul ar cardi ac rhyt hm and t hos e t hat produce an i rregul ar cardi ac rhyt hm. In general , at ri al t achyarrhyt hmi as do not i nt erfere wi t h i nt er- or i nt ravent ri cul ar conduct i on of t he cardi ac i mpul s e, and t herefore t he QRS compl ex (whi ch i s generat ed from t he vent ri cl es ) remai ns narrow i n form. Occas i onal l y, however, at ri al arrhyt hmi as caus e aberrant vent ri cul ar conduct i on wi t h a wi de QRS compl ex, whi ch may mi mi c arrhyt hmi as of vent ri cul ar ori gi n. 

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1. Regular atrial tachycardias o

o

a. Sinus tachycardia. Si nus t achycardi a repres ent s an i ncreas e i n t he s i nus rat e (>100 bpm) and i s us ual l y s econdary t o s ome ot her di s eas e proces s . In general , t he phys i ci an s houl d t reat t he condi t i on t hat i s caus i ng t he s i nus t achycardi a, not t he t achycardi a i t s el f. However, i n s ome pat i ent s , s uch as t hos e wi t h coronary art ery di s eas e, s i nus t achycardi a mus t be cont rol l ed t o prevent

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myocardi al i s chemi a. In t hi s i ns t ance, Î²-bl ocki ng agent s or cal ci um ant agoni s t s (ei t her verapami l or di l t i azem) may be effect i ve i n cont rol l i ng heart rat e. o

o

b. Supraventricular tachycardia (SVT ). The mos t common form of SVT i s AV nodal reent ry t achycardi a (AVNRT). 

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(1) ECG identification. In SVT, t he ECG s hows regul ar, narrow QRS compl exes wi t hout i dent i fi abl e P waves at a rat e of 150â€“200 bpm (Fi gure 1-2A).

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(2) T herapy. AVNRT i s due t o re-ent ry wi t hi n t he compact AV node. Therapi es t hat s l ow conduct i on or i ncreas e refract ori nes s us ual l y s ucceed. 

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(a) Mechanical maneuvers s uch as carotid sinus massage and t he Valsalva maneuver are oft en effect i ve i n t ermi nat i ng t he arrhyt hmi a. Thes e are es peci al l y i mport ant becaus e t hey can be s el f-admi ni s t ered by t he pat i ent pri or t o s eeki ng medi cal as s i s t ance.

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(b) Medical therapy. Intravenous (IV) adenosine i s t he medi cal t reat ment of choi ce. Les s commonl y us ed agent s i ncl ude verapamil or Î²-blockers.

o

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o

c. Atrial flutter us ual l y occurs i n pat i ent s wi t h ant ecedent heart di s eas e, i ncl udi ng coronary art ery di s eas e, peri cardi t i s , val vul ar heart di s eas e, and cardi omyopat hy. At ri al fl ut t er i s charact eri zed by an at ri al rat e of 220â€“400 bpm and i s us ual l y conduct ed t o t he vent ri cl e wi t h bl ock s o t hat t he vent ri cul ar rat e i s a fract i on of t he at ri al rat e. Occas i onal l y, at ri al fl ut t er may be conduct ed i rregul arl y. Treat ment i s t he s ame as for regul ar at ri al fl ut t er. 

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(1) ECG identification. As s hown i n Fi gure 1-2B, t hi s arrhyt hmi a produces a cl as s i c s awt oot h pat t ern on t he ECG. In t hi s exampl e, t here i s 4:1 AV bl ock wi t h an at ri al rat e of 300 bpm and a vent ri cul ar rat e of 75 bpm.

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(2) T herapy 

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(a) Al t hough i nt ravenous admi ni s t rat i on of digoxin, esmolol, or verapamil may be effect i ve i n convert i ng t he arrhyt hmi a t o normal s i nus rhyt hm, convers i on i s l es s l i kel y t han P.8

i n paroxys mal at ri al t achycardi a. Us ual l y t hes e medi cat i ons cont rol t he vent ri cul ar res pons e, whi ch, i n t urn, hel ps mai nt ai n hemodynami c s t abi l i t y. Once t he vent ri cul ar rat e has s l owed as a res ul t of i ncreas ed AV bl ock (3:1 or 4:1 conduct i on), ibutilide or anot her ant i arrhyt hmi c

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agent can be admi ni s t ered t o res t ore s i nus rhyt hm.

FIGURE 1-2 At ri al t achycardi as : A. Supravent ri cul ar t achycardi a, B. At ri al fl ut t er, C. At ri al fi bri l l at i on, D. Mul t i focal at ri al t achycardi a. (From St ei n E. Rapi d Anal ys i s of Arrhyt hmi as : A Sel f-St udy Program. 3rd ed. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 1999:91,66,68. ) 

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(b) If medi cal t herapy does not convert t he pat i ent t o normal s i nus rhyt hm, at ri al fl ut t er wi l l us ual l y s el f-convert over t i me, ei t her t o at ri al fi bri l l at i on or t o normal s i nus rhyt hm.

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(c) As i n al l arrhyt hmi as , direct current (DC) cardioversion i s neces s ary i f t he arrhyt hmi a has al ready produced hemodynami c i ns t abi l i t y.

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2. Irregular atrial tachycardias o

o

a. Atrial fibrillation. At ri al fi bri l l at i on i s an

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irregularly irregular arrhyt hmi a i n whi ch t here i s no ordered cont ract i on of t he at ri a but , rat her, mul t i pl e di s coordi nat e wave front s of depol ari zat i on t hat s end a l arge number of i rregul ar i mpul s es t o depol ari ze t he AV node. The i rregul ar i mpul s es produce an i rregul ar vent ri cul ar res pons e, t he rat e of whi ch depends on t he number of i mpul s es t hat are conduct ed t hrough t he AV node. Sel ect ed caus es of at ri al fi bri l l at i on i ncl ude s t res s , fever, exces s i ve al cohol i nt ake, vol ume depl et i on, peri cardi t i s , coronary art ery di s eas e, MI, pul monary embol i s m, mi t ral val ve di s eas e, t hyrot oxi cos i s , and i di opat hi c at ri al fi bri l l at i on. 

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(1) ECG identification. An exampl e of at ri al fi bri l l at i on i s s hown i n Fi gure 1-2C.

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(2) T herapy 

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(a) If pat i ent s wi t h at ri al fi bri l l at i on are hemodynami cal l y uns t abl e or demons t rat e an i ncreas e i n angi na pect ori s or wors eni ng of CHF, i mmedi at e DC s ynchronous cardi overs i on i s i ndi cat ed.

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(b) If pat i ent s are hemodynami cal l y s t abl e, t he phys i ci an s houl d fi rs t focus on cont rol l i ng t he vent ri cul ar res pons e t o t he at ri al fi bri l l at i on by t he i nt ravenous admi ni s t rat i on of Î²-bl ockers , nondi hydropyri di ne cal ci um channel bl ockers , or di goxi n.

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(c) In t he abs ence of a cont rai ndi cat i on, systemic anticoagulation s houl d be i ns t i t ut ed wi t h unfract i onat ed or l owâ€“mol ecul ar-wei ght hepari n (LMW H). Oral warfari n s houl d be s t art ed aft er hepari n.

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(d) Cardioversion can be cons i dered i mmedi at el y aft er a t rans es ophageal echocardi ogram, provi ded no i nt racardi ac t hrombus i s vi s ual i zed, or aft er 4â€“6 weeks of adequat e oral ant i coagul at i on wi t h warfari n.

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(e) In t he abs ence of a revers i bl e caus e, long-term anticoagulation s houl d be cons i dered.

o

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b. Multifocal atrial tachycardia. In t hi s arrhyt hmi a, t here i s s ynchronous at ri al cont ract i on, but t he cont ract i on ari s es from many s i t es i n t he at ri a, not from t he s i nus node. In t he majori t y of cas es of mul t i focal at ri al t achycardi a, pat i ent s have s i gni fi cant medi cal comorbi di t i es . 

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(1) ECG identification. The mul t i pl e s i t es of ori gi n of t he at ri al cont ract i on produce many di fferent P-wave confi gurat i ons and di fferent R-R i nt erval s . At l eas t t hree di fferent P-wave morphol ogi es are requi red t o make t hi s

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di agnos i s (Fi gure 1-2D). P.9

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(2) T herapy. Treat ment i s di rect ed pri mari l y at managi ng medi cal comorbi di t i es . If t hes e meas ures fai l , Î²-bl ockers or nondi hydropyri di ne cal ci um channel bl ockers may be us eful i n cont rol l i ng t he heart rat e.

C. Bradyarrhythmias Bradyarrhythmias occur when s i nus node i mpul s e generat i on i s s l owed or when normal s i nus node i mpul s es cannot be conduct ed t o t he vent ri cl es becaus e of AV nodal bl ock or vent ri cul ar conduct i ng s ys t em di s eas e. In general , bradyarrhyt hmi as are a caus e for concern onl y when pat i ent s have become s ympt omat i c wi t h pres yncope or s yncope from t he reduced cardi ac out put t hat t he l ow heart rat e produces . Medi cat i ons s uch as Î²-bl ockers , nondi hydropyri di ne cal ci um channel bl ockers , and di goxi n may cont ri but e t o bradyarrhyt hmi as . 

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1. Sinus bradycardia o

o

a. Si nus bradycardi a may be a phys i ol ogi c and normal res pons e t o cardi ovas cul ar condi t i oni ng, as i n t rai ned at hl et es . In s uch cas es , t he arrhyt hmi a i s obvi ous l y a normal fi ndi ng and requi res no t herapy. However, ext reme s i nus bradycardi a (< 35 bpm) as a res ul t of s i nus node dys funct i on may caus e s ympt oms .

o

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b. T herapy. Atropine may be us eful i n t emporari l y

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i ncreas i ng t he s i nus rat e. Withdrawal of offending medications may be neces s ary. 



2. Sinus pauses. Thi s bradyarrhyt hmi a i s caus ed by t he fai l ure of t he s i nus node t o generat e an i mpul s e on t i me. Such paus es may l as t for s everal s econds and i nduce s yncope. Defi ni t i ve t herapy requi res pacemaker i mpl ant at i on.





3. AV block. In AV bl ock, s ome of t he i mpul s es generat ed from t he s i nus node are not conduct ed t o t he vent ri cl es . o

o

a. T ypes of AV block (Fi gure 1-3) 



(1) First-degree AV block. Every at ri al beat i s conduct ed t o t he vent ri cl e, but t he P-R i nt erval exceeds 0.20 s econds and remai ns cons t ant (Fi gure 1-3A). Thi s i s mos t commonl y due t o a del ay i n t he AV node. Treat ment i s rarel y neces s ary.





(2) Second-degree AV block 



(a) Mobitz type I (Wenckebach) block. There i s a progres s i ve prol ongat i on i n t he P-R i nt erval unt i l a generat ed P wave i s not conduct ed (Fi gure 1-3B). Thi s t ype of bl ock us ual l y occurs at t he l evel of t he AV node. It rarel y produces s ympt oms .



Pa g e 5 2




(b) Mobitz type II block. There i s no prol ongat i on of t he P-R i nt erval before t he dropped beat (Fi gure 1-3C). Oft en conduct i on i n a 2:1 rat i o i s of s uffi ci ent durat i on t o caus e s ympt omat i c bradycardi a. Thi s t ype of bl ock can occur at t he AV node or i n t he Hi s -Purki nje s ys t em. Mobi t z t ype II bl ock i s t he t ype of great es t concern becaus e i t can progres s t o compl et e heart bl ock.

FIGURE 1-3 AV bl ocks . A. Fi rs t degree AV bl ock. B. Type II AV bl ock, Mobi t z I. C. Type II AV bl ock, Mobi t z II. D. Thi rd degree/compl et e AV bl ock. (From St ei n E. Rapi d Anal ys i s of Arrhyt hmi as : A Sel f-St udy Program. 3rd ed. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 1999:127,131,132,135. ) o

P.10

o





(3) T hird degree/complete heart block. No i mpul s es are conduct ed (Fi gure 1-3D), and t he vent ri cul ar rat e becomes dependent on s pont aneous vent ri cul ar depol ari zat i ons .

Pa g e 5 3


Severe s ympt omat i c bradycardi a charact eri zed by a heart rat e of 25â€“40 bpm i s s een. 



b. T herapy. Atropine and isoproterenol are effect i ve i n t emporari l y i ncreas i ng t he vent ri cul ar res pons e for bl ock occurri ng at t he AV node. Conduct i on bl ock bel ow t he l evel of t he AV node requi res i ns ert i on of ei t her a t emporary or a permanent cardiac pacemaker.

D. Ventricular tachyarrhythmias 



1. T ypes of ventricular arrhythmias (Figure 1-4) o

o

a. Premature ventricular contraction (PVC). In t hi s arrhyt hmi a, heart beat s ari s e di rect l y from t he vent ri cl es , bypas s i ng t he s peci al i zed cardi ac Hi s -Purki nje conduct i on s ys t em. 



(1) ECG identification 



(a) Becaus e t he Hi s -Purki nje s ys t em i s bypas s ed, t he QRS configuration i s t ypi cal l y widened and bizarre i n appearance.





(b) PVCs us ual l y do not affect at ri al depol ari zat i on, whi ch proceeds normal l y and i n di s s oci at i on wi t h t he PVC. Thus , t he next s i nus beat occurs at t he s ame

Pa g e 5 4


t i me i t woul d have occurred i f no PVC had been pres ent . Accordi ngl y, a full compensatory pause us ual l y fol l ows a PVC (Fi gure 1-4A). The normal l y occurri ng P wave i s us ual l y buri ed i n t he PVCâ€“QRS compl ex. 



(2) T herapy. Mos t i s ol at ed PVCs are beni gn and s houl d not be t reat ed.

o

o

b. Ventricular tachycardia i s a regul ar rhyt hm t hat occurs paroxys mal l y and exceeds 120 bpm. AV dissociation, whi ch caus es t he vent ri cul ar arrhyt hmi a t o proceed i ndependent l y of t he normal at ri al rhyt hm, i s t he hal l mark of t he arrhyt hmi a. Duri ng vent ri cul ar t achycardi a, cardi ac rel axat i on i s i mpai red. Thi s fact or, t oget her wi t h l os s of AV s ynchrony (i .e., l os s of t he at ri al â€œki ckâ€•) and l os s of t he el ect ri cal coordi nat i on of t he cont ract i on by t he Hi s -Purki nje s ys t em, us ual l y l eads t o s everel y reduced cardi ac out put , produci ng hypot ens i on. Sustained ventricular tachycardia is usually a life-threatening arrhythmia that degenerates into ventricular fibrillation and death if untreated. 



(1) Physical examination. In many cas es of vent ri cul ar t achycardi a, s evere decompens at i on precl udes performance of a det ai l ed phys i cal exami nat i on. 



(a) If pat i ent s are rel at i vel y s t abl e, phys i cal di agnos i s reveal s AV

Pa g e 5 5


di s s oci at i on, mani fes t ed by t he appearance of cannon a waves i n t he neck vei ns . Thes e waves occur i nt ermi t t ent l y when ri ght at ri al cont ract i on occurs duri ng vent ri cul ar cont ract i on. Becaus e t he at ri al bl ood cannot go forward agai ns t t he cl os ed t ri cus pi d val ve, backward fl ow produces a l arge bul ge i n t he neck vei ns .

FIGURE 1-4 Vent ri cul ar arrhyt hmi as . A. Premat ure vent ri cul ar cont ract i on, B. Monomorphi c vent ri cul ar t achycardi a, C. Pol ymorphi c vent ri cul ar t achycardi a (t ors ades de poi nt es ), D. Vent ri cul ar fi bri l l at i on. (From St ei n E. Rapi d Anal ys i s of Arrhyt hmi as : A Sel f-St udy Program. 3rd ed. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 1999:100,110â€“112. ) 

P.11







(b) Variability in intensity of the S 1 , caus ed by vari abl e pos i t i oni ng of at ri al and vent ri cul ar cont ract i on, can be aus cul t at ed.



Pa g e 5 6




(2) ECG identification (Fi gure 1-4B,C) 



(a) The QRS complex is widened and bizarre in appearance becaus e t he arrhyt hmi a does not us e t he s peci al i zed conduct i ng s ys t em of t he heart . Becaus e t he vent ri cl es are operat i ng i ndependent l y of t he at ri a, t here i s no constant relationship between the P wave and the QRS complex.





(b) The QRS compl ex may be monomorphic (i .e., of one s hape), as s hown i n Fi gure 1-4B, or i t may be polymorphic, as s hown i n Fi gure 1-4C. W hen t he axi s of a pol ymorphi c arrhyt hmi a appears t o revol ve about a cent ral poi nt and i s as s oci at ed wi t h a prol onged QT i nt erval , t he arrhyt hmi a i s t ermed torsades de pointes.





(3) T herapy 



(a) In hemodynami cal l y uns t abl e pat i ent s , DC cardioversion i s urgent l y requi red.





(b) St abl e pat i ent s wi t h monomorphi c vent ri cul ar t achycardi a may be t reat ed wi t h IV amiodarone.



Pa g e 5 7




(c) Pol ymorphi c vent ri cul ar t achycardi a requi res defi bri l l at i on. Common caus es are i s chemi a, el ect rol yt e abnormal i t i es , and drugs t hat prol ong t he QT i nt erval .



c. Ventricular fibrillation i s charact eri zed by a l ack of



ordered cont ract i on of t he vent ri cl es ; t herefore, t here i s no cardi ac out put . Thus , ventricular fibrillation is synonymous with death unless conversion to an effective rhythm can be accomplished. The phys i ci an s houl d begi n cardi ac res us ci t at i on, i ncl udi ng mechani cal vent i l at i on, cardi ac compres s i on, and drug and el ect ri cal t herapy, i mmedi at el y on recogni zi ng t he pres ence of vent ri cul ar fi bri l l at i on (Fi gure 1-4D). 

2. Prevention and treatment of ventricular arrhythmias. Onl i ne Tabl e 1-1 l i s t s t he current cl as s i fi cat i on and s ome of t he s i de effect s of drugs current l y avai l abl e for l ong-t erm prevent i on of vent ri cul ar arrhyt hmi as . Drug t herapy i s us ed when a pat i ent has had s ympt omat i c or s us t ai ned vent ri cul ar t achycardi a or fi bri l l at i on. Today, i ns ert i on of an i mpl ant abl e cardi ac defi bri l l at or accompani es ant i -arrhyt hmi c agent s i n mos t cas es of l i fe-t hreat eni ng arrhyt hmi as . Some pat i ent s wi t h heart fai l ure s ympt oms and decreas ed l eft vent ri cul ar eject i on fact i on may qual i fy for i ns ert i on of an i mpl ant abl e cardi ac defi bri l l at or for pri mary prevent i on of s udden cardi ac deat h. 

ONLINE TABLE 1-1 Antiarrhythmic Agents

Pa g e 5 8


Cl Maj a

or

ss Elec trop hysi olog ic P S M r p aj o e o p ci r e fi Si rt c d ie A e s g Ef e fe nt ct s s S Ia Q Pr o In ui o di hi ni ar u bi di rh m t n yt ch ra e h a pi

m

n d

ia

n in el w ar d cu rr e nt Bl Pr

Di

oc ol

ar

Pa g e 5 9


k o

rh

er n

e

s g

a

re p ol ar iz at io n Pr Pr oc o ai ar n rh a yt mh id m e ia L u p u sli k e sy n dr o m e Di Pr s o o ar

Pa g e 6 0


p rh yr yt a h mm id ia e C o n g e st iv e h e ar t fa il ur e A nt ic h ol in er gi c ef fe ct s Ib Li C

Pa g e 6 1


In d N hi oc S bi ai ef t n fe ra e ct pi

s

d in w ar d cu rr e nt Pr o ar rh yt h m ia C N S ef fe ct s A T N cc oc e el ai ut er ni ro at d p e e e

Pa g e 6 2


re

ni

p

a

ol ar iz at io n M C e N xi S l e ef t i fe n ct e s P C h N e S n ef yt fe oi ct n s Ic Fl C In ec o hi ai n bi ni g t d e ra e s t pi

iv

d

e

in

h

w

e

ar

ar

d

t

cu

fa

rr

il

Pa g e 6 3


e

ur

nt Li

e Pr

tt

o

le

ar

ef

rh

fe

yt

ct

h

o

m

n

ia

re p ol ar iz at io n Î² II Pr Br -b R o a l o e pr d ck d a yc er uc n ar s e ol di i s ol a ch e m ia Br o nc h o s p

Pa g e 6 4


a s m C o n g e st iv e h e ar t fa il ur e R A C e ce o d b n uc ut g e ol e s y ol s t m

iv

p

e

at

h

h

e

et

ar

ic

t

ar

fa

rh

il

yt

ur

h

e

m

Pa g e 6 5


o g e ni ci ty P II A P ot I m ul a Pr i o m s s ol d o i u o ar n m n o ar ch g n y a ac e fi n ti

br

n o

o

el n

si

p

s

ot e nt ia l d ur at io n bl

H

oc

y

k

p

er

o-

s

a n d h

Pa g e 6 6


y p er th yr oi di s m Br O et rt yl h iu o m st at ic h y p ot e n si o n S Pr ot o al ar ol rh yt h m ia Ib Pr ut o i l i ar

Pa g e 6 7


d rh e yt h m ia C IV V Br al D er a ci e a d u pr p yc m e a ar ch s s m di a sl il a n o (a n w tr el i n i a bl w l oc ar ar k d rh er cu yt s rr h e m nt i a s) CNS, cent ral nervous s ys t em.

III. Ischemic Heart Disease A. Atherosclerotic coronary artery disease (ASCAD) 



1. Definition. ASCAD i s t he focal narrowi ng of t he coronary art eri es as a res ul t of a plaque compos ed of:

Pa g e 6 8


o

a. Lipids (chol es t erol es t ers and crys t al s ), whi ch are depos i t ed at t he cent er of t he pl aque and accumul at e wi t hi n macrophages

o

o

b. Intimal secretory smooth muscle cells, whi ch prol i ferat e

o

o

c. A fibrous cap made of connect i ve t i s s ue





2. Incidence and risk factors. Current l y i n t he Uni t ed St at es , t he overal l i nci dence of deat h as a res ul t of ASCAD i s 0.5 i n 1,000 and decreas i ng. However, ASCAD di ffers i n frequency i n s ubpopul at i ons wi t h t he fol l owi ng ri s k fact ors : o

o

a. Age. The i nci dence of ASCAD i ncreas es progres s i vel y wi t h age. The ri s k of deat h i s 1.5 i n 1,000 i ndi vi dual s at age 50.

o

o

b. Gender. ASCAD i s more preval ent i n men t han i n women. Thi s di fference i s mos t marked i n premenopaus al women compared wi t h men of s i mi l ar age. By t he t i me men reach t he age of 50 years , t hey are affect ed fi ve t i mes more oft en t han women of t he s ame age. Thi s di fference decl i nes as age i ncreas es .

o

c. Serum cholesterol. The i nci dence of ASCAD i ncreas es wi t h i ncreas i ng t ot al s erum chol es t erol l evel s

(Onl i ne Fi gure 1-5).

Pa g e 6 9


ONLINE FIGURE 1-5 Graph s howi ng t he effect of i ncreas i ng s erum chol es t erol concent rat i on on t he i nci dence of at heros cl erot i c coronary art ery di s eas e i n men age 30â€“49 years . (Adapt ed from Cohn PF: Di agnos i s and T herapy of Coronary Art ery Di s eas e. Bos t on: Li t t l e, Brown, 1979:27. ) 



(1) Tot al s erum chol es t erol i s carri ed i n t he bl ood by low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL). 



(a) The hi gher t he percent age of t ot al chol es t erol carri ed by LDL i n rel at i on t o HDL, t he hi gher t he ri s k of ASCAD. Hi gh l evel s of HDL s eem t o be prot ect i ve. P.12



Pa g e 7 0


(b) Tot al chol es t erol l evel s houl d be l es s t han 200 mg/dL. 



(i) The LDL chol es t erol l evel s houl d be l es s t han 130 mg/dL; i n pat i ent s wi t h known coronary di s eas e, i t s houl d be l es s t han 100 mg/dL. In hi gh-ri s k pat i ent s , cons i der l oweri ng t o 70 mg/dL.





(ii) The HDL chol es t erol l evel s houl d exceed 40 mg/dL.



(2) Several t ypes of hyperl i pi demi a exi s t , and many are as s oci at ed wi t h an i ncreas ed i nci dence of coronary art ery di s eas e.

Onl i ne Tabl e 1-2 pres ent s an overvi ew of t he

hyperl i pi demi as . 

ONLINE TABLE 1-2 The Hyperlipidemias T Li Li Cl y pi p in p d o ic e

p al

of

r

H

ot

y

ei

p e rli pi d e

n A A M T b b a h n n ni e o o fe r r r st a

Pa g e 7 1


m m m at p ia al al io y it it n y y s I â â P F Li †‘ †‘ a at p Tr C nc -f o i g h re re pr l y yl at e ot ce o i t i di ei ri m s et n d i c Er l i e ro u p s n pt a

s iv

s

e

e

x

d

a

ef

nt

ic

h

ie

o

nc

m

y

a s Li p e m ia re ti n al

is II â â C R a †‘ †‘ or e

Pa g e 7 2


L C L o st D h D n ri L ol L ar ct re e

y e

ce s t

di d

pt er

s di

or ol

e et

d

a Bi

ef

s le

ic

e ac

ie

T id

nc

e â

y

n €“ d bi o n n di x n a g nt re h si o n ms a Ni s co X ti a ni nt c h ac el i d a H s M mG a -C o A

Pa g e 7 3


re d uc ta s e in hi bi to rs II â â C R b †‘ †‘ or e C L o st h D n ri ol L ar ct e â y e s t †‘ di d er V s di ol L e et â D a Bi †‘ L s l e Tr

e ac

ig

id

ly

â

ce

€“

ri

bi

d

n

e

di

s

n g re si n s

Pa g e 7 4


Ni co ti ni c ac id G e m fi br o zi l H M G -C o A re d uc ta s e in hi bi to rs II â â P G I †‘ †‘ al e D Tr V m m

Pa g e 7 5


ys i g L ar fi b l y D fa br et ce L t t o al ri R y zi ip d e st l o e m re pr s n a ot â a ks ei †‘ nt T n C s u e h â b m ol †‘ er ia e V o st L u er D s ol L x a nt h o m a s C or o n ar y di s e a s e

Pa g e 7 6


P er ip h er al v a sc ul ar di s e a s e H y p ot h yr oi di s m IV â â Er R †‘ †‘ u e Tr V pt s t i g L i v ri l y D e ct ce L x e ri

a d

d

nt di

Pa g e 7 7


e

h et

s

o G me a m s fi P br a o nc zi re l at iti s Di a b et e s Â ± C or o n ar y ar te ry di s e a s e

Pa g e 7 8


V â â Er R †‘ †‘ u e Tr C pt s t i g h i v ri l y yl e ct ce o x e ri m a d d i c nt di e ro h et s n o G s me a m s fi P br a o nc zi re l at iti s Di a b et e s Â ± C or o n ar y ar

Pa g e 7 9


te ry di s e a s e HMG-CoA, Î²-hydroxyÎ²-met hyl g l ut aryl coenzyme A; LDL, l ow-dens i t y l i poprot ei n s ; VLDL, very-l ow-d ens i t y l i poprot ei n s. 



d. Smoking. Compared wi t h nons mokers , ci garet t e s mokers are 60% more l i kel y t o devel op ASCAD when ot her ri s k fact ors are cont rol l ed for s t at i s t i cal l y. Smoki ng i ncreas es carbon monoxi de l evel s i n t he bl ood, whi ch may, i n t urn, damage t he coronary endot hel i um. Smoki ng al s o i ncreas es pl at el et adhes i venes s and t hus t he l i kel i hood of t hrombot i c coronary occl us i on.





e. Hypertension. The hi gher t he s ys t ol i c or

Pa g e 8 0


di as t ol i c bl ood pres s ure, t he more l i kel y t he devel opment of ASCAD. Thi s l i kel i hood i s apparent i n bot h men and women and becomes more pronounced wi t h advanci ng age. 



f. Diabetes mellitus i s as s oci at ed wi t h a 50% i ncreas e i n t he i nci dence of ASCAD i n men and a 100% i ncreas e i n women. In l i ght of t hi s , di abet es mel l i t us s houl d be cons i dered an ASCAD equi val ent .





g. Family history. A fami l y hi s t ory of premat ure heart di s eas e i s cons i dered t o be pres ent when coronary art ery di s eas e has occurred i n a fi rs t -degree mal e rel at i ve age 55 or younger or a femal e fi rs t -degree rel at i ve age 65 or younger. A fami l i al predi s pos i t i on t o coronary art ery di s eas e exi s t s i n part due t o i nheri t ance of t he above ri s k fact ors (except s moki ng). However, fami l y hi s t ory i s t he onl y ri s k fact or i n about one-t hi rd of i ndi vi dual s wi t h ASCAD.

o

3.

Pathogenesis (Online Figures 1-6 and 1-7). The previ ous l y

ment i oned ri s k fact ors do not cons t i t ut e a known mechani s m for ASCAD. The major t heory of at herogenes i s i s t he response to injury theory.

Pa g e 8 1


ONLINE FIGURE 1-6 Di agrammat i c repres ent at i on of an at heros cl erot i c pl aque, s howi ng i t s compos i t i on. The fi brous c ap of t he pl aque i s l i nked t o cl i ni cal event s becaus e of i t s t endency t o fract ure and ul cerat e. The nec rot i c c ore of t he pl aque has cl i ni cal cons equence as a res ul t of i t s s i ze, cons i s t ency, and t hrombopl as t i c component s . (Adapt ed from Braunwal d E: Heart Di s eas e. 2nd ed. Phi l adel phi a: W B Saunders , 1984:1186. )

ONLINE FIGURE 1-7 Schemat i c evol ut i on of t he at heros cl erot i c pl ague. 1, Li poprot ei n part i cl es accumul at e i n t he i nt i ma. The modi fi cat i on of t hes e l i poprot ei ns i s depi ct ed by t he darker col or. 2, Oxi dat i ve s t res s (i ncl udi ng product s found i n modi fi ed l i poprot ei ns ) i nduce l ocal cyt oki ne el aborat i on. 3, The cyt oki nes i nduce i ncreas ed expres s i on of mol ecul es t hat di rect t hei r mi grat i on i nt o t he i nt i ma. 4, Bl ood monocyt es ent er t he art ery wal l i n res pons e t o chemoat t ract ant cyt oki nes s uch as monocyt e

Pa g e 8 2


chemoat t ract ant prot ei n 1 (MCP-1). They encount er s t i mul i s uch as macrophage col ony s t i mul at i ng fact or (M-CSF) t hat augment t hei r expres s i on of s cavenger recept ors . 5, Scavenger recept ors medi at e t he upt ake of modi fi ed l i poprot ei n part i cl es and promot e devel opment of foam cel l s . Foam cel l s produce cyt oki nes and effect or mol ecul es i ncl udi ng hypochl orous aci d, s uperoxi de ani on (O 2

), and mat ri x met al l oprot ei nas es . 6, Smoot h mus cl e cel l s i n t he

i nt i ma prol i ferat e and ot her s moot h mus cl e cel l s mi grat e i nt o t he i nt i ma from t he medi a. 7, The s moot h mus cl e cel l s el aborat e ext racel l ul ar mat ri x, promot i ng i t s accumul at i on i n t he growi ng at heros cl erot i c pl aque. The fat t y s t reak evol ves i nt o a fi brofat t y l es i on. 8, In l at er s t ages , cal ci fi cat i on can occur (not depi ct ed) and fi bros i s cont i nues , s omet i mes accompani ed by s moot h mus cl e cel l deat h. The res ul t i s a rel at i vel y acel l ul ar caps ul e s urroundi ng a l i pi d-ri ch core t hat may al s o cont ai n dyi ng or dead cel l s and t hei r debri s . LDL, l ow-dens i t y l i poprot ei n; IL-1, i nt erl euki n-1. (Modi fi ed from Zi pes D, Li bby P, Bonow RO, Braunmwal d Ed, eds . Braunw al d's Heart Di s eas e: A T ext book of Cardi ovas c ul ar Medi c i ne. 7t h ed. Phi l adel phi a: El s evi er Saunders , 2005:925. ) 



a. Thi s t heory s t at es t hat s ome i njuri ous s t i mul us (e.g., hypert ens i on or hyperchol es t erol emi a) caus es endot hel i al damage, res ul t i ng i n t he rel eas e of vari ous growt h fact ors . Thes e growt h fact ors caus e s moot h cel l prol i ferat i on and mi grat i on of macrophages i nt o t he ves s el wal l . At t he s ame t i me, t he now i njured endot hel i um becomes more permeabl e, admi t t i ng l i pi d and chol es t erol i nt o t he i nt i ma.





b. Thes e changes res ul t i n pl aque format i on, whi ch may event ual l y compromi s e t he ves s el

Pa g e 8 3


l umen enough t o i mpede bl ood fl ow. If t he pl aque i s di s rupt ed, pl at el et s are act i vat ed, l eadi ng t o t hrombus format i on and wors eni ng obs t ruct i on. o

o

4. Pathophysiology of ischemia 



a. Supplyâ€“demand relationship. As wal l s t res s and heart rat e i ncreas e (e.g., wi t h exerci s e), myocardi al oxygen cons umpt i on ri s es . Aut oregul at ed i ncreas es i n coronary bl ood fl ow normal l y meet t hi s i ncreas ed demand. However, i f demand exceeds s uppl y, i s chemi a res ul t s . The product of heart rat e and l eft vent ri cul ar s ys t ol i c pres s ure or wal l s t res s roughl y approxi mat e t he oxygen needs of t he myocardi um (s ee I B 1 b). 



(1) Increased demand. In pat i ent s wi t h ASCAD, s t enos i s of t he coronary art ery prevent s t he i ncreas e i n coronary bl ood fl ow needed t o compens at e for an i ncreas ed demand, res ul t i ng i n an oxygen demand t hat exceeds t he oxygen s uppl y. Myocardial ischemia i s t he res ul t of t hi s i mbal ance.





(2) Reduced supply. At heros cl erot i c s t enos i s was once vi ewed as a fi xed obs t ruct i on t o coronary bl ood fl ow. In fact , t he di s eas ed area of t he coronary art ery oft en remai ns dynami c, and t he effect i ve l umen of t he art ery undergoes

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cons t ant change. Changes are produced by vas ocons t ri ct i on of t he coronary art ery, by product i on and degradat i on of l ocal t hrombi at t he s i t e of s t enos i s , and by progres s i ve enl argement of t he at heros cl erot i c pl aque. Acut e changes i n l umen di amet er may reduce t he s uppl y of coronary bl ood fl ow and, t hus , produce i s chemi a wi t hout an i ncreas e i n demand. 



b. Myocardial infarction (MI). The necros i s of myocardi al t i s s ue occurs as a res ul t of prol onged i s chemi a. The rapi di t y and ext ent of t he i nfarct i on proces s are det ermi ned by t he ext ent of reduct i on of bl ood fl ow t o t he area. In s ome cas es , collateral flow from ot her coronary art eri es may s uppl y enough bl ood fl ow t o prevent i nfarct i on des pi t e a t ot al coronary occl us i on. 



(1) ST -segment elevation myocardial infarction (ST EMI) i s as s oci at ed wi t h occl us i on of a coronary art ery by a thrombus. Aggres s i ve l ys i s of t he t hrombus wi t h agent s s uch as streptokinase and tissue plasminogen activator (t-PA) or bal l oon angi opl as t y can rees t abl i s h coronary bl ood fl ow, rel i eve pai n, rees t abl i s h cont ract i l e funct i on of t he s egment of myocardi um s uppl i ed by t he t hrombos ed art ery, and reduce myocardi al damage [s ee III A 5 b (4) (b) i i ].



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

(2) Nonâ€“ST EMI (NST EMI) i s due t o s evere coronary art ery obs t ruct i on wi t hout t ot al occl us i on.





5. Clinical consequences. At heros cl erot i c pl aques may produce s t abl e angi na or an acute coronary syndrome (ACS) (uns t abl e angi na, NSTEMI, or STEMI). 



a. Angina pectoris i s ches t pai n or pres s ure produced by myocardial i s chemi a. P.13





(1) Characteristic features 



(a) Relation to exertion. The s i ngl e mos t i mport ant feat ure of angi na pect ori s i s i t s preci pi t at i on by exert i on. Exert i on i ncreas es myocardi al oxygen demand beyond t he s uppl y capabi l i t i es of di s eas ed coronary art eri es , produci ng i s chemi a. Ot her fact ors t hat i ncreas e myocardi al oxygen demand (e.g., emot i onal ups et , eat i ng a meal , or t he peri pheral vas ocons t ri ct i on

Pa g e 8 6


caus ed by wal ki ng i n col d weat her) al s o may preci pi t at e angi na. 



(b) Quality of pain. Al t hough many pat i ent s percei ve angi na as chest pain, ot hers report a feel i ng of pressure i n t he ches t area or compl ai n of a burning s ens at i on. In s ome pat i ent s , exertional dyspnea may repres ent an angi nal equi val ent .





(c) Radiation of pain. Radi at i on of angi nal pai n t o t he l eft arm i s wel l known. Pai n al s o may radi at e t o t he ri ght arm, jaw, t eet h, or t hroat . Occas i onal l y, t hes e radi at i on s i t es may be t he onl y s i t es of pai n, and t he ches t i s free of di s comfort ; or t he ches t di s comfort , when pres ent , may not radi at e at al l .





(d) Progression of ischemia and duration of symptoms. W hat ever t he angi nal s ympt om qual i t y for a gi ven pat i ent , repeat ed epi s odes of i s chemi a us ual l y reproduce t hat s ame

Pa g e 8 7


qual i t y. The s ympt om compl ex us ual l y begi ns at a l ow i nt ens i t y, i ncreas es over 2â€“3 mi nut es , and l as t s a t ot al of l es s t han 15 mi nut es . Epi s odes l onger t han 30 mi nut es s ugges t t hat MI may have occurred. 



(2) T ypes of ischemic episodes 



(a) Chronic stable angina i s angi na t hat recurs under s i mi l ar ci rcums t ances and wi t h a s i mi l ar frequency over t i me.





(b) Unstable angina (UA) i s a t erm appl i ed t o angi na when a change i n s t at us occurs (e.g., new-ons et angi na; angi na of i ncreas i ng s everi t y, durat i on, or frequency; or angi na occurri ng at res t for t he fi rs t t i me). It repres ent s a more s eri ous cl i ni cal s i t uat i on t han chroni c s t abl e angi na becaus e uns t abl e angi na i ndi cat es a progres s i on of di s eas e and may be an i mmedi at e precurs or of MI. 



(i) Rest angina. Angi na at res t i s part i cul arl y

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worri s ome becaus e i t i mpl i es t hat decreas ed s uppl y, rat her t han i ncreas ed demand, i s caus i ng t he angi na. Thi s concept i n t urn s ugges t s t hat art eri al occl us i on and pos s i bl e i nfarct i on may be i mmi nent . 



(ii) New-onset angina. In cas es of new-ons et angi na, i t i s di ffi cul t t o general i ze about cl i ni cal out come. New-ons et angi na t hat progres s es i n frequency, s everi t y, or durat i on over 1 or 2 mont hs i s worri s ome. Convers el y, s ome cas es of new-ons et angi na may s i mpl y be t he fi rs t epi s ode i n what becomes a chroni c s t abl e angi nal pat t ern.





(c) Variant (Prinzmetal' s) angina 



(i) The hallmark of vari ant angi na i s t he appearance of t rans i ent ST -segment elevation

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on t he ECG duri ng t he angi na at t ack. The ST-s egment el evat i on repres ent s transmural ischemia produced by a s udden reduct i on i n coronary bl ood fl ow. 



(ii) The reduct i on i n fl ow res ul t s from transient coronary spasm, whi ch may or may not be as s oci at ed wi t h a fi xed at heros cl erot i c l es i on. The s pas m produces t ot al but t rans i ent coronary occl us i on.





(iii) Vari ant angi na us ual l y occurs at res t (oft en at ni ght ), and epi s odes frequent l y are compl i cat ed by compl ex vent ri cul ar arrhyt hmi as .





(3) Diagnosis. W hen a pat i ent exhi bi t s ches t pai n charact eri s t i c of angi na, t he di agnos i s can be s us pect ed s t rongl y on t he bas i s of pat i ent hi s t ory al one. The s us pi ci on t hat coronary di s eas e i s pres ent i s hei ght ened by t he pres ence of one or more coronary ri s k fact ors .

Pa g e 9 0




(a) Physical examination. Pat i ent s experi enci ng an epi s ode of angi na are us ual l y uncomfort abl e and anxi ous . Bl ood pres s ure and pul s e rat e are i ncreas ed i n mos t cas es .





(b) Resting electrocardiography. The ECG t aken i n t he abs ence of pai n i n pat i ent s wi t h angi na pect ori s wi t h no hi s t ory of MI i s normal i n 50% of cas es . Every effort s houl d be made t o obt ai n an ECG whi l e t he pat i ent i s experi enci ng ches t pai n. 



(i) The pres ence of new horizontal or downsloping ST segments on t he ECG i s hi ghl y s ugges t i ve of myocardi al i s chemi a. New T -wave inversion al s o may occur, but t hi s fi ndi ng al one wi t hout ST s egment depres s i on i s l es s s peci fi c. P.14



Pa g e 9 1




(ii) In t he pres ence of vari ant angi na, an acut e current of i njury i ndi cat ed by t rans i ent ST s egment el evat i on i s di agnos t i c. The ST s egment el evat i on normal i zes as t he pai n wanes and no Q waves appear.





(c) Stress electrocardiography. Recordi ng t he ECG duri ng exerci s e s ubs t ant i al l y i ncreas es t he s ens i t i vi t y and s peci fi ci t y of el ect rocardi ography. In addi t i on, a formal exerci s e t es t permi t s quant i fi cat i on of t he pat i ent 's exerci s e t ol erance and obs ervat i on of t he effect s of exerci s e on t he pat i ent 's s ympt oms , heart rat e, and bl ood pres s ure. 



(i) The appearance of hori zont al or downs l opi ng ST-s egment depres s i on of 1 mm or more duri ng exerci s e has a s ens i t i vi t y of approxi mat el y 70% and a s peci fi ci t y of 90% for t he det ect i on of

Pa g e 9 2


coronary di s eas e. 



(ii) The ST cri t eri a for pos i t i vi t y are l es s accurat e i n women t han i n men. An abnormal ST s egment on a res t i ng ECG, as s een i n l eft bundle branch block, left ventricular hypertrophy, or t he us e of digoxin by t he pat i ent all reduce the accuracy of this test.





(d) Stress scintigraphy, when us ed i n combi nat i on wi t h t he s t res s ECG, has yi el ded i ncreas ed s ens i t i vi t y (80%) and s peci fi ci t y (92%) over t he s t andard s t res s ECG al one. Therefore, i t i s a part i cul arl y us eful di agnos t i c t ool when t he s t andard s t res s ECG i s expect ed t o be of l ow yi el d (e.g., i n women and i n pat i ent s wi t h bundl e branch bl ock) and i n pat i ent s i n whom a previ ous s t res s ECG has produced equi vocal res ul t s . 

(i) Method. W hen t he radi oact i ve i s ot ope thallium 201 (

201

TI) or

t he t echnet i um-bas ed i s oni t ri l e sestamibi i s i nject ed i nt o t he peri pheral venous bl ood, t he myocardi al di s t ri but i on of t he

Pa g e 9 3


s ubs t ance i s affect ed by bl ood fl ow and i s chemi a, wi t h areas of l es s bl ood fl ow and i s chemi a t aki ng up l es s

201

TI or s es t ami bi t han

areas of normal bl ood fl ow. W i t h exerci s e, bl ood fl ow i ncreas es , but i n pat i ent s wi t h coronary art ery di s eas e, t hos e part s of t he myocardi um s uppl i ed by di s eas ed coronary art eri es and areas of MI t ake up l es s s ci nt i gram i n

201

TI or s es t ami bi t han normal areas , as s hown i n t he Onl i ne Fi gure 1-8. In pat i ent s who are unabl e t o

exerci s e, i nfus i on of dobut ami ne (t o i ncreas e oxygen demand) or di pyri damol e or adenos i ne (t o caus e coronary vas odi l at i on) are us ed t o al t er coronary fl ow. 

ONLINE FIGURE 1-8 Si ngl e Phot on Emi s s i on Comput ed Tomography (SPECT) i mages of myocardi al perfus i on ut i l i zi ng a radi o-l abel ed t racer were obt ai ned at peak s t res s (t op rows ) and at res t (mat ched bot t om rows ). Tomographi c â€œs l i ces â€• of t he heart were obt ai ned i n t hree axes (from t op t o bot t om): s hort axi s i mages â€œs l i ci ngâ€• from apex t o bas e; vert i cal l ong-axi s i mages â€œs l i ci ngâ€• from s ept um t o l at eral wal l ; and hori zont al l ong axi s i mages â€œs l i ci ngâ€• from pos t eri or t o ant eri or. The i mage i n (A) demons t rat es mat ched perfus i on of al l s egment s at bot h peak

Pa g e 9 4


s t res s and at res t . Thi s woul d be cons i dered an exampl e of a â€œnormal â€• myocardi al perfus i on s t res s t es t . The i mage i n (B) demons t rat es a rel at i vel y phot openi c regi on on t he peak s t res s i mages i nvol vi ng t he i nt ervent ri cul ar s ept um, ant eri or wal l and apex. Thi s defect normal i zes on t he res t i mages , and woul d be t ermed a â€˜revers i bl eâ€™ defect , whi ch i s charact eri s t i c of i s chemi a. The pat i ent had s evere proxi mal l eft ant eri or des cendi ng s t enos i s on angi ography. 



(e) Stress echocardiography. Two-di mens i onal echocardi ography can det ect regi onal i s chemi a by i dent i fyi ng areas of wal l mot i on abnormal i t i es t hat occur wi t h s t res s and are not pres ent at res t . Thi s regi onal dys funct i on i ndi cat es t hat t he area i nvol ved i s not recei vi ng adequat e bl ood fl ow. The s ens i t i vi t y i s s i mi l ar t o radi onucl eot i de i magi ng.





(f) Cardiac catheterization with coronary arteriography al l ows for di rect vi s ual i zat i on of t he coronary art eri es by s el ect i ve i nject i on of radi ographi c cont ras t mat eri al . Thi s procedure i s t he most sensitive and specific test commonly used for coronary artery disease. 

Pa g e 9 5




(i) Risk. Unl i ke t he previ ous l y ment i oned t es t s , cardi ac cat het eri zat i on i s an i nvas i ve procedure t hat carri es a s mal l but fi ni t e ri s k. The overal l ri s k of mort al i t y duri ng coronary art eri ography i s approxi mat el y 0.2%.





(ii) Applications. Cardi ac cat het eri zat i on s houl d be res erved for cas es i n whi ch t he di agnos i s i s uncert ai n aft er noni nvas i ve t es t i ng, when more i nformat i on i s needed t o hel p det ermi ne whet her medi cal or s urgi cal t herapy i s mos t appropri at e for t he pat i ent 's coronary di s eas e, or when i nt ervent i on i s neces s ary, as i n pat i ent s wi t h acut e STEMI or UA. If s urgery i s cont empl at ed, t he art eri ograms obt ai ned at cat het eri zat i on gui de t he s urgeon's pl acement of t he bypas s graft s .



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(g) Cardiac computed tomography (CT ). An emergi ng and pot ent i al l y powerful t ool for det ect i ng coronary art ery di s eas e i s cardi ac CT. The rol e of t hi s modal i t y has not yet been cl earl y es t abl i s hed.





(4) T herapy. Treat ment of angi na pect ori s i s di rect ed ei t her at reduci ng myocardi al oxygen demand t o compens at e for i mpai red fl ow t hrough di s eas ed coronary art eri es or at i ncreas i ng myocardi al oxygen s uppl y (i .e., bl ood fl ow). 



(a) Nitrates. Thi s cl as s of drugs produces venodi l at i on and, t o a l es s er ext ent , art eri ol ar vas odi l at i on. They may i ncreas e coronary bl ood fl ow and decreas e myocardi al oxygen demand by decreas i ng prel oad and aft erl oad. P.15





(b) Î²-Adrenergic blocking agents. Î²-Adrenergi c recept or s t i mul at i on res ul t s i n an i ncreas e i n heart rat e and i n

Pa g e 9 7


t he force of myocardi al cont ract i on. Bot h event s i ncreas e myocardi al oxygen demand. Î²-bl ockers count eract t hes e effect s and reduce myocardial oxygen demand. 



(c) Calcium channel blockers. Cal ci um regul at es t he cont ract i on of s moot h mus cl e, whi ch i s pres ent i n t he wal l s of t he coronary and peri pheral art eri es . Cal ci um channel bl ockers are part i cul arl y effective in preventing the coronary spasm that causes variant angina. They are al s o us eful i n t reat i ng cas es of t ypi cal angi na, i n whi ch t hey act as coronary and peripheral arterial vasodilators. The nondi hydropyri di ne cal ci um channel bl ockers , di l t i azem and verapami l , al s o reduce heart rat e and al l cal ci um channel bl ockers may decreas e bl ood pres s ure.





(d) Percutaneous coronary intervention (PCI). Removi ng or reduci ng t he obs t ruct i ve coronary at heros cl erot i c l es i on

Pa g e 9 8


can al l evi at e t he angi na. 



(i) Duri ng angi opl as t y, a s mal l bal l oon i s i ns ert ed i nt o a femoral or brachi al art ery and gui ded t o t he obs t ruct i on of t he affect ed coronary art ery. The bal l oon i s i nfl at ed, di l at i ng t he s t enos i s and reduci ng t he obs t ruct i on.





(ii) The i ni t i al s ucces s rat e of s i mpl e bal l oon angi opl as t y approaches 90%, al t hough t here i s a 33% res t enos i s rat e aft er 6 mont hs , maki ng i t neces s ary t o repeat t he procedure i n s ome pat i ent s . Pl acement of s mal l wi re stents reduces t he rat e of res t enos i s and now accompani es t he majori t y of angi opl as t i es . Today s ome s t ent s are coat ed wi t h s i rol i mus or pacl i t axel , whi ch reduces t he res t enos i s rat e t o approxi mat el y 5%. Co-admi ni s t rat i on of abci xi mab, a IIbâ€“IIIa pl at el et recept or ant i body, or ept i fi bat i de,

Pa g e 9 9


a IIbâ€“IIIa recept or ant agoni s t , al s o enhances s hort - and l ong-t erm pat ency. The us e of a t hi enopyri di ne, s uch as cl opi dogrel , i s es s ent i al aft er s t ent i ng t o prevent acut e t hrombos i s . 



(e) Coronary artery bypass grafting (CABG). CABG ext ends s urvi val i n pat i ent s wi t h s evere l eft mai n coronary art ery di s eas e or pat i ent s wi t h s evere t hree-ves s el di s eas e and depres s ed l eft vent ri cul ar funct i on. There i s cont i nued debat e regardi ng t he rol e of CABG vers us mul t i ves s el PCI i n pat i ent s wi t h s evere mul t i ves s el di s eas e and normal l eft vent ri cul ar funct i on. CABG may be preferabl e i n di abet i c pat i ent s wi t h mul t i ves s el di s eas e t hat i ncl udes t he l eft ant eri or des cendi ng art ery.





(f) Refractory angina. Several new t herapi es have emerged for t reat ment of refract ory angi na i ncl udi ng t rans myocardi al l as er

Pa g e 1 0 0


revas cul ari zat i on, enhanced ext racorporeal count er pul s at i on, and ranol azi ne. Thes e met hods can be cons i dered i n pat i ent s who cont i nue t o experi ence angi na des pi t e maxi mal t reat ment on convent i onal medi cal t herapy and revas cul ari zat i on. 



b. Myocardial infarction (MI) occurs when t he myocardi um i s depri ved of i t s bl ood s uppl y (and t herefore, oxygen) for a s i gni fi cant amount of t i me. 



(1) Pathogenesis. An abrupt change i n t he at heros cl erot i c pl aque s eems t o be one of t he event s preci pi t at i ng an MI. Pl aque rupt ure at t ract s pl at el et s t hat t ri gger t hrombus format i on, l eadi ng t o s evere s t enos i s or t ot al occl us i on of t he ves s el .





(2) Symptoms. The pat i ent us ual l y experi ences severe, oppressive chest pain or pressure t hat pers i s t s for more t han 30 mi nut es and i s unrel i eved by ni t rogl yceri n. The pai n radi at es i n a pat t ern s i mi l ar t o t hat of angi na pect ori s . 



(a) Frequent l y, nausea,

Pa g e 1 0 1


vomiting, diaphoresis, and shortness of breath accompany t he pai n. 



(b) An unus ual l y l arge number of i nfarct i ons occur between 6 A.M. and 10 A.M., when catecholamine levels increase on awakening.





(3) Diagnosis 



(a) Physical examination. The pat i ent experi enci ng MI i s i n obvi ous pai n, i s qui t e apprehens i ve, and oft en appears as hen. If t he i nfarct i on i s ext ens i ve, hypot ens i on and t achycardi a may be pres ent . There al s o may be s i gns of CHF (e.g., el evat i on of t he neck vei ns , pul monary ral es , and a cardi ac gal l op rhyt hm). The new murmur of mi t ral regurgi t at i on may be pres ent .





(b) Electrocardiography. The ECG i s di agnos t i c i n approxi mat el y 85% of cas es . The remai ni ng 15% of pat i ent s may experi ence MI wi t hout mani fes t i ng cl ear-cut evi dence

Pa g e 1 0 2


on t he ECG. P.16



(i) STEMI i s demons t rat ed by ST-s egment el evat i on i n t hos e l eads refl ect i ng t he area of t he MI. As t he ST s egment s fal l , Q waves appear, and t he T waves become i nvert ed

(onl i ne Fi gure 1-9).



Online Figure 1-9 Sequence of ECG changes duri ng t he evol ut i on of a myocardi al i nfarct . A. Smoot hi ng of ST s egment and T waves , maki ng i t di ffi cul t t o s ee where one ends and t he ot her begi ns . B. St rai ght eni ng of t he ST s egment , l os i ng t he upward concavi t y. C. El evat i on of t he s t rai ght ened ST s egment . D. ST el evat i on may al s o occur wi t hout l os s of t he upward concavi t y. E. Invers i on of t he T waves wi t h concave downward ST s egment s . F. Devel opment of Q waves wi t h i nvert ed T waves . The ST s egment remai ns el evat ed and concave downward. 



(ii) NSTEMI wi l l have l es s s peci fi c fi ndi ngs , s uch as ST depres s i on or T-wave i nvers i on.





(c) Cardiac enzyme studies 

Pa g e 1 0 3




(i) As myocardi al necros i s occurs , t he myocardi um rel eas es creatine kinase (CK), including the MB isoform, and troponins, t hereby i ncreas i ng s erum concent rat i ons of t hes e enzymes .





(ii) CK and t roponi n el evat i on appear 3 hours aft er i nfarct i on. CK and CK-MB us ual l y ret urn t o bas el i ne wi t hi n 2 days , but t roponi n may remai n el evat ed for up t o 10 days fol l owi ng an MI.





(4) T herapy 



(a) Initial medical therapy. For pat i ent s pres ent i ng wi t h ei t her an STEMI or NSTEMI, s everal medi cal t herapi es s houl d be i ni t i at ed, provi di ng t here are no cont rai ndi cat i ons . 



(i) Aspirin s houl d be gi ven i mmedi at el y t o bl ock pl at el et aggregat i on.



Pa g e 1 0 4




(ii) Oxygen s houl d be del i vered t o ens ure adequat e oxygenat i on of t i s s ues .





(iii) Nitroglycerin can al l evi at e pai n by vas odi l at i on, whi ch i ncreas es bl ood fl ow, t hereby decreas i ng oxygen demand and coronary vas os pas m.





(iv) Heparin s houl d be s t art ed i nt ravenous l y t o decreas e furt her cl ot format i on. IV hepari n i s preferred for STEMI, when an earl y i nt ervent i on i s pl anned, as i t can eas i l y be t urned off. LMW H may be preferabl e i n NSTEMI, when i nt ervent i on can be del ayed, as t here i s no need for dos e adjus t ment , and t he mort al i t y ri s k may be s l i ght l y l ower.





(v) Î²-blockers reduce vent ri cul ar arrhyt hmi as and t he ri s k of rei nfarct i on and decreas e t he workl oad and oxygen demand of t he heart . They s houl d be us ed wi t h caut i on i n pat i ent s wi t h s evere CHF, bradyarrhyt hmi as , or bronchos pas m.

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

(b) ST EMI. In STEMI, pers i s t ent t hrombot i c occl us i on i s pres ent i n t he majori t y of pat i ent s , l eadi ng t o necros i s of myocardi al t i s s ue t hat i s not bei ng perfus ed. Mort al i t y and morbi di t y are decreas ed wi t h t he es t abl i s hment of earl y reperfus i on of t he occl uded ves s el s , res t ori ng bl ood fl ow t o t he myocardi um. 



(i) PCI. If t he pat i ent pres ent s wi t hi n 12 hours of s ympt om ons et and i s abl e t o undergo PCI wi t hi n 90 mi nut es of pres ent at i on or i s i n cardi ogeni c s hock, PCI i s t he preferred met hod of t reat ment for an STEMI as i t offers t he bes t chance for reperfus i on and has i mproved out comes compared t o fi bri nol ys i s .





(ii) Fibrinolysis. If PCI i s not readi l y avai l abl e, fi bri nol ys i s t o di s s ol ve t he t hrombus and promot e reperfus i on s houl d be cons i dered. Fi bri nol yt i c agent s (s t rept oki nas e, t -PA, and uroki nas e) s houl d be admi ni s t ered wi t hi n 30 mi nut es of pres ent at i on. There i s a s i gni fi cant ri s k of bl eedi ng

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wi t h t hrombol yt i c t herapy and cont rai ndi cat i ons need t o be rul ed out before admi ni s t rat i on. 



(c) UA/NST EMI. In NSTEMI or UA, t here i s s evere coronary obs t ruct i on us ual l y wi t hout t ot al occl us i on of t he coronary art ery, and t hus t reat ment i s focus ed at s t abi l i zi ng t he pl aque and t reat i ng res i dual i s chemi a. 



(i) PCI. Immedi at e PCI i s not i ndi cat ed i n mos t pat i ent s , and i s as s oci at ed wi t h wors ened out comes i n UA/NSTEMI. Angi ography and pos s i bl e PCI are performed aft er s t abi l i zat i on i n hi gh-ri s k pat i ent s , pat i ent s who cont i nue t o have pai n des pi t e ant i -i s chemi c t herapy, or i n l ow-ri s k pat i ent s wi t h evi dence of i s chemi a on noni nvas i ve s t res s t es t i ng.





(ii) Additional antiplatelet agents are admi ni s t ered wi t h as pi ri n and have been s hown t o decreas e t he mort al i t y and morbi di t y as s oci at ed wi t h UA/NSTEMI. Clopidogrel

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furt her i nhi bi t s pl at el et act i vi t y by bl ocki ng adenos i ne di phos phat e (ADP) recept ors and prevent i ng aggregat i on. A l oadi ng dos e s houl d be gi ven fol l owed by dai l y oral dos i ng. Glycoprotein IIb/IIIa inhibitors s uch as ept i fi bat i de, t i rofi ban or abci xi mab prevent t he fi nal pat hway of pl at el et aggregat i on and are admi ni s t ered vi a IV i nfus i on. 



(d) Long-term secondary prevention therapy. In addi t i on t o modi fyi ng ri s k fact ors t hrough s moki ng ces s at i on and cont rol of hypert ens i on, di abet es , and hyperl i pi demi a, P.17

s everal cl as s es of medi cat i ons have been s hown t o have a mort al i t y benefi t when us ed pos t -MI. 



(i) Aspirin. Long-t erm as pi ri n t herapy i ncreas es t he l i kel i hood of pat ency of t he affect ed art eri es . If pat i ent s have an as pi ri n al l ergy, cl opi dogrel may be s ubs t i t ut ed.



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(ii) Î²-blockers. Long-t erm mort al i t y benefi t i s l i kel y due t o a combi nat i on of an ant i arrhyt hmi c effect and neurohormonal modul at i on.





(iii) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). Decreas i ng LDL i s es s ent i al i n l oweri ng t he ri s k of coronary heart di s eas e. St at i n t herapy al s o has an ant i -i nfl ammat ory effect t hat benefi t s mort al i t y i ndependent l y of l i pi d reduct i on.





(iv) Inhi bi t i on of t he reni nâ€“angi ot ens i nâ€“al dos t er one s ys t em wi t h ACEinhibitors or ARBs prevent s remodel i ng and decreas es t he ri s k of i s chemi c event s , and s houl d be us ed i n pat i ent s wi t h ant eri or MI or s ys t ol i c dys funct i on.



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(v) Clopidogrel added t o as pi ri n i mproves out comes aft er hos pi t al i zat i on i n pat i ent s wi t h NSTEMI,

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regardl es s of i n-hos pi t al t reat ment approach. 



(e) Automated implantable cardioverter-defibrillator (AICD). Pat i ent s wi t h pri or MI and a l eft vent ri cul ar eject i on fract i on (LVEF) of â‰¤40% or pat i ent s who have s urvi ved res us ci t at i on aft er cardi ac col l aps e not as s oci at ed wi t h acut e i nfarct i on s houl d be eval uat ed by a cardi ac el ect rophys i ol ogi s t . Such pat i ent s may be candi dat es for i ns ert i on of an AICD. AICDs moni t or t he heart rhyt hm and defi bri l l at e t he heart i f a l et hal rhyt hm i s det ect ed. Pat i ent s who recei ve frequent s hocks may be candi dat es for t he addi t i on of ant i arrhyt hmi c drugs or cat het er-bas ed abl at i on.



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(5) Prognosis. Fol l owi ng an MI, a pat i ent 's prognos i s i s l argel y det ermi ned by pump funct i on and res i dual i s chemi c burden. 



(a) Pump function. LV funct i on s houl d be as s es s ed fol l owi ng an MI by l eft vent ri cul ography, mul t i pl e gat ed acqui s i t i on s can (MUGA), or echocardi ogram. Prognos i s i s markedl y wors e for pat i ent s wi t h an LVEF of â‰¤40%.

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

(b) Residual ischemic risk. Al l pat i ent s who have an MI s houl d be eval uat ed by cardi ac cat het eri zat i on or s t res s t es t i ng t o det ermi ne t he ri s k of recurrent i s chemi a or i nfarct i on.





(6) Complications. An MI can occur wi t h l i t t l e cl i ni cal cons equence; i ndeed, many are s i l ent . The compl i cat i ons of MI, however, produce cl i ni cal l y s i gni fi cant event s . 



(a) Arrhythmias. A pat i ent havi ng an acut e MI i s s ubject t o acut e, lethal ventricular arrhythmias (i .e., vent ri cul ar t achycardi a or vent ri cul ar fi bri l l at i on), as wel l as less serious atrial arrhythmias (e.g., at ri al fi bri l l at i on, at ri al fl ut t er). The ri s k for a l et hal arrhyt hmi a i s great es t wi t hi n t he fi rs t 48 hours , requi ri ng cl os e moni t ori ng.





(b) Acute conduction system abnormalities. The s peci al i zed conduct i ng s ys t em of t he heart i s i t s el f myocardi um, whi ch may become i s chemi c or i nfarct ed duri ng an MI. Thi s may l ead t o bradyarrhyt hmi as , heart bl ock, or

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bot h. 



(i) Inferior MI us ual l y occurs when t he ri ght coronary art ery i s di s eas ed. Becaus e t hi s art ery s uppl i es t he SA node i n 55% of pat i ent s and t he AV node i n 85% of pat i ent s , sinus bradycardia and varyi ng degrees of AV nodal block can occur. Heart bl ock occurri ng duri ng i nferi or i nfarct i on i s al mos t al ways t rans i ent .





(ii) Anterior MI us ual l y occurs from occl us i on of t he ant eri or des cendi ng coronary art ery, whi ch s uppl i es t he i nt ervent ri cul ar s ept um. Becaus e t he bundl e branches cours e t hrough t he s ept um, acut e right or left bundle branch block may occur duri ng ant eri or MIs . Complete heart block al s o may occur due t o dys funct i on of bot h bundl e branches or t he bundl e of Hi s .





(c) Pump failure. W hen 30% of t he myocardi um i s i nfarct ed from one or more MIs , CHF i s l i kel y t o ens ue. If more t han 40% of t he myocardi um becomes i nfarct ed, cardiogenic

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shock i s l i kel y t o devel op. 



(d) Mitral regurgitation. The papillary muscles, whi ch are project i ons of t he myocardi um, t et her t he mi t ral val ve. Dys funct i on or i nfarct i on of t he papi l l ary mus cl es t oget her wi t h vent ri cul ar di l at at i on may l ead t o s ys t ol i c prol aps i ng of t he mi t ral val ve i nt o P.18

t he l eft at ri um, caus i ng varyi ng degrees of mi t ral regurgi t at i on. Thi s may l ead t o a preci pi t ous ri s e i n t he l eft vent ri cul ar fi l l i ng pres s ure t hat i s t rans mi t t ed t o t he l ungs , res ul t i ng i n pul monary edema. 



(e) Ventricular septal defect. The l eft vent ri cul ar s ept um may become i nfarct ed i n ei t her ant eri or or i nferi or MI, l eadi ng t o rupt ure of t he s ept um. Thi s occurs i n approxi mat el y 2% of pat i ent s , us ual l y 2â€“5 days aft er i nfarct i on.





(f) Cardiac rupture. MI of t he free wal l may l ead t o event ual perforat i on of t he heart . Thi s compl i cat i on, whi ch res ul t s i n overwhel mi ng cardiac tamponade, i s nearl y al ways fat al . Rarel y,

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rupt ure may be cont ai ned by adherent peri cardi um formi ng a ps eudoaneurys m. Surgi cal correct i on i s neces s ary. 



(g) Left ventricular aneurysm. The i nfarct ed zone of t he myocardi um may evagi nat e and heal wi t h fi brous connect i ve t i s s ue, formi ng an aneurys m. Left vent ri cul ar aneurys ms may produce cardi ac fai l ure and angi na, and t hey al s o may be t he s ource of s evere l eft vent ri cul ar arrhyt hmi as and s ys t emi c embol i .



(7) T reatment of complications 



(a) Antiarrhythmic therapy. If s eri ous vent ri cul ar arrhyt hmi as occur, ami odarone or l i docai ne i s i nfus ed. Addi t i onal drugs may be neces s ary t o cont rol arrhyt hmi as i f l i docai ne i s i neffect i ve. Bretylium tosylate, procainamide, and intravenous Î²-blockers may be us eful i n cont rol l i ng acut e recal ci t rant arrhyt hmi as . Thes e agent s are gi ven i nt ravenous l y wi t h caut i on.

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(b) Correction of serious conduction disturbances. As

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not ed, hi gh-degree AV nodal bl ock may occur duri ng acut e MI, produci ng s i gni fi cant bradycardi a and hypot ens i on. Therapi es for res t ori ng heart rat e i ncl ude: 



(i) Atropine (1 mg i nt ravenous l y) may res t ore conduct i on and i ncreas e heart rat e, es peci al l y i n i nferi or i nfarct i ons . If t hi s fai l s , an i nfus i on of a pos i t i ve chronot ropi c agent s uch as isoproterenol (or us e of a transcutaneous electronic pacemaker) i ncreas es heart rat e. Thes e t herapi es are di rect ed at mai nt ai ni ng heart rat e unt i l temporary transvenous pacemaking can be performed.





(i i ) In cas es of s evere l eft vent ri cul ar dys funct i on, at ri al s ys t ol e mus t be pres erved t o mai nt ai n cardi ac out put , and AV sequential pacemaking i s t he preferred t reat ment .

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(i i i ) The occurrence of new bundle branch block â€”part i cul arl y t he combi nat i on of ri ght bundl e branch bl ock

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and l eft ant eri or hemi bl ockâ€”may be an i ndi cat i on for temporary prophylactic pacemaking becaus e t hes e di s t urbances may pres age t he occurrence of compl et e heart bl ock; however, t hi s t act i c i s cont rovers i al and obvi at ed by t he avai l abi l i t y of t rans cut aneous paci ng. 



(c) T reatment of heart failure 



(i) Mi l d CHF i n pat i ent s wi t h MI can be t reat ed wi t h diuretics.





(ii) The us e of digitalis duri ng acut e MI i s s afe but of l i mi t ed effi cacy.



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(iii) In more advanced cas es of CHF, vasodilators may be us eful i n reduci ng cardi ac aft erl oad, al l owi ng i ncreas ed cardi ac out put .



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(d) T reatment of cardiogenic shock. Shock i n t he pres ence of MI us ual l y i s at t ri but abl e t o i nadequat e l eft vent ri cul ar fi l l i ng,

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s evere mus cl e damage, or a mechani cal compl i cat i on of t he MI. W hen s hock ens ues , an echocardiogram i s performed t o as s es s vent ri cul ar funct i on, and a Swan-Ganz catheter s houl d be pl aced t o meas ure l eft vent ri cul ar fi l l i ng pres s ure. 



(i) If t he pul monary capi l l ary wedge pres s ure i s l es s t han 18 mm Hg, volume is infused to maximize left ventricular filling and cardi ac out put . In addi t i on, i f a new cardi ac murmur i s det ect ed, t he echocardi ogram and t he Swan-Ganz cat het er are us eful i n maki ng t he di agnos i s of acut e mi t ral regurgi t at i on or acut e vent ri cul ar s ept al defect .

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(ii) Al t ernat i vel y, i f cardi ogeni c s hock i s caus ed by s evere mus cl e damage, inotropic agents (e.g., dobut ami ne, mi l ri none) and intra-aortic balloon pumping may be us ed t o s t abi l i ze t he pat i ent unt i l coronary art eri ography and rees t abl i s hment of coronary bl ood fl ow by PCI are carri ed

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out . However, t he prognos i s for s uch pat i ent s remai ns very poor des pi t e t herapy. 

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(e) T reatment of mitral regurgitation and acute ventricular septal defect 



(i) Arteriolar vasodilator therapy t o l ower s ys t emi c vas cul ar res i s t ance i s t he mai ns t ay of medi cal t herapy for t hes e compl i cat i ons . Reduct i on of s ys t emi c vas cul ar res i s t ance preferent i al l y i ncreas es forward cardi ac out put and reduces nonproduct i ve cardi ac out put , ei t her i nt o t he l eft at ri um (i n t he cas e of mi t ral regurgi t at i on) or t hrough t he vent ri cul ar s ept al defect .



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(ii) Intra-aortic balloon pumping, whi ch al s o i ncreas es forward cardi ac out put and reduces nonproduct i ve cardi ac out put , i s us eful i n s t abi l i zi ng pat i ent s wi t h mi t ral regurgi t at i on or acut e vent ri cul ar s ept al defect , es peci al l y i n hypot ens i ve pat i ent s , where t he us e of

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vas odi l at ors i s cont rai ndi cat ed. 

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(iii) Surgical correction of mechanical complications oft en i s requi red.

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c. Sudden death i n pat i ent s wi t h coronary art ery di s eas e i s common; i n fact , approxi mat el y one-t hi rd of pat i ent s wi t h coronary di s eas e experi ence s udden deat h wi t hout ant ecedent angi na or MI. 



(1) Precipitating causes. It i s bel i eved t hat mos t pat i ent s di e of acute ventricular arrhythmias preci pi t at ed by i s chemi a. Al t hough s udden deat h may be t he res ul t of an MI s econdary t o coronary art ery di s eas e, mos t pat i ent s who di e s uddenl y and are res us ci t at ed do not have an acut e MI document ed. It i s l i kel y t hat i n t hes e pat i ent s , i s chemi a produces het erogeneous depol ari zat i on of t he vent ri cl e, whi ch l eads t o vent ri cul ar t achycardi a and vent ri cul ar fi bri l l at i on.



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(2) Acute therapy 

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(a) Cardiopulmonary resuscitation (i .e., mout h-t o-mout h res us ci t at i on and ext ernal ches t

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compres s i on) mus t be i ni t i at ed i n t he eut hermi c pat i ent wi t hi n 4 mi nut es of t he ces s at i on of effect i ve vent ri cul ar cont ract i on t o pres erve neurol ogi c and myocardi al funct i on. 



(b) Electrical defibrillation and drug support s houl d be provi ded as s oon as pos s i bl e.

B. Nonatherosclerotic coronary artery disease Al t hough t he majori t y of cardi ac i s chemi c event s are caus ed by at heros cl erot i c coronary di s eas e, nonat heros cl erot i c di s eas e al s o may produce cl i ni cal i s chemi a. 



1. Coronary embolism occurs i n i nfect i ve endocardi t i s , from mural t hrombus format i on fol l owi ng MI, and i n t he pres ence of at ri al fi bri l l at i on. Coronary embol i s m frequent l y produces MI.

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2. Collagen vascular disease. The col l agen vas cul ar di s eas es t hat affect medi um-s i zed art eri es , i ncl udi ng t he coronary art eri es , are: polyarteritis nodosa, Wegener' s granulomatosis, systemic lupus erythematosus (SLE), and, occas i onal l y, rheumatoid arthritis.

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3. Radiation therapy. Tumor i rradi at i on, i n whi ch t he

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fi el d of radi at i on i ncl udes t he heart , damages t he coronary art eri es and l eads t o nonat heros cl erot i c coronary art ery di s eas e. 

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4. T ransplantation. The devel opment of coronary di s eas e fol l owi ng cardi ac t rans pl ant at i on i s a major fact or i n l i mi t i ng t he s ucces s of t hi s t herapy. Pos t -t rans pl ant at i on coronary di s eas e t ends t o be di s t al i n l ocat i on and di ffus e i n nat ure. It i s probabl y part i al l y at t ri but abl e t o chroni c reject i on of t he organ and i s not cl os el y rel at ed t o t he pres ence of t he s t andard ri s k fact ors for coronary di s eas e.

IV. Valvular Heart Disease A. Aortic stenosis 



1. Etiology o

o

a. Congenital aortic stenosis us ual l y i s det ect ed i n pedi at ri c pat i ent s but occas i onal l y becomes apparent i n earl y adul t hood.

o

o

b. Senile calcific aortic stenosis occurs when s carri ng and cal ci fi cat i on of a t ri cus pi d aort i c val ve l ead t o ori fi ce narrowi ng i n t he s i xt h, s event h, and ei ght h decades of l i fe. Al t hough once cons i dered a â€œdegenerat i veâ€• i di opat hi c di s eas e, i t i s now cl ear t hat t he pat hol ogy l eadi ng up t o s evere aort i c s t enos i s i s due t o prol i ferat i ve and i nfl ammat ory changes l eadi ng t o cal ci fi cat i on, s i mi l ar t o t he devel opment of t he pl aque i n ASCAD.

o

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o

c. Bicuspid aortic valve i s a common congeni t al cardi ac abnormal i t y. The fl ow charact eri s t i cs of t he bi cus pi d val ve are more t urbul ent t han t hos e of t he normal val ve, l eadi ng t o val ve i njury, cal ci fi cat i on, and s t enos i s i n t he fourt h and fi ft h decades of l i fe.

o

o

d. Rheumatic aortic stenosis never occurs al one and i s al ways as s oci at ed wi t h mi t ral val ve di s eas e.

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

2. Pathophysiology. Aort i c val ve s t enos i s produces a pres s ure overl oad on t he l eft vent ri cl e due t o t he great er pres s ure t hat mus t be generat ed t o force bl ood pas t t he s t enot i c val ve. Thi s commonl y l eads t o compens at ory l eft vent ri cul ar hypert rophy.

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

3. Clinical features o

o

a. Symptoms. As ympt omat i c pat i ent s wi t h aort i c s t enos i s are at l i t t l e ri s k for s udden deat h. However, t hi s ri s k i ncreas es dramat i cal l y when s ympt oms devel op. 

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(1) Angina occurs i n 35%â€“50% of pat i ent s wi t h aort i c s t enos i s . 

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(a) Fi ft y percent of pat i ent s who devel op t hi s s ympt om di e wi t hi n 5 years of i t s ons et unl es s aort i c val ve repl acement i s performed.



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(b) Al t hough t he exact mechani s m of angi na i s unknown, current dat a s ugges t t hat coronary bl ood fl ow res erve i s i mpai red i n t he s everel y hypert rophi ed l eft vent ri cl e. Impai rment of t he coronary bl ood fl ow res erve l i mi t s oxygen del i very t o t he myocardi um and produces angi na duri ng exerci s e.

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(2) Syncope occurs duri ng exerci s e when t ot al peri pheral res i s t ance fal l s due t o l ocal aut oregul at ory mechani s ms [s ee IX B, C 1 b (2) (b)]. W hen aort i c s t enos i s i s pres ent , cardi ac out put acros s t he s t enot i c aort i c val ve cannot i ncreas e duri ng exerci s e. Becaus e t ot al peri pheral res i s t ance fal l s , bl ood pres s ure mus t al s o fal l , and s yncope occurs . 

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(a) Other causes of s yncope i n aort i c s t enos i s i ncl ude a refl ex vas odepres s or res pons e t o hi gh i nt ravent ri cul ar pres s ure, atrial or ventricular arrhythmias, and heart block as a res ul t of conduct i on s ys t em cal ci fi cat i on. P.19

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(b) Aft er s yncope occurs i n pat i ent s wi t h aort i c s t enos i s , expect ed s urvi val i s 2â€“3 years wi t hout val ve repl acement .

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(3) Heart failure. Fi ft y percent of pat i ent s who devel op heart fai l ure di e wi t hi n 1â€“2 years of pres ent at i on i f t he s t enos i s i s not correct ed. Heart fai l ure occurs becaus e t he aft erl oad pl aced on t he myocardi um becomes exces s i ve and bot h cont ract i l e dys funct i on and di as t ol i c mus cl e dys funct i on occur when t he myocardi um i s expos ed t o a prol onged, s evere pres s ure overl oad.

o

o

b. Physical signs 



(1) Delayed carotid upstroke. In t he pres ence of aort i c s t enos i s , t he carot i d ups t roke t ypi cal l y i s del ayed i n t i mi ng and reduced i n vol ume (pul s us parvus et t ardus ). Thi s fi ndi ng i s t he mos t rel i abl e phys i cal s i gn i n gaugi ng t he s everi t y of t he di s eas e.

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(2) Systolic ejection murmur. A hars h, l at e-peaki ng s ys t ol i c eject i on murmur i s heard i n t he aort i c area and i s t rans mi t t ed t o t he carot i d art eri es . The murmur al s o may be refl ect ed t o t he mi t ral area, produci ng t he fal s e i mpres s i on t hat mi t ral regurgi t at i on al s o i s pres ent (Gallavardin' s phenomenon).

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(3) Soft, single S 2 . Becaus e t he aort i c val ve i s s t enot i c, i t s mot i on i s s everel y i mpai red. The reduct i on i n mot i on of t he val ve caus es t he aortic component (A 2 ) of t he S 2 t o be abs ent . Thus , t he onl y component of t he S 2

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t hat i s heard i s t he pulmonic component (P 2 ) , whi ch i s normal l y s oft . 

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(4) S 4 . An S 4 us ual l y i s heard as a res ul t of t he reduced l eft vent ri cul ar compl i ance t hat occurs i n l eft vent ri cul ar hypert rophy.

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(5) Sustained, forceful apex beat. The poi nt of maxi mal cardi ac i mpul s e us ual l y i s not di s pl aced unl es s heart fai l ure has occurred. However, t he i mpul s e i s s us t ai ned and forceful t hroughout s ys t ol e.





4. Laboratory diagnosis o

o

a. Electrocardiography. The ECG us ual l y s hows evi dence of l eft vent ri cul ar hypert rophy.

o

o

b. Echocardiography can rul e out s i gni fi cant aort i c s t enos i s i f val ve mot i on i s s hown t o be normal . However, Doppl er exami nat i on of t he aort i c out fl ow t ract duri ng echocardi ography can accurat el y meas ure t he pres s ure gradi ent acros s t he aort i c val ve, and can be us ed t o cal cul at e t he val ve area.

o

o

c. Cardiac catheterization. Di agnos i s and eval uat i on of t he s everi t y of aort i c s t enos i s may be confi rmed by cardi ac cat het eri zat i on, duri ng whi ch t he pres s ure gradi ent acros s t he val ve i s meas ured and t he degree of s t enos i s i s cal cul at ed.



Pa g e 1 2 5




5. T herapy o

o

a. Palliative therapy 



(1) Medical therapy has no defi ni t i ve rol e i n t he t reat ment of aort i c s t enos i s , but diuretics may t emporari l y rel i eve t he s ympt oms of vol ume overl oad unt i l mechani cal rel i ef of t he obs t ruct i on i s performed.





(2) Ins ert i on and i nfl at i on of a l arge bal l oon i n t he aort i c val ve ori fi ce (balloon valvuloplasty) al s o may produce a moderat e i mprovement i n t he amount of obs t ruct i on and i n t he s ympt oms , but rel i ef from us i ng t hi s t echni que i s us ual l y onl y t emporary. It does not reduce t he mort al i t y expect ed i f t he di s eas e i s l eft unt reat ed.





b. Curative therapy requi res aortic valve replacement, whi ch may be performed us i ng a pres erved human homograft val ve, a bi opros t het i c het erograft val ve, a mechani cal val ve, or a pul monary aut ograft . 



(1) Homograft valves. The hemodynami c fl ow pat t ern i s excel l ent , and pat i ent s wi t h homograft val ves do not requi re ant i coagul at i on t herapy. Avai l abi l i t y of t hes e val ves i s l i mi t ed, becaus e mos t s ui t abl e donors are al s o

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accept abl e for whol e heart donat i on i n cardi ac t rans pl ant at i on. 



(2) Heterograft valves. Pat i ent s wi t h het erograft val ves do not requi re ant i coagul at i on t herapy, but t he durabi l i t y of t he val ve i s l i mi t ed, and det eri orat i on aft er 10 years i s common.





(3) Mechanical valves. Pat i ent s wi t h mechani cal val ves do requi re ant i coagul at i on t herapy. However, t hes e val ves are more durabl e t han bi opros t hes es .





(4) Autograft (Ross procedure). In t hi s procedure, t he pat i ent 's normal pul monary val ve i s t rans pl ant ed i nt o t he aort i c pos i t i on, where i t has excel l ent durabi l i t y and l ongevi t y. A P.20

homograft i s t hen i ns ert ed i nt o t he pul monary pos i t i on, where l ow pres s ure enhances homograft l ongevi t y. In pract i ced hands , t he res ul t s of t hi s procedure are excel l ent .

B. Mitral stenosis 



1. Etiology. Al mos t al l cas es of mi t ral s t enos i s i n adul t s are secondary to rheumatic heart disease. Mos t cas es

Pa g e 1 2 7


occur i n women. 



2. Pathophysiology o

o

a. Mi t ral val ve s t enos i s i mpedes l eft vent ri cul ar fi l l i ng, t hereby i ncreas i ng l eft at ri al pres s ure as a pres s ure gradi ent devel ops acros s t he mi t ral val ve. El evat ed l eft at ri al pres s ure i s referred t o t he l ungs , where i t produces pulmonary congestion. As t he s t enos i s becomes more s evere, i t may s i gni fi cant l y reduce forward cardi ac out put .

o

o

b. Becaus e t he ri ght vent ri cl e i s res pons i bl e for fi l l i ng t he l eft vent ri cl e, t he burden of propel l i ng bl ood acros s t he s t enot i c mi t ral val ve i s borne by t he ri ght vent ri cl e. The overl oad on t he ri ght vent ri cl e may be i ncreas ed furt her when s econdary pul monary vas ocons t ri ct i on occurs . Thus , t he ri ght vent ri cl e mus t generat e enough force bot h t o overcome t he res i s t ance offered by t he s t enot i c val ve and t o propel bl ood t hrough cons t ri ct ed pul monary art eri es . Cons equent l y, pul monary art eri al pres s ure may i ncreas e t o t hree t o fi ve t i mes normal , event ual l y res ul t i ng i n right ventricular failure.






o

a. Symptoms 



(1) Left-sided failure. Dyspnea on exertion,

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orthopnea, and paroxysmal nocturnal dyspnea occur as a res ul t of reduced l eft vent ri cul ar out put and i ncreas ed l eft at ri al pres s ure. In mi t ral s t enos i s , t he s ympt oms of l eft vent ri cul ar fai l ure us ual l y are not at t ri but abl e t o l eft vent ri cul ar dys funct i on but , rat her, t o t he mi t ral s t enos i s i t s el f. 



(2) Right-sided failure. W hen pul monary hypert ens i on occurs , t he ri ght vent ri cl e may fai l , produci ng edema, ascites, anorexia, and fatigue.





(3) Hemoptysis. The hi gh l eft at ri al pres s ure produced i n mi t ral s t enos i s may l ead t o rupt ure of s mal l bronchi al vei ns , produci ng hemopt ys i s .





(4) Systemic embolism. St agnat i on of bl ood i n t he enl arged l eft at ri um and l eft at ri al appendage occurs i n mi t ral s t enos i s , part i cul arl y i f at ri al fi bri l l at i on i s pres ent . Under t hes e ci rcums t ances , a t hrombus may form i n t he l eft at ri um and can become a s ource of s ys t emi c embol i s m.





(5) Hoarseness may occur i n mi t ral s t enos i s as t he enl arged l eft at ri um i mpi nges on t he l eft recurrent l aryngeal nerve (Ort ner's s yndrome).

o

o

b. Physical signs

Pa g e 1 2 9




(1) Atrial fibrillation. Frequent l y, an i rregul arl y i rregul ar cardi ac rhyt hm i ndi cat i ve of at ri al fi bri l l at i on i s pres ent .





(2) Pulmonary rales. Bi l at eral pul monary ral es occur s econdary t o el evat ed l eft at ri al and pul monary venous pres s ures .





(3) Increased intensity of the S 1 . The S 1 us ual l y i ncreas es i n i nt ens i t y becaus e t he t rans mi t ral gradi ent l i mi t s s pont aneous di as t ol i c mi t ral val ve cl os ure. Thus , t he mi t ral val ve remai ns open unt i l vent ri cul ar s ys t ol e cl os es i t forci bl y, res ul t i ng i n an i ncreas e i n S 1 i nt ens i t y. Lat e i n t he cours e of t he di s eas e, t he val ve may become s o s t enot i c t hat i t no l onger opens or cl os es , reduci ng t he i nt ens i t y of S 1 .





(4) Increased intensity of the P 2 component of t he S 2 . The P 2 component of t he S 2 i s us ual l y i ncreas ed i n i nt ens i t y i f pul monary hypert ens i on has devel oped.





(5) Opening snap. An opening snap is heard following the S 2 as t he s t enot i c val ve i s forced open i n di as t ol e by t he hi gh l eft at ri al fi l l i ng pres s ure. The hi gher t he pres s ure, t he s ooner t he mi t ral val ve opens . Thus , a s hort i nt erval ( T able of Cont ent s > Chapt er 2 - Pulmonary Diseases

Chapter 2

Pulmonary Diseases Alexandra Pratt Pamela J. Amelung

I. Pulmonary Function Studies (

Onl i ne Fi gures 2-1, 2-2, 2-3, 2-4, 2-5, 2-6; Onl i ne Tabl e 2-1)

ONLINE FIGURE 2-1. Typi cal fl ow-vol ume l oop (obs erved duri ng s pi romet ry) i n (A) a s ubject wi t h normal l ung funct i on, and i n s ubject s wi t h (B) obs t ruct i ve or (C) res t ri ct i ve l ung di s eas e. FEF, forced expi at ory fl ow; TLC, t ot al l ung capaci t y; VC, vi t al capaci t y; RV, res i dual vol ume.

Pa g e 2 3 1


ONLINE FIGURE 2-2. The s ubdi vi s i ons of l ung vol ume as recorded by a s pi romet er. The record i s generat ed on paper cal i brat ed for vol ume i n t he vert i cal di rect i on and t i me i n t he hori zont al . The t erm capacity i s appl i ed t o a s ubdi vi s i on compos ed of t wo or more vol umes .

Page 232


ONLINE FIGURE 2-3. Pres s ureâ€“vol ume curves of t he l ung. The curves for emphys ema and as t hma (duri ng bronchos pas m) are s hi ft ed upward and t o t he l eft , whereas t hos e for rheumat i c val ve di s eas e and i nt ers t i t i al fi bros i s are fl at t ened. (Repri nt ed wi t h permi s s i on from Bat es DV, Mackl em PT, Chri s t i e RV. Res pi rat ory Funct i on i n Di s eas e, 2nd ed. Phi l adel phi a: W B Saunders , 1971:9. )

Pa g e 2 3 3


ONLINE FIGURE 2-4 Exampl es of vent i l at i on perfus i on and t he qual i t y: (A) normal i deal i zed al veol ar capi l l ary exchange uni t ; (B) exampl es of decreas ed vent i l at i onâ€“perfus i on uni t s , as a res ul t of al veol ar s ecret i ons or ai rway obs t ruct i on; (C) exampl es of i ncreas ed vent i l at i onâ€“perfus i on uni t s owi ng t o t he pres ence of emphys ema or probl ems i n t he pul monary vas cul ar bed, s uch as pul monary embol i s m or pul monary vas os pas m. (Repri nt ed wi t h permi s s i on from Cri ner GJ, D'Al onzo GE, eds .: Pul monary Pat hophys i ol ogy, Fence Creek Publ i s hi ng, LLC: Madi s on, Connect i cut , 1999. )

Page 234


ONLINE FIGURE 2-5. Exampl es of i nt rapul monary s hunt : (A) col l aps e of fl ui d-fi l l ed al veol us ; (B) t he effect of anomal ous bl ood ret urn of mi xed bl ood bypas s i ng t he al veol us , and cont ri but i ng t o i nt rapul monary s hunt . (Repri nt ed wi t h permi s s i on from Cri ner GE, D'Al onzo GE, eds .: Pul monary Pat hophys i ol ogy, Fence Creek Publ i s hi ng, LLC: Madi s on, Connect i cut , 1999. )

ONLINE FIGURE 2-6. Res pons e of vent i l at i onâ€“perfus i on i nequal i t y and i nt rapul monary s hunt t o s uppl ement al oxygen: (A) Even wi t h t he pres ence of s evere [V wi t h dot above]/[Q wi t h

Page 235


dot above] i nequi t y, hi gh l evel s of s uppl ement al oxygen have a profound i mpact on i ncreas i ng art eri al PO 2 ; (B) By cont ras t , i nt rapul monary s hunt s of 30% or great er are rel at i vel y refract ory t o s uppl ement al oxygen. (Adapt ed from Dant z ker MD, Davi d R. Pul monary Gas Exchange, i n Bone R. ed., Pul monary and Cri t i cal Care Medi ci ne. St . Loui s : Mos by, 1997. )

A. Introduction Tes t s of pul monary funct i on provi de t hree bas i c ki nds of i nformat i on: 



1. Lung volumes are t he vol umes of t he vari ous i nt rapul monary compart ment s . o

o

a. Static lung volumes refl ect t he el as t i c propert i es of t he l ungs and ches t wal l .

o

o

b. Dynamic lung volumes refl ect t he pat ency of t he ai rways .





2. The expiratory flow rate i s t he maxi mum rat e of ai rfl ow duri ng forced expi rat i on. o

o

a. The rat e of ai rfl ow i s i nfl uenced by l ung vol ume and by effort (i .e., force of expi rat i on). Ai rfl ow i ncreas es wi t h i ncreas i ng effort , es peci al l y at hi gh l ung vol umes [>75% of t he vi t al capaci t y (VC)].

o

o

b. Ot her fact ors i nfl uenci ng fl ow rat e i ncl ude t he el as t i c recoi l of t he l ung, s mal l peri pheral ai rway res i s t ance, and t he cros s -s ect i onal area of l arger

Pa g e 2 3 6


cent ral ai rways . 



3. Diffusing capacity of the lung for carbon monoxide (D L C O ) i s t he effi ci ency of gas t rans fer from t he al veol i t o pul monary capi l l ary bl ood.

B. Spirometry 



1. Definition. Spi romet ry i s a s i mpl e t es t of pul monary funct i on. The s pi romet er devi ce pl ot s a t raci ng (t he spirogram) of t he l ung vol ume agai ns t t i me (i n s econds ) whi l e t he pat i ent t akes as deep a breat h as pos s i bl e and t hen exhal es al l of t he i ns pi red ai r as rapi dl y and forceful l y as pos s i bl e.





2. Uses. Spi romet ry can ai d i n di s t i ngui s hi ng obs t ruct i ve from res t ri ct i ve l ung di s eas es (onl i ne Tabl e 2-1) as wel l as s ugges t t he s everi t y of funct i onal i mpai rment and i t s revers i bi l i t y wi t h t reat ment . It i s us eful bot h as a di agnos t i c ai d and as a moni t ori ng t ool .

ONLINE TABLE 2-1 Obstructive and Restrictive Lung Disorders

Pa g e 2 3 7


Pri ma rily ob str uct ive ve ntil ato ry def ect s (di s or der s cha rac t eri z ed by red uce d fl o w rat es ) Chr oni c obs t ru

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ct i ve pul mo nar y di s eas e Chr oni c bro nch itis Pul mo nar y em phy se ma As t hm a Cys tic fi br os i s Pri ma rily res

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tric tiv e ve ntil ato ry def ect s (di s or der s cha rac t eri z ed by red uce d l un g vol um es ) Par enc hy ma l di s ord ers

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Al v eol ar an d i nt ers titi al pro ces s es (e. g., ed em a, fi br os i s, i nf ect i on ) Lar ge s pa ceocc upy i ng l es i on s At e

Pa g e 2 4 1


l ec t as is Re s ec tio n of pul mo nar y tis s ue Ch es t wal l di s eas e Ob es i ty Ky ph os c ol i os i s An kyl os i ng s po

Pa g e 2 4 2


ndy liti s Pl e ura l di s eas e Eff us i on Pn eu mo t ho rax Fi b rot hor ax Ne uro mu s cu l ar di s eas es Gui l l ai n Bar rÃ ©

Pa g e 2 4 3


s yn dro me Spi nal cor d i nj ury Mu s cu l ar dys t ro phi es Pol io my el i t is

C. Values obtainable from the spirogram Many s pi rogram meas urement s are s t at ed as a percent age of predicted values t hat are det ermi ned from many normal i ndi vi dual s grouped on t he bas i s of s ex, age, and hei ght . The range of normal i s 80%â€“120% of t he predi ct ed val ue. 



1. T idal volume (VT ) i s t he vol ume of ai r i n one breat h duri ng normal qui et breat hi ng. The VT (normal , 500â€“800 mL) vari es accordi ng t o effort and l evel of vent i l at i on. The port i on of t he VT t hat part i ci pat es i n gas exchange i s t he alveolar volume (VA); t he remai n der, approxi mat el y 30% of t he VT, i s â€œwas t edâ€• or dead space.

Pa g e 2 4 4




2. Vital capacity (VC) i s t he maxi mum vol ume of ai r t hat can be expel l ed from t he l ungs aft er a maxi mal i ns pi rat i on. Becaus e VC decreas es progres s i vel y wi t h res t ri ct i ve l ung di s eas e, i t i s us eful , i n conjunct i on wi t h D LC O (s ee I E 1), for moni t ori ng t he cours e and res pons e t o t herapy i n a pat i ent wi t h a res t ri ct i ve l ung di s order.





3. Forced vital capacity (FVC) i s t he s ame as VC, except t hat t he i nhal at i on i s performed as rapi dl y and forceful l y as pos s i bl e. Forced expi rat i on caus es t he ai rways t o narrow, t hereby s l owi ng t he rat e of expi rat i on.





4. Forced expiratory volume in 1 second (FEV 1 ) i s t he vol ume of ai r forceful l y expi red duri ng t he fi rs t s econd aft er a deep breat h, or t he port i on of t he FVC exhal ed i n 1 s econd. The FEV 1 pri mari l y refl ect s t he s t at us of l arge ai rways .





5. FEV 1 /FVC i s t he rat i o of t he FEV 1 t o FVC, expres s ed as a percent age (normal , â‰¥70%). (Not e: In t hi s cas e, percent age i s not a percent age of predi ct ed normal .) The FEV 1 /FVC i s effort dependent (i .e., i t i ncreas es wi t h i ncreas i ng expi rat ory effort ). FEV 1 /FVC i s part i cul arl y us eful i n eval uat i ng obs t ruct i ve di s orders but i s al s o hel pful i n t he eval uat i on of res t ri ct i ve di s orders . If onl y t he FEV 1 i s l ow (FEV 1 /FVC 60 years ). There i s progres s i ve exert i onal dys pnea, wei ght l os s , and l i t t l e or no cough and expect orat i on. 



(a) Pul monary funct i on t es t i ng i ndi cat es mi l d hypoxi a, hypocapni a, decreas ed D LC O , onl y a mi l d i ncreas e i n Raw, and l i t t l e i mprovement i n ai rfl ow aft er t reat ment wi t h bronchodi l at ors .





(b) Thes e pat i ent s us ual l y undergo a s l owl y progres s i ve downhi l l cours e.





(2) Blue bloaters have predomi nant chroni c

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bronchi t i s and, at a rel at i vel y young age, experi ence chroni c cough and expect orat i on, epi s odi c dys pnea, and wei ght gai n. W heezi ng and rhonchi frequent l y are heard i n t he ches t , and cor pul monal e oft en devel ops , accompani ed by edema and cyanos i s . 



(a) Pul monary funct i on t es t i ng i ndi cat es s evere hypoxi a, hypercapni a, pol ycyt hemi a, i ncreas ed Raw, i mproved ai rfl ow aft er t reat ment wi t h bronchodi l at ors , and rel at i vel y pres erved l ung vol umes and D LC O .





(b) Pat hol ogi cal l y, t here i s mi ni mal emphys ema but s i gni fi cant bronchi ol i t i s , bronchi t i s , mucous gl and hyperpl as i a, and ri ght vent ri cul ar hypert rophy. Thi s cont ras t s wi t h pat hol ogi c fi ndi ngs i n pi nk puffers , whi ch s how pri mari l y emphys ema.

o

o

b. Pat i ent s wi t h emphys ema have proport i onal and mat ched l os s es of vent i l at i on and perfus i on and, hence, are s pared s evere hypoxemi a. In cont ras t , pat i ent s wi t h chroni c bronchi t i s have P.55

marked [V wi t h dot above]/[Q wi t h dot above] mi s mat ch, res ul t i ng i n s evere hypoxemi a. The hypoxi a i n chroni c bronchi t i s i s wors ened by t he hypercapni a, whi ch may be t he res ul t of res pi rat ory mus cl e dys funct i on.

Pa g e 2 7 1


F. Diagnosis The di agnos i s of COPD may be s us pect ed bas ed on t he pat i ent 's hi s t ory, s ympt oms , and phys i cal s i gns , or i t may become obvi ous t hrough ches t radi ograph and cl i ni cal ci rcums t ances . 



1. Spi romet ri c s creeni ng may be us ed t o di agnos e COPD i n mi ddl e-aged s mokers . Object i ve document at i on of expi rat ory fl ow obs t ruct i on by pul monary funct i on t es t i ng i s neces s ary for t he di agnos i s of COPD.





2. On phys i cal exami nat i on, t he fi ndi ngs mi ght i ncl ude hyperi nfl at i on, poor di aphragmat i c movement , t he us e of acces s ory mus cl es of res pi rat i on, and decreas ed breat h s ounds and wheezi ng on aus cul t at i on.





3. The ches t radi ograph may s how hyperi nfl at i on, a l os s of vas cul ari t y, a fl at t ened di aphragm, and a s mal l heart . In addi t i on, pat i ent s wi t h chroni c bronchi t i s oft en exhi bi t t hi ckened bronchi al wal l s and â€œdi rt yâ€• l ung fi el ds . Di agnos i s s houl d not res t s ol el y on t he bas i s of radi ographi c fi ndi ngs .

G. Clinical course and prognosis 



1. COPD t ends t o be a progres s i ve di s order unl es s t here i s s ome form of i nt ervent i on (i .e., ces s at i on of s moki ng, removal of ot her i rri t ant s , or medi cal t herapy). Once COPD i s wel l advanced, s peci fi c medi cal t reat ment may not s l ow t he progres s i on of di s eas e. However, ces s at i on of s moki ng may al t er t he decl i ne i n pul monary funct i on i n al l but far-advanced di s eas e.



Pa g e 2 7 2




2. The FEV 1 decl i nes by approxi mat el y 50â€“75 mL/yr i n t ypi cal pat i ent s wi t h COPD, as compared wi t h a normal decl i ne of approxi mat el y hal f t hat rat e.





3. Survi val i s s t at i s t i cal l y rel at ed t o t he degree of vent i l at ory funct i on t hat exi s t s when pat i ent s are fi rs t eval uat ed. For exampl e, among pat i ent s wi t h an i ni t i al FEV 1 of l es s t han 0.75 L, t he 5-year s urvi val rat e i s 25%, whereas among t hos e wi t h an i ni t i al FEV 1 of 1 L, t he 5-year s urvi val rat e i s approxi mat el y 50%.

H. Therapy (see Figure 2-10) 



1. Bronchodilation. Overal l , mos t pat i ent s wi t h COPD s how i mprovement i n pul monary funct i on aft er s uffi ci ent bronchodi l at or t herapy. o

o

a. COPD i s not al ways an i rrevers i bl e proces s . A pat i ent may have ai rfl ow react i vi t y even when pul monary funct i on s t udi es performed aft er bron chodi l at or t herapy have i ndi cat ed nonrevers i bl e ai rfl ow obs t ruct i on. It appears t hat 15%â€“20% of pat i ent s wi t h COPD i n t hi s cat egory have revers i bl e ai rfl ow obs t ruct i on.

o

o

b. The t hree major cl as s es of bronchodi l at ors are Î²-adrenergic agonists (al but erol and ot hers ), anticholinergics (i prat ropi um bromi de), and xanthines (t heophyl l i ne-t ype agent s ). Thes e agent s may be us ed s eparat el y or i n combi nat i on. The s el ect i ve Î²-adrenergi c agoni s t s offer

Pa g e 2 7 3


advant ages over t he ol der agent s i n t erms of a l onger durat i on of bronchodi l at i ng act i on (Î² 2 effect ) and reduced cardi ac s t i mul at i on (Î² 1 effect ). Some newer Î² agoni s t s have acut e as wel l as l ong-act i ng effect s . 



2. Corticosteroid therapy. The us e of cort i cos t eroi ds i n t he t reat ment of t he bronchos pas m as s oci at ed wi t h COPD i s cont rovers i al . However, s ome pat i ent s cl earl y have an as t hma-l i ke component t o t hei r di s eas e and may l i kel y res pond t o s t eroi d t herapy t o s ome ext ent . Del i very of i nhal ed cort i cos t eroi ds by a met ered-dos e i nhal er (MDI) i s t he preferred rout e of admi ni s t rat i on. Current gui del i nes s t at e t hat i nhal ed cort i cos t eroi ds are appropri at e for s ympt omat i c COPD pat i ent s wi t h an FEV 1 90% and major cyt ogenet i c revers al i n >50% of cas es , and has become t he i ni t i al t herapy of choi ce i n CML. Drug res i s t ance over t i me i s a probl em

Pa g e 4 6 2


(i .e., durabi l i t y of res pons e), Ot her t yros i ne ki nas e i nhi bi t ors (e.g., des at i ni b and MN-107) have s hown s i mi l ar act i vi t y and can be effect i ve i n pat i ent s who become refract ory t o i mat i ni b. The el uci dat i on of how abnormal , mal i gnant genet i c t rans format i on res ul t s i n di s eas e and t he abi l i t y t o s peci fi cal l y, pharmacol ogi cal l y i nt ervene i n t hat proces s marks a mi l es t one i n cancer t herapeut i cs . 

(iv) Marrow transplantation i s curat i ve and i s t he t herapy of choi ce for younger pat i ent s (s ee

IV D 4).

o

o

b. Neutropenia i s an abs ol ut e decreas e i n t he number of ci rcul at i ng neut rophi l s . Neut ropeni a occurs rarel y as an earl y mani fes t at i on of i nt ri ns i c marrow di s eas e (e.g., acut e l eukemi a) but more commonl y s econdary t o exogenous s t i mul i . 



(1) Infections. Cert ai n vi ral i nfect i ons (e.g., hepat i t i s , i nfl uenz a) and bact eri al i nfect i ons (e.g., t yphoi d fever) caus e neut ropeni a.





(2) Drugs (e.g., phenot hi azi nes , fl uoxet i ne, ant i t hyroi d medi cat i ons ) are as s oci at ed wi t h neut ropeni a and, i n s evere i ns t ances , can caus e agranul ocyt os i s . Agranul ocyt os i s i s charact eri zed by: 

Pa g e 4 6 3


(a) Profoundl y l owered neut rophi l count s 3

(i .e., bl l o 1 as m Ã t o — fo n 1 r

Pa g e 4 8 9


9

oc 0 m yt /L s ic le uk e m ia (C M M L) FAB, French -Ameri can-Bri t i s h. DIC, di s s em i nat ed i nt rava s cul ar coagul at i on; HMW K, hi ghâ€ “mol ec ul ar-w ei ght ki ni no gen; SD, s t anda rd devi at i

Pa g e 4 9 0


on.

G. Clinical features Clinical features of t he myel odys pl as i as al l rel at e t o bone marrow fai l ure. 



1. Hi s t ory and phys i cal fi ndi ngs i ncl ude anemi a feat ures (progres s i ve fat i gue, dys pnea on exert i on, pal l or); neut ropeni a feat ures (frequent i nfect i ons ); and t hrombocyt openi a feat ures (bl eedi ng and brui s i ng). MDS part i cul arl y affect s t he el derl y (medi an age of ons et i s t he s event h decade), and MDS has repl aced i ron defi ci ency as t he mos t frequent caus e of anemi a i n t hi s age-group.





2. Laborat ory fi ndi ngs i ncl ude cyt openi as , wi t h anemi a bei ng t he mos t frequent pres ent i ng feat ure (90%).

H. Diagnosis A pat i ent wi t h cyt openi a wi l l have normal i ron, B 1 2 , and fol at e l evel s and wi l l be â€œrefract oryâ€• t o t herapy wi t h t hes e hemat i ni cs . Peri pheral s mear demons t rat es a vari et y of abnormal i t i es t hat are s ugges t i ve (t eardrop forms , Pel ger Huet hypogranul at ed hypol obul ar W BC forms , and abnormal pl at el et forms )(

onl i ne Fi gure 3-7). Event ual l y, exami nat i on of bone

marrow i s performed and s hows morphol ogi c abnormal i t i es i ncl udi ng

Pa g e 4 9 1


megal obl as t i c RBC, as ynchronous mat urat i on of cyt opl as m and nucl ei , ri nged s i derobl as t forms , mi cromegakaryocyt es , and exces s bl as t forms . Det ai l ed, refi ned cyt ogeni c s t udi es , i ncl udi ng PCR anal ys i s , wi l l reveal t he frequent chromos omal abnormal i t i es ci t ed previ ous l y.

Online Figure 3-7 Peri pheral bl ood s mear wi t h s i gni fi cant l eukocyt os i s . Not e t he mul t i pl e degrees of granul ocyt e mat urat i on i ncl udi ng bands and mat ure neut rophi l s as wel l as marked bas ophi l i a. (From Tkachuk DC, Hi rs chmann JV. Wi nt robe's At l as of Cl i ni c al Hemat ol ogy. Bal t i more: Li ppi ncot t W i l l i ams & W i l ki ns , 2007:4â€“10)

I. Therapy T herapy of MDS i s compl ex and rel at es t o t he many s yndromes t hat have an ext remel y vari abl e prognos i s . 



1. Support i ve t herapy i s t he mos t wi del y offered s t rat egy. The us e of eryt hropoi et i n (EPO) and G-CSF t o amel i orat e anemi a and s evere neut ropeni a i s s upport ed by evi dence-bas ed t ri al s . Becaus e EPO i s effect i ve onl y i n t he mi nori t y, t rans fus i ons are us ed for s ympt omat i c anemi a. Aggres s i ve P.107

Pa g e 4 9 2


and judi ci ous us e of ant i bi ot i cs and pl at el et t rans fus i on t echni ques are s i mi l ar t o t hos e us ed i n AML s i t uat i ons . 



2. Novel agent s are cont i nuous l y bei ng eval uat ed i n t hi s di ffi cul t pat i ent popul at i on. They i ncl ude l enal i domi de (Revl i mi d), an i mmunomodul ary agent , and az acyt i di ne, an ant i met abol i t e t hat i mpai rs DNA met hyl at i on.





3. In t he s mal l s ubs et of hi gh-ri s k, hi gh-mort al i t y pat i ent s of appropri at e age-group, BMT has been s ucces s ful l y us ed and i s t he onl y curat i ve t herapy avai l abl e.

J. Prognosis Prognosis i s vari abl e. As s t at ed, mos t MDS t ends t o t ermi nat e i n AML. Medi an s urvi val s range from 6 mont hs t o 6 years , dependi ng on a compl ex s et of vari abl es , i ncl udi ng number and s everi t y of cyt openi as ; pres ence or abs ence of cyt ogeni c abnormal i t i es , and percent age of myel obl as t s i n t he bone marrow. In es s ent i al l y al l s ubs et s , t he pres ence of MDS negat i vel y i mpact s s urvi val s i gni fi cant l y even when MDS i s not t he pri mary caus e of deat h.

V. Disorders of Coagulation and Hemostasis A. General considerations Hemos t as i s requi res an i nt act coagul at i on s ys t em of vas cul ar and t i s s ue component s , pl at el et s , and coagul at i on prot ei ns . Defi ci ency or di s eas e of any of t hes e component s may caus e ei t her s pont aneous or t rauma-rel at ed hemorrhage. 



1. History. A careful hi s t ory provi des cl ues t o t he pat hogenes i s of bl eedi ng. Immedi at e, mucocut aneous bl eedi ng s ugges t s vas cul ar or pl at el et di s eas e; del ayed

Pa g e 4 9 3


deep-t i s s ue bl eedi ng and hemart hros i s s ugges t coagul at i on prot ei n defi ci ency. Genet i c t rans mi s s i ons of bl eedi ng di s orders (e.g., t he X-l i nked hemophi l i as ) al s o are el i ci t ed by hi s t ory, as i s i nges t i on of drugs (e.g., as pi ri n). 



2. Physical findings ai d i n di fferent i at i on of bl eedi ng s yndromes . Mucocut aneous pet echi ae and purpura s ugges t pl at el et di s orders ; hemat omas and hemart hros i s s ugges t coagul opat hy.





3. Laboratory testing i s vi t al i n t he eval uat i on of bl eedi ng di s orders . Si ngl e t es t s rarel y provi de concl us i ve res ul t s , s o vari ous bat t eri es of t es t s have been devel oped. The coagul at i on cas cade i s s hown i n Fi gure 3-8 and t he di agnos i s of common bl eedi ng di s orders bas ed on commonl y us ed t es t s i s s hown i n Tabl e 3-4.

B. Disorders of blood vessels and vascular tissues The fol l owi ng bl eedi ng di s orders res ul t from pat hol ogy i n t he ves s el area i t s el f, wi t h s econdary l eakage of bl ood. Mos t of t hes e di s orders have as t hei r hal l mark a vi s i bl e and us ual l y pal pabl e s ki n l es i on. Tes t i ng performed on pat i ent s wi t h t hes e bl eedi ng di s orders reveal s normal coagul at i on. 



1. Autoimmune (allergic) purpura (Henoch-SchÃ¶nlein purpura) occurs mos t commonl y i n chi l dren and young adul t s . o

o

a. Etiology. The s yndrome i s as s oci at ed wi t h s t rept ococcal i nfect i ons and drugs (e.g., peni ci l l i n).

Pa g e 4 9 4


o

b. Clinical signs. Perivascular inflammatory lesions wi t h s eros angui neous l eakage i nt o t he s ki n, s ubmucos a, and s eros a are t he hal l mark of t he di s eas e. The l es i ons are s ymmet ri c and pal pabl e and are us ual l y found on t he di s t al ext remi t i es . Bowel l es i ons may caus e gas t roi nt es t i nal s ympt oms ; joi nt l es i ons caus e art hri t i s .

o

o

c. T herapy and prognosis. No s peci fi c t herapy i s uni forml y hel pful . Prognos i s i s good, except i n t he 5%â€“10% of pat i ent s who devel op gl omerul onephri t i s .





2. Purpura associated with infections may be due t o embol i c occl us i on of t he mi crovas cul at ure (e.g., endocardi t i s ) or t o endot hel i al i njury by t he i nfect i ous agent (e.g., Ri c ket t s i a). Bi ops y and cul t ure of t he mat eri al may be hel pful .





3. Structural malformations of vessels and vascular tissues are as s oci at ed wi t h t he fol l owi ng condi t i ons : o

o

a. Scurvy i s caus ed by vi t ami n C defi ci ency; col l agen s ynt hes i s i s i mpai red as a res ul t of t hi s defi ci ency. Ves s el wal l s wi t h poor col l agen s upport are pl i abl e and eas i l y rupt ured. 



(1) Phys i cal fi ndi ngs as s oci at ed wi t h s curvy i ncl ude peri fol l i cul ar pet echi ae, gi ngi val

Pa g e 4 9 5


bl eedi ng, and s ubperi os t eal hemorrhages . Bl eedi ng t i me us ual l y i s prol onged. 



(2) Therapy wi t h 1 g/day of vi t ami n C rapi dl y correct s al l bl eedi ng.

P.108

FIGURE 3-8 The coagul at i on cas cade. Each coagul at i on fact or, when act i vat ed, act i vat es t he next fact or i n t he s eri es . (Fact ors are numbered i n order of t hei r di s covery, not i n order of act i vat i on.) In t he i nt ri ns i c s ys t em, fact or XII i s i ni t i al l y act i vat ed by an unknown mechani s m and s ubs equent l y by kal l i krei n duri ng t he cont act phas e. Al t ernat i vel y, fact or VII and t i s s ue fact or can i ni t i at e t he ext ri ns i c s ys t em. Int ri ns i c and ext ri ns i c pat hways each end wi t h act i vat i on of fact or X, s et t i ng off a fi nal ; common pat hway t hat ends wi t h format i on of t he fi bri n cl ot . Open arrow s i ndi cat e convers i on of a s ubs t rat e or a react ant t o a product . HMW K, hi ghâ€“mol ecul ar-wei ght ki ni nogen; TF, t i s s ue fact or; PL,

Pa g e 4 9 6


phos phol i pi d. o

o

b. Hereditary hemorrhagic telangiectasia i s an aut os omal domi nant di s order as s oci at ed wi t h abnormal l y t hi n ves s el wal l s and i mpai red vas cul ar cont ract i l i t y. Such ves s el s are markedl y fri abl e, l i abl e t o burs t wi t h t rauma, and unabl e t o cont ract appropri at el y for pri mary hemos t as i s . 



(1) Physical findings i ncl ude s mal l , nodul ar vi ol aceous l es i ons on t he l i ps , face, ears , t ongue, and gas t roi nt es t i nal mucos a; t hes e l es i ons bl anch on pres s ure. Bl eedi ng i s common, es peci al l y gas t roi nt es t i nal bl eedi ng and epi s t axi s , wi t h res ul t ant i ron defi ci ency anemi a.

TABLE 3-4 Presumptive Diagnosis of Common Bleeding Disorders by Primary Screening Tests P C r o e m Bl

s m

Pl e

u o

at e

m n

el di

pt Et

et n

iv io

C g

e lo

o Ti P

Di gi

u mT P a e nt e T T g s

Pa g e 4 9 7


n o si s D Pr N N T IT ec ol or or hr P; re o m m o dr a n al al m u s g

b g

e e

oc s

d d

yt o p e ni

a N Pr Pr N v â or ol ol or o €¦ mo o mn al n n al W g g

ill

e e

e

d d

br a n d' s di s e a s

e N Pr N N T Dr or ol or or hr u mo mmo g

Pa g e 4 9 8


al n al al m s ; g

b ur

e

oc e

d

yt m o ia p at h

y N N Pr N C H or or ol or o e mmo ma m al al n al g o g

ul p

e

o hi

d

p li at a h A y or of h in e tr m in o si p c hi p li at a h B; w fa a ct y or VI II a n

Pa g e 4 9 9


d lu p u sty p e in hi bi to rs N N Pr Pr C Li or or ol ol o v m m o o a er al al n n g di g g ul s e e o e d d p a at s h e; y vi of t a co m m in mK o d n ef or i c m ie ul nc t i y; pl D e IC

Pa g e 5 0 0


p ; at h h e w p a ar ys i n N N N Pr C F or or or ol o ac m m m o a to al al al n g r g ul VI e o I d p d at ef h ic y ie of nc e y xt ri n si c p at h w a y N N N N â H or or or or €¦ er mmmm

e

al al al al

di ta ry

Pa g e 5 0 1


te la n gi ec ta si a; al le rg ic p ur p ur a Adapt ed wi t h permi s s i on from Lee GR, et al : Wi nt robe's Cl i ni c al Hemat ol ogy, 9t h ed. Phi l adel phi a: Lea and Febi ger, 1993:1315. DIC, di s s emi nat ed i nt ravas cul ar coagul at i on; ITP, i di opat hi c

Pa g e 5 0 2


t hrombocyt op eni c purpura; PTT, part i al t hrombopl as t i n t i me; PT, prot hrombi n t i me.

o

P.109

o





(2) Diagnosis i nvol ves t he as s oci at i on of t hree fact ors : recurrent hemorrhage, mul t i pl e t el angi ect as es , and fami l i al occurrence.





(3) Improvement i n s upport i ve meas ures s uch as l ocal meas ures (nas al emol l i ent s ), EPO, eps i l on ami no caproi c aci d, and s afer parent eral i ron forms have i mproved qual i t y of l i fe and prognos i s i n t hes e pat i ent s .

o

o

c. Diminished collagen synthesis due t o steroid therapy res ul t s i n a s yndrome of vas cul ar fragi l i t y and s ki n bl eedi ng.





4. Miscellaneous vascular conditions o

o

a. Paraproteinemias, i ncl udi ng cryogl obul i nemi as

Pa g e 5 0 3


and amyl oi dos i s , are as s oci at ed wi t h s ki n bl eedi ng. Di agnos i s requi res demons t rat i on of t he paraprot ei n. o

o

b. Senile purpura occurs i n el derl y i ndi vi dual s as a res ul t of degenerat i on and l os s of dermal col l agen, el as t i n, and s ubcut aneous fat . Thi s di s order, whi ch i s t hought t o be caus ed by s heari ng i njury t o bl ood ves s el s from t he hypermobi l i t y of t he s ki n on t he t hi nned underl yi ng t i s s ue, i s charact eri zed by beni gn purpura of t he arms .

C. Disorders of platelets Pl at el et s pl ay a rol e i n t he pri mary arres t of bl eedi ng; abnormal i t i es i n t hes e hemos t at i c component s l ead t o hemorrhagi c di at hes i s . Pl at el et abnormal i t i es are cl as s i fi ed accordi ng t o di s orders of number and funct i on. 



1. T hrombocytopenia (i .e., decreas ed numbers of pl at el et s ) i s t he most common cause of abnormal bleeding. o

o

a. General considerations 



(1) W i t h a pl at el et count of l es s t han 3

100,000/mm , t here i s a pot ent i al i ncreas ed ri s k of bl eedi ng wi t h t rauma and cert ai n s urgi cal procedures . Mos t i ndi vi dual s experi ence an i ncreas ed t endency t o brui s e wi t h pl at el et count s of bet ween 30,000 and 3

10,000/mm . Format i on of s pont aneous pet echi ae wi t h bl eedi ng may occur wi t h 3

pl at el et count s l es s t han 10,000/mm , wi t h

Pa g e 5 0 4


s eri ous s pont aneous bl eedi ng (e.g., CNS) occurri ng wi t h pl at el et count s of l es s t han 3

5,000/mm . 



(2) Thrombocyt openi a i s frequent l y an i ndi cat i on for a marrow exami nat i on, whi ch reveal s t he pres ence of t he pl at el et precurs ors , megakaryocytes. The abs ence of megakaryocyt es i ndi cat es pl at el et product i on probl ems . The pres ence of megakaryocyt es i ndi cat es ei t her peri pheral des t ruct i on of pl at el et s or, i n t he pres ence of s pl enomegal y, s pl eni c s eques t rat i on of pl at el et s .

o

o

b. Mechanisms of t hrombocyt openi a i ncl ude i mpai red pl at el et product i on, abnormal pl at el et pool i ng, and i ncreas ed peri pheral des t ruct i on. Vari ous exampl es , marrow fi ndi ngs , and t herapi es are s ummari zed i n Tabl e 3-5. 



(1) Impaired platelet production 



(a) Etiology 



(i) Megakaryocyt es may be s el ect i vel y s uppres s ed by cert ai n agent s (e.g., t hi azi de di uret i cs , et hanol ).





(ii) Impai red pl at el et product i on i s as s oci at ed wi t h t he megal obl as t i c

Pa g e 5 0 5


hemat opoi es i s s een i n vi t ami n B 1 2 and fol at e defi ci enci es , as wel l as i n cas es of myel odys pl as t i c and prel eukemi c s yndromes . 



(iii) A rare caus e i s amegakaryocyt i c t hrombocyt openi a caus ed by congeni t al defi ci ency of megakaryocyt e CFUs .





(b) Diagnosis i s confi rmed by a bone marrow s mear t hat reveal s marrow megakaryocyt i c hypopl as i a.





(c) T herapy i nvol ves removal of t he offendi ng agent , i f pos s i bl e, or t reat ment of t he underl yi ng di s eas e. Pat i ent s have es s ent i al l y normal pl at el et hal f-l i ves and s houl d be t rans fus ed wi t h exogenous pl at el et s i f t hey are t hrombocyt openi c and bl eedi ng. Thrombocyt openi a as s oci at ed wi t h vi t ami n B 1 2 or fol at e defi ci ency i s rapi dl y correct ed by t herapy wi t h t he defi ci ent vi t ami n.





(d) Associated conditions Impai red pl at el et product i on i s as s oci at ed wi t h apl as t i c anemi a, myel opht hi s i c proces s es (repl acement of marrow by t umor or fi bros i s ), and cert ai n rare congeni t al s yndromes (e.g., t hrombocyt openi a wi t h abs ent radi i ).

Pa g e 5 0 6


P.110

 

TABLE 3-5 Mechanisms of Thrombocytopenia Cli Ma nic Me rro al ch w Co T h ani Fin ndi er sm din tio ap s gs ns y Im Me Ind Re pai gak uce mo red ary d

val

pro ocy che of duc t es mi c off t i o red al l en n

uce y

of

d

di n

or g

pl a or phy ag t el abs s i c ent et s ent al l s ; y

s up

(e. por g., t i v che e mo t he rap y, rad i at i

Pa g e 5 0 7


on) Apl Mar as t row ic

t ra

an ns p em l an i a, t at par i on oxy sm al noc t ur nal he mo gl o bi n uri a, l eu ke mi a Inf Tre ect at i on me (e. nt g., of vi r i nf al

ect

he i on pat itis ,

Pa g e 5 0 8


cyt om eg al o vi r us , t ub erc ul o sis ) Ine Ab Me B 1 2 ffe nor gal or ct i ma obl fol ve l

as t at e

pro an i c

s up

duc d/o di s pl e tio r

ord me

n

dys er nt a

of

pl a (vi t t i o

pl a s t i am n t el c

in

et s me B 1 2 gak def ary i ci e ocy ncy t es , fol at e def i ci e ncy ) My Tre el o at

Pa g e 5 0 9


dys me pl a nt s i a of s

un

an der d

l yi

my ng el o di s pro ord l i fe er rat i ve di s ord ers En Inc Idi Se ha rea op e V nce s ed at h C 1 d

me i c

b

des gak t hr (3) t ru ary om ct i ocy boc on t es yt o of

pe

pl a

ni c

t el

pur

et s

pur

(i m

a Pos Pl a

mu neme di a t ed )

t -t r s m ans ap fus her i on es i pur s pur

Pa g e 5 1 0


a Dru Re g-i mo nd val uce of d

off

(e. en g., di n ri fa g mp ag i n, ent me t hi ci l l i n, s ul fon am i de s, ph eny t oi n, qui ni n e, qui ni d i ne , he par i n) Ly Tre

Pa g e 5 1 1


mp at ho me ma nt s

of un der l yi ng di s ord er St e roi ds

Im mu ne co mp l ex di s ord er (e. g., s ys te mi c l up us ery t he ma t os us )

Pa g e 5 1 2


En Inc Thr Pl a ha rea om s m nce s ed bot ap d

me i c

her

des gak t hr es i t ru ary om s ct i ocy boc on t es yt o of

pe

pl a

ni c

t el

pur

et s

pur

(no

a He Pl a

t im mu nerel at e d)

mo s m l yt i ap c

her

ure es i mi c s s yn dro me Di s Tre s e at mi me nat nt ed of i nt r un ava der s cu l yi l ar ng coa di s gul ord at i ers on

Pa g e 5 1 3


Di l Su ut i pp on ort i an ve d car di o pul mo nar y byp as s Spl Us en ual om l y eg not al y req ui r ed; s pl en ect om y ma y be nec es s ary occ as i on al l

Pa g e 5 1 4


y





(2) Abnormal platelet pooling res ul t s when pl at el et s are s eques t ered from t he ci rcul at i on. Splenic platelet sequestration i s t he mos t common caus e of abnormal pl at el et pool i ng. 



(a) Pathophysiology. Normal l y, t he s pl een hol ds one-t hi rd of t he ci rcul at i ng pl at el et pool . As s pl enomegal y occurs , hi gher numbers of pl at el et s are s eques t ered and, t hus , are unavai l abl e for hemos t as i s . In very l arge s pl eens , as much as 90% of t he pl at el et pool may be s eques t ered; however, pl at el et s i n t he peri pheral ci rcul at i on do have normal s urvi val t i mes .





(b) Diagnosis of hypers pl eni s m i s s ugges t ed by a moderat e t hrombocyt openi a (pl at el et count s of 3

T able of Cont ent s > Chapt er 4 - Onc ologic Diseases

Chapter 4

Oncologic Diseases Evonne Fontanilla Katherine T kaczuk

I. U.S. Cancer Statistic and Screening Guidelines (Fi gures 4-1 and 4-2; Tabl e 4-1).

II. Tumor Growth Uncontrolled growth di s t i ngui s hes mal i gnant from normal cel l s . Mal i gnant cel l s are charact eri zed by a l os s of res pons i venes s t o growt h-i nhi bi t ory s i gnal s . More rapi dl y growi ng t umors may be more poorl y di fferent i at ed, but t hey may be more s ens i t i ve t o cert ai n ki nds of chemot herapy t reat ment s .

A. Patterns of tumor growth Cancer growt h fol l ows t wo general pat t erns . 



1. Direct invasion of t he t i s s ue i n whi ch t he cancer aros e





2. Metastasis (di s s emi nat i on) t o di s t ant organs vi a t he bl oods t ream, l ymphat i c s ys t em, or by i nt racavi t ary ext ens i on o

o

a. Di fferent t ypes of tumors vary in metastatic potential. For exampl e, pri mary brai n cancers t end t o remai n l ocal i zed and rarel y s pread t o di s t ant foci . However, many carci nomas s uch as s mal l cel l

Pa g e 5 7 7


l ung cancer (SCLC) are al ready wi del y di s s emi nat ed i n mos t pat i ent s at t he t i me of di agnos i s . o

o

b. Each cancer al s o exhi bi t s a di s t i nct pattern of spread di ct at ed by t he bi ol ogy of t he t umor cel l â€“hos t i nt eract i on. For exampl e, common s i t es of met as t as es i n col on cancer i ncl ude t he l i ver, l ungs , and peri t oneal cavi t y, and common s i t es i n SCLC i ncl ude t he l ungs , l i ver, bones , and neuraxi s .

B. Tumor growth rate and prognosis Growt h rat e and pat t erns of s pread are i mport ant det ermi nant s of prognos i s i n t he abs ence of t reat ment and i n t he res pons e t o part i cul ar t herapeut i c modal i t i es s uch as s urgery, chemot herapy, or radi at i on t herapy. 



1. Rapidly growing neoplasms s uch as acut e l eukemi as , SCLC, and l ymphomas are general l y hi ghl y res pons i ve t o chemot herapy and radi at i on t herapy. However, t here are numerous except i ons .





2. Slow-growing tumors s uch as l ow-grade s arcomas are l es s res pons i ve t o s ys t emi c t reat ment modal i t i es . Surgi cal res ect i on and radi at i on t herapy are more effect i ve t reat ment opt i ons for s uch neopl as ms .





3. Growt h rat es can be es t i mat ed us i ng flow cytometry t o det ermi ne t he percent age of t umor nucl ei i n t he S phas e of t he cel l cycl e. Immunohi s t ochemi s t ry can be us ed t o det ermi ne Ki -67, anot her refl ect i on of cel l prol i ferat i on. S-phas e det ermi nat i on may hel p predi ct t he prognos i s and pot ent i al need for adjuvant chemot herapy i n earl y s t age breas t cancer.

Pa g e 5 7 8


C. Genetic changes and cancer 



1. Cancers are genetic diseases characterized by mutations or overexpression of genes that regulate vital cell processes. Oncogenes (cancer-promot i ng genes ) i nt erfere wi t h t he regul at ory cont rol s of t he cel l . Mos t oncogenes are deri ved from proto-oncogenes, normal genes t hat ordi nari l y regul at e cel l growt h proces s es . P.128

FIGURE 4-1 2006 Estimated U.S. Cancer Cases (Repri nt ed wi t h t he permi s s i on of t he Ameri can Cancer Soci et y, Inc. Al l ri ght s res erved.)

Pa g e 5 7 9


FIGURE 4-2 2006 Estimated U.S. Cancer Deaths (Repri nt ed wi t h t he permi s s i on of t he Ameri can Cancer Soci et y, Inc. Al l ri ght s res erved.) P.129

TABLE 4.1 Screening Guidelines for the Early Detection of Cancer in Asymptomatic People

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Sit Recomm e endation Bre o Y ear as t ly mam mog rams are reco mme nded s t art i ng at age 40. The age at whi c h s cre eni n g s hou ld be s t op ped s hou ld be i ndi v i dua

Pa g e 5 8 1


l i zed by cons i deri ng t he pot e nt i al ri s ks and bene fi t s of s cre eni n g in t he cont ext of over al l heal th s t at us and l ong evi t y. o

Cl i ni cal brea st

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exa m s hou ld be part of a peri odi c heal th exa m abou t ever y 3 year s for wom en in t hei r 20s and 30s and ever y year for wom en 40

Pa g e 5 8 3


and ol de r. o

Wo men s hou ld kno w how t hei r brea sts nor mal l y feel and repo rt any brea st chan ge pro mpt l y to t hei r heal th care prov i der

Pa g e 5 8 4


s. Brea st s el fexa m is an opt i on for wom en s t art i ng in t hei r 20s . o

Wo men at i ncre as ed ri s k (e.g. , fami ly hi s t ory, gene tic t end ency ,

Pa g e 5 8 5


pas t brea st canc er) s hou ld t al k wi t h t hei r doct ors abou t t he bene fi t s and l i mi t at i o ns of s t art i ng mam mog raph y s cre eni n g earl i er, havi

Pa g e 5 8 6


ng addi t i on al t es t s (i .e. , brea st ul t ra s oun d and MRI) , or havi ng mor e freq uent exa ms . Col Begi nni ng on at age &

50, men

rec and t u women m

s houl d begi n s creeni ng wi t h 1 of t he

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exami nat i on s chedul es bel ow: o

A fecal occu lt bl oo d t es t (FOB T) or fecal i mm unoc hemi cal t es t (FIT ) ever y year

o

A fl exi bl e s i gm oi do s cop y (SFI G) ever

Pa g e 5 8 8


y 5 year s o

Ann ual FOB T or FIT and fl exi bl e s i gm oi do s cop y ever y 5 year s*

o

A doub l e-c ont r as t bari um ene ma ever y 5 year s.

Pa g e 5 8 9


o

A col o nos c opy ever y 10 year s *Co mbi n ed t es t i ng is pref erre d over ei t h er annu al FOB T or FIT, or FSIG ever y 5 year s, al on e. Peop

Pa g e 5 9 0


le who are at mod erat e or hi gh ri s k for col or ect a l canc er s hou ld t al k wi t h a doct or abou t a di ffe rent t es t i ng s che dul e . Pro The PSA s t a t es t and t e t he

Pa g e 5 9 1


di gi t al rect al exami nat i on s houl d be offered annual l y, begi nni ng at age 50, t o men who have a l i fe expect anc y of at l eas t 10 years . Men at hi gh ri s k (Afri can Ameri can men and men wi t h a s t rong fami l y hi s t ory of 1 or more fi rs t -degr ee rel at i ves di agnos e d wi t h pros t at e cancer at an earl y

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age) s houl d begi n t es t i ng at age 45. For bot h men at average ri s k and hi gh ri s k, i nformat i on s houl d be provi ded about what i s known and what is uncert ai n about t he benefi t s and l i mi t at i on s of earl y det ect i on and t reat ment of pros t at e cancer s o t hat t hey can make an i nformed

Pa g e 5 9 3


deci s i on about t es t i ng. Ut e Cervix: rus Screeni ng s houl d begi n approxi m at el y 3 years aft er a woman begi ns havi ng vagi nal i nt ercours e, but no l at er t han 21 years of age. Screeni ng s houl d be done every year wi t h regul ar Pap t es t s or every 2 years us i ng l i qui d-bas ed t es t s . At or aft er age 30,

Pa g e 5 9 4


women who have had 3 normal t es t res ul t s i n a row may get s creened every 2 to 3 years . Al t ernat i v el y, cervi cal cancer s creeni ng wi t h HPV DNA t es t i ng and convent i o nal or l i qui d-bas ed cyt ol ogy coul d be performed every 3 years . However, doct ors may s ugges t a woman

Pa g e 5 9 5


get s creened more oft en i s s he has cert ai n ri s k fact ors , s uch as HIV i nfect i on or a weak i mmune s ys t em. W omen aged 70 years and ol der who have had 3 or more cons ecut i ve normal Pap t es t s i n t he l as t 10 years may choos e t o s t op cervi cal cancer s creeni ng . Screeni ng aft er

Pa g e 5 9 6


t ot al hys t erect omy (wi t h removal of t he cervi x) i s not neces s ary unl es s t he s urgery was done as a t reat ment for cervi cal cancer. Endomet rium: The Ameri can Cancer Soci et y recommen ds t hat at t he t i me of menopaus e al l women s houl d be i nformed about t he ri s ks and s ympt oms of

Pa g e 5 9 7


endomet ri al cancer, and s t rongl y encourag ed t o report any unexpect ed bl eedi ng or s pot t i ng t o t hei r phys i ci an s . Annual s creeni ng for endomet ri al cancer wi t h endomet ri al bi ops y begi nni ng at age 35 s houl d be offered t o women wi t h or at ri s k for heredi t ar y nonpol yp os i s col on cancer

Pa g e 5 9 8


(HNPCC). Ca For nce i ndi vi dual r-r s el a undergoi n t ed g peri odi c che heal t h cku exami nat i p

ons , a cancer-rel at ed checkup s houl d i ncl ude heal t h couns el i n g and, dependi n g on a pers on's age and gender, mi ght i ncl ude exami nat i ons for cancers of t he t hyroi d, oral cavi t y, s ki n, l ymph nodes , t es t es ,

Pa g e 5 9 9


and ovari es , as wel l as for s ome nonmal i g nant di s eas es . *Repri nt ed from Ameri can Cancer Soci et y. Cancer Fact s and Fi gures 2007. At l ant a: Ameri can Cancer Soci et y, Inc. Ameri can Cancer Soci et y gui del i nes for earl y cancer det ect i on are as s es s ed annual l y i n order t o i dent i fy whet her t here i s new s ci ent i fi c evi dence

Pa g e 6 0 0


s uffi ci ent t o warrant a reeval uat i on of current recommendat i ons . If evi dence i s s uffi ci ent l y compel l i ng t o cons i der a change or cl ari fi cat i on i n a current gui del i ne or t he devel opment of a new gui del i ne, a formal procedure i s i ni t i at ed. Gui del i nes are formal l y eval uat ed every 5 years regardl es s of whet her new evi dence s ugges t s a change i n t he exi s t i ng recommendat i ons . There are 9 s t eps i n t hi s

Pa g e 6 0 1


procedure, and t hes e â€œgui del i ne s for gui del i ne devel opment â€• were formal l y es t abl i s hed t o provi de a s peci fi c met hodol ogy for s ci ence and expert judgment t o form t he underpi nni ng s of s peci fi c s t at ement s and recommendat i ons from t he Soci et y. Thes e procedures cons t i t ut e of del i berat e proces s t o ens ure t hat al l Soci et y recommendat i ons have t he s ame met hodol ogi c al and

Pa g e 6 0 2


evi dence-bas ed proces s at t hei r core. Thi s proces s al s o empl oys a s ys t em for rat i ng s t rengt h and cons i s t ency of evi dence t hat i s s i mi l ar t o t hat empl oyed by t he Agency for Heal t h Care Res earch and Qual i t y (AHCRQ) and t he U.S. Prevent i ve Servi ces Tas k Force (USPSTF). P.130

o

o

a. Oncogenes modi fy t he affect ed cel l , res ul t i ng i n t he acqui s i t i on of mal i gnant charact eri s t i cs s uch as changes i n s hape, aut ocri ne growt h fact or s ecret i on, l os s of cont act i nhi bi t i on, and anchorage i ndependence.

Pa g e 6 0 3


Oncogenes may funct i on i n a number of ways : 



(1) They may caus e t he t umor cel l t o s ecret e mi t ogeni c growt h fact ors t hat t hen s t i mul at e growt h of t he s ame cel l , l eadi ng t o aut os t i mul at i on of cel l growt h, or autocrine growth.





(2) They may affect growt h fact orâ€“i nduced s i gnal t rans duct i on. 



(a) Typi cal l y, cel l s urface recept ors engaged by t hei r res pect i ve l i gands t rans mi t s i gnal s t hrough a s eri es of defi ned i nt racel l ul ar pat hways t hat cul mi nat e i n t he regul at i on of DNA s ynt hes i s or t rans cri pt i on.





(b) Mut at i ons or al t ered gene expres s i on i n any of t hes e pat hways may di s t urb s uch regul at ed s i gnal i ng, l eadi ng t o a l os s of regul at ed cel l growt h or funct i on. The prot ei n product s of s ome oncogenes s uch as ras mut at e s o t hat t hey cons t i t ut i vel y promot e cel l growt h i n t he abs ence of growt h fact or i nt eract i ons wi t h t hei r recept ors .

o

o

b. Si ngl e oncogenes t ypi cal l y do not i nduce t he t rans format i on of ful l y normal cel l s i nt o ful l y mal i gnant cel l s . Each oncogene induces only a subset of changes as s oci at ed wi t h ful l mal i gnancy. A s eri es of genet i c

Pa g e 6 0 4


changes i s t ypi cal l y requi red. o

o

c. Activation of proto-oncogenes 



(1) Point mutations. A poi nt mut at i on i s a s i ngl e-bas e change i n a gene. A s i ngl e mut at i on i n codon 12 of t he ras gene caus es act i vat i on of ras , t he mos t commonl y act i vat ed oncogene i n s ol i d mal i gnanci es .





(2) Gene fusion. In chroni c myel ogenous l eukemi a (CML), t he abl prot o-oncogene i s t ypi cal l y fus ed wi t h a ful l y unrel at ed gene, t he BCR gene. The prot ei n encoded by t he BCR-abl hybri d (p210) has a novel s t ruct ure and funct i on.





(3) Amplification. Di fferences i n t he l evel of expres s i on of encoded prot ei ns al s o can caus e prot o-oncogenes t o become oncogeni c. For exampl e, i n chi l dhood neurobl as t oma, t he amount of t he N-myc gene i s i ncreas ed from a di pl oi d number t o many dozens per cel l . Nmyc gene ampl i fi cat i on i s as s oci at ed wi t h a poor prognos i s and i s a s i gni fi cant fact or i n t he aggres s i venes s of t hi s t umor.





2. T umor suppressor genes funct i on i n t he normal cel l t o res t ri ct or repres s cel l ul ar prol i ferat i on. The i nact i vat i on of t umor s uppres s or genes can promot e t umori genes i s .

o

Pa g e 6 0 5


o

a. Inact i ve al l el es of t umor s uppres s or genes may be acqui red i n t wo ways : 



(1) Somat i c mut at i on





(2) Incorporat i on i n t he germ l i ne t o creat e a congeni t al predi s pos i t i on t o cancer (e.g., as i n ret i nobl as t oma)

o

o

b. Inact i vat i on of t umor s uppres s or genes i s as s oci at ed wi t h neurobl as t oma, SCLC, ki dney cancer, col on carci noma, W i l ms ' t umor, bl adder cancer, os t eobl as t oma, and l i ver cancer, among ot her mal i gnanci es .

o

o

c. Speci fi c mut at i ons i n t he BRCA1 gene i n affect ed women i ncreas e t he ri s k of earl y ons et breas t cancer. Res earch has recent l y s hown t hat t he BRCA1 gene, a heri t abl e s omat i c gene preval ent i n As hkenazi Jews , i s normal l y i nvol ved i n es t rogen recept or (ER) funct i on.

III. Cancer Staging For ful l s t agi ng i nformat i on, pl eas e s ee t he mos t recent edi t i on of t he AJCC Cancer St agi ng Handbook. At pres s t i me, t he mos t recent edi t i on i s t he Ameri c an Joi nt Commi t t ee on Canc er: AJCC Canc er St agi ng Handbook, 6t h ed. New Y ork: Spri nger-Verl ag, 2002.

Convent i onal t umorâ€“nodeâ€“met as t as i s (TNM) s t agi ng s ys t ems defi ne a s eri es of cat egori es or s t ages , each of whi ch defi nes a prognos t i c s t age of a t umor.

A. Objectives of staging Pa g e 6 0 6






1. Estimating prognosis. Hi gher s t ages are as s oci at ed wi t h progres s i vel y poorer prognos es .





2. Determining the best course of therapy. Accurat e s t agi ng i s neces s ary t o det ermi ne t he appropri at e s equence of l ocal , regi onal , and s ys t emi c t reat ment approaches .





3. Facilitating investigation. St agi ng provi des a uni form cl as s i fi cat i on s ys t em t o devel op uni form t reat ment cri t eri a and t o eval uat e t he cl i ni cal t ri al s l i t erat ure.

B. Staging systems St agi ng s ys t ems for al l s ol i d t umors are bas ed pri nci pal l y on t he anatomic extent of disease. Di fferences i n t umor bi ol ogy precl ude a uni vers al s t agi ng s ys t em appl i cabl e t o al l cancers . 



1. The T NM classification system i s t he mos t wi del y us ed s t agi ng s ys t em for carci nomas and s arcomas . Thi s s ys t em as s i gns t he t umor t o a T level, whi ch corres ponds t o t he s i ze and ext ent of t he pri mary t umor; an N level, whi ch des cri bes t he degree of regi onal nodal i nvol vement ; and an M level, whi ch des cri bes t he pres ence and ext ent of di s t ant met as t as es . Si t e-s peci fi c defi ni t i ons of TNM s t ages have been compi l ed for a wi de range of neopl as ms .





2. Ol der cl as s i fi cat i on s ys t ems s t i l l are frequent l y us ed t o s t age l ymphomas and carci nomas of t he col on, rect um, pros t at e, and t es t i cl e.

Pa g e 6 0 7


C. Staging procedures The AJCC has defi ned t he fol l owi ng t hree l evel s of s t agi ng i nformat i on. 



1. Clinical staging us es al l avai l abl e pretreatment data , i ncl udi ng di agnos t i c dat a obt ai ned from phys i cal exami nat i on, radi ol ogi c or nucl ear i magi ng t echni ques , l aborat ory t es t s , and endos copy or ot her i nvas i ve procedures .





2. Pathologic staging i s bas ed on dat a obt ai ned duri ng s urgery and from pat hol ogi c exami nat i on of t he res ect ed s peci men.





3. Retreatment staging may be us ed t o res t age t he t umor before addi t i onal t herapy, aft er fai l ure of i ni t i al t reat ment .

IV. Treatment Modalities A. General principle 



1. Cancer t reat ment may be ei t her curative or palliative i n i nt ent . o

o

a. Curative t reat ment s ai m t o permanent l y eradi cat e t he t umor.

o

o

b. Palliative t reat ment s s eek t o opt i mi ze qual i t y of l i fe and, when pos s i bl e, t o prol ong l i fe when cure cannot be achi eved.

Pa g e 6 0 8


P.131





2. Succes s ful t reat ment programs t ypi cal l y i ncl ude one or more of t he fol l owi ng component s : s urgery, radi at i on t herapy, chemot herapy, and ot her noncyt ot oxi c s ys t emi c t herapi es .





3. Therapy mus t be cus t omi zed t o meet t he s peci fi c needs of i ndi vi dual pat i ent s . In many di s eas e pres ent at i ons , a mul t i di s ci pl i nary approach t hat coordi nat es t he effort s of t he pat hol ogi s t , s urgi cal oncol ogi s t , medi cal oncol ogi s t , radi at i on oncol ogi s t , and ot her s peci al i s t s i s des i rabl e.





4. Clinical trials, whi ch are es s ent i al t o progres s i n cancer t herapy, are i nt egrat ed i nt o t he rout i ne care of many cancer pat i ent s . Tri al s can be conduct ed t o i dent i fy new t reat ment opt i ons i n pat i ent s for whom no effect i ve t herapy i s avai l abl e or t o furt her refi ne exi s t i ng effect i ve t reat ment s t rat egi es . The cl i ni cal t ri al proces s t ypi cal l y i nvol ves t hree di s t i nct t ypes of t ri al s . o

o

a. Phase I trials us e new agent s or new combi nat i ons of agent s t o i dent i fy t oxi ci t i es and maximally tolerated doses, t o es t abl i s h a worki ng dos e for furt her s t udi es , and t o det ermi ne t he di s pos i t i on (pharmacokinetics) and bi ol ogi c effect s as t hey rel at e t o di s pos i t i on (pharmacodynamics). W hen pos s i bl e, s t udi es s houl d provi de a proof-of-concept t hat t he agent has t he des i red effect s on i t s put at i ve t arget at

Pa g e 6 0 9


dos es t o be us ed i n phas e II s t udi es . For each drug t es t ed, phas e I t ri al s t ypi cal l y i nvol ve fewer t han 25 pat i ent s wi t h advanced di s eas e. o

o

b. Phase II trials are des i gned t o eval uat e t he effi cacy of new agent s or drug combi nat i ons i n a part i cul ar s t age of di s eas e. Us ual l y, phas e II t ri al s are conduct ed i n 30â€“50 pat i ent s , wi t h earl y s t oppi ng rul es i f t he new t reat ment proves i neffect i ve.

o

o

c. Phase III trials. If phas e II t ri al s yi el d encouragi ng res ul t s , randomi zed phase III trials are conduct ed t o compare t he new t reat ment wi t h t he exi s t i ng s t andard of care. Phas e III t ri al s t ypi cal l y requi re hundreds t o t hous ands of pat i ent s .

B. Radiation therapy Fi ft y percent of al l cancer pat i ent s requi re radi at i on t herapy at s ome poi nt duri ng t he cours e of t hei r di s eas e. 



1. Applications o

o

a. Radi at i on t herapy, ei t her al one or i n conjunct i on wi t h chemot herapy and s urgery, i s curat i ve i n s ome cancers (e.g., Hodgki n's di s eas e, head and neck cancer, cervi cal cancer, and rect al cancer).

o

o

b. Radi at i on t herapy al s o has i mport ant pal l i at i ve appl i cat i ons (e.g., rel i ef from met as t at i c bone pai n i n advanced breas t cancer).



Pa g e 6 1 0




2. Uses. Radi at i on t herapy can be us ed al one or i n combi nat i on wi t h chemot herapy or s urgery. o

a. In combination with chemotherapy.

Chemot herapy may be

us ed concurrent l y wi t h or before radi at i on t o enhance effi cacy. 



(1) For exampl e, t he pyri mi di ne anal og 5-fl uorouraci l (5-FU), t he al kyl at i ng agent ci s pl at i n, gemci t abi ne, a nucl eos i de anal og t hat pri mari l y ki l l s cel l s undergoi ng DNA s ynt hes i s (S-phas e) and bl ocks t he progres s i on of cel l s t hrough t he G1/S-phas e boundary, and t he mi crot ubul e s t abi l i zer pacl i t axel (Taxol ) al l act as radi at i on s ens i t i zers when admi ni s t ered concurrent l y wi t h radi at i on t herapy.





(2) However, combi ned-modal i t y t herapy al s o can cont ri but e t o s evere t oxi ci t y react i ons . The radiation recall effect, an enhanced or re-act i vat ed res pons e i n a previ ous l y i rradi at ed area preci pi t at ed by t he concurrent admi ni s t rat i on of doxorubi ci n or met hot rexat e, i s a cl as s i c exampl e.

o

o

b. Surgery. Radi at i on t herapy may be us ed before surgery t o i nduce t umor regres s i on and faci l i t at e t he s urgi cal procedure. Radi at i on al s o may be us ed postoperatively t o reduce t he ri s k of l ocal recurrence. In mos t cancers , t he opt i mal t i mi ng of adjunct i ve radi at i on t herapy (e.g., preoperat i ve vers us pos t operat i ve) has not been det ermi ned.

Pa g e 6 1 1




3. Side effects. Radi at i on t herapy i s as s oci at ed wi t h l ocal s i de effect s , es peci al l y i n pat i ent s who are recei vi ng curat i ve-i nt ent hi gh-dos e radi at i on (e.g., for t he t reat ment of head or neck cancer). o

o

a. T ime course 



(1) Acute effects, pri nci pal l y i nfl ammat i on, may occur wi t hi n days or weeks of t reat ment .





(2) Chronic effects s uch as fi bros i s and s carri ng may not be apparent unt i l mont hs or even years aft er t herapy.

o

o

b. The severity of advers e react i ons i s a funct i on of t he t reat ment s i t e, t he s i ze of t he radi at i on port , t he amount of radi at i on energy, and dos age vari abl es (e.g., t ot al dos e, radi at i on dos e per fract i on, and dos e rat e). The t oxi ci t y of hi gh-dos e radi at i on t herapy may be reduced by t he us e of t ai l ored, conformal radi at i on fi el ds . Si de effect s can be mi ni mi zed by: 



(1) Accurat el y t arget i ng t he t umor area by us i ng s ophi s t i cat ed radi ol ogi c t echni ques [e.g., comput ed t omography (CT), magnet i c res onance i magi ng (MRI)]





(2) Di rect i ng radi at i on t o avoi d cri t i cal organs

Pa g e 6 1 2


wi t h l ow t ol erance t o radi at i on (e.g., t he s pi nal cord) 



(3) Bl ocki ng normal t i s s ue from radi at i on





(4) Reduci ng t he t reat ment fi el d over t he cours e of t herapy

o

o

c. Systemic effects of radi at i on t herapy i ncl ude mal ai s e, fat i gue, anorexi a, and depres s ed bl ood count . Thes e general i zed s ympt oms are es peci al l y common i n pat i ent s t reat ed concurrent l y wi t h radi at i on and chemot herapy.

o

o

d. Skin reactions occur aft er hi gh-dos e t herapy di rect ed t o s i t es on or near t he s ki n s urface (e.g., ches t wal l aft er mas t ect omy) or femal e reproduct i ve organs (e.g., vul va). Acute reactions cons i s t of eryt hema, dry des quamat i on wi t h pruri t us , and moi s t des quamat i on. React i ons are l es s common aft er hi gh-energy phot on beam t herapy. Ret reat ment or t he us e of overl appi ng fi el ds may res ul t i n s evere and pers i s t ent s ki n react i ons . 



(1) The affect ed area s houl d be kept as cl ean and dry as pos s i bl e. Addi t i onal t reat ment meas ures i ncl ude: 



(a) Topi cal appl i cat i on of vi t ami n A and D oi nt ment , moi s t uri zers , baby oi l , or

Pa g e 6 1 3


corns t arch 



(b) Topi cal appl i cat i on of cort i cos t eroi ds





(2) Pat i ent s s houl d avoi d i rri t at i ng cl ot hi ng and di rect expos ure t o t he s un.

o

o

e. React i ons of t he oral cavity and pharynx s uch as mucos i t i s , pai n, anorexi a, xeros t omi a, and dent al cari es occur aft er hi gh-dos e radi at i on t o t he head or neck area. P.132





(1) St ri ct at t ent i on t o dent al hygi ene, t opi cal anes t het i cs , art i fi ci al s al i va preparat i ons , and nut ri t i onal couns el i ng may be hel pful .





(2) Severe cas es of naus ea or gas t roi nt es t i nal i nt ol erance may requi re i ns ert i on of a gas t ri c feedi ng t ube or percut aneous gas t ros t omy.

o

o

f. Gastrointestinal reactions occur wi t h cumul at i ve radi at i on dos es exceedi ng 4000â€“5500 cGy. 



(1) Esophagitis us ual l y s ubs i des i n 7â€“10 days but predi s pos es pat i ent s t o

Pa g e 6 1 4


s uperi mpos ed Candi da i nfect i ons . Treat ment meas ures i ncl ude us e of ant aci ds , a bl and di et , and t opi cal anes t het i cs . 



(2) Radiation gastritis or enteritis may mani fes t as naus ea, vomi t i ng, di arrhea, abdomi nal pai n, anorexi a, or bl eedi ng. Treat ment meas ures i ncl ude: ant i emet i cs ; ant i di arrheal s ; a bl and, l ow-fat , l ow-res i due, hi gh-gl ut en di et ; and di et ary s uppl ement s .





(3) Rectal inflammation may res ul t i n bl eedi ng or pai n. A l ow-res i due di et , s t ool s oft eners , or s t eroi d enemas may gi ve rel i ef.

o

o

g. Radiation pneumonitis, charact eri zed by cough, dys pnea, and ches t pai n, us ual l y occurs 2â€“3 mont hs aft er del i very of radi at i on t o a s i gni fi cant l ung vol ume. Cort i cos t eroi ds are us ual l y effect i ve. St eroi ds s houl d be di s cont i nued gradual l y t o avoi d recurrence of s ympt oms .

o

o

h. Central nervous system (CNS) symptoms may occur duri ng t herapy or may not appear unt i l weeks or mont hs l at er. 



(1) Acute symptoms accompanyi ng i nt racrani al i rradi at i on i ncl ude headache and s i gns of i ncreas ed i nt racrani al pres s ure (ICP); gas t roi nt es t i nal s ympt oms (i .e., naus ea and vomi t i ng) al s o may occur. Dexamet has one us ual l y provi des rapi d rel i ef.

Pa g e 6 1 5




(2) Delayed symptoms i ncl ude s hort -t erm memory l os s , vi s ual memory di s t urbances , and whi t e mat t er abnormal i t i es s uch as cal ci fi cat i ons and vent ri cul ar di l at i on. Thes e t oxi ci t i es are part i cul arl y common i n pat i ent s undergoi ng prophyl act i c crani al radi at i on for l i mi t ed-s t age SCLC.





(3) A somnolence syndrome charact eri zed by hypers omni a and fat i gue has been obs erved s everal weeks or mont hs aft er i nt racrani al i rradi at i on, es peci al l y i n pat i ent s who are recei vi ng concurrent i nt rat hecal chemot herapy.

o

o

i. Bone marrow suppression may fol l ow t he l arge-fi el d i rradi at i on us ed i n t he t reat ment of Hodgki n's di s eas e or pel vi c mal i gnanci es , es peci al l y i f pat i ent s are recei vi ng concurrent chemot herapy. Leukopeni a or t hrombocyt openi a may requi re s us pens i on of t herapy; however, anemi a i s rare. Hemogl obi n val ues bel ow 9 g/dL may requi re t rans fus i on.

o

o

j. In Hodgki n's di s eas e, medi as t i nal i rradi at i on i s as s oci at ed wi t h l ong-t erm t oxi ci t i es s uch as hypot hyroi di s m and coronary art ery di s eas e.





4. Newer T echniques: Int ens i t y modul at ed radi at i on t herapy (IMRT) and s t ereot act i c radi at i on t herapy are newer modal i t i es t hat mi ni mi ze damage t o normal t i s s ue whi l e del i veri ng hi gher dos es of radi at i on t o t he t arget

Pa g e 6 1 6


organs .

C. Chemotherapy 



1. General comments o

o

a. Combi nat i ons of chemot herapy agent s us ed i n conjunct i on wi t h ot her cyt oreduct i ve t reat ment modal i t i es may i ncreas e cure rat es i n pat i ent s wi t h col orect al neopl as ms , es ophageal cancer, and breas t cancer.

o

o

b. Chemot herapy pl ays an i mport ant rol e i n t he pal l i at i ve t reat ment of pat i ent s wi t h advanced or met as t at i c cancers . In t hi s s et t i ng, t he s equent i al us e of modes t l y act i ve s i ngl e agent s may be preferabl e t o t he us e of more act i ve, but more t oxi c, combi nat i ons .

o

o

c. Recent i mprovement s i n drug devel opment and t he s creeni ng of new agent s have l ed t o t he i nt roduct i on of numerous new agent s , offeri ng pat i ent s more t reat ment opt i ons . Thes e advances have been coupl ed wi t h an i ncreas ed unders t andi ng of t umor bi ol ogy.





2. Uses. Chemot herapy s houl d be us ed onl y when pat i ent s benefi t from t he t reat ment . W hen cure i s t he object i ve, compl et e res pons es are general l y requi red, and cons i derabl e hos t t oxi ci t y i s accept abl e [e.g., t he

Pa g e 6 1 7


us e of bone marrow t rans pl ant at i on (BMT) for pat i ent s wi t h acut e l eukemi as ]. However, when pal l i at i on i s t he goal , accept abl e t oxi ci t y mus t be coupl ed wi t h an abs ence of di s eas e progres s i on. In general , i ndi vi dual s who exhi bi t an object i ve (e.g., compl et e or part i al ) res pons e t o chemot herapy l i ve bet t er and l onger t han do t hos e wi t h s t abl e or progres s i ve di s eas e. Meas urabl e di s eas e i s defi ned as t he pres ence of at l eas t one meas urabl e l es i on. If t he meas urabl e di s eas e i s res t ri ct ed t o a s ol i t ary l es i on, i t s neopl as t i c nat ure s houl d be confi rmed by cyt ol ogy/hi s t ol ogy. Meas urabl e l es i ons are defi ned as l es i ons t hat can be accurat el y meas ured i n at l eas t one di mens i on wi t h great es t di amet er â‰¥20 mm us i ng convent i onal t echni ques or â‰¥10 mm wi t h s pi ral CT s can. Nonmeas urabl e l es i ons are defi ned as al l ot her l es i ons , i ncl udi ng s mal l l es i ons (great es t di amet er 4 cm

Pa g e 7 2 9




(2) More t han t hree pos i t i ve axi l l ary nodes





(3) Tumors i nvol vi ng t he margi n of s urgi cal res ect i on, i nvas i on of pect oral fas ci a or mus cl e, or ext ranodal ext ens i on i nt o t he axi l l ary fat

o

o

c. In patients at high risk for distant metastases, radi at i on t herapy can be gi ven concurrent l y or del ayed unt i l t he compl et i on of adjuvant chemot herapy. The ri s k of i ps i l at eral arm l ymphedema i s i ncreas ed by pos t operat i ve axi l l ary radi at i on.

TABLE 4.15 Contraindications for Breast Conservation Surgery Lar ge tu mo r in a sm al l bre as t (i n cre as e s

Pa g e 7 3 0


lik el i ho od of po or cos me tic res ul t s) Su bar eol ar pri ma ry tu mo rs Mor e t ha n on e tu mo r in t he bre as t

Pa g e 7 3 1


Co nt r ai n di c at i ons to rad i at i on t he rap y Ad van ced di s eas e (i .e ., bey on d sta ge II) L arg e are as of i nt r

Pa g e 7 3 2


ad uct al di s eas e or mi c roc al ci fi c at i ons T um ors wi t h an ext ens i ve i nt r ad uct al co mp on ent (i .e ., 25 % of

Pa g e 7 3 3


t he pri ma ry tu mo r is in sit u an d t he re is at l ea st on e foc us of bre as t can cer t ha t is in sit u in nor ma

Pa g e 7 3 4


l bre as t tis s ue an d is s ep ara te fro m t he bre as t pri ma ry) P.144





3. Adjuvant chemotherapy. Thi s t echni que del ays or prevent s recurrence and i mproves s urvi val i n pat i ent s wi t h pos i t i ve axi l l ary nodes as wel l as i n s ome pat i ent s wi t h negat i ve axi l l ary nodes . Premenopaus al pat i ent s wi t h pos i t i ve axi l l ary nodes are mos t l i kel y t o benefi t from chemot herapy; s uch pat i ent s experi ence a 25%â€“30% reduct i on i n mort al i t y. o

o

a. Combination chemotherapy. Thi s approach i s commonl y us ed i n t he hi gh-ri s k adjuvant s et t i ng,

Pa g e 7 3 5


and 4â€“6 mont hs of t reat ment (4â€“8 cycl es of combi nat i on chemot herapy every 2â€“3 weeks ) i s us ual l y s uffi ci ent t o obt ai n maxi mum benefi t . In pat i ent s wi t h met as t at i c breas t cancer, t he us e of effect i ve s i ngl e agent s may be as effect i ve as t he us e of more act i ve but more t oxi c combi nat i on chemot herapy regi mens . Hi gh-dos e t herapy wi t h aut ol ogous s t em cel l res cue, whi ch does not i mprove t reat ment out comes i n women wi t h met as t at i c di s eas e, i s not s t andard t herapy i n t he hi gh-ri s k s et t i ng. Four t o ei ght cycl es of t herapy (dependi ng on t he regi men empl oyed) over 3 t o 6 mont hs are as effect i ve as l onger t reat ment peri ods . o

o

b. Drug regimens. Maxi mal l y t ol erat ed dos es s houl d be us ed unl es s s i gni fi cant t oxi ci t y devel ops . 



(1) The mos t commonl y us ed adjuvant t herapy regi mens cont ai n s ome combi nat i on of t he agent s doxorubi ci n, cycl ophos phami de, met hot rexat e, and 5-FU. Taxanes are now i mport ant component s of adjuvant t herapy i n pat i ent s wi t h node-pos i t i ve di s eas e. The ant i -HER2-neu monocl onal ant i body, t ras t uzumab (Hercept i n) was recent l y FDA-approved for us e i n t he adjuvant s et t i ng for pat i ent s wi t h HER2/neu-pos i t i ve cancers .





(2) Pat i ent s at hi gher ri s k for devel opi ng recurrent or met as t at i c di s eas e are t ypi cal l y offered doxorubi ci n- or t axane-cont ai ni ng regi mens (6â€“8 cycl es ).

Pa g e 7 3 6




(3) Ot her active chemotherapeutic agents may be us ed t o pal l i at e pat i ent s wi t h met as t at i c di s eas e. Thes e i ncl ude t he t axanes [pacl i t axel (Taxol ) or docet axel (Taxot ere)], t he ant i -HER2/neu ant i body t ras t uzumab (Hercept i n), vi norel bi ne, gemci t abi ne, or capeci t abi ne as s i ngl e agent s or i n combi nat i on.





4. Adjuvant endocrine therapy o

o

a. Hormonal therapy. Bot h pre- and pos t menopaus al pat i ent s wi t h pos i t i ve hormone recept ors (ERs and/or PGRs ) are offered endocri ne t herapy aft er compl et i on of chemot herapy. 



(1) The s el ect i ve es t rogen recept or modul at or (SERM) t amoxi fen and hormonal agent s cal l ed aromat as e i nhi bi t ors (AIs ; anas t rozol e, l et rozol e, and exemes t ane) are t he preferred agent s . AIs are FDA approved for p os t menopaus al women onl y and can be us ed up front for 5 years or s equent i al l y aft er 2â€“5 years of t amoxi fen t herapy for a t ot al of 5â€“10 years of adjuvant hormonal t herapy. Tamoxi fen and AIs del ay recurrence and i mprove s urvi val .





(2) Tamoxi fen adjuvant hormonal t herapy for 5 years s omet i mes i n combi nat i on wi t h l ut ei ni zi ng hormoneâ€“rel eas i ng hormone

Pa g e 7 3 7


(LH-RH) agoni s t s or oophorect omy are i ndi cat ed i n premenopaus al pat i ent s wi t h ER/PGR-pos i t i ve t umors . 



(3) Pat i ent s wi t h ER-negat i ve t umors exhi bi t l i t t l e or no res pons e t o hormonal t herapy and t herefore i t i s not i ndi cat ed i n ei t her adjuvant or met as t at i c s et t i ng.

o

o

b. Hormonal therapy for metastatic breast cancer 



(1) Hormonal t herapy i s appropri at e for pat i ent s wi t h s ubcut aneous met as t as es , l ymph node i nvol vement , pl eural effus i ons , bone met as t as es , and nonl ymphangi t i c l ung met as t as es . Mos t pat i ent s wi t h l i ver met as t as es , l ymphangi t i c di s eas e of t he l ung, peri cardi al met as t as es , or ot her pot ent i al l y l i fe-t hreat eni ng met as t as es are t reat ed i ni t i al l y wi t h chemot herapy t o obt ai n a rapi d res pons e, but s uch t reat ment deci s i ons mus t be cus t omi zed.





(1) Pat i ent s wi t h ER-pos i t i ve pri mary t umors exhi bi t res pons e rat es of at l eas t 30% t o hormone t herapy. If t he t umor cont ai ns bot h pos i t i ve ERs and PGRs , res pons e rat es are hi gher.





(3) Pos t menopaus al pat i ent s whos e hormone recept or s t at us i s unknown may res pond t o

Pa g e 7 3 8


hormone t herapy. 



(4) Pat i ent s wi t h a previ ous res pons e t o hormonal t herapy may res pond t o di s cont i nuat i on of t he ori gi nal agent and s ubs t i t ut i on of a s econd agent .





(5) Ot her hormonal t herapi es /mani pul at i ons i ncl ude, ful ves t rant (Fas l odex), anas t rozol e (Ari mi dex), Let rozol e (Femara), exemes t ane (Aromas i n), meges t rol (Megace), fl uoxymes t erone (Hal ot es t i n), and l LH-RH ant agoni s t s .

o

o

c. The res ul t s of s t udi es of ovarian ablation by radiation, oophorectomy, or chemical ablation i n premenopaus al pat i ent s have been mi xed. Cert ai n s ubgroups may gai n l ong-t erm benefi t s .

P.145





5. Other types of breast cancer and treatment recommendations o

o

a. Intraductal breast cancer. Becaus e t he t umor i s noni nvas i ve (i .e., confi ned t o t he duct s ), careful pat hol ogi c revi ew can excl ude any ri s k of l ymph node i nvol vement or di s t ant met as t as es . The prognos i s i s excel l ent . 

Pa g e 7 3 9


(1) Pat i ent s may be t reat ed by t ot al mas t ect omy or by l umpect omy fol l owed by radi at i on t o t he whol e breas t .





(2) Axi l l ary node di s s ect i on i s cont rovers i al ; mos t expert s bel i eve i t i s unneces s ary.





(3) Duct al carci noma i n s i t u (CIS) requi res defi ni t i ve s urgery. Tamoxi fen i s wi del y us ed i n t he pos t operat i ve s et t i ng.

o

o

b. Lobular CIS. Pat i ent s wi t h t hi s noni nvas i ve l es i on are at hi gher ri s k for devel opment of i nvas i ve cancer i n bot h breas t s . Treat ment opt i ons i ncl ude ri gorous obs ervat i on and fol l ow-up, and t amoxi fen prophyl axi s t herapy. Rarel y bi l at eral mas t ect omy i s performed for prophyl axi s .

o

o

c. Stage I and stage II disease. Mos t pat i ent s have t he opt i on of ei t her breas t cons ervat i on wi t h l umpect omy or modi fi ed radi cal mas t ect omy wi t h s ent i nel l ymph node bi ops y. Axi l l ary l ymph node di s s ect i on i s res erved for pat i ent s wi t h pos i t i ve s ent i nel l ymph node bi ops y. Pos t operat i ve radi at i on t herapy i s al s o avai l abl e for al l pat i ent s who had l umpect omy s urgery. Adjuvant t herapy s houl d be offered t o hi gh-ri s k s t age I pat i ent s and al l s t age II pat i ent s .

o

o

d. Stage III disease. Treat ment opt i ons are det ermi ned by t umor res ect abi l i t y. 

Pa g e 7 4 0




(1) Patients with operable tumors are general l y t reat ed wi t h modi fi ed radi cal mas t ect omy and pos t operat i ve radi at i on t herapy. Thes e pat i ent s al s o recei ve preoperat i ve (neoadjuvant ) or pos t operat i ve adjuvant chemot herapy.





(2) Patients with inoperable stage III disease have a hi gh rat e of l ocal and di s t ant recurrence and poor s urvi val rat es . 



(a) A combi ned-modal i t y approach i s requi red, us i ng s ys t emi c neoadjuvant chemot herapy i n addi t i on t o s urgery and radi at i on.





(b) In mos t cas es , aggres s i ve combi nat i on chemot herapy i s i ni t i at ed aft er bi ops y t o reduce t umor bul k, faci l i t at e l ocal t reat ment , and t reat di s t ant mi cromet as t as es .

VII. Gastrointestinal Cancers A. Carcinoma of the colon, rectum, and anus 



1. Incidence. Cancers of t he col on and rect um occur i n 145,600 i ndi vi dual s annual l y i n t he Uni t ed St at es and account for 56,000 deat hs each year.



Pa g e 7 4 1




2. Etiology/ Risk Factors. Up t o 70% of pat i ent s have no i dent i fi abl e ri s k fact ors . However, genet i c and epi demi ol ogi c s t udi es have l i nked col on and rect al cancer t o t he fol l owi ng fact ors : o

o

a. Inherited predisposition. Fami l i al s yndromes s uch as adenomat ous pol ypos i s col i (APC), an aut os omal domi nant di s order caus ed by mut at i ons i n t he FAP gene on chromos ome 5, may l ead t o an i ncreas ed ri s k of col on cancer. In APC, cancers commonl y devel op i n adol es cence and young adul t hood, and t he i nci dence of col orect al neopl as ms i s nearl y 100% by age 50. Heredi t ary nonpol ypos i s col on cancer (HNPCC), whi ch i s al s o fami l i al , i s as s oci at ed wi t h a l ower but s i gni fi cant ri s k of cancer of t he col on and rect um. Mut at i ons i n t umor s uppres s or genes s uch as MCC, DCC, BRCA1, and p53 al s o confer hi gher ri s ks for col orect al neopl as ms .

o

o

b. Somatic mutation. The wel l -es t abl i s hed genet i c changes t hat accompany t he progres s i on from epi t hel i al hyperpl as i a t hrough pol yp format i on and event ual cancer devel opment form a cont i nuum. Thes e changes i ndi cat e an as s oci at i on among i nheri t ed predi s pos i t i ons (e.g., mut at ed p53) and acqui red mut at i ons i n ei t her t umor s uppres s or genes s uch as DCC or i n oncogenes s uch as ras .

o

o

c. Dietary influence. The hi gher i nci dence of col orect al neopl as ms i n i ndus t ri al i zed s oci et i es has l ed t o hypot hes es t hat hi gh-fat , l ow-fi ber di et s

Pa g e 7 4 2


t hat are defi ci ent i n cal ci um, s el eni um, fol at e, vi t ami ns D and E, and ot her t race el ement s predi s pos e i ndi vi dual s t o t he devel opment of col orect al neopl as ms . o

o

d. Preexisting inflammatory disease. Infl ammat ory bowel di s eas e, part i cul arl y ul cerat i ve col i t i s wi t h pancol i t i s , i s as s oci at ed wi t h a hi gher i nci dence of col orect al neopl as ms .





3. Screening o

o

a. Al l adul t s ol der t han 40 years wi t h s i gns or s ympt oms cons i s t ent wi t h col orect al neopl as ms s houl d undergo t es t i ng t o excl ude t he pres ence of a mas s l es i on i n t he col on or rect um. P.146

o

o

b. Al l average ri s k adul t s aged 50 years or ol der s houl d undergo one of t he fol l owi ng opt i ons : (i ) annual fecal occul t bl ood t es t (FOBT) or fecal i mmunochemi cal t es t (FIT), (i i ) fl exi bl e s i gmoi dos copy every 5 years , (i i i ) annual FOBT or FIT, pl us fl exi bl e s i gmoi dos copy, (i v) doubl e cont ras t bari um enema (DCBE) every 5 years , or (v) col onos copy every 10 years . Al l pos i t i ve t es t s s houl d be fol l owed up wi t h a col onos copy.





4. Pathology o

Pa g e 7 4 3


o

a. The l arge majori t y of col orect al neopl as ms are adenocarcinomas, and mos t are wel l or moderat el y di fferent i at ed. Poorl y di fferent i at ed neopl as ms are as s oci at ed wi t h poor prognos i s .

o

o

b. Squamous cell carcinomas can ari s e i n t he anus . Such neopl as ms di ffer from adenocarci nomas i n t erms of bi ol ogy and t herapy.






o

a. Local symptoms i ncl ude a change i n bowel habi t s t hat may i nvol ve cons t i pat i on, di arrhea, and a change i n s t ool cal i ber, crampy abdomi nal pai n, and rect al bl eedi ng. Si gns of obs t ruct i on, perforat i on, or earl y s at i et y may occur. Tenes mus may be pres ent i n rect al pri mari es . Pat i ent s wi t h l ocal l y advanced rect al carci noma may pres ent wi t h s ympt oms of peri neal pai n.

o

o

b. Systemic manifestations are uncommon i n i ndi vi dual s wi t h l ocal i zed neopl as ms . W hen t he cancer has met as t as i zed t o di s t ant organs , t he mos t common mani fes t at i ons are: 



(1) Anorexi a, fat i gue, and wei ght l os s





(2) Hepat omegal y, pai n, or fever due t o l i ver i nvol vement



Pa g e 7 4 4




6. Diagnosis o

o

a. Barium enema, flexible sigmoidoscopy, or colonoscopy are us ual l y requi red t o i dent i fy a s us pi ci ous mas s l es i on.

o

o

b. Biopsy of s us pi ci ous l es i ons i s needed t o es t abl i s h a di agnos i s .

o

o

c. W hen a di agnos i s of col orect al neopl as i a has been es t abl i s hed, addi t i onal s t udi es may be neces s ary bot h t o eval uat e t he ext ent of l ocal di s eas e and t o s creen for met as t at i c di s eas e. 



(1) CT scans of the pelvis and endorectal ultrasound may be appropri at e for rect al neopl as ms .





(2) CT scans of the chest and abdomen can s creen for t he pres ence of i nt ra-abdomi nal (e.g., mes ent eri c or ret roperi t oneal l ymph node enl argement ), hepat i c, or pul monary met as t as es .





7. Prognosis. Five-year survival rate for stage 0â€“1 patients is >90%; for stage 2, 70%â€“85%; stage 3, 55%â€“70%; and stage 4, 10%, di ffus e vers us i nt es t i nal hi s t ol ogy, and l ocat i on of t he t umor proxi mal and ent i re s t omach i nvol vement carryi ng wors e prognos i s . o

o

a. Surgically resectable cancer. Cures res ul t i n t he majori t y of pat i ent s who undergo s urgery for earl y (e.g., T 1 N 0 M 0 ) l es i ons , but s urgi cal cure rat es decl i ne rapi dl y wi t h advanci ng di s eas e s t age.

o

o

b. Metastatic cancer. The average s urvi val of unt reat ed pat i ent s i s approxi mat el y 6 mont hs , and t reat ment wi t h combi nat i on chemot herapy i ncreas es t hi s t i me by onl y s everal mont hs .





8. Staging. For ful l s t agi ng i nformat i on, pl eas e s ee t he mos t recent edi t i on of t he AJCC Cancer St agi ng Handbook.





9. T herapy o

o

a. Surgery. Surgery i s t he t reat ment of choi ce for

Pa g e 7 6 2


pat i ent s wi t h l ocal i zed gas t ri c cancer. The probability of surgical cure is directly related to the stage of the cancer. Pat i ent s wi t h t rans mural , l ymph nodeâ€“i nvol ved cancers have l ow s urgi cal cure rat es of onl y 15%. 



(1) Becaus e gas t ri c cancer i s t ypi cal l y di agnos ed at rel at i vel y advanced s t ages i n t he Uni t ed St at es , rel at i vel y few pat i ent s are cured. More ext ens i ve s urgery, pi oneered i n Japan, has not P.151

been s hown defi ni t i vel y t o i mprove out comes i n pat i ent s wi t h l ocal i zed but advanced-s t age cancers . 



(2) Adjuvant chemotherapy and chemotherapy. Pos t operat i ve radi at i on t herapy has not been s hown t o i mprove s urgi cal out comes i n pat i ent s who have undergone s urgery wi t h curat i ve i nt ent . However, adjuvant t herapy wi t h radi at i on t herapy pl us 5-FU chemot herapy i mproves s urvi val .

o

o

b. Palliative approach to metastatic disease. Narcot i c anal ges i cs or cel i ac pl exus bl ocks may reduce pai n. Ei t her operat i ve bypas s or t he pl acement of bi l i ary s t ent s or cat het ers may pal l i at e obs t ruct i ve jaundi ce. Al t hough chemot herapeut i c agent s s uch as 5-FU, doxorubi ci n, mi t omyci n-C, et opos i de, met hot rexat e,

Pa g e 7 6 3


pacl i t axel , docet axel , or ci s pl at i n have modes t s i ngl e-agent act i vi t y and may provi de pal l i at i on of s ympt oms , t hey have no meani ngful i mpact on s urvi val . Combi nat i on t herapy wi t h t wo or more of t hes e agent s may i mprove qual i t y of l i fe and s urvi val , but t he overal l i mpact i s not great . o

o

c. Additional use of chemotherapy. The t reat ment of gastric lymphomas t ypi cal l y i nvol ves chemot herapy. Aggres s i ve chemot herapy of t umors t hat res pond rapi dl y may res ul t i n gas t ri c perforat i on, however.

D. Carcinoma of the esophagus 



1. Incidence. Cancers of t he es ophagus occur i n approxi mat el y 14,500 i ndi vi dual s annual l y i n t he Uni t ed St at es and account for more t han 13,700 deat hs each year. St ri ki ng i ncreas es i n t he i nci dence of es ophageal adenocarci nomas have been not ed i n t he Uni t ed St at es s i nce t he earl y part of t he t went i et h cent ury; t he caus es of t hi s change are not known.





2. Etiology. The et i ol ogy of es ophageal cancers remai ns l argel y unknown. Mos t adenocarcinomas ari s e i n Barrett' s esophagus, but rel at i vel y few i ndi vi dual s wi t h Barret t 's es ophagus devel op es ophageal mal i gnanci es . Gas t roes ophageal refl ux di s eas e (GERD), whi ch can be caus ed by obes i t y, may cont ri but e t o t he format i on of Barret t 's es ophagus . Alcohol abuse and tobacco use predi s pos e i ndi vi dual s t o s quamous cel l carci nomas .



Pa g e 7 6 4


3. Screening. Recommendat i ons for screening for Barrett' s esophagus include: o

o

a. For no dys pl as i a, endos copy every 2 t o 3 years

o

o

b. For l ow-grade dys pl as i a, endos copy every 6 mont hs for 12 mont hs and t hen yearl y.

o

o

c. For hi gh-grade dys pl as i a, es ophagect omy or t hree mont hl y endos copi es or phot odynami c t herapy.





4. Pathology. The vas t majori t y of es ophageal adenocarci nomas are poorl y or moderat el y di fferent i at ed. Adenocarcinomas t ypi cal l y ari s e i n or near t he gas t roes ophageal junct i on i n Barret t 's es ophagus . In t he l as t few decades , t he i nci dence of adenocarci nomas ari s i ng i n or near t he gas t roes ophageal junct i on has i ncreas ed.






o

a. Local symptoms mos t commonl y i ncl ude dys peps i a, dys phagi a or odynophagi a, epi gas t ri c or ret ros t ernal pai n, and occas i onal l y gas t roi nt es t i nal bl eedi ng.

o

o

b. Systemic manifestations are common and may i ncl ude: 

Pa g e 7 6 5




(1) Anorexi a, wei ght l os s





(2) Fat i gue due t o anemi a





(3) Pai n due t o bone met as t as es










6. Diagnosis o

o

a. Bari um s wal l ow or upper gas t roi nt es t i nal endos copy es t abl i s hes t he pres ence of a mas s l es i on.

o

o

b. Typi cal l y, endoscopic biopsy di agnos es t he pres ence of a gas t ri c cancer.

o

o

c. Commonl y us ed staging studies i ncl ude t he fol l owi ng: 



(1) CT scanning may i dent i fy medi as t i nal or cel i ac l ymph node i nvol vement . It can i dent i fy t he pres ence of pul monary, l i ver, ret roperi t oneal l ymph node, or pel vi c met as t as es .





(2) Endoscopic ultrasound may defi ne t he

Pa g e 7 6 6


ext ent of t umor i nvas i on i n t he es ophagus and t he pres ence of peri es ophageal l ymph node enl argement . 



(3) Laparoscopy may be us ed preoperat i vel y t o eval uat e t he oment um, whi ch i s a common s i t e of met as t as i s t hat i s poorl y vi s ual i zed on CT s cans . P.152





(4) Bone scans and brain imaging are not indicated i n pat i ent s wi t h no s ympt oms of brai n or bone met as t as es .





7. Prognosis. Es ophageal cancer i s hi ghl y curabl e i n i t s earl i es t s t ages ; however, t he majori t y of pat i ent s pres ent wi t h l ocal l y advanced or met as t at i c di s eas e and many requi re concurrent neoadjuvant chemot herapy and i rradi at i on t herapy t o achi eve res ect abi l i t y. o

o

a. Surgically resectable cancer. Mos t pat i ent s who undergo s urgery for earl y (e.g., T 1 N 0 M 0 ) l es i ons are cured, but s urgi cal cure rat es decreas e rapi dl y as t he s t age of cancer i ncreas es .

o

o

b. Metastatic cancer. The s urvi val of unt reat ed pat i ent s averages about 6 mont hs , and chemot herapy i ncreas es average s urvi val by s everal mont hs i n res pons i ve pat i ent s .



Pa g e 7 6 7









9. T herapy o

o

a. Localized cancer 



(1) Surgery. Cure may res ul t from s urgery al one, chemot herapy and radi at i on t herapy, or chemot herapy and radi at i on t herapy fol l owed by s urgery. Surgery, ei t her al one or preceded by chemot herapy and radi at i on t herapy, i s t he mos t commonl y us ed curat i ve t reat ment modal i t y i n es ophageal di s eas e. The probabi l i t y of s urgi cal cure rel at es di rect l y t o t he s t age of t he cancer. A mi nori t y of pat i ent s wi t h t rans mural or l ymph nodeâ€“i nvol ved cancers are cured by es ophagect omy. A curat i ve approach i s not us ual l y t aken for s upracl avi cul ar or cel i ac l ymph node met as t as es .





(2) Preoperative chemotherapy and radiation therapy. Preoperat i ve chemot herapy wi t h 5-FU and ci s pl at i n i n conjunct i on wi t h radi at i on t herapy has been s hown t o i mprove s urgi cal out comes i n pat i ent s who have undergone s urgery wi t h curat i ve i nt ent . W hen us ed al one, nei t her chemot herapy nor radi at i on t herapy i mproves s urgi cal out come i n ei t her preoperat i ve or pos t operat i ve

Pa g e 7 6 8


s et t i ngs . o

o

b. Metastatic disease. Treat ment i s pal l i at i ve. 



(1) Radiation therapy in conjunction with chemotherapy wi t h agent s s uch as 5-FU or ci s pl at i n may pal l i at e l ocal s ympt oms caus ed by es ophageal obs t ruct i on.





(2) Esophageal stents and feeding tubes may mai nt ai n ent eral nut ri t i on and reduce t he ri s ks of as pi rat i on of es ophageal cont ent s .





(3) Narcotic analgesics may pal l i at e pai n.





(4) Other chemotherapeutic approaches may be us eful . Single-agent chemotherapy wi t h agent s s uch as 5-FU, et opos i de, i ri not ecan, pacl i t axel , docet axel , or ci s pl at i n may di s pl ay moderat e act i vi t y and may provi de pal l i at i on of s ympt oms but wi t hout meani ngful i mpact on s urvi val . Combination chemotherapy wi t h t wo or more of t hes e drugs may i mprove qual i t y of l i fe but has mi ni mal overal l i mpact on s urvi val .

E. Carcinoma of the hepatobiliary system 



1. Incidence. Hepat obi l i ary cancers occur i n approxi mat el y 20,000 i ndi vi dual s annual l y i n t he Uni t ed St at es and account for more t han 16,000 deat hs each

Pa g e 7 6 9


year. 



2. Etiology. Hepatocellular carcinoma i s as s oci at ed wi t h di s eas es t hat caus e chroni c l i ver i njury s uch as chronic active hepatitis caus ed by hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic cirrhosis, hemochromatosis, di et ary i ron overl oad, and W i l s on's di s eas e. Bi l i ary t ract neopl as ms s uch as cholangiocarcinoma and gallbladder cancer have i ncreas ed i nci dence i n i ndi vi dual s wi t h i nfl ammat ory bowel di s eas e.





3. Screening. Becaus e s i gns and s ympt oms do not us ual l y appear unt i l t he cancer i s i n i t s l at er s t ages , l i ver cancer i s s el dom di agnos ed earl y. However, i n hi gh-ri s k popul at i ons at ri s k for hepat ocel l ul ar cancer, recommendat i ons i ncl ude checki ng a Î±-fet oprot ei n (AFP) s erum t umor marker and ul t ras ound every 6 mont hs .





4. Pathology. Mos t hepat obi l i ary neopl as ms are adenocarci nomas .






o

a. Local symptoms of hepatocellular carcinoma i ncl ude pain res ul t i ng from di s t ent i on of t he l i ver caps ul e, pal pabl e mas s i n t he ri ght upper quadrant , or abdomi nal s wel l i ng. Obstructive jaundice i s a charact eri s t i c pres ent at i on for cholangiocarcinoma. Jaundi ce may be a mani fes t at i on of gallbladder cancer.

Pa g e 7 7 0


P.153

o

o

b. Systemic manifestations are common and may i ncl ude: 



(1) Si gns and s ympt oms of l i ver fai l ure s uch as edema, as ci t es , pruri t us , and port al hypert ens i on





(2) Anorexi a, wei ght l os s , naus ea and vomi t i ng





(3) Fat i gue due t o anemi a





(4) Pai n due t o bone met as t as es or peri t oneal met as t as es





(5) Dys pnea or cough due t o pul monary met as t as es










6. Diagnosis. Hepatocellular carcinoma may be i ni t i al l y s us pect ed i n at -ri s k i ndi vi dual s by a ri s e i n the AFP serum tumor marker or by t he pres ence of mas s on a s creeni ng l i ver ultrasound. On occas i on, gallbladder carcinoma i s di s covered at chol ecys t ect omy for

Pa g e 7 7 1


s ympt omat i c, apparent l y beni gn gal l bl adder di s eas e. o

o

a. CT scans and MRI imaging may i dent i fy a mas s or mas s es i n t he l i ver. Typi cal l y, t he di agnos i s of hepat ocel l ul ar carci noma i s es t abl i s hed by a CT-gui ded or ul t ras ound-gui ded fi ne-needl e as pi rat i on bi ops y.

o

o

b. In pat i ent s who pres ent wi t h ri ght upper quadrant pain or jaundice, CT scan or ERCP may det ect ei t her a mas s , obs t ruct i on of bi l i ary fl ow, or a fi l l i ng defect i n a major bi l i ary radi cl e. Ei t her fi ne-needl e as pi rat i on bi ops y or ERCP-gui ded bi ops y can es t abl i s h a di agnos i s of cholangiocarcinoma.

o

o

c. Commonly used staging studies i ncl ude t he fol l owi ng: 



(1) CT scanning may i dent i fy medi as t i nal or cel i ac l ymph node i nvol vement . It can i dent i fy t he pres ence of pul monary, l i ver, ret roperi t oneal l ymph node, or pel vi c met as t as es .





(2) Bone scans and brain imaging are not indicated i n pat i ent s wi t h no s ympt oms of brai n or bone met as t as es .





7. Prognosis o

Pa g e 7 7 2


o

a. Surgically resectable cancer. Surgi cal cure rat es decreas e rapi dl y wi t h i ncreas i ng di s eas e s t age.

o

o

b. Metastatic cancer. The average s urvi val of unt reat ed pat i ent s i s approxi mat el y 6 mont hs .










9. T herapy o

o

a. Localized cancer 



(1) Surgery 



(a) In localized hepatobiliary neoplasms, s urgery al one may provi de a cure i n s ome i ns t ances . Some pat i ent s wi t h t echni cal l y unres ect abl e but l i ver-confi ned neopl as ms may be candi dat es for liver transplantation. Radi at i on t herapy and s t andard chemot herapy have no defi ned rol es i n t he management of hepat ocel l ul ar carci noma, al t hough chemot herapy i s occas i onal l y us ed t o reduce t umor s i ze and faci l i t at e curat i ve-at t empt s urgery.



Pa g e 7 7 3




(b) In biliary tract neoplasms, adjunct i ve 5-FUâ€“bas ed chemot herapy pl us ext ernal beam or hi gh dos e-rat e i nt ral umi nal radi at i on i s commonl y us ed, al t hough pros pect i ve, randomi zed cl i ni cal t ri al s have not val i dat ed i t s ut i l i t y.





(2) Other locoregional approaches. Pat i ent s wi t h s mal l but unres ect abl e l es i ons may benefi t from t he i ns t i l l at i on of intralesional alcohol or chemoembolization, whi ch i nvol ves i nject i on of a s l urry of chemot herapeut i c agent s i n an oi l emul s i on di rect l y i nt o t he ves s el s uppl yi ng t he neopl as t i c l es i on. Nei t her of t hes e ext ens i vel y us ed approaches has been val i dat ed i n randomi zed cl i ni cal t ri al s . Radi ofrequency abl at i on of l es i ons and i ns t i l l at i on of radi ol abel ed mi cros pheres i n t he hepat i c t umors are t wo promi s i ng newer t echni ques t hat are under i nves t i gat i on.





(3) Metastatic disease. St andard chemot herapeut i c agent s are i neffect i ve i n pat i ent s wi t h advanced hepat ocel l ul ar carci noma. Admi ni s t rat i on of chemot herapy i s compl i cat ed by comorbi di t i es as s oci at ed wi t h l i ver fai l ure. No one chemotherapeutic agent or regimen has emerged as a standard of care in biliary neoplasms, but several agents have antitumor effects, and patients with metastatic disease may be treated with palliative intent. In addi t i on, stenting of

Pa g e 7 7 4


obs t ruct ed bi l e duct s , when feas i bl e, can pal l i at e jaundi ce. Narcotic analgesics may pal l i at e pai n. P.154

VIII. Gynecologic Malignancies A. Ovarian cancer 



1. Incidence. Ovari an cancer devel ops i n 1 i n 68 women and i s t he mos t common caus e of deat h from gynecol ogi c mal i gnancy. Inci dence rat es are hi ghes t i n i ndus t ri al i zed nat i ons . In 2007, t he ACS es t i mat es t hat t here wi l l be about 22,430 new cas es of ovari an cancer di agnos ed t hat year i n t he Uni t ed St at es .





2. Risk factors for ovari an cancer i ncl ude: o

o

a. Nul l i pari t y

o

o

b. Fewer t han average number of pregnanci es or a hi s t ory of mi s carri age

o

o

c. Fami l y hi s t ory of ovari an cancer

o

o

d. Hi s t ory of endocri ne di s orders

o

o

e. Age

Pa g e 7 7 5


o

f. Genetic ri s k fact ors i ncl udi ng, heredi t ary breas t and ovari an cancer s yndromes as s oci at ed wi t h BRCA1 and BRCA2 and wi t h heredi t ary nonpol ypos i s col orect al cancer s yndrome.





3. Screening. Ovari an cancer i s rarel y di agnos ed before t he di s eas e has reached an advanced s t age (s t age 3 or 4). o

o

a. Screeni ng i s recommended i n women wi t h known genet i c s yndromes s uch as BRCA1 and BRCA2 mut at i ons and Lynch II s yndrome, whi ch are as s oci at ed wi t h s i gni fi cant l y i ncreas ed ri s k of devel opi ng t hi s di s eas e; and for women wi t h a s t rong fami l y hi s t ory of ovari an cancer. Pel vi c ul t ras ound and CA 125 i n addi t i on t o pel vi c exam are ut i l i zed for s creeni ng.

o

o

b. Early detection. W omen wi t h average ri s k for ovari an cancer s houl d obt ai n rout i ne gynecol ogi c exami nat i ons . No exi s t i ng di agnos t i c modal i t y exhi bi t s s uffi ci ent s ens i t i vi t y and s peci fi ci t y t o permi t t he rel i abl e earl y det ect i on of s urgi cal l y curabl e cancers .





4. Pathology. The majori t y of ovari an cancers are epi t hel i al i n ori gi n. Thi s i ncl udes s erous , muci nous , endomet ri oi d, t rans i t i onal , and cl ear cel l ; wi t h cl ear cel l t ypes havi ng t he wors e prognos i s . Les s common are t he germ cel l and s t romal t umors .



Pa g e 7 7 6





o

a. Local symptoms i ncl ude abdomi nal di s comfort , l ow back pai n, bl oat i ng, and abdomi nal di s t ent i on.

o

o

b. Sys t emi c manifestations i ncl ude: 



(1) Virilization from germ cel l t umors





(2) Precocious puberty i n premenarchal women, amenorrhea i n women of reproduct i ve age, vaginal bleeding i n pos t menopaus al women can be caus ed by granul os e cel l t umors .





6. Diagnosis o

o

a. Initial evaluation 



(1) Pelvic ultrasound det ect s s mal l l es i ons i n t he ovary, even t hos e t hat cannot be pal pat ed duri ng bi manual exami nat i on.





(2) Det ermi nat i on of l evel s of t he tumor marker CA 125 and an annual pelvic ultrasound are recommended for pat i ent s wi t h a fami l y hi s t ory of ovari an cancer.

o

Pa g e 7 7 7


o

b. Pretreatment evaluation 



(1) Al l pat i ent s wi t h a new di agnos i s of ovari an cancer s houl d undergo abdomi nal and pel vi c CT s canni ng and/or MRI and a pel vi c ul t ras ound. Ches t radi ography, bari um enemas , cys t os copy, and fl exi bl e s i gmoi dos copy may be cons i dered, dependi ng on t he pres ent at i on of t he di s eas e.





(2) Rout i ne bl ood chemi s t ri es , i ncl udi ng al bumi n, magnes i um, and renal and l i ver funct i on t es t i ng, s houl d be performed. An el evat ed CA 125 i s found i n 80%â€“85% of pat i ent s wi t h di s eas e t hat i s not l ocal i zed t o t he ovari es . If a germ cel l t umor i s s us pect ed, t he fol l owi ng t umor markers s houl d be drawn: l act at e dehydrogenas e (LDH), AFP, and human chori oni c gonadot ropi n (hCG).





(3) A careful l aparot omy es t abl i s hes t he s t age and ext ent of t he di s eas e and may permi t t he reduct i on of t umor mas s es . 



(a) The ent i re abdomi nal cont ent s s houl d be expl ored, and any s us pi ci ous l es i ons s houl d be removed or exami ned by bi ops y. P.155



Pa g e 7 7 8




(b) In addi t i on t o checki ng t he pri mary t umor for rupt ure or adherence, t he s urgeon s houl d not e t he amount and t ype of as ci t es (i f pres ent ). Sampl es of fl ui d s houl d be col l ect ed for cyt ol ogi c anal ys i s by peri t oneal was hi ng.





(c) The para-aort i c nodes i n t he regi on of t he renal hi l a s houl d be exami ned by bi ops y.





(d) The di aphragmat i c s urfaces s houl d be careful l y expl ored.





7. Prognosis o

o

a. The stage of disease i s t he mos t i mport ant prognos t i c fact or. 



(1) Pat i ent s wi t h di s t ant met as t as es are rarel y cured, even aft er combi nat i on chemot herapy.





(2) Pat i ent s wi t h di s eas e l i mi t ed t o t he ovary may be cured wi t h s urgery al one.





(3) Pat i ent s wi t h mi ni mal s t age III di s eas e have an excel l ent prognos i s wi t h debul ki ng s urgery fol l owed by combi nat i on chemot herapy, es peci al l y i f t he res i dual t umor

Pa g e 7 7 9


mas s es meas ure l es s t han 2 cm i n di amet er. o

o

b. Histologic grade has great er prognos t i c s i gni fi cance t han t ype. Borderl i ne t umors , whi ch di s pl ay nucl ear charact eri s t i cs of mal i gnancy but l ack s t romal i nvas i on, behave i n an i ndol ent fas hi on and are not res pons i ve t o chemot herapy.










9. T herapy o

o

a. Surgery 



(1) Procedures 



(a) Mos t pat i ent s undergo bilateral salpingo-oophorectomy and transabdominal hysterectomy. Al l gros s res i dual di s eas e s houl d be res ect ed i f pos s i bl e. In mos t cas es , i f a pat i ent has met as t at i c di s eas e out s i de t he abdomi nal and pel vi c areas , debul ki ng s urgery i s not i ndi cat ed.





(b) Becaus e ovari an cancer frequent l y s preads t hroughout t he peri t oneal cavi t y and us ual l y i s as s oci at ed wi t h oment al

Pa g e 7 8 0


and peri t oneal s eedi ng, t he ent i re abdomi nal and pel vi c cavi t i es s houl d be expl ored, a partial omentectomy performed, and t he paracol i c gut t ers i ns pect ed. 



(2) Adjuvant therapy and follow-up 



(a) Pat i ent s wi t h s t age IA or s t age IB di s eas e wi t h wel l -di fferent i at ed or moderat el y di fferent i at ed t umors requi re no addi t i onal adjuvant t herapy aft er s urgery. Ot herwi s e, pat i ent s wi t h s t age III and IV di s eas e s houl d recei ve adjuvant t herapy, whi ch us ual l y cons i s t s of chemotherapy with carboplatin and paclitaxel for six cycles postoperatively. Al t ernat i ves i ncl ude total abdominal radiation therapy or intraperitoneal radioisotopes. Advanced ovari an cancer (i .e., s t age III or IV) i s not curabl e by s urgery al one. However, reduction of bul ky cancer i s as s oci at ed wi t h an i mproved res pons e t o ei t her radi at i on or chemot herapy, i f t he l arges t res i dual mas s i s reduced t o l es s t han 2 cm i n di amet er. Les s ext ens i ve reduct i ons are not benefi ci al , even i f l arge amount s of t he t umor are removed.





(b) Second-look surgery. Surgi cal reexpl orat i on at t he concl us i on of chemot herapy can det ect remi s s i on,

Pa g e 7 8 1


as s es s res pons e, and al l ow furt her cyt oreduct i ve s urgery i n an at t empt t o prol ong s urvi val . Approxi mat el y 50% of pat i ent s wi t h cl i ni cal l y compl et e res pons es have s urgi cal l y document ed compl et e remi s s i ons . The val ue of t he rout i ne us e of t hi s procedure has not been es t abl i s hed. o

o

b. Chemotherapy. Sys t emi c chemot herapy res ul t s i n hi gh res pons e rat es i n pat i ent s wi t h ovari an cancer and i ncreas es t he l i kel i hood of a cure i n pat i ent s wi t h res ect abl e di s eas e. 



(1) Drug regimens. The mos t commonl y us ed agent s are pacl i t axel , cycl ophos phami de, ci s pl at i n, and carbopl at i n. Few dat a s upport t he us e of doxorubi ci n-bas ed regi mens . Cont emporary regi mens commonl y us e pacl i t axel i n conjunct i on wi t h carbopl at i n or ci s pl at i n. 



(a) Carbopl at i n (dos e-adjus t ed for renal funct i on t o area-under-t he-curve) i s equi val ent i n effi cacy t o ci s pl at i n and i s as s oci at ed wi t h l es s emes i s , peri pheral neuropat hy, and ot ot oxi ci t y, al t hough i t has an i ncreas ed rat e of bone marrow t oxi ci t y compared wi t h ci s pl at i n. Becaus e carbopl at i n can be admi ni s t ered eas i l y i n t he out pat i ent s et t i ng, i t i s general l y preferred over ci s pl at i n t o t reat ovari an cancer.

Pa g e 7 8 2


P.156





(b) Taxanes are as s oci at ed wi t h approxi mat el y 30% res pons e rat es i n pat i ent s who have fai l ed t o res pond t o ot her t herapi es . Taxaneâ€“pl at i num combi nat i ons i nduce compl et e cl i ni cal remi s s i on i n more t han 60% of women wi t h previ ous l y unt reat ed s t age III ovari an cancer.





(2) T reatment of residual disease after induction chemotherapy. Radi at i on t herapy has cons i s t ent l y fai l ed t o prol ong s urvi val and i s as s oci at ed wi t h unaccept abl e rat es of bowel t oxi ci t y. 



(a) Intraperitoneal chemotherapy i s bas ed on t he s l ow peri t oneal cl earance of many chemot herapeut i c agent s rel at i ve t o t ot al body cl earance. Some s t udi es demons t rat e t hat i nt raperi t oneal chemot herapy i s advant ageous compared wi t h s ys t emi c chemot herapy i n t he t reat ment of ovari an cancer. 



(i) Drugs are admi ni s t ered i n l arge vol umes (1â€“2 L) t hrough s emi permanent s ys t ems (e.g., cat het ers ).



Pa g e 7 8 3




(ii) Agent s t hat have been us ed i nt raperi t oneal l y i n ovari an cancer i ncl ude met hot rexat e, 5-FU, carbopl at i n, and ci s pl at i n.





(b) Salvage chemotherapy opt i ons i ncl ude t opot ecan, gemci t abi ne, and hexamet hyl mel ami ne. Bot h t opot ecan and gemci t abi ne are act i ve agent s undergoi ng t es t i ng i n pat i ent s wi t h chemot herapy-nai ve di s eas e. Hi gh-dos e t herapy wi t h aut ol ogous s t em cel l res cue i s feas i bl e, but i t has fai l ed t o s how s i gni fi cant i mprovement over convent i onal dos i ng.





(c) Radiation therapy. For pat i ent s wi t h advanced di s eas e, radi at i on t herapy i s an opt i on for pal l i at i on of s ympt oms . Succes s i s di rect l y rel at ed t o t he l ocat i on and vol ume of di s eas e at t he t i me of t herapy.

B. Cervical cancer 



1. Incidence. Carci noma of t he cervi x was once one of t he mos t common caus es of deat h from cancer, but i nci dence rat es have decreas ed by one-hal f i n t he l as t 30 years . Cervi cal cancer affect s 9,700 women annual l y. o

o

a. Thi s decl i ne i n mort al i t y rat e i s l argel y at t ri but abl e t o t he i nt roduct i on of t he Papani col aou

Pa g e 7 8 4


(Pap) s mear for t he di agnos i s of dys pl as i a or CIS. o

o

b. Invas i ve cancer i s mos t frequent l y s een i n pat i ent s bet ween 45 and 55 years of age from l ower s oci oeconomi c groups .





2. Etiology o

o

a. Risk factors for cervi cal cancer i ncl ude: 



(1) Earl y i ni t i al s exual act i vi t y





(2) Mul t i pl e s exual part ners





(3) Earl y age at fi rs t pregnancy and mul t i pl e pregnanci es





(4) Hi s t ory of venereal i nfect i on





(5) Oral cont racept i ve us e

o

o

b. Recent s t udi es have i mpl i cat ed i nfect i on wi t h human papi l l omavi rus (HPV), whi ch caus es common geni t al wart s , i n t he progres s i on of cervi cal cancer. Several oncogenes have been i mpl i cat ed as wel l , i ncl udi ng c-myc and ras .





3. Screening. The Pap smear i s us eful for det ect i ng

Pa g e 7 8 5


earl y l es i ons and has a s ens i t i vi t y of 90%â€“95%. o

o

a. As a prevent i ve meas ure, women s houl d begi n s creeni ng 3 years aft er t he ons et of vagi nal i nt ercours e or at 21 years , whi chever i s earl i er. W omen s houl d have a negat i ve t es t every 2 years i f us i ng l i qui d-bas ed cyt ol ogy or annual l y wi t h convent i onal cervi cal cyt ol ogy s mears unt i l t he age of 30. Aft er t he age of 30 and i f t hey have had t hree normal t es t s res ul t s cons ecut i vel y, t hey can cont i nue s creeni ng every 2â€“3 years . Screeni ng s houl d end at age 70 i f t hey have had no abnormal /pos i t i ve cyt ol ogy t es t s wi t hi n t he previ ous 10 years or earl i er i f a women has had a compl et e hys t erect omy.

o

o

b. Hemorrhage, i nfl ammat ory react i ons (e.g., a fungat i ng mas s ), or i nvas i ve cancer may res ul t i n fal s e-negat i ve s mears .





4. Pathology o

o

a. Squamous metaplasia i s t he precurs or of cervical intraepithelial neoplasia (CIN), whi ch i s s ubdi vi ded i nt o t hree grades accordi ng t o s everi t y. P.157





(1) Grade I (mi l d-t o-moderat e dys pl as i a)



Pa g e 7 8 6




(2) Grade II (moderat e-t o-s evere dys pl as i a)





(3) Grade III (s evere dys pl as i a and CIS)

o

o

b. CIS exhi bi t s cyt ol ogi c evi dence of neopl as i a wi t hout i nvas i on of t he bas ement membrane. Thi s s t age can pers i s t as l ong as 3â€“10 years before progres s i ng t o i nvas i ve cervi cal carci noma.






o

a. Local symptoms i ncl ude: abnormal vagi nal bl eedi ng, vagi nal di s charge.

o

o

b. Systemic features i ncl ude: 



(1) Fatigue and anemia s econdary t o chroni c bl eedi ng





(2) Pain in the lumbosacral or gluteal area s ugges t i ng hydronephros i s or i nvol vement of t he i l i ac or peri aort i c l ymph nodes





(3) Urinary or rectal symptoms





(4) Leg pain or edema res ul t i ng from l ymphat i c or venous bl ockage



Pa g e 7 8 7




6. Diagnosis o

o

a. Early detection. W omen wi t h epi t hel i al abnormal i t i es i n t he Pap s mear s houl d undergo cervical biopsy. Vi s i bl e l es i ons neces s i t at e bi ops y, regardl es s of Pap s mear fi ndi ngs . If t here are no vi s i bl e l es i ons , col pos copy (us i ng a bi nocul ar mi cros cope and l i ght s ource) reduces t he need for cervi cal coni zat i on.

o

o

b. Pretreatment evaluation s houl d i ncl ude ches t radi ograph, CT s cans of t he abdomen and pel vi s , compl et e bl ood count (CBC), l i ver and renal funct i on s t udi es , and a bari um enema i n pat i ent s wi t h s ympt oms i nvol vi ng t he col on or rect um. 



(1) Becaus e of t he pos s i bi l i t y of upper ext ens i on of t he t umor, curettage of t he endocervi cal canal and endomet ri um i s recommended duri ng t he i ni t i al eval uat i on.





(2) Cystoscopy and rectosigmoidoscopy are performed i n s el ect ed pat i ent s wi t h advanced di s eas e.





7. Prognosis. The 5-year s urvi val rat e for s t age I cervi cal cancer i s 75%â€“90%; for s t age II, 50%â€“70%; for s t age III, 30%â€“35%; and for s t age IV, 10%â€“15%. o

Pa g e 7 8 8


a. T umor volume i s an i mport ant prognos t i c fact or wi t hi n s t ages . Bot h t he grade and t umor vol ume wi t hi n a gi ven grade have prognos t i c s i gni fi cance. Hi s t ol ogi c t ype has l i t t l e s i gni fi cance, except for s ome unus ual vari ant s .

o

o

b. Lymph node metastases are as s oci at ed wi t h a poor prognos i s . Ot her poor prognos t i c fact ors i ncl ude tumor grade, depth of invasion, and lymphovascular space invasion.





8. Staging. For ful l s t agi ng i nformat i on, pl eas e s ee t he mos t recent edi t i on of t he AJCC Cancer St agi ng Handbook. Cl i ni cal s t agi ng i s oft en i naccurat e, and s t agi ng l aparot omy s t udi es have s hown t hat approxi mat el y 30% of pat i ent s have more ext ens i ve di s eas e t han i s s ugges t ed by cl i ni cal s t agi ng procedures .





9. T herapy. Cervi cal cancer i n mos t pat i ent s i s t reat ed wi t h surgery, radiation therapy, or a combination of both. Chemot herapy wi t h ci s pl at i n al s o may be pres cri bed as a radi at i on s ens i t i zer. Ci s pl at i n has document ed act i vi t y as a s i ngl e agent . o

o

a. T otal abdominal hysterectomy i s t he us ual t reat ment for CIS and CIN. In women who wi s h t o bear chi l dren, management wi t h cervi cal coni zat i on and careful fol l ow-up may be appropri at e. Therapy for s t age I mi croi nvas i ve cancer (i .e., an i nvas i on of 5 years ) di s eas e-free s urvi val .

H. Staging Hodgki n's di s eas e t ends t o s pread i n an orderl y fas hi on from node group t o node group. Thi s cont i guous nat ure i s i n marked cont ras t t o non-Hodgki n's l ymphomas , whi ch are mul t i cent ri c earl y i n t hei r devel opment . The modi fi ed Ann Arbor classification i s us ed for staging Hodgkin' s disease (for ful l s t agi ng i nformat i on, pl eas e s ee t he mos t recent edi t i on of t he AJCC Cancer St agi ng Handbook). W orkup i s bas ed on t he pri nci pl e t hat early-stage Hodgki n's di s eas e can be treated locally but late-stage Hodgki n's di s eas e requires systemic therapy. Therefore, pat i ent s are aggres s i vel y s t aged t o i ncl ude or excl ude s t age IIIA 2 , s t age IIIB, and s t age IV di s eas e. (Thi s s t agi ng i s far more ext ens i ve t han s t agi ng for non-Hodgki n's l ymphomas .)

I. Therapy Treat ment for Hodgki n's di s eas e cont i nues t o evol ve. However,

Pa g e 8 4 5


cert ai n pri nci pl es have been es t abl i s hed and s houl d be fi rml y adhered t o, becaus e even advanced disease is curable. Indi vi dual vari at i ons i n t reat ment s houl d be avoi ded and, i f us ed, s houl d be l i mi t ed t o wel l -cont rol l ed cl i ni cal t ri al s . 



1. Stage I or II di s eas e i s t reat ed wi t h extended-field radiation therapy.





2. Stage IIIA 1 disease (pathologically staged) is treated with total nodal radiation therapy. Pat i ent s who rel aps e aft er radi at i on t herapy can be s ucces s ful l y gi ven chemotherapy. More t han 50% of s uch pat i ent s have l ong-t erm di s eas e-free s urvi val when s uch t echni ques are us ed. Cl i ni cal s t age IIIA 1 di s eas e (e.g., no s t agi ng l aparot omy) i s us ual l y t reat ed wi t h chemot herapy.





3. Stage IIIA 2 , IIIB, or IV di s eas e requi res systemic chemotherapy. Bone marrow t rans pl ant at i on has been us ed i n cas es of rel aps e. o

o

a. Regimens 



(1) Many regi mens are avai l abl e. The cl as s i c mechlorethamineâ€“vincristine (Oncovin)â€“procarbazineâ€“prednisone (MOPP) regimen, whi ch i s gi ven for at l eas t s i x cycl es pl us t wo addi t i onal cycl es aft er compl et e remi s s i on i s document ed, was t he fi rs t curat i ve regi men. However, The doxorubicin (Adriamycin) â€“bleomycinâ€“vinblastineâ€“dacarbazine

Pa g e 8 4 6


(DT IC) [ABVD] regimen i s current l y t he fi rs t l i ne combi nat i on chemot herapy of choi ce. P.173

Thi s regi men has been s hown t o be more effect i ve and l es s t oxi c t han MOPP and as effect i ve as and l es s t oxi c t han t he MOPP/ABVD combi nat i ons . 



(2) Ot her regi mens s uch as St anford V, whi ch us es a combi nat i on of mul t i pl e chemot herapy agent s and radi at i on t reat ment t o bul ky (>5 cm) l ymph nodes , are al s o i n us e. A phas e III randomi zed cl i ni cal t ri al of ABVD vers us St anford V i s underway

o

o

b. Principles 



(1) Combi ned chemot herapy and radi at i on t herapy s houl d not be us ed rout i nel y unt i l furt her cl i ni cal t ri al s prove t he effect i venes s of s uch regi mens .





(2) Unl es s chemot herapeut i c agent s are gi ven i n ful l dos es and accordi ng t o pres cri bed s chedul es , t hei r effect i venes s can be s i gni fi cant l y compromi s ed.

o

o

c. Side effects. Bot h combi nat i on chemot herapy and t ot al nodal i rradi at i on are t oxi c and have many predi ct abl e s i de effect s , i ncl udi ng s evere naus ea and vomi t i ng, mucos i t i s , di arrhea, bone marrow

Pa g e 8 4 7


s uppres s i on, cardi ot oxi ci t y, hypot hyroi di s m, s t eri l i t y (i n s ome cas es ), and devel opment of s econdary marrow probl ems , i ncl udi ng acut e l eukemi a.

XVI. Non-Hodgkin's Lymphoma A. Incidence More t han 58,000 pat i ent s are di agnos ed wi t h non-Hodgki n's l ymphoma i n t he Uni t ed St at es each year. An i ncreas ed i nci dence i n ol der peopl e i s at t ri but abl e t o a ri s i ng i nci dence i n di ffus e l arge cel l l ymphoma. Non-Hodgki n's l ymphomas (es peci al l y CNS l ymphomas ) are more common i n pat i ent s wi t h acqui red i mmunodefi ci ency s yndromes and i n pat i ent s recei vi ng i mmunos uppres s i ve drugs s uch as t hos e wi t h ki dney and heart t rans pl ant s .

B. Etiology 



1. Cytogenetic abnormalities s uch as chromos ome t rans l ocat i ons are commonl y obs erved i n l ymphoma cel l s .





2. Viral infection o

o

a. The Epstein-Barr virus has been l i nked t o Burkitt' s lymphoma, a di s eas e us ual l y found i n Afri ca.

o

o

b. An aggres s i ve T-cel l l eukemi a or l ymphoma occurs i n Japan and t he Cari bbean, and i s as s oci at ed wi t h human T l ymphot ropi c vi rus t ype I (HT LV-I) infection.

Pa g e 8 4 8


C. Screening There are current l y no s creeni ng gui del i nes for earl y det ect i on i n as ympt omat i c i ndi vi dual s .

D. Pathology A number of hi s t ol ogi c cl as s i fi cat i on s chemes are i n us e; t he one mos t wi del y us ed i n t he cl i ni cal l i t erat ure i s t he W HO cl as s i fi cat i on s ys t em. The W HO cl as s i fi cat i on for l ymphoi d neopl as ms i s found i n t he AJCC Cancer St agi ng Handbook. 



1. The low-grade lymphomas are predomi nant l y B-cel l t umors . The intermediate-grade lymphomas i ncl ude bot h B- and s ome T-cel l l ymphomas , whereas immunoblastic lymphomas are predomi nant l y B-cel l t umors and lymphoblastic lymphomas are T-cel l t ypes . Mos t B-cel l t umors are monocl onal and produce ei t her a Îº or a Î» l i ght chai n i mmunogl obul i n.





2. Follicular small-cleaved cell lymphomas are t he mos t common hi s t ol ogi c t ype, account i ng for approxi mat el y 40% of cas es . Thes e pat i ent s have predomi nant l y s t age III or s t age IV di s eas e wi t h a hi gh i nci dence of bone marrow i nvol vement and an i ndol ent cours e, evol vi ng over many years .





3. Follicular mixed small-cleaved and large-cell lymphomas repres ent 20%â€“40% of pat i ent s . Large cel l s may account for as much as 25% of t he cel l popul at i on. The l ymph node archi t ect ure s hows di s t i nct nodul es , whi ch are us ual l y pres ent t hroughout t he node. Marrow i nvol vement i s common. Thi s s ubt ype i s i ndol ent but more aggres s i ve t han fol l i cul ar s mal l -cl eaved cel l l ymphoma.

Pa g e 8 4 9




4. Diffuse large-cell lymphomas are charact eri zed by l arge mal i gnant l ymphocyt es wi t h i ncreas ed nucl ear di amet ers . Thes e cel l s have cyt ol ogi c feat ures of l arge cl eaved or noncl eaved fol l i cul ar cel l s , wi t h nucl eol i , abundant cyt opl as m, and frequent mi t os es .





5. Immunoblastic lymphomas and ot her hi gh-grade non-Hodgki n's l ymphomas i ncl ude plasmacytoid, clear cell, and polymorphic cat egori es . Thes e s ubt ypes are rapi dl y fat al unl es s effect i ve t reat ment i s admi ni s t ered prompt l y.

P.174

E. Clinical features 



1. Mos t pat i ent s are asymptomatic. Twent y percent of pat i ent s have fever, night sweats, or weight loss.





2. Pat i ent s wi t h i ndol ent l ymphomas may have waxing and waning adenopathy for s everal mont hs before di agnos i s , al t hough persistent nodal enlargement i s more common. Ext ranodal di s eas e mos t oft en i nvol ves t he s t omach, l ung, and bone, res ul t i ng i n s ympt oms charact eri s t i c of t he affect ed organ.

F. Diagnosis 



1. A compl et e history and physical examination, wi t h part i cul ar emphas i s on al l l ymph nodeâ€“beari ng areas ,

Pa g e 8 5 0


i ncl udi ng W al deyer's ri ng, as wel l as l i ver and s pl een s i z e. 



2. Hematologic studies, i ncl udi ng a CBC, di fferent i al , pl at el et count , l i ver and ki dney funct i on s t udi es , LDH, and uri c aci d l evel s t udi es . Serum prot ei n el ect rophores i s rul es out hypogammagl obul i nemi a or a monocl onal gammopat hy.





3. Bone marrow biopsies and aspirates. An adequat e s urgi cal l ymph node biopsy exami ned by an experi enced pat hol ogi s t .





4. Radiologic studies, i ncl udi ng ches t radi ography; CT of t he ches t , abdomen, and pel vi s .

G. Prognosis Many pat i ent s who achi eve a compl et e res pons e, part i cul arl y t hos e wi t h di ffus e l arge cel l l ymphoma, remai n di s eas e-free for an ext ended peri od and wi l l be cured. Aggres s i ve combi nat i on chemot herapy regi mens cont ai ni ng doxorubi ci n have hi gh compl et e res pons e rat es rangi ng from 40% t o 80%. Prognos t i c fact ors (Int ernat i onal Prognos t i c Indi cat ors ) for l arge cel l l ymphoma i ncl ude i ncreas i ng pat i ent age, s t age, LDH l evel , performance s t at us , and i n ol der pat i ent s , t he pres ence or abs ence of ext ranodal di s eas e.

H. Staging The Ann Arbor s t agi ng s ys t em us ed t o cl as s i fy Hodgki n's di s eas e i s al s o us ed t o s t age non-Hodgki n's l ymphomas (s ee t he AJCC Cancer St agi ng Handbook).

I. Therapy Treat ment us ual l y requi res a mul t i di s ci pl i nary approach. Radi at i on t herapy and chemot herapy aft er s urgi cal bi ops y are t he mos t

Pa g e 8 5 1


common t reat ment modal i t i es . 



1. Radiation therapy. Non-Hodgki n's l ymphomas are hi ghl y radi os ens i t i ve. o

o

a. In l ocal i zed di s eas e, radi at i on s houl d be t arget ed t o t he affect ed s i t e (4,000 cGy t o t he i nvol ved fi el d). The nodal s i t e and drai ni ng l ymphat i cs s houl d be i ncl uded i n t he radi at i on fi el d.

o

o

b. Radi at i on t herapy i s us ed palliatively i n di s s emi nat ed di s eas e or t o â€œcons ol i dat eâ€• a compl et e res pons e t o chemot herapy i n areas of bul ky di s eas e.

o

o

c. Electron beam therapy has been us ed i n t he management of cut aneous l ymphomas s uch as t he earl y s t ages of mycos i s fungoi des .

o

o

d. Stage I indolent lymphomas. Long-t erm pat i ent fol l ow-up aft er i nvol ved or ext ended fi el d radi at i on t herapy for l ocal i z ed s t age I and s t age II l ow-grade l ymphoma reveal s a 10-year rel aps e-free s urvi val rat e of great er t han 50%, es peci al l y i n younger pat i ent s .





2. Chemotherapy o

o

a. Low-grade indolent lymphomas may not

Pa g e 8 5 2


requi re t reat ment for many years . W hen t herapy i s i ndi cat ed, chlorambucil or cyclophosphamide, wi t h or wi t hout predni s one, i s t he agent of choi ce. Ini t i al res ul t s wi t h hi gh-dos e chemot herapy fol l owed by aut ol ogous marrow t rans pl ant at i on are favorabl e, but s ucces s needs t o be meas ured by l ong-t erm fol l ow-up becaus e t hes e pat i ent s general l y have l ong-t erm s urvi val rat es , even wi t h l es s t oxi c t reat ment . The ant i -CD20 ant i body, ri t uxi mab, i s us eful i n rel aps ed pat i ent s , as i s t he nucl eos i de anal og, fl udarabi ne. o

o

b. Stage I or II intermediate and high-grade lymphomas oft en res pond t o combi nat i on chemot herapy and ri t uxi mab, wi t h or wi t hout radi at i on t herapy. Cure rat es approach 80%â€“90%.

o

o

c. Aggressive intermediate or high-grade lymphomas (e.g., l ymphobl as t i c or Burki t t 's l ymphoma) requi re i mmedi at e combi nat i on chemot herapy wi t h prot ocol s s i mi l ar t o t hos e us ed i n t he t reat ment of acut e l ymphobl as t i c l eukemi a (ALL). Prophyl act i c i nt rat hecal chemot herapy may al s o be gi ven for hi gh-grade l ymphomas . Salvage combination chemotherapy produces s econd compl et e or part i al remi s s i ons but i s rarel y curat i ve unl es s t he pat i ent undergoes BMT. P.175





(1) The most common regimen involves

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cyclophospha mideâ€“doxorubicinâ€“vincristine (Oncovin)â€“prednisone (CHOP) plus rituximab. Aggres s i ve chemot herapy wi t h aut ol ogous s t em cel l s upport may i mprove s urvi val i n newl y di agnos ed hi gh-ri s k pat i ent s . 



(2) Becaus e of encouragi ng res ul t s wi t h combi nat i on chemot herapy i n pat i ent s wi t h s t age III and s t age IV di s eas e fol l owed by radi at i on t herapy, randomi zed cl i ni cal t ri al s are underway t o compare chemot herapy al one and chemot herapy fol l owed by radi at i on t herapy.





(3) Colony-stimulating factors has t en granul ocyt e recovery and may permi t hi gher dos es and bet t er cure rat es .





(4) Radiolabeled monoclonal antibodies i bri t umomab t i uxet an (Zeval i n) and t os i t umomab (Bexxar) are now approved for s al vage t herapy i n pat i ent s who have fai l ed ri t uxi mab and convent i onal chemot herapy.

XVII. Paraneoplastic Syndromes A. Endocrine syndromes Endocrine syndromes res ul t i ng from ect opi c pol ypept i de hormone product i on are t he mos t common and bes t unders t ood of t he paraneopl as t i c proces s es . Many t umors produce more t han one bi ol ogi cal l y act i ve hormone, l eadi ng t o mul t i pl e endocri ne paraneopl as t i c s yndromes . 

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

1. Criteria for es t abl i s hi ng ect opi c hormone s ecret i on by t umor cel l s i ncl ude: o

o

a. Increased hormone levels, as evi denced by radi oi mmunoas s ay or ot her t echni ques . However, s ome pat i ent s wi t h el evat ed hormone l evel s do not have cl i ni cal s ympt oms .

o

o

b. Decreased hormone levels after removal or treatment of the tumor

o

o

c. Persistent hormone elevation after removal of the normal gland t hat s ecret es t he normal hormone

o

o

d. An arteriovenous gradient for hormone levels acros s t he t umor vas cul ar bed





2. T ypes o

o

a. Ectopic growth hormone secretion has been det ect ed i n pat i ent s wi t h lung and gastric carcinomas. The el evat ed hormone l evel s may l ead t o hypert rophi c pul monary os t eoart hropat hy. Organomegal y may occur wi t h s l ow-growi ng carci noi d t umors .

o

o

b. Ectopic ACT H secretion was t he fi rs t paraneopl as t i c endocri ne s yndrome des cri bed i n t he

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l i t erat ure. 



(1) The mos t common tumors associated with ectopic ACT H production are SCLC and atypical carcinoids. Hi gh cort i s ol l evel s have al s o been des cri bed i n pat i ent s wi t h adenocarci noma and l arge-cel l carci noma of t he l ung, ot her carci noi d t umors , t hymoma, neural cres t t umors , medul l ary carci noma of t he t hyroi d, and bronchi al adenomas .





(2) Clinical features. Mos t pat i ent s have hypokalemia and metabolic alkalosis. 



(a) Pat i ent s rarel y l i ve l ong enough for frank Cus hi ng's s yndrome t o devel op. However, di abet es , hypert ens i on, edema, mus cl e was t i ng, cent ral obes i t y, moon faci es , and s t ri ae may devel op i n t hos e wi t h ext remel y hi gh cort i s ol l evel s .





(b) Al t erat i ons i n ment al s t at us , fat i gue, and anorexi a caus ed by opi at e-l i ke pept i de fragment s are rare s ympt oms .





(3) Diagnosis i s confi rmed by a pl as ma ACTH 3

l evel of more t han 200 pg/mm , a pl as ma cort i s ol l evel of more t han 40 mg/dL wi t hout di urnal vari at i on, or a pos i t i ve dexamet has one s uppres s i on t es t .

B. Hematologic syndromes Pa g e 8 5 6


Hematologic syndromes may affect cel l ul ar bl ood el ement s , t he coagul at i on s ys t em, or ci rcul at i ng i mmunogl obul i ns . 



1. Paraneoplastic syndromes of cellular blood components o

o

a. Erythrocytosis occurs i n renal cancer and hepat oma.

o

o

b. Pure red cell aplasia. Severe anemi a due t o a compl et e l ack of RBC product i on i s uncommon. However, 50% of pat i ent s wi t h pure red cel l apl as i a have thymoma. Many pat i ent s wi t h pure red cel l apl as i a al s o have ot her i mmunol ogi c abnormal i t i es s uch as hypogammagl obul i nemi a, paraprot ei nemi a, pos i t i ve ant i nucl ear ant i bodi es , or aut oi mmune hemol yt i c anemi a. 



(1) Etiology. The caus e may rel at e t o effect s of s uppres s or T cel l s on RBC product i on, l eadi ng t o a s evere ret i cul ocyt openi c anemi a. P.176





(2) T herapy. In t hymoma, s urgery or radi at i on t herapy i s not uni forml y s ucces s ful i n revers i ng t he anemi a. Corticosteroids, splenectomy, and immunosuppressive therapy wi t h cycl ophos phami de may be us eful .

o

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o

c. Autoimmune hemolytic anemia, or cold agglutinin disease, i s us ual l y caus ed by an i mmunogl obul i n produced by l ymphoma or chroni c l ymphocyt i c l eukemi a cel l s . 



(1) RBC i ndi ces may be hi gh or l ow dependi ng on t he ret i cul ocyt e res pons e. If t he ret i cul ocyt e count i s hi gh, due t o normal marrow funct i on, t he i ndi ces are normal or hi gh. If i mmune hemol ys i s i s pres ent , mul t i pl e s pherocyt es are pres ent .





(2) T herapy wi t h prednisone (1â€“1.5 mg/kg/day) i s oft en effect i ve. Splenectomy i s al s o occas i onal l y us eful . In mos t cas es , however, nei t her s pl enect omy nor cort i cos t eroi ds are effect i ve for l ong peri ods unl es s t he underl yi ng mal i gnancy i s effect i vel y t reat ed.

o

o

d. Microangiopathic hemolytic anemia occurs wi t h muci n-produci ng adenocarci nomas , es peci al l y gas t ri c cancer. 



(1) DIC can be di agnos ed by meas urement of fi bri nogen and fi bri n s pl i t product s .





(2) There i s no effect i ve treatment except t reat i ng t he underl yi ng t umor. Hepari n s houl d not be us ed unl es s t here i s concomi t ant DIC.

o

Pa g e 8 5 8


o

e. Granulocytosis occurs even i n t he abs ence of bone marrow i nvol vement . Ot her caus es of i nfl ammat i on or i nfect i on mus t be excl uded. The mos t common mal i gnanci es as s oci at ed wi t h granul ocyt os i s i ncl ude gas t ri c, l ung, and pancreat i c carci noma; mel anoma; CNS t umors ; Hodgki n's di s eas e; and l arge cel l l ymphomas .

o

o

f. T hrombocytosis occurs i n as many as one t hi rd of al l cancer pat i ent s . If es s ent i al t hrombocyt hemi a i s pres ent , hydroxyurea s houl d be gi ven t o keep 3

t he pl at el et count bel ow 500,000/mm . o

o

g. T hrombocytopenia i s oft en due t o s econdary effect s of chemot herapy, bone marrow i nvol vement , or radi at i on t herapy, but i s al s o s een i n s evere mi croangi opat hi c hemol yt i c anemi a and DIC. A s yndrome res embl i ng aut oi mmune t hrombocyt openi a has been des cri bed i n Hodgki n's di s eas e, l ymphoma, s ome t ypes of l eukemi a, and cert ai n s ol i d t umors . Thi s form of i di opat hi c t hrombocyt openi c purpura (ITP) i s t reat ed wi t h cort i cos t eroi ds , s pl enect omy, or i mmunos uppres s i ve drugs .





2. Paraneoplastic syndromes of the coagulation system o

o

a. Primary DIC occurs mos t frequent l y wi t h muci n-produci ng adenocarci nomas s uch as pancreat i c, gas t ri c, l ung, pros t at e, and col on cancers . Bot h acut e and chroni c DIC are as s oci at ed

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wi t h t hrombophl ebi t i s , art eri al embol i , endocardi t i s , ci rcul at i ng i nhi bi t ors of coagul at i on, and abnormal ci rcul at i ng prot ei ns t hat may preci pi t at e hemorrhagi c compl i cat i ons . 



(1) Acute DIC i s oft en obs erved i n acut e promyel ocyt i c l eukemi a, as t he res ul t of t he rel eas e of a procoagul ant cont ai ned i n t he abnormal granul es of t he l eukemi a promyel ocyt e. 



(a) Clinical features. El evat i on of t he prot hrombi n t i me (PT) i s one of t he earl i es t det ect abl e s ympt oms al ong wi t h el evat i on of fi bri n s pl i t product s and l owered fi bri nogen l evel s . Furt her decreas es i n fi bri nogen l evel s and an i ncreas e i n t he part i al t hrombopl as t i n t i me (PTT) occur i n more s evere cas es .





(b) T herapy. Improved management of acut e DIC has l ed t o a bet t er s hort -t erm prognos i s for mos t pat i ent s . 



(i) Meas ures i ncl ude aggressive transfusion support t o mai nt ai n t he pl at el et count bet ween 35,000 3

and 50,000/mm , intravenous vitamin K, and clotting factor replacement wi t h fres h-frozen pl as ma or cryopreci pi t at e i f t he fi bri nogen l evel i s l es s t han 75 mg/dL.

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

(ii) Heparin i s cont rovers i al but can be admi ni s t ered caut i ous l y t o refractory patients.





(2) Chronic DIC i s mos t common i n pat i ent s wi t h adenocarci nomas . 



(a) Clinical features i ncl ude mi l d prol ongat i ons of t he PT, hi gh fi bri nogen l evel s , and el evat i on of t he fi bri n s pl i t product s . Pat i ent s oft en have t hrombophl ebi t i s or pul monary embol i .





(b) Heparin i s t he t reat ment of choi ce; thrombolytic therapy al s o may be cons i dered i f t here are no cont rai ndi cat i ons .

o

o

b. Syndromes associated with paraproteins 



(1) Coagulopathy. Abnormal hemos t as i s and coagul at i on may devel op i n pat i ent s wi t h pl as ma cel l dys pl as i as s uch as mul t i pl e myel oma as a res ul t of t he effect s of paraprot ei ns on normal cl ot t i ng fact ors and pl at el et recept or funct i on. Paraprot ei ns can al s o i nhi bi t fi bri n P.177

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monomer aggregat i on and act as i nhi bi t ors of fact or VIII. If pat i ent s have i nt ract abl e bl eedi ng, pl as mapheres i s may be requi red i n combi nat i on wi t h chemot herapy. 



(2) Hyperviscosity. In mul t i pl e myel oma and macrogl obul i nemi a, pat i ent s wi t h a s erum vi s cos i t y great er t han 4 (rel at i ve t o wat er) may have s i gns of decreas ed bl ood fl ow, i ncl udi ng headaches , di zzi nes s , epi s t axi s , s ei zures , heari ng l os s , al t ered ment al s t at us , and cardi ac di s eas e. Treat ment cons i s t s of prompt pl as mapheres i s t o remove t he exces s i ve paraprot ei n and avoi d dehydrat i on, as wel l as t reat ment of t he underl yi ng pl as ma cel l dys cras i a.

C. CNS syndromes are rare The mos t common (and t he mal i gnanci es as s oci at ed wi t h t hem) are l i s t ed i n Tabl e 4-17.

TABLE 4.17 Central Nervous System Paraneoplastic Syndromes and Associated Malignancies

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As soc iat ed Ma Sy lig nd na ro nc me y Li m Sm bi c al l enc cel l ep l un hal g i t i s can cer Su Sm bac al l ut e cel l cel l l un ul a g r

can

de cer ge , ner ova at i ri a on n can cer Su Ly bac mp ut e ho mo ma t or ne uro

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pat hy Su Sm bac al l ut e cel l s en l un s or g y

can

ne cer uro pat hy Se Sm ns o al l ri m cel l ot o l un r

g

pol car yne ci n uro om pat a, hy Ho dgk i n's di s eas e Eat Lun on- g La can mb cer ert , my ova as t ri a he n ni a can

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cer Pol Var ym i ed yos ; i t i s bre or as t der , ma l un t o g, my gas os i t roi t i s nt e sti nal , an d ova ri a n car ci n om as are mo st co mm on

XVIII. Oncologic Emergencies A. Spinal cord compression (SCC) 

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

1. Etiology Mos t cas es of SCC are due t o met as t at i c t umors from pri mary breas t , l ung and pros t at e cancer; l ymphoma; mul t i pl e myel oma; renal and gas t roi nt es t i nal s t umors .





2. Clinical Features can i ncl ude back or radi cul ar pai n wi t h or wi t hout ot her s ympt oms s uch as mus cl e weaknes s ; acut e or s l owl y evol vi ng changes i n bowel or bl adder funct i on; or s ens ory l os s or aut onomi c dys funct i on. Thes e fi ndi ngs s houl d prompt a t horough phys i cal and neurol ogi c exami nat i on.





3. Diagnosis MRI wi t h gadol i ni um cont ras t i s t he gol d s t andard for di agnos i ng SCC becaus e of i t s hi gh s ens i t i vi t y and s peci fi ci t y.





4. T herapy The goal s of t herapy for SCC i ncl ude pai n cont rol , recovery of normal neurol ogi c funct i on, l ocal t umor cont rol , and avoi dance of compl i cat i ons . Al l pat i ent s who are s ympt omat i c and have an abnormal neurol ogi c exami nat i on s houl d recei ve s t eroi d t herapy i mmedi at el y. In addi t i on, s urgery and radi at i on oncol ogy cons ul t at i ons s houl d be purs ued i mmedi at el y upon cl i ni cal s us pi ci on of SCC i n a pat i ent wi t h mal i gnancy.

B. Superior vena cava syndrome (SVCS) 



1. Etiology SVCS i s pri mari l y caus ed by di rect ext ri ns i c compres s i on of t he s uperi or vena cava (SVC) by t umors as s oci at ed wi t h bronchogeni c carci noma and non-Hodgki n l ymphoma affect i ng t he ant eri or medi as t i num. Ot her caus es i ncl ude met as t at i c di s eas e

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t o t he medi as t i num, cent ral l i ne t hrombos i s , fi bros i ng medi as t i ni t i s , or a ret ros t ernal goi t er. 



2. Clinical features Si gns and s ympt oms of SVCS may appear acut el y or chroni cal l y. Many pat i ent s wi l l exhi bi t neck or ches t wal l s uperfi ci al venous di s t ens i on, faci al and peri orbi t al edema, faci al pl et hora, cyanos i s , and upper ext remi t y edema. Ot her s ympt oms i ncl ude dys pnea, ort hopnea, cough, and hoars enes s .





3. Diagnosis Al t hough t he di agnos i s of SVCS can be made on phys i cal exami nat i on al one, noni nvas i ve i magi ng can al s o be us ed t o faci l i t at e t he di agnos i s . Such modal i t i es i ncl ude CT wi t h cont ras t , MRI, and Doppl er ul t ras onography exami nat i on of t he jugul ar or s ubcl avi an vei ns . P.178





4. T herapy If t here i s evi dence of res pi rat ory compromi s e or CNS i nvol vement , emergent radi at i on t herapy and ai rway s t abi l i zat i on mus t occur fi rs t . Nonemergent t reat ment cons i s t s of s ympt om rel i ef and t reat ment of t he underl yi ng mal i gnancy or i nfect i on caus i ng t he SVCS. If at al l pos s i bl e, i t i s i mport ant t o obt ai n t i s s ue pri or t o t reat ment i n order t o es t abl i s h t he di agnos i s .

C. Hypercalcemia 



1. Etiology A l arge percent age of pat i ent s who pres ent wi t h hypercal cemi a have s ol i d t umor met as t as i s t o t he

Pa g e 8 6 7


bone. Ot her common mal i gnanci es as s oci at ed wi t h hypercal cemi a i ncl ude nonâ€“s mal l cel l l ung cancer, breas t cancer, mul t i pl e myel oma, and geni t ouri nary t umors . 



2. Clinical features Pat i ent s may pres ent wi t h general i zed fat i gue, weaknes s , and dehydrat i on. Hypercal cemi a can al s o t arget s peci fi c organ s ys t ems s uch as CNS (ment al s t at us changes , s ei zures ), gas t roi nt es t i nal or geni t ouri nary t ract (naus ea/vomi t i ng, cons t i pat i on, i l eus ), and cardi ac (arrhyt hmi as ).





3. Diagnosis In hypercal cemi a of mal i gnancy, t he s erum i nt act parat hormone (i PTH) i s l ow or undet ect abl e and s erum parat hormone (PTH-RP) l evel s are el evat ed. Bot h 1, 25-di hydroxyergocal ci ferol and i norgani c phos phat e l evel s are l ow or normal .





4. T herapy Pat i ent s who are s ympt omat i c and found t o have s evere hypercal cemi a s houl d be hydrat ed vi gorous l y wi t h normal s al i ne pri or t o cons i derat i on of furos emi de. Once a pat i ent i s rehydrat ed and uri nary out put opt i mi zed, t he need for bi s phos phonat e t herapy wi t h zol edroni c aci d 4 mg i nt ravenous l y 15 mi nut es i nfus i on or pami dronat e or cal ci t oni n mus t be addres s ed. The mos t effect i ve t reat ment of hypercal cemi a, however, s houl d be di rect ed at t he underl yi ng mal i gnancy.

D. Tumor lysis syndrome (TLS) 



1. Etiology Cel l deat h, wi t h s ubs equent rel eas e of i nt racel l ul ar cont ent s , i s a common occurrence aft er chemot herapy or i n t umors wi t h rapi d cel l t urnover. TLS

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can occur i n t hes e s i t uat i ons , and i t can al s o be s een i n t he s et t i ng of t reat ment of l eukemi a or hi gh grade l ymphomas . Thi s phenomenon oft en res ul t s i n l i fe-t hreat eni ng l act i c aci dos i s , hyperuri cemi a, hyperkal emi a, hyperphos phat emi a, and hypocal cemi a. 



2. Clinical features Many of t he s ympt oms of TLS are as s oci at ed wi t h t he el ect rol yt e abnormal i t i es . For i ns t ance, pat i ent s can devel op cardi ac arrhyt hmi as from s evere hyperkal emi a or hypocal cemi a. The hyperphos phat emi a and hyperuri cemi a of TLS may res ul t i n acut e renal fai l ure.





3. T herapy Correct i ve meas ures s houl d be di rect ed t oward t he met abol i c derangement s pres ent i n TLS. Oft en t hes e pat i ent s may requi re cl os er moni t ori ng ei t her on a t el emet ry uni t or i nt ens i ve care uni t i f t hey s houl d have s evere hemodynami c i ns t abi l i t y. The t reat ment of hyperuremi c acut e renal fai l ure fol l owi ng chemot herapy s houl d cons i s t s of al l opuri nol , l oop di uret i cs , i nt ravenous fl ui ds , and pos s i bl y recombi nant urat e oxi das e (ras buri cas e). It i s i mport ant t o i dent i fy i ndi vi dual s at ri s k for TLS pri or t o admi ni s t rat i on of chemot herapy. Thes e pat i ent s s houl d recei ve prehydrat i on, al l opuri nol , and met abol i c moni t ori ng for 24â€“28 hours aft er s t art i ng t herapy.

P.179

Study Questions/Answers and Explanations 1. A 55-year-old, postmenopausal woman presents for a yearly visit. A 1-cm nodule is palpated in the upper, outer quadrant of her right breast. Her most recent mammogram 6 months ago was negative. Her family history is significant for her mother

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and a sister both diagnosed with breast cancer in their early to mid-50s. She has hypertension and hypercholesterolemia. What is the most appropriate next step in her management? A. Repeat mammogram and ul t ras ound now B. Repeat mammogram i n 6 mont hs C. Repeat cl i ni cal exami nat i on i n 1 mont h and refer for mammography i f t here i s an i ncreas e i n t he s i ze of t he nodul e D. Begi n t amoxi fen E. Refer her t o a s urgeon Vi ew Ans wer 1. T he answer is A [VI C]. A pal pabl e mas s duri ng t he phys i cal exami nat i on warrant s an i mmedi at e eval uat i on. Even t hough s he had undergone a mammography 6 mont hs ago, mos t oncol ogi s t s , radi ol ogi s t s , and s urgeons woul d repeat t hi s s t udy. In addi t i on, an ul t ras ound eval uat i on mi ght reveal whet her t hi s i s a cys t or a more s ol i d mas s . Repeat i ng t he mammogram i n 6 mont hs i s not a good opt i on, becaus e t hi s wi l l del ay t reat ment i f t he abnormal fi ndi ng i s i n fact a mal i gnancy. The s ame i s t rue for ans wer C. Vi rt ual l y no one wi l l begi n t herapy wi t hout a fi rm di agnos i s ; t herefore, ans wer D i s i ncorrect . 2. T he yearly mammogram in a 65-year-old postmenopausal woman shows an irregular area of microcalcification, which has grown in size compared with her mammogram from 2 years ago. She missed her mammogram last year. Physical examination is unrevealing, without lymphadenopathy or any nodularity in the breasts. You refer her to a surgeon. Eventually a 2-cm invasive ductal carcinoma is removed from her left breast. Sentinel lymph node biopsy shows two positive lymph nodes, and axillary lymph node dissection indicates five more positive lymph nodes. T he tumor expresses the estrogen receptor (ER+). Which of the following interventions would increase her chance of cure? A. Chemot herapy fol l owed by hormonal t herapy B. Radi at i on t herapy C. Tot al mas t ect omy D. Hormonal t herapy al one

Pa g e 8 7 0


E. Hi gh-dos e chemot herapy wi t h s t em cel l s upport Vi ew Ans wer 2. T he answer is A [VI H 3]. Thi s pat i ent i s at hi gh ri s k of recurrence by vi rt ue of havi ng di s eas e i n her l ymph nodes . Radi at i on t herapy or s urgi cal exci s i on of t he breas t cancer us ual l y provi de l ocal cont rol and provi de adequat e prot ect i on agai ns t recurrence of di s eas e i n t he t umor bed. However, mi cromet as t at i c di s eas e can onl y be addres s ed t hrough t he admi ni s t rat i on of s ys t emi c t herapy s uch as cyt ot oxi c chemot herapy. In pat i ent s wi t h hormonal l y s ens i t i ve t umors (e.g., es t rogen recept or pos i t i ve), hormonal t herapy has been s hown t o be very effect i ve i n t he prevent i on of di s eas e recurrence aft er chemot herapy and can be us ed as a s ol e t reat ment opt i on i n s el ect ed pat i ent s . Randomi zed cl i ni cal t ri al s have s hown t hat l umpect omy and radi at i on t herapy i s equal t o a t ot al mas t ect omy i n t erms of overal l s urvi val . For t umors t hat can be removed t ot al l y wi t h adequat e margi ns (>10 mm), l umpect omy offers bet t er cos met i c and ps ychol ogi cal res ul t s . It i s a l es s i nvas i ve s urgery and al l ows for fas t er recovery t i me. 3. An 18-year-old man presents with swollen lymph nodes in his neck for 2 weeks. He has been treated with antibiotics for 10 days, but the lymph nodes continue to grow. He has had a 10-lb. weight loss in the past 2 months and is experiencing drenching night sweats. He reports fatigue and inability to play basketball like he used to. He has not been sexually active in the last 1 year. T he next best course of action is: A. Changi ng t he ant i bi ot i cs B. CT s can of t he ches t C. Refer t o a s urgeon for l ymph node bi ops y D. Check t he HIV s t at us of t hi s pat i ent E. As s ure hi m t hat he has a s el f-l i mi t i ng vi ral i l l nes s Vi ew Ans wer 3. T he answer is C [XV H]. Any l ymph node t hat does not res pond t o t he us ual t reat ment , s uch as t wo cours es of di fferent ant i bi ot i cs , s houl d rai s e t he s us pi ci on of t he t reat i ng phys i ci ans . For eas i l y acces s i bl e l ymph nodes , t he preferred met hod of i nves t i gat i on i s a

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ful l exci s i onal bi ops y. The exami nat i on of an i nt act l ymph node al l ows pat hol ogi s t s t o exami ne t he l ymph node archi t ect ure and arri ve at a defi ni t i ve di agnos i s . Al t hough a CT s can mi ght event ual l y be needed, i t s houl d not be t he fi rs t choi ce. Al s o, t he HIV s t at us of a pat i ent wi t h hi gh-ri s k behavi or needs t o be det ermi ned, but t here i s no i ndi cat i on from t he cas e pres ent at i on t hat t hi s pat i ent fal l s i n t hi s cat egory and i t s houl d not be t he fi rs t choi ce. 4. Eventually he is diagnosed with nodular sclerosing Hodgkin' s disease. His bone marrow biopsy is negative, and he is found to have disease in both sides of the diaphragm (stage III). T reatment of choice in the United States is: A. Chemot herapy wi t h t he ABVD regi men B. Radi at i on t o al l t he affect ed l ymph nodes C. Surgi cal res ect i on of al l t he affect ed l ymph nodes D. Treat ment wi t h ri t uxi mab E. Hi gh-dos e chemot herapy wi t h s t em cel l s upport Vi ew Ans wer 4. T he answer is A [XV I 3 a]. Thi s combi nat i on chemot herapy i s t he t reat ment of choi ce i n mos t part s of t he Uni t ed St at es . Ot her mul t i -agent chemot herapy regi mens are al s o accept abl e. Ongoi ng cl i ni cal t ri al s are compari ng effect i ve regi mens t o det ermi ne whet her t here are s uperi or al t ernat i ves t o t he ABVD regi men. There i s no i ndi cat i on t hat t he removal of al l i nvol ved l ymph nodes i s s urgi cal l y feas i bl e or t herapeut i c. Di s s emi nat ed Hodgki n's l ymphoma i s a s ys t emi c di s eas e and s houl d be t reat ed as s uch. In addi t i on, radi at i on t herapy i s res erved for cas es i n whi ch t here i s ei t her bul ky di s eas e or a focal area of t he body i s i nvol ved. Del i very of radi at i on t o mul t i pl e s i t es i s general l y not feas i bl e becaus e of t he t oxi ci t y of t hi s approach. Choi ce D, t reat ment wi t h ri t uxi mab, i s for non-Hodgki n's l ymphomas . 5. T he most serious long-term side effect of this treatment is: A. Conges t i ve heart fai l ure B. Peri pheral neuropat hy C. Myel odys pl as t i c s yndrome/acut e myel ogenous l eukemi a

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D. Earl y myocardi al i nfarct i on E. Earl y ons et cat aract Vi ew Ans wer 5. T he answer is C [XV I c]. Cyt ot oxi c chemot herapy coul d l ead t o vari ous chromos omal abnormal i t i es t hat coul d res ul t i n acut e l eukemi a or myel odys pl as t i c s yndrome. The ri s k of s econdary myel oi d mal i gnanci es approaches 2% wi t h t he ABVD regi men, and i ncreas ed i nci dence of non-Hodgki n's l ymphoma i s not ed as wel l . A number of chemot herapeut i c agent s t hat al kyl at e DNA are t hought t o be i nvol ved i n t hi s proces s . In general , hi gh-dos e t herapy wi t h any of t hes e agent s i s as s oci at ed wi t h t he devel opment of AML/MDS. Conges t i ve heart fai l ure as a res ul t of expos ure t o doxorubi ci n (Adri amyci n) i s known t o occur. However, us ual l y t hi s 2

t oxi ci t y i s s een wi t h dos es exceedi ng 480 mg/m . The ri s k of myocardi al i nfarct i on at a young age s houl d not be an i s s ue i f radi at i on t o t he ches t and t horax i s not needed. Peri pheral neuropat hy i s al s o a manageabl e t oxi ci t y s een wi t h vi nca al kal oi ds s uch as vi ncri s t i ne. P.180

6. A 55-year-old African American man is seen in the emergency room with a 2-day history of hematuria, back pain, double vision, and altered mental status. He is an engineer with an office-based occupation with no exposure to chemicals or radiation. Family history is positive for an uncle with â€œ bone cancer.â€• He smokes half pack of cigarettes a day but does not drink alcohol. Laboratory evaluation in the emergency department shows an elevated total protein of 22 mg/dL, elevated gamma globulins, a serum creatinine of 2.5 mg/dL, and hemoglobin of 9 g/L. Blood smear shows roulette formation. You suspect: A. Acut e renal fai l ure of unknown et i ol ogy B. Hypervi s cos i t y s yndrome s econdary t o mul t i pl e myel oma C. A geni t ouri nary mal i gnancy

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D. Drug t oxi ci t y E. Int ravas cul ar hemol ys i s Vi ew Ans wer 6. T he answer is B [XIV E 2]. Thi s chal l engi ng cas e requi res a cl os e exami nat i on of t he l aborat ory res ul t s and of t he pat i ent pres ent at i on i n an at t empt t o arri ve at a uni fyi ng di agnos i s t hat expl ai ns al l of t he obs erved abnormal i t i es . The el evat ed t ot al prot ei n and t he pres ence of roul et t es i n t he bl ood s mear are cl as s i c s i gns of paraprot ei nemi a. The hi s t ory of change i n ment al s t at us and doubl e vi s i on, i n a pat i ent wi t h el evat ed t ot al prot ei n, s houl d rai s e concerns for t he devel opment of hypervi s cos i t y s yndrome. Once t he pres ence of anemi a and renal i ns uffi ci ency has been es t abl i s hed, t he di agnos i s of mul t i pl e myel oma s houl d s t rongl y be cons i dered. A GU mal i gnancy us ual l y does not l ead t o an el evat ed t ot al prot ei n or changes i n t he bl ood s mear as di s cus s ed i n t hi s cas e. 7. Best management option at this point is: A. Pl as mapheres i s B. Trans fus i on of red bl ood cel l s C. Hemodi al ys i s D. Broad-s pect rum ant i bi ot i cs E. Support i ve care Vi ew Ans wer 7. T he answer is A [XIV I 2 c (4)]. Pl as mapheres i s offers t he onl y opt i on for reduci ng t he amount of prot ei n i n t he ci rcul at i on t o al l evi at e s ome of t he s ympt oms . Bl ood t rans fus i ons coul d be det ri ment al unt i l t he hypervi s cos i t y has been i mproved, becaus e bl ood t rans fus i ons wi l l rai s e bl ood vi s cos i t y. The ot her t wo opt i ons woul d not addres s t he i s s ue wi t h hi gh prot ei n cont ent i n t he ci rcul at i on. 8. A 75-year-old woman with metastatic breast cancer to her bones presents to the emergency department because she fell down at home after getting up from her chair. Her family states that she has been lethargic, nauseated, and notes that she has complained of dizziness and increasing thirst. She is found to be

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orthostatic on examination. 



Laboratory studies:





Blood urea nitrogen 42 mg/dL

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

T otal serum calcium 12.2 mg/dL

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

Serum creatinine 1.4 mg/dL

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

Serum albumin 2.8 g/dL





What is the most appropriate initial treatment?

A. Sl ow rehydrat i on wi t h hal f-normal s al i ne B. Int ravenous admi ni s t rat i on of a bi s phos phonat e C. Vi gorous rehydrat i on wi t h normal s al i ne D. Int ravenous admi ni s t rat i on of furos emi de al ong wi t h s al i ne rehydrat i on E. Int ravenous admi ni s t rat i on of cort i cos t eroi ds Vi ew Ans wer 8. T he answer is C [XVIII C 4]. The pat i ent has hypercal cemi a, t he mos t common met abol i c compl i cat i on of mal i gnancy. She i s profoundl y dehydrat ed, as wi t nes s ed by her ort hos t as i s and s ubs equent fal l at home. Ini t i al l y, t he pat i ent s houl d be adequat el y rehydrat ed wi t h normal s al i ne pri or t o admi ni s t rat i on of furos emi de. Admi ni s t rat i on of a bi s phos phonat e woul d not be appropri at e i n t he acut e s et t i ng becaus e of t he pat i ent 's vol ume depl et i on. For t he s ame reas on, whi l e cort i cos t eroi ds can be cons i dered an adjunct i ve t herapy i n a pat i ent wi t h a pot ent i al l y hormone-res pons i ve t umor, t he mai n pri ori t y i n t hi s s everel y dehydrat ed pat i ent s houl d be vol ume repl et i on.

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9. A 50-year-old executive undergoes his first screening colonoscopy. He has been constipated for 1 year, relieved by laxatives. T here has been no blood in his stools. A fungating mass is seen in the sigmoid colon. Subsequent surgery shows a lesion that has penetrated through the muscularis propria. T hree regional lymph nodes are positive for adenocarcinoma. His best chance for cure would occur with which form of therapy? A. No furt her t herapy needed B. Adjuvant chemot herapy C. Radi at i on t reat ment D. Concurrent chemot herapy and radi at i on t herapy E. Immunot herapy Vi ew Ans wer 9. T he answer is B [VII 9 a (3) (a)]. Of t he opt i ons pres ent ed, onl y adjuvant chemot herapy woul d i ncreas e t he l i kel i hood of cure for a pat i ent who has had res ect i on of s t age III (e.g., l ymph node met as t as i s pos i t i ve, T a n y , N 1

or 2

, M 0 ) adenocarci noma of t he col on.

Thi s has been repeat edl y demons t rat ed i n a number of cl i ni cal t ri al s . Once cancer has been found i n t he l ymph nodes , t he pat i ent has a hi gh rat e of s ys t emi c di s s emi nat i on. The gui del i nes are l es s cl ear for t he management of pat i ent s wi t h t rans mural l y i nvas i ve cancers t hat do not met as t as i ze t o regi onal l ymph nodes (e.g., s t age II, T 3 N 0 M 0 ). Al t hough met a-anal ys i s s ugges t s a very s mal l advant age for t he us e of 5-fl uorouraci l â€“bas ed adjuvant chemot herapy, mos t aut hori t i es bas ed t reat ment recommendat i ons on t he bal ance of ant i ci pat ed benefi t wi t h pat i ent fi t nes s and t reat ment preferences . The prel i mi nary res ul t s of a randomi zed cl i ni cal t ri al empl oyi ng mul t i -agent chemot herapy wi t h 5-fl uorouraci l and oxal i pl at i n s hows a s urvi val advant age for t he combi nat i on i n pat i ent s wi t h bot h s t age II and s t age III di s eas es , and may change t he adjuvant t herapy paradi gm i n t he fut ure. 10. A 26-year-old black woman is back in your office after the return of her Pap screening. It showed a low-grade squamous intraepithelial lesion. T here was no inflammation found. She was

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also found to be HIV-negative, and a Pap smear 2 years ago was negative. T he most appropriate next step in her treatment is: A. Bi ops y B. Coni z at i on C. Cryo- or l as er t herapy D. Ret urn (4 t o 6 mont hs ) for repeat Pap s mear E. Hys t erect omy Vi ew Ans wer 10. T he answer is A. [VIII B 6 a]. The correct ans wer i s bi ops y. Cervi cal cancer mort al i t y i s s o prevent abl e becaus e i t i s eas i l y reveal ed by Pap s mear. But i t i s onl y a s creeni ng t es t . If t he Pap s mear ret urns wi t h l ow grade s quamous i nt raepi t hel i al l es i on (or hi gh grade) t hen a punch bi ops y i s requi red for di agnos i s of CIN or i nvas i ve carci noma. If t he bi ops y t hen s hows CIN I (s l i ght dys pl as i a) t hi s may res ol ve, and does not requi re t reat ment . Fol l ow-up wi t h a repeat Pap s mear i n 4-6 mont hs . CIN II and III (moderat e and s evere dys pl as i a) are t reat ed wi t h abl at i ve t herapy, ei t her cryot herapy or l as er. If t he punch bi ops y ret urns s howi ng i nvas i ve carci noma, s t agi ng i s done, and t he pat i ent i s t reat ed wi t h hys t erect omy or radi at i on, or bot h. If t he bi ops y di d not make t he s t age of t he premal i gnancy cl ear, t hen coni zat i on i s i ndi cat ed. P.181

11. A 57-year-old postmenopausal woman has completed her adjuvant treatment for a stage II, ER-/PR-positive breast cancer. She is presenting for a discussion regarding initiation of hormonal treatment with tamoxifen. T he optimal duration of treatment with this agent is: A. 10 years B. 5 years C. 2 years D. Li fet i me E. Int ermi t t ent t reat ment for 5 years

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Vi ew Ans wer 11. T he answer is B [VI I 4 a (1) (a-b)]. The opt i mal durat i on of t reat ment wi t h t amoxi fen i s 5 years . Large randomi zed cl i ni cal t ri al s have proved t hat s hort er t reat ment durat i on i s not as prot ect i ve as 5 years of t reat ment . Al s o, l onger durat i on of t reat ment (10 years ) i s as s oci at ed wi t h more s i de effect s s uch as t hromboembol i c phenomenon. 12. A 67-year-old man with a significant smoking history has had a persistent right upper lobe infiltrate. A CT scan shows a 3-cm solitary lesion with irregular borders. A fine-needle aspiration shows adenocarcinoma. Appropriate staging workup at this point includes: A. Bone marrow bi ops y B. PA and l at eral ches t radi ograms C. Lymphangi ogram D. CT s cans of t he ches t , abdomen, and pel vi s and a PET s can E. Vi deo-as s i s t ed t horaci c s urgery (VATS) Vi ew Ans wer 12. T he answer is D [V F]. The appropri at e s t agi ng of a pat i ent wi t h a di agnos i s of l ung cancer requi res al l t he t es t s ment i oned i n t hi s ans wer. The goal i s t o rul e out t he pres ence of gros s di s eas e i n al l t he areas where l ung cancer can pot ent i al l y met as t as i ze. Thi s i ncl udes l i ver, t he adrenal gl ands , medi as t i nal l ymph nodes , and cont ral at eral ches t . Rout i ne ches t fi l ms are not s uffi ci ent l y s ens i t i ve t o det ect s mal l er l ymph nodes i n t he hi l ar regi on. Nei t her bone marrow bi ops i es nor l ymphangi ograms are i ndi cat ed for s t agi ng of l ung cancer. In fact , l ymphangi ograms are no l onger rout i nel y performed. PET s cans are i ncreas i ngl y us ed i n t he i ni t i al s t agi ng of pat i ent s wi t h l ung cancer becaus e of t hei r s ens i t i vi t y i n det ect i ng mi ni mal di s eas e. Accurat e s t agi ng i nformat i on has a major i mpact on t he choi ce of t herapy for t hi s di s eas e. A pat i ent who, bas ed on i ni t i al CT s cans , i s cons i dered t o be a candi dat e for pot ent i al l y curat i ve s urgery mi ght be found t o have met as t at i c di s eas e by PET s can and t herefore be a candi dat e for pal l i at i ve chemot herapy.

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13. A 48-year-old woman, smoker, with a history of Hodgkin' s disease at the age of 29, treated with chest radiation, has developed a squamous cell carcinoma of the lung. Staging workup shows only a 2.5-cm solitary lesion in the left upper lobe. Her FEV1 and FVC are 70% of the predicted values, respectively. T he best treatment option for her is: A. Radi at i on B. Chemot herapy wi t h carbopl at i n and Taxol C. Lobect omy D. Concurrent chemot herapy and radi at i on E. Radi at i on fol l owed by s urgery Vi ew Ans wer 13. T he answer is C [V I 1]. Treat ment of choi ce for s t age I l ung cancer i s s urgi cal res ect i on of t he t umor. Thi s can be accompl i s hed by a l obect omy or a wedge res ect i on of t he i nvol ved l ung s egment . Surgi cal res ect i on for s t age I or II nonâ€“s mal l cel l l ung cancer i s pot ent i al l y curat i ve, wi t h 5-year s urvi val of cl os e t o 70%. Nei t her chemot herapy al one nor concurrent chemoradi at i on t herapy i s appropri at e for a young ot herwi s e heal t hy pat i ent wi t h earl y s t age l ung cancer. 14. A 60-year-old man who is newly diagnosed with prostate carcinoma comes to see you. He underwent transrectal ultrasonography with a needle biopsy showing adenocarcinoma. Except for elevated PSA, he is currently asymptomatic. T he first test to order in staging for his prostate cancer is: A. Ful l body pl ai n fi l m x-rays B. Bone s can C. CT of head D. CEA l evel E. Repeat PSA now Vi ew Ans wer 14. T he answer is B [X C 6 b (2)]. The correct ans wer i s t o do a bone s can. Thi s i s t he fi rs t s t agi ng t es t done i n t he workup of pros t at e cancer. If abnormal i t i es are found on t he bone s can you t hen proceed t o do pl ai n fi l m x-rays of t he areas t o excl ude ot her

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pos s i bl e caus es . Then you woul d do s urgi cal s t agi ng wi t h removal and exami nat i on of t he s urroundi ng nodes (oft en done wi t h pros t at ect omy).

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Editors: Wolfsthal, Susan T itle: NMS Medicine, 6th Edition Copyri ght Â©2008 Li ppi ncot t W i l l i ams & W i l ki ns > T able of Cont ent s > Chapt er 5 - Gast roint est inal Diseases

Chapter 5

Gastrointestinal Diseases Darryn Potosky Bruce Greenwald

I. Diseases of the Esophagus The es ophagus i s bas i cal l y an organ of t rans port , wi t h no s i gni fi cant abs orpt i ve or s ecret ory funct i on.

A. Features common to clinical disorders 

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1. Dysphagia, or di ffi cul t y i n s wal l owi ng, i s a s ympt om oft en des cri bed as a sticking sensation. o

o

a. Dysphagia for solids i ndi cat es an es ophageal obs t ruct i on as a res ul t of: 

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(1) Carci noma

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(2) An es ophageal web or ri ng

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(3) Beni gn es ophageal s t ri ct ure

o

o

b. Dysphagia for solids and liquids i ndi cat es an es ophageal abnormal i t y as a res ul t of mot or dys funct i on, s uch as : 

Pa g e 8 8 1


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(1) Scl eroderma

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(2) Achal as i a

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(3) Sympt omat i c di ffus e es ophageal s pas m (SDES)

o

o

c. T ransfer dysphagia i ndi cat es a di ffi cul t y i n i ni t i at i ng s wal l owi ng and i s oft en as s oci at ed wi t h: 

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(1) A neuromus cul ar di s order of t he pharynx or proxi mal es ophagus (e.g., aft er a cerebrovas cul ar acci dent )

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(2) Proxi mal mus cl e weaknes s of t he pharynx or es ophagus (e.g., pol ymyos i t i s )

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(3) Or ot her neuromus cul ar di s orders (myas t heni a gravi s , myot oni a dys t rophi ca, or Parki ns on's di s eas e).

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2. Odynophagia, or pai n on s wal l owi ng, may be due t o: o

o

a. Motor disorders of t he es ophagus , es peci al l y achal as i a and SDES

o

o

b. Mucosal disruption caus ed by: 

Pa g e 8 8 2


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(1) Severe pept i c es ophagi t i s

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(2) Severe i nfect i ons of t he es ophagus [candi dal es ophagi t i s , herpet i c es ophagi t i s , cyt omegal ovi rus (CMV)],

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(3) Drug-i nduced es ophagi t i s (s ee I B 4 f)

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(4) Radi at i on es ophagi t i s

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(5) Inges t i on of l ye or ot her caus t i c agent s

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3. Heartburn i s a s ubs t ernal burni ng s ens at i on t hat radi at es t owards t he mout h and may be i ni t i at ed by bendi ng forward.

B. Specific disorders 

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1. Reflux esophagitis i s caus ed by t he recurrent refl ux of gas t ri c cont ent s i nt o t he di s t al es ophagus . o

o

a. Etiology and pathogenesis 

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(1) Lower esophageal sphincter (LES) dysfunction. Normal l y, t he LES bl ocks refl ux of gas t ri c jui ce i nt o t he es ophagus . Refl ux es ophagi t i s i s t hought t o s t em from a defect i n t hi s LES mechani s m, s uch as : 

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(a) Decreas ed res t i ng LES t one P.186

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(b) Prol onged or repeat ed i nt ermi t t ent t rans i ent rel axat i on of t he LES

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(c) Trans i ent i ncreas e i n abdomi nal pres s ure

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(2) Secondary causes of refl ux es ophagi t i s s houl d al ways be s us pect ed and correct ed i f pos s i bl e. The fol l owi ng condi t i ons appear t o decreas e LES t one: 

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(a) Pregnancy. Es peci al l y duri ng t he l as t t ri mes t er, heart burn may be s evere and probabl y i s caus ed by proges t erone's i nhi bi t ory effect s on t he LES.

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(b) Drugs. Medi cat i ons t hat may decreas e t he LES t one as a s i de effect of s moot h mus cl e rel axat i on i ncl ude: 

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(i) Ant i chol i nergi c agent s

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(ii) Î² 2 -Adrenergi c agoni s t s and t heophyl l i ne

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(iii) Cal ci um channel â€“bl ocki ng agent s and ni t rat es

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(c) Scleroderma. W eakeni ng of t he es ophageal s moot h mus cl e and t he LES regi on caus es s evere refl ux es ophagi t i s .

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(d) Surgical vagotomy. Thi s procedure al s o may produce anat omi c al t erat i ons t hat l ead t o refl ux es ophagi t i s .

o

o

b. Clinical features 

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(1) Heartburn or acid regurgitation i s a s peci fi c s ympt om of gas t roes ophageal refl ux.

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(2) Dysphagia i n t he es ophagi t i s pat i ent general l y i s for s ol i ds and may i ndi cat e a devel opi ng s t ri ct ure.

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(3) Anemia may occur i f recurrent es ophageal bl eedi ng i s pres ent .

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(4) Extra-esophageal manifestations i ncl ude recurrent l aryngi t i s , refl ux-i nduced as t hma, cough, atypical chest pain, and hi ccups .

o

o

c. Diagnosis. 

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

(1) Barium swallow and upper gastrointestinal series. Thi s i s t he l eas t s ens i t i ve t es t . General l y, i t i s pos i t i ve onl y i n s evere gas t roes ophageal refl ux wi t h a very weakened LES or i n t he pres ence of es ophageal ul cerat i on.

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(2) T wenty-four hour pH monitoring. Thi s meas ures t he number of epi s odes and l engt h of t i me t hat t he di s t al es ophageal pH i s l es s t han 4.





(3) Endoscopy with biopsy. Thi s procedure i s es peci al l y hel pful i n rul i ng out as s oci at ed Barret t 's es ophagus [s ee I B 1 e (5)]. However, eros i ve changes are s een i n onl y a mi nori t y of pat i ent s who undergo endos copy. A s quamous papi l l oma i s a s mal l beni gn pol yp at t he end of t he es ophagus , t hought t o be s econdary t o chroni c refl ux es ophagi t i s .





(4) Esophageal manometry. Thi s procedure i s us eful i n eval uat i ng LES pres s ure. Pres s ures cons i s t ent l y meas ured at l es s t han one-t hi rd of t he l ower l i mi t of normal us ual l y are as s oci at ed wi t h s i gni fi cant refl ux. Thi s t echni que i s es peci al l y us eful i n t he preoperat i ve eval uat i on of es ophageal refl ux when a fundopl i cat i on i s cont empl at ed.

o

o

d. T herapy 

Pa g e 8 8 6




(1) Increasing the reflux barrier may be accompl i s hed by: 



(a) Li fes t yl e modi fi cat i on s uch as el evat i ng t he head of t he bed 4â€“6 i nches , avoi di ng eat i ng for 3 hours before bedt i me, and avoi di ng fat t y or l arge-vol ume meal s





(b) Admi ni s t rat i on of al gi ni c aci d and ant aci d combi nat i ons





(c) Admi ni s t rat i on of drugs t hat i ncreas e LES t one (e.g., bet hanechol , met ocl oprami de, domperi done, ci s apri de)





(d) Ant i refl ux s urgery, es peci al l y Ni s s en fundopl i cat i on





(2) Decreasing gastric acid effects may be accompl i s hed by: 



(a) Admi ni s t rat i on of ant aci ds





(b) Admi ni s t rat i on of hi s t ami ne 2 (H 2 )-recept or ant agoni s t s (e.g., ci met i di ne, famot i di ne, rani t i di ne, and ni zat i di ne)





(c) Admi ni s t rat i on of

Pa g e 8 8 7


hydrogen/pot as s i um prot on pump bl ockers (prot on pump i nhi bi t ors ) s uch as omeprazol e, l ans oprazol e, pant oprazol e, es omeprazol e, and rabeprazol e 



(3) Maintaining LES pressure. The fol l owi ng agent s decreas e LES pres s ure and s houl d be avoi ded: 



(a) Medi cat i ons (ant i chol i nergi cs , Î²-adrenergi cs , cal ci um channel â€ “bl ockers , and ni t rat es )





(b) Foods (chocol at e, fat s , and peppermi nt )





(c) Ot her (ni cot i ne and caffei ne)

P.187

o

o

e. Complications 



(1) Benign esophageal stricture probabl y occurs i n a s mal l port i on of al l refl ux es ophagi t i s cas es and i s bes t di agnos ed by a bol us bari um s wal l ow, endos copy wi t h bi ops y, or cyt ol ogy.





(2) Esophageal ulceration may be

Pa g e 8 8 8


accompani ed by hemorrhage. However, t he pri mary s ympt om i s s evere and unrel ent i ng pai n. 



(3) Reflux-induced laryngitis i s a common caus e of recurrent hoars enes s i n adul t s .





(4) Pulmonary aspiration i s a s eri ous s equel a of refl ux es ophagi t i s . Pat i ent s ol der t han 30 years of age who devel op repeat ed pneumoni a or as t hma s houl d be eval uat ed for es ophageal refl ux.





(5) Barrett' s esophagus refers t o a condi t i on i n whi ch col umnar epi t hel i um repl aces t he normal s quamous epi t hel i um of t he es ophagus , pos s i bl y as a res ul t of cont i nuous i nfl ammat i on. Thi s i s cons i dered a premal i gnant s t at e, wi t h a 40-fol d i ncreas ed ri s k of adenocarci noma.





2. Obstructive esophageal conditions o

o

a. Carcinoma 



(1) Epidemiology. In t he Uni t ed St at es , t he i nci dence of adenocarci noma of t he es ophagus i s equi val ent t o t hat of s quamous cel l carci noma of t he es ophagus . Carci noma occurs predomi nant l y i n men and wi t h varyi ng i nci dence t hroughout t he worl d. The

Pa g e 8 8 9


popul at i on of t he Uni t ed St at es i s cons i dered at l ow ri s k; es ophageal cancer occurs i n onl y 4 of 100,000 i ndi vi dual s . 



(2) Etiology. Cert ai n fact ors appear t o i ncreas e t he ri s k of es ophageal cancer. 



(a) T obacco smoking, whi ch i ncreas es t he ri s k of s quamous cel l carci noma t wofol d t o fourfol d





(b) Alcohol consumption, whi ch has been s hown t o i ncreas e t he ri s k of s quamous cel l carci noma up t o 12 t i mes i n France. Al cohol and t obacco appear t o have an addi t i ve effect .



(c) Geographic factors. Inci dence l evel s , whi ch were found t o be 400 t i mes great er i n cert ai n regi ons i n Chi na and Iran, may be at t ri but abl e t o a di et t hat i ncl udes i ncreas ed amount s of pi ckl ed food, ni t ros ami nes , and mol ds as wel l as decreas ed amount s of s el eni um, fres h frui t s , and veget abl es .

See ot her fact ors onl i ne.





(d) Vitamin deficiency, es peci al l y vi t ami ns A and C, whi ch may be as s oci at ed wi t h an i ncreas ed ri s k of es ophageal cancer





(e) Lye ingestion, whi ch i s as s oci at ed wi t h t he devel opment of es ophageal cancer many years aft er expos ure



Pa g e 8 9 0




(f) Achalasia, whi ch may be as s oci at ed wi t h a 10% ri s k of s ubs equent carci nomas





(g) Barrett' s esophagus [s ee I B 1 e (5)]. Adenocarci noma event ual l y may devel op i n 10% of pat i ent s wi t h t hi s condi t i on.





(h) T ylosisâ€“hyperkeratosis of the palms and soles. More t han 80% of pat i ent s wi t h t hi s aut os omal domi nant condi t i on devel op s quamous cel l carci noma of t he es ophagus .





(i) Celiac sprue





(j) Esophageal dysplasia as s oci at ed wi t h human papi l l oma vi rus (HPV)





(3) Clinical features 



(a) Progressive dysphagia for solids i ndi cat es t he pres ence of an ongoi ng obs t ruct i ve l es i on. Us ual l y, when t he es ophageal l umen narrows t o 1.2 cm or l es s , a persistent dysphagia for s ol i d food i s obs erved.





(b) Pain us ual l y s i gni fi es ext ens i on of

Pa g e 8 9 1


t he t umor beyond t he wal l of t he es ophagus . 



(c) Dysphagia for liquids, cough, hoarseness, and weight loss general l y are s ympt oms of advanced es ophageal carci noma.





(4) Diagnosis 



(a) Endoscopy with biopsy and cytologic study, i f performed t oget her, es t abl i s hes a di agnos i s i n approxi mat el y 90% of cas es and i s t he di agnos t i c procedure of choi ce.





(b) Endoscopic ultrasound (EUS) i s us eful for s t agi ng es ophageal carci nomas .





(c) Computed tomography (CT ) and bronchoscopy s houl d be us ed t o eval uat e t he pres ence and ext ent of nodal met as t as es and bronchi al i nvas i on.





(d) Barium radiograph wi t h a bari um-coat ed bol us (e.g., bread or a mars hmal l ow) s houl d be performed when obs t ruct i ve dys phagi a i s s us pect ed.



Pa g e 8 9 2


(5) T herapy (s ee Chapt er 4 VII D 9)

o

o

b. Benign esophageal stricture may be a s equel a of prol onged refl ux es ophagi t i s . Heart burn may l es s en as s ol i d-food dys phagi a wors ens wi t h progres s i on of t he s t ri ct ure. Di agnos i s i s es t abl i s hed by a bol us bari um s wal l ow and endos copy. Treat ment general l y i s wi t h t apered bougi es or wi t h bal l oon di l at at i on cat het ers .

o

o

c. Esophageal webs s een i n t he upper one-third of t he es ophagus may be caus ed by a fai l ure of compl et e embryol ogi c recanal i zat i on. W ebs i n t hi s area al s o may be as s oci at ed wi t h i ron defi ci ency anemi a i n t he Plummer-Vinson (Paterson-Kelly) syndrome. Effect i ve t reat ment of P.188

t hi s s yndrome i ncl udes admi ni s t eri ng i ron for t he anemi a and us i ng an es ophageal bougi e t o fract ure t he webs . o

o

d. Esophageal rings mos t commonl y occur at t he squamocolumnar junction and are cal l ed Schatzki' s rings. Dys phagi a for s ol i ds oft en i s i nt ermi t t ent i n t hi s condi t i on, es peci al l y i f t he narrowes t poi nt of t he es ophagus meas ures bet ween 1.2 and 2 cm. Es ophageal bougi enage oft en i s effect i ve t herapy.





3. Esophageal motor disorders o

Pa g e 8 9 3


a. Oropharyngeal dysphagia (transfer dysphagia) i s a des cri pt i ve t erm appl i ed t o a di s order of t he neuromus cul ar apparat us of t he di s t al pharynx and upper es ophagus . Sympt oms i ncl ude di ffi cul t y i n i ni t i at i ng s wal l owi ng, nas al regurgi t at i on, and cough wi t h pul monary as pi rat i on.

See onl i ne for t ypes di s orders

as s oci at ed wi t h oropharyngeal dys phagi a 



(1) Cerebrovascular accident (CVA), whi ch may be t he mos t common of t hes e di s orders and us ual l y i s at t ri but abl e t o t rans i ent brai ns t em edema





(2) Myasthenia gravis





(3) Myotonic dystrophy





(4) Polymyositis





(5) Bulbar poliomyelitis





(6) Parkinson' s disease





(7) Multiple sclerosis (MS)





(8) Amyotrophic lateral sclerosis





(9) Hypothyroidism

o

Pa g e 8 9 4


b. SDES 



(1) Pathology. LES abnormal i t i es (s i mi l ar t o achal as i a), wi t h i ncompl et e rel axat i on, have been des cri bed i n 30% of cas es , wi t h document ed progres s i on t o cl as s i c achal as i a. Thi s l eads mos t i nves t i gat ors t o t hi nk t hat SDES res ul t s from a neural defect .








(a) Dysphagia for bot h s ol i ds and l i qui ds occurs .





(b) Odynophagia may occur, es peci al l y aft er i nges t i on of ext remel y hot or col d s ol i ds or l i qui ds .





(c) Spontaneous chest pain s i mi l ar t o angi na pect ori s may be evi dent . Noct urnal pai n, whi ch i s oft en des cri bed, i s rel i eved by t he s moot h mus cl e rel axant ni t rogl yceri n (t he s ame t reat ment pres cri bed for angi nal pai n). The abi l i t y of ni t rogl yceri n t o provi de rel i ef may furt her confus e t he di agnos i s .





(3) Diagnosis. Cl i ni cal evi dence i s t he bas i s of di agnos i s . 

Pa g e 8 9 5


(a) Radiography may reveal a corks crew-s haped es ophagus .





(b) Esophageal manometry s houl d reveal : 



(i) Hi gh-ampl i t ude, repet i t i ve, s i mul t aneous cont ract i ons i n approxi mat el y 30% of t he bas al s t at e or aft er ergonovi ne or edrophoni um s t i mul at i on (not a rout i nel y performed t es t ). (In a vari ant of SDES cal l ed t he nutcracker esophagus, hi gh-ampl i t ude prol onged cont ract i ons may be as s oci at ed wi t h ches t pai n.)





(ii) Several normal peri s t al t i c s equences t o di fferent i at e SDES from achal as i a





(iii) Incompl et e rel axat i on of t he LES i n approxi mat el y 30% of pat i ent s





(c) Balloon distention of the esophageal lumen can be us ed as a s t i mul us . A s mal l er-t han-normal amount of ai r or wat er i ns uffl at i on of t he bal l oon i ndi cat es a l ower t hres hol d for pai n.



Pa g e 8 9 6




(4) T herapy (s ucces s ful i n approxi mat el y 50% of cas es ) 



(a) Ant i chol i nergi c agent s





(b) Ni t rat es (s hort - or l ong-act i ng)





(c) Cal ci um channel â€“bl ocki ng agent s





(d) Es ophageal bougi enage





(e) Hydral azi ne t o decreas e peri s t al t i c ampl i t ude





(f) Surgery wi t h a l ongi t udi nal es ophageal myot omy (i n s evere, i ncapaci t at i ng cas es onl y)

o

o

c. Achalasia 



(1) Epidemiology. Achal as i a occurs i n approxi mat el y 1 i n 100,000 i ndi vi dual s i n t he Uni t ed St at es and equal l y i n bot h s exes . The mos t common age of ons et i s bet ween 20 and 40 years .





(2) Pathology. A neural defect i s s ugges t ed by decreas ed gangl i on cel l s , wi t h fi bros i s and

Pa g e 8 9 7


s carri ng i n Auerbach's pl exus . Wallerian degeneration i s s ugges t ed by exami nat i on of vagal es ophageal fi bers . The dors al vagal nucl eus i s al s o abnormal . Supers ens i t i vi t y t o chol i nergi c s t i mul at i on and exogenous gas t ri n i s des cri bed. 






(a) Dys phagi a for s ol i ds and l i qui ds i n 95%â€“100% of pat i ent s





(b) W ei ght l os s i n 90% of pat i ent s





(c) Ches t pai n, whi ch i s s evere i n 60% of pat i ent s





(d) Noct urnal cough i n 30% of pat i ent s , i ndi cat i ng pos s i bl e overfl ow as pi rat i on of unempt i ed es ophageal cont ent s and, i n s uch cas es , t he need for i mmedi at e t reat ment





(e) Recurrent bronchi t i s or pneumoni a i n approxi mat el y 7%â€“8% of pat i ent s

P.189





(4) Diagnosis. Di agnos i s i nvol ves excl udi ng

Pa g e 8 9 8


mal i gnancy (i .e., carci noma or l ymphoma) at t he es ophagogas t ri c junct i on, whi ch may mi mi c achal as i a (â€œs econdary achal as i aâ€• ). Secondary achal as i a may be charact eri zed by great er wei ght l os s , s hort er durat i on of s ympt oms , and l es s es ophageal di l at at i on i n an ol der pers on. 



(a) Radiography may reveal a fl acci d, di l at ed, fl ui d-fi l l ed es ophagus wi t h a beak-like tapering over t he LES regi on. A CT s can of t he ches t and abdomen or an endos copi c ul t ras ound of t he es ophagogas t ri c junct i on may be needed t o rul e out s econdary (oft en mal i gnant ) achal as i a.





(b) Manometry i s t he mos t s ens i t i ve di agnos t i c met hod and s houl d reveal : 



(i) Abs ence of normal peri s t al s i s i n t he ent i re es ophagus





(ii) El evat ed LES pres s ure





(iii) Incompl et e rel axat i on of t he LES, res ul t i ng i n a pers i s t ent obs t ruct i ng barri er aft er s wal l owi ng





(5) T herapy 

Pa g e 8 9 9




(a) Drugs s uch as ni t rat es , ant i chol i nergi c agent s , Î² 2 -adrenergi c agoni s t s , and cal ci um channel -bl ocki ng agent s are effect i ve i n l es s t han 50% of pat i ent s .





(b) Pneumatic dilation i s effect i ve i n 70%â€“90% of pat i ent s , has a mort al i t y rat e of approxi mat el y 0.2%, and has a perforat i on rat e of roughl y 2%â€“3%.





(c) Endoscopic injection of botulinum toxin i nt o t he LES res ul t s i n decreas ed LES pres s ure and decreas ed dys phagi a i n 70%â€“80% of pat i ent s . Repeat ed i nject i ons may be neces s ary, and l ong-t erm effi cacy i s not ed i n l es s t han 50% of pat i ent s .





(d) Surgical therapy. The favored procedure i s a Heller myotomy, whi ch has a 65%â€“90% s ucces s rat e and a 3%â€“4% s urgi cal compl i cat i on rat e. For operat i ons t hat do not i ncorporat e an ant i refl ux procedure, t he rat e of pos t operat i ve refl ux may i ncreas e t o 25%â€“30% aft er s everal years . Laparos copi c t echni ques are favored.

o

o

d. Systemic sclerosis (scleroderma) i s a s ys t emi c col l agen vas cul ar di s eas e i nvol vi ng t he s ki n i n 98% of cas es . The es ophagus i s found t o be abnormal i n

Pa g e 9 0 0


75% of aut ops i es and i n 80% of cas es s t udi ed manomet ri cal l y. 



(1) Pathology. The earl y es ophageal effect s are t hought t o be neural becaus e no anat omi c abnormal i t y of t he s moot h mus cl e can be i dent i fi ed at a t i me when marked weaknes s of t he es ophagus i s not ed. A l at e defect may i ncl ude a di s us e t ype of at rophy of t he ci rcul ar s moot h mus cl e el ement s of t he es ophagus ; t he l ongi t udi nal mus cul ar l ayers remai n i nt act .








(a) Dys phagi a for s ol i ds and l i qui ds





(b) Severe heart burn i n 50% of pat i ent s





(c) Es ophageal s t ri ct ure i n 25% of l ong-t erm s urvi vors





(3) Diagnosis 



(a) Radiography. Supi ne es ophagography may i ndi cat e poor es ophageal empt yi ng becaus e of an abs ence of peri s t al s i s .





(b) Manometry. Thi s procedure, whi ch i s t he mos t rel i abl e di agnos t i c t echni que,

Pa g e 9 0 1


reveal s : 



(i) Decreas ed LES pres s ure





(ii) Very weak, l ow-ampl i t ude peri s t al t i c cont ract i ons i n t he di s t al s moot h mus cl e port i on (l ower t wo-t hi rds ) of t he es ophagus





(4) T herapy. The es ophageal di s order i s t reat ed wi t h ant i refl ux meas ures (s ee I B 1 d).





4. Other esophageal disorders o

o

a. Diverticula 



(1) Zenker' s diverticulum i s a mucos al herni at i on (not a t rue di vert i cul um) above t he cri copharyngeal regi on. Obs t ruct i ve s ympt oms may occur i f t here i s i ncompl et e empt yi ng of t hi s di vert i cul um. Large di vert i cul a are t reat ed s urgi cal l y.





(2) T raction diverticula occur i n t he mi d and di s t al regi ons and are t hought t o be s econdary t o an adjacent i nfl ammat ory proces s s uch as t ubercul os i s .





(3) Epiphrenic diverticula occur i n t he di s t al

Pa g e 9 0 2


es ophagus , above t he LES, and oft en are as ympt omat i c. o

o

b. Infections. Bact eri al and vi ral s ources of es ophageal i nfect i on are common, but s everal i nfect i ous agent s are of part i cul ar i nt eres t . P.190





(1) Candidal esophagitis us ual l y occurs i n di abet i c pat i ent s , i mmunocompromi s ed hos t s (e.g., pat i ent s i nfect ed wi t h human i mmunodefi ci ency vi rus [HIV] or pat i ent s undergoi ng cancer chemot herapy or s t eroi d t reat ment ), and i n t hos e wi t h poor es ophageal empt yi ng (e.g., pat i ent s wi t h achal as i a or s evere s t ri ct ure). Odynophagi a i s a major s ympt om, and di agnos i s i s made by endos copy and cyt ol ogi c s t udi es . Treat ment i s wi t h nys t at i n, fl uconazol e, or, i n res i s t ant cas es , l ow dos es of amphot eri ci n B.





(2) Herpes simplex virus (HSV) may caus e es ophagi t i s i n i mmunocompromi s ed hos t s . The es ophagi t i s i s charact eri zed by rel at i vel y s mal l , i s ol at ed ul cers . Bi ops y of t he ul cerat i ng edges may s how charact eri s t i c mul t i nucl eat ed cel l s wi t h nucl ear i ncl us i ons . Treat ment i s wi t h acycl ovi r.





(3) CMV i nfect i on of t he es ophagus i s oft en

Pa g e 9 0 3


s een i n i mmunocompromi s ed pat i ent s and may produce very l arge ul cerat i ons of t he es ophagus . Int ranucl ear i ncl us i on bodi es are obs erved on bi ops y. Treat ment i s wi t h ganci cl ovi r. 



(4) HIV esophagitis may res ul t i n a di ffus e i nfl ammat ory es ophagi t i s . Treat ment of i s ol at ed acqui red i mmunodefi ci ency s yndrome (AIDS) es ophagi t i s i s wi t h s t eroi ds .

o

o

c. Esophageal burns. Inges t i on of caus t i c agent s (i .e., s t rong al kal i or aci d) can caus e s eri ous es ophageal burns . Inges t i on of l ye or det ergent s s uch as chl ori ne bl each i s a common s ui ci dal ges t ure i n adul t s and a common acci dent i n chi l dren. Emergency endos copy s houl d be performed t o as s es s t he ext ent of damage. St eroi ds and broad-s pect rum ant i bi ot i cs are recommended i ni t i al l y i n management of es ophageal burns . Long-t erm s equel ae i n s urvi vors may i ncl ude es ophageal s t ri ct ure and es ophageal carci noma.

o

o

d. Esophageal tears. Thes e condi t i ons are s een mos t commonl y aft er vomi t i ng (75% of cas es ), s t rai ni ng, or coughi ng. 



(1) A mucos al t ear (Mallory-Weiss syndrome) produces s i gni fi cant hemat emes i s aft er an i ni t i al nonbl oody vomi t us . Surgery i s requi red i n l es s t han 10% of t hes e cas es .



Pa g e 9 0 4




(2) A rupt ure of t he es ophagus (Boerhaave' s syndrome) us ual l y occurs above t he es ophagogas t ri c junct i on. Ai r i n t he l eft medi as t i nal regi on s ugges t s t he di agnos i s , and i mmedi at e s urgi cal i nt ervent i on i s neces s ary i f t he pat i ent i s t o s urvi ve.

o

o

e. Paraesophageal hernia. Unl i ke t he much more common and cl i ni cal l y i ns i gni fi cant hi at al herni a, a paraes ophageal herni a may l ead t o gas t ri c vas cul ar compromi s e. The es ophagogas t ri c junct i on t ravers es t he di aphragm i n t he appropri at e l ocat i on. The body of t he s t omach t hen t ravel s above t he di aphragm, and gas t ri c vol vul us wi t h i ncarcerat i on may occur. Surgery may be neces s ary t o al l evi at e s ympt oms of pai n, upper gas t roi nt es t i nal bl eedi ng, and i s chemi a.

o

o

f. Pill-induced esophagitis. Thi s condi t i on i s oft en caus ed by medi cat i ons s uch as oral bisphosphonates, as pi ri n and ot her nons t eroi dal ant i -i nfl ammat ory drugs (NSAIDs ), pot as s i um chl ori de t abl et s , i ron preparat i ons , qui ni di ne, t et racycl i nes , and ot her ant i bi ot i cs . Thes e medi cat i ons are oft en t emporari l y l odged i n t he es ophagus becaus e of ei t her i nadequat e l i qui d wi t h s wal l owi ng or a rel at i ve narrowi ng of t he es ophagus . Severe eros i ons and s t ri ct ures may devel op i n a mi nori t y of cas es . Treat ment i s s ympt omat i c.

II. Diseases of the Stomach A. Gastritis

Pa g e 9 0 5






1. Acute gastritis i s an i nfl ammat i on of t he gas t ri c mucos a, whi ch may be di ffus e or l ocal i zed and us ual l y i s s el f-l i mi t ed. o

o

a. Etiology 



(1) Drugs t hat can damage t he mucos al barri er and l ead t o back-di ffus i on of aci d and peps i n i ncl ude: 



(a) As pi ri n and NSAIDs





(b) Al cohol , whi ch may produce an addi t i ve effect wi t h as pi ri n





(2) Accidental ingestion of caustic substances s uch as s t rong al kal i (e.g., l ye), s t rong aci d [e.g., s ul furi c aci d (H 2 SO 4 ), HCl ], or fi xat i ves [e.g., formal dehyde, t ri ni t rophenol (pi cri c aci d)] can be fat al . Pat i ent s who s urvi ve t he i nges t i on of s uch corros i ves s us t ai n i njuri es t hat l eave cons i derabl e s cars and s ubs equent ant ral narrowi ng.





(3) Stress rel at ed t o s evere i l l nes s , es peci al l y i l l nes s i nvol vi ng many organ s ys t ems , caus es acut e gas t ri t i s . Is chemi a and gas t ri c aci d, even at normal l evel s , may be i nvol ved.

Pa g e 9 0 6


P.191





(4) Infections 



(a) Helicobacter pylori i nfect i ous gas t ri t i s (s ee III C 4)





(b) Infections with CMV, herpesvirus, Mycobacterium avium complex (MAC), Candida, T reponema pallidum, and Mycobacterium tuberculosis have been as s oci at ed wi t h gas t ri t i s , es peci al l y i n i mmunocompromi s ed pat i ent s .

o

o

b. Clinical features (pres ent i n 70% of pat i ent s ) 



(1) Epigastric burning and pain, nausea, and vomiting





(2) Gastrointestinal bleeding, whi ch may be s evere and as s oci at ed wi t h hemat emes i s and s hock

o

o

c. Diagnosis. In mos t cas es , di agnos i s i s made on t he bas i s of endos copi c vi s ual i zat i on wi t h or wi t hout bi ops y. Conges t i on, fri abi l i t y, s uperfi ci al ul cerat i on, and pet echi ae frequent l y are s een i n t he gas t ri c mucos a.

Pa g e 9 0 7


o

d. T herapy. Treat ment begi ns wi t h removal of offendi ng agent s . Ant aci ds , ant i vi ral and ant i fungal agent s , H 2 -recept or ant agoni s t s , prot on pump i nhi bi t ors , and s urface-act i ng agent s (e.g., s ucral fat e) are us eful as wel l . Pat i ent s wi t h acut e hemorrhagi c gas t ri t i s us ual l y res pond t o fl ui d or bl ood repl acement combi ned wi t h a regi men of ant aci ds , H 2 -recept or ant agoni s t s , and omepraz ol e or l ans opraz ol e, whi ch keep t he gas t ri c pH above 3.5. Surgery rarel y i s neces s ary for t hes e pat i ent s and i s as s oci at ed wi t h hi gh morbi di t y and mort al i t y rat es .





2. Chronic gastritis i s charact eri zed by a s uperfi ci al l ymphocyt e i nfi l t rat e i n t he l ami na propri a. o

o

a. Etiology. Chroni c gas t ri t i s can be caus ed by: 



(1) Prol onged us e of al cohol , as pi ri n, and ot her i rri t at i ng drugs





(2) Radi at i on or t hermal i njury





(3) Immunol ogi c fact ors





(4) Infect i ons (e.g., H. pyl ori ) H. pylori i nfect i ous gas t ri t i s i s caus ed by a gram-negat i ve, s pi ral -s haped bact eri um t hat s urvi ves i n t he aci di c mi l i eu of t he s t omach by

Pa g e 9 0 8


produci ng ureas e, whi ch l i berat es ammoni a. Chroni c gas t ri t i s i nvol vi ng H. pyl ori has been as s oci at ed wi t h 80%â€“90% of duodenal ul cer pat i ent s (s ee III C 4) and wi t h 60%â€“70% of gas t ri c ul cer pat i ent s . o

o

b. T ypes 



(1) Chronic type A gastritis i nvol ves t he fundus and body of t he s t omach; t he ant rum i s s pared. Thi s t ype of gas t ri t i s i s as s oci at ed wi t h pari et al cel l ant i bodi es , hi gh s erum gas t ri n l evel s , and perni ci ous anemi a.





(2) Chronic type B gastritis i nvol ves t he ant rum of t he s t omach; t he body and fundus are rel at i vel y s pared. Gas t ri n cel l ant i bodi es have been det ect ed i n s ome pat i ent s wi t h t hi s gas t ri t i s . More commonl y, refl ux of duodenal or bi l i ary s ecret i ons or H. pyl ori i nfect i ons are l i nked caus at i vel y t o t ype B gas t ri t i s .

o

o

c. Clinical features. Cl i ni cal evi dence may be l i mi t ed i n pat i ent s wi t h chroni c gas t ri t i s . Type A gas t ri t i s i s as s oci at ed wi t h hypochl orhydri a or achl orhydri a, whereas t ype B gas t ri t i s i s as s oci at ed wi t h normal aci d l evel s . Hypot hyroi di s m, di abet es mel l i t us , and vi t i l i go occur more frequent l y wi t h t ype A t han wi t h t ype B gas t ri t i s .

o

o

d. Clinical course. Dat a s ugges t t hat t hes e l es i ons may remai n unchanged for s everal years . Gas t ri c

Pa g e 9 0 9


at rophy devel ops i n approxi mat el y 50% of pat i ent s wi t h s uperfi ci al gas t ri t i s over 10â€“20 years . There i s an i ncreas ed as s oci at i on wi t h gas t ri c pol yps , gas t ri c ul cer, and gas t ri c cancer i n bot h t ypes of chroni c gas t ri t i s , wi t h t ype B bei ng as s oci at ed wi t h a hi gher i nci dence of gas t ri c cancer t han t ype A. o

o

e. T herapy. Treat ment us ual l y i s unneces s ary; however, condi t i ons as s oci at ed wi t h gas t ri t i s (e.g., perni ci ous anemi a, H. pyl ori i nfect i ons , hypot hyroi di s m, and di abet es ) s houl d be t reat ed accordi ngl y. Some i nves t i gat ors s ugges t yearl y gas t ri c cyt ol ogi c anal ys i s as a means of di agnos i ng an earl y cancer i n affect ed pat i ent s .





3. Special types of gastritis o

o

a. Eosinophilic gastroenteritis refers t o t he i nfi l t rat i on of eos i nophi l s i nt o t he gas t ri c ant rum, s mal l bowel , or bot h. Thi s i nfi l t rat i on, whi ch i s bel i eved t o be i mmunol ogi cal l y medi at ed, caus es t hi ckeni ng of t he i nt es t i nal wal l wi t h s ubs equent ant ral obs t ruct i on. Peripheral edema due to protein-losing enteropathy may occur. Peri pheral eos i nophi l i a is common. Di fferent i at i on from ot her i nfi l t rat i ve di s eas es (e.g., t ubercul os i s , s arcoi dos i s , l ymphoma, s yphi l i s , hi s t opl as mos i s , Crohn's di s eas e, and carci noma) may be di ffi cul t and depends on endos copi c bi ops y. Cort i cos t eroi d t herapy has been s ucces s ful i n provi di ng prol onged remi s s i on.

o

Pa g e 9 1 0


b. Granulomatous gastritis i s an i nfi l t rat i ve di s eas e charact eri zed by noncas eat i ng granul omas , wi t h or wi t hout gi ant cel l s . Crohn's di s eas e, s arcoi dos i s , beryl l i um poi s oni ng, or i di opat hi c caus es may res ul t i n granul omat ous gas t ri t i s . Gas t ri c out l et obs t ruct i on i s common. Treat ment wi t h s t eroi ds or s urgery i s oft en requi red.

o

o

c. Hypertrophic gastritis i s an uncommon condi t i on as s oci at ed wi t h mas s i ve enl argement of t he gas t ri c fol ds . 



(1) Clinical features. In i t s mos t ext reme form (i .e., MÃ©nÃ©t ri er's di s eas e), t here i s hypos ecret i on of gas t ri c aci d, prot ei n l os s from t he s t omach, peri pheral edema, wei ght l os s , and abdomi nal pai n.





(2) Diagnosis. Endos copy and bi ops y, oft en wi t h a s uct i on apparat us , provi de t he di agnos i s . 



(a) On bi ops y, gas t ri c mucous cel l s are hyperpl as t i c, and i nfl ammat ory cel l s are pres ent i n s ome pat i ent s .





(b) Lymphoma, amyl oi d i nfi l t rat i on, carci noma, and Zol l i nger-El l i s on s yndrome al s o can caus e l arge rugal fol ds and s houl d be excl uded.



Pa g e 9 1 1


(c) A t ype of hypers ecret ory hypert rophi c gas t ri t i s i s s i mi l ar t o MÃ©nÃ©t ri er's di s eas e but i s as s oci at ed wi t h hi gh aci d out put and hyperpl as i a of pari et al gas t ri c cel l s .





(3) T herapy. Treat ment i ncl udes ant i chol i nergi c agent s , whi ch appear t o cl os e t he t i ght junct i ons bet ween cel l s and decreas e prot ei n l os s ; H 2 -recept or ant agoni s t s ; and s t eroi ds . Surgery (gas t ri c res ect i on) i s res erved for i nt ract abl e cas es .

B. Gastric neoplasms (see Chapter 4, â€œOncologyâ€•) 



1. T rue gastric lymphoma us ual l y occurs as a bul ky mas s as s oci at ed wi t h l arge, t hi ckened gas t ri c fol ds . Pai n i s t he mos t common pres ent i ng s ympt om. Hi s t ol ogi c exami nat i on us ual l y s hows di ffus e hi s t i ocyt i c non-Hodgki n's l ymphoma, but non-Hodgki n's l ymphomas of al l t ypes are more common t han Hodgki n's di s eas e i n t he s t omach. Gas t ri c l ymphoma, es peci al l y of t he P.192

mucos a-as s oci at ed l ymphat i c t i s s ue (MALT) t ype, has been s t rongl y as s oci at ed wi t h H. pyl ori i nfect i on. o

o

a. Diagnosis. Gas t ri c l ymphoma s houl d be di fferent i at ed from MÃ©nÃ©t ri er's di s eas e, Zol l i nger-El l i s on s yndrome, and hypert rophi c gas t ri t i s . Di agnos i s i s confi rmed by bi ops y, ei t her

Pa g e 9 1 2


at endos copy wi t h a s uct i on apparat us or at s urgery. o

o

b. T herapy. Surgery and l ocal i zed radi at i on t herapy are t he general l y accept ed forms of t herapy, wi t h 5-year s urvi val rat es approachi ng 50% i n non-Hodgki n's l ymphoma pat i ent s whos e l ymphoma i s confi ned t o t he s t omach. Chemot herapy i s val uabl e i n pat i ent s wi t h s ys t emi c di s eas e. If H. pyl ori l ymphoma i s i dent i fi ed, t reat ment for t he H. pyl ori al one may l ead t o res ol ut i on.





2. Other gastric tumors o

o

a. Gastrointestinal stromal tumors (GIST S). The s t omach i s t he mos t common s i t e for GISTS, wi t h t he s mal l bowel bei ng t he s econd mos t frequent l ocat i on. GIST t umors cons t i t ut e 1%â€“3% of al l gas t ri c t umors and devel op from t he i nt ers t i t i al cel l s of Cajal (or pacemaker cel l s ). They may be beni gn or mal i gnant and pres ent wi t h GI bl eedi ng (40%), abdomi nal mas s (40%), or abdomi nal pai n (20%). Mal i gnancy i s oft en det ermi ned by t he s i ze (>4 cm) or t he number (>25) of mi t ot i c fi gures s een i n a hi gh-power fi el d (HPF). Treat ment i s wi t h s urgery or a t yros i ne ki nas e i nhi bi t or s uch as i mat i ni b mes yl at e (Gl eevec) or s uni t i ni b (Sut ent ).

o

o

b. Gastric malignancies s uch as fibrosarcomas, neurogenic sarcomas, carcinoids, and metastatic carcinomas (es peci al l y from breas t and l ung

Pa g e 9 1 3


carci nomas and mel anoma) mus t be di fferent i at ed from pri mary gas t ri c carci noma.

C. Disorders of gastric emptying 



1. Pyloric stenosis o

o

a. Acquired pyloric stenosis occurs t rans i ent l y, as t he res ul t of edema from pept i c ul cer di s eas e, or chroni cal l y, as t he res ul t of pyl ori c s carri ng from recurrent ul cer di s eas e or neopl as m.

o

o

b. Congenital pyloric stenosis us ual l y mani fes t s i n i nfancy. 



(1) Incidence. Congeni t al pyl ori c s t enos i s occurs i n approxi mat el y 2â€“4 of 1000 bi rt hs and us ual l y i s s een i n fi rs t born mal e chi l dren. There i s a fami l i al i nci dence.





(2) Clinical features. Pos t prandi al project i l e vomi t i ng of nonbi l i ous mat eri al , dehydrat i on, and wei ght l os s may occur. Vi s i bl e peri s t al s i s may be not ed, wi t h a mas s pal pat ed i n t he epi gas t ri um.





(3) Diagnosis. Radi ographi c evi dence i s t he bas i s of di agnos i s . A pl ai n fi l m s hows ai r i n t he s t omach, and a bari um s wal l ow confi rms t he di agnos i s .



Pa g e 9 1 4




(4) T herapy. Treat ment i s s urgi cal (Rams t edt operat i on) and cons i s t s of a myot omy of t he ci rcul ar mus cl e of t he pyl orus .

o

o

2. Gastric bezoars are col l ect i ons of nondi ges t i bl e s ubs t ances t hat s omet i mes form and cannot pas s t hrough t he pyl orus . Tri chobezoars are compos ed of hai r, and phyt obez oars are compos ed of pl ant fi bers . Bez oars general l y are s een i n pat i ent s who have undergone previ ous gas t ri c s urgery or i n ment al l y ret arded i ndi vi dual s who cons ume nondi ges t i bl e s ubs t ances . The s ympt oms i ncl ude t hos e of gas t ri c out l et obs t ruct i on and bl eedi ng from s uperfi ci al ul cerat i ons . It i s i mport ant t o excl ude a gas t ri c mas s or cancer, and t he di agnos i s can be es t abl i s hed endos copi cal l y. Bez oars s omet i mes can be enzymat i cal l y di s s ol ved wi t h papai n, acet yl cys t ei ne, or cel l ul as e; ot herwi s e, endos copi c or s urgi cal removal i s neces s ary.

o

o

3. Gastric diverticula occur on t he pos t eri or wal l of t he s t omach i n approxi mat el y 75% of cas es and us ual l y are wi t hi n 2 cm of t he es ophagogas t ri c junct i on. Unl es s t hey bl eed or perforat e t hes e congeni t al l es i ons are as ympt omat i c. Pseudodiverticula, s een mos t commonl y i n t he ant rum, are s carred remnant s of previ ous pept i c di s eas e.

o

o

4. Gastric volvulus may occur as a res ul t of weak l i gament ous at t achment s or may be s econdary t o a paraes ophageal herni a, an i nt ri ns i c gas t ri c l es i on,

Pa g e 9 1 5


or an adjacent mas s . Di agnos i s i s s upport ed by t he fi ndi ng of t wo s eparat e fl ui d l evel s i n t he l eft upper quadrant and by a l ack of bari um pas s age i nt o t he pyl orus . Therapy cons i s t s of t emporary nas ogas t ri c s uct i on. Recurrent or acut e vol vul us wi t h gas t ri c vas cul ar compromi s e may requi re s urgery. o

o

5. Gastroparesis i s a di s order of gas t ri c empt yi ng t hat i s not caus ed by an obs t ruct i on. The di agnos i s s houl d be made by a nucl ear s ol i d-phas e gas t ri c empt yi ng s t udy aft er mechani cal obs t ruct i on has been rul ed out by an upper gas t roi nt es t i nal s eri es or by endos copy. Gas t ropares i s mos t frequent l y i s caus ed by t ype 1 (i ns ul i n-dependent ) di abet es mel l i t us of l onger t han 10 years ' durat i on. Ot her condi t i ons as s oci at ed wi t h gas t ropares i s i ncl ude s ys t emi c s cl eros i s , pos t vagot omy s t at es , and t herapy wi t h ant i chol i nergi c agent s or narcot i cs . In di abet es , l os s of gas t ri c phas e III act i vi t y i s not ed on el ect ri cal recordi ngs , wi t h ot her s i gns of di abet i c vi s ceral neuropat hy oft en bei ng s een as wel l . Treat ment wi t h proki net i c agent s s uch as met ocl oprami de, domperi done, or eryt hromyci n has been effect i ve. El ect ri cal gas t ri c paci ng may be neces s ary i n res i s t ant cas es .

III. Peptic Ulcer Disease A. Introduction Pept i c ul cer di s eas e refers t o a group of di s orders of t he gas t roi nt es t i nal t ract . The di s orders al l i nvol ve areas of di s cret e t i s s ue des t ruct i on caus ed by aci d and peps i n. Pept i c ul cers occur mos t commonl y i n t he s t omach or proxi mal duodenum, l es s commonl y i n t he di s t al es ophagus , and rarel y i n t he s mal l i nt es t i ne. (Pept i c ul cers i n t he di s t al s mal l i nt es t i ne us ual l y are

Pa g e 9 1 6


as s oci at ed wi t h a Meckel 's di vert i cul um t hat cont ai ns gas t ri c mucos a.) In general , t he cl i ni cal feat ures and t reat ment of pept i c ul cer di s eas e are s i mi l ar regardl es s of l ocat i on, al t hough pept i c es ophagi t i s caus ed by refl ux of gas t ri c cont ent s has s ome uni que feat ures (s ee I B 1).

B. Incidence Pept i c ul cer di s eas e occurs more commonl y i n men t han i n women. Duodenal ul cers are t hree t i mes more common t han gas t ri c ul cers and occur approxi mat el y 10 years earl i er; t he peak i nci dence for duodenal ul cers i s at approxi mat el y 40 years of age, as oppos ed t o 50 years of age for gas t ri c ul cers . Duodenal ul cers have a 1-year rel aps e rat e of approxi mat el y 80% (much l ower i f as s oci at ed wi t h H. pyl ori t hat has been eradi cat ed). Pat i ent s wi t h gas t ri c ul cers have a 33% chance of devel opi ng s ubs equent duodenal ul cers .

C. Pathogenesis Aci d and peps i n are neces s ary for devel opment of ul cers . However, s everal fact ors , es peci al l y H. pyl ori i nfect i on, are t hought t o cont ri but e t o t he pat hogenes i s . 



1. Social factors o

o

a. T obacco smoking i ncreas es t he ri s k of pept i c ul cer di s eas e. Smoki ng al s o rai s es t he morbi di t y and mort al i t y rat es and l owers t he heal i ng rat e for pept i c ul cers .

o

o

b. Drugs s uch as NSAIDs are i mpl i cat ed i n ul cer di s eas e, wi t h an ant i pros t agl andi n effect s ugges t ed as an underl yi ng fact or. Ul cers devel op i n approxi mat el y 30% of art hri t i s pat i ent s who t ake hi gh dos es of as pi ri n. St eroi ds al s o are t hought t o break t he mucos al barri er and may doubl e t he ri s k

Pa g e 9 1 7


of pept i c ul cer di s eas e. o

o

c. Alcohol compromi s es t he mucos al barri er and i ncreas es gas t ri c aci d s ecret i on.





2. Physiologic factors o

o

a. Gastric acid, al t hough es s ent i al for ul cer product i on, general l y i s meas ured at normal or decreas ed l evel s i n gas t ri c ul cer pat i ent s . Sl i ght l y el evat ed l evel s of gas t ri c aci d are not ed i n t he bas al and s t i mul at ed s t at es i n duodenal ul cer pat i ent s .

o

o

b. Serum gastrin l evel s are normal duri ng fas t i ng and i ncreas ed i n t he pos t prandi al s t at e i n duodenal ul cer pat i ent s . Bot h fas t i ng and pos t prandi al l evel s of s erum gas t ri n are hi gher t han normal i n gas t ri c ul cer pat i ent s .

P.193





3. Genetic factors o

o

a. First-degree relatives of gas t ri c ul cer pat i ent s have t hree t i mes t he ri s k of devel opi ng gas t ri c ul cers as t he general popul at i on. Si mi l arl y, t he ri s k of duodenal ul cer i s i ncreas ed i n t he fi rs t -degree rel at i ves of duodenal ul cer pat i ent s .

o

Pa g e 9 1 8


o

b. An i ncreas ed i nci dence of duodenal ul cer has been document ed among i ndi vi dual s wi t h bl ood group O, t hos e who demons t rat e el evat ed s erum l evel s of peps i nogen I, and t hos e who are nons ecret ors of bl ood group s ubs t ances .





4. Helicobacter pylori o

o

a. Microbiology. H. pyl ori has been i dent i fi ed on cul t ures of t he gas t ri c ant rum i n 90% of pat i ent s wi t h duodenal ul cer di s eas e or ant ral t ype B gas t ri t i s , and t he as s oci at i on for pat i ent s wi t h gas t ri c ul cer di s eas e i s 60%â€“70%.

o

o

b. Pathophysiology. H. pyl ori i s found on gas t ri c epi t hel i um and does not penet rat e t he cel l . If i t i s a pri mary offender, i t may act as a â€œbarri er breaker,â€• al l owi ng aci d back-di ffus i on and pept i c ul cer di s eas e t o devel op. H. pyl ori el aborat es ammoni a, whi ch damages cel l s urfaces , and l i berat es a number of ot her i nfl ammat ory cel l recrui t i ng fact ors and adhes i on mol ecul es .

o

o

c. H. pylori detection. H. pyl ori l i berat es ureas e, and a bi ops y of t he gas t ri c ant rum may change a pH col or moni t or. A urea breat h t es t us i ng carbon 13

13 ( C)- or

14

C-l abel ed urea meas ures exhal ed

l abel ed carbon di oxi de. Suppl ement ed cul t ure medi um (s t arch, bl ood, or charcoal ) may be opt i mal under mi croaerophi l i c condi t i ons at 37Â°C. W art hi n-St arry s i l ver, Gi ems a, or hemat oxyl i n and eos i n s t ai ns may s how t he organi s m i n an

Pa g e 9 1 9


ext racel l ul ar l ocat i on. Ant i bodi es t o H. pyl ori det ect ed by enz yme-l i nked i mmunos orbent as s ay (ELISA) i ndi cat e act i ve or pri or i nfect i on. o

o

d. T reatment. Antibiotics are us ed t o t reat H. pyl ori i nfect i on. Regi mens t ypi cal l y i nvol ve combi nat i ons of an ant i bi ot i c (e.g., met roni dazol e, amoxi ci l l i n, t et racycl i ne preparat i ons , and cl ari t hromyci n), a bi s mut h-cont ai ni ng product , and a prot on pump i nhi bi t or (doubl e or t ri pl e t herapy). Treat ment i s for approxi mat el y 2 weeks , wi t h a 70%â€“90% res pons e rat e, dependi ng on t he regi men s el ect ed.

o

o

c. Outcome. St udi es have s hown a decreas ed rel aps e rat e i n duodenal ul cers t reat ed wi t h ant i bi ot i cs and bi s mut h as compared wi t h H 2 bl ockers .





5. Associated diseases. Some pat i ent s wi t h multiple endocrine neoplasia, type I (MEN I), pres ent wi t h gas t ri n-s ecret i ng t umors . Thi s probabl y account s for t he report ed as s oci at i on of duodenal ul cer di s eas e wi t h hyperparat hyroi di s m. Ot her di s eas es as s oci at ed wi t h gas t ri c ul cers i ncl ude ant ral at rophi c gas t ri t i s , rheumat oi d art hri t i s , chroni c obs t ruct i ve pul monary di s eas e (COPD), hepat i c ci rrhos i s , and chroni c renal fai l ure.





6. Psychosomatic factors i ncl ude chroni c anxi et y and â€œt ype Aâ€• pers onal i t y.

D. Clinical features Pa g e 9 2 0






1. Pain i s t he predomi nant s ympt om, al t hough i t may be abs ent i n 25% of gas t ri c ul cer pat i ent s . The pai n charact eri s t i cal l y i s des cri bed as an epi gas t ri c burni ng s ens at i on and may be accompani ed by bl oat i ng or naus ea. Eat i ng may exacerbat e t he pai n i n gas t ri c ul cer pat i ent s , whereas i n duodenal ul cer pat i ent s , t he pai n us ual l y i s di mi ni s hed by eat i ng, onl y t o recur 2â€“3 hours l at er. Pai n may awaken pat i ent s from s l eep, es peci al l y t hos e wi t h duodenal ul cers .





2. Upper gastrointestinal hemorrhage may be t he pres ent i ng s i gn of pept i c ul cer di s eas e, and anemi a from chroni c bl ood l os s may be s een.





3. Less common symptoms o

o

a. Repeated vomiting, whi ch may i ndi cat e gas t ri c out l et obs t ruct i on

o

o

b. Weight loss, whi ch i s s omewhat more common wi t h gas t ri c ul cer

E. Diagnosis Becaus e pat i ent s may compl ai n onl y of vague s ympt oms , a hi gh i ndex of s us pi ci on i s needed. 



1. Radiography i s a us eful s creeni ng t ool ; however, an upper gas t roi nt es t i nal s eri es may mi s s up t o 30% of gas t ri c ul cers , and s carri ng of t he duodenal bul b from chroni c or recurrent ul cer di s eas e may make radi ographi c

Pa g e 9 2 1


i nt erpret at i on di ffi cul t . Doubl e-cont ras t t echni ques may i mprove P.194

di agnos t i c accuracy. Duodenal ulcers always are benign; however, gastric ulcers may be benign or malignant. Radi ographi c cri t eri a for beni gn gas t ri c ul cers i ncl ude: o

o

a. Ul cer crat er ext endi ng beyond t he gas t ri c wal l

o

o

b. Gas t ri c fol ds radi at i ng i nt o t he bas e of t he ul cer

o

o

c. Thi ck radi ol ucent col l ar of edema (Hampt on's l i ne) s urroundi ng t he ul cer bas e

o

o

d. Smoot h, regul ar, round, or ovoi d ul cer crat er

o

o

e. Pl i abl e and normal l y di s t ens i bl e gas t ri c wal l i n t he area of t he ul cer





2. Endoscopy may be us ed as t he pri mary di agnos t i c maneuver or t o confi rm a radi ographi c di agnos i s . Becaus e 5% of gas t ri c ul cers t hat occur i n t he Uni t ed St at es are mal i gnant , many aut hors advocat e endos copy wi t h mul t i pl e bi ops i es at t he margi n of t he ul cer and s i mul t aneous cyt ol ogi c brus hi ngs for t he eval uat i on of al l gas t ri c ul cers , wi t h s ubs equent endos copy i n 6â€“8 weeks t o document heal i ng.



Pa g e 9 2 2


3. Gastric acid analysis may hel p di s t i ngui s h beni gn from mal i gnant gas t ri c ul cers . Becaus e beni gn ul cers rarel y exi s t i n t he s et t i ng of achl orhydri a, t he abs ence of aci d s houl d prompt furt her work-up wi t h gas t ri c bi ops i es and cyt ol ogi c s t udi es . Al t hough gas t ri c ul cers i n t he pres ence of achl orhydri a nearl y al ways are mal i gnant , mos t mal i gnant ul cers occur i n s t omachs wi t h normal aci d s ecret i on.





4. H. pylori detection. (s ee III C 4 c)

F. Therapy Treat ment i s vi rt ual l y t he s ame for es ophageal , gas t ri c, and duodenal ul cers . 



1. Intensive antacids, whi l e t hey have been s hown t o promot e t he heal i ng of gas t ri c and duodenal ul cers , are general l y of hi s t ori cal s i gni fi cance onl y.





2. H 2 -receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine), and proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole, and rabeprazole) are t he mai ns t ay of t reat ment becaus e of pat i ent conveni ence, s us t ai ned aci d reduct i on, and i ncreas ed heal i ng rat es wi t h di mi ni s hed rel aps e rat es â€”particularly in combination with antibiotics if H. pylori is present.





3. Antibiotics are us ed t o t reat H. pyl ori i nfect i on (s ee III C 4 d). Treat ment i s us ual l y wi t h amoxi ci l l i n, doxycycl i ne wi t h met roni dazol e, or cl ari t hromyci n i n combi nat i on wi t h a prot on pump i nhi bi t or and a bi s mut h preparat i on for 2 weeks .

Pa g e 9 2 3




4. Dietary factors may be of s ome i mport ance. There i s no proof t hat bl and di et s promot e heal i ng i n pept i c ul cer di s eas e. In fact , mi l k may be harmful becaus e i t i ncreas es aci d s ecret i on, probabl y by cal ci um- and prot ei n-s t i mul at ed gas t ri n rel eas e. Caffei ne and al cohol s t i mul at e gas t ri c aci d s ecret i on and, t herefore, s houl d be res t ri ct ed i n acut e cas es . Decaffei nat ed coffee al s o may s t i mul at e aci d rel eas e. Ul cer pat i ent s who s moke s houl d be urged t o s t op s moki ng.





5. Other therapeutic agents and approaches o

o

a. Sucralfate i s a nons ys t emi c agent t hat , i n t he pres ence of an aci d pH, coat s t he ul cer bed and promot es heal i ng. Sucral fat e i s as effect i ve as H 2 -recept or ant agoni s t s and ant aci ds and has no s i gni fi cant s i de effect s .

o

o

b. Bismuth has bot h ul cer-i ns ul at i ng and peps i n-i nact i vat i ng propert i es but does not decreas e gas t ri c aci d product i on. Heal i ng rat es are s l i ght l y bet t er i n gas t ri c t han i n duodenal ul cer pat i ent s , and t he overal l rat e of advers e react i on i s l ow. In H. pyl ori â€“as s oci at ed di s eas e, bi s mut h may caus e t he organi s ms t o di s l odge from gas t ri c epi t hel i al cel l s . Mi l k and ant aci ds may i nt erfere wi t h i t s act i on and s houl d be avoi ded for 1 hour before and aft er i nges t i on of bi s mut h.

o

o

c. Prostaglandin E 2 (PGE 2 ) and PGF 2 may have a cyt oprot ect i ve effect on gas t ri c mucos a. Thes e

Pa g e 9 2 4


agent s al s o i ncreas e gas t ri c bl ood fl ow and decreas e gas t ri n-s t i mul at ed aci d s ecret i on. A PGE 2 anal og, misoprostol, has been s hown t o be effect i ve i n t reat i ng pept i c ul cer di s eas e and has been rel eas ed for us e i n prevent i ng gas t ri c ul cers i n pat i ent s t aki ng NSAIDs . The major s i de effect s of pros t agl andi ns are di arrhea and naus ea. o

o

d. T ricyclic antidepressants (e.g., doxepi n) have proved effect i ve i n t reat i ng pept i c ul cers , probabl y becaus e of t hei r H 2 -recept or ant agoni s t effect s .





6. Gastric irradiation decreas es aci d product i on for approxi mat el y 1 year and may pl ay a rol e i n t reat i ng recurrent di s eas e i n el derl y pat i ent s who cannot t ol erat e drugs or s urgery.





7. Surgery i s effect i ve t herapy for pept i c ul cer di s eas e and reduces recurrence rat es . o

o

a. Procedures. The mos t commonl y performed operat i on i s distal subtotal gastrectomy, wi t h wedge res ect i on of a gas t ri c ul cer i f one i s pres ent . Vagotomy with drainage (V + D) and vagotomy with antrectomy (V + A) are t he us ual procedures for compl i cat ed pept i c ul cer di s eas e. V + D i s as s oci at ed wi t h a hi gher recurrence rat e (approxi mat el y 7%â€“15%) t han V + A (3%), but i t i s as s oci at ed wi t h l es s pos t operat i ve wei ght l os s . A proxi mal s el ect i ve vagot omy appears t o l es s en pos t operat i ve compl i cat i ons .

o

Pa g e 9 2 5


o

b. Indications. The hi gh i nci dence of pos t operat i ve compl i cat i ons , regardl es s of t he t ype of procedure, has l i mi t ed t he rol e of s urgery t o treatment of complications (i ncl udi ng acut e emergenci es ) and intractable cases.

G. Complications 



1. Hemorrhage occurs i n 20% of pat i ent s and i s t he mos t s eri ous compl i cat i on, havi ng a 10% mort al i t y rat e. If bl ood requi rement s exceed 3 U i n 24 hours for l onger t han 48â€“72 hours or i f i n-hos pi t al rebl eedi ng occurs , s urgi cal i nt ervent i on i s i ndi cat ed. Repeat ed bl eedi ng epi s odes occur i n approxi mat el y 30%â€“40% of cas es and may requi re s urgery.





2. Perforation occurs i n approxi mat el y 5%â€“10% of al l pept i c ul cers and i s far more common wi t h duodenal ul cers t han wi t h gas t ri c ul cers . Of ul cers t hat perforat e, 10% bl eed s i mul t aneous l y. Sympt oms and s i gns i ncl ude i nt ens e pai n, a ri gi d abdomen, decreas ed bowel s ounds , and di rect or rebound t endernes s . Thi s cat as t rophi c compl i cat i on i s confi rmed i n approxi mat el y 75%â€“85% of cas es by an erect abdomi nal radi ograph s howi ng free ai r under t he di aphragm. Mos t cas es requi re i mmedi at e s urgi cal i nt ervent i on, but s el ect ed pat i ent s have been t reat ed s ucces s ful l y wi t h nas ogas t ri c s uct i on and ant i bi ot i cs .





3. Gastric outlet obstruction occurs i n approxi mat el y 5%â€“10% of ul cer pat i ent s . Earl y s at i et y, epi gas t ri c ful l nes s , naus ea, and vomi t i ng of undi ges t ed food

Pa g e 9 2 6


(frequent l y i nges t ed s everal hours earl i er) s ugges t t he di agnos i s . W ei ght l os s i s common. Treat ment cons i s t s of nas ogas t ri c as pi rat i on for at l eas t 72 hours . Approxi mat el y 25%â€“40% of pat i ent s requi re s urgery becaus e 20%â€“40% of medi cal l y t reat ed pat i ent s have recurrent obs t ruct i on. P.195





4. Penetration i nt o an adjacent organ us ual l y i s a compl i cat i on of pos t eri or duodenal ul cers , wi t h penet rat i on i nt o t he pancreas . Pai n us ual l y i s s udden i n ons et and radi at es t o t he back. Serum amyl as e and l i pas e l evel s frequent l y are el evat ed. Treat ment i s s urgi cal .

H. Postsurgical complications 



1. Stomal ulceration aft er s urgery may i ndi cat e an unrecogni zed hypers ecret ory s t at e (e.g., Zol l i nger-El l i s on s yndrome, ret ai ned gas t ri c ant rum, or i ncompl et e vagot omy). The di agnos i s of a s t omal ul cer i s bes t made by endos copy. Treat ment i s wi t h l ong-t erm prot on pump i nhi bi t ors , and repeat s urgery may be neces s ary.





2. Afferent loop obstruction i s a rare compl i cat i on. The pat i ent us ual l y compl ai ns of bl oat i ng and vomi t i ng of a cl ear or bi l i ous mat eri al approxi mat el y 30â€“60 mi nut es aft er eat i ng. The di agnos i s i s s ugges t ed by t he fai l ure of oral l y i nges t ed bari um t o ent er t he l oop or by t he

Pa g e 9 2 7


ret ent i on i ns i de t he l oop of t echnet i um-i mi nodi acet i c aci d (Tc-HIDA), whi ch i s cl eared by t he l i ver and bi l i ary s ys t em aft er i nt ravenous i nject i on but does not ent er t he gas t roi nt es t i nal t ract . Bact eri al overgrowt h can occur, and s urgi cal revi s i on of t he afferent l oop may be neces s ary. 



3. Alkaline gastritis oft en i s s een endos copi cal l y i n pat i ent s who have undergone ant rect omy or s ubt ot al gas t rect omy. Gas t ri t i s oft en i s as ympt omat i c but may caus e naus ea, vomi t i ng, wei ght l os s , and epi gas t ri c pai n. Di agnos i s may be ai ded by meas urement of HIDA-l abel ed bi l e refl uxi ng back i nt o t he s t omach. Becaus e t he gas t ri t i s i s s econdary t o t hi s i ncreas ed refl ux of duodenal s ecret i ons i nt o t he s t omach, pat i ent s may requi re s urgery (a Roux-en-Y anas t omos i s ) t o di vert t hes e s ecret i ons furt her down t he gas t roi nt es t i nal t ract . Some cas es may be t reat ed effect i vel y wi t h s ubs t ances t hat bi nd bi l e aci ds (e.g., al umi num-cont ai ni ng ant aci ds and chol es t yrami ne) or wi t h s ucral fat e.





4. Dumping syndrome i s a nons peci fi c t erm t hat refers t o a vari et y of pos t prandi al s ympt oms . o

o

a. Early dumping syndrome occurs approxi mat el y 30 mi nut es aft er a meal and i s as s oci at ed wi t h di zzi nes s , fl us hi ng, di aphores i s , and pal pi t at i ons . Thes e s ympt oms have been as cri bed t o os mot i c s hi ft s of fl ui d or rel eas e of mas s i ve amount s of i nt es t i nal hormones as food empt i es rapi dl y from t he s t omach. The earl y dumpi ng s yndrome can be mi ni mi zed by decreas i ng t he carbohydrat e cont ent of meal s and by avoi di ng l i qui ds wi t h meal s .

Pa g e 9 2 8


Synt het i c s omat os t at i n has been us ed i n res i s t ant cas es . o

o

b. Late dumping syndrome occurs s everal hours aft er a meal and i s charact eri zed by di zzi nes s , weaknes s , and drows i nes s . Thi s s yndrome may be caus ed by react i ve hypogl ycemi a.





5. Nutritional problems o

o

a. Anemia occurs i n approxi mat el y 25% of pat i ent s aft er s urgery for pept i c ul cer di s eas e. Fact ors t hat may cont ri but e t o i ron defi ci ency i ncl ude l ow-grade bl ood l os s from al kal i ne pouch gas t ri t i s , di vers i on of i ron away from i t s preferent i al abs orpt i on s i t e (i .e., t he duodenum), and l ack of gas t ri c aci d needed for convers i on of i ron t o t he preferred form 3+

for abs orpt i on (i .e., Fe ). A l ack of i nt ri ns i c fact or l eads t o vi t ami n B 1 2 defi ci ency i n pat i ent s who have undergone a s ubs t ant i al gas t ri c res ect i on. o

o

b. Weight loss occurs i n approxi mat el y 50% of pos t operat i ve pat i ent s but i s not s evere unl es s a l arge gas t ri c res ect i on has been performed.

o

o

c. Significant steatorrhea us ual l y i ndi cat es a s econdary probl em (e.g., bact eri al overgrowt h or unmas ked cel i ac di s eas e), al t hough 50% of pat i ent s have an i ncreas e i n s t ool fat s econdary t o rapi d t rans i t and poor mi xi ng of food wi t h bi l e s al t s and pancreat i c enzymes .

o

Pa g e 9 2 9


o

d. Bone thinning may be due t o decreas ed abs orpt i on of vi t ami n D and cal ci um.





6. Gastric pouch cancer rat es are t wo t o four t i mes great er i n ul cer pat i ent s who have undergone s urgery t han i n pat i ent s whos e ul cers are t reat ed medi cal l y, es peci al l y 15â€“20 years aft er Bi l l rot h II gas t ri c res ect i on.

I. Zollinger-Ellison syndrome Zollinger-Ellison syndrome refers t o a nonâ€“Î² i s l et cel l t umor t hat produces gas t ri n and i s as s oci at ed wi t h gas t ri c aci d hypers ecret i on and pept i c ul cer di s eas e. The t umors are bi ol ogi cal l y mal i gnant i n 60% of cas es and mos t commonl y i nvol ve t he pancreas . Ot her t umor s i t es i ncl ude t he s t omach, duodenum, s pl een, and l ymph nodes . Tumor s i ze vari es from 2 mm t o 20 cm. Approxi mat el y 10% of t he pat i ent s wi t h Zol l i nger-El l i s on s yndrome have a res ect abl e l es i on. 




o

a. Pain from pept i c ul cer di s eas e i s common i n Zol l i nger-El l i s on s yndrome. In approxi mat el y 75% of cas es , t he ul cers are l ocat ed i n t he duodenal bul b. The remai ni ng cas es i nvol ve ul cers i n t he di s t al duodenum or jejunum or ul cers i n mul t i pl e l ocat i ons .

o

o

b. Diarrhea occurs i n approxi mat el y 50% of cas es becaus e of gas t ri c aci d hypers ecret i on. The hi gh aci d l evel s may damage t he s mal l i nt es t i nal mucos a, i nact i vat e pancreat i c l i pas e, and

Pa g e 9 3 0


preci pi t at e bi l e aci ds , caus i ng s t eat orrhea. The hi gh gas t ri n l evel s caus e i ncompl et e Na

+

and wat er

abs orpt i on and i ncreas e i nt es t i nal mot i l i t y. In addi t i on, t he vol ume of gas t ri c s ecret i on al one may caus e di arrhea. o

o

c. Endocrine abnormalities are common. Approxi mat el y 20% of t hes e pat i ent s have hyperparat hyroi di s m. Pi t ui t ary, adrenal , ovari an, and t hyroi d t umors al s o have been report ed wi t h Zol l i nger-El l i s on s yndrome. A di s t i nct s yndrome of pancreat i c, pi t ui t ary, and parat hyroi d t umors (i .e., MEN I) s hows an aut os omal domi nant pat t ern of i nheri t ance.





2. Diagnosis o

o

a. Gastrin levels. Pat i ent s demons t rat e el evat ed bas al -s t at e gas t ri n l evel s t hat do not i ncreas e 1 hour aft er a meal . Gas t ri n l evel s i ncreas e (rat her t han decl i ne) by 200 U aft er i nt ravenous s ecret i n admi ni s t rat i on and ri s e markedl y (rat her t han modes t l y) aft er i nt ravenous cal ci um admi ni s t rat i on.

o

o

b. Gastric acid output. Pat i ent s wi t h Zol l i nger-El l i s on s yndrome oft en have bas al gas t ri c aci d out put rat es of more t han 10 mEq/hour and bas al -t o-peak out put rat i os of great er t han 0.6.

o

o

c. Angiography. Becaus e gas t ri n-s ecret i ng t umors may be hi ghl y vas cul ar, angi ography may be hel pful .

Pa g e 9 3 1




3. T herapy o

o

a. Surgical treatment 



(1) T otal gastrectomy i s t he t radi t i onal t herapy. The 10-year s urvi val rat e of 50% wi t h t hi s procedure i s t hought t o be at t ri but abl e pri mari l y t o t he s l ow-growi ng nat ure of t hi s l es i on. Mos t of t he l at e deat hs are caus ed by met as t at i c di s eas e.





(2) T umor localization, whi ch i nvol ves s ampl i ng gas t ri n l evel s t hrough cannul at i on of mul t i pl e pancreat i c and abdomi nal vei ns , may be us eful . Thi s t echni que offers t he hope of s urgi cal cure i n cas es of mul t i pl e pri mary t umors and i n cas es i nvol vi ng a t umor t hat i s t oo s mal l t o be vi s ual i zed by ordi nary means .

o

o

b. Medical treatment 



(1) Proton pump inhibitors are t he medi cal t reat ment of choi ce and may requi re hi gh-dos e t herapy, dependi ng on t he res pons e t o aci d-s uppres s i ve t herapy us i ng gas t ri c anal ys i s for document at i on of aci d s uppres s i on.





(2) H 2 -recept or ant agoni s t s i n combi nat i on

Pa g e 9 3 2


wi t h anticholinergic agents have been us ed, es peci al l y i n conjunct i on wi t h a V + D procedure. Pat i ent s who have been unres pons i ve t o H 2 -recept or bl ockade may become res pons i ve as a res ul t of s urgery.

J. Other disorders of the stomach 



1. Portal hypertensive gastropathy i s t he t erm gi ven t o di ffus e s ubmucos al di l at at i on of gas t ri c ves s el s t hat may rupt ure. It account s for upper gas t roi nt es t i nal bl eedi ng i n approxi mat el y 10% of pat i ent s wi t h port al hypert ens i on. A di ffus e but i rregul ar pat t ern of red s pot s or l i near s t reaks produces a charact eri s t i c pat t ern at endos copy. Treat ment wi t h Î²-bl ockade or bi cap (el ect rocaut ery) or l as er t herapy t o t he gas t ri c wal l may decreas e rebl eedi ng.





2. Dieulafoy' s ulcer i s a di ffi cul t -t o-di agnos e vas cul ar l es i on general l y s een i n t he gas t ri c fundus . Thi s ul cer may be a caus e of s i gni fi cant recurrent upper gas t roi nt es t i nal bl eedi ng. Men ol der t han 50 years of age are mos t commonl y affect ed. The l es i on appears as an expos ed art eri al defect wi t h no or mi ni mal mucos al ul cerat i on. Endos copy wi t h l as er or bi cap t reat ment i s effect i ve i n s t oppi ng t he bl eedi ng, but angi ography or s urgery i s oft en neces s ary becaus e of t he di ffi cul t y of i dent i fyi ng t he s mal l vas cul ar defect duri ng endos copy.

IV. Diseases of the Small Intestine A. Intestinal obstruction Intestinal obstruction i s a t erm us ed t o denot e fai l ure of pas s age of i nt es t i nal cont ent s and may be due t o mechani cal obs t ruct i on or adynami c i l eus .

Pa g e 9 3 3




1. Mechanical obstruction o

o

a. Etiology 



(1) Extrinsic causes: Adhes i ons from pri or s urgery, i ncarcerat ed herni a, met as t at i c t umors , vol vul us , endomet ri os i s , and NSAID-i nduced s t ri ct ures (oft en mul t i pl e)





(2) Intramural causes: Hemat omas from t rauma, s t ri ct ures , and i nt ramural t umors





(3) Intraluminal causes: Epi t hel i al t umors (es peci al l y col oni c), i nt us s us cept i on, and forei gn bodi es

o

o




(1) Crampy pai n t hat waxes and wanes i n i nt ens i t y





(2) Hi gh-pi t ched bowel s ounds wi t h rus hes and t i nkl es





(3) Cons t i pat i on and obs t i pat i on





(4) Vomi t i ng, whi ch i s more promi nent i n

Pa g e 9 3 4


proxi mal i nt es t i nal obs t ruct i on 



(5) Di s t ent i on, whi ch i s more promi nent i n di s t al i nt es t i nal obs t ruct i on





(6) Int es t i nal i s chemi a, l eadi ng fi rs t t o edema, t hen t o pet echi al hemorrhages , and fi nal l y t o necros i s and gangrene (Thi s i s s econdary t o i ncreas ed i nt ral umi nal pres s ure occurri ng aft er 6â€“12 hours of obs t ruct i on, when abs orpt i on ceas es and s ecret i on commences .)

o

o

c. Diagnosis us ual l y i s made wi t h pl ai n and upri ght abdomi nal radi ographs . Charact eri s t i c ai r-fl ui d l evel s exi s t above t he area of obs t ruct i on, and no ai r i s s een i n t he rect um. A bari um enema may be us eful i n di agnos i ng col oni c obs t ruct i on. Refl ux of bari um i nt o t he s mal l bowel al s o may be hel pful i n t he di agnos i s of l ow s mal l bowel obs t ruct i on.

o

o

d. T herapy 



(1) Repl acement of fl ui d and el ect rol yt es





(2) Int es t i nal decompres s i on wi t h nas ogas t ri c s uct i on or s mal l bowel i nt ubat i on





(3) Surgery, whi ch us ual l y i s requi red for defi ni t i ve t reat ment of t he underl yi ng probl em

Pa g e 9 3 5


P.196





2. Adynamic, or paralytic, ileus i s a nonobs t ruct i ve l ack of propul s i on t hrough t he i nt es t i nal t ract . o

o

a. Etiology. Adynami c i l eus commonl y i s l i nked t o t he fol l owi ng condi t i ons : 



(1) Recent abdomi nal s urgery, whi ch res ul t s i n i l eus t hat us ual l y i s t rans i ent (l as t i ng 2â€“3 days )





(2) El ect rol yt e i mbal ance, es peci al l y hypokal emi a





(3) Chemi cal or bact eri al peri t oni t i s





(4) Severe i nt ra-abdomi nal i nfl ammat i on s uch as pancreat i t i s and chol ecys t i t i s





(5) Sys t emi c i l l nes s s uch as pneumoni a

o

o

b. Clinical features. Phys i cal exami nat i on s hows a di s t ended abdomen and di mi ni s hed bowel s ounds .

o

o

c. Diagnosis. Radi ographs s how di ffus e i nt es t i nal gas and ai r i n t he rect um wi t hout ai r fl ui d l evel s .

Pa g e 9 3 6


o

d. T herapy 



(1) Bowel res t and pl acement of a nas ogas t ri c t ube





(2) Correct i on of underl yi ng caus es





(3) Int ravenous neos t i gmi ne (wi t h careful cardi ac moni t ori ng) may be us ed i n res i s t ant cas es wi t h careful cardi ac moni t ori ng.

B. Intestinal pseudo-obstruction Intestinal pseudo-obstruction i s a rare but i mport ant ent i t y charact eri zed by apparent l y recurrent epi s odes of mechani cal obs t ruct i on but wi t h no demons t rabl e s ource of obs t ruct i on. 



1. Classification. o

o

a. Secondary pseudo-obstruction. Ps eudo-obs t ruct i on occurs s econdary t o many condi t i ons t hat affect ei t her t he s moot h mus cl e of t he gas t roi nt es t i nal t ract or t he neurol ogi c and hormonal cont rol of i nt es t i nal mot i l i t y. 



(1) Underl yi ng di s eas es t hat i nvol ve t he s moot h mus cl e i ncl ude col l agen vas cul ar di s eas e (es peci al l y s cl eroderma), amyl oi dos i s , and myot oni c dys t rophy.



Pa g e 9 3 7


(2) Underl yi ng neurol ogi c di s eas es i ncl ude Chagas ' di s eas e, Parki ns on's di s eas e, and Hi rs chs prung's di s eas e.





(3) Underl yi ng endocri ne di s orders i ncl ude hypot hyroi di s m, di abet es mel l i t us , hypoparat hyroi di s m, and pheochromocyt oma.





(4) Drugs t hat depres s i nt es t i nal s moot h mus cl e funct i on i ncl ude phenot hi azi nes , t ri cycl i c ant i depres s ant s , gangl i oni c bl ockers , and cl oni di ne.





(5) Nont ropi cal s prue and ceroi d depos i t s i n t he bowel (mahogany bowel ) are rare caus es of ps eudo-obs t ruct i on.

o

o

b. Primary pseudo-obstruction. There are t wo forms of t hi s condi t i on. 



(1) Heredi t ary hollow visceral myopathy i s a vacuol i zat i on and at rophy of i nt es t i nal s moot h mus cl e. Thi s di s order, whi ch i s t rans mi t t ed as an aut os omal domi nant t rai t , al s o affect s es ophageal and uri nary t ract s moot h mus cl e.





(2) An autonomic nervous system abnormality has been des cri bed i n s ome fami l i es wi t h pri mary ps eudo-obs t ruct i on. There may be a decreas e i n t ot al myent eri c pl exus neurons or neuronal eos i nophi l i c

Pa g e 9 3 8


i nt ranucl ear i ncl us i ons . Pos s i bl e s ympt oms i ncl ude ort hos t at i c hypot ens i on, at axi c gai t , dys art hri a, and abs ent deep t endon refl exes . o

o

2. Diagnosis. Ri gorous excl us i on of caus es of mechani cal obs t ruct i on wi t h document at i on of abnormal mot i l i t y i s neces s ary. 



a. Esophageal manometry s howi ng normal or l ow LES pres s ure wi t h decreas ed ampl i t ude of peri s t al s i s di s t al l y i ndi cat es t he s moot h mus cl e vacuol i zat i on t ype of ps eudo-obs t ruct i on. Incompl et e rel axat i on of t he LES wi t h abs ent peri s t al s i s and repet i t i ve es ophageal cont ract i ons may i ndi cat e an aut onomi c nervous s ys t em abnormal i t y.





b. Radionuclide gastric emptying scans may s how del ayed empt yi ng.





c. Barium studies yi el d nons peci fi c fi ndi ngs . Mos t pat i ent s s how di l at ed areas of t he i nt es t i ne.

o

o

3. T herapy. Treat ment i s s upport i ve duri ng acut e exacerbat i ons . Chol i nergi c agent s and proki net i c agent s have been us ed wi t h l i mi t ed s ucces s , and s urgery s houl d be avoi ded. Home parent eral hyperal i ment at i on may be requi red for nut ri t i onal s upport . Int es t i nal s t as i s wi t h bact eri al overgrowt h s houl d be t reat ed wi t h ant i bi ot i cs .

Pa g e 9 3 9


C. Small bowel diverticula 



1. Duodenal diverticula us ual l y are found i nci dent al l y duri ng an upper gas t roi nt es t i nal s eri es , at endos copy, or at aut ops y. They occur mos t frequent l y i n t he proxi mal duodenum, wi t hi n 1â€“2 cm of t he ampul l a of Vat er, and are as ympt omat i c i n mos t pat i ent s , al t hough duodenal di vert i cul a may rarel y caus e upper gas t roi nt es t i nal bl eedi ng. In s ome cas es , t he common bi l e duct empt i es di rect l y i nt o t he di vert i cul um, and common bi l e duct obs t ruct i on may occur becaus e of anat omi c i nt erference wi t h empt yi ng.





2. Jejunal diverticula probabl y are acqui red rat her t han congeni t al and us ual l y are as ympt omat i c. Jejunal di vert i cul a may l ead t o mal abs orpt i on s econdary t o bi l e s al t deconjugat i on when s t as i s i s s uffi ci ent t o al l ow an i ncreas e i n s mal l bowel bact eri a. Thi s l eads t o di arrhea, s t eat orrhea, wei ght l os s , and anemi a. Hypochl orhydri a or achl orhydri a al s o may be pres ent . Cont i nuous or al t ernat i ng ant i mi crobi al t herapy oft en correct s mal abs orpt i on, al t hough s urgi cal removal of mul t i pl e di vert i cul a or of a s i ngl e l arge di vert i cul um may be neces s ary i n refract ory cas es .





3. Meckel' s diverticulum i s a common congeni t al s t ruct ural defect t hat repres ent s t he remnant of t he vi t el l i ne duct . It i s found i n approxi mat el y 2% of aut ops i es and us ual l y i s l ocat ed i n t he t ermi nal i l eum wi t hi n 60 cm of t he i l eocecal val ve. Meckel 's di vert i cul a average 5â€“7 cm i n l engt h and may be qui t e l arge. Approxi mat el y one-t hi rd of Meckel 's di vert i cul a cont ai n

Pa g e 9 4 0


gas t ri c mucos a, whi ch may produce aci d. Di vert i cul i t i s , ul cerat i on, bl eedi ng, perforat i on, and obs t ruct i on are compl i cat i ons t hat requi re s urgi cal i nt ervent i on and frequent l y mi mi c t he s ympt oms of acut e appendi ci t i s . Becaus e of t he pres ence of gas t ri c mucos a, t he di agnos i s s omet i mes can be made by means of pert echnet at e s canni ng aft er H 2 -recept or bl ockade.

D. Diarrhea Diarrhea i s defi ned as an i ncreas e i n s t ool frequency and vol ume. The s t ool us ual l y i s l i qui d, and 24-hour out put exceeds 250 g. Pat i ent s may experi ence l ower abdomi nal crampy pai n and fecal urgency. 



1. Classification. Pat hophys i ol ogi c cri t eri a are us ed t o cl as s i fy di arrhea as one of t hree di s t i nct t ypes . o

o

a. Secretory diarrhea 



(1) Pathophysiology. Secret ory di arrhea occurs when t he s ecret i on of fl ui d and el ect rol yt es i s i ncreas ed or when t he normal abs orpt i ve capaci t y of t he bowel i s decreas ed. 



(a) Agent s t hat act i vat e t he adenyl cycl as eâ€“cycl i c adenos i ne 3â€²,5â€²-monophos phat e (cAMP) s ys t em i ncl ude chol era t oxi n, heat -l abi l e Es c heri c hi a c ol i t oxi n, Sal monel l a ent erot oxi n, and vas oact i ve i nt es t i nal pept i de (VIP).



Pa g e 9 4 1


(b) Agent s t hat probabl y do not act i vat e t he adenyl cycl as eâ€“cAMP s ys t em i ncl ude heat -s t abl e E. c ol i t oxi n, a vari et y of ot her bact eri al ent erot oxi ns (e.g., t hos e produced by Cl os t ri di um perfri ngens , Ps eudomonas aerugi nos a, and Kl ebs i el l a pneumoni ae), cas t or oi l , and phenol pht hal ei n.





(c) Chroni c s ecret ory di arrhea i s s een i n t he pancreat i c chol era s yndrome wi t h VIP s ecret i on, i n medul l ary carci noma of t he t hyroi d gl and wi t h cal ci t oni n s ecret i on, i n carci noi d s yndrome wi t h s erot oni n s ecret i on, and i n vi l l ous adenoma of t he rect um.





(2) Diagnosis. Pers i s t ent di arrhea i n t he abs ence of food i nt ake or t he pres ence of a +

s t ool os mot i c gap [St ool os mol ari t y - 2(Na + +

K 3500 cGy), az at hi opri ne t herapy, or i nges t i on of cert ai n t ypes of Jamai can t ea. Aft er bone marrow t rans pl ant at i on (BMT), veno-occl us i ve di s eas e i s s een i n approxi mat el y 20% of pat i ent s . o

o

c. Complications of cirrhosis. 



(1) Ascites 



(a) Pathogenesis. Increas ed back-pres s ure i nt o capi l l ari es as wel l as decreas ed oncot i c pres s ure as t he res ul t of decreas ed al bumi n s ynt hes i s al l ows accumul at i on of a t rans udat i ve P.227

fl ui d i n t he peri t oneal cavi t y. In addi t i on, i ncreas ed ci rcul at i ng al dos t erone (pos s i bl y s econdary t o al t ered l i ver met abol i s m) cont ri but es t o Na

+

and wat er ret ent i on.





(b) Diagnosis. If fl ui d accumul at i on i s l arge, di agnos i s may be obvi ous on phys i cal exami nat i on. Ul t ras onography i s effect i ve for det ect i ng s mal l amount s of fl ui d. Paracent es i s , whi ch may requi re gui dance t hrough ul t ras onography, yi el ds a s t raw-col ored fl ui d wi t h l es s t han 2.5 g/dL prot ei n, a W BC count of l es s t han 3

300/mm (us ual l y mononucl ear), a normal gl ucos e l evel , and a l ow s erum amyl as e

Pa g e 1 0 9 6


l evel . A s erum al bumi nâ€“as ci t es gradi ent (SAAG) great er t han 1.1 g/dL i s i ndi cat i ve of port al hypert ens i on. 



(c) T herapy. Treat ment i s bas ed on s odi um res t ri ct i on Fl ui d res t ri ct i on may be neces s ary i f hyponat remi a devel ops . Al dos t erone ant agoni s t s (e.g., s pi ronol act one) and l oop di uret i cs (e.g., furos emi de) are us ed i f i ni t i al meas ures fai l . Large-vol ume paracent es i s can be us ed. If t here i s concern for hypot ens i on or fl ui d s hi ft s , al bumi n can be gi ven peri procedural l y. Some s t udi es s ugges t t hat 10 g of al bumi n for each 1 L of as ci t i c fl ui d removed i s effect i ve. Surgi cal s hunt i ng (Le Veen or Denver s hunt ) may be us eful i n recal ci t rant cas es , but bact eremi a and di s s emi nat ed i nt ravas cul ar coagul at i on (DIC) are pot ent i al compl i cat i ons of t hes e s hunt s . Pl acement of a TIPS t o connect t he hepat i c and port al vei ns can reduce port al hypert ens i on and rel i eve as ci t es .





(d) Complications. Res pi rat ory compromi s e and rupt ure of an umbi l i cal herni a may occur i n cas es of mas s i ve as ci t es . Infect i on of even a s mal l amount of fl ui d (e.g., due t o s pont aneous bact eri al peri t oni t i s ) can be fat al .



Pa g e 1 0 9 7


(2) Varices occur as a res ul t of t he devel opment of col l at eral ves s el s t hat bypas s t he obs t ruct ed l i ver. Vari ces are common i n t he es ophagus and s omewhat l es s common i n t he s t omach, duodenum, and hemorrhoi dal pl exus . Portal hypertensive gastropathy i nvol ves di l at i on of venous and capi l l ary ves s el s i n t he mucos a and s ubmucos a wi t h mi ni mal i nfl ammat ory i nfi l t rat e (s ee III J 1). Affect ed pat i ent s may s uffer bl eedi ng from t he mucos al l i ni ng of t he s t omach i t s el f. In mos t pat i ent s , port al decompres s i on res ul t s i n a decreas e of port al hypert ens i ve gas t ropat hy and ces s at i on of bl eedi ng. 



(a) Diagnosis of es ophagogas t ri c vari ces may be s ugges t ed by an upper gas t roi nt es t i nal s eri es but i s bes t made by endos copy. Endos copy i s es s ent i al i n t he acut el y bl eedi ng pat i ent becaus e t he mort al i t y rat e i s hi gh (40%â€“50% for each epi s ode of bl eedi ng), and earl y t reat ment can be l i fes avi ng.





(b) Short-term therapy wi t h oct reot i de by cont i nuous i nt ravenous i nfus i on i s effect i ve i n 60%â€“70% of pat i ent s . Bal l oon t amponade wi t h a Sengs t aken-Bl akemore t ube cont rol s bl eedi ng i n 80% of pat i ent s , but i s as s oci at ed wi t h a ri s k of as pi rat i on and es ophageal rupt ure. Emergency s urgery has a 50% mort al i t y rat e. Endos copi c band l i gat i on or s cl erot herapy i s

Pa g e 1 0 9 8


effect i ve i n approxi mat el y 80%â€“90% of acut e cas es . A TIPS can s t op vari ceal bl eedi ng. 



(c) Long-term therapy t o reduce t he chance of rebl eedi ng i ncl udes repeat endos copi c band l i gat i on or s cl erot herapy t o obl i t erat e al l vari ces and nons el ect i ve Î²-adrenergi c bl ockers (e.g., propranol ol and nadol ol ) t o reduce port al pres s ure. Surgi cal port al decompres s i on does not i ncreas e s urvi val rat es becaus e t here i s i ncreas ed encephal opat hy and l i ver fai l ure. Li ver t rans pl ant at i on i s res erved for good-ri s k al cohol -abs t i nent i ndi vi dual s .





(3) Portosystemic encephalopathy i s a revers i bl e neurol ogi c s yndrome charact eri zed by mood changes , confus i on, drows i nes s , di s ori ent at i on, and coma. 



(a) Etiology. The pri mary caus e of hepat i c encephal opat hy i s uncl ear. El evat ed ammoni a l evel s are found i n t he bl ood. However, more recent l y, fal s e neurot rans mi t t ers and el evat ed l evel s of mercapt ans and fat t y aci ds have been i mpl i cat ed. Increas ed l evel s of endogenous benzodi azepi ne s ubs t ances may be not ed. In addi t i on, i ncreas ed l evel s of aromat i c ami no aci ds and decreas ed l evel s of branched-chai n

Pa g e 1 0 9 9


ami no aci ds are found i n t he bl ood, brai n, and uri ne. Secondary caus es of hepat i c encephal opat hy are t hought t o i ncl ude: 



(i) Azot emi a, due t o i ncreas ed ni t rogen l oad





(ii) Increas ed product i on of ammoni a or i ncreas ed prot ei n l oad due t o cons t i pat i on, i ncreas ed di et ary prot ei n, or gas t roi nt es t i nal bl eed





(iii) Infect i on, whi ch l eads t o i ncreas ed t i s s ue cat abol i s m and i ncreas ed prot ei n l oad





(iv) Sedat i ves , whos e di rect depres s ant effect on t he brai n i s compounded by decreas ed hepat i c cat abol i s m of t he drugs P.228





(v) El ect rol yt e abnormal i t i es i ncl udi ng hypokal emi a and al kal os i s , whi ch l ead t o i mpai red renal excret i on of ammoni a and t o i ncreas ed t rans fer of ammoni a acros s t he bl oodâ€“brai n barri er

Pa g e 1 1 0 0




(b) T herapy. Treat ment i ncl udes revers al of any of t he s econdary caus es . In addi t i on, t he fol l owi ng meas ures may be effect i ve. 



(i) Lact ul os e effect i vel y decreas es col oni c pH and t raps ammoni um i on +

(NH 4 ) i n t he gas t roi nt es t i nal t ract . It al s o i s an effect i ve cat hart i c. 



(ii) Ant i bi ot i cs s uch as met roni dazol e, ri faxi mi n, and neomyci n may decreas e i nt es t i nal fl ora t hat convert gas t roi nt es t i nal prot ei ns i nt o ammoni a.





(iii) Di et ary prot ei n s houl d be l i mi t ed t o l es s t han 40 g/day i f ot her meas ures are i neffect i ve.





(iv) The us e of branched-chai n ami no aci ds , al t hough academi cal l y appeal i ng, may not i mprove encephal opat hy.





(v) Predi s pos i ng fact ors (e.g., hypokal emi a, cons t i pat i on, and al kal os i s ) s houl d be correct ed.



Pa g e 1 1 0 1


(4) Hepatorenal syndrome i s a progres s i ve renal fai l ure t hat occurs i n pat i ent s wi t h s evere l i ver di s eas e. It i s a funct i onal renal fai l ure becaus e t he ki dneys are morphol ogi cal l y normal and funct i on wel l when t rans pl ant ed i nt o normal reci pi ent s . The mort al i t y rat e i s 90%â€“100%. 



(a) Etiology. Al t hough t he exact mechani s m of hepat orenal s yndrome i s not known, s everal fact ors are i mpl i cat ed, i ncl udi ng: 



(i) Afferent art eri ol ar vas ocons t ri ct i on, whi ch l eads t o i ncreas ed renal vas cul ar cons t ri ct i on





(ii) Rel at i ve s hunt i ng of bl ood from t he cort ex t o t he medul l a of t he ki dney





(iii) Decreas ed gl omerul ar fi l t rat i on rat e (GFR)





(iv) Decreas ed renal bl ood fl ow





(b) Diagnosis. The combi nat i on of 3

ol i guri a (i .e., uri ne out put 20,000/mm ), s erum t rans ami nas e l evel s , and s erum bi l i rubi n l evel s . Serum al kal i ne phos phat as e l evel s are abnormal i n approxi mat el y 80% of affect ed i ndi vi dual s . 



(3) Diagnosis. Demons t rat i on of a fi l l i ng defect i n t he l i ver t hrough t he us e of

Pa g e 1 1 0 6


ul t ras onography, CT, or MRI i s s ugges t i ve of t he di agnos i s . As pi rat i on of a cys t i c cavi t y may reveal â€œanchovy pas t eâ€• fl ui d wi t h t rophozoi t es . Serol ogi c t es t s (e.g., i ndi rect hemaggl ut i nat i on i nhi bi t i on and gel di ffus i on t es t s ) are pos i t i ve i n 95% of cas es . 



(4) T herapy. Amebi ci des (e.g., met roni dazol e, chl oroqui ne, and di i odohydroxyqui n) may be effect i ve al one or may be combi ned wi t h CT or ul t ras ound-di rect ed as pi rat i on of t he abs ces s cavi t y. Li ver s canni ng s houl d be cont i nued unt i l heal i ng occurs .





(5) Complications. Rupt ure of t he cys t i nt o t he pl eural s pace, l ung, bowel , and ret roperi t oneum may occur. Rarel y, a cys t ext ends t o t he body s urface

o

o

c. Focal hepatic candidiasis i s an ent i t y cons i s t i ng of hepat i c and s pl eni c granul omas cont ai ni ng Candi da al bi c ans hyphae i n i mmunocompromi s ed hos t s . Mos t pat i ent s have previ ous l y recei ved cyt os i ne arabi nos i de for acut e l eukemi a. 



(1) Clinical features i ncl ude a fever of unknown ori gi n i n i mmunocompromi s ed hos t s . Si gns of oropharyngeal candi di as i s may be pres ent , and t here may be ri ght upper quadrant pai n or t endernes s .



Pa g e 1 1 0 7


(2) Diagnosis i s made by liver biopsy. At l aparot omy or l aparos copy, s mal l whi t e nodul es l es s t han 5 mm i n wi dt h are s een. Li ver funct i on abnormal i t i es i ncl ude modes t bi l i rubi n and enz yme el evat i on wi t h an i ncreas e i n al kal i ne phos phat as e.





(3) T herapy i nvol ves s ys t emi c amphot eri ci n B, oft en i n conjunct i on wi t h fl uconazol e.





4. Hepatic cysts o

o

a. Solitary cysts, general l y found i n t he ri ght l obe of t he l i ver, us ual l y are as ympt omat i c but may caus e pai n and fever s econdary t o bl eedi ng, i nfect i on, or rupt ure.

o

o

b. Polycystic liver disease i s t he pres ence of mul t i pl e cys t s t hat range from s everal mi l l i met ers t o great er t han 10â€“15 cm i n di amet er. Li ke s ol i t ary cys t s , mos t cys t s i n pol ycys t i c l i ver di s eas e are as ympt omat i c except i n cas es i nvol vi ng hemorrhage, i nfect i on, or rupt ure. Renal cys t s are found i n 50% of pat i ent s ; cys t s al s o may be found i n t he pancreas , s pl een, and l ungs . Res ul t s of l i ver funct i on t es t i ng us ual l y are normal , al t hough mi l d el evat i on of s erum al kal i ne phos phat as e l evel s may be s een. Surgi cal as pi rat i on or decompres s i on occas i onal l y i s neces s ary.

o

o

c. Hydatid cysts are mos t common i n i ndi vi dual s who l i ve i n Greece, France, It al y, t he Mi ddl e Eas t ,

Pa g e 1 1 0 8


Sout h Ameri ca, and Icel and. Thi s di s eas e may be found el s ewhere i n t he des cendant s of i ndi vi dual s from t hes e regi ons . 



(1) Etiology. Hydat i d cys t s are formed when t he i nfect i ng organi s m (i .e., Ec hi noc oc c us granul os us or Ec hi noc oc c us mul t i l oc ul ari s ) i s i nges t ed and t ravel s t hrough t he port al ci rcul at i on t o t he l i ver.





(2) Clinical features. The cys t us ual l y enl arges for 10â€“20 years aft er t he i ni t i al i nfect i on before becomi ng s ympt omat i c. There i s cal ci fi cat i on of a s ol i t ary cys t (s een i n 50% of pat i ent s ) and t he pres ence of daught er cys t s wi t hi n a l arger cys t .





(3) Diagnosis. Di agnos i s i s made by pos i t i ve compl ement fi xat i on or i ndi rect hemaggl ut i nat i on t es t s . Eos i nophi l i a i s occas i onal l y s een. Li ver bi ops y and as pi rat i on are not s ugges t ed becaus e l eakage may caus e fat al anaphyl axi s .





(4) T herapy. Treat ment may be s urgi cal . Recent l y, ul t ras ound-gui ded i nject i on of al cohol i nt o cys t cavi t i es has been us ed.





(5) Complications. Rupt ure, i nfect i on, hemorrhage, and s l ow l eakage caus i ng al l ergi c mani fes t at i ons may devel op.

o

Pa g e 1 1 0 9


d. Peliosis hepatis i s a rare condi t i on i nvol vi ng mul t i pl e bl ood-fi l l ed hepat i c cys t s .

See onl i ne for more i nformat i on. The

l i ver oft en has a mot t l ed bl ue appearance. Rupt ure wi t h bl eedi ng may be fat al . There i s an as s oci at i on bet ween t hi s condi t i on and t ubercul os i s , t herapy wi t h androgeni c s t eroi ds , and t he us e of oral cont racept i ves . There i s al s o an as s oci at i on wi t h AIDS pat i ent s , es peci al l y t hos e wi t h angi omat os i s (Roc henel l i a). Progres s i ve hepat omegal y wi t h l i ver fai l ure may occur. CT s canni ng may s how mul t i pl e defect s . Percut aneous l i ver bi ops y s hows charact eri s t i c changes but i s dangerous becaus e of t he vas cul ar nat ure of t he l es i ons . 



5. Granulomatous hepatitis o

o

a. Etiology. Granul omat ous hepat i t i s mos t oft en i s s econdary t o s ys t emi c i nfect i ons (e.g., t ubercul os i s ), s arcoi dos i s , fungal i nfect i ons , s yphi l i s , and vi ral i nfect i ons (e.g., i nfect i ous mononucl eos i s , CMV i nfect i on, and vari cel l a). Q fever, paras i t i c di s eas es , MAC (es peci al l y i n HIV-i nfect ed pat i ent s ), Hodgki n's di s eas e, and beryl l i um t oxi ci t y al s o may caus e granul omat ous hepat i t i s . In addi t i on, granul omat ous hepat i t i s may be a mani fes t at i on of drug react i ons i nvol vi ng s ul fa drugs , hydral azi ne, or al l opuri nol . Occas i onal l y, no caus e can be found. P.230

o

o

b. Clinical features. Sympt oms i ncl ude weaknes s , fat i gue, markedl y i ncreas ed eryt hrocyt e s edi ment at i on rat e, and fever.

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o

c. Diagnosis. Li ver bi ops y i s us ed t o make t he di agnos i s .

o

o

d. T herapy. Treat ment of t he s econdary form i ncl udes wi t hdrawal of t he offendi ng agent and t reat ment of t he underl yi ng l es i on. The i di opat hi c form may res pond t o cort i cos t eroi d t herapy.

C. Systemic diseases with prominent liver involvement 

1. Î± 1 -Antitrypsin deficiency i s a genet i c defect of t he gl ycoprot ei n t hat normal l y i nhi bi t s prot eol yt i c enzymes s uch as t ryps i n, chymot ryps i n, and el as t as e.

See onl i ne for more

i nformat i on. There are 24 al l el es i n t he prot eas e i nhi bi t or (Pi ) s ys t em. Ni net y percent of t he popul at i on of t he Uni t ed St at es i s genot ype Pi MM. The 22 genot ype i s homoz ygous for t he di s eas e s t at e, and pat i ent s have l es s t han 20% of normal s erum l evel s of Î± 1 -ant i t ryps i n. Indi vi dual s wi t h genot ype Pi MZ have approxi mat el y 50%â€“60% of normal l evel s . Homozygot es (Pi ZZ) us ual l y have l i ver di s eas e i n chi l dhood. Li ver di s eas e may devel op i n Pi SZ or Pi MZ het eroz ygot es , es peci al l y t hos e who s moke, and COPD may devel op i n t hes e i ndi vi dual s as adul t s (s ee Chapt er 2 II B). Di s eas e does not devel op i n al l i ndi vi dual s wi t h t he abnormal genot ypes . Di agnos i s i s made bas ed on a decreas ed Î± 1 -gl obul i n l evel obs erved on a prot ei n el ect rophores i s , a decreas ed Î± 1 -ant i t ryps i n l evel i n t he s erum, and by Pi t ypi ng. Li ver bi ops y s hows di as t as e-res i s t ant PAS-pos i t i ve gl obul es i n port al areas . There i s no effect i ve t herapy. Li ver t rans pl ant at i on may be us ed i n advanced cas es . 



2. Amyloidosis i nvol ves t he l i ver i n 50% of cas es . Pat i ent s have hepat omegal y on phys i cal exami nat i on but

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us ual l y are as ympt omat i c. Res ul t s of l i ver funct i on t es t i ng oft en are normal but may i ndi cat e a marked el evat i on of s erum al kal i ne phos phat as e. 



3. Hemochromatosis i s an i nheri t ed di s order (t hought t o be aut os omal reces s i ve) i n whi ch i ncreas ed abs orpt i on of i ron l eads t o i ron depos i t i on i n t he l i ver, heart , pancreas , and ot her organs . Men are more commonl y affect ed t han women (at a rat i o of 8:1). In t he Uni t ed St at es , approxi mat el y 8%â€“9% of t he popul at i on are het eroz ygot es and 1 i n every 220 are homoz ygot es , maki ng hemochromat os i s one of t he mos t common genet i c l i ver di s eas es . o

o

a. Clinical features. Hepat omegal y, hyperpi gment at i on, and abnormal i t i es of t he cardi ac conduct i on s ys t em, t es t es , and joi nt s may occur. Fi ft y percent of t he pat i ent s have abdomi nal pai n. Ci rrhos i s and di abet es al s o may devel op.

o

o

b. Laboratory findings. El evat ed l evel s of s erum t rans ami nas es , i ncreas ed s erum i ron wi t h el evat ed percent s at urat i on (general l y >80%), and hi gh s erum l evel of ferri t i n are s een. The HFE gene i s l i nked t o HLA-A 3 l ocus on chromos ome 6. Approxi mat el y 85% of pat i ent s wi t h hemochromat os i s have t hi s C282Y mut at i on. Li ver bi ops y s hows i ron depos i t s i n bot h hepat ocyt es and Kupffer cel l s . Thi s fi ndi ng rul es out s econdary i ron overl oad (hemos i deros i s ) i n whi ch i ron i s depos i t ed i n Kupffer cel l s al one. A s ki n or i nt es t i nal bi ops y as wel l as an anal ys i s of fami l y members for el evat ed i ron, t ot al i ron-bi ndi ng capaci t y, or ferri t i n l evel s

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al s o may be hel pful i n t he di fferent i al di agnos i s . Screeni ng fami l y members for t he el evat ed HLA hapl ot ypes may be us ed. CT or MRI of t he l i ver s hows charact eri s t i c changes . o

o

c. T herapy. Repeat ed phl ebot omy (us ual l y once or t wi ce weekl y for s everal mont hs or years ) decreas es t ot al body i ron s t ores , whi ch may be at 10 t i mes t he normal l evel . Phl ebot omy i s cont i nued unt i l anemi a devel ops or s erum i ron and ferri t i n l evel s normal i ze. Unt reat ed pat i ent s have an i ncreas ed ri s k of hepat oma.

o

o

d. Prognosis. If hemochromat os i s i s di agnos ed before ci rrhos i s devel ops , t he prognos i s wi t h t reat ment i s good (80% s urvi val at 15 years ). If ci rrhos i s or di abet es mel l i t us i s pres ent at t he t i me of di agnos i s , or i f t he i ron s t ores do not decreas e t o normal l evel s aft er 18 mont hs of t reat ment , t he prognos i s i s not as favorabl e. Pat i ent s wi t h hemochromat os i s and ci rrhos i s have approxi mat el y a 220-fol d i ncreas ed ri s k of l i ver cancer





4. Sarcoidosis. Approxi mat el y 70% of pat i ent s wi t h s arcoi dos i s have granul omas i n t he l i ver. Pat i ent s us ual l y do not have s ympt oms referabl e t o t he l i ver but may have i ncreas ed s erum al kal i ne phos phat as e l evel s . Fort y percent of pat i ent s have hepat omegal y. A l i ver bi ops y s howi ng noncas eat i ng granul omas may ai d i n t he di agnos i s .



5. Wilson' s disease i s an aut os omal reces s i ve di s eas e charact eri zed by exces s i ve copper depos i t i on, whi ch, i f unt reat ed,

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may l ead t o ful mi nant hepat i c fai l ure. Copper may al s o be depos i t ed i n t he brai n, ki dney, and cornea; copper depos i t i ons i n t he cornea caus e Kayser-Fleischer rings.

See onl i ne for more

i nformat i on CNS di s eas e may be promi nent i f t he di agnos i s i s made i n adul t hood. Di agnos i s i s s ugges t ed by decreas ed s erum cerul opl as mi n l evel s and i ncreas ed uri nary copper excret i on (>100 Âµg/24 h); i t i s confi rmed by an i ncreas ed hepat i c copper concent rat i on i n a l i ver bi ops y s ampl e. Treat ment i s wi t h D-peni ci l l ami ne, t ri ent i ne, or zi nc i n combi nat i on wi t h a l ow-copper di et . Hepat i c t rans pl ant at i on has been us ed for ful mi nant hepat i c f ai l ure. 



6. Liver disease of pregnancy o

a. Cholestasis us ual l y i s s een i n t he l as t t ri mes t er of pregnancy and i s beni gn. Pat i ent s may compl ai n of pruri t us and jaundi ce, and al l s ympt oms di s appear rapi dl y aft er del i very.

See onl i ne for

more i nformat i on The s yndrome i s t hought t o be medi at ed by es t rogens , proges t erone, or bot h, and s ubs equent us e of oral cont racept i ves or pregnancy may caus e a recurrence of s ympt oms . Recent l y, urs odeoxychol i c aci d t herapy has rel i eved pruri t us and al l owed t he del ay of del i very for great er fet al mat uri t y. o o

b. Acute fatty liver i s a s evere di s eas e us ual l y occurri ng i n a pri mi gravi da i n t he l as t t ri mes t er of pregnancy. Ful mi nant l i ver fai l ure may devel op, and an as s oci at i on wi t h t oxemi a has been report ed.

See onl i ne for more i nformat i on Prognos i s i s poor but i s

i mproved by prompt del i very. Pat hol ogi c changes i n t he l i ver i ncl ude s mal l -dropl et fat t y change s i mi l ar t o t hat s een i n fat t y l i ver i nduced by t et racycl i ne and val proi c aci d. o

o

c. HELLP syndrome (hemol ys i s , el evat ed l i ver enzymes , l ow pl at el et count ) i s oft en s een i n t he

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t hi rd t ri mes t er of pregnancy. Thi s condi t i on i s as s oci at ed wi t h t oxemi a i n approxi mat el y 50% of pat i ent s . Abdomi nal pai n and vomi t i ng may be s evere. Treat ment i s del i very of t he i nfant . o

o

d. Hepatic rupture rarel y occurs aft er necros i s of t he l i ver i n ecl ampt i c pat i ent s i n t hei r l as t t ri mes t er. Pat i ent s wi t h hepat i c rupt ure have general l y been ol der and mul t i parous .

D. Inherited disorders of bilirubin metabolism 



1. Gilbert' s syndrome i s an es s ent i al l y beni gn condi t i on t hat occurs i n approxi mat el y 7% of t he popul at i on of t he Uni t ed St at es . Decreas ed uri di ne di phos phat e (UDP) gl ucuronyl t rans feras e act i vi t y l eads t o mi l d unconjugat ed hyperbi l i rubi nemi a (us ual l y 20,000/mm ) s upport s t he di agnos i s , whi ch i s confi rmed by abdomi nal angi ography. Doppl er ul t ras onography al s o may s how decreas ed fl ow t hrough t he s uperi or mes ent eri c art eri al or cel i ac t ree. o

o

c. T herapy. Treat ment i s s urgi cal removal of t he

Pa g e 1 1 3 2


embol us or t hrombus , al t hough occas i onal l y ant i t hrombot i c agent s , bal l oon angi opl as t y of narrowed ves s el s , or bypas s s urgery i s us ed. 



3. Chronic mesenteric ischemia us ual l y i s s een onl y when t here i s s i gni fi cant occl us i on of t wo of t he t hree major s pl anchni c art eri es . The s yndrome us ual l y i s s een i n ol der pat i ent s wi t h a hi s t ory of cardi ovas cul ar di s eas e. o

o

a. Clinical features i ncl ude i nt ermi t t ent crampy abdomi nal pai n occurri ng 15â€“30 mi nut es aft er eat i ng and l as t i ng s everal hours . Becaus e of t he as s oci at i on of pai n wi t h eat i ng, pat i ent s P.234

charact eri s t i cal l y become fearful of eat i ng and decreas e t hei r i nt ake t o t he poi nt of s ubs t ant i al wei ght l os s . Phys i cal exami nat i on frequent l y di s cl os es evi dence of peri pheral vas cul ar di s eas e, but t here are no s peci fi c fi ndi ngs i ndi cat i ng i nt es t i nal i s chemi a. The pres ence or abs ence of an abdomi nal brui t i s not hel pful . o

o

b. Diagnosis i s di ffi cul t and mus t be bas ed on s t rong cl i ni cal s us pi ci on combi ned wi t h angi ographi c demons t rat i on of s i gni fi cant narrowi ng (>50%) of t wo of t he t hree major s pl anchni c art eri es .

o

o

c. T herapy i s s urgi cal vas cul ar recons t ruct i on. Vas odi l at ors have not been s hown t o be effect i ve.

Pa g e 1 1 3 3




4. Ischemic colitis i s due t o a l ack of art eri al bl ood t o t he col on. Al t hough any port i on of t he col on may be affect ed, t he mos t common s i t e i s t he l eft col on and, i n part i cul ar, t he s o-cal l ed â€œwat ers hed areaâ€• at t he s pl eni c fl exure. Thi s area i s vul nerabl e becaus e i t i s t he s i t e where t he s uperi or mes ent eri c art eri al s uppl y ends and t he i nferi or mes ent eri c art eri al s uppl y begi ns . The rect um us ual l y i s s pared becaus e i t has a generous dual bl ood s uppl y. o

o

a. Clinical features i ncl ude bl oody di arrhea, l ower abdomi nal pai n, and occas i onal vomi t i ng. Infarct i on rarel y occurs . The ol der adul t who has a hi s t ory of heart di s eas e or abdomi nal aort i c aneurys m s urgery (wi t h l i gat i on of t he i nferi or mes ent eri c art ery) i s part i cul arl y s us cept i bl e.

o

o

b. Diagnosis i s s ugges t ed by negat i ve fi ndi ngs for ot her caus es of bl oody di arrhea i n t he el derl y popul at i on (i .e., pol yp, carci noma, di vert i cul os i s , and angi odys pl as i a). The W BC count may be 3

el evat ed t o approxi mat el y 20,000/mm . A fl at -pl at e radi ograph of t he abdomen may s how t humbpri nt i ng. Abdomi nal CT s can may s how s egment al t hi ckeni ng of t he bowel wal l . Pneumat os i s and gas i n t he mes ent eri c vei ns may be s een i n more advanced s t ages . Si gmoi dos copy or col onos copy s how mucos al i s chemi a. o

o

c. T herapy i s s upport i ve wi t h NPO i nt ravenous fl ui ds , bl ood repl acement , and ant i bi ot i cs t o

Pa g e 1 1 3 4


prevent s econdary i nvas i on. o

o

d. Prognosis general l y i s good. Lat e s t ri ct ures may devel op, whi ch coul d requi re bal l oon di l at at i on or s urgery.





5. Vasculitis. Invol vement of t he mes ent eri c ves s el s by pol yart eri t i s nodos a, l upus eryt hemat os us , or rheumat oi d vas cul i t i s mi mi cs art eri al embol i zat i on (caus i ng bowel i nfarct i on) or chroni c mes ent eri c i s chemi a. The di agnos i s i s s ugges t ed by t he s ys t emi c feat ures of t he di s eas e. Surgery i s requi red for acut e i nfarct i on. Ot herwi s e, medi cal t reat ment wi t h cort i cos t eroi ds , i mmunos uppres s i ve agent s , or bot h, frequent l y i s effect i ve.





6. Splenic infarction i s charact eri zed by s evere abdomi nal pai n i n young pat i ent s (500 mg/day) of as corbi c aci d, and admi ni s t rat i on of hypocal ci uri c di uret i cs (t hi azi des or ami l ori de) or oral neut ral pot as s i um phos phat e. Oral admi ni s t rat i on of pot as s i um ci t rat e may be us eful i n i ncreas i ng t he uri nary excret i on of ci t rat e, a major uri nary

Pa g e 1 2 3 2


chel at or of i oni zed cal ci um and an i nhi bi t or of cal ci um oxal at e crys t al growt h. Cal ci um phos phat e, uri c aci d, and s t ruvi t e s t ones are covered onl i ne.

FIGURE 6-3 Ul t ras ound i mage demons t rat i ng a renal cal cul us (arrow). Not i ce t he s hadowi ng bel ow t he s t one. (From Daffner RH. Cl i ni cal Radi ol ogy: The Es s ent i al s . 3rd ed. Bal t i more: Li ppi ncot t W i l l i ams & W i l ki ns , 2007:9-28. ) 



3. Ext racorporeal or s urgi cal removal may be requi red i f s t one s i ze exceeds 5 mm. o

o

a. Calcium phosphate stones. Pri mary hyperparat hyroi di s m neces s i t at es prompt t reat ment wi t h parat hyroi dect omy, di s t al t ubul ar aci dos i s requi res i ndependent eval uat i on, and i di opat hi c hypercal ci uri a requi res di uret i cs (t hi azi des or ami l ori de) or oral neut ral pot as s i um phos phat e.

o

Pa g e 1 2 3 3


o

b. Uric acid stones. Therapy i ncl udes admi ni s t rat i on of oral s odi um bi carbonat e t o mai nt ai n an al kal i ne uri ne (i .e., pH >6) and, i n s el ect ed pat i ent s , res t ri ct i on of di et ary puri ne or admi ni s t rat i on of al l opuri nol .

o

o

c. Cystine stones. Sodi um bi carbonat e i s admi ni s t ered t o keep uri ne pH above 7.5, and acet azol ami de i s gi ven at bedt i me t o mai nt ai n uri ne al kal i ni t y duri ng t he ni ght . Uri ne out put s houl d be mai nt ai ned at more t han 4 L/day. Noncompl i ant pat i ent s and t hos e wi t h s evere or refract ory s t one di s eas e may be candi dat es for oral D-peni ci l l ami ne or i nt rarenal s t one di s s ol ut i on by al kal i ne or acet yl cys t ei ne i rri gat i on.

o

o

d. Struvite stones. Treat ment i s ai med at mai nt ai ni ng uri nary as eps i s , whi ch may requi re ant i bi ot i cs .

VIII. Urinary Tract Obstruction A. Introduction An obs t ruct i on i n t he uri nary t ract may occur at any poi nt bet ween t he renal t ubul es and t he uret hra. Uri nary obs t ruct i on may be acut e or chroni c, uni l at eral or bi l at eral , and part i al or compl et e. Chroni c uri nary obs t ruct i on oft en i s part i al and may be as ympt omat i c, part i cul arl y i n s l owl y progres s i ve cas es . The cons equences of uri nary obs t ruct i on i ncl ude s t ruct ural changes i n t he l ower uri nary t ract as a res ul t of i ncreas es i n pres s ure oppos i ng normal uri ne fl ow (obstructive uropathy), gros s di l at i on of t he cal yces and col l ect i ng s ys t em of t he affect ed ki dney (hydronephrosis), and, ul t i mat el y, renal parenchymal damage (obstructive nephropathy).

B. Etiology

Pa g e 1 2 3 4


The caus es of uri nary obs t ruct i on can be di vi ded i nt o mechanical caus es , whi ch may be i nt ri ns i c or ext ri ns i c, and functional caus es . 



1. Intrinsic mechanical causes o

o

a. Intrarenal tubular obstruction res ul t s from preci pi t at i on of uri c aci d, s ul fonami de, or paraprot ei n crys t al s . Drugs s uch as i ndi navi r, and acycl ovi r may l ead t o i nt rat ubul ar preci pi t at i on of crys t al s .

o

o

b. Extrarenal pelvic or ureteral obstruction i s caus ed by cal cul us , t hrombus , papi l l ary necros i s , or t umor.

o

o

c. Structural lesions of the ureter or bladder i ncl ude s t ri ct ure, t umor, uret hral val ves , uret erocel es , and forei gn body.

P.255





2. Extrinsic mechanical causes o

o

a. Compression may be caus ed by: 



(1) Pros t at i c hypert rophy or carci noma





(2) Ut eri ne prol aps e or t umor

Pa g e 1 2 3 5




(3) Ovari an abs ces s , cys t , or t umor





(4) Endomet ri os i s





(5) Pregnancy





(6) Ret roperi t oneal t umor, i nfect i on, l ymphadenopat hy, or fi bros i s

o

o

b. Surgical errors i ncl ude acci dent al uret eral l i gat i on.





3. Functional causes. Uret eral or bl adder dys funct i on res ul t s from myel odys pl as i a; i njury or congeni t al defect of t he s pi nal cord; t abes dors al i s ; di abet es mel l i t us ; mul t i pl e s cl eros i s (MS), and aut onomi c neuropat hy, i ncl udi ng drug-i nduced neuropat hy (e.g., due t o di s opyrami de).

C. Clinical features Si gns and s ympt oms vary dependi ng on t he s i t e of t he obs t ruct i on and t he s peed wi t h whi ch t he obs t ruct i on devel ops . 



1. An absence of symptoms oft en occurs i n chroni c, s l owl y advanci ng obs t ruct i ve di s eas e. The cl i ni cal pi ct ure oft en i s overs hadowed by s i gns of t he pri mary di s eas e (e.g., i n a cas e of met as t at i c t umor or s urgi cal compl i cat i ons ) unt i l bi ochemi cal evi dence of renal i mpai rment devel ops .



Pa g e 1 2 3 6




2. Pain and renal enlargement (abdomi nal or fl ank mas s ) us ual l y are pres ent i n acut e obs t ruct i on. The pai n charact eri s t i cal l y i s a s t eady cres cendo, i s mos t s evere i n t he fl ank, and radi at es t oward t he i ps i l at eral t es t i s or l abi um.





3. Urinary symptoms predomi nat e i n obs t ruct i ve di s eas e of t he bl adder or uret hra. Hes i t ancy, decreas ed force of uri nary s t ream, uri nary frequency, and dri bbl i ng are common i n t he cont ext of obs t ruct i on.





4. Renal functional impairment t ypi cal l y i s expres s ed as t ubul ar defect s i n aci d and pot as s i um t rans port as wel l as defect i ve t ubul ar res pons i venes s t o hormone act i on. Cl i ni cal l y, hyperkal emi a, mi l d aci demi a, and pol yuri a precede azot emi a, whi ch may progres s t o renal fai l ure.

D. Diagnosis 



1. Urinalysis vari es but may reveal i nappropri at el y di l ut e uri ne, hemat uri a (i n cas es of obs t ruct i on due t o cal cul us or t umor), or bact eri uri a. Becaus e i nfect i on oft en compl i cat es obs t ruct i on, caus i ng s eri ous det ri ment t o renal funct i on, uri ne cul t ure i s es s ent i al . Exami nat i on of t he uri nary s edi ment oft en s hows no abnormal i t y but may reveal crys t al s of uri c aci d or s ul fonami de.





2. Blood chemistries us ual l y are not di agnos t i c but are hel pful i n as s es s i ng t he s everi t y of i mpai red renal funct i on.



Pa g e 1 2 3 7


3. Radiography provi des t he cl i ni cal es s ent i al evi dence of obs t ruct i on. Ul t ras onography or CT rel i abl y det ect s evi dence of hydronephros i s s uch as cal yceal bl unt i ng and di l at i on of t he renal pel vi s , uret er, or bot h

(Onl i ne Fi gure 6-4). Doppl er

ul t ras onography may be effect i ve i n demons t rat i ng t he rat e of uri ne fl ow from each uret er. Int ravenous urography may fai l t o vi s ual i ze t he ki dneys i f t he GFR i s decreas ed s ubs t ant i al l y. Ret rograde urography occas i onal l y may hel p i dent i fy uni l at eral (part i cul arl y part i al ) uret eral obs t ruct i on. Nucl ear s canni ng of t he ki dney oft en i s s peci fi c enough t o confi rm t he di agnos i s . 

FIGURE 6-4 Obs t ruct i ve uropat hy i n t wo pat i ent s as demons t rat ed by CT. A. CT i mage s hows di l at i on of t he uret er (U) as wel l as t he cal yces (arrows ). B. Image more di s t al l y s hows t he cal ci fi ed s t one i n t he uret er (arrow). C. CT i mage i n anot her pat i ent s hows mas s i ve cal yceal di l at i on (C). D. Image more di s t al s hows t he l arge obs t ruct i ng s t one i n t he uret er (arrow). The l ower pol e of t he ki dney i s enl arged. (From Daffner RH. Cl i ni cal Radi ol ogy: The Es s ent i al s . 3rd ed. Bal t i more: Li ppi ncot t W i l l i ams & W i l ki ns , 2007:9-13 )

E. Therapy 



1. Relief of obstruction i s paramount and s houl d be appropri at e t o t he s t ruct ural nat ure of t he occl udi ng l es i on. Met hods i ncl ude pl acement of a t rans uret hral

Pa g e 1 2 3 8


(Fol ey) cat het er, s urgery, percut aneous nephros t omy, uret eral s t ent , and nephros copi c s t one removal . 



2. Medical management fol l owi ng rel i ef of obs t ruct i on i s ai med at correct i ng pos t obs t ruct i ve di ures i s . Cont ri but i ng fact ors i ncl ude t he excret i on of s ol ut e (urea) t hat was ret ai ned duri ng t he peri od of obs t ruct i on and t he i mpai red concent rat i ng abi l i t y t hat us ual l y exi s t s i n t he recent l y obs t ruct ed ki dney. Management i nvol ves careful , adequat e fl ui d repl acement wi t h frequent as s es s ment of body wei ght , i nt ravas cul ar vol ume, and bl ood and uri ne el ect rol yt e concent rat i on.

P.256

F. Complications 



1. Infection, part i cul arl y i n t he cont ext of obs t ruct i ng cal cul i , mus t be det ect ed and prompt l y t reat ed t o prevent ext ens i ve pyel onephri t i s , peri renal abs ces s , and s eps i s .





2. Hypertension occurs s econdary t o bot h i nt ravas cul ar vol ume expans i on and i s chemi c s t i mul at i on of reni n s ecret i on.





3. Polycythemia has been report ed i n as s oci at i on wi t h hydronephros i s and i s purport edl y due t o i ncreas ed eryt hropoi et i n rel eas e.





4. Persistent tubular defects may cont i nue beyond 1

Pa g e 1 2 3 9


year fol l owi ng rel i ef of obs t ruct i on. Impai red concent rat i ng abi l i t y and l i mi t ed excret i on of a pot as s i um l oad are t he mos t common defect s . 



5. Chronic renal failure can devel op from obs t ruct i ve di s eas e, mos t commonl y wi t h l ongs t andi ng obs t ruct i on or wi t h compl i cat i ng uri nary t ract i nfect i on.

IX. Urinary Tract Infection See Chapt er 8 V F for coverage of uri nary t ract i nfect i ons .

X. Glomerular Disease A. Hereditary nephritis (Alport's syndrome) 



1. Inheritance and incidence. Heredi t ary nephri t i s i s i nheri t ed as an X-l i nked or aut os omal domi nant t rai t wi t h vari abl e penet rance. Recent s t udi es have s hown t hat t he di s eas e i s caus ed by a defect i n one of t he genes encodi ng t he s ubuni t s of t ype IV col l agen, a bas ement membrane prot ei n.






o

a. Hematuria, RBC casts, pyuria, proteinuria, and progressive renal failure occur wi t h vari abl e s everi t y. Renal fai l ure i s more common i n men.

o

o

b. High-frequency sensorineural hearing loss, oft en wi t hout cl i ni cal l y s i gni fi cant deafnes s , i s charact eri s t i c.



Pa g e 1 2 4 0




3. T herapy and prognosis. No t reat ment i s s ucces s ful i n s l owi ng or prevent i ng t he renal fai l ure, and prognos i s i s vari abl e. Occas i onal l y, affect ed pat i ent s who undergo renal t rans pl ant at i on devel op ant i gl omerul ar bas ement membrane (ant i -GBM) ant i body di s eas e (Goodpas t ure's s yndrome) i f t he Al port hos t recogni zes t he normal t ype IV col l agen of t he t rans pl ant ed ki dney as a â€œforei gnâ€• ant i gen.

B. Minimal change disease 



1. Incidence. Mi ni mal change di s eas e account s for t hree-fourt hs of cas es of i di opat hi c nephrot i c s yndrome i n chi l dren but onl y one-fourt h of cas es i n adul t s .





2. Pathology. Informat i on i s s cant and nons peci fi c. Fus i on of epi t hel i al foot proces s es i s s een wi t h el ect ron mi cros copy, but t hi s l es i on i s common t o al l prot ei nuri c s t at es .






o

a. Nephrotic syndrome i s t he t ypi cal pres ent at i on by pat i ent s of al l ages .

o

o

b. Hypert ens i on occurs i n 10% of chi l dren and i n 35% of adul t s .

o

o

c. Hemat uri a i s uncommon.

o

Pa g e 1 2 4 1


o

d. Azot emi a devel ops i n 23% of chi l dren and i n 34% of adul t s .





4. T herapy o

o

a. Glucocorticoids. The remi s s i on rat e wi t h adequat e s t eroi d t reat ment i s 90% for bot h chi l dren and adul t s . Prol onged remi s s i on i s s een i n 10%â€“60% of pat i ent s ; however, rel aps e i s common and i s mul t i pl e i n 25%â€“50% of pat i ent s . Rel aps es t ypi cal l y are res pons i ve t o s t eroi ds , wi t h onl y 5% of i ni t i al l y s t eroi d-res pons i ve pat i ent s devel opi ng s t eroi d res i s t ance or dependence. Recent s t udi es have demons t rat ed t hat adul t s may have a poorer res pons e t o gl ucocort i coi ds t han previ ous l y bel i eved.

o

o

b. Cytotoxic agents. Drugs s uch as cycl ophos phami de and chl orambuci l have been effect i ve i n s t eroi d-res i s t ant and mul t i pl e rel aps i ng cas es . Occas i onal l y, s t eroi d-res i s t ant pat i ent s devel op s t eroi d s ens i t i vi t y fol l owi ng t reat ment wi t h cyt ot oxi c al kyl at i ng agent s . The pos s i bi l i t y of gonadal (chromos omal ) damage caus ed by t hes e drugs mus t be careful l y cons i dered. P.257

o

o

c. Other immunosuppressive agents. Current res earch demons t rat es t hat t he us e of agent s s uch as cycl os pori ne and mycophenol at e mofet i l i s

Pa g e 1 2 4 2


effect i ve i n refract ory cas es . o

o

d. ACE i nhi bi t ors and ARBs are al s o neces s ary for t he reduct i on of prot ei nuri a.





5. Prognosis. Mi ni mal change di s eas e i s as s oci at ed wi t h l ow mort al i t y rat es (i .e., 10% among adul t s and 1.5% among chi l dren), wi t h onl y 10% of deat hs caus ed by renal fai l ure.

C. Membranous glomerulonephritis (or glomerulopathy) 



1. Etiology o

o

a. Primary (idiopathic) membranous glomerulonephritis account s for 30%â€“50% of cas es of i di opat hi c nephrot i c s yndrome i n adul t s but l es s t han 1% of cas es i n chi l dren.

o

o

b. Secondary membranous glomerulonephritis may occur wi t h a vari et y of underl yi ng condi t i ons , i ncl udi ng: 



(1) Infection [e.g., chroni c hepat i t i s B vi rus (HBV) i nfect i on or hepat i t i s C vi rus (HCV) i nfect i on, s yphi l i s , mal ari a, s chi s t os omi as i s , and fi l ari as i s ]



Pa g e 1 2 4 3


(2) Rheumatic disease (e.g., SLE)





(3) Neoplasm (e.g., carci noma of t he l ung, col on, s t omach, breas t , and ki dney; non-Hodgki n's l ymphoma; l eukemi a; W i l ms ' t umor)





(4) Drug therapy (e.g., mercury, gol d, D-peni ci l l ami ne, capt opri l )



2. Pathology. The fi ndi ngs pres ent ed i n

Onl i ne Tabl e 6-7

charact eri ze t he s t ages of membranous gl omerul onephri t i s . Charact eri s t i c el ect ron mi cros cope fi ndi ngs can be s een i n Fi gure 6-5. 

Online TABLE 6-7 Stages of Membranous Glomerulonephritis Ch ar act eri Sta sti ge cs I Nor ma l ap pe ara nce wi t h

Pa g e 1 2 4 4


lig ht mi c ros cop y; s ub epi t he l i al el e ct r onde ns e de pos its wi t h el e ct r on mi c ros cop II

y Spi kelik e pro jec tio ns

Pa g e 1 2 4 5


of bas em ent me mb ran e ma t eri al wi t h lig ht mi c ros cop y (be st vi s ual ize d wi t h a silv er im pre gn at i on sta

Pa g e 1 2 4 6


i n) ; var i ab le bas em ent me mb ran e t hi cke ni n g III Thi ck gl o me rul ar bas em ent me mb ran e (G BM ), wi t h a â€

Pa g e 1 2 4 7


œ mo t heat en â€ • or â€ œS wi s s -c he es e â€ • ap pe ara nce du e to enc i rcl em ent of im mu ne de pos its by

Pa g e 1 2 4 8


s pi kelik e pro jec tio ns of nor ma l GB M IV Thi cke ni n g of t he cap illa ry wal l, wi t h are as of s eg me nt a l or gl o

Pa g e 1 2 4 9


bal gl o me rul os c l er os i s; pos sib le t ub ul o i nt ers titi al fi br os i s 



3. Clinical features. More t han 85% of adul t s pres ent 2

wi t h prot ei nuri a (>3 g/day/1.73 m body s urface area). The GFR us ual l y i s normal at di agnos i s and oft en remai ns normal for 4â€“5 years t hereaft er. 



4. Clinical course. Membranous gl omerul onephri t i s has a vari abl e cours e. About 20%â€“30% of pat i ent s achi eve a l as t i ng s pont aneous remi s s i on, 20%â€“30% devel op vari abl e degrees of pers i s t ent prot ei nuri a and nonuremi c az ot emi a, and t he res t advance t o end-s t age renal di s eas e, us ual l y over a 5-year peri od. Mal e pat i ent s , t hos e wi t h heavy prot ei nuri a (>10 g/day), and t hos e who do not res pond wi t h a remi s s i on i n prot ei nuri a have

Pa g e 1 2 5 0


a wors e prognos i s . 



5. T herapy. A combi nat i on of s t eroi ds and cyt ot oxi c agent s i n addi t i on t o ACE i nhi bi t or and ARB t herapy has proved effect i ve, but t he unpredi ct abl e out come of t he di s eas e makes t he eval uat i on of t herapy di ffi cul t . Recent randomi zed t ri al s fi nd t hat s t eroi ds al one s houl d not be us ed as pri mary t herapy. The us e of al t ernat i ng cycl es of chl orambuci l or cycl ophos phami de and predni s one i s effect i ve i n hal t i ng progres s i on t o end-s t age renal fai l ure i n pat i ent s wi t h nephrot i c s yndrome and mi l d renal i ns uffi ci ency. Pat i ent s t reat ed wi t h cyt ot oxi c drugs are more l i kel y t o experi ence remi s s i on of prot ei nuri a.





6. Complications. Probl emat i c condi t i ons may i nt ervene, caus i ng an abrupt decreas e i n renal funct i on. o

o

a. A hypercoagulable state exi s t s i n nephrot i c pat i ent s . Renal vei n t hrombos i s i s a recogni zed probl em; pul monary embol i s m and art eri al t hrombos i s al s o have been des cri bed.

o

o

b. Intravascular volume depletion s econdary t o vi gorous di uret i c admi ni s t rat i on l eads t o decreas ed renal bl ood fl ow.

o

o

c. Hypertension, obstruction, or infection may i mpai r fi l t rat i on.

Pa g e 1 2 5 1


FIGURE 6-5 El ect ron mi cros copi c fi ndi ngs of s ubepi t hel i al dens e depos i t s i n bas ement membrane i n a pat i ent wi t h membranous nephropat hy (From W i l l i ams G, Mal l i ck NP. Col or At l as of Renal Di s eas es . 2nd ed. Barcel ona: W ol fe Publ i s hi ng/Mos by-Y ear Book Europe Lt d, 1994:3.10. ) P.258

D. Mesangial proliferative glomerulonephritis 



1. Etiology. The caus e i s unknown.





2. Pathology. The mes angi al prol i ferat i ve l es i on i s a gl obal and di ffus e i ncreas e i n t he number of mes angi al cel l s and i n t he mes angi al mat ri x.





3. Clinical features. As ympt omat i c prot ei nuri a or hemat uri a may occur. Al t hough 24-hour uri nary prot ei n excret i on can exceed 3.0 g, t he compl et e nephrot i c s yndrome i s i ncons i s t ent l y s een. One-t hi rd of pat i ent s are hypert ens i ve at t he t i me of di agnos i s . Creat i ni ne

Pa g e 1 2 5 2


cl earance i s reduced i n onl y 25% of pat i ent s at pres ent at i on. Serum compl ement component l evel s are normal . 

4. Clinical course. The di s eas e has an ext remel y



vari abl e cours e. 

5. T herapy. Hi gh-dos e (1â€“2 mg/kg/day)



gl ucocort i coi ds are report edl y effect i ve i n remi s s i on i nduct i on. Some s t eroi d fai l ures res pond t o t reat ment wi t h cycl ophos phami de or chl orambuci l .

E. Membranoproliferative glomerulonephritis 

1. Incidence and etiology



o

o

a. Col l ect i vel y, t he di s orders i n t hi s group account for 41% of cas es of i di opat hi c nephrot i c s yndrome i n chi l dren and 30% of cas es i n adul t s . Mal es and femal es are affect ed equal l y.

o

o

b. Membranoprol i ferat i ve gl omerul onephri t i s may be i di opat hi c or s econdary t o SLE, cryogl obul i nemi a, or chroni c vi ral or bact eri al i nfect i on (e.g., hepat i t i s C, s yphi l i s , t ubercul os i s ).



2. Pathology. The t hree pat hol ogi c t ypes of membranoprol i ferat i ve gl omerul onephri t i s , each wi t h di s t i nct feat ures , are des cri bed i n

ONLINE Tabl e 6-8.



Page 1253


Online TABLE 6-8 Pathologic Types of Membranoproliferative Glomerulonephritis Fe T y atu pe res I Int act gl o me rul ar bas em ent me mb ran e, s ub en dot hel i al an d me s an gi a l de pos its,

Pa g e 1 2 5 4


sig ni fi can t me s an gi a l pro mi ne nce wi t h ma t ri x i nt erp os i tio n Im mu nof l uo res cen t pos itiv ity for im mu no

Pa g e 1 2 5 5


gl o bul in G (Ig G), co mp le me nt co mp ou nds (C1 q, C4, an d C2) , an d pro per II

di n Int

(al ra s o me cal l mb ed ran de ous ns e an de d

Pa g e 1 2 5 6


pos s ub it

epi

di s t he eas l i al e) de pos its (â€ œh um ps â €• ) in 50 % of cas es , me s an gi a l de pos its, mo der at e me s an gi a l pro mi ne

Pa g e 1 2 5 7


nce wi t h i nt erp os i tio n Im mu nof l uo res cen t pos itiv ity for IgG , C3, an d pro per di n III Fea t ur es of t ru e me mb

Pa g e 1 2 5 8


ran ous gl o me rul on ep hri t is (i .e ., wi t h s ub epi t he l i al de pos its) an d fea t ur es of t yp e I me mb ran opr ol i f era tiv

Pa g e 1 2 5 9


e gl o me rul on ep hri t is





3. Clinical features. The pres ent at i on i s hi ghl y vari abl e. Hypocompl ement emi a i s t he mos t charact eri s t i c l aborat ory fi ndi ng but i s not uni vers al l y pres ent . The degree of compl ement C3 depres s i on may be us ed as a rough gui de t o di s eas e act i vi t y.





4. Clinical course. Chroni c gl omerul onephri t i s wi t h end-s t age renal di s eas e devel ops i n mos t cas es . Rapi d progres s i on t o renal fai l ure wi t h edema and s evere hypert ens i on (acut e nephri t i s ) has been des cri bed.





5. T herapy. Treat ment i s not predi ct abl y effect i ve, al t hough occas i onal report s cl ai m s ome t herapeut i c benefi t . In chi l dren wi t h prot ei nuri a or i mpai red renal funct i on, hi gh-dos e s t eroi d t herapy s houl d be t ri ed and mai nt ai ned for 6â€“12 mont hs . In adul t s wi t h heavy prot ei nuri a (>3 g/day), t he antiplatelet agents di pyri damol e and as pi ri n may be us ed. However, evi dence does not defi ni t i vel y s upport t he effect i venes s of t hi s regi men.

F. Focal glomerulosclerosis 

Pa g e 1 2 6 0




1. Incidence and etiology o

o

a. Focal gl omerul os cl eros i s account s for 30% of cas es of i di opat hi c nephrot i c s yndrome i n adul t s and i s t he mos t common caus e of s t eroi d-res i s t ant nephrot i c s yndrome i n chi l dren.

o

o

b. Thi s condi t i on i s report ed t o recur i n 30%â€“40% of renal al l ograft s wi t hi n 3 weeks t o 1 year fol l owi ng t rans pl ant at i on.

o

o

c. The et i ol ogy i s unknown. Focal gl omerul os cl eros i s i s s een occas i onal l y i n t he cont ext of AIDS, heroi n and ot her i nt ravas cul ar drug us e, and chroni c ves i couret eral refl ux, but t he caus al rel at i ons hi ps are uncert ai n.





2. Pathology. The hal l mark l es i on of focal and s egment al gl omerul os cl eros i s evol ves t hrough s everal s t ages , i ncl udi ng mi l d mes angi al promi nence, l os s of gl omerul ar cel l ul ari t y, and col l aps e of capi l l ary l oops .





3. Clinical features and diagnosis o

o

a. Nephrotic syndrome i s t he mos t common cl i ni cal pres ent at i on. Hypert ens i on and renal fai l ure occur i nfrequent l y i n chi l dhood but become more preval ent wi t h advanci ng age.

o

Pa g e 1 2 6 1


b. There are no s peci fi c l aborat ory fi ndi ngs . Prot ei nuri a t ends t o be heavy (i .e., >15 g/24 hours ), and t he bi ochemi cal derangement s of nephrot i c s yndrome are accordi ngl y s evere.





4. T herapy o

o

a. Recent s t udi es s ugges t t hat prol onged gl ucocort i coi d t herapy (i .e., â‰¥6 mont hs ) may l ead t o remi s s i on of prot ei nuri a, al t hough no randomi zed t ri al s s upport t hi s recommendat i on.

o

o

b. Cycl os pori ne as wel l as ACE i nhi bi t ors and ARBs may be effect i ve i n reduci ng prot ei nuri a.

P.259

G. Goodpasture's syndrome 



1. Definition. Goodpas t ure's s yndrome refers t o a group of i l l nes s es defi ned by t he fol l owi ng t ri ad of fi ndi ngs : glomerulonephritis (us ual l y cres cent i c), pulmonary hemorrhage, and anti-GBM antibody i n s erum. The renal and pul monary component s may be s evere or cl i ni cal l y s i l ent . The pres ence of t he ant i -GBM ant i body, however, has become t he es s ent i al feat ure of t he di agnos i s .






Pa g e 1 2 6 2


o

a. Clinical presentation i s hi ghl y vari abl e. 



(1) Generalized, systemic symptoms may precede organ-s peci fi c compl ai nt s . Fever and myal gi a are common.





(2) Renal involvement us ual l y i s i n t he form of rapi dl y progres s i ve renal fai l ure. Prot ei nuri a us ual l y i s mi l d, and t he uri nary s edi ment cont ai ns eryt hrocyt es and RBC cas t s . Thi s â€œnephri t i câ€• pi ct ure may be mi l d or s evere.





(3) Pulmonary manifestations i ncl ude radi ographi c i nfi l t rat es , hemopt ys i s , cough, and dys pnea. The l ung di s eas e us ual l y precedes ki dney di s eas e by a peri od of days t o weeks .

o

o

b. Laboratory findings 



(1) The mos t i mport ant fi ndi ng i s evi dence of ci rcul at i ng i mmunogl obul i n G (IgG) ant i -GBM ant i body, whi ch i s pres ent i n more t han 90% of pat i ent s .





(2) The pat hol ogi c appearance of t he ki dney i s t ypi cal l y t hat of a cres cent i c, prol i ferat i ve gl omerul onephri t i s . Cres cent s i nvol ve 80%â€“100% of gl omerul i and are hi ghl y

Pa g e 1 2 6 3


cel l ul ar. 



3. Clinical course. Li ke t he cl i ni cal pres ent at i on, t he cours e of di s eas e i s vari abl e, rangi ng from a mi nor recurrent pul monary hemorrhage t hat occurs for years â€”unt i l an abnormal uri nary s edi ment prompt s meas urement of ant i -GBM ant i bodyâ€”t o abrupt -ons et , ful mi nant di s eas e, compl et e renal fai l ure, and a s phyxi at i on by mas s i ve pul monary bl eedi ng over a peri od of hours t o days .





4. T herapy. Several t reat ment met hods appear t o benefi t pat i ent s . Poor prognos t i c i ndi cat ors i ncl ude ol i goanuri a, s erum creat i ni ne above 6 mg/dL for many weeks , and advanced hi s t opat hol ogi c l es i ons . o

o

a. Hi gh-dos e predni s one s houl d be gi ven as an i ni t i al t herapy. Cycl ophos phami de s houl d al s o be admi ni s t ered t o pat i ent s under 55 years of age. A vari et y of s ucces s ful but uncont rol l ed cl i ni cal t ri al s have i nvol ved combi nat i ons of cort i cos t eroi ds and al kyl at i ng i mmunos uppres s i ve agent s .

o

o

b. Int ens i ve, dai l y pl as mapheres i s s houl d be admi ni s t ered for 14 days or unt i l ant i -GBM ant i body di s appears .

H. Idiopathic crescentic glomerulonephritis Indi vi dual s wi t h t hi s pat hol ogi cal l y defi ned ent i t y t ypi cal l y pres ent wi t h rapi d, progres s i ve det eri orat i on of renal funct i on. It i s i mperat i ve t o recogni ze t hat ot her l es i ons may i nduce t he cl i ni cal s yndrome of rapidly progressive glomerulonephritis (RPGN) (Tabl e 6-9). Thi s s ect i on cons i ders onl y t he i di opat hi c cas es (i .e.,

Pa g e 1 2 6 4


t hos e cas es not due t o ot her cres cent i c gl omerul ar di s eas es ). Idi opat hi c cres cent i c gl omerul onephri t i s may be cl as s i fi ed i nt o t hree ent i t i es : anti-GBM antibody disease (s ee Part I: X G); immune complex RPGN; and pauci-immune RPGN, i n whi ch gl omerul ar i nfl ammat i on and necros i s are pres ent but wi t hout i mmune depos i t s . 



1. Incidence and etiology. Idi opat hi c cres cent i c gl omerul onephri t i s account s for about one-t hi rd of al l cas es of cres cent i c gl omerul onephri t i s . Mal es are affect ed t wi ce as oft en as femal es .





2. Clinical features. Pat i ent s pres ent wi t h abrupt -ons et renal fai l ure, wi t h rapi d l os s of renal funct i on (i n l es s t han 3 mont hs ); frequent l y normal bl ood pres s ure; and normal ki dney s i ze. Nons peci fi c s ympt oms (e.g., weaknes s , naus ea, cough, wei ght l os s , fever, myal gi a, art hral gi a) oft en announce t he di s eas e. Ext rarenal i nvol vement , wi t h t he except i on of l ung i nvol vement , i s rare. o

o

a. Renal manifestations. Approxi mat el y 50% of pat i ent s are ol i guri c and azot emi c at t he t i me of pres ent at i on.

o

o

b. Pulmonary manifestations. Trans i ent , mi l d pul monary i nfi l t rat es or hemopt ys i s i s s een i n one hal f of pat i ent s .





3. Diagnosis. There are no di agnos t i c l aborat ory fi ndi ngs . However, when i nt rarenal vas cul i t i s (i .e., pauci -i mmune gl omerul onephri t i s ) i s t he underl yi ng

Pa g e 1 2 6 5


caus e, t he antineutrophilic cytoplasmic P.260

antibody (ANCA) t es t i s pos i t i ve. The di agnos i s i s bas ed on t he di s covery of epi t hel i al cres cent s i n a majori t y of gl omerul i i n t he renal bi ops y s peci men.

TABLE 6-9 Causes of Acute Renal Failure with Crescentic Glomerulonephritis In pri ma ry glo me rul ar dis ea ses Pri ma ry (i di op at h i c) di ff us e cre s ce nt i c

Pa g e 1 2 6 6


gl o me rul on ep hri t is Typ e I: ant i -G BM ant i bo dy di s eas e wit ho ut pul mo nar y he mo rrh ag e Typ e II: im

Pa g e 1 2 6 7


mu ne co mp l ex di s eas e Typ e III: pa uci -i m mu ne gl o me rul on ep hri t is (A NC A-a sso ci a t ed ) Me s an gi o cap illa

Pa g e 1 2 6 8


ry gl o me rul on ep hri t is (es pec i al l y t yp e II) Me mb ran ous gl o me rul on ep hri t is wi t h or wi t ho ut s up eri mp

Pa g e 1 2 6 9


os e d ant i -G BM ant i bo dy di s eas e IgA ne phr op at h y (Be rge r's di s eas e) In ass oci ati on wit h inf ect iou s dis

Pa g e 1 2 7 0


ea ses Pos tst rep t oc occ al gl o me rul on ep hri t is Inf ect i ve en doc ard itis Occ ul t vi s cer al bac t eri al s ep sis Ot her i nf

Pa g e 1 2 7 1


ect i on s (e. g., he pat itis B) In as s oci at i on wi t h mu ltis ys t em di s eas es SLE Go od pas t ur e's s yn dro me (an t i -G

Pa g e 1 2 7 2


BM ant i bo dy di s eas e wi t h pul mo nar y he mo rrh ag e) He noc h-S chÃ ¶nl ei n pur pur aâ €”d iss em i na t ed vas cul i tis

Pa g e 1 2 7 3


We ge ner 's gra nul om at o sis Mi c ros cop ic pol yar t eri tis (hy per s en siti vi t y an gi i t is) Ot her var i an ts Cry oi mm un

Pa g e 1 2 7 4


ogl ob ul i ne mi a (mi xed , es s ent i al ) Rel aps i ng pol ych on dri t is Lun g can cer , l ym ph om a Ant i -G BM , ant i -gl

Pa g e 1 2 7 5


om eru l ar bas em ent me mb ran e; IgA , im mu no gl o bul in A; SLE , s ys te mi c l up us ery t he ma t os us . 



4. Clinical course and prognosis. The prognos i s may be very bl eak, dependi ng on t he l evel of renal funct i on at

Pa g e 1 2 7 6


t he t i me of pres ent at i on. Renal fai l ure requi ri ng renal repl acement t herapy devel ops i n 3â€“6 mont hs i n more t han 50% of pat i ent s . However, recent dat a us i ng aggres s i ve i mmunos uppres s i ve regi mens have demons t rat ed t hat 50%â€“75% of pat i ent s may ent er remi s s i on. 



5. T herapy. In ant i -GBM di s eas e, pl as mapheres i s and i mmunos uppres s i ves s houl d be us ed as des cri bed for Goodpas t ure's s yndrome (s ee Part I: X G). In i mmune compl ex gl omerul onephri t i s , t reat ment depends on t he i ndi vi dual caus at i ve di s order. In pauci -i mmune depos i t di s eas e, t reat ment i nvol ves pul s e met hyl predni s ol one and cycl ophos phami de.

I. Postinfectious glomerulonephritis Thi s acut e gl omerul onephri t i s occurs wi t h a vari et y of l ocal or s ys t emi c i nfect i ons . (Gl omerul onephri t i s as s oci at ed wi t h i nfect i ve endocardi t i s and vi s ceral abs ces s i s di s cus s ed i n Part I: X Q.) Pos t i nfect i ous gl omerul onephri t i s has been des cri bed as a s equel a of di s eas e caus ed by vi rus es , fungi , prot ozoa, and hel mi nt hs . However, t he prot ot ypi cal pos t i nfect i ous gl omerul onephri t i s i s poststreptococcal glomerulonephritis. 



1. Incidence and etiology o

o

a. The di s eas e pri mari l y affect s s chool -aged chi l dren. The di s eas e i s rare before 2 years of age but has been report ed i n adul t s . Mal es are affect ed t wi ce as oft en as femal es .

o

o

b. Precedi ng i nfect i on wi t h nephri t ogeni c s t rai ns of group A Î²-hemol yt i c s t rept ococci (part i cul arl y t ype

Pa g e 1 2 7 7


12) i s t he rul e, al t hough pos i t i ve cul t ure of t he organi s m i s demons t rat ed i n l es s t han 20% of cas es at t he t i me of renal di s eas e. The s i t e of i nfect i on (i .e., s ki n or pharynx) appears t o vary wi t h t he geographi c area of s t udy. The l at ent peri od bet ween i nfect i on and cl i ni cal gl omerul ar di s eas e i s 7â€“15 days ; rarel y, i t i s as l ong as 3 weeks . 



2. Pathology. Pos t s t rept ococcal gl omerul onephri t i s i s a di ffus e prol i ferat i ve di s eas e wi t h mes angi al and endot hel i al hypercel l ul ari t y. El ect ron-dens e depos i t s (s ubepi t hel i al â€œhumps â€•) and foot proces s P.261

fus i on are s een by el ect ron mi cros copy (Fi gure 6-6). Immunofl uores cence oft en i dent i fi es granul ar depos i t s of compl ement C3 al ong t he capi l l ary bas ement membrane.

FIGURE 6-6 El ect ron mi cros copi c fi ndi ngs of dens e s ubepi t hel i al depos i t s (humps ) i n a pat i ent wi t h pos t s t rept ococcal gl omerul onephri t i s . (From W i l l i ams G, Mal l i ck NP. Col or At l as of Renal Di s eas es . 2nd ed. Barcel ona: W ol fe Publ i s hi ng/Mos by-Y ear Book Europe Lt d, 1994:3.17.

Pa g e 1 2 7 8


) 




o

a. The t ypi cal cl i ni cal pres ent at i on i s a s udden ons et of hemat uri a and edema. Nephrot i c s yndrome devel ops i n l es s t han 15% of pat i ent s .

o

o

b. The charact eri s t i c, but not di agnos t i c, l aborat ory profi l e i s azot emi a, hypocompl ement emi a (CH 5 0 or C3), hemat uri a, l eukocyt uri a, and prot ei nuri a. Support i ng dat a i ncl ude el evat ed t i t ers of ant i s t rept ol ys i n O, ant i hyal uroni das e, and ant i -deoxyri bonucl eas e B ant i bodi es , al l of whi ch s ugges t precedi ng s t rept ococcal i nfect i on.





4. Clinical course and diagnosis o

o

a. The t ypi cal cours e of acut e di s eas e i s recovery, part i cul arl y among chi l dren. The acut e nephri t i s res ol ves wi t h amel i orat i on of edema and hypert ens i on 1â€“3 weeks aft er ons et . Prot ei nuri a may pers i s t for s everal mont hs , exacerbat ed by erect pos t ure and exerci s e. Mi cros copi c hemat uri a s i mi l arl y di s appears s l owl y over a peri od of s everal mont hs .

o

o

b. Long-t erm prognos i s i s cont rovers i al . Some pat i ent s advance t o end-s t age renal di s eas e. Fact ors as s oci at ed wi t h t hi s poor prognos i s are s evere ol i guri a or anuri a, cres cent s i n t he bi ops y

Pa g e 1 2 7 9


s peci men, pers i s t ent heavy prot ei nuri a, and rel at i vel y ol der age. Pers i s t ence of hypocompl ement emi a and progres s i ve renal fai l ure may, however, i ndi cat e an al t ernat i ve di agnos i s (e.g., membranoprol i ferat i ve gl omerul onephri t i s ). 



5. T herapy. Hypert ens i on mus t be t reat ed aggres s i vel y, part i cul arl y i n chi l dren, who devel op fl ori d hypert ens i ve encephal opat hy at normal adul t bl ood pres s ures . Furos emi de or bumet ani de may l i kel y be requi red for t he underl yi ng edema-i nduci ng di s eas e. Ant i bi ot i c us e i s cont rovers i al , al t hough a 10-day cours e of peni ci l l i n i n nonal l ergi c pat i ent s i s s afe enough for rout i ne us e. Prophyl axi s fol l owi ng pos t s t rept ococcal gl omerul onephri t i s i s not i ndi cat ed becaus e recurrences are exceedi ngl y rare. Immunos uppres s i ve agent s or cort i cos t eroi ds have no t herapeut i c rol e.

J. IgA glomerulonephritis (Berger's disease) 



1. Definition and incidence. The di s eas e i s charact eri zed by mes angi al depos i t s of IgA i n renal bi ops i es from pat i ent s wi t h recurrent hemat uri a but normal renal funct i on. The i nci dence of t hi s di s eas e vari es remarkabl y wi t h geographi c l ocat i on, and men are affect ed t hree t o four t i mes more oft en t han women.





2. Pathology. Fi ndi ngs are charact eri s t i c. o

o

a. Di ffus e, s omet i mes i rregul arl y di s t ri but ed IgA depos i t s are s een i n t he mes angi um. IgM or IgG al s o may be pres ent .

Pa g e 1 2 8 0


o

b. Focal and s egment al gl omerul onephri t i s wi t h mes angi al prol i ferat i on i s common. Mes angi al promi nence may be t he onl y pat hol ogi c fi ndi ng.

P.262





3. Clinical features and diagnosis. Affect ed pat i ent s , who us ual l y are bet ween 20 and 40 years of age, mos t commonl y pres ent wi t h recurrent , oft en macros copi c hemat uri a but a normal GFR and normal t ubul ar funct i on. Bi ops y s peci mens from normal -appeari ng s ki n have i mmunofl uores cent pos i t i vi t y for IgA i n 50% of cas es . Meas uri ng s erum IgA l evel s i s not us eful .





4. Clinical course and prognosis. Cours e and out come are vari abl e. The 20-year s urvi val rat e i s about 50%. A mi nori t y of pat i ent s progres s t o renal fai l ure. Fact ors t hat predi ct a poor prognos i s i ncl ude advanced age at di s eas e ons et , heavy prot ei nuri a, hypert ens i on, and t he pres ence of cres cent s or s egment al s cl eros i s on renal bi ops y.





5. T herapy. Pat i ent s wi t h mi l d hi s t ol ogi c changes and prot ei nuri a of more t han 3 g/day s houl d recei ve predni s one for 4â€“6 mont hs , as wel l as ACE i nhi bi t or or ARB t herapy. Recent dat a s ugges t t hat fi s h oi l cont ai ni ng a number of ant i -i nfl ammat ory fat t y aci ds may be us eful i n s ome pat i ent s wi t h s l owl y progres s i ve di s eas e.

K. Henoch-SchÃ¶nlein purpura

Pa g e 1 2 8 1






1. Definition. Thi s s ys t emi c di s eas e i s charact eri zed by purpura (whi ch may be s l i ght and go unnot i ced), art hri t i s , abdomi nal pai n, bl oody di arrhea, and nephri t i s .





2. Incidence. Henoch-SchÃ¶nl ei n purpura pri mari l y affect s chi l dren. Cl i ni cal nephri t i s affect s 30% of pat i ent s , but al mos t al l pat i ent s have an abnormal ki dney bi ops y.





3. Pathology. The hi s t opat hol ogy ranges from mi l d, di ffus e mes angi al promi nence t o focal and s egment al prol i ferat i ve gl omerul onephri t i s on a background of di ffus e mes angi al prol i ferat i on. The hal l mark of Henoch-SchÃ¶nl ei n purpura i s t he i nvari abl e i mmunofl uores cent pos i t i vi t y for IgA i n t he mes angi um.






o

a. The cl i ni cal pres ent at i on oft en i s preceded by an i nfect i on [caus ed by a vi rus (e.g., herpes zos t er), mycopl as ma, or s t rept ococcus ], vacci nat i on, i ns ect bi t e, or drug admi ni s t rat i on. Ras h us ual l y devel ops earl y and evol ves from morbi l l i form t o purpuri c. The l egs and but t ocks are affect ed mos t commonl y. Art hri t i s t ypi cal l y i s mi l d and nondeformi ng. Gas t roi nt es t i nal bl eedi ng and pai n may domi nat e t he pres ent at i on.

o

o

b. Laborat ory fi ndi ngs are exceedi ngl y nons peci fi c,

Pa g e 1 2 8 2


al t hough el evat ed s erum IgA i s report ed frequent l y. Serum compl ement component l evel s us ual l y are normal . 



5. Clinical course and prognosis o

o

a. The cl i ni cal cours e i s vari abl e. Pat i ent s wi t h recurrent purpura, heavy prot ei nuri a, and cl i ni cal l y s evere nephri t i s at t he t i me of pres ent at i on and pat i ent s whos e bi ops i es s how epi t hel i al cres cent format i on t end t o fare poorl y.

o

o

b. Among al l chi l dren wi t h Henoch-SchÃ¶nl ei n purpura, t he 15-year s urvi val rat e i s 90%. By 10 years , however, 15% of t hes e pat i ent s have pers i s t i ng di s eas e and 8% have renal i mpai rment . Among adul t s , 50% heal compl et el y, 15% progres s t o renal fai l ure, and approxi mat el y 35% have pers i s t ent di s eas e.





6. T herapy. Several t reat ment met hods have been at t empt ed (e.g., i mmunos uppres s i on, s t eroi d t herapy, ant i coagul at i on) but wi t hout proven benefi t .

L. Diabetic nephropathy 



1. Incidence. End-s t age renal di s eas e devel ops i n 30% of al l pat i ent s wi t h di abet es . Among pat i ent s wi t h juveni l e-ons et di abet es , 30% devel op renal di s eas e wi t hi n 20 years of t he ons et of di abet es . Among new pat i ent s cons i dered for mai nt enance renal repl acement t herapy (l argel y chroni c hemodi al ys i s ), at l eas t 40%

Pa g e 1 2 8 3


have chroni c renal fai l ure s econdary t o di abet es . Afri can Ameri can, Hi s pani c, and Nat i ve Ameri can i ndi vi dual s have a hi gher l i kel i hood of devel opi ng di abet i c nephropat hy t han Caucas i an pat i ent s who have di abet es . 



2. Pathogenesis o

o

a. The evol ut i on of di abet i c nephropat hy i s s ympt omat i cal l y qui et unt i l l at e i n t he di s eas e proces s . Earl y i n di abet es , t he GFR oft en i s above normal . Thi s earl y hyperfi l t rat i on may be mos t s t ri ki ng i n t hos e pat i ent s who s ubs equent l y devel op gl omerul ar damage.

o

o

b. Ini t i al l y, microalbuminuria [t he l os s of s mal l amount s of prot ei n (range: 30â€“300 mg/day)] occurs , whi ch progres s es t o macroprot ei nuri a, fol l owed by azot emi a, and ul t i mat el y end-s t age renal di s eas e. The rapi di t y of t hi s cours e i s hi ghl y vari abl e.

P.263





3. Pathology. Two major pat hol ogi c l es i ons are as s oci at ed wi t h di abet es . o

o

a. Diffuse glomerulosclerosis i s uni forml y pres ent i n pat i ent s wi t h di abet i c nephropat hy. It i s charact eri zed by an eos i nophi l i c t hi ckeni ng of t he mes angi um and bas ement membrane due t o

Pa g e 1 2 8 4


accumul at i on of ext racel l ul ar mat ri x prot ei ns . o

b. Nodular glomerulosclerosis, al s o known as Kimmelstiel-Wilson syndrome, cons i s t s of round nodul es t hat are homogeneous at t he cent er and have ci rcumferent i al l ayeri ng of nucl ei

(Onl i ne Fi gure

6-7). Thes e nodul es oft en are mul t i pl e wi t hi n a gi ven gl omerul us and may be confl uent . Nodul ar gl omerul os cl eros i s i s s peci fi c for di abet es , but i t i s found i n onl y 50% of pat i ent s wi t h di abet i c nephropat hy. o

ONLINE FIGURE 6-7 Pat hognomi c nodul es (N) from a pat i ent wi t h di ffus e i nt ercapi l l ary gl omerul os cl eros i s caus ed by di abet es mel l i t us . (From W i l l i ams G, Mal l i ck NP. Col or At l as of Renal Di s eas es . 2nd ed. Barcel ona: W ol fe Publ i s hi ng/Mos by-Y ear Book Europe Lt d, 1994:4.5. ) 



4. Laboratory findings. Res ul t s are i ndi cat i ve of a s l owl y decl i ni ng GFR.



Pa g e 1 2 8 5




5. Clinical course. Fact ors t hat accel erat e renal det eri orat i on i ncl ude hypert ens i on, poor gl ycemi c cont rol , uri nary obs t ruct i on, i nfect i on, t he admi ni s t rat i on of nephrot oxi c drugs , and t he us e of i nt ravenous radi ocont ras t mat eri al .





6. T herapy o

o

a. Diabetic nephropathy s houl d be aggres s i vel y t reat ed. 



(1) Ti ght cont rol of bl ood gl ucos e ret ards progres s i on of renal di s eas e, es peci al l y i n t hos e pat i ent s wi t h t he earl i es t l es i ons (mi croal bumi nuri a).





(2) Res t ri ct i on of di et ary prot ei n (i .e., t o 20%) of i ndi vi dual s wi t h end-s t age renal fai l ure; t hey have angi ographi cal l y s i gni fi cant renal art ery s t enos i s . St udi es are underway t o det ermi ne t he opt i mal s t rat egi es for i dent i fyi ng and t reat i ng t hes e pat i ent s . The ri s ks of cont ras t -dyeâ€“as s oci at ed acut e renal fai l ure, chol es t erol embol i zat i on, and acut e renal art ery di s s ect i on have prevent ed many cl i ni ci ans from s ugges t i ng an aggres s i ve approach i n mos t pat i ent s . Int ervent i on i s i ndi cat ed i n t hos e wi t h s evere, uncont rol l abl e hypert ens i on, and i n t hos e pat i ent s wi t h di ffus e vas cul ar di s eas e wi t h cl earl y progres s i ve renal i ns uffi ci ency.






o

a. Acute, complete renal arterial occlusion us ual l y mani fes t s as fl ank pai n, hemat uri a, fever, naus ea, t i s s ue necros i s [as evi denced by el evat ed l act at e dehydrogenas e (LDH) and as part at e t rans ami nas e (AST)], and acut e renal fai l ure. The di agnos i s i s confi rmed us i ng radi onucl i de s canni ng or angi ography. Bi l at eral occl us i on and occl us i on of a s ol i t ary funct i oni ng ki dney produce s evere anuri c acut e renal fai l ure.

o

Pa g e 1 3 4 2


o

b. Chronic or segmental occlusion produces s ympt oms and s i gns commens urat e wi t h t he degree of i s chemi c damage i ncl udi ng progres s i ve renal fai l ure.

P.273





3. T herapy o

o

a. Therapy for renal art eri al t hrombos i s i s s urgi cal removal of t he cl ot t o res t ore renal bl ood fl ow. Bes t res ul t s are obt ai ned when t he operat i on i s conduct ed wi t hi n 48â€“72 hours fol l owi ng t he ons et of di s eas e.

o

o

b. Therapy for renal art eri al embol i s m, whi ch us ual l y i s di ffus e and i nvol ves l arge numbers of s mal l er art eri al branches , i s ant i coagul at i on wi t h hepari n and res ol ut i on of t he underl yi ng focus of embol i .

o

o

c. Therapy for i s chemi c nephropat hy may i nvol ve angi opl as t y, s t ent pl acement , or s urgi cal revas cul ari zat i on. W hi l e t he rol e of each of t hes e t herapi es cont i nues t o be expl ored, t here i s l i t t l e evi dence t hat ki dney funct i on can be s ubs t ant i al l y pres erved or t hat acut e renal i ns uffi ci ency due t o i s chemi c nephropat hy can be revers ed.

B. Renal vein thrombosis Obs t ruct i on of renal venous drai nage by a cl ot may be caus ed by

Pa g e 1 3 4 3


ext ens i on of cl ot s i n t he vena cava, i nvas i on of t he renal vei n by t umor, s evere dehydrat i on i n i nfant s , renal amyl oi dos i s , and cert ai n gl omerul ar di s eas es as s oci at ed wi t h nephrot i c s yndrome, part i cul arl y membranous gl omerul onephri t i s . Renal vei n t hrombos i s general l y i s not a caus e of gl omerul ar di s eas e. Renal vei n t hrombos i s may devel op duri ng nephros i s becaus e of l os s of ant i coagul ant prot ei ns and procoagul ant deact i vat ors i n t he uri ne prot ei n. 



1. Clinical features and diagnosis. Sl owl y evol vi ng renal vei n t hrombos i s may be compl et el y as ympt omat i c, whereas acut e renal vei n t hrombos i s may produce pai n, hemat uri a, cos t overt ebral angl e t endernes s , and, ul t i mat el y, s i gns of wors eni ng renal funct i on. The affect ed ki dney appears t o be enl arged when vi s ual i zed wi t h t he ai d of i nt ravenous urography. Sel ect i ve venography i s di agnos t i c. New t echni ques s uch as Doppl er ul t ras onography may be part i cul arl y us eful as a noni nvas i ve approach t o di agnos i s .





2. T herapy. Treat ment i s cont rovers i al , as i s t he bel i ef t hat renal vei n t hrombos i s predi s pos es t o pul monary embol i s m. Current t herapy i s l ong-t erm (3â€“6 mont hs ) ant i coagul at i on wi t h warfari n s odi um or l ow-mol ecul ar-wei ght hepari ns . Longer t reat ment i s recommended i f embol i c phenomena occur.

C. Renal artery stenosis In experi ment al ani mal s , i t has been cl earl y s hown t hat part i al reduct i on i n t he l umi nal s i ze of one or bot h renal art eri es produces renovas cul ar hypert ens i on, whi ch i s medi at ed i n mos t cas es by i ncreas ed reni n product i on wi t h res ul t ant act i vat i on of angi ot ens i n and al dos t erone. In humans , renal art ery s t enos i s i s a recogni zed caus e of renovas cul ar hypert ens i on. However, t he coi nci dence of radi ographi cal l y demons t rat ed renal art ery s t enos i s and cl i ni cal l y

Pa g e 1 3 4 4


demons t rat ed renovas cul ar hypert ens i on does not es t abl i s h a caus al rel at i ons hi p. 



1. Etiology o

o

a. Medial fibromuscular dysplasia occurs more commonl y i n young women.

o

o

b. Adul t s ol der t han 50 years of age have renal artery atherosclerosis, whi ch i s t wi ce as common i n men as i n women.

o

o

c. Rare caus es i ncl ude T akayasu' s arteritis, arterial wall disease (e.g., hemat oma, di s s ect i ng aneurys m, and t umor), and external arterial compression due t o t umor, fi bros i s , or cys t .





2. Clinical features. Si gns and s ympt oms i ncl ude a nearl y cont i nuous abdomi nal or fl ank brui t , hypokal emi a, mi l d met abol i c al kal os i s , and as ymmet ri c ki dney s i ze. None of t hes e i s a cons t ant fi ndi ng, and oft en t here i s no feat ure t o di s t i ngui s h renal art ery s t enos i s from es s ent i al hypert ens i on.





3. Diagnosis. Di agnos t i c s t rat egi es vary accordi ng t o cl i ni cal s us pi ci on. o

o

a. MRA, or rarel y, t radi t i onal angi ography i s t he met hod of choi ce for a defi ni t i ve di agnos i s . St enot i c s egment s are rel i abl y i dent i fi ed by t hi s

Pa g e 1 3 4 5


s t udy. o

o

b. Duplex ultrasonography al l ows noni nvas i ve det ermi nat i on of renal bl ood fl ow. Thi s procedure i s operat or-dependent and may not be t echni cal l y feas i bl e i n al l pat i ent s .

o

o

c. Renal vein renin studies. Angi ographi c proof t hat renal art ery s t enos i s i s et i ol ogi cal l y i mport ant i s di ffi cul t t o obt ai n. Fi ndi ng t hat t he renal vei n reni n from t he affect ed s i de i s 1.5 t i mes great er t han t hat from t he unaffect ed s i de i s hel pful , but pat i ent s may res pond t o t reat ment wi t hout t hi s bi ochemi cal fi ndi ng.





4. T herapy. Therapeut i c opt i ons are ant i hypert ens i ve drugs , percut aneous t rans l umi nal angi opl as t y (PCTA) wi t h or wi t hout s t ent i ng, and s urgi cal repai r of t he affect ed ves s el .

P.274

D. Microangiopathy: hemolyticâ€“uremic syndrome and thrombotic thrombocytopenic purpura (TTP) As members of t he di s eas e group t ermed mi croangi opat hi c hemol yt i c anemi a, hemol yt i câ€“uremi c s yndrome and TTP are s i mi l ar cl i ni cal s yndromes t hat s hare feat ures wi t h DIC, mal i gnant hypert ens i on, pos t part um renal fai l ure, s eps i s , and s ys t emi c s cl eros i s . 

Pa g e 1 3 4 6



o

a. T T P charact eri s t i cal l y mani fes t s as fever, mi croangi opat hi c hemol yt i c anemi a, t hrombocyt openi a, fl uct uat i ng neurol ogi c s i gns , purpura, and renal fai l ure. Gas t roi nt es t i nal i nvol vement (e.g., mucos al bl eedi ng and jaundi ce) i s common. In s ome cas es , t he et i ol ogi c agent i s an aut oant i body di rect ed t oward a prot eas e, whi ch cl eaves von W i l l ebrand's fact or.

o

o

b. Hemolyticâ€“uremic syndrome i s pri mari l y a pedi at ri c di s order charact eri zed by mi croangi opat hi c hemol yt i c anemi a, t hrombocyt openi a, and acut e renal fai l ure. The di s order may occur i n epi demi cs and has been report ed t o fol l ow s hi gel l os i s . Hemol yt i câ€“uremi c s yndrome us ual l y has a s udden and dramat i c ons et , wi t h renal fai l ure t he domi nant cl i ni cal feat ure. As i n TTP, ot her organ s ys t ems may be i nvol ved. Renal funct i on ret urns i n mos t pat i ent s who recover from s ys t emi c di s eas e, but rel aps es have been report ed.





2. Diagnosis o

o

a. Laboratory findings are s i mi l ar i n bot h di s orders . 



(1) Anemi a i s a cons t ant fi ndi ng, occurri ng i n as s oci at i on wi t h a vari et y of s t ruct ural l y damaged RBCs i n t he peri pheral ci rcul at i on. The ret i cul ocyt e count , fi bri n s pl i t product s ,

Pa g e 1 3 4 7


and i ndi rect bi l i rubi n l evel s are el evat ed. Serum LDH i s al s o el evat ed and i s t he mos t us eful cl i ni cal marker for fol l owi ng di s eas e progres s . Leukocyt os i s i s common, and t hrombocyt openi a i s s evere (i .e., 50â€“100 mOs m/kg i n t he pres ence of pl as ma hypot oni ci t y





(2) Uri ne s odi um concent rat i on: hi gh when pl as ma vol ume i s expanded i n SIADH but l ow when effect i ve art eri al bl ood vol ume i s reduced, as i n edemat ous condi t i ons . A uri ne s odi um concent rat i on l es s t han 20 mEq/L s t rongl y argues agai ns t SIADH.

o

o

c. Water loading test. W hen an i nt ravas cul arl y vol ume-expanded i ndi vi dual i s gi ven 20 mL wat er/kg oral l y or i nt ravenous l y over a peri od of 20â€“40 mi nut es , t he normal res pons e i s excret i on of 80% of t hi s wat er l oad wi t hi n 4 hours and reduct i on of uri ne os mol al i t y t o bel ow 100 mOs m/kg. Fai l ure t o achi eve t hes e res ul t s s ugges t s an i mpai rment i n t he ki dney's abi l i t y t o excret e wat er.





5. T herapy o

o

a. Fluid restriction. Al l pat i ent s who are s everel y hyponat remi c s houl d reduce free wat er i nt ake t o approxi mat el y 800 mL/day.

o

Pa g e 1 3 8 0


b. Inhibition of water reabsorption 



(1) Demeclocycline. Thi s agent has been s hown t o al t er ADH-i nduced wat er fl ow i n t he col l ect i ng t ubul e. Thi s drug mus t be gi ven i n dos es of 600â€“1200 mg/day and requi res 4â€“5 days t o achi eve i t s peak act i on. Demecl ocycl i ne cannot be admi ni s t ered t o pat i ent s wi t h l i ver di s eas e, heart fai l ure, or ki dney di s eas e, becaus e i t may accumul at e t o t oxi c l evel s i n t hes e condi t i ons .





(2) Furosemide. Acut e admi ni s t rat i on of t hi s agent i n combi nat i on wi t h l arge amount s of s al i ne may l ead t o i ncreas ed wat er excret i on.





(3) T olvaptan. Thi s agent i s an oral vas opres s i n wi t h rel at i ve affi ni t y for t he V2 recept or, whi ch has been s hown t o i nduce a di ures i s wi t h proport i onal i t y more free-wat er t han s odi um l os s . Current s t udi es are eval uat i ng t he us e of t hi s drug i n mi l d t o moderat e hyponat remi a.

o

o

c. Hypertonic infusions. The i nfus i on of 3% s odi um chl ori de rapi dl y rai s es t he t oni ci t y of t he ext racel l ul ar fl ui d. Thi s i s rarel y done due t o t he ri s k of del et eri ous effect s , i ncl udi ng pul monary or cerebral edema, pont i ne demyel i nat i on, and s evere neurol ogi c damage. W hen us ed, s erum s odi um concent rat i on s houl d not i ncreas e fas t er t han 0.5 mEq/L/hour.



Pa g e 1 3 8 1




6. Complications o

o

a. Acute hyponatremia. Acut e reduct i on of s erum os mol al i t y can produce i nt racrani al hypert ens i on and brai n damage, part i cul arl y i f t he s erum s odi um concent rat i on fal l s bel ow 125 mEq/L over a peri od of hours .

o

o

b. Chronic hyponatremia. Brai n cel l s adapt t o chroni c hyponat remi a by l os s of net i nt racel l ul ar s ol ut e (pri mari l y pot as s i um chl ori de and organi c mol ecul es , t ermed os mol yt es ). Thi s adapt at i on, whi ch can occur over a peri od of a few days , l eads t o marked reduct i on i n t he degree of cel l s wel l i ng.

C. Hypernatremia 



1. Definition. Hypernat remi a refers t o s erum s odi um concent rat i on t hat i s above normal . Cl i ni cal l y s i gni fi cant effect s are produced at s erum s odi um l evel s great er t han 155 mEq/L. Hypernat remi a al ways i mpl i es hypert oni ci t y of al l body fl ui ds , becaus e t he ri s e i n t he ext racel l ul ar fl ui d os mol al i t y obl i gat es movement of wat er from t he i nt racel l ul ar s pace, produci ng i ncreas ed i nt racel l ul ar os mot i c act i vi t y and cel l dehydrat i on.





2. Etiology o

o

a. Extrarenal causes 

Pa g e 1 3 8 2


(1) Decreased fluid intake. Adequat e wat er i nt ake i s requi red t o mai nt ai n t he t oni ci t y of body fl ui ds i n t he face of cont i nuous wat er l os s es t hrough t he s ki n as wel l as l os s es t hrough t he uri ne and gas t roi nt es t i nal t ract . In cool envi ronment s , t hi s i nt ake equal s approxi mat el y 700 mL/day. If i nt ake i s l es s t han ext ernal l os s es , body fl ui d os mol al i t y ri s es . P.279





(2) Increased skin losses. Profus e s weat i ng may l ead t o exces s wat er l os s es t hrough t he s ki n. In addi t i on, burns and ot her wi des pread i nfl ammat ory l es i ons of t he s ki n may caus e marked fl ui d l os s es .





(3) Increased gastrointestinal losses. Di arrhea and prot ract ed vomi t i ng al s o may res ul t i n wat er defi ci t s .

o

o

b. Renal causes 



(1) Osmotic diuresis. The pres ence of os mot i cal l y act i ve, nonreabs orbabl e s ol ut e i n t he gl omerul ar fi l t rat e prevent s wat er and s odi um reabs orpt i on and l eads t o i ncreas ed renal wat er l os s es . Hypergl ycemi a wi t h gl ycos uri a i s a common caus e of os mot i c di ures i s . Becaus e wat er l os s es are rel at i vel y great er t han s odi um l os s es , t he s erum s odi um

Pa g e 1 3 8 3


concent rat i on ri s es progres s i vel y duri ng os mot i c di ures i s . 



(2) Decreased ADH effect 



(a) Central diabetes insipidus (i .e., fai l ure of ADH s ynt hes i s or rel eas e) may occur i n t he fol l owi ng s et t i ngs : 



(i) T umor. ADH defi ci ency may occur ei t her t hrough di rect i nvas i on of t he neurohypophys i s or t hrough i ncreas ed i nt racrani al pres s ure compres s i ng t he brai ns t em.





(ii) Histiocytosis. Hand-SchÃ¼l l er-Chri s t i an di s eas e, i n part i cul ar, has a predi l ect i on for neurohypophys eal i nvol vement , produci ng ADH defi ci ency.





(iii) Sarcoidosis. The neurohypophys i s may be i nvol ved, produci ng di abet es i ns i pi dus .





(iv) T rauma. Cl as s i cal l y, aft er res ect i on of t he pi t ui t ary s t al k, a phas e of acut e ADH rel eas e i s fol l owed by a prol onged peri od of cent ral di abet es i ns i pi dus .



Pa g e 1 3 8 4




(b) Nephrogenic diabetes insipidus (i .e., fai l ure of renal wat er cons ervat i on des pi t e hi gh l evel s of pl as ma ADH) may occur i n t he fol l owi ng s et t i ngs . 



(i) Renal disease. St ruct ural di s eas e i mpai rs t he i nt egri t y of t he renal medul l a and, t hereby, t he uri ne concent rat i ng abi l i t y.





(ii) Hypercalcemia. El evat i on of s erum cal ci um concent rat i on above 12 mg/dL may i mpai r uri ne concent rat i ng abi l i t y, mos t l i kel y as a res ul t of i nhi bi t i on of s odi um chl ori de reabs orpt i on i n t he t hi ck as cendi ng l i mb of Henl e's l oop, i ncreas ed medul l ary bl ood fl ow, di s s i pat i on of medul l ary hypert oni ci t y, and i nt erference wi t h ADH-medi at ed wat er fl ow i n t he medul l ary col l ect i ng t ubul e.





(iii) Hypokalemia. Reduct i on of s erum pot as s i um concent rat i on bel ow 3.5 mEq/L l eads t o a di rect s t i mul at i on of t hi rs t and a mi l d i mpai rment of uri ne concent rat i ng abi l i t y.





(iv) Lithium ingestion. Thi s act i on bl ocks ADH-s t i mul at ed os mot i c

Pa g e 1 3 8 5


wat er fl ow i n t he col l ect i ng t ubul e. 



(v) Demeclocycline. Thi s t et racycl i ne ant i bi ot i c al t ers ADH-i nduced wat er fl ow t hrough a di rect effect on t he cel l membrane.





(vi) Sickle cell anemia. Reduced medul l ary bl ood fl ow produced by s i ckl i ng eryt hrocyt es wi t hi n t he vas a rect a al s o may i mpai r uri ne concent rat i ng abi l i t y.





(vii) Urinary tract obstruction and t he postobstructive state. Thes e condi t i ons are as s oci at ed wi t h nephrogeni c di abet es i ns i pi dus .






o

a. CNS disorders. General i zed CNS depres s i on, i ncl udi ng obt undat i on, coma, and s ei zures , devel ops i n young chi l dren and el derl y pat i ent s . Int racerebral and s ubarachnoi d hemorrhage may occur i f s hri nkage of brai n vol ume l eads t o t ears i n t he bri dgi ng vei ns .

o

o

b. Extracellular volume depletion. Exces s i ve wat er l os s i n hypernat remi c s t at es may l ead t o t hi s condi t i on. Al t hough t he i nt racel l ul ar fl ui d account s for t wo-t hi rds of wat er defi ci t s , t he ext racel l ul ar

Pa g e 1 3 8 6


fl ui d vol ume al s o cont ract s mi l dl y. If l os s of wat er as wel l as s ol ut e occurs , t he cont ract i on i s more pronounced. However, i f t he et i ol ogy of t he hypernat remi a i s due t o exces s s al t i nt ake (e.g., hypert oni c s odi um bi carbonat e i nfus i on or s ea-wat er drowni ng), t he ext racel l ul ar fl ui d vol ume i ncreas es . o

o

c. Abnormal urine output. If t he ki dneys caus e wat er l os s es , pol yuri a (i .e., uri ne out put t hat i s i nappropri at el y hi gh gi ven t he l evel of pl as ma os mol al i t y or ext racel l ul ar fl ui d vol ume) may be pres ent . If t he ki dneys are normal and wat er l os s es are ext rarenal , uri ne vol ume t ypi cal l y i s reduced.

P.280





4. Diagnosis o

o

a. Dehydration test. Uri ne concent rat i ng abi l i t y may be t es t ed aft er overni ght dehydrat i on t o det ermi ne whet her a pat i ent has renal wat er was t i ng. 



(1) W at er depri vat i on begi ns at 8:00 p.m. and l as t s 14 hours , aft er whi ch t he uri ne os mol al i t y s houl d exceed 800 mOs m/kg. The pat i ent t hen i s gi ven a s ubcut aneous dos e of ADH (5 U aqueous vas opres s i n). The uri ne os mol al i t y s houl d not be furt her i ncreas ed by t hi s maneuver.



Pa g e 1 3 8 7




(2) If t he uri ne os mol al i t y i s l es s t han 800 mOs m/kg aft er wat er depri vat i on or i f i t i ncreas es by great er t han 15% aft er ADH admi ni s t rat i on, s ome degree of ADH defi ci ency i s pres ent .





(3) If t he uri ne os mol al i t y does not exceed 300 mOs m/kg aft er wat er depri vat i on and t here i s no furt her i ncreas e aft er ADH admi ni s t rat i on, s ome form of nephrogeni c di abet es i ns i pi dus i s pres ent .

o

o

b. Plasma ADH assay. In nephrogeni c di abet es i ns i pi dus , t he uri ne os mol al i t y may not be a t rue refl ect i on of ADH rel eas e, and, t hus , pl as ma ADH l evel s s houl d be meas ured.

o

o

c. Assay of urine osmolality and composition 



(1) It i s us eful t o meas ure t he s ol ut e compos i t i on of t he uri ne i n t he eval uat i on of pol yuri a. Uri ne os mol al i t y l es s t han 200 mOs m/L s ugges t s a pri mary defect i n wat er cons ervat i on. Uri ne os mol al i t y great er t han 200 mOs m/L duri ng pol yuri a s ugges t s an os mot i c di ures i s .





(2) Aft er meas uri ng uri ne os mol al i t y, t he uri ne s houl d be anal yzed for s odi um, gl ucos e, and urea t o det ermi ne t he et i ol ogy of t he di ures i s . A uri ne pH great er t han 6 may

Pa g e 1 3 8 8


i ndi cat e bi carbonat e di ures i s . o

o

d. Physical examination. Al t hough exami nat i on may be hel pful i n det ermi ni ng i f hypovol emi a or hypervol emi a i s pres ent , i t i s general l y not us eful i n det ermi ni ng t he et i ol ogy and pat hogenes i s of pol yuri a.





5. T herapy o

o

a. Free water may be admi ni s t ered oral l y, whi ch i s t he preferred rout e, or i nt ravenous l y as a 5% dext ros e s ol ut i on (D 5 W ). The dext ros e i s readi l y met abol i zed, l eavi ng behi nd free wat er. Infus i on of a fl ui d wi t h an os mol al i t y l es s t han 150 mOs m/L i s dangerous and may l ead t o acut e hemol ys i s at t he i nfus i on s i t e.

o

o

b. Vasopressin may be admi ni s t ered i n s everal di fferent forms . Current l y, t he agent of choi ce for t reat ment of ADH defi ci ency i s 1-deamino-8-D-arginine vasopressin (DDAVP or desmopressin), whi ch may be admi ni s t ered oral l y or as a nas al s pray every 12 hours .

o

o

c. T hiazide diuretics i mpai r di l ut i on i n t he di s t al nephron and s t i mul at e proxi mal t ubul ar reabs orpt i on of s odi um and wat er as a res ul t of vol ume depl et i on. The l at t er act i on reduces t he del i very of fl ui d t o t he di s t al nephron, t hereby reduci ng t he degree of pol yuri a. Thi azi des are us eful as adjunct t herapy i n pat i ent s wi t h

Pa g e 1 3 8 9


nephrogeni c di abet es i ns i pi dus . o

o

d. Other drugs s uch as cl ofi brat e, carbamazepi ne, and chl orpropami de enhance t he renal t ubul ar effect s of ADH and pos s i bl y cont ri but e t o t he s t i mul at i on of ADH rel eas e i n cert ai n s et t i ngs .





6. Complications. Di s eas es of wat er cons ervat i on are dangerous onl y i f pat i ent s are not al l owed acces s t o wat er. In s uch s et t i ngs , cel l ul ar dehydrat i on, CNS depres s i on, and s evere vol ume depl et i on may occur. The s eri ous mani fes t at i ons of acut e hypernat remi a are pri mari l y due t o brai n cel l s hri nkage. Brai n cel l s adapt t o chroni c hypernat remi a by net gai n of i nt racel l ul ar s ol ut e (mai nl y s odi um chl ori de and organi c os mol yt es s uch as myo-i nos i t ol , t auri ne, bet ai ne, and ot her met hyl ami nes ). Thi s adapt at i on, occurri ng over s everal days , l eads t o marked reduct i on i n t he degree of cel l s hri nkage.

II. Sodium Metabolism A. Normal physiology Sodi um i s t he pri mary os mot i c component of t he ext racel l ul ar fl ui d, and det ermi nes t he vol ume of t hat s pace and t he â€œful l nes s ,â€• or effect i ve vol ume, of t he s ys t emi c ci rcul at i on. A l es s t han 1% change i n renal s odi um excret i on can produce major changes i n ext racel l ul ar fl ui d vol ume. 



1. Renal handling. Sodi um i s freel y fi l t ered at t he gl omerul us , and t he majori t y mus t be reabs orbed t o mai nt ai n s odi um homeos t as i s . Al t hough onl y 10%â€“15% of t he gl omerul ar fi l t rat e i s reabs orbed P.281

Pa g e 1 3 9 0


i n t he di s t al t ubul e and col l ect i ng duct , t hi s s i t e i s t he major regul at or for det ermi ni ng fi nal uri ne s odi um compos i t i on. 



2. Hormonal regulation. Many hormones may al t er t ubul ar handl i ng of s odi um, but none i s as wel l s t udi ed as al dos t erone, whi ch i s regul at ed by t he reninâ€“angiotensin system. o

o

a. Reni n s ecret i on by t he ki dney i s s t i mul at ed by renal hypoperfus i on, adrenergi c s t i mul at i on, and ci rcul at i ng cat echol ami nes . Reni n i s rel eas ed from t he juxtaglomerular apparatus, whi ch i s l ocat ed bet ween t he afferent and t he efferent art eri ol es of t he gl omerul i .

o

o

b. Reni n i s an enz yme t hat cat al yzes t he convers i on of angiotensinogen t o t he decapept i de angiotensin I (i n pl as ma). Angi ot ens i n I i s convert ed t o t he oct apept i de angiotensin II (i n t he l ung and ki dney) by ACE. Angi ot ens i n II i s a pot ent vas ocons t ri ct i ve agent as wel l as a pot ent s t i mul us for i ncreas ed al dos t erone rel eas e from t he adrenal gl and.

o

o

c. Al dos t erone s t i mul at es s odi um reabs orpt i on i n t he cort i cal col l ect i ng duct .

o

d. Ot her hormones t hat regul at e s odi um handl i ng are l i s t ed i n Onl i ne Tabl e 6-15.

Pa g e 1 3 9 1


o

Online TABLE 6-15 Other Hormones and Their Reactions to Sodium Handling Act ion on So diu m Ho T r rm an on sp e ort At r Inh i al i bi t nat s ri ur ren et i al c

rea

pe bs o pt i rpt i de on (co l l ec tin g duc t) Do Int pa rar mi en ne al l y ge

Pa g e 1 3 9 2


ner at e d; i nh i bi t s pro xi m al t ub ul e s od iu m rea bs o rpt i on Pro Int s t a rar gl a en ndi al l ns y ge ner at e d; i nh i bi t t ub ul a r s od iu m

Pa g e 1 3 9 3


rea bs o rpt i on an d vas odi l at e t he ki d ney

B. Edema 



1. Definition o

o

a. Edema general l y i s defi ned as an i ncreas e i n t he i nt ers t i t i al compart ment of t he ext racel l ul ar fl ui d. 



(1) Normal l y, t he ext racel l ul ar fl ui d vol ume equal s approxi mat el y 14 L and account s for one-t hi rd of t he t ot al body wat er. About 25% of t he ext racel l ul ar fl ui d i s repres ent ed by pl as ma vol ume and i s cont ai ned wi t hi n t he ci rcul at i on. The ot her 75% or 11 L i s repres ent ed by t he i nt ers t i t i al fl ui d bet ween cel l s .





(2) If t he i nt ers t i t i al fl ui d vol ume i ncreas es by approxi mat el y 2 L, cl i ni cal l y evi dent edema

Pa g e 1 3 9 4


may res ul t ; edema may be observable (as swelling) or palpable (as pitting). o

o

b. Al t hough edema general l y i s a funct i on of i ncreas ed ext racel l ul ar fl ui d vol ume, i n s ome i ns t ances i ncreas ed t rans capi l l ary hydros t at i c pres s ure (e.g., as occurs i n t he port al ci rcul at i on i n ci rrhos i s ) al s o may cont ri but e t o edema.





2. Pathophysiology. Edema, or t he pat hol ogi c i ncreas e i n ext racel l ul ar fl ui d vol ume, pri mari l y i s a funct i on of exces s i ve renal t ubul ar reabs orpt i on of s odi um. Decreas ed renal perfus i on (e.g., as occurs i n CHF wi t h reduced cardi ac out put , i n ci rrhos i s wi t h reduced effect i ve art eri al bl ood vol ume, and i n t he nephrot i c s yndrome) i s t he proxi mat e caus e of t he i ncreas ed renal s odi um reabs orpt i on, whi ch repres ent s t he body's at t empt t o mai nt ai n adequat e effect i ve art eri al bl ood vol ume.





3. Etiology o

o

a. CHF. W hen cardi ac out put i s reduced, effect i ve art eri al bl ood vol ume i s decreas ed as wel l . The decreas e i n effect i ve art eri al bl ood vol ume t ri ggers t he rel eas e of reni n and al dos t erone, l eadi ng t o s t i mul at i on of di s t al t ubul ar reabs orpt i on of s odi um. In addi t i on, al t erat i ons i n renal hemodynami cs s t i mul at e an i ncreas e i n t he proxi mal t ubul ar reabs orpt i on of s odi um.

o

o

b. Cirrhosis. The pri mary caus e of s odi um ret ent i on

Pa g e 1 3 9 5


i n l i ver di s eas e may be as ci t es format i on as a res ul t of hi gh pres s ure i n t he port al ci rcul at i on. Port al hypert ens i on l eads t o i nt ravas cul ar fl ui d vol ume depl et i on and s econdary renal s odi um ret ent i on. W hen hypoal bumi nemi a occurs , effect i ve art eri al bl ood vol ume drops , s t i mul at i ng renal s odi um ret ent i on. Secondary hyperal dos t eroni s m i s common and i s caus ed by i nt ravas cul ar vol ume cont ract i on as wel l as i mpai red hepat i c cl earance of al dos t erone; t hes e fact ors l ead t o s t i mul at i on of di s t al t ubul ar reabs orpt i on of s odi um. A pri mary i ncreas e i n renal s odi um reabs orpt i on may occur i n ci rrhos i s . o

o

c. Nephrotic syndrome. Hypoal bumi nemi a l eads t o reduced effect i ve art eri al bl ood vol ume, as a res ul t of renal prot ei n l os s es , whi ch s t i mul at es renal t ubul ar reabs orpt i on of s odi um.

o

o

d. Chronic renal failure. W hen t he GFR fal l s t o l es s t han 10 mL/mi nut e, t he capaci t y of t he ki dney t o excret e t he t ypi cal di et ary s odi um l oad i s l i mi t ed, and edema may res ul t .

o

o

e. Excessive mineralocorticoid activity. Tumors of t he adrenal gl and and pi t ui t ary t umors t hat s ecret e l arge amount s of ACTH may be as s oci at ed wi t h marked s odi um ret ent i on.






o

a. Peripheral edema. Sodi um ret ent i on may

Pa g e 1 3 9 6


mani fes t as s wel l i ng i n t he dependent regi ons of t he body. o

o

b. Pulmonary edema. If pul monary venous pres s ure acut el y ri s es above 18 mm Hg, pul monary edema may devel op.

P.282





5. Diagnosis o

o

a. On physical examination, peri pheral edema may be i dent i fi ed by t he pers i s t ence of an i ndent at i on fol l owi ng pal pat i on of t he s oft t i s s ues i n t he dependent areas . Pul monary edema i s i dent i fi ed by t he phys i cal fi ndi ngs of ral es or wheezes or by ches t radi ography.

o

o

b. Urine sodium assay reveal s a uri ne s odi um l evel t hat i s l es s t han s odi um i nt ake and t hat us ual l y i s s i gni fi cant l y l es s t han 20 mEq/L.





6. T herapy o

o

a. Dietary sodium restriction i s es s ent i al . A s odi um i nt ake of 2 g/day i s t he l owes t pract i cal i nt ake l evel t hat can be achi eved.

o

o

b. Diuretics are us eful for i ncreas i ng s odi um

Pa g e 1 3 9 7


excret i on. 



(1) Loop diuretics s uch as furos emi de, t ors emi de, and bumet ani de are part i cul arl y effect i ve. Si de effect s of t hes e drugs i ncl ude i nt ravas cul ar vol ume depl et i on wi t h azot emi a, hyperuri cemi a, hypokal emi a, met abol i c al kal os i s , and hypomagnes emi a.





(2) T hiazide diuretics s uch as hydrochl orot hi azi de i nhi bi t s odi um reabs orpt i on i n t he di s t al convol ut ed t ubul e. They can be us ed effect i vel y, al t hough t hey are l es s pot ent t han l oop di uret i cs . Si de effect s are s i mi l ar t o t hos e of l oop di uret i cs .





(3) Potassium-sparing diuretics s uch as ami l ori de and t ri amt erene act pri mari l y t o bl ock s odi um reabs orpt i on and s econdari l y t o bl ock pot as s i um s ecret i on i n t he di s t al t ubul e. Us e of t hes e agent s may l ead t o pot as s i um ret ent i on and i ncreas ed s odi um excret i on.





(4) Aldosterone antagonists s uch as t he compet i t i ve agent s pi ronol act one or epl erenone al s o l ead t o pot as s i um ret ent i on and i ncreas ed s odi um excret i on.

III. Potassium Metabolism

A. Normal physiology

Pa g e 1 3 9 8


Pot as s i um i s t he pri mary cat i oni c component of t he i nt racel l ul ar fl ui d, whi ch cont ai ns approxi mat el y 4000 mEq pot as s i um. In compari s on, t he ext racel l ul ar fl ui d cont ai ns very l i t t l e pot as s i umâ€”about 65 mEq. The rat i o of ext racel l ul ar t o i nt racel l ul ar pot as s i um concent rat i on i s an i mport ant det ermi nant of el ect ri cal act i vi t y i n exci t abl e membranes (e.g., t he cardi ac conduct i on s ys t em and s omat i c nerve endi ngs ). The normal di et ary pot as s i um i nt ake of 60â€“90 mEq/day mus t be excret ed by t he ki dney t o pres erve pot as s i um homeos t as i s . Al s o, di et ary pot as s i um i nt ake mus t be t aken up rapi dl y by cel l s i n preparat i on for renal excret i on; ot herwi s e, t he s erum pot as s i um rapi dl y ri s es t o l i fe-t hreat eni ng l evel s . 



1. Extrarenal handling. Cel l ul ar upt ake of pot as s i um i s i nfl uenced by t he fol l owi ng ext rarenal fact ors : o

o

a. Insulin. Hi gh i ns ul i n l evel s s t i mul at e cel l ul ar upt ake of pot as s i um.

o

o

b. Epinephrine. Thi s Î² 2 -act i ve cat echol ami ne di rect l y s t i mul at es cel l ul ar upt ake of pot as s i um. Thi s act i on may be part i cul arl y i mport ant duri ng s evere exert i on, when s erum pot as s i um l evel s ri s e becaus e of mus cl e i s chemi a.





2. Renal handling. Mos t uri ne pot as s i um i s t he res ul t of di s t al t ubul ar s ecret i on. Several fact ors are known t o al t er pot as s i um s ecret i on. o

o

a. Aldosterone secretion. Al dos t erone di rect l y s t i mul at es pot as s i um s ecret i on and s odi um reabs orpt i on i n t he col l ect i ng t ubul e of t he ki dney.

Pa g e 1 3 9 9


o

b. Sodium reabsorption. The del i very of fl ui d and s odi um t o t he col l ect i ng t ubul e al s o s t i mul at es pot as s i um s ecret i on. Thi s mechani s m account s for t he i ncreas ed pot as s i um s ecret i on caus ed by di uret i cs , whi ch act at more proxi mal s i t es i n t he nephron t o bl ock s odi um reabs orpt i on.

B. Hypokalemia 



1. Definition. Hypokal emi a i s defi ned as s erum pot as s i um concent rat i on of l es s t han 3.5 mEq/L. Becaus e mos t of t he pot as s i um cont ent of t he body i s wi t hi n cel l s and cel l ul ar pot as s i um concent rat i on i s about 155 mEq/L, cel l ul ar pot as s i um can be s everel y depl et ed wi t hout caus i ng l arge changes i n s erum pot as s i um.





2. Etiology. Hypokal emi a can res ul t from ext rarenal or renal caus es . o

o




(1) Dietary deficiency and gastrointestinal losses 



(a) Inadequate dietary intake. Becaus e pot as s i um cons ervat i on i n t he ki dney i s l i mi t ed, a s evere reduct i on of i nt ake t o l es s t han 10 mEq/day for many days or weeks can l ead t o a l arge negat i ve

Pa g e 1 4 0 0


pot as s i um bal ance and hypokal emi a. 



(b) Diarrhea. Becaus e t he pot as s i um cont ent of di arrheal fl ui d may be as hi gh as 100 mEq/L, di arrhea can l ead t o s evere pot as s i um depl et i on.





(c) Vomiting. Al t hough t he pot as s i um cont ent of vomi t us i s rel at i vel y s mal l , t he s econdary effect of i nt ravas cul ar vol ume depl et i on, whi ch produces s econdary hyperal dos t eroni s m, s t i mul at es renal pot as s i um excret i on.





(2) Potassium redistribution 



(a) Insulin administration. A t herapeut i c or repl acement dos e of i ns ul i n can dri ve pot as s i um i nt o cel l s , produci ng acut e hypokal emi a.





(b) Epinephrine infusions. Epi nephri ne al s o can produce acut e hypokal emi a by an i ndependent act i on i nvol vi ng Î² 2 -recept ors .





(c) Folic acid and vitamin B 1 2 therapy. In pat i ent s wi t h megal obl as t i c anemi a, fol i c aci d and vi t ami n B 1 2 s t i mul at e cel l prol i ferat i on, t hus produci ng acut e hypokal emi a, becaus e pot as s i um i s us ed

Pa g e 1 4 0 1


i n cel l s ynt hes i s . Thi s effect al s o may be s een i n pat i ent s wi t h rapi dl y growi ng t umors . 



(d) Alkalemia. In t he pres ence of exces s bas e, hydrogen i ons s hi ft out of cel l s i n exchange for pot as s i um.





(e) Hypokalemic periodic paralysis. In t hi s rare s yndrome, pot as s i um l evel s fal l acut el yâ€”wi t hout a l os s of pot as s i um from t he bodyâ€”pri or t o epi s odes of paral ys i s . Thi s s yndrome, whi ch i s commonl y as s oci at ed wi t h t hyroi d di s eas e i n As i ans , probabl y repres ent s a defect i n cat echol ami ne s ens i t i vi t y.

P.283

o

o

b. Renal causes. Any hyperact i vi t y of t he normal component s of renal pot as s i um excret i on can produce a negat i ve pot as s i um bal ance vi a i ncreas ed renal l os s es . 



(1) Drug-induced renal losses 



(a) Diuretics. Agent s t hat act proxi mal t o t he s i t e of pot as s i um s ecret i on s t i mul at e uri nary excret i on of pot as s i um by i ncreas i ng t he del i very of s odi um and fl ui d t o t he di s t al t ubul es .

Pa g e 1 4 0 2




(b) Penicillins. Carbeni ci l l i n, t i carci l l i n, and rel at ed drugs act as nonreabs orbabl e ani ons i n t he di s t al t ubul e and t hereby s t i mul at e pot as s i um s ecret i on. Si gni fi cant hypokal emi a i s commonl y s een.





(c) Aminoglycosides. Tubul ar defect s wi t h magnes i um was t i ng and s econdary pot as s i um was t i ng occas i onal l y may be s een i n pat i ent s t reat ed wi t h l arge dos es of gent ami ci n or rel at ed compounds .





(d) Amphotericin B. Thi s ant i fungal agent caus es damage t o t he api cal membrane of t he renal t ubul ar cel l , t hus i ncreas i ng pot as s i um l os s from t he cel l .





(2) Hormone-induced renal losses 



(a) Primary hyperaldosteronism 



(i) Primary adrenal adenomas are as s oci at ed wi t h hypokal emi a, hypert ens i on, and met abol i c al kal os i s .





(ii) Diffuse bilateral adrenal hyperplasia may be as s oci at ed wi t h

Pa g e 1 4 0 3


a mi l der hypokal emi a t han i s s een wi t h pri mary adrenal adenoma. 



(iii) In ectopic ACT H syndrome, mas s i ve mi neral ocort i coi d i ncreas e and renal pot as s i um was t i ng may occur i n pat i ent s wi t h s mal l cel l l ung carci noma (a t umor t hat produces and s ecret es ACTH).





(iv) Exogenous mineralocorticoid. Licorice produced i n Europe (ani s e) cont ai ns glycyrrhetinic acid, whi ch prevent s convers i on of cort i s ol t o cort i s one i n t he renal di s t al t ubul e, t hereby s t i mul at i ng mi neral ocort i coi d recept ors and produci ng an al dos t erone-l i ke act i on. Inges t i on of t hi s agent may l ead t o hypokal emi a wi t h hypert ens i on and met abol i c al kal os i s . Cert ai n tobacco compounds al s o cont ai n gl ycyrrhet i ni c aci d and may caus e hypokal emi a.





(b) Secondary hyperaldosteronism 



(i) Renin-secreting tumor. Thi s rare ent i t y, di agnos ed by art eri ography, i s charact eri zed by i nt rarenal t umors of t he juxt agl omerul ar apparat us . Severe

Pa g e 1 4 0 4


hypert ens i on and hypokal emi a may occur. 



(ii) Renal artery stenosis may be as s oci at ed wi t h hypokal emi a and hypert ens i on as a res ul t of s econdary hyperal dos t eroni s m produced by hyperreni nemi a.





(iii) In malignant hypertension, s evere underperfus i on of t he ki dney may occur and may l ead t o hyperreni nemi a, s econdary hyperal dos t eroni s m, and hypokal emi a.





(iv) Disorders with reduced effective arterial blood volume produce onl y mi l d hypokal emi a des pi t e hyperreni nemi a and hyperal dos t eroni s m. Reduced t ubul ar fl ow rat e reduces pot as s i um s ecret i on. In CHF, s econdary hyperal dos t eroni s m may devel op, caus i ng mi l d hypokal emi a even i n t he abs ence of di uret i c us e. In cirrhosis, s evere hypokal emi a i s common becaus e of l ow i nt ake of pot as s i um and s econdary hyperal dos t eroni s m.





(3) Potassium loss due to primary renal tubular disorders

Pa g e 1 4 0 5




(a) Renal tubular acidosis i s oft en as s oci at ed wi t h pot as s i um was t i ng, whi ch may be s econdary t o s odi um depl et i on and met abol i c aci dos i s or di rect l y at t ri but abl e t o t ubul ar defect s i n pot as s i um cons ervat i on. Pot as s i um was t i ng i s a feat ure of di s t al (t ype I) as wel l as proxi mal (t ype II) renal t ubul ar aci dos i s of any et i ol ogy.





(b) Bartter' s syndrome and Gitelman' s syndrome are charact eri zed by renal pot as s i um was t i ng, met abol i c al kal os i s , and pol yuri a. Bl ood pres s ure us ual l y i s normal or reduced, but reni n and al dos t erone l evel s are very hi gh. In Bartter' s syndrome, t he pri mary defect l i es i n one of t he epi t hel i al t rans port prot ei ns i nvol ved i n t he reabs orpt i on of s odi um chl ori de, mos t commonl y t he +

+

furos emi de-s ens i t i ve Na â€“K â€“2Cl

-

cot rans port er i n t he as cendi ng l i mb of Henl e's l oop. In Gitelman' s syndrome, t he pri mary defect i nvol ves t he +

t hi azi de-s ens i t i ve Na â€“Cl

-

cot rans port er i n t he di s t al convol ut ed t ubul e. P.284





(c) Chronic magnesium depletion

Pa g e 1 4 0 6


produces a s yndrome of renal t ubul ar pot as s i um was t i ng wi t hout ot her as s oci at ed defect s i n i on t rans port . The pot as s i um was t i ng can be s evere and i s unres pons i ve t o pot as s i um repl et i on unt i l magnes i um defi ci t s have been correct ed. 



(4) Potassium loss due to surreptitious diuretic use i s as s oci at ed wi t h a cl i ni cal pres ent at i on i dent i cal t o t hat of Bart t er's or Gi t el man's s yndrome, i ncl udi ng hypokal emi a, magnes i um was t i ng, met abol i c al kal os i s , hyperreni nemi a, and hyperal dos t eroni s m.






o

a. Neuromuscular disorders. Pot as s i um depl et i on may caus e weaknes s and paral ys i s .

o

o

b. Cardiac disorders. Arrhyt hmi a, part i cul arl y i n t he pres ence of di gi t al i s i nt oxi cat i on, i s a hal l mark of s evere hypokal emi a.

o

o

c. Endocrine disorders. Hypokal emi a i s as s oci at ed wi t h abnormal i t i es i n pancreat i c i ns ul i n rel eas e. Gl ucos e i nt ol erance has been s hown t o wors en as a res ul t of di uret i c-i nduced hypokal emi a.

o

o

d. Polyuria. The pol yuri a of hypokal emi a i s a funct i on of pol ydi ps i a as wel l as i mpai red ADH

Pa g e 1 4 0 7


act i on. 



4. Diagnosis o

o

a. Physical examination. The pres ence or abs ence of hypert ens i on i s a us eful di fferent i at i ng feat ure i n t he approach t o t he pat i ent wi t h hypokal emi a. 



(1) If t he pat i ent i s hypert ens i ve, t he hypokal emi a may be caus ed by exces s i ve mi neral ocort i coi d act i vi t y. Becaus e many hypert ens i ve pat i ent s are t reat ed wi t h di uret i cs , any hypokal emi a coul d be a s i de effect of s uch t herapy.





(2) If t he pat i ent i s normot ens i ve, t he hypokal emi a repres ent s ei t her a gas t roi nt es t i nal or a pri mary renal l os s of pot as s i um.

o

o

b. Serum electrolyte assay. Thi s t es t rarel y i s us eful for eval uat i ng t he s peci fi c caus e of hypokal emi a. However, t he fi ndi ng of combi ned aci dos i s and hypokal emi a, whi ch s ugges t s renal t ubul ar aci dos i s , i s an except i on.

o

o

c. Urine potassium assay. Uri ne pot as s i um l evel s bel ow 20 mEq/L s ugges t ext rarenal pot as s i um l os s es , whereas l evel s exceedi ng 30 mEq/L s ugges t renal l os s es .

o

Pa g e 1 4 0 8


o

d. Reninâ€“aldosterone axis assay 



(1) Noninvasive tests. Several noni nvas i ve t ext s can be us ed t o det ermi ne whet her exces s i ve mi neral ocort i coi d act i vi t y i s due t o exces s i ve reni n product i on or t o a pri mary adrenal di s order (Tabl e 6-16).





(2) Invasive tests i ncl ude meas urement of bi l at eral renal venous reni n as wel l as adrenal venous al dos t erone and cort i s ol concent rat i ons . However, t hes e t es t s are rarel y performed, as t he di agnos i s can us ual l y be made by noni nvas i ve means .

TABLE 6-16 Reninâ€“Aldosterone Axis Assay Sig nifi Me ca T e tho nc st d e Re 40 No ni n mg s t i s t i fur mu mu os e l at i l at i mi on on de of t es i s t

ren

ad i n mi l ev ni s el s

Pa g e 1 4 0 9


t er i n ed; upr t he i gh n

t

pl a pos sm itio a

n

ren i nd in

i ca

is

t es

me ren as u i n red s up in

pre

bot s s i h

on

s up i ne an d upr i gh t pos itio ns Al d 1â Lac os t €“2 k ero L

of

ne of

al d

s up s al os t pre i ne ero s s i are ne on i nf s up t es us e pre

Pa g e 1 4 1 0


t

d; s s i t he on n

to

pl a bel s

ow

ma nor al d ma os t l ero ma ne y is

i nd

me i ca as u t e red pri in

ma

bot ry h

al d

s up os t i ne ero an ne d

ove

upr rpr i gh od t

uct

pos i on itio ns Pl a Ser Val s m um ue a

ren gre

al d i n

at e

os t an r ero d

t ha

neal d n t o- os t 15

Pa g e 1 4 1 1


ren ero i s in

ne hi g

rat i l ev hl y o

el s s ug are ges me t i v as u e red of pri ma ry hyp era l do ste ron

ism Bi l (s e Hy at e e

per

ral â€ t en ren œT s i o al

es t n

ven â€ of ous •

al d

ren col os t i n; um ero adr n) no en

ma

al

is

ven

res

ous

po

al d

ns i

os t

ve

ero

to

ne

tu

Pa g e 1 4 1 2


an

mo

d

r

cor

re

tis

mo

ol

val

con

(hy

cen

per

t ra

t en

tio

sio

ns

n as s oci at e d wi t h bi l at e ral di s eas e is not )



P.285



o

o

e. Urine chloride assay. In cas es of mi neral ocort i coi d exces s , Bart t er's or Gi t el man's s yndrome, and di uret i c abus e, uri ne chl ori de l evel s t end t o be el evat ed i n t he pres ence of met abol i c al kal os i s and hypokal emi a. The abs ence of

Pa g e 1 4 1 3


el evat ed uri ne chl ori de l evel s i s hi ghl y s ugges t i ve of gas t roi nt es t i nal pot as s i um l os s es s uch as s urrept i t i ous vomi t i ng. o

o

f. Diuretic assay. If Bart t er's or Gi t el man's s yndrome i s s us pect ed, t he uri ne mus t be anal yzed for chl ori de and di uret i cs , i ncl udi ng l oop-act i ve agent s and t hi azi des , before a di agnos i s of a pri mary t ubul ar di s order can be es t abl i s hed. Such di uret i c as s ays are commerci al l y avai l abl e.





5. T herapy. In many cas es , hypokal emi a can be correct ed by admi ni s t rat i on of pot as s i um s al t s . o

o

a. Forms of potassium salts. Pot as s i um may be admi ni s t ered wi t h a vari et y of ani ons . Pot as s i um chl ori de i s t he preferred form of t herapy, becaus e many pat i ent s have concurrent chl ori de defi ci t s . In cas es of hypokal emi a wi t h coi nci dent renal t ubul ar aci dos i s , pot as s i um ci t rat e, pot as s i um l act at e, or pot as s i um gl uconat e may be gi ven.

o

o

b. Routes of administration. Pot as s i um may be gi ven i nt ravenous l y or oral l y. 



(1) Int ravenous pot as s i um s ol ut i ons s houl d not exceed a concent rat i on of 60 mEq/L, and t he rat e of admi ni s t rat i on s houl d not exceed 60 mEq/hour. Normal l y, pot as s i um defi ci t s are on t he order of 300â€“1000 mEq. Thes e defi ci t s s houl d be repl aced s l owl y, over days , except when di gi t al i s i nt oxi cat i on or

Pa g e 1 4 1 4


l i fe-t hreat eni ng arrhyt hmi as are pres ent . 



(2) Oral pot as s i um i s abs orbed effect i vel y and s houl d be s ubs t i t ut ed for i nt ravenous pot as s i um whenever pos s i bl e.

o

o

c. Chronic potassium therapy. Hypokal emi c pat i ent s recei vi ng di uret i cs s houl d be gi ven pot as s i um s uppl ement at i on t o mai nt ai n t he s erum pot as s i um l evel above 3.5 mEq/L. This l evel may be accompl i s hed wi t h oral pot as s i um s uppl ement at i on. Al t hough s ome foods are hi gh i n pot as s i um, i t i s di ffi cul t t o overcome t hes e defi ci t s s ol el y by i nges t i ng pot as s i um-ri ch food.

C. Hyperkalemia 



1. Definition. Hyperkal emi a i s defi ned as s erum pot as s i um concent rat i on great er t han 5.5 mEq/L.





2. Etiology. Pseudohyperkalemia may be caus ed by rel eas e of pot as s i um from coagul at ed cel l s and pl at el et s aft er bl ood i s wi t hdrawn for anal ys i s . It can al s o occur i f t he pl at el et or whi t e bl ood cel l (W BC) count i s ext remel y hi gh, as i n myel oprol i ferat i ve di s orders . Meas urement of pl as ma pot as s i um i s requi red t o el i mi nat e t hi s art i fact . T rue hyperkalemia may res ul t from ext rarenal or renal caus es . o

o


Pa g e 1 4 1 5


(1) Insulin deficiency. Hyperkal emi a i n di abet i c pat i ent s may be due t o a l ack of i ns ul i n and t o t he pres ence of as s oci at ed renal and adrenal abnormal i t i es .





(2) Cell lysis syndromes. Acut e cel l necros i s fol l owi ng ei t her chemot herapy or a mas s i ve crus hi ng i njury (rhabdomyolysis) produces hyperkal emi a by rapi d cel l ul ar rel eas e of pot as s i um.





(3) Succinylcholine therapy. The mus cl e rel axant s ucci nyl chol i ne may produce hyperkal emi a i n s us cept i bl e i ndi vi dual s wi t h general i zed mus cl e or neurol ogi c di s eas e.





(4) Hyperkalemic periodic paralysis. Thi s rare, fami l i al s yndrome t hat may be as s oci at ed wi t h an acut e s hi ft of ext racel l ul ar pot as s i um. [The hypokal emi c form of t hi s s yndrome, whi ch i s more common, i s di s cus s ed onl i ne Part II: III B 2 a (2) (e).]





(5) Hyperosmolality. Acut e i ncreas es i n ext racel l ul ar fl ui d os mot i c act i vi t y may produce a t rans cel l ul ar s hi ft of pot as s i um and res ul t i n hyperkal emi a. Thi s may occur wi t h admi ni s t rat i on of i nt ravenous cont ras t or gl ucos e.





(6) Acidosis. Mi neral aci dos i s , not organi c aci dos i s , may be as s oci at ed wi t h an acut e

Pa g e 1 4 1 6


s hi ft of pot as s i um from t he i nt racel l ul ar t o t he ext racel l ul ar fl ui d as hydrogen i ons ent er cel l s . o

o

b. Renal causes. The renal capaci t y t o excret e pot as s i um i s approxi mat el y 500â€“1000 mEq/day, whi ch i s 10â€“20 t i mes t he normal i nt ake. An i mpai rment of t he normal component s of renal pot as s i um excret i on may reduce t hi s excret ory capaci t y s o t hat normal i nt ake may produce hyperkal emi a. 



(1) Severe renal failure. W hen t he GFR fal l s t o bel ow 10 mL/mi nut e, hyperkal emi a may occur, even wi t h normal i nt ake. At a GFR above t hi s l evel , hyperkal emi a i s not a res ul t of gl omerul ar i ns uffi ci ency per s e but i s t he res ul t of a s peci fi c di s order i n t ubul ar pot as s i um t rans port or an ext rarenal pot as s i um di s t urbance.





(2) Aldosterone insufficiency. Al dos t erone i s t he major hormonal det ermi nant of renal pot as s i um s ecret i on. P.286





(a) Acquired aldosterone deficiency. Thi s condi t i on may res ul t from renal di s eas e as s oci at ed wi t h reduced reni n product i on. (Recal l t hat reni n i s an

Pa g e 1 4 1 7


enzyme t hat cl eaves precurs or mol ecul es t o produce t he al dos t erone s ecret agogue, angi ot ens i n II.) Pri mary adrenal di s eas e al s o may be as s oci at ed wi t h reduced al dos t erone product i on. Al dos t erone defi ci ency due t o i mpai red reni n product i on or adrenal di s eas e may be produced by: 



(i) Int ers t i t i al renal di s eas e





(ii) Lead nephropat hy





(iii) Di abet i c nephropat hy (i ns ul i n defi ci ency i n t hi s condi t i on may pot ent i at e hyperkal emi a)





(iv) Obs t ruct i ve uropat hy





(v) Angi ot ens i n ant agoni s t t herapy





(vi) Addi s on's di s eas e





(b) Inherited aldosterone deficiency. Several adrenal enzyme defect s as s oci at ed wi t h defi ci ency of t he 17- or 21-hydroxyl as e enzymes may be as s oci at ed wi t h al dos t erone defi ci ency.





(c) Drug-induced aldosterone

Pa g e 1 4 1 8


deficiency. NSAIDs and hepari n act t o reduce reni n s ecret i on or i nduce res i s t ance and may produce hyperkal emi a t hrough al dos t erone defi ci ency. 



(3) Aldosterone resistance. The fol l owi ng condi t i ons are charact eri zed by t ubul ar defect s as s oci at ed wi t h el evat ed al dos t erone l evel s but i mpai red pot as s i um s ecret i on. 



(a) Si ckl e cel l nephropat hy





(b) SLE





(c) Amyl oi dos i s





(d) Int ers t i t i al renal di s eas e





(e) Obs t ruct i ve uropat hy





(f) Heredi t ary al dos t erone res i s t ance





(g) Us e of t ri amt erene, ami l ori de, or s pi ronol act one






o

a. Neuromuscular disorders. By al t eri ng

Pa g e 1 4 1 9


t rans membrane el ect ri cal pot ent i al , s evere hyperkal emi a may al t er mus cl e funct i on or neuromus cul ar t rans mi s s i on, l eadi ng t o s evere weaknes s or paral ys i s . o

o

b. Cardiac disorders. Cardi ac arrhyt hmi as may occur at any l evel above normal but general l y are not ed onl y when s erum pot as s i um concent rat i on exceeds 6 mEq/L. As s erum pot as s i um l evel ri s es , a s eri es of el ect rocardi ographi c (ECG) changes may be s een, i ncl udi ng: 



(1) Prol ongat i on of t he P-R i nt erval





(2) T-wave peaki ng





(3) Prol ongat i on of t he QRS i nt erval





(4) Vent ri cul ar t achycardi as , vent ri cul ar fi bri l l at i on, and as ys t ol e





4. Diagnosis o

o

a. Elimination of pseudohyperkalemia. In vi t ro l ys i s of eryt hrocyt es , l eukocyt es , or pl at el et s can produce hyperkal emi a as a res ul t of i nt racel l ul ar pot as s i um rel eas e (ps eudohyperkal emi a). Al l hyperkal emi c pat i ent s s houl d be checked for ps eudohyperkal emi a by meas uri ng bot h pl as ma and s erum pot as s i um concent rat i ons and by i ns pect i ng

Pa g e 1 4 2 0


t he s erum for di s col orat i on s ugges t i ng hemol ys i s . The pres ence of a myel oprol i ferat i ve di s order may al s o produce ps eudohyperkal emi a. o

o

b. Urine potassium assay. Al t hough onl y a rough correl at i on exi s t s bet ween uri ne and s erum pot as s i um l evel s , hyperkal emi a i nduced by i ncreas ed i nt ake or i ncreas ed cel l l ys i s s houl d be as s oci at ed wi t h uri ne pot as s i um l evel s exceedi ng 50 mEq/L. Val ues l es s t han 30 mEq/L i n t he s et t i ng of hyperkal emi a s ugges t i mpai red renal s ecret i on of pot as s i um.

o

o

c. Reninâ€“aldosterone axis assay. In cert ai n pat i ent s , eval uat i on of al dos t erone and reni n l evel s may hel p defi ne t he et i ol ogy of hyperkal emi a.





5. T herapy. Treat ment i s di vi ded i nt o acut e and chroni c phas es . o

o

a. Acute antagonism and redistribution 



(1) Calcium. The i nt ravenous admi ni s t rat i on of 1â€“2 ampul es of cal ci um chl ori de acut el y ant agoni zes t he cardi ac effect s of hyperkal emi a. ECG changes may t rans i ent l y i mprove, but s erum pot as s i um l evel remai ns el evat ed. P.287



Pa g e 1 4 2 1




(2) Glucose and insulin. The i nt ravenous i nfus i on of 25 g (1 ampul e) of dext ros e pl us 15 uni t s of i ns ul i n l owers s erum pot as s i um wi t hi n 10â€“15 mi nut es .





(3) Î² 2 -Adrenergic agonists, gi ven by i nhal at i on or i nt ravenous l y, rapi dl y i nduce pot as s i um upt ake i nt o cel l s , but t hey are not uni forml y effect i ve.

o

o

b. Acute removal 



(1) Diuretics. Furos emi de, bumet ani de, and, es peci al l y, acet azol ami de i ncreas e pot as s i um excret i on i n i ndi vi dual s wi t h adequat e renal funct i on.





(2) Cation-exchange resins. The admi ni s t rat i on of s odi um pol ys t yrene s ul fonat e bi nds pot as s i um i n t he gas t roi nt es t i nal t ract . About 2 mEq of s odi um are exchanged for every 1 mEq of pot as s i um removed, s o t hat a s ubs t ant i al s odi um l oad may res ul t . Sorbi t ol i s admi ni s t ered oral l y t o prevent s evere cons t i pat i on. Cat i on-exchange res i ns can remove 50â€“100 mEq of pot as s i um over a 6-hour peri od and may be gi ven oral l y or rect al l y.

o

o

c. Chronic removal. Aft er t he acut e removal of pot as s i um, pot as s i um homeos t as i s may be

Pa g e 1 4 2 2


mai nt ai ned wi t h any of t he fol l owi ng agent s . 



(1) Diuretics. Furos emi de or acet azol ami de may be us ed i n combi nat i on wi t h fl udrocort i s one acet at e t o i ncreas e pot as s i um excret i on.





(2) Cation-exchange resins may be gi ven on a chroni c bas i s t o i ncreas e gas t roi nt es t i nal excret i on of met abol i s m.

IV. Acidâ€“Base Metabolism

A. Normal physiology Aci dâ€“bas e bal ance refers t o t he mai nt enance of t he hydrogen i on concent rat i on of body fl ui ds by t hree cont rol s ys t ems : body buffers (e.g., bi carbonat e), t he l ungs , and t he ki dneys . Becaus e hydrogen i ons (prot ons ) are hi ghl y react i ve part i cl es , even s l i ght changes i n hydrogen i on concent rat i on can caus e marked al t erat i ons i n phys i ol ogi c proces s es . 



1. Hydrogen ion concentration and pH. The hydrogen i on concent rat i on of body fl ui ds i s l ow compared wi t h t he concent rat i ons of ot her i ons . It i s more conveni ent , t herefore, t o expres s t he concent rat i on as pH, or t he negative logarithm of hydrogen ion concentration. The pH of t he ext racel l ul ar fl ui d i s mai nt ai ned at about 7.4.





2. Generation and elimination of hydrogen ion. Normal met abol i c proces s es generat e l arge amount s of carboni c as wel l as noncarboni c (nonvol at i l e) aci ds , whi ch ent er

Pa g e 1 4 2 3


t he body fl ui ds and mus t be buffered and el i mi nat ed. o

o

a. Carbonic acid. Hydrogen i ons are produced t hrough compl et e oxi dat i on of gl ucos e and fat t y aci ds t o carboni c aci d. On dehydrat i on, carboni c aci d forms a vol at i l e end product (carbon di oxi de), whi ch can be el i mi nat ed by t he l ungs .

o

o

b. Nonvolatile acid. Approxi mat el y 1 mEq of nonvol at i l e aci d per ki l ogram of body wei ght i s produced dai l y and excret ed pri mari l y by t he ki dneys . Thi s aci d i s produced t hrough i ncompl et e met abol i s m of gl ucos e and fat t y aci ds t o organi c aci ds (e.g., acet oacet i c and Î²-hydroxybut yri c aci ds ) as wel l as met abol i s m of prot ei ns s uch as met hi oni ne and phos phoprot ei n t o s ul furi c and phos phori c aci ds , res pect i vel y.





3. Henderson-Hasselbalch equation. The bi carb -

onat eâ€“carboni c aci d (HCO 3 â€“CO 2 ) s ys t em i s t he major buffer component of t he ext racel l ul ar fl ui d. Aci dâ€“bas e di s t urbances oft en are charact eri zed i n t erms of changes i n ei t her t he bi carbonat e (bas e) or di s s ol ved carbon di oxi de (aci d) component of t hi s buffer pai r. The cl as s i c expres s i on of aci dâ€“bas e s t at e i s bas ed on t he Henders on-Has s el bal ch equat i on, whi ch rel at es t hree vari abl es â€”pH, carbon di oxi de t ens i on (Pco 2 ), and -

pl as ma bi carbonat e concent rat i on ([HCO 3 ])â€”as wel l as t wo cons t ant s â€”pK and Sâ€”as :

where: pK = t he negat i ve l ogari t hm of t he di s s oci at i on cons t ant for carboni c aci d (6.1) and S = t he s ol ubi l i t y cons t ant

Pa g e 1 4 2 4


for carbon di oxi de i n pl as ma (0.03 mmol /L/mm Hg). Normal l y, -

t he pl as ma [HCO 3 ] i s 24 mmol /L and t he art eri al Pco 2 i s 40 mm Hg. Thus :





4. Respiratory regulation of arterial PCO 2 . By regul at i ng t he rat e of al veol ar vent i l at i on, t he l ungs may ret ai n or excret e carbon di oxi de and i n t hi s way regul at e t he â€œaci dâ€• component of t he bi carbonat e buffer s ys t em.





5. Renal regulation of plasma bicarbonate content. There are t wo i mport ant as pect s of hydrogen i on met abol i s m i n t he ki dney: t he reabs orpt i on of bi carbonat e i on and t he s ecret i on of hydrogen i on. o

o

a. Reabsorption of bicarbonate ion. Approxi mat el y 4500 mEq of bi carbonat e are fi l t ered dai l y at t he gl omerul us , vi rt ual l y al l of whi ch are reabs orbed i nt o t he proxi mal t ubul es . The remai ni ng mi nut e port i on of t he fi l t ered bi carbonat e i s reabs orbed i nt o t he di s t al and col l ect i ng t ubul es . Proxi mal t ubul ar reabs orpt i on of bi carbonat e occurs i ndi rect l y by t he fol l owi ng proces s . 



(1) Fi l t ered bi carbonat e i on t oget her wi t h s ecret ed hydrogen i on form carboni c aci d wi t hi n t he t ubul ar l umen. Sodi um i on reabs orpt i on i s l i nked t o t hi s s ecret i on of hydrogen i on t o mai nt ai n el ect roneut ral i t y.

Pa g e 1 4 2 5




(2) Carboni c anhydras e i n t he brus h border of t he proxi mal t ubul e cat al yzes t he dehydrat i on of carboni c aci d t o carbon di oxi de and wat er. Bei ng readi l y di ffus i bl e, carbon di oxi de di ffus es i nt o t he proxi mal t ubul ar cel l , where i nt racel l ul ar carboni c anhydras e cat al yzes i t s rehydrat i on t o carboni c aci d.





(3) The bi carbonat e i on formed by t he di s s oci at i on of carboni c aci d i s pas s i vel y reabs orbed i nt o t he peri t ubul ar bl ood al ong wi t h equi mol ar amount s of s odi um i on, whi ch i s act i vel y t rans port ed i nt o t he peri t ubul ar bl ood. The hydrogen i on formed by t he di s s oci at i on of carboni c aci d wi t hi n t he cel l s erves as a s ource of anot her hydrogen i on t o be s ecret ed. Thi s may occur i n exchange for s odi um i ons acros s t he api cal epi t hel i al membrane.

o

o

b. Addition of â€œ newâ€• bicarbonate. In addi t i on t o cons ervi ng bi carbonat e, t he ki dneys add newl y s ynt hes i zed bi carbonat e t o t he pl as ma via secretion of hydrogen ion. Thi s proces s repl eni s hes t he bi carbonat e us ed t o buffer aci d produced by i ncompl et e met abol i s m of neut ral foods t uffs and by met abol i s m of nonvol at i l e aci d precurs ors i n t he di et . 



(1) The addi t i on of new bi carbonat e does not i nvol ve t he bi carbonat e reabs orbed i nt o t he proxi mal t ubul e but , rat her, t he bi carbonat e

Pa g e 1 4 2 6


generat ed wi t hi n t he di s t al t ubul ar cel l vi a t he hydrat i on of carbon di oxi de and t he di s s oci at i on of carboni c aci d. Thi s proces s i s s i mi l ar t o t hat for t he reabs orpt i on of t he fi l t ered bi carbonat e; however, t he formed bi carbonat e i n t he cel l i s â€œnew.â€• 



(2) The renal cont ri but i on of new bi carbonat e i s accompani ed by t he excret i on of an equi val ent amount of aci d i n t he uri ne i n t he form of t i t rat abl e aci d, ammoni um i on, or bot h. 



(a) T itratable acid formation and secretion. The exchange of hydrogen i on for s odi um i on convert s di bas i c s odi um phos phat e or s ul fat e i n t he gl omerul ar fi l t rat e i nt o monobas i c s odi um phos phat e or s ul fat e, whi ch i s excret ed i n t he uri ne as t i t rat abl e aci d. The hydrogen i on s ecret ed i nt o t he di s t al t ubul es , t herefore, can react wi t h fi l t ered phos phat e rat her t han fi l t ered bi carbonat e.





(b) Ammonia formation and secretion. Unl i ke phos phat e, ammoni a ent ers t he t ubul ar l umen by t ubul ar s ynt hes i s and s ecret i on, rat her t han fi l t rat i on. Ammoni a i s s ynt hes i zed i n t he proxi mal t ubul e as a product of gl ut ami ne met abol i s m, and t hen i t di ffus es acros s t he renal parenchyma t o be s ecret ed i nt o

Pa g e 1 4 2 7


t he l umen of t he col l ect i ng t ubul es . Vi rt ual l y al l of t he nonpol ar ammoni a t hat ent ers t he t ubul ar l umen i mmedi at el y combi nes wi t h hydrogen i on t o form ammoni um i on, whi ch i s nondi ffus i bl e becaus e i t i s l i pi d i ns ol ubl e. The renal excret i on of ammoni um i on res ul t s i n t he addi t i on of bi carbonat e t o t he pl as ma. 



6. Concept of compensation. Compens at i on can be defi ned as t he phys i ol ogi c res pons e t o an al t erat i on i n ei t her t he respiratory or metabolic (renal ) component of aci dâ€“bas e bal ance t o res t ore t he body pH val ue t oward normal . Physiologic compensation generally is not complete.





7. Concept of correction of metabolic acidosis. Compens at ory proces s es do not normal i ze t he l ow pH and s erum bi carbonat e concent rat i on i n met abol i c aci dos i s (e.g., i n di arrhea). However, t he normal ki dney can res t ore t hes e paramet ers t oward normal by i ncreas i ng net aci d excret i on i n t he uri ne (i .e., excret i on of exces s hydrogen i ons ). In l arge part , t he ki dney i ncreas es renal t ubul ar cel l product i on of ammoni a, t hereby i ncreas i ng excret i on of ammoni um i ons . The res ul t ant generat i on of new bi carbonat e i n t he di s t al t ubul e res t ores t he s erum bi carbonat e concent rat i on t oward t he normal range.

B. Respiratory acidosis 



1. Definition. Increased blood PaCO 2 (i .e., >40 mm Hg)

Pa g e 1 4 2 8


and decreased blood pH (i .e., aci demi a) are charact eri s t i c. 



2. Etiology. Res pi rat ory aci dos i s i s as s oci at ed wi t h a reduced capaci t y t o excret e carbon dioxide vi a t he l ungs . Caus es i ncl ude al l di s orders t hat reduce pul monary funct i on and carbon di oxi de cl earance. o

o

a. Primary pulmonary disease t hat i s as s oci at ed wi t h al veol arâ€“art eri al mi s mat ch may l ead t o ca rbon di oxi de ret ent i on, us ual l y as a l at e mani fes t at i on.

o

o

b. Neuromuscular disease. Any weaknes s of t he pul monary mus cul at ure t hat l eads t o reduced vent i l at i on (e.g., myas t heni a gravi s ) may produce carbon di oxi de ret ent i on.

o

o

c. Primary CNS dysfunction. Any s evere i njury t o t he brai ns t em may be as s oci at ed wi t h reduced vent i l at ory dri ve and carbon di oxi de ret ent i on.

o

o

d. Drug-induced hypoventilation. Any agent t hat caus es s evere depres s i on of CNS or neuromus cul ar funct i on may be as s oci at ed wi t h res pi rat ory aci dos i s .






o

a. CNS disorders. Becaus e bl ood fl ow t o t he brai n

Pa g e 1 4 2 9


i s regul at ed by bl ood PaCO 2 , res pi rat ory aci dos i s i s as s oci at ed wi t h i ncreas ed bl ood fl ow t o t he brai n and i ncreas ed cerebros pi nal fl ui d (CSF) pres s ure. Thes e effect s may l ead t o a vari et y of s ympt oms of general i zed CNS depres s i on. o

o

b. Cardiac disorders. The aci demi a i n res pi rat ory aci dos i s i s as s oci at ed wi t h reduced cardi ac out put and pul monary hypert ens i on (effect s t hat may l ead t o cri t i cal l y reduced bl ood fl ow t o vi t al organs ).





4. Diagnosis o

o

a. Acute respiratory acidosis. Acut e carbon di oxi de ret ent i on l eads t o an i ncreas e i n bl ood PaCO 2 wi t h mi ni mal change i n pl as ma bi carbonat e cont ent . For each 10 mm Hg ri s e i n PaCO 2 , t he pl as ma bi carbonat e l evel i ncreas es by approxi mat el y 1 mEq/L and t he bl ood pH decreas es by approxi mat el y 0.08. Serum el ect rol yt e l evel s are cl os e t o normal i n i ndi vi dual s wi t h acut e res pi rat ory aci dos i s .

o

o

b. Chronic respiratory acidosis. Aft er 2â€“5 days , renal compens at i on (i .e., i ncreas ed hydrogen i on s ecret i on and bi carbonat e product i on i n t he di s t al nephron) occurs ; t hat i s , t he pl as ma bi carbonat e l evel s t eadi l y i ncreas es . Art eri al bl ood gas anal ys i s s hows t hat i n t he chroni c phas e of res pi rat ory aci dos i s , for each 10 mm Hg ri s e i n PaCO 2 , t he pl as ma bi carbonat e l evel i ncreas es by 3â€“4 mEq/L and t he bl ood pH decreas es by 0.03.

Pa g e 1 4 3 0


P.288





5. T herapy o

o

a. Correction of the underlying disorder. At t empt s s houl d be made t o correct mus cul ar dys funct i on or revers i bl e pul monary di s eas e, i f ei t her i s t he caus e of t he res pi rat ory aci dos i s . In t he cas e of drug-i nduced hypovent i l at i on, vi gorous at t empt s s houl d be made t o cl ear t he offendi ng agent from t he body.

o

o

b. Respiratory therapy. A bl ood PaCO 2 of more t han 60 mm Hg may be an i ndi cat i on for as s i s t ed vent i l at i on.

C. Respiratory alkalosis 



1. Definition. Decreased blood PaCO 2 and an increased blood pH (al kal emi a) are charact eri s t i c.





2. Etiology. Res pi rat ory al kal os i s i s as s oci at ed wi t h exces s i ve el i mi nat i on of carbon di oxi de vi a t he l ungs . Caus es i ncl ude any di s order as s oci at ed wi t h i nappropri at el y i ncreas ed vent i l at ory rat e and carbon di oxi de cl earance. o

o

a. Anxiety (hys t eri cal hypervent i l at i on). Thi s condi t i on i s t he mos t common caus e of res pi rat ory

Pa g e 1 4 3 1


al kal os i s . o

o

b. Salicylate toxicity. Ini t i al l y, s al i cyl at e exces s caus es overs t i mul at i on of t he res pi rat ory cent er, res ul t i ng i n res pi rat ory al kal os i s . Met abol i c aci dos i s may devel op from t he s al i cyl at e l oad, whi ch enhances t he hypervent i l at i on.

o

o

c. Hypoxia. Any di s order as s oci at ed wi t h decreas ed oxygen t ens i on (Pao 2 ) of bl ood may l ead t o an i ncreas ed res pi rat ory rat e and, t hus , res pi rat ory al kal os i s .

o

o

d. Intrathoracic disorders. Any i nfl ammat ory or s pace-occupyi ng l es i on i n t he l ung may be as s oci at ed wi t h pri mary s t i mul at i on of vent i l at ory rat e, l eadi ng t o a l ow PaCO 2 . Such condi t i ons i ncl ude: 



(1) Pul monary embol i s m





(2) Pneumoni a





(3) As t hma





(4) Pul monary fi bros i s

o

o

e. Primary CNS dysfunction. CNS di s orders t hat may be as s oci at ed wi t h i nappropri at e s t i mul at i on

Pa g e 1 4 3 2


of vent i l at i on i ncl ude: 



(1) Cerebrovas cul ar acci dent (CVA)





(2) Tumor





(3) Infect i on





(4) Trauma

o

o

f. Gram-negative septicemia. An earl y mani fes t at i on of gram-negat i ve s ept i cemi a or bact eremi a i s a pri mary s t i mul at i on of vent i l at i on wi t h res pi rat ory al kal os i s . The mechani s m i s unknown.

o

o

g. Liver failure. The mos t common aci dâ€“bas e di s order i n l i ver di s eas e i s pri mary res pi rat ory al kal os i s t hrough a di rect CNS effect of hyperammonemi a.

o

o

h. Pregnancy. Pri mary s t i mul at i on of vent i l at i on i s t ypi cal l y s een t hroughout pregnancy.





3. Clinical features. Acut e al kal emi a may be as s oci at ed wi t h s everal organ s ys t em di s orders . o

o

a. CNS disorders. A general i zed feel i ng of anxi et y may be pres ent and may progres s t o more s evere

Pa g e 1 4 3 3


obt undat i on and even precoma. o

o

b. Neuromuscular disorders. Acut e al kal emi a may produce a t et any-l i ke s yndrome, whi ch may be i ndi s t i ngui s habl e from t hat of acut e hypocal cemi a.





4. Diagnosis o

o

a. Acute respiratory alkalosis. Increas ed res pi rat ory rat e l eads t o a l os s of carbon di oxi de vi a t he l ungs , whi ch i n t urn i ncreas es t he bl ood pH. For each 10 mm Hg decreas e i n bl ood PaCO 2 acut el y, t he pl as ma bi carbonat e l evel decreas es by 2 mEq/L and t he bl ood pH i ncreas es by 0.08.

o

o

b. Chronic respiratory alkalosis. W i t hi n hours aft er an acut e decreas e i n art eri al PaCO 2 , hydrogen i on s ecret i on i n t he di s t al nephron decreas es , l eadi ng t o a decreas e i n pl as ma bi carbonat e. For each 10 mm Hg decreas e i n bl ood PaCO 2 chroni cal l y, t he pl as ma bi carbonat e l evel decreas es by 5â€“6 mEq/L and t he bl ood pH i ncreas es by onl y about 0.02. Serum chl ori de l evel al s o i s el evat ed.





5. T herapy. The pri mary goal of t herapy i s t o correct t he underl yi ng di s order. Us e of carbon di oxi deâ€“enri ched breat hi ng mi xt ures or cont rol l ed vent i l at i on may be requi red i n cas es of s evere res pi rat ory al kal os i s (pH >7.6).

P.289

Pa g e 1 4 3 4


D. Metabolic acidosis 



1. Definition. Met abol i c aci dos i s i s charact eri zed by a decreas ed bl ood pH and a decreas ed pl as ma bi carbonat e concent rat i on. Thi s condi t i on may be caus ed by one of t wo bas i c mechani s ms : t he l os s of bi carbonat e or t he accumul at i on of an aci d ot her t han carboni c aci d (e.g., l act i c aci d).





2. Etiology. The caus es of met abol i c aci dos i s may be di vi ded i nt o t hos e as s oci at ed wi t h a normal ani on gap and t hos e as s oci at ed wi t h an i ncreas ed ani on gap. T he anion gap reflects the concentrations of those anions that actually are present in serum but are not routinely assayed, i ncl udi ng negat i vel y charged pl as ma prot ei ns (mai nl y al bumi n), phos phat es , s ul fat e, and organi c aci ds (e.g., l act i c aci d). The ani on gap, meas ured i n mEq/L, repres ent s t he di fference bet ween t he concent rat i on of unmeas ured ani ons and cat i ons . It can be cal cul at ed as fol l ows : +

-

-

[eq] Anion gap = [Na ] â€“ ([Cl ] + [HCO 3 ]) The normal val ue of t he ani on gap i s 8 Â± 4 mEq/L. An i ncreas e repres ent s an i ncreas e i n one moi et y, us ual l y t he organi c aci ds . No change wi t h decreas es i n bot h pl as ma bi carbonat e concent rat i on and s erum pH s ugges t s a pri mary l os s of bi carbonat e or t he addi t i on of mi neral aci d. o

o

a. Metabolic acidosis with an increased anion gap 



(1) Ketoacidosis. Thi s condi t i on refers t o a

Pa g e 1 4 3 5


s t at e of i ncreas ed ket oaci d format i on, whi ch l eads t o t i t rat i on of bi carbonat e and cons equent met abol i c aci dos i s . Ket oaci dos i s occurs as a compl i cat i on of di abet es mel l i t us , prol onged s t arvat i on, and prol onged al cohol abus e. 



(2) Lactic acidosis. Decreas ed oxygen del i very t o t i s s ues res ul t s i n i ncreas ed l act at e product i on, wi t h accompanyi ng s evere met abol i c aci dos i s . Lact i c aci dos i s i s a charact eri s t i c feat ure of many condi t i ons as s oci at ed wi t h l ow t i s s ue perfus i on (e.g., s hock and s eps i s ).





(3) Renal failure. Met abol i c aci dos i s res ul t s from t he i nabi l i t y of t he ki dney t o excret e t he dai l y hydrogen i on l oad, deri ved from food and met abol i s m, as a res ul t of a decl i ne i n ammoni um excret i on res ul t i ng from decreas ed renal mas s . The aci dos i s of renal fai l ure i s charact eri zed by ei t her a normal or el evat ed ani on gap, dependi ng on t he s everi t y of t he decl i ne i n renal fi l t eri ng funct i on. In ei t her cas e, t he s erum bi carbonat e i s reduced due t o t he t i t rat i on by t he ret ai ned hydrogen i ons . 



(a) The ani on gap i s el evat ed onl y when t he GFR i s s everel y reduced ( T able of Cont ent s > Chapt er 7 - Allergic and Immunologic Disorders

Chapter 7 Allergic and Immunologic Disorders Mary E Bollinger Jefferson Lee

I. Overview of The Immune System Immune res pons es are generat ed by nat ural and adapt i ve mechani s ms t hat cons i s t of bot h cel l ul ar and humoral component s .

A. Natural immunity Natural immunity i s nons peci fi c; t hat i s , i t i s not i nfl uenced by previ ous ant i genâ€“ant i body i nt eract i ons . 



1. Phagocytic cells, including polymorphonuclear leukocytes (PMNLs) [neutrophils and eosinophils], monocytes, and macrophages, form t he cel l ul ar component of t he nat ural i mmune res pons e. Thes e cel l s i nges t and des t roy pat hogeni c organi s ms and ot her forei gn mat eri al .





2. Natural killer (NK) cells are pot ent cyt ot oxi c cel l s whos e t arget s are not ant i gen-s peci fi c.





3. The complement system, a compl ex group of at l eas t 15 s erum prot ei ns , medi at es i nfl ammat ory react i ons by at t ract i ng granul ocyt es and macrophages , promot i ng

Pa g e 1 5 1 3


cel l â€“cel l i nt eract i ons neces s ary for ant i gen proces s i ng, and s t i mul at i ng t he l ys i s of envel oped vi rus es and bact eri a.

B. Adaptive immunity Adaptive immunity i s charact eri zed by di rect res pons es t o i ni t i al ant i gen pres ent at i on and memory (anamnestic) res pons es on re-expos ure. 



1. Humoral immunity i nvol ves t he product i on of immunoglobulins by mature B lymphocytes. Ant i gen bi ndi ng t o membrane-bound i mmunogl obul i n t ri ggers t he di fferent i at i on of t hes e B cel l s i nt o mat ure pl as ma cel l s capabl e of s ecret i ng ant i gen-s peci fi c i mmunogl obul i n. o

o

a. Immunogl obul i ns are vi t al t o t he i mmune res pons e i n t hree pri mary ways . 



(1) Immunogl obul i ns coat i nvadi ng organi s ms , t hereby i mpedi ng t hei r acces s t o t he hos t .





(2) Immunogl obul i n M (IgM) and IgG fi x compl ement (s ee I A 3).

o

o

(3) Immunogl obul i ns promot e ops oni zat i on, whi ch i ncreas es t he effi ci ency of phagocyt os i s .





b. Immunogl obul i ns are di vi ded i nt o fi ve cl as s es , or isotypes. o

o

(1) IgG, t he mos t preval ent s erum i mmunogl obul i n

Pa g e 1 5 1 4


i s ant i gen s peci fi c and has memory (anamnes t i c res pons e), meani ng t hat l evel s wi l l i ncreas e more rapi dl y wi t h s ubs equent ant i gen expos ure. Speci fi c IgG l evel s i ncreas e aft er expos ure t o an ant i gen as a res ul t of active i mmune res pons e (e.g., aft er expos ure t o a vi rus ) and as a res ul t of passive i mmune res pons e (e.g., aft er expos ure t o a vacci ne). In addi t i on t o memory, IgG i s ant i gen s peci fi c; for exampl e, mos t i ndi vi dual s wi l l onl y devel op vari cel l a once due t o devel opment of vari cel l a ant i body, whi ch i s s peci fi c and general l y l i fel ong. W i t h l at er expos ure, IgG l evel s wi l l i ncreas e s peci fi cal l y i n res pons e. Four IgG s ubcl as s es â€”IgG1, IgG2, IgG3, and IgG4â€”have been i dent i fi ed. o

o

(2) IgA i s t he pri nci pal i mmunogl obul i n i n s ecret ory fl ui ds , maki ng i t an i mport ant fi rs t -l i ne hos t defens e ant i body at s i t es of ant i gen ent ry. IgA exi s t s as a di mer l i nked t o an as s oci at ed s ecret ory component by a J chai n.

o

o

(3) IgM exi s t s i n s erum as a cl us t er of fi ve monomeri c uni t s l i nked by a J chai n and di s ul fi de bonds . It i s t he i ni t i al cl as s of ant i body produced as a pri mary res pons e t o ant i gens , wi t h l evel s i ncreas i ng wi t hi n XX of expos ure. IgM di ffers from IgG i n t hat i t does not mount an anamnes t i c res pons e and i s not ant i gen s peci fi c.

o

o

(4) IgD and IgE are monomeri c prot ei ns pres ent i n s erum i n t race amount s . IgE i s t he ant i body res pons i bl e for t ri ggeri ng t he al l ergi c react i on.

Pa g e 1 5 1 5




2. Cellular immunity i s medi at ed by T lymphocytes. o

o

a. Subpopulations of T cells have been defi ned on t he bas i s of funct i on and t he pres ence of charact eri s t i c s urface ant i gens . 



(1) Cytotoxic T (T c) cells expres s t he CD8 s urface marker and are res pons i bl e for ki l l i ng cel l s t hat expres s forei gn ant i gens .





(2) Helper T (T h) cells enhance t he act i vi t y of B cel l s , macrophages , and ot her T cel l s . They expres s t he s urface marker CD4.





(3) Suppressor T (T s) cells are al s o CD8 pos i t i ve and i nhi bi t t he act i vi t y of ot her cel l s of t he i mmune s ys t em.

o

o

b. Vari ous t ypes of antigen-presenting cells interact with T cells, s t i mul at i ng t he rel eas e of lymphokines, i ncl udi ng i nt erl euki ns , granul ocyt eâ€“macrophage col ony-s t i mul at i ng fact or (GM-CSF), t umor necros i s fact or (TNF), i nt erferon-Î³ (IFN-Î³), and ot her fact ors . Thes e s ubs t ances regul at e vari ous as pect s of t he i mmune res pons e.

II. Pathogenesis of The IgE-Mediated Allergic Reaction Ant i gen-s t i mul at ed rel eas e of medi at ors by cros s -l i nki ng IgE

Pa g e 1 5 1 6


mol ecul es ont o IgE-s ens i t i zed mas t cel l s i s an IgE-mediated hypersensitivity reaction. Thes e react i ons are t he caus e of many al l ergi c di s orders , i ncl udi ng al l ergi c rhi ni t i s , urt i cari a, general i zed anaphyl axi s , i ns ect s t i ng s ens i t i vi t y, and s ome drug react i ons (s ee IIIâ€“VII). Thes e react i ons al l requi re pri or expos ure t o t he ant i gen and s omet i mes s everal expos ures are needed for t he al l ergi c res pons e t o occur.

A. The IgE-mediated allergic response T he IgE-mediated allergic response can be di vi ded i nt o an earl y phas e and a l at e phas e. The earl y phas e i s domi nat ed by IgE, whereas t he l at e phas e i s domi nat ed by hel per T cel l s , whi ch t ake t i me t o mani fes t t hems el ves .

B. Initial exposure to antigen Initial exposure to antigen s t i mul at es t he product i on of s peci fi c IgE mol ecul es , whi ch bi nd t o hi gh-affi ni t y Fc recept ors on t he s urface of mas t cel l s . On re-expos ure, ant i gen cros s -l i nki ng of t hes e membrane-bound IgE mol ecul es res ul t s i n t he rel eas e of i nfl ammat ory medi at ors from t he mas t cel l and t he recrui t ment of hel per T cel l s . Exampl es of i nfl ammat ory medi at ors i ncl ude hi s t ami ne and pros t agl andi ns .

III. Allergic Rhinitis A. Definition Thi s i nfl ammat ory di s order of t he nas al mucos a i s charact eri zed by nas al bl ockage, rhi norrhea, s neezi ng, and pruri t us . It i s i ni t i at ed by mas t -cel l medi at ors rel eas ed duri ng t he IgE-medi at ed hypers ens i t i vi t y react i on. There are t wo major cl as s i fi cat i ons of al l ergi c rhi ni t i s . 



1. Seasonal allergic rhinitis has peri odi c s ympt oms t hat occur onl y duri ng t he pol l i nat i ng s eas on of t he ant i gen t o whi ch t he pat i ent i s s ens i t i ve.



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2. Perennial allergic rhinitis has cont i nuous or i nt ermi t t ent s ympt oms t hat occur year round.

B. Incidence Al t hough accurat e es t i mat es are di ffi cul t t o obt ai n, i t i s bel i eved t hat 10%â€“30% of adul t s and up t o 40% of chi l dren have al l ergi c rhi ni t i s , maki ng t hi s t he mos t common chroni c di s order of t he res pi rat ory t ract . There i s no apparent mal e or femal e predi l ect i on for al l ergi c rhi ni t i s , and no et hni c or raci al pat t erns have been i dent i fi ed. Sympt oms may begi n at any age but devel op i n mos t pat i ent s before age 20 years . A hi s t ory of al l ergi c di s orders i n t he i mmedi at e fami l y i s common.

C. Etiology Vari ous aeroal l ergens (e.g., s pores , pol l ens , and ani mal al l ergens ) t ri gger t he IgE-medi at ed hypers ens i t i vi t y react i on t hat underl i es al l ergi c rhi ni t i s . 



1. Specific seasonal allergens have t ypi cal cal endar pat t erns , t hough t hi s can vary dependi ng on a l ocat i on's al t i t ude, l at i t ude, and predomi nant veget at i on. For exampl e, i n t he Nort heas t : o

o

a. T ree pollen s eas on runs from February t o May.

o

o

b. Grass pollen s eas on i s heavi es t i n May and June. P.314

o

o

c. Ragweed pollen s eas on runs from mi d-Augus t t i l l t he fi rs t fros t .

Pa g e 1 5 1 8


o

d. Mold spores are wors t i n t i mes of damp weat her, es peci al l y wi t h wet l eaves on t he ground i n t he aut umn.





2. Specific perennial allergens o

o

a. Dust mites l i ve pri mari l y i n beddi ng and feed on des quamat ed s ki n. They produce al l ergeni c feces , whi ch can be a s i gni fi cant caus e of chroni c s ympt oms .

o

o

b. Epidermal antigens are produced pri mari l y by furry pet s s uch as cat s , dogs , and rabbi t s .

o

o

c. Indoor molds (i .e., s pores found i n homes ) i ncl ude As pergi l l us and Peni c i l l i um.

o

o

d. Other allergen sources i ncl ude cockroaches and mi ce.

o

o

e. Nonspecific irritants, whi ch are not t rue al l ergens , i ncl ude ci garet t e s moke, ai r pol l ut i on, perfumes , cooki ng odors , and chemi cal fumes .

D. Clinical features 



1. Characteristic symptoms o

Pa g e 1 5 1 9


o

a. Sneezingâ€”oft en wi t h paroxys ms of 15â€“20 s neezes i n qui ck s ucces s i onâ€”i s charact eri s t i c and l i kel y t o occur i n t he earl y morni ng hours , but can vary t hroughout t he day and ni ght dependi ng on t he t ri gger.

o

o

b. Pruritus of t he nos e, pal at e, and pharynx i s common and may l ead t o t he â€œal l ergi c s al ut e s i gn,â€• from repeat ed pus hi ng up on t he end of t he nos e), caus i ng a t rans vers e nas al creas e.

o

o

c. A thin, watery nasal discharge us ual l y i s pres ent and i s as s oci at ed wi t h varyi ng amount s of nas al obs t ruct i on and pos t nas al drai nage. Mout h breat hi ng i s common due t o nas al obs t ruct i on.

o

o

d. Excess lacrimation as wel l as ocul ar pruri t us and s orenes s are common.

o

o

e. Loss of olfaction and taste may res ul t from chroni c s evere nas al conges t i on.

o

o

f. Otitis media, res ul t i ng from i mpai red drai nage of t he eus t achi an t ube, and sinusitis, res ul t i ng from i mpai red drai nage of t he paranas al s i nus es , s omet i mes occur.





2. Characteristic physical findings us ual l y are s een at t he t i me of maxi mal expos ure t o t he offendi ng ant i gens (e.g., duri ng t he hei ght of t he pol l en s eas on).

Pa g e 1 5 2 0


o

a. Nasal findings 



(1) The nas al cavi t y charact eri s t i cal l y cont ai ns t hi n nas al s ecret i ons , and t he mucos al s urface i s edemat ous , boggy, and us ual l y pal e or bl ui s h.





(2) Nas al pol yps may be s een but are not common i n al l ergi c rhi ni t i s . Thei r pres ence us ual l y s ugges t s cys t i c fi bros i s i n chi l dren and as pi ri n i nt ol erance i n adul t s and chi l dren.





(3) Evi dence of recent epi s t axi s i n t he ant eri or nas al vaul t may be s een i f a pat i ent 's nas al conges t i on has l ed t o frequent nos e-rubbi ng.

o

o

b. Conjunctival findings i ncl ude i nject i on and s wel l i ng, exces s l acri mat i on, granul ari t y, and, occas i onal l y, chemos i s . Infraorbi t al â€œs hi ners â€• (i nfraorbi t al venous conges t i on) may devel op.

o

o

c. Oropharyngeal findings include mucus streaming down the posterior pharynx and cobblestoning of the lymphoid tissue of the same area.

o

o

d. Possible findings in children who have severe chronic nasal congestion i ncl ude broadened bony

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dors um of t he nos e, narrowed pal at al arch, hal i t os i s , ret rognat hi c faci es , exces s gi ngi val and pharyngeal l ymphoi d t i s s ue, and dent al abnormal i t i es .

E. Evaluation 



1. Diagnostic tests o

o

a. Accurat el y appl i ed skin tests wi t h pot ent and s peci fi c ant i gens are t he bes t di agnos t i c procedures t o i dent i fy t he ant i gens caus i ng IgE-medi at ed al l ergi c rhi ni t i s .

o

o

b. The radioallergosorbent test (RAST ) i s an al t ernat i ve t o s ki n t es t i ng and can be ordered by any pract i t i oner. It s s ens i t i vi t y and s peci fi ci t y have i mproved dramat i cal l y, and for many al l ergens i t i s as accurat e as s ki n t es t s . It i s rout i nel y us ed for pat i ent s wi t h ext ens i ve ecz emat oi d dermat i t i s , s i gni fi cant dermat ographi s m, or a compl i cat ed hi s t ory wi t hout corroborat i ve s ki n t es t s . IgG-bl ocki ng ant i bodi es and hi gh t ot al IgE l evel s may i nt erfere wi t h t he RAST.

o

o

c. An elevated IgE level i s pres ent i n onl y 30%â€“40% of pat i ent s wi t h al l ergi c rhi ni t i s . Cl i ni ci ans al s o mus t cons i der ot her pos s i bl e caus es of el evat ed IgE l evel s s uch as i mmunodefi ci ency di s orders (s ee VIII). Tot al s erum IgE s houl d not be rout i nel y us ed i n t he di agnos i s of al l ergi c rhi ni t i s . P.315

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o

o

d. Peripheral eosinophilia may be s een but i s an inconsistent fi ndi ng i n pat i ent s wi t h al l ergi c rhi ni t i s .

o

o

e. A stained smear of nasal secretions at t he t i me of cl i ni cal l y act i ve di s eas e oft en s hows a hi gher number of eos i nophi l s , but t hi s fi ndi ng al s o may be s een i n pat i ent s wi t h eos i nophi l i c nonal l ergi c rhi ni t i s (s ee III E 2 c) or hyperpl as t i c s i nus i t i s , as wel l as i n normal i nfant s younger t han 6 mont hs of age.





2. Differential diagnosis for nonallergic causes of rhinitis o

o

a. Nas al conges t i on wi t h mi l d rhi norrhea s omet i mes i s s een i n pregnant women and i n pat i ent s wi t h hypothyroidism.

o

o

b. Vasomotor rhinitis i s a s yndrome charact eri zed by nas al bl ockage and rhi norrhea wi t hout evi dence of i mmunol ogi c or i nfect i ous nas al di s eas e. Res pons e t o medi cal t herapy oft en i s poor.

o

o

c. Sympt oms of eosinophilic nonallergic rhinitis are s i mi l ar t o t hos e of vas omot or rhi ni t i s ; however, i n eos i nophi l i c nonal l ergi c rhi ni t i s , nas al eos i nophi l i a i s pres ent , nas al pol yps are common,

Pa g e 1 5 2 3


and s ympt oms us ual l y res pond t o medi cal management . o

o

e. Infectious rhinitis oft en occurs i n pat i ent s wi t h underl yi ng al l ergi c rhi ni t i s and us ual l y i s as s oci at ed wi t h reddened nas al mucos a, t hi ck nas al s ecret i ons , s ore t hroat , cervi cal adenopat hy, and l ow-grade fever.

o

o

f. A s ympt om compl ex known as t he aspirin triad cons i s t s of nas al pol yps , chroni c s i nus di s eas e, and pot ent i al l y l i fe-t hreat eni ng as t hma. Sympt oms are exacerbat ed aft er admi ni s t rat i on of as pi ri n or ot her nons t eroi dal ant i -i nfl ammat ory drugs (NSAIDs ).

o

o

g. Anatomic abnormalities, t he mos t common of whi ch i s a part i al l y devi at ed s ept um, may caus e nas al obs t ruct i on. W hen uni l at eral di s charge wi t h a foul odor i s pres ent , obs t ruct i on by a forei gn body s houl d be s us pect ed.

o

o

h. Atrophic rhinitis i s s een i n ol der pat i ent s and i s oft en s econdary t o t rauma, s peci fi c i nfect i on, granul oma, or s urgery.

F. Therapy Management i s s t epwi s e and i nvol ves avoi dance of any offendi ng al l ergens and provocat i ve s ubs t ances , admi ni s t rat i on of s el ect i ve pharmacol ogi c agent s , and, i n s ome i ns t ances , i ni t i at i on of i mmunot herapy. 



1. Avoidance. A fi rs t -l i ne t herapy. Thi s as pect of

Pa g e 1 5 2 4


management i s mos t s ucces s ful when a s i ngl e ant i gen (e.g., ani mal dander) i s res pons i bl e for s ympt oms . In pat i ent s wi t h mul t i pl e s ens i t i vi t i es , s ens i bl e envi ronment al precaut i ons are recommended and appear t o l i mi t s evere exacerbat i on of s ympt oms . 



2. Pharmacologic agents o

o

a. H 1 -receptor antagonists (i .e., antihistamines) are us eful i n cont rol l i ng rhi norrhea and pruri t us but have l i t t l e cl i ni cal effect on nas al conges t i on. Sedat i on wi t h i mpai red s chool or job performance i s an undes i rabl e s i de effect of fi rs t -generat i on H 1 -recept or ant agoni s t s . Becaus e s econd-generat i on ant i hi s t ami nes are not as s oci at ed wi t h t hes e s i de effect s , t hey are us ual l y cons i dered fi rs t as as t he i ni t i al pharmacol ogi cal t reat ment for al l ergi c rhi ni t i s . 



(1) First-generation H 1 -receptor antagonists 



(a) Et hanol ami nes (e.g., di phenhydrami ne) are effect i ve but oft en produce s i gni fi cant s edat i on and at ropi ne-l i ke s i de effect s .





(b) Et hyl enedi ami nes (e.g., pyri l ami ne) al s o are effect i ve, produce l es s s edat i on t han et hanol ami nes , and have mi ni mal gas t roi nt es t i nal s i de effect s .



Pa g e 1 5 2 5




(c) Al kyl ami nes (e.g., chl orpheni rami ne) are effect i ve and produce mi ni mal t o modes t s edat i on.





(2) Second-generation H 1 -receptor antagonists 



(a) Lorat adi ne, des l orat adi ne, cet i ri zi ne, and fexofenadi ne are admi ni s t ered once dai l y; t hey have not been as s oci at ed wi t h advers e cardi ovas cul ar effect s .





(b) Al l s econd-generat i on H 1 recept or ant agoni s t s l ack ant i chol i nergi c s i de effect s but may produce mi l d s edat i on i f gi ven at hi gher-t han-us ual dos es . Cet i ri zi ne wi l l produce s edat i on i n s ome pat i ent s at recommended dos ages .





(3) Intranasal H 1 -receptor antagonists. Azel as t i ne hydrochl ori de, whi ch i s approved for us e i n t he Uni t ed St at es , has an effi cacy equal t o t hat of oral H 1 - and H 2 -recept or ant agoni s t s . It al s o may reduce nas al bl ockage. Twent y percent of pat i ent s percei ve a bi t t er t as t e.

P.316





b. Adrenergic agonists (al s o known as

Pa g e 1 5 2 6


sympathomimetic medications) o

o

(1) Oral administration of Î±-adrenergi c agent (e.g., ps eudoephedri ne) i s effect i ve i n reduci ng nas al conges t i on but not rhi norrhea. Cent ral nervous s ys t em (CNS) s t i mul at i on may occur, as wel l as hypert ens i on and l os s of appet i t e. Short -t erm us e i s preferabl e (< 10 days ).

o

o

(2) T opical application of s hort -act i ng phenyl ephri ne or l ong-act i ng oxymet azol i ne decreas es nas al conges t i on, but regul ar admi ni s t rat i on for more t han 3â€“4 days res ul t s i n s evere rebound nas al conges t i on (rhi ni t i s medi cament os a).





c. Cromolyn sodium. A 4% s ol ut i on of cromol yn s odi um i s avai l abl e for t opi cal nas al us e. It mus t be a dmi ni s t ered frequent l y (3â€“6 t i mes dai l y) but i s effect i ve i n t reat i ng bot h s eas onal and perenni al al l ergi c rhi ni t i s . Becaus e s i de effect s are mi ni mal , cromol yn s odi um may at t i mes be preferred t o t opi cal nas al s t eroi ds , but i t i s l es s effect i ve. Pret reat ment before al l ergen expos ure may s i gni fi cant l y reduce nas al al l ergi c res pons e.





d. Corticosteroids o

o

(1) T opical agents. Hi ghl y effect i ve and rapi dl y met abol i zed t opi cal s t eroi d preparat i ons (e.g., momet as one furoat e monohydrat e, budes oni de, fl uni s ol i de acet at e, t ri amci nol one acet oni de, and

Pa g e 1 5 2 7


fl ut i cas one propi onat e) are benefi ci al i n t he t reat ment of s eas onal and perenni al al l ergi c rhi ni t i s . Thi s cl as s of medi cat i ons i s cons i dered t he t reat ment of choi ce. Thes e preparat i ons have mi ni mal s ys t emi c s i de effect s ; i rri t at i on and bl eedi ng rarel y occur, and Candi da overgrowt h i s very uncommon. o

o

(2) Systemic agents. Sys t emi c cort i cos t eroi ds s i gni fi cant l y i mprove s ympt oms duri ng t he hei ght of a s peci fi c pol l en s eas on. Thi s t reat ment i s rarel y i ndi cat ed, however, and us e of l ong-t erm oral cort i cos t eroi d t herapy for perenni al al l ergi c rhi ni t i s i s i l l -advi s ed becaus e of t he del et eri ous s i de effect s .





e. Intranasal anticholinergics. Iprat ropi um bromi de nas al s pray (0.03% and 0.06%) i s avai l abl e for t opi cal us e. Rhi norrhea but not ot her nas al s ympt oms are effect i vel y reduced. Si de effect s , al t hough mi ni mal (5%), i ncl ude drynes s and t rans i ent epi s t axi s .





f. Oral antileukotriene agents. Dat a s ugges t t hat t hes e medi cat i ons may be hel pful , and mont el ukas t s odi um has been approved for t hi s i ndi cat i on. Furt her s t udi es are needed t o defi ne t he rol e of t hes e agent s i n t he t reat ment of al l ergi c rhi ni t i s .





3. Immunotherapy. Such t reat ment may be i ndi cat ed i f pat i ent s cont i nue t o experi ence cl i ni cal l y s i gni fi cant s ympt oms aft er appropri at e envi ronment al avoi dance, and pharmacol ogi c meas ures have been t aken. Al t hough t reat ment i s t i me-cons umi ng and does not provi de

Pa g e 1 5 2 8


compl et e rel i ef for al l pat i ent s , i ncreas ed cos t s of ot her medi cat i ons makes i mmunot herapy rel at i vel y cos t -effect i ve.

IV. Urticaria and Angioedema A. Definitions 



1. Urticaria (commonl y known as hives) i s a pruri t i c and t rans i ent s ki n erupt i on, wi t h i ndi vi dual l es i ons pres ent i ng as eryt hemat ous ci rcums cri bed papul es , or wheal s , oft en wi t h whi t e edemat ous cent ers . Les i ons are annul ar, round, fi gurat e, or confl uent . Repeat ed s crat chi ng oft en res ul t s i n t hi ckeni ng of t he s ki n, whi ch i s cal l ed lichenification. In acute urticaria, t he hi ves occur for l es s t han 6 weeks , and a t ri gger can be i dent i fi ed i n mos t cas es . In chronic urticaria, however, t he hi ves occur for great er t han s i x weeks , and t he t ri gger us ual l y remai ns unknown.





2. Angioedema may occur al one or joi nt l y wi t h urt i cari a. Angi oedema, or s wel l i ng, i s us ual l y of l onger durat i on t han urt i cari a, and oft en i nvol ves t he deeper s ubcut aneous t i s s ueâ€”part i cul arl y i n l oos e areas around t he mout h, eyel i ds , and mal e geni t al i a. Angi oedema i n t he s ubmucos a of t he upper res pi rat ory t ract may l ead t o l aryngeal obs t ruct i on, whi ch repres ent s an ai rway emergency. Cl i ni cal l y s i gni fi cant caus es of angi oedema i ncl ude angi ot ens i n-convert i ng enzyme (ACE) inhibitors, NSAIDs, and heredi t ary defi ci enci es i n t he compl ement s ys t ems (al s o known as hereditary angioedema).

C. Clinical syndromes according to etiology 

Pa g e 1 5 2 9




1. Idiopathic urticaria. Thi s t ype of urt i cari a l as t s s everal mont hs , and i n mos t cas es no s peci fi c caus e can be i dent i fi ed. Al s o known as chronic idiopathic urticaria . P.317





2. IgE-mediated urticaria. Many cas es of acute urticaria can be at t ri but ed t o an IgE-medi at ed react i on. The mos t common ant i gens el i ci t i ng t hi s res pons e are foods, latex, drugs, and venoms. Inhal ed pol l en may i nduce acut e urt i cari al l es i ons i n very s ens i t i ve i ndi vi dual s . Pol l en expos ure on t he s ki n al s o may i nduce urt i cari al -t ype l es i ons .





3. Complement-related disorders, al t hough rare, are wel l recogni zed. T wo major syndromes exi s t . o

o

a. Disorders associated with complement pathway activation. Connect i ve t i s s ue di s orders s uch as s ys t emi c l upus eryt hemat os us (SLE), hypocompl ement emi c vas cul i t i s , and s erum s i cknes s caus ed by drugs or bl ood product s are s omet i mes as s oci at ed wi t h chronic urticaria or angioedema. In t hes e di s orders , compl ement l evel s are oft en decreas ed but t hey al s o may be normal .

o

o

b. A deficiency in the inhibitor of the complement component C1 (C1-INH) may be heredi t ary (e.g., i n hereditary angioedema), i di opat hi c, or

Pa g e 1 5 3 0


as s oci at ed wi t h underl yi ng di s orders s uch as SLE or B-cel l l ymphomas . 



4. Systemic diseases. Urt i cari a or angi oedema s omet i mes may be t he i ni t i al s i gn or a s equel a of an underl yi ng s ys t emi c i l l nes s . o

o

a. Acute infectious diseases i n chi l dren s uch as vi ral upper res pi rat ory i nfect i on or s t rept ococcal pharyngi t i s may be as s oci at ed wi t h acut e urt i cari a.

o

o

b. Systemic inflammatory disorders s uch as SLE, i nfl ammat ory bowel di s eas e, hepat i t i s B and C, macrogl obul i nemi a, and t he earl y phas e of ei t her hepat i t i s A or i nfect i ous mononucl eos i s may be as s oci at ed wi t h urt i cari a.

o

o

c. T hyroid disorders (wi t h or wi t hout hypot hyroi di s m) are s omet i mes as s oci at ed wi t h pers i s t ent i nt ract abl e urt i cari a. There i s a marked femal e predi l ect i on for t hi s condi t i on, and ant i t hyroi d ant i bodi es are commonl y s een i n affect ed pat i ent s .





5. Physical urticaria and angioedemas are i nduced by a phys i cal s t i mul us s uch as t emperat ure, s unl i ght , or phys i cal pres s ure. The pat hogeni c mechani s m for mos t of t hes e condi t i ons i s unknown. Feat ures of t he phys i cal urt i cari as and angi oedemas are des cri bed i n Tabl e 7-1.

D. Therapy 

Pa g e 1 5 3 1




1. Prevention of further episodes i nvol ves avoi dance of known evocat i ve agent s (e.g., foods , medi cat i ons , and phys i cal fact ors ) and i dent i fi cat i on and management of underl yi ng medi cal di s orders .





2. Drug treatment of existing episodes us ual l y proceeds i n s t epwi s e fas hi on. o

o

a. H 1 -receptor blockers al one oft en are effect i ve. Fi rs t -generat i on ant i hi s t ami nes s uch as cyprohept adi ne, hydroxyz i ne, and di phenhydrami ne may be us ed, s o l ong as t he s i de effect of s edat i on can be s afel y t ol erat ed. Second-generat i on ant i hi s t ami nes s uch as l orat adi ne, des l orat adi ne, cet i ri zi ne, and fexofenadi ne may al s o be effect i ve t reat ment for urt i cari a, wi t hout t he s i de effect of s edat i on.

o

o

b. Adding an H 2 -receptor blocker s uch as ci met i di ne oft en has a s ynergi s t i c effect , becaus e H 2 recept ors make up approxi mat el y 15% of t he hi s t ami ne recept ors i n cut aneous bl ood ves s el s . H 2 -recept or bl ockers al one, however, are not effect i ve. Doxepi n, whi ch bl ocks bot h H 1 and H 2 recept ors , i s s omet i mes us eful i n t reat i ng refract ory urt i cari a.

o

o

c. Systemic steroids are res erved for s evere cas es . A s ki n bi ops y i s s ugges t ed before mai nt enance s t eroi d t herapy i s s t art ed.

o

Pa g e 1 5 3 2


o

d. Limited androgens s uch as danazol are effect i ve i n t reat i ng C1-INH defi ci ency, t hat i s , heredi t ary angi oedema.

V. Generalized Anaphylaxis A. Definition Anaphyl axi s i s an acut e l i fe-t hreat eni ng hypers ens i t i vi t y s yndrome. It affect s mul t i pl e organ s ys t ems and res ul t s from t he preci pi t ous and mas s i ve rel eas e of i nfl ammat ory medi at ors from bot h mas t cel l s and bas ophi l s . Sympt oms us ual l y begi n wi t hi n mi nut es of expos ure t o t he caus at i ve fact or and peak wi t hi n 1 hour, but can t ake up t o 4 hours for t he mos t s evere s ympt oms (s ee V D).

B. Incidence Exact i nci dence rat es are unknown, probabl y becaus e of i ncons i s t ent di agnos es of t he anaphyl axi s s yndrome. P.318

TABLE 7-1 Physical Urticarias and Angioedemas Cl in Di ic a al g F n St e o i at st T m u ic y ul r T p u e e e s s st

Pa g e 1 5 3 3


D St E St er ro x ro m ki a ki at n g n o g g g gr t h er t h a e at e p ske sk hi i n d i n s

tr

m

ip le re s p o n s e of L e wi s ( w h e al , fl ar e, a n

Pa g e 1 5 3 4


d e d e m a) , wi th oc ca si o n al p a ss iv e tr a n sf er to n or m al sk in ; p o

Pa g e 1 5 3 5


ss ib le i m m e di at epr e ss ur e a n gi o e d e m a; m a y fo ll o w e m ot io

Pa g e 1 5 3 6


n al st re ss or in fe ct io n D S D A el u e p a s t e pl y ai p, i c e n er at d e yt i o pr d h n e h e of s s e m pr ur a at e e vy o s s a pr u ur n e s e gi s s s u o ur w s i e e el n d

li g

e

n in

m

g er

a

ty t pi w ca ei ll g y ht

Pa g e 1 5 3 7


af s fe ct in g th e h a n d s or fe et ; di s a bi lit y s ec o n d ar y to di sc o m fo

Pa g e 1 5 3 8


rt C In In M h cr t e et ol e n h i n a s ac er s el h gi e y ol c i n pr i n ur co ur e t i re i t i s k ca b c i n ri o t r t e a d u st y nc ; t e al e m 1- x p t o er er 3- ci at m s ur m e e w ch (e h al .g e l e ., al n fe s , g v s e er o , m e et x i er m ci e s s e, ac h co

Pa g e 1 5 3 9


e m at p e a x ni p e o d s b ur y e, e s t xc re e ss ss ) iv e s w e at in g, la cr i m at io n, s al iv at io n, a n

Pa g e 1 5 4 0


d a b d o m in al cr a m pi n g C S L Ic ol u oc e d d al cu ur d i z b ti e e e ca n d ch ri e pr al a x ur l e (i p i t n di o u g o s s, e p ur er at e yt hi t o h c co e or l d m in

a,

h

a

er

n

it

d

e

s

Pa g e 1 5 4 1


d)

w el li n g in id io p at hi c fo r m ; p a p ul ar le si o n s ac co m p a ni e d b

Pa g e 1 5 4 2


y ch ill s, ar th ra lg ia , m y al gi a, a n d h e a d ac h e in in h er it e d fo r m

Pa g e 1 5 4 3


; p o ss ib le lif eth re at e ni n g e d e m a of u p p er or lo w er re s pi ra to ry

Pa g e 1 5 4 4


tr ac t Vi Pr S A br ol e p at o v pl or n er i c y g e at a e pr i o n d ur n gi oc i t of o cu u l a e p s b d at

or

e io

at

mn

or

a al

y

(h e

v

er x

or

e p

te

di o

x

ta s

to

ry ur

fo

or e

re

ac t o

ar

q vi

m

ui br re at d) i o n S E Pr E ol x o x ar p gr p ur o e o ti s ss s

Pa g e 1 5 4 5


ca ur i v ur ri e e e a to e to (s s xc s i x u or p t y n i a ec p or t i i fi e U o c s, V n U b li a V a g n w s ht d a e

li v

d

ch el

o

e e

n

ni n

w

fi gt

a

ca h

v

ti

el

o

e

n

n

of

gt

af

h

fe

tr

ct

ig

e

g

d

er

ar

in

e

g

a

th

s;

e

p

re

o

ac

ss

ti

ib

Pa g e 1 5 4 6


o

le

n)

pr e s e nc e of ot h er m et a b ol ic or i m m u n ol o gi c di s or d er s (i .e

Pa g e 1 5 4 7


., er yt hr o p oi et ic pr ot o p or p h yr ia a n d S L E) A E Pr A q x ur p u p i t pl a o u ic g s s at e ur s i o ni e o n c t o m of ur w et w t i at i

at

ca er m er

Pa g e 1 5 4 8


ri

e co

a

s m ac pr co e m ss p e a s ni of e v d ar b yi y n s g m te al m l

p

w er h at e ur al e s s re s e m bl in g th o s e of ch ol

Pa g e 1 5 4 9


in er gi c ur ti ca ri a SLE, s ys t emi c l upus eryt hem at os us ; UV, ul t ravi ol et .

C. Etiology A vari et y of mechani s ms , s ummari zed i n Tabl e 7-2, can i ni t i at e anaphyl act i c medi at or rel eas e. 



1. IgE-mediated release. The bi ndi ng of IgE ant i bodi es ei t her t o compl et e ant i gens or t o ant i geni c det ermi nant s on hapt enâ€“carri er compl exes can preci pi t at e t he rel eas e of i nfl ammat ory medi at ors . The mos t common caus es of IgE-medi at ed anaphyl axi s i ncl ude food (mos t not abl y peanuts, tree nuts, shellfish, and scaled fish), latex (es peci al l y i n health care workers, who have frequent expos ure), medications, insect venoms, and inhaled allergens.





2. Nonâ€“IgE-mediated release. Cert ai n s ubs t ances [e.g., opi at e anal ges i cs , radi ocont ras t medi a, NSAIDs

Pa g e 1 5 5 0


(as pi ri n)] can s t i mul at e degranul at i on of effect or cel l s di rect l y. Thi s i s cal l ed an anaphylactoid reaction. 



3. Anaphylatoxin-mediated release. Si gni fi cant compl ement act i vat i on generat es l arge amount s of t he compl ement degradat i on product s C3a and C5a. Thes e fragment s bi nd t o mas t -cel l recept ors , t ri ggeri ng medi at or rel eas e.

D. Clinical Features and Diagnosis Cl i ni cal and l aborat ory fi ndi ngs charact eri s t i c of ext ens i ve medi at or rel eas e are t he bas i s for di agnos i s (Tabl e 7-3). P.319

TABLE 7-2 Etiologic Mechanisms of Anaphylaxis Ty pic al Me All ch er ani ge sm ns IgE Dru -m gs edi

S

at e ul f d

on

me am di a i de t or s rel

T

Pa g e 1 5 5 1


eas et r e

acy cl i n es P eni ci l l i ns Ce ph al o s po ri n s L oca l an es t het i cs Ins ect ven om s Al l erg en ext rac ts Ch ym

Pa g e 1 5 5 2


op ap ai n St r ept oki nas e Ins ul i n Foo d S hel l fi s h Nut s E ggs Mi l k An y foo d can cau se a rea ct i

Pa g e 1 5 5 3


on Di r Dru ect gs ma st

P ol y

cel l my me xi n di a B t or rel Opi eas at e e

s Va nco my ci n Ra di o con t ra st me

di a An Hu ap ma hyl n at o bl o xi n od -i n pro duc duc ed t s me

P

di a l as

Pa g e 1 5 5 4


t or ma rel

I

eas mm e

un

(vi ogl a

ob

co ul i mp ns le me Cry nt opr act eci i va pi t t i o at e n) s Ot No her ns t me ero cha i da ni s l ms ant i -i n fl a mm at o ry ag ent s Sul fi t e ad di t i ves Exe

Pa g e 1 5 5 5


rci s e Hor mo nes





1. Essential diagnostic findings i ncl ude at l eas t t wo of t he fol l owi ng s ympt oms : o

o

a. Bronchi al obs t ruct i on

o

o

b. Upper ai rway obs t ruct i on

o

o

c. Acut e hypot ens i on

o

o

d. Urt i cari a

o

o

e. Vomi t i ng or di arrhea





2. Risk factors for devel opi ng anaphyl axi s i ncl ude underl yi ng asthma or cardiac disease and nut allergy.

F. Therapy 

Pa g e 1 5 5 6




1. Epinephrine. Thi s i s t he mos t effect i ve t herapy and s houl d be gi ven i mmedi at el y t o t reat anaphyl axi s . Int ramus cul ar i nject i on of epi nephri ne i s t he mos t effect i ve met hod of medi cat i on del i very. Ti mi ng i s cri t i cal â€”del ays i n epi nephri ne i nject i on are as s oci at ed wi t h i ncreas ed mort al i t y. Pat i ent s at ri s k of anaphyl axi s s houl d carry pen-l i ke epi nephri ne i nject ors wi t h t hem at al l t i mes .





2. Diphenhydramine (25â€“50 mg) i s gi ven i nt ravenous l y. Thi s t herapy wi l l not s t op an anaphyl act i c react i on but i s us ed as adjunct i ve t herapy t o epi nephri ne.





3. Corticosteroids (1â€“2 mg/kg) are admi ni s t ered i nt ravenous l y. Cort i cos t eroi ds are us ed t o decreas e t he l at er i nfl ammat ory res pons e.





4. Intravenous fluids, volume expanders, and pressor agents are us ed t o mai nt ai n bl ood pres s ure. Supplemental oxygen and even mechanical ventilation may be needed for res pi rat ory s upport . P.320

TABLE 7-3 Signs and Symptoms of Anaphylaxis

Pa g e 1 5 5 7


Or ga n or Or ga n Sy ste Ch m ar Aff act ect eri ed sti (% c In Sig div ns idu an als d Inv Sy olv mp ed to ) ms Ski Pru n

ri t u

(88 s %) Fl u s hi ng Urt i ca ri a An gi o ed em

Pa g e 1 5 5 8


a Eye Oc s

ul a

(16 r %) pru ri t u s Exc es s l ac ri m at i on Co nju nct i va l i nj ect i on Re Na s pi s al rat con ory ges s ys t i o te n m

Rhi nor

Up rhe per a ai r Co wa ug y

h

ed Ho

Pa g e 1 5 5 9


em ars a

en

(56 es s %) St ri dor Dy W h s pn eez ea i ng an Lar d

yng

wh eal eez ed i ng em (47 a %) Car W e di o akn vas es s cul Pal ar pi t s ys at i t e ons m

Tac

(33 hyc %) ard ia Hy pot ens i on Arr hyt hm i as Sh

Pa g e 1 5 6 0


ock Car di a c arr es t Ga Cra s t r mp oi n i ng t es Na t i n us e al

a

s ys Di a t e rrh m

ea

(30 Vo %) mi t i ng Ab do mi nal di s t en tio n Me t al l ic t as te 



5. Pat i ent s on Î²-blockers may be refract ory t o t reat ment of anaphyl axi s . In t hi s cas e, glucagon can be gi ven i n addi t i on t o epi nephri ne t o provi de bot h

Pa g e 1 5 6 1


i not ropi c effect s and chronot ropi c effect s on t he heart by i ncreas i ng i nt racel l ul ar l evel s of cycl i c adenos i ne 3,'5'-monophos phat e, i ndependent of t he Î²-adrenergi c recept ors .

VI. Insect Sting Sensitivity St i ngs by a honeybee, yellow jacket, wasp, hornet, or fire ant may l ead t o s ens i t i zat i on and s ubs equent IgE-medi at ed hypers ens i t i vi t y react i ons .

A. Incidence Popul at i on s t udi es s how t hat up t o 25% of peopl e wi t h no hi s t ory of a s ys t emi c react i on aft er an i ns ect s t i ng nonet hel es s may be s ens i t i ve, as judged by pos i t i ve s ki n t es t s and t he pres ence of venom-s peci fi c IgE ant i bodi es . As many as 20% of t hes e i ndi vi dual s may have a s ys t emi c al l ergi c react i on i f s t ung agai n. It i s es t i mat ed t hat 75â€“100 deat hs occur i n t he Uni t ed St at es each year from i ns ect s t i ng react i ons .

B. Clinical features A nonallergic reaction t o an i ns ect s t i ng cons i s t s of t rans i ent s wel l i ng, pai n, and rednes s s urroundi ng t he i nject i on s i t e, al l of whi ch us ual l y s ubs i de i n 1â€“2 hours but can l as t up t o 48 hours . Allergic reactions vary from s cat t ered pat ches of urt i cari a t o s evere and fat al anaphyl axi s . 



1. Large local reactions ext end a s i gni fi cant di s t ance from t he s t i ng s i t e â‰¥8 cm), peak i n 24 hours , and oft en t ake 5â€“7 days t o res ol ve.





2. Anaphylactic reactions occur wi t hi n a few mi nut es of t he s t i ng and may i nvol ve t he s ki n (urt i cari a, angi oedema, and pruri t us ), t he res pi rat ory t ract (l aryngeal edema and bronchos pas m), t he vas cul ar s ys t em (hypot ens i on), and t he gas t roi nt es t i nal s ys t em

Pa g e 1 5 6 2


(di arrhea, abdomi nal cramps , and naus ea). Repeat s t i ngs may caus e s i mi l ar, but more s evere s ympt oms . P.321





3. Delayed reactions i ncl ude s erum s i cknes s , vas cul i t i s , Gui l l ai n-BarrÃ© s yndrome, gl omerul onephri t i s , and myocardi t i s . The et i ol ogy of t hes e react i ons i s uncl ear.

C. Diagnosis 



1. An accurat e history of t he s ympt oms and s i gns of a s ys t emi c al l ergi c react i on aft er a s t i ng i s neces s ary.





2. Specific antivenom IgE antibodies are det ect ed by pri ck or i nt radermal t es t s .

D. Therapy 



1. Immediate therapeutic measures are s i mi l ar t o t hos e us ed i n t he t reat ment of anaphyl axi s from any caus e (s ee V F).





2. Prophylactic therapy o

o

a. Avoidance of i ns ect s t hat i nduce s ens i t i vi t y.

o

o

b. Al l at -ri s k i ndi vi dual s s houl d own and know how t o us e a self-injectable epinephrine kit.

Pa g e 1 5 6 3


o

c. Indi vi dual s who have had an anaphyl act i c react i on t o an i ns ect s t i ng requi re specific venom immunotherapy, whi ch woul d t hen decreas e t hei r ri s k of anaphyl axi s t o t hat of t he general popul at i on.

VII. Drug Reactions A. Definitions Advers e drug react i ons can be cl as s i fi ed as predictable or unpredictable. Unpredi ct abl e res pons es i ncl ude hypersensitivity, or allergic, react i ons , whi ch cons t i t ut e 7%â€“10% of all adverse reactions. 



1. T ype A or predictable responses mos t oft en i nvol ve known pharmacol ogi c act i ons , are dos e-dependent , and occur i n normal i ndi vi dual s . Nearl y 80% of advers e drug react i ons are t ype A, whi ch i ncl ude s i de effect s , overdos e/t oxi ci t y s econdary drug effect s , and drugâ€“drug i nt eract i ons . The effect of ci profl oxaci n on warfari n us e [i ncreas i ng i nt ernat i onal normal i zed rat i o (INR)] and dys peps i a res ul t i ng from eryt hromyci n us e are bot h exampl es of t ype A res pons es .





2. T ype B or unpredictable responses t end t o occur i n predi s pos ed popul at i ons , are not rel at ed t o t he expect ed pharmacol ogi c act i on, and are mos t oft en i ndependent of dos e. T hree types of t ype B res pons es have been charact eri zed. o

o

a. Intolerance refers t o an advers e react i on t hat occurs at a s ubt herapeut i c dos e, for exampl e,

Pa g e 1 5 6 4


vomi t i ng at l ow dos es of t heophyl l i ne. o

o

b. Idiosyncrasy i s an unexpect ed and qual i t at i vel y abnormal res pons e, for exampl e, i s oni azi d-i nduced neuri t i s . Idi os yncrat i c react i ons may occur on a heredi t ary bas i s , for exampl e, hemol yt i c anemi a preci pi t at ed by qui nol ones i n a pat i ent wi t h gl ucos e-6-phos phat e dehydrogenas e (G6PD) defi ci ency.

o

o

c. Hypersensitivity res ul t s from an i mmunol ogi c react i on t hat t ri ggers an abnormal res pons e t o t he drug, for exampl e, peni ci l l i n-i nduced urt i cari a. Drug hypers ens i t i vi t y react i ons are cat egori zed accordi ng t o et i ol ogy, t ypi cal l y i nt o four t ypes . 



(1) IgE-mediated reactions, al s o known as type I reactions, occur when a pharmacol ogi c agent or one of i t s met abol i t es bi nds wi t h drug-s peci fi c IgE ant i bodi es on mas t cel l or bas ophi l membranes , ul t i mat el y t ri ggeri ng t he rel eas e of medi at ors , whi ch l ead t o urticaria and angioedema, As not ed previ ous l y i n t hi s chapt er, bot h urt i cari a and angi oedema can occas i onal l y progres s t o anaphylaxis.





(2) Cytotoxic reactions, al s o known as type II reactions, res ul t from compl ement -medi at ed damage t o cel l membranes preci pi t at ed by t he bi ndi ng of IgM or IgG ant i bodi es t o drug ant i gens on cel l s urfaces . Thes e react i ons us ual l y i nvol ve bl ood cel l s , for exampl e, drug-i nduced

Pa g e 1 5 6 5


t hrombocyt openi a and hemol yt i c anemi a. 



(3) Immune complexâ€“mediated reactions, al s o known as type III reactions, devel op when s ol ubl e compl exes of IgM or IgG ant i bodi es and drug ant i gen are deposited in tissues. Compl ement act i vat i on occurs i n t he s ol ubl e phas e or when t he compl ex at t aches t o ves s el wal l s , l eadi ng t o i nfl ammat i on and s ubs equent t i s s ue i njury. Rash and fever are t he mos t common cl i ni cal mani fes t at i ons , but lymphadenopathy and arthralgia may al s o occur, for exampl e, s erum s i cknes s s yndrome caus ed by i nject i on of forei gn prot ei n or s erum.





(4) Cell-mediated reactions, al s o known as type IV reactions, requi re s ens i t i zed T l ymphocyt es t hat recogni ze a drug or i t s met abol i t e. The ant i genâ€“T-cel l i nt eract i on l eads t o a P.322

l ymphoki ne-i nduced i nfl ammat ory res pons e occurri ng 24â€“72 hours aft er drug admi ni s t rat i on. Contact dermatitis, for exampl e, from neomyci n, i s t he mos t common cl i ni cal exampl e of a cel l -medi at ed react i on. Drug-induced interstitial nephritis, for exampl e, from met hi ci l l i n, i s al s o an exampl e of a cel l -medi at ed react i on.

B. Clinical features Organ-s peci fi c s yndromes res ul t i ng from drug al l ergy i ncl ude t he fol l owi ng:

Pa g e 1 5 6 6




1. Dermatologic reactions are t he mos t common mani fes t at i ons of drug s ens i t i vi t y. o

o

a. Urticaria, occas i onal l y progres s i ng t o anaphyl axi s , can be preci pi t at ed by a vari et y of medi cat i ons ; t he mos t common offenders are peni ci l l i n, s ul fonami des , cephal os pori ns , and al l ergen ext ract s . Mos t urt i cari al react i ons are t he res ul t of IgE-medi at ed or di rect hi s t ami ne rel eas e.

o

o

b. Fixed drug eruptions, whi ch are mos t l i kel y at t ri but abl e t o a cel l -medi at ed react i on, may devel op aft er i nges t i on of t et racycl i ne, s ul fonami des , and peni ci l l i n. In t hi s react i on, di s cret e, nonpruri t i c l es i ons wi t h a macul ar t o bul l ous appearance occur at t he s ame pl ace each t i me t he medi cat i on i s t aken.

o

o

c. Photodermatitis i s charact eri zed by a bri ght eryt hemat ous erupt i on or eczemat oi d l es i ons i n areas expos ed t o ul t ravi ol et l i ght . Two pres ent at i ons are recogni zed. 



(1) Phototoxicity as a res ul t of ul t ravi ol et l i ght expos ure occurs earl y i n drug t reat ment . Drugs i mpl i cat ed i n phot ot oxi c react i ons i ncl ude doxycycl i ne, coal t ar deri vat i ves , and ps oral ens .





(2) Photoallergy occurs 4â€“21 days aft er t he

Pa g e 1 5 6 7


i nges t i on of t he caus at i ve agent . It appears t o be a cel l -medi at ed proces s i n whi ch ul t ravi ol et l i ght i nduces a chemi cal al t erat i on of t he drug, l eadi ng t o t i s s ue s ens i t i zat i on and s ubs equent i njury. Phenot hi azi nes , gri s eoful vi n, and s ul fonami des are common offenders . o

o

d. Contact dermatitis devel ops 48â€“72 hours aft er t opi cal appl i cat i on of t he i mpl i cat ed medi cat i on and i s charact eri zed by a ves i cul ar T-cel l â€“medi at ed i nfl ammat ory react i on. Common preparat i ons caus i ng t hes e s ki n l es i ons are para -ami nobenzoi c aci d (PABA), neomyci n, and ant i hi s t ami nes .

o

o

e. Febrile mucocutaneous reactions are uncommon but may be s evere. Cyt ot oxi c, i mmune compl ex, and cel l -medi at ed react i ons al l cont ri but e t o t he pat hogenes i s of t hes e s yndromes . 



(1) Stevens-Johnson syndrome, a s evere form of eryt hema mul t i forme, may mani fes t as papul ar, urt i cari al , ves i cul ar, or purpuri c l es i ons i nvol vi ng t wo or more mucos al s urfaces .





(2) T oxic epidermal necrolysis mani fes t s as epi t hel i al bul l ae wi t h s ubs equent des quamat i on. Fever and vi s ceral i nvol vement are common.



Pa g e 1 5 6 8




(3) Drugs i mpl i cat ed i n bot h s yndromes i ncl ude ri fampi n, phenobarbi t al , phenyt oi n, t ri met hopri mâ€“s ul famet hoxaz ol e, and peni ci l l i ns .





2. Hepatic syndromes res ul t pri mari l y i n hepat ocel l ul ar changes , granul oma format i on, or chol es t as i s . Hydant oi n and hal ot hane, for exampl e, can caus e hepat ocel l ul ar damage, as can as pi ri n when admi ni s t ered t o chi l dren wi t h juveni l e rheumat oi d art hri t i s . Al l opuri nol , met hyl dopa, or s ul fonami des may caus e granul omat ous changes . Phenot hi azi nes , az at hi opri ne, and eryt hromyci n es t ol at e have been l i nked t o chol es t as i s and pai nl es s jaundi ce.





3. Renal involvement mos t oft en t akes t he form of acut e i nt ers t i t i al i nfl ammat i on. Met hi ci l l i n, s ul fonami des , and cephal os pori ns have been i mpl i cat ed i n t hi s react i on. Membranous gl omerul onephri t i s may occur aft er admi ni s t rat i on of capt opri l , gol d, peni ci l l ami ne, or probeneci d.





4. Pulmonary reactions i ncl ude pul monary i nfi l t rat i on and bronchos pas m. Pul monary i nfi l t rat i on has been report ed wi t h us e of ni t rofurant oi n, gol d compounds , and met hot rexat e. Drug-i nduced bronchos pas m may occur i n as t hmat i c pat i ent s aft er admi ni s t rat i on of as pi ri n or ot her NSAIDs . Exces s l eukot ri ene product i on, res ul t i ng from i nhi bi t i on of t he cycl ooxygenas e pat hway, pres umabl y i s res pons i bl e for t hi s react i on.

C. Diagnosis Becaus e s o few s peci fi c di agnos t i c l aborat ory t es t s are avai l abl e t o

Pa g e 1 5 6 9


confi rm drug al l ergy, obt ai ni ng an accurat e hi s t ory i s es s ent i al . Drug al l ergy s houl d be cons i dered as t he pos s i bl e caus e of al mos t any cl i ni cal s ympt om or s i gn becaus e drug al l ergy react i ons may mi mi c s o many ot her cl i ni cal condi t i ons . 



1. Cl i ni cal feat ures t hat s ugges t drug hypers ens i t i vi t y o

o

a. Pri or expos ure t o t he drug

o

o

b. Ons et of s ympt oms wi t hi n 48 hours wi t h previ ous expos ure or 7 or more days aft er i ni t i at i ng drug t reat ment i f t here i s no pri or expos ure. P.323

o

o

c. Admi ni s t rat i on of t he drug at t he recommended dos e

o

o

d. Sympt oms and s i gns commonl y as s oci at ed wi t h known al l ergi c react i ons

o

o

e. Prompt di s appearance of t he s ympt oms aft er di s cont i nuat i on of t he i mpl i cat ed drug





2. Specific diagnostic tests o

o

a. Immediate skin tests for IgE-medi at ed react i ons (e.g., peni ci l l i n, i ns ul i n, and chymopapai n)

Pa g e 1 5 7 0


b. Delayed skin tests (pat ch t es t i ng; a pres umed

o

ant i gen i s pl aced on t he s ki n, covered, and t hen reas s es s ed for a react i on at 48 hours aft er appl i cat i on) for cel l -medi at ed react i ons (e.g., PABA, ni ckel ) o

c. RAST testing for s peci fi c IgE ant i bodi es (e.g.,

o

peni ci l l i n) o

d. Coombs' antiglobulin test for cyt ot oxi c

o

react i ons caus i ng hemol yt i c anemi a

D. Reactions to selected drugs and biologic agents 



1. Reactions to penicillin and i t s s emi s ynt het i c deri vat i ves are among t he mos t common advers e drug react i ons . From 1% t o 10% of pat i ent s recei vi ng t hes e drugs experi ence an al l ergi c res pons e. Monobact ams rarel y cros s -react wi t h peni ci l l i n, but carbapenems s houl d be cons i dered equal l y cros s -react i ve. Ni net y percent of s ens i t i zed i ndi vi dual s out grow t hi s al l ergy aft er 10 years . o

o

a. Diagnosis. W hen a Î²-l act am ant i bi ot i c i s t he onl y drug of choi ce for pat i ent s wi t h a hi s t ory s ugges t i ve of a peni ci l l i n al l ergy, skin testing i s recommended al t hough t es t i ng mat eri al s are l i mi t ed and des ens i t i zat i on may be requi red i n hi gh ri s k cas es . Pat i ent s wi t h a pos i t i ve s ki n t es t s houl d

Pa g e 1 5 7 1


not recei ve peni ci l l i n or s emi s ynt het i c peni ci l l i ns . Cephal os pori ns s houl d be admi ni s t ered t o s uch pat i ent s caut i ous l y, becaus e up t o 2% of pat i ent s who are al l ergi c t o peni ci l l i n have a cros s -react i on t o cephal os pori ns . Fi rs t -generat i on cephal os pori ns appear t o carry a great er ri s k t han s econd- or t hi rd-generat i on cephal os pori ns . o

o

b. T herapy. Des ens i t i zat i on t o peni ci l l i n-rel at ed I gE-medi at ed react i ons may be accompl i s hed by admi ni s t eri ng peni ci l l i n i n i ncrement s of i ncreas i ng s t rengt h over 4â€“6 hours . The des ens i t i zat i on procedure s houl d be carri ed out i n a cont rol l ed s et t i ng wi t h acces s t o appropri at e emergency t reat ment . The oral rout e, whi ch has been found t o be s afer t han t he parent eral rout e, i s preferred. Parent eral admi ni s t rat i on may be i ni t i at ed aft er t he compl et i on of oral des ens i t i zat i on. The refract ory, or des ens i t i zed, s t at e may be mai nt ai ned for weeks t o mont hs by admi ni s t eri ng t he drug at l eas t every 12 hours . Once t he pat i ent has di s cont i nued t he medi cat i on, prot ect i on i s l os t , and repeat i ng t he des ens i t i zat i on woul d be needed onl y i f t he drug needed t o be readmi ni s t ered.





2. Reactions to radiographic contrast dye occur i n 4%â€“8% of pat i ent s s t udi ed, wi t h anaphyl act oi d res pons es occurri ng i n as many as 1.7% of pat i ent s wi t h react i ons . Thi s i s caus ed by t he hi gh os mol ari t y of t he dye. Repeat anaphyl act oi d react i ons may occur i n 16%â€“44% of pat i ent s . Becaus e recent l y i nt roduced lower osmolarity contrast dyes appear t o be as s oci at ed wi t h a decreas ed ri s k of anaphyl act oi d react i ons , t hey are now t he agent s of choi ce,

Pa g e 1 5 7 2


part i cul arl y for t hos e pat i ent s wi t h a hi s t ory of previ ous al l ergi c react i on. There i s no as s oci at i on bet ween radi ocont ras t dye react i ons and s hel l fi s h or i odi ne s ens i t i vi t y. o

o

a. Pathogenesis. Anaphyl act oi d res pons es cl i ni cal l y mi mi c IgE-medi at ed anaphyl axi s but do not i nvol ve IgE or any ot her i mmune mechani s m.

o

o

b. Clinical features. Sympt oms of exces s vagal s t i mul at i on s uch as bradycardi a, hypot ens i on, naus ea, or vomi t i ng may occur. Thes e s ympt oms may be part i cul arl y s evere, s omet i mes cul mi nat i ng i n s hock, part i cul arl y i n pat i ent s t aki ng Î²-adrenergi c bl ockers and ACE i nhi bi t ors .

o

o

c. T herapy. Treat ment of an anaphyl act oi d react i on i s i dent i cal t o t hat for anaphyl axi s from ot her caus es (s ee V F). Vagal react i ons can be t reat ed wi t h at ropi ne. A pret reat ment prophylactic regi men of predni s one and di phenhydrami ne s i gni fi cant l y decreas es t he l i kel i hood of a repeat anaphyl act oi d react i on. Some expert s al s o recommend t he addi t i on of ephedri ne and an H 2 -s peci fi c ant i hi s t ami ne.





3. Insulin allergy and resistance o

o

a. Allergic reactions. Becaus e bovi ne i ns ul i n di ffers from human i ns ul i n by t hree ami no aci ds and porci ne i ns ul i n di ffers by onl y one ami no aci d, t he bovi ne-bas ed preparat i on i s more al l ergeni c.

Pa g e 1 5 7 3


Bovi ne i ns ul i n i s no l onger avai l abl e i n t he Uni t ed St at es . Human i ns ul i n, produced by recombi nant DNA t echnol ogy, i s much l es s al l ergeni c t han t he ani mal preparat i ons but rarel y may s t i l l preci pi t at e IgE-medi at ed hypers ens i t i vi t y react i ons . Cert ai n hi s t ocompat i bi l i t y ant i gens (HLA-DR2, HLA-DR3, and HLA-B7) may be as s oci at ed wi t h al l ergi c react i ons t o P.324

i ns ul i n, and as many as 50% of peopl e exhi bi t i ng i ns ul i n al l ergy al s o have experi enced al l ergi c react i ons t o ot her drugs . 



(1) Local allergic reactions are charact eri zed by pruri t us , s wel l i ng, and mi l d eryt hema, us ual l y occurri ng duri ng t he fi rs t few mont hs of t herapy. Thes e react i ons oft en s ubs i de compl et el y aft er a few weeks ; i f not , ant i hi s t ami nes may be ei t her admi ni s t ered s ys t emi cal l y or mi xed wi t h t he i ns ul i n. Di vi di ng t he dos e among t wo or more i nject i on s i t es al s o may be effect i ve. Prol onged l ocal react i ons may res ul t i n l i poat rophy.





(2) Systemic allergic reactions are much l es s common t han l ocal react i ons (i .e., t hey occur i n 42Â°C) or when t he accompanyi ng t achycardi a and ci rcul at ory changes are

Pa g e 1 6 4 8


poorl y t ol erat ed, i t i s wi s e t o t ry t o reduce body t emperat ure. However, i n mos t s et t i ngs , fever i s merel y uncomfort abl e. 



4. Beneficial effects of fever. Fever does pl ay a rol e i n hos t defens e, becaus e many i nfect i ve mi crobes prefer normal body t emperat ure for opt i mal s urvi val and growt h. However, t he cl i ni cal s i gni fi cance of t hi s prot ect i on i s unknown. In addi t i on, s ome el ement s of t he i mmune s ys t em are more effi ci ent at hi gher t emperat ures , whereas ot hers are l es s effi ci ent . The net effect of fever on recovery from infect i on i s not known.

P.338

D. Microbial virulence factors Microbial virulence factors are i mport ant i n det ermi ni ng t he l i kel i hood of i nfect i on. To i nfect a hos t , mi croorgani s ms or t hei r product s mus t adhere t o hos t t i s s ue. 



1. Some microbes invade host cells or breach barriers t o reach s us cept i bl e body s i t es and, al ong t he way, avoi d or overcome hos t defens es . In s ome s i t uat i ons (e.g., chi ckenpox or meas l es ), mi crobes can eas i l y i nfect ot herwi s e heal t hy i ndi vi dual s who have normal hos t defens es but no pri or expos ure t o t he mi crobe.





2. Some microbes have a special ability to produce a toxin or virulence factor t o caus e di s eas e. For exampl e, a t oxi n el aborat ed by s ome s t rai ns of St aphyl oc oc c us aureus [t oxi c s hock s yndrome t oxi n-1 (TSST-1)] i s res pons i bl e for toxic shock syndrome (TSS; s ee VII D 1 a).

Pa g e 1 6 4 9




3. In some situations, microbes can only cause disease in the presence of another pathogen. An exampl e i s delta hepatitis virus (HDV), whi ch cannot i nfect humans except i n t he pres ence of ongoi ng hepat i t i s B vi rus (HBV) i nfect i on, but , when pres ent , wors ens t he di s eas e cours e of HBV hepat i t i s .



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4. Becaus e of t he s el ect i ve pres s ures i nduced by us i ng ant i mi crobi al agent s t o t reat or prevent i nfect i ons i n humans and ani mal s , microorganisms that are resistant to antibiotics may have a propensity for causing infections. Thi s i s es peci al l y t rue where ant i bi ot i c us e i s wi des pread, s uch as i n hos pi t al s and nurs i ng homes . Si mi l ar probl ems have appeared i n ambul at ory s et t i ngs , where ant i bi ot i c us e i s wi des pread. Thi s i s mos t not abl e i n chi l dren who recei ve repeat ed cours es of ant i bi ot i cs (e.g., for recurrent ot i t i s medi a) and harbor a more res i s t ant mi crobi al fl ora as a res ul t .

E. Epidemiologic considerations In addi t i on t o hos t and mi crobi al charact eri s t i cs , envi ronment al ci rcums t ances al s o hel p det ermi ne t he nat ure and s everi t y of an i nfect i on. 

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1. Contagious spread. Some i nfect i ous agent s are s pread from pers on t o pers on t hrough di rect phys i cal cont act (e.g., s yphi l i s ) or by i nfect i ous aeros ol s (e.g., t ubercul os i s ).

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2. Vectors and fomites o

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a. Vect ors are ani mal s t hat act as hos t s or carri ers of a di s eas e wi t hout becomi ng i l l t hems el ves . Mos t vect ors are i ns ect s or art hropods . In general , i nfect i ons t hat are rel at ed t o ani mal s or t hei r product s (e.g., meat , mi l k, or eggs ) are cal l ed zoonoses.

o

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b. Fomites are i nani mat e object s capabl e of s preadi ng i nfect i on. Fomi t es are mos t commonl y i dent i fi ed i n hos pi t al s , where enhanced pat i ent s us cept i bi l i t y and a hi gh concent rat i on of vi rul ent organi s ms coexi s t .

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3. Geography. Some di s eas es occur excl us i vel y or at s ubs t ant i al l y great er frequency i n cert ai n areas . For exampl e, mos qui t o bi t es al mos t never res ul t i n t he t rans mi s s i on of mal ari a i n t he Uni t ed St at es . W hen cons i deri ng s uch a di s eas e i n a di agnos i s , a hi s t ory of t ravel t o or res i dence i n an endemi c area i s i mport ant . Durat i on of expos ure can al s o be i mport ant . For exampl e, fi l ari as i s l eads t o el ephant i as i s onl y aft er repeat ed expos ure t o t he mos qui t o vect or over a peri od of mont hs t o years .

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4. Season. Many i nfect i ons occur more commonl y duri ng a part i cul ar t i me of t he year. Thi s may be becaus e of cert ai n act i vi t i es t hat mi ght expos e an i ndi vi dual t o ri s k and t hat are s eas onal i n nat ure (e.g., hunt i ng and fi s hi ng) or t o envi ronment al fact ors t hat favor t he growt h of t he mi crobe or i t s i ns ect vect or.

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5. Institutions. Cert ai n s et t i ngs t hat bri ng t oget her s us cept i bl e i ndi vi dual s may al t er t he ri s k of i nfect i on.

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Hos pi t al s and nurs i ng homes can ampl i fy and al t er t he nat ure of i nfect i ons among t he s i ck and t he el derl y, whereas day-care cent ers can have a s i mi l ar effect on t he young.

II. Use of Anti-Infective Therapy A. General principles Becaus e t he us e of ant i bi ot i cs can be l i fes avi ng, i t i s i mport ant t o recogni z e when t o i ni t i at e t reat ment . However, any t ype of medi cal i nt ervent i on pres ent s pot ent i al hazards , and t he i ndi s cri mi nat e us e of ant i bi ot i cs i s no except i on. In general , four ci rcums t ances prompt ant i mi crobi al t herapy. 

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1. Organism-based treatment o

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a. W hen cul t ures or s t ai ns from a pat i ent demons t rat e a credi bl e mi croorgani s m, appropri at e ant i bi ot i c t reat ment i s i ni t i at ed. Not e t he fol l owi ng exampl es : P.339

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(1) A wet mount of vagi nal s ecret i ons s howi ng T ri c homonas vagi nal i s

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(2) Bl ood cul t ures t hat are pos i t i ve for St rept oc oc c us s angui s i n a pat i ent wi t h a hi s t ory of mi t ral val ve di s eas e and a fever

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b. Techni ques for recogni zi ng s peci fi c ant i gens of

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mi croorgani s ms al s o may be us ed t o hel p i ni t i at e t herapy. An exampl e i s t he fi ndi ng of crypt ococcal ant i gens i n t he cerebros pi nal fl ui d (CSF) i n a pat i ent wi t h chroni c meni ngi t i s . o

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c. Is ol at i on of an organi s m al l ows i n vi t ro t es t i ng of ant i bi ot i c s us cept i bi l i t y. However, for many mi crobes , res i s t ance pat t erns are predi ct abl e enough t o permi t t reat ment wi t hout t hes e furt her t es t s .

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2. Syndrome-based treatment i s i ni t i at ed when al l t hree of t he fol l owi ng condi t i ons appl y: o

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a. The cl i ni cal pi ct ure s t rongl y s ugges t s s peci fi c organ di s eas e.

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b. The t es t s needed t o make a mi crobi ol ogi c di agnos i s are not avai l abl e or pract i cal .

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c. The mos t l i kel y caus at i ve organi s ms al l res pond t o t he s ame t reat ment . 

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(1) For exampl e, i f an ot herwi s e heal t hy young woman has pai nful uri nat i on and a pos i t i ve t es t for whi t e bl ood cel l s (W BCs ) i n t he uri ne, t reat ment can be i ni t i at ed for a uri nary t ract i nfect i on wi t hout even s ubmi t t i ng a uri ne s peci men for cul t ure.

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(2) However, pat i ent s wi t h a poor res pons e t o i ni t i al t reat ment , rel aps e, or compl i cat i ng concomi t ant medi cal i l l nes s cannot be opt i mal l y managed wi t hout furt her di agnos t i c eval uat i on.

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3. Empiric therapy i s gi ven when t he di agnos i s i s uncert ai n but cl i ni cal experi ence s ugges t s t hat t he pat i ent out come i n a part i cul ar s et t i ng i s i mproved wi t h ant i mi crobi al t herapy. 

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a. General l y, empi ri c t herapy i s i ni t i at ed whi l e awai t i ng t he res ul t s of di agnos t i c t es t s t o i dent i fy a s peci fi c caus at i ve organi s m.

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b. Fever oft en devel ops as t he fi rs t s i gn of i nfect i on i n pat i ent s wi t h s evere neut ropeni a from cancer t herapy. Thes e pat i ent s may s uccumb t o t hei r i nfect i on before fi nal report s are recei ved from t he l aborat ory. Thus , ant i mi crobi al t herapy s houl d begi n at t he fi rs t s i gn of fever.

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4. Prophylaxis i s us ed when a s peci fi c i nfect i on or compl i cat i on i s ant i ci pat ed and can be prevent ed. General l y, t hi s form of empi ri c t herapy i s res t ri ct ed t o a fi xed and bri ef peri od duri ng whi ch t here i s a ri s k of i nfect i on. Exampl es i ncl ude t he us e of peni ci l l i n before dent al procedures i n pat i ent s wi t h heart val ve di s eas e and t he us e of peri operat i ve ant i bi ot i cs i n s urgery. Longer durat i on of t he prophyl axi s l eads t o hi gher l i kel i hood of devel opi ng ant i mi crobi al t oxi ci t y or acqui s i t i on/s el ect i on of

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res i s t ant fl ora.

B. Dosage and route (Online Figure 8-1)

ONLINE FIGURE 8-1 (A) Det ermi nat i on of mi ni mum i nhi bi t ory concent rat i on (MIC). (B) Ant i bi ot i c s us cept i bi l i t y t es t s . W hen cons i deri ng t he us e of ant i bi ot i cs , t he appropri at e dos age and rout e of admi ni s t rat i on mus t be es t abl i s hed. 

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1. Dosage o

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a. Dos i ng i s bas ed on pharmacol ogi c and cl i ni cal dat a rel at ed t o t he s i ze and age of t he pat i ent , t he des i red l evel of t he drug i n t he t arget t i s s ue, t he drug's rat e of el i mi nat i on (oft en es t i mat ed by exami ni ng ki dney and l i ver funct i on), and t he

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expect ed penet rat i on of t he drug i nt o t he i nfect ed t i s s ue. o

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b. Gui del i nes for proper dos i ng are wi del y avai l abl e. Occas i onal l y dos age can be adjus t ed t hrough t he us e of bl ood or t i s s ue l evel s of t he drug. Thi s i s commonl y done, for exampl e, t o provi de a s afe and effect i ve cours e of vancomyci n t herapy i n a pers on wi t h reduced or abs ent ki dney funct i on.

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2. Route. In t erms of comfort and conveni ence, oral t herapy i s us ual l y preferred. But parent eral l y admi ni s t ered (i .e., i nt ravenous or i nt ramus cul ar) drugs are us ual l y more rel i abl y abs orbed t han oral l y admi ni s t ered drugs . They are us ed i n t he fol l owi ng s i t uat i ons : o

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a. In pat i ent s who cannot t ol erat e oral l y admi ni s t ered drugs becaus e of vomi t i ng, decreas ed peri s t al s i s , s wal l owi ng di ffi cul t y, or depres s ed ment al s t at e

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b. In pat i ent s i n whom i ns t i t ut i on of t herapy i s urgent

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c. W hen no oral form of t he drug exi s t s or when adequat e amount s of t he oral forms cannot be admi ni s t ered

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C. Cost Thi s i s s ue has become more i mport ant wi t h i ncreas ed at t ent i on t o cos t cont ai nment . W hen al l ot her fact ors are equal , cos t may i nfl uence whi ch drug i s pres cri bed. W i t h i nt ravenous l y admi ni s t ered drugs , t he cos t of di l uent s and of l abor i nvol ved i n prepari ng and i nfus i ng t he drugs mus t be cons i dered. The cos t of admi ni s t rat i on i s l ower wi t h i nt ramus cul arl y gi ven drugs and i s general l y l owes t wi t h oral agent s . Newer drugs are oft en s t rongl y market ed t o pat i ent s and phys i ci ans , but are not neces s ari l y more effect i ve t han â€œol derâ€• drugs , whi ch may be avai l abl e i n generi c form.

D. Specific antibiotic spectrum The range or spectrum of mi croorgani s ms i nhi bi t ed or ki l l ed by an ant i bi ot i c i s an i mport ant cons i derat i on i n deci di ng whi ch drug t o us e. The res ul t s of i n vi t ro t es t i ng are hel pful i n s el ect i ng an ant i bi ot i c t hat i s mos t l i kel y t o be effect i ve agai ns t an i nfect i ve organi s m. The t wo mos t common ways t o pres ent t he res ul t s of i n vi t ro s us cept i bi l i t y t es t i ng are t o not e whet her t he organi s m bei ng t es t ed i s s us cept i bl e, i nt ermedi at e, or res i s t ant t o t he drug or t o not e t he concent rat i on of t he drug needed t o i nhi bi t t he organi s m (t hi s l at t er val ue i s cal l ed t he mi ni mum i nhi bi t ory concent rat i on, or MIC). Even when t he part i cul ar organi s m has not been t es t ed, i t may be as s umedâ€”on t he bas i s of ei t her l ocal pat t erns of ant i bi ot i c s us cept i bi l i t y or general experi ence i n t reat i ng cert ai n s yndromes â€”t hat a gi ven drug i s l i kel y t o be effect i ve. However, s us cept i bi l i t y pat t erns meri t cl os e s crut i ny becaus e t hey change over t i me.

E. Concentration- or time-dependent effect

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Some ant i mi crobi al s have no great er effect on bact eri al i nhi bi t i on or ki l l i ng when t he t i s s ue l evel s are rai s ed above a t hres hol d (s uch as t he MIC) needed t o s ee an effect . Thi s i s time-dependent act i on, s i nce t he benefi t of t he drug i s rel at ed t o t he amount of t i me t hat i t i s pres ent at or above t hi s t hres hol d l evel . Î²-Lact ams are, i n general , t i me-dependent ant i bi ot i cs . Ot her drugs are mos t effect i ve when t hey can reach hi gh peak l evel s or s pend prol onged peri ods at mul t i pl es of t he t hres hol d needed t o i nhi bi t or ki l l mi crobes , even i f t hei r concent rat i on fal l s bel ow t hat t hres hol d for a cons i derabl e peri od. Thi s i s cal l ed concentration-dependent act i vi t y and i s t ypi cal of ami nogl ycos i des .

F. Interpreting antimicrobial susceptibility tests I n vi t ro t es t i ng of ant i mi crobi al s us cept i bi l i t y can provi de us eful i nformat i on about t he s peci fi c mi crobe caus i ng an i nfect i on. For many bact eri a, t hes e t es t s can be accompl i s hed rapi dl y, wi t h res ul t s s omet i mes avai l abl e i n hours . However, the conditions used in susceptibility testing do not necessarily simulate conditions in the patient. 

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1. The res ul t s of s us cept i bi l i t y t es t i ng may s how t he mi croorgani s m t o be s us cept i bl e, i nt ermedi at el y s us cept i bl e, or res i s t ant t o t he drug bei ng t es t ed. Thi s i nformat i on pres uppos es t hat t he drug concent rat i on at t he s i t e of i nfect i on wi l l be s i mi l ar t o what us ual l y i s found i n s erum. It al s o as s umes t hat t he organi s m wi l l be i nhi bi t ed or ki l l ed at t he i nfect i on s i t e i f i t i s expos ed t o s uch a drug concent rat i on.

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2. Anot her way t o as s es s s us cept i bi l i t y i s t o det ermi ne

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t he act ual concent rat i on of ant i bi ot i c needed t o i nhi bi t t he mi croorgani s m. Thi s us ual l y i s done by expos i ng t he mi crobe t o varyi ng concent rat i ons of t he drug and obs ervi ng whi ch i s t he l owes t one t o i nhi bi t growt h [minimum inhibitory concentration (MIC)]. (onl i ne Fi gure 8-1). The l ower t he MIC, t he more s us cept i bl e t he organi s m. The Eps i l omet er t es t (E-t es t ) i s us ual l y a rel i abl e way t o obt ai n an MIC wi t hout t he i nconveni ence of prepari ng s eri al di l ut i ons of drug. In s ome i ns t ances , cl i ni cal experi ence s hows t hat a drug i s i neffect i ve des pi t e i n vi t ro dat a t hat s ugges t i t woul d work. For exampl e, cephal os pori ns are not us eful i n t reat i ng i nfect i ons caus ed by met hi ci l l i n-res i s t ant S. aureus , al t hough bl ood and t i s s ue l evel s i n exces s of t he MIC are eas i l y achi evabl e. 

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3. Di rect meas urement of s erum or t i s s ue l evel s of t he drug bei ng us ed may be des i rabl e s o t hat t he dos age can be adjus t ed t o avoi d t oxi ci t y and t o maxi mi ze t herapeut i c benefi t . Thi s i s es peci al l y t rue for pat i ent s who may have l es s predi ct abl e bl ood or t i s s ue l evel s of ant i bi ot i c becaus e of al t ered drug met abol i s m or excret i on s econdary t o renal or hepat i c dys funct i on. For exampl e, vancomyci n i s a t i me-dependent ant i bi ot i c, and l evel s s houl d be >8 Âµg/mL at al l t i mes . For mos t pat i ent s , s t andard dos i ng regi mens can achi eve t hi s goal , but pat i ent s wi t h fl uct uat i ons of renal funct i on or cert ai n forms of cont i nuous di al ys i s can have unpredi ct abl y l ow l evel s and may need t o be re-dos ed. Hi gh l evel s of vancomyci n have not been as s oci at ed cl earl y wi t h t oxi ci t y, but peak l evel s hi gher t han 40 Âµg/mL are unneces s ary.

G. Toxicity and side effects Al t hough l i fe-t hreat eni ng t oxi ci t y rarel y occurs wi t h ant i bi ot i c

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t reat ment , phys i ci ans s houl d be fami l i ar wi t h t he s peci fi c ri s ks of each drug admi ni s t ered s o t hat s i de effect s can be ant i ci pat ed and mi ni mi z ed. 

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1. Allergic reactions, whi ch are s omet i mes fat al , can occur wi t h al mos t any pharmaceut i cal agent but are more common wi t h t he Î²-lactam antibiotics and s ul fonami des t han wi t h ot her ant i mi crobi al s .

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2. Chloramphenicol, whi ch i s s el dom us ed i n t he Uni t ed St at es , i s as s oci at ed wi t h bone marrow suppression, i ncl udi ng i rrevers i bl e apl as t i c anemi a. It i s al s o as s oci at ed wi t h â€œGray Baby s yndrome.â€•

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3. Many drugs can caus e renal dysfunction, t he mos t promi nent bei ng t he aminoglycosides. Thi s t oxi ci t y i s revers i bl e and us ual l y of mi nor cl i ni cal s i gni fi cance, but ful l recovery may t ake weeks or mont hs . In rare i ns t ances , di al ys i s may be needed. In addi t i on, vari ous forms of amphotericin B are us ed i n t he t reat ment of fungal i nfect i ons . Careful at t ent i on t o t he pat i ent 's fl ui d s t at us may mi t i gat e t he revers i bl e nephrot oxi ci t y t hat i s oft en as s oci at ed wi t h t hi s agent . P.340

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4. Abnormalities in blood coagulation (e.g., changes i n t he l evel s of cl ot t i ng fact ors or i n t he number or funct i on of pl at el et s ) have been as s oci at ed wi t h s everal Î²-lactam antibiotics and s omet i mes res ul t i n cl i ni cal l y s i gni fi cant bl eedi ng.

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5. Ototoxicity i s an i nfrequent but pot ent i al l y debi l i t at i ng s i de effect of aminoglycosides. Ei t her audi t ory or ves t i bul ar i mpai rment can occur; oft en i t i s i rrevers i bl e.

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6. Phototoxicity i s an exaggerat ed res pons e of t he s ki n t o s un expos ure. Thi s can res ul t i n s evere â€œs unburnâ€ • and i s as s oci at ed wi t h us e of s ome fl uoroqui nol ones .

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7. T oxicity to cardiac conduction can ari s e from any number of drugs (i ncl udi ng nonant i bi ot i c compounds ). The mos t common arrhyt hmi a i s as s oci at ed wi t h QT prol ongat i on. At t he ext reme end of QT prol ongat i on i s a s el f-s us t ai ni ng arrhyt hmi a cal l ed t ors ade de poi nt es , whi ch can be l i fe-t hreat eni ng. A number of ant i bi ot i cs (macrol i des and fl uoroqui nol ones ) have been as s oci at ed wi t h QT prol ongat i on, and t hei r act i ons are more l i kel y t o be s eri ous i f ot her medi cat i ons al s o prol ong t he QT i nt erval or i f t he pat i ent has a predi s pos i t i on t o a l ong QT t o begi n wi t h.

H. Adult immunization 

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1. It i s i mport ant for adul t s t o have i mmuni t y t o all of the childhood diseases o

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a. For adul t s wi t h Hi s t ory of Incompl et e or Unknown Tet anus , Di pht heri a, or Pert us s i s Vacci nat i on, a s eri es of t hree Td

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(t et anus /di pht heri a t oxoi d) vacci nes wi t h one of t he Td admi ni s t rat i ons i n t he s eri es repl aced by Tdap (t et anus /di pht heri a t oxoi d pl us acel l ul ar pert us s i s ) s houl d be admi ni s t ered. Boos t er dos es of t et anus s houl d be gi ven every 10 years t o al l adul t s but may be gi ven earl i er i f an i ndi vi dual has a t et anus -prone wound and t he previ ous dos e of t oxoi d was gi ven more t han 5 years earl i er. Pas s i ve i mmuni zat i on wi t h t et anus i mmunogl obul i n i s i ndi cat ed i f a wound has been ext ens i vel y cont ami nat ed wi t h di rt . Di pht heri a t oxoi d i s us ual l y co-admi ni s t ered wi t h t et anus . o

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b. Ki l l ed pol i ovi rus vacci ne s houl d be gi ven t o adul t s who are not al ready i mmune, es peci al l y t hos e wi t h chi l dren who are due t o recei ve l i ve pol i ovi rus vacci ne. Al t hough pol i o may be eradi cat ed worl dwi de i n t he earl y years of t he t went y-fi rs t cent ury, ces s at i on of s t andard chi l dhood pol i o vacci nat i on may not fol l ow unt i l s everal years of eradi cat i on have el aps ed.

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c. Becaus e rubel l a i n a pregnant woman can res ul t i n a devas t at i ng i nfect i on of t he fet us , al l women of chi l dbeari ng age s houl d be i mmune t o rubel l a. Serum t es t s for ant i body t o rubel l a are wi del y avai l abl e t o hel p i dent i fy adul t s who need vacci nat i on. Rubel l a i s a part of t he s t andard panel of chi l dhood vacci nes .

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d. If t here i s no hi s t ory of mumps or meas l es i l l nes s or vacci nat i on, t he appropri at e l i ve vi rus vacci nes for t hes e i l l nes s es s houl d be gi ven.

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Al t hough meas l es may rarel y occur i n vacci nat ed i ndi vi dual s , t hi s i s a rare event when t wo dos es of vacci ne have been appropri at el y admi ni s t ered. 

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2. Speci al vacci nat i on i s s ues concern t he elderly (aged 65 years and ol der) and chronically ill pat i ent s â€”i ncl udi ng human i mmunodefi ci ency vi rus (HIV)/acqui red i mmunodefi ci ency di s eas e (AIDS) â€”es peci al l y t hos e wi t h cardi ac or pul monary di s eas e. Al l s uch pat i ent s s houl d recei ve pneumococcal vaccination once and, i n t he appropri at e s eas on, s houl d have annual influenza vaccination. Re-i mmuni zat i on wi t h pneumococcal vacci ne may be cons i dered for t hos e i ndi vi dual s who had t hei r fi rs t dos e before t he age of 65, i f more t han 5 years has el aps ed s i nce t hat dos e. A new conjugat e vacci ne t o prevent pneumococcal i nfect i ons has been devel oped for chi l dren, and i t has reduced t he burden of pneumococcal di s eas e.

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3. T ravelers t o count ri es where yellow fever i s endemi c (mos t of t ropi cal Afri ca and Sout h Ameri ca) s houl d recei ve t hi s vacci ne. T yphoid i mmuni zat i ons may be recommended for cert ai n t ravel ers . Hepatitis A vi rus (HAV) vacci ne i s recommended for t ravel ers who expect t o encount er poor s ani t ary faci l i t i es , es peci al l y t hos e res ul t i ng i n human fecal cont ami nat i on of food or wat er. Hepat i t i s A vacci ne has l argel y s uppl ant ed t he us e of i mmune s erum gl obul i n (ISG), whi ch has been i n s hort s uppl y. Di rect i nt ramus cul ar i nject i on of ISG i s s t i l l s ugges t ed i f t here i s not a wi ndow of at l eas t 2 weeks before a hi gh-ri s k expos ure t o hepat i t i s A vi rus .

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4. Uni vers al i mmuni t y t o hepat i t i s B vi rus (HBV) and

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varicella are current publ i c heal t h goal s . Al t hough i ndi vi dual s who are al ready i mmune by vi rt ue of pri or i nfect i on or vacci nat i on do not us ual l y benefi t from vacci nat i on, bot h vacci nes can be gi ven s afel y t o pers ons whos e expos ure hi s t ory i s unknown. Bot h vacci nes are l es s effect i ve i n i ndi vi dual s wi t h i mpai red i mmune s t at us . Becaus e vari cel l a vacci ne i s a l i ve vi rus vacci ne, i t s houl d be us ed caut i ous l y or not at al l i n pat i ent s wi t h known advanced i mmunodefi ci ency. o

o

a. Adul t s who have durabl e i mmuni t y t o vari cel l a-zos t er vi rus from a cl i ni cal bout of chi ckenpox i n chi l dhood do not need vacci nat i on.

o

o

b. Adul t s wi t h no hi s t ory of chi ckenpox or no s erol ogi c evi dence of i mmuni t y s houl d recei ve t wo dos es of vacci ne.

o

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c. Adul t s wi t h no hi s t ory of HBV or vacci nat i on for i t s houl d recei ve t hree dos es of vacci ne i n an appropri at e s chedul e. Al t hough uni vers al admi ni s t rat i on of hepat i t i s A vacci ne i s not yet recommended, t here i s a formul at i on of hepat i t i s A and hepat i t i s B vacci ne combi ned t hat woul d reduce t he t ot al number of i nject i ons .

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5. Asplenic individuals s houl d have pneumococcal and meningococcal vaccinations, even t hough prot ect i on from t hes e i nfect i ons i s i ncompl et e. In preparat i on for el ect i ve s pl enect omy, i mmuni zat i ons s houl d i deal l y be performed before s urgery, i f pos s i bl e.

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6. HAV vacci ne i s hi ghl y effect i ve and s afe. It i s recommended i n areas wi t h unus ual l y hi gh rat es of HAV, for t ravel ers t o part s of t he worl d where HAV i s more common, and for peopl e wi t h chroni c HBV or chroni c hepat i t i s C vi rus (HCV) i nfect i ons .

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7. Meningococcal vaccine has been recommended for col l ege-age s t udent s â€”es peci al l y t hos e l i vi ng i n dormi t ori es . There have been out breaks of s eri ous meni ngococcal i nfect i ons on col l ege campus es , al t hough t he number of cas es per year i s s mal l . The vacci ne i s wel l t ol erat ed but has a l i mi t ed durat i on of effect i venes s (a few years ) and does not prot ect agai ns t t ype b meni ngococcal i nfect i ons .

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8. Human papilloma virus (HPV) vacci ne i s recommended for femal es age 9â€“26 t o prevent cancerous and precancerous cervi cal l es i ons . Durat i on of prot ect i on i s uncert ai n and i mmuni zat i on has not been s hown t o prevent di s eas e i n t hos e al ready i nfect ed.

III. Effective Use of The Microbiology Laboratory To maxi mi ze t he us eful nes s of any mi crobi ol ogy l aborat ory, i t i s neces s ary t o be fami l i ar wi t h i t s s peci fi c capabi l i t i es and procedures . The fol l owi ng are general gui del i nes .

A. Obtaining and handling specimens 

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1. Fresh specimens are superior to old ones. Thi s i s es peci al l y t rue when quant i t at i ve res ul t s are i mport ant (e.g., col ony count s of uri ne cul t ures ) or when t he t arget

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organi s m i s fragi l e (e.g., prot ozoal t rophozoi t es i n s t ool ). If i mmedi at e del i very of a s peci men i s not pos s i bl e, proper mai nt enance of t he s peci men s houl d be ens ured unt i l i t can be proces s ed. o

o

a. Some bact eri a (e.g., N. gonorrhoeae) are s ens i t i ve t o col d, and s peci mens s houl d not be refri gerat ed.

o

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b. Speci mens t o be cul t ured for anaerobes s houl d be mai nt ai ned i n a pre-reduced, oxygen-free envi ronment or i n a s yri nge wi t hout any ai r and wi t hout a needl e. They s houl d be t rans port ed t o t he l aborat ory for i mmedi at e pl at i ng.

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2. Large specimens are better than small ones. W hen col l ect i ng s peci mens for mi crobi ol ogi cal cul t ure and s t ai ni ng, s ubmi t as much mat eri al as can be obt ai ned. W hen cul t uri ng a wound, us e pres s ure on t he wound t o expres s as much purul ent fl ui d as pos s i bl e from any fl uct uant areas , or as pi rat e fl ui d us i ng as ept i c t echni que. Somet i mes , mul t i pl e s peci mens are needed t o i dent i fy mi croorgani s ms (e.g., M. t uberc ul os i s ) t hat are s hed i nfrequent l y or i n s mal l numbers .

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3. Biological hazards should be labeled and handled properly. Laborat ori es have i ns t i t ut ed universal precautions and t reat al l s peci mens as pot ent i al l y i nfect i ous . Some bact eri a and fungi may be es peci al l y haz ardous i n pure cul t ure (e.g., Bruc el l a, Franc i s el l a, and Coc c i di oi des ), and t he l aborat ory s houl d be not i fi ed i f t hes e organi s ms are s us pect ed cl i ni cal l y s o t hat appropri at e care can be t aken.

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4. Newer techniques may bypass or accelerate culture results. Di rect DNA Probe t es t for C. t rac homat i s and N. gonorrhoeae can now be done wi t hout concern for mai nt ai ni ng bact eri al vi abi l i t y (neces s ary for cul t ure) and res ul t s are avai l abl e much fas t er t han wi t h cul t ure res ul t s . Si mi l arl y, cul t ure t es t i ng for mycobact eri a i s now fas t er t han before (pos i t i ve res ul t s back i n 10 days vs . 30 days ), and DNA probes can i dent i fy mycobact eri a i n l es s t han a day once cul t ures are pos i t i ve.

B. Interpreting negative and positive culture results W hen a di agnos i s res t s on i dent i fyi ng an organi s m obt ai ned from a cl i ni cal s peci men, i t i s cruci al t o recogni ze what repres ent s s i mpl e cont ami nat i on by ot her body fl ora or i nani mat e s ources . Laborat ory res ul t s are more credi bl e when a s peci men has been s t ai ned and s hown t o cont ai n t he appropri at e cel l t ype (e.g., neut rophi l or al veol ar macrophage i n s put um) and l acks evi dence of cont ami nat i on (e.g., s quamous epi t hel i al cel l s i n s put um or uri ne). W hen care and at t ent i on have been l avi s hed on a good s peci men, al mos t any pos i t i ve res ul t i s s i gni fi cant . 

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1. If ant i bi ot i cs have been admi ni s t ered, t he pot ent i al for pos i t i ve cul t ures i s reduced, and t he predi ct i ve val ue of negat i ve cul t ures al s o i s di mi ni s hed.

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2. W hen cul t ures are t rul y negat i ve, t he us e of s peci al medi a and growt h condi t i ons s houl d be cons i dered. Suppl ement ary nut ri ent s or s uppres s i on of ot her

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organi s ms may be neces s ary t o permi t growt h and i dent i fi cat i on. 

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3. Cul t ures t hat are repeat edl y pos i t i ve for a gi ven organi s m are more convi nci ng t han a s i ngl e pos i t i ve s peci men. Thi s i s es peci al l y t rue for bl ood cul t ures . Speci mens t aken from normal l y s t eri l e s i t es s uch as CSF and joi nt and pl eural fl ui ds us ual l y are rel i abl e when obt ai ned as ept i cal l y. However, i f t hey are cul t ure-pos i t i ve for s ki n or mucous membrane commens al s , repeat cul t ures may be requi red.

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4. Corroborat i ve t es t s s uch as ant i gen det ect i on, s peci fi c nucl ei c aci d probes , and s eroconvers i on (i .e., t he devel opment of ant i bodi es t o a pat hogen) can es t abl i s h t he s i gni fi cance of a s i ngl e cul t ure-pos i t i ve s peci men or es t abl i s h a di agnos i s when cul t ures have not been obt ai ned or are negat i ve.

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5. Quant i t at i ve t es t s s uch as vi ral l oad for HIV and quant i t at i ve bronchoal veol ar l avage (BAL) fl ui d cul t ures may be us eful i n as s es s i ng t he s everi t y of di s eas e or t he probabi l i t y t hat a pos i t i ve cul t ure repres ent s t rue i nfect i on.

IV. Risk Factors for Infection Somet i mes i t i s pos s i bl e t o i dent i fy pat i ent charact eri s t i cs t hat modi fy t he l i kel i hood or s everi t y of an i nfect i on. In general , t he i nt ens i t y or frequency of expos ure and t he degree of s us cept i bi l i t y correl at e wi t h pot ent i al hazard of i nfect i on. P.341

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A. Diabetes In general , pat i ent s wi t h di abet es are more prone t o cert ai n i nfect i ons t han i ndi vi dual s wi t hout gl ucos e i nt ol erance. 

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1. Foot and lower leg ulcers, whi ch may become i nfect ed, are more l i kel y t o occur i n pat i ent s wi t h di abet es due t o neuropat hy or peri pheral vas cul ar di s eas e. Such s oft t i s s ue i nfect i ons are more l i kel y t o i nvol ve Gram-negat i ve rods , and t hey are more di ffi cul t t o cure t han t hos e occurri ng i n nondi abet i c i ndi vi dual s .

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2. Candida infections, es peci al l y vul vovagi nal candi di as i s or t hrus h, are more l i kel y t o occur i n pat i ent s wi t h di abet es .

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3. Urinary tract infections may be more common and more s evere i n di abet i c pat i ent s , and t he i ncreas ed morbi di t y probabl y i s rel at ed t o bl adder dys funct i on i n t hos e pat i ent s wi t h di abet i c neuropat hy. It i s oft en recommended t hat uri nary t ract i nfect i ons be more vi gorous l y t reat ed i n pat i ent s wi t h di abet es .

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4. Some rare diseases occur al mos t excl us i vel y i n di abet i c pat i ent s . o

o

a. Malignant otitis externa i s a pai nful , rapi dl y progres s i ve, and l ocal l y des t ruct i ve di s eas e of t he ext ernal audi t ory canal t hat may ext end t o t he t emporal bone and t he brai n. Ps eudomonas aerugi nos a i s t he caus at i ve agent (s ee V B 1 a).

o

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o

b. Rhinocerebral mucormycosis, a fungal i nfect i on t hat s t art s i n t he nos e or paranas al s i nus es , i s l ocal l y des t ruct i ve. It i s found i n pat i ent s wi t h s evere met abol i c aci dos i s (e.g., i n pat i ent s wi t h di abet es and ket oaci dos i s ).

o

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c. Synergistic gangrene i s a s oft t i s s ue i nfect i on t hat oft en i s at t ri but abl e t o s t rept ococci and obl i gat e anaerobes . It may i nvol ve t he s ki n or t he underl yi ng fas ci al s t ruct ures and t ends t o progres s rel ent l es s l y unl es s t reat ed wi t h ext ens i ve s urgi cal dÃ©bri dement .

o

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d. Emphysematous cholecystitis i s a rare but s evere i nfect i on of t he gal l bl adder. Unl i ke ordi nary chol ecys t i t i s , i t requi res urgent ant i bi ot i c admi ni s t rat i on and cons i derat i on of s urgery. The cl i ni cal cl ues are s i mi l ar t o t hat of chol ecys t i t i s but t here i s oft en hi gh fever, t achycardi a, hypot ens i on, and ot her evi dence of s eps i s . X-rays , comput ed t omography (CT) s can, and ot her i magi ng s t udi es s how gas i n t he gal l bl adder wal l .

B. Alcoholism Acut e and chroni c al cohol us e can i mpai r neurol ogi c funct i on and decreas e t he effi cacy of neut rophi l s . In addi t i on, chroni c al cohol us e can res ul t i n s evere organ damage, es peci al l y t o t he l i ver. 

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1. The i nci dence of pneumococcal , as pi rat i on, and Gram-negat i ve baci l l ary pneumonias i s great er i n al cohol i cs t han i t i s i n t he general popul at i on. Tubercul os i s , anaerobi c l ung abs ces s , and empyema al s o are more common.

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2. W hen as ci t es i s pres ent , al cohol i cs may devel op spontaneous bacterial peritonitis, a bact eri al i nfect i on of as ci t i c fl ui d t hat occurs i n t he abs ence of bowel perforat i on. Thi s i nfect i on, us ual l y caus ed by Gram-negat i ve aerobi c baci l l i or ent erococci , al s o occurs i n nonal cohol i c pat i ent s wi t h as ci t es (e.g., nephrot i c s yndrome).

C. Injection drug use Several i nfect i ons are more common i n i nject i on drug us ers t han i n comparabl e i ndi vi dual s who do not us e s uch s ubs t ances . Fever i n s uch drug us ers mus t be eval uat ed careful l y becaus e pyogeni c bact eri al i nfect i ons can progres s rapi dl y i f t reat ment i s del ayed. 

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1. Infections related to unsterile techniques. Inject i on drug us ers are prone t o a vari et y of s uppurat i ve compl i cat i ons becaus e, i n mos t cas es , t he preparat i on of t he drug i s not as ept i c, equi pment i s not s t eri l e, and s ki n cl eans i ng i s i nadequat e. o

o

a. Bacterial endocarditis, whi ch oft en occurs on t he t ri cus pi d val ve (a val ve rarel y i nfect ed i n ot her popul at i ons ), i s t he mos t s eri ous i nfect i on. Us ual l y, t he bact eri um res pons i bl e i s S. aureus .

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b. Superficial skin infections are common, and i nfect i ous art hri t i s , us ual l y caus ed by P. aerugi nos a or S. aureus , i s s een frequent l y.

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c. T etanus, al t hough rare, occurs more frequent l y, becaus e i nject i on drug us ers are more l i kel y t o

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have i mproperl y cl eaned wounds . 

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2. Infections related to needle sharing. Some cont agi ous di s eas es can be t rans mi t t ed effi ci ent l y vi a t he s mal l amount of bl ood i n us ed needl es and s yri nges . The i nci dence of HBV, HCV, and HIV i nfect i on i s i ncreas ed i n i nject i on drug us ers who s hare needl es .

P.342

D. Occupational exposure 

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1. The ri s k of occupat i on-rel at ed i nfect i on may be unpredictable, as i n t he out breaks of Pontiac fever, whi ch were rel at ed t o t he aeros ol i zat i on of Legi onel l a pneumophi l aâ€“cont ami nat ed wat er vi a ai r-condi t i oni ng duct s t hroughout an offi ce bui l di ng.

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2. The ri s k of i nfect i on al s o may be i nfl uenced by fact ors out s i de t he i mmedi at e work envi ronment . For exampl e, t he ri s k of brucel l os i s among s l aught erhous e workers i s det ermi ned l argel y by t he number of l i ves t ock i nfect ed and t o a l es s er ext ent by t he degree of t he worker's expos ure t o t he bl ood of i nfect ed l i ves t ock.

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3. W hen an i ncreas ed ri s k i s predictable, cert ai n prevent i ve meas ures can be i ns t i t ut ed (e.g., i mmuni zat i on of heal t h care workers agai ns t hepat i t i s B).

E. Internal prostheses W hen a pros t hes i s (s uch as art i fi ci al hi p or knee joi nt s and heart

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val ves , ei t her mechani cal or bi ol ogi c mat eri al ) i s i ns ert ed i nt o t he body, t here i s a pos s i bi l i t y t hat an i nfect i on wi l l devel op at t he s i t e of i ns ert i on. Becaus e t he i mmune s ys t em react s t o any forei gn mat eri al , a pros t het i c organ i s s us cept i bl e t o i nfect i on by a great er number and vari et y of organi s ms t han i s t he nat i ve organ, even i f t hat organ i s damaged. In addi t i on, t he cl i ni cal pres ent at i on of t hes e i nfect i ons may be at ypi cal , and t he i nt erval bet ween s urgery and any mani fes t at i on of s eps i s may be l ong (e.g., many years ). In mos t cas es , bact eri a are i nocul at ed at t he t i me of s urgery, al t hough s econdary hemat ogenous or percut aneous s pread al s o occurs .

F. Indwelling catheters Des pi t e t he hi gh ri s k of i nfect i on wi t h t he us e of cat het ers , t here i s no i ndi cat i on for s ys t emi c ant i bi ot i c prophyl axi s before or duri ng cat het eri zat i on. 

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1. Li ke i nt ernal pros t hes es , cat het ers s uch as i nt ravenous or i nt ra-art eri al l i nes , bl adder cat het ers , and endot racheal t ubes offer s i t es of di mi ni s hed hos t res pons i venes s . Furt hermore, t hey provi de communi cat i on bet ween t he ext ernal envi ronment and t he ordi nari l y s t eri l e i nt ernal envi ronment of t he body.

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2. In addi t i on t o i nt ri ns i c hos t fact ors , two important factors determine the likelihood of catheter-related infection: t he duration of catheterization and t he degree of cleanliness maintained during catheterization. Durat i on i s t he mos t i mport ant fact or i n t racheal and uret hral cat het eri zat i on. Bot h fact ors are i mport ant i n vas cul ar cat het eri zat i on.

More det ai l i s onl i ne.

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a. For l ong-t erm i nt ravenous acces s wi t h a s urgi cal l y i mpl ant ed cat het er s uch as a Hi ckman s i l as t i c cat het er, t he ri s k of i nfect i on can be

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reduced, al t hough not el i mi nat ed, by met i cul ous at t ent i on t o s t eri l e t echni que duri ng i ns ert i on and by avoi di ng i ns ert i on s i t es s uch as t he groi n t hat are prone t o mi crobi al cont ami nat i on. o

o

b. For t he pat i ent who needs i nt ravenous acces s for a s hort or an i nt ermedi at e peri od and has cat het ers pl aced i n t he arms , t he s i t es s houl d be changed every 48â€“72 hours . W hen a cent ral vei n cat het er i s pl aced for t emporary i nt ravenous acces s , t he maxi mal durat i on of t he cat het eri zat i on at a gi ven s i t e i s not abs ol ut e; however, t here i s a s ubs t ant i al ri s k of i nfect i on aft er a few days , and cat het ers s houl d be removed as s oon as pos s i bl e or at t he fi rs t s i gn of s eps i s . Long cat het ers can be i ns ert ed i n t he arm but have t hei r t i p i n t he vena cava. Thes e peri pheral l y i ns ert ed cent ral cat het ers (PICCs ) are us ed t o del i ver medi cat i ons t hat can i rri t at e peri pheral vei ns or caus e probl ems i f t he cat het er get s di s l odged.

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c. Vas cul ar cat het ers general l y are mai nt ai ned wi t h a hi gh degree of care t o avoi d i nfect i on (e.g., as ept i c dres s i ng changes and t he appl i cat i on of ant i bi ot i c-cont ai ni ng oi nt ment s t o t he i ns ert i on s i t e); however, t he i mport ance of t hes e meas ures i n prevent i ng i nfect i on i s unknown. Mos t cat het er-rel at ed i nfect i ons s how l i t t l e or no evi dence of di s eas e at t he cat het er i ns ert i on s i t e, al t hough pus or s i gni fi cant rednes s at t he i ns ert i on s i t e i s us ual l y as s oci at ed wi t h i nfect i on of t he cat het er.

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d. Some cat het ers are i mpregnat ed wi t h s i l ver or wi t h ant i bi ot i cs , and t hes e are as s oci at ed wi t h fewer i nfect i ons . However, whet her t he rat e of s eri ous i nfect i on s uch as bact eremi a i s s i gni fi cant l y l ower wi t h t hes e cat het ers i s not cert ai n.

G. Granulocytopenia A s peci fi c ri s k t hat has been i dent i fi ed and careful l y s t udi ed i s rel at ed t o granulocytopenia, t he abs ence of adequat e numbers of ci rcul at i ng neut rophi l s . The ri s k of i nfect i on i s i nvers el y rel at ed t o t he durat i on and degree of granul ocyt openi a. Neut rophi l count s 3

great er t han 500/mm are adequat e prot ect i on agai ns t mos t opport uni s t i c i nfect i ons . 

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1. In mos t pat i ent s wi t h granul ocyt openi a, t he underl yi ng di s eas e i s a hematologic malignancy, al t hough reduced neut rophi l l evel s can be s een i n as s oci at i on wi t h apl as t i c anemi a, drug-i nduced agranul ocyt os i s , and cyt ot oxi c chemot herapy for non-hemat ol ogi c mal i gnanci es . Pat i ent s wi t h hemat ol ogi c mal i gnancy have an addi t i onal i nfect i on ri s k when t hey recei ve chemot herapy, whi ch al s o di s rupt s t he l i ni ng of t he gas t roi nt es t i nal t ract and permi t s bact eri al and fungal i nvas i on.

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2. The i ndi genous fl ora of pat i ent s wi t h granul ocyt openi a i s l i kel y t o be al t ered duri ng hos pi t al i zat i on and wi t h t he admi ni s t rat i on of ant i bi ot i cs . The mi crofl ora mos t commonl y as s oci at ed wi t h i nfect i ons i n affect ed pat i ent s i s deri ved from t hei r i ndi genous fl ora. Bact eri a s uch as Es c heri c hi a c ol i and P. aerugi nos a, as wel l as fungi s uch as Candi da al bi c ans , are mos t oft en found.

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3. Mol ds s uch as As pergi l l us s peci es may caus e s eri ous , oft en fat al , i nfect i ons i n pat i ent s wi t h granul ocyt openi a. Spores are i nhal ed from t he envi ronment .

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4. Pers i s t ent fever i s t he hal l mark of i nfect i on i n pat i ent s wi t h neut ropeni a. Becaus e uncont rol l ed i nfect i on can res ul t i n rapi d cl i ni cal det eri orat i on, ant i mi crobi al s are gi ven i mmedi at el y aft er appropri at e cul t ure s peci mens are obt ai ned.

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5. Granul ocyt es rel eas ed i nt o t he ci rcul at i on aft er t he us e of colony-stimulating factors s uch as fi l gras t i m are ful l y funct i onal . Thus , granul ocyt openi a aft er chemot herapy of s ol i d t umors i s oft en bri ef and unaccompani ed by s eri ous i nfect i on.

H. Immunosuppressive agents Thes e agent s are us ed t o t reat a vari et y of medi cal probl ems , s uch as prevent i on of reject i on of t rans pl ant ed organs , and cont rol of aut oi mmune di s orders . P.343

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1. The expres s i on of t hi s i mmunodefi ci ency i s s een mos t l y i n t he i ncreas ed i nci dence of i nfect i on us ual l y cont rol l ed by cellular immunity (e.g., mycobact eri al , fungal , nocardi al , and cyt omegal ovi ral i nfect i ons ). St eroi ds al s o al t er s ome di agnos t i c t es t s , mos t not abl y t he expres s i on of del ayed hypers ens i t i vi t y.

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2. St eroi ds are us ed wi del y i n t rans pl ant at i on procedures i nvol vi ng t he ki dney, heart , l ung, l i ver, and

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bone marrow. In part , t he i nfect i ons experi enced by t hes e pat i ent s are rel at ed t o cort i cos t eroi ds and t he ot her drugs (i .e., cycl os pori ne, t acrol i mus , az at hi opri ne, and mycophenol at e mofet i l ) us ed t o prevent organ reject i on. Thes e l at t er drugs are s omet i mes referred t o as â€œs t eroi d s pari ng,â€• but t hi s refers t o t hei r us e i n reduci ng ri s k of s t eroi d-as s oci at ed s i de-effect s s uch as di abet es mel l i t us and os t eopeni a. 



3. Inject abl e t umor necros i s fact or (TNF)â€“i nhi bi t i ng drugs are us eful i n t he t reat ment of rheumatoid arthritis and inflammatory bowel disease. However, t hes e drugs (es peci al l y i nfl i xi mab) have been as s oci at ed wi t h an exces s of cas es of t ubercul os i s (TB; i ncl udi ng ext rapul monary TB).

I. Neurologic deficits Neurol ogi c dys funct i on may predi s pos e pat i ent s t o i nfect i on i f s uch defi ci t s caus e body defens es t o be more eas i l y breached. The fol l owi ng are exampl es . 



1. El i mi nat i on of t he gag refl ex, whet her by s t roke or coma, predi s pos es pat i ent s t o as pi rat i on of oral or gas t ri c cont ent s , res ul t i ng i n pneumonia.





2. Secondary i nfect i on of a hypoes t het i c l i mb. Diabetic neuropathy can res ul t i n s ki n ul cerat i on and i nfect i on.





3. Los s of neuromus cul ar cont rol of t he bl adder. Long-term catheterization (wi t h i t s at t endant compl i cat i ons , s uch as i nfect i on) may be neces s ary.

J. Age The l i kel i hood of acqui ri ng cert ai n i nfect i ons vari es cons i derabl y

Pa g e 1 6 7 7


wi t h age. In general , t he mat urat i on of t he i mmune s ys t em i s res pons i bl e for t he changi ng pat t ern of i nfect i ons i n earl y chi l dhood, and t he pres ence of ot her medi cal i l l nes s es account s for mos t of t he changes i n l at e adul t hood. Di mi ni s hed i mmune res pons e i n t he el derl y may predi s pos e t hem s l i ght l y t o i nfect i on. For exampl e, l ower t i t ers of ant i body t o i nfl uenz a vi rus are found aft er i mmuni zat i on i n t he el derl y t han i n younger adul t s .

K. Nosocomial infection Al t hough nos ocomi al i nfect i ons (i .e., i nfect i ons acqui red aft er 2 or more days i n t he hos pi t al ) can i nvol ve any body s i t e, t hey have s ome i mport ant common charact eri s t i cs . 



1. Etiology and pathogenesis o

o

a. Residence in the hospital predi s pos es pat i ent s t o s ki n and mucos al col oni zat i on by mi crobi al fl ora di fferent from t hat found i n ambul at ory pat i ent s . Speci fi cal l y, ent eri c Gram-negat i ve rods (e.g., E. c ol i , Kl ebs i el l a) or P. aerugi nos a i n t he al i ment ary t ract may s pi l l over ont o t he s ki n or i nt o t he res pi rat ory t ree. The degree of i l l nes s i nfl uences t he l i kel i hood and rapi di t y of acqui ri ng hos pi t al fl ora.

o

o

b. Antimicrobials gi ven t o prevent or t reat i nfect i on may predi s pos e pat i ent s t o col oni zat i on and s ubs equent i nfect i on by hos pi t al fl ora.

o

o

c. Instrumentation (e.g., endot racheal t ubes and i nt ravenous cat het ers ) may bypas s s ome of t he nat ural hos t defens es .

o

Pa g e 1 6 7 8


o

d. Failure to observe appropriate infection control measures may permi t t he di s s emi nat i on of hos pi t al fl ora. The mos t i mport ant rout e for s uch di s s emi nat i on i s on t he hands of heal t h care workers .

o

o

e. Environmental factors, s uch as t hos e t hat permi t col oni zat i on of wat er by l egi onel l a or i mperfect ai r fi l t rat i on t hat al l ows for fungal s pores , may permi t i nfect i on t o occur at exces s rat es becaus e of t he i nherent l y decreas ed res i s t ance t o i nfect i on of s ome pat i ent s .





2. T herapy. The durat i on of hos pi t al i zat i on and t he l i kel i hood t hat t he i nfect i on was acqui red nos ocomi al l y i nfl uence t he us e of empi ri c ant i bi ot i cs t o t reat s us pect ed i nfect i ons . Knowl edge of t he ant i mi crobi al s us cept i bi l i t y pat t erns of nos ocomi al mi crobes i n one's i ns t i t ut i on can be es peci al l y hel pful .



3. Prevention

See onl i ne for det ai l s , i ncl udi ng res pi rat ory

precaut i ons . 

P.344



o

o

a. Hands must be washed and gl oves changed bet ween pat i ent cont act s . Al cohol -bas ed gel s or creams are effect i ve and eas i er t o us e regul arl y t han i s t horough handwas hi ng before and aft er each pat i ent encount er.

o

Pa g e 1 6 7 9


o

b. Proper technique on insertion of devi ces s uch as endot racheal t ubes and i nt ravenous cat het ers i s es s ent i al . Prompt di s cont i nuat i on when t hey are no l onger needed may reduce t he burden of nos ocomi al i nfect i ons .

o

o

c. Universal precautions have been i ns t i t ut ed i n heal t h care faci l i t i es t o reduce t he ri s k of t rans mi s s i on of many pot ent i al l y hazardous mi crobes , i ncl udi ng bl ood-borne vi rus es s uch as HIV t ype 1 (HIV-1) and HBV. It i s ext remel y i mport ant t o be fami l i ar wi t h t he i ns t i t ut i onal pol i cy of t he heal t h care faci l i t y i n whi ch one works . The es s ent i al pri nci pl es of uni vers al precaut i ons are t o t reat each cl i ni cal s peci men as pot ent i al l y i nfect i ve, t o reduce s harp (e.g., needl es t i ck) expos ures , t o avoi d s pl as hes of body fl ui ds ont o mucous membranes , and t o di s pos e of pot ent i al l y hazardous s ubs t ances s afel y.

o

o

d. Protective isolation i s i nt ended t o prot ect pat i ent s from exogenous s ources of col oni zat i on or i nfect i on. Thi s meas ure i s us ual l y appl i ed t o pat i ent s wi t h ext ens i ve burns or wi t h ext reme neut ropeni a. There are many di fferent pract i ces of prot ect i ve i s ol at i on, but careful handwas hi ng and us e of gl oves are probabl y mos t i mport ant .

o

o

e. Contact isolation Cohort i ng pat i ent s col oni zed wi t h res i s t ant organi s ms t oget her. For i ns t ance, pat i ent s known t o be col oni zed wi t h met hi c i l l i n-res i s t ant S. aureus (MRSA) onl y s hare

Pa g e 1 6 8 0


s emi -pri vat e rooms wi t h s i mi l arl y col oni zed pat i ent s . 



Respiratory precautions For s ome di s eas es , es peci al l y t ubercul os i s , reduction of exposure of health care workers and other patients t o aeros ol dropl et s exhal ed by an i nfect ed pat i ent i s i mport ant . In t he s et t i ng of document ed or s us pect ed i nfect i on by s uch organi s ms , a pri vat e room wi t h appropri at e vent i l at i on i s requi red. Reduct i on of t i me s pent i n t he room and fas t i di ous us e of mas ks by vi s i t ors and heal t h care workers can reduce ri s k of t rans mi s s i on. Such pat i ent s mus t wear mas ks when out of t hei r rooms (i .e. goi ng for t es t s l i ke ches t radi ographs or CT s cans ).

V. Specific Infections According to Body Site A. Central nervous system (CNS) infections 



1. Meningitis o

o

a. Acute meningitis i s an i nfl ammat ory di s eas e i nvol vi ng t he arachnoi d l ayer of t he meni nges and t he fl ui d t hat ci rcul at es i n t he vent ri cl es and t he s ubarachnoi d s paceâ€”t he CSF. 



(1) Classification. (Tabl e 8-2) There are t wo major cl as s i fi cat i ons of meni ngi t i s : bacterial and aseptic. In bot h forms , fever, headache, and s t i ff neck occur.



Pa g e 1 6 8 1




(2) Etiology. (Tabl e 8-3). 



(a) Bacterial meningitis. The causes vary with the age of the patient. E. c ol i and St rept oc oc c us agal ac t i ae occur mos t frequent l y i n i nfant s ; H. i nfl uenzae, whi ch us ed t o predomi nat e i n young chi l dren (2 mont hs t o 6 years ), has been pract i cal l y eradi cat ed by uni vers al vacci nat i on; N. meni ngi t i di s i s mos t common i n adol es cent s and young adul t s ; and S. pneumoni ae i s mos t common i n adul t s ol der t han 25 years . Li s t eri a monoc yt ogenes , whi ch ent ers t he body t hrough t he gas t roi nt es t i nal t ract , i s found mos t commonl y i n cancer pat i ent s and i mmunos uppres s ed i ndi vi dual s .





(b) Aseptic meningitis. Us ual l y a viral disease, as ept i c meni ngi t i s may al s o refl ect an inflammatory process adjacent to the meninges (e.g., cerebri t i s , brai n abs ces s , s i nus i t i s , or ot i t i s ). In part i al l y t reat ed bact eri al meni ngi t i s , t he CSF us ual l y has a pyogeni c nat ure, al t hough ant i bi ot i cs may modi fy t he di s eas e i n s uch a way as t o creat e an as ept i c pat t ern. Drug hypers ens i t i vi t y al s o may caus e an as ept i c meni ngi t i s (us ual l y wi t h a predomi nance of neut rophi l s i n t he W BCs ) and may occur rarel y wi t h

Pa g e 1 6 8 2


i buprofen or a vari et y of ot her agent s . 



(3) Clinical features. W hen bact eri a caus e meni ngi t i s , t hi s mani fes t at i on us ual l y i s part of a systemic, bacteremic infection. An except i on occurs when bact eri a gai n acces s t o t he meni nges aft er t rauma or s urgery or vi a a bony defect (us ual l y i n t he t emporal area or t he cri bri form pl at e). Typi cal pres ent at i on i ncl udes fever, nuchal ri gi di t y, and al t ered ment al s t at us . 



(a) W i t h di s eas e due t o H. i nfl uenzae or S. pneumoni ae, focal i nfect i on s uch as pneumonia or otitis al s o may be apparent .





(b) W i t h di s eas e due t o N. meni ngi t i di s , t here may be a charact eri s t i c s ys t emi c i nfect i on cons i s t i ng of a petechial or purpuric skin rash and hypotension, whi ch can devel op rapi dl y.





(c) W i t h as ept i c meni ngi t i s due t o echovi rus es or coxs acki e vi rus es , t here may be a charact eri s t i c rash resembling rubella or a vesicular or petechial rash.





(4) T herapy 



(a) Bacterial meningitis. Antibiotics

Pa g e 1 6 8 3


have a s i gni fi cant i mpact on t he out come of t hi s di s eas e. W i t hout t reat ment , deat h i s al mos t cert ai n; wi t h t reat ment , however, t he mort al i t y rat e i s reduced t o approxi mat el y 20% of t hos e pat i ent s who are not mori bund at t he t i me of di agnos i s . Bact eri ci dal ant i bi ot i cs s houl d be gi ven i n dos ages t hat permi t t he drug t o achi eve ki l l i ng l evel s i n t he CSF. Becaus e t he bl oodâ€“brai n barri er bl ocks vi rt ual l y al l drugs and reduces drug penet rat i on from t he bl ood i nt o t he CSF, maxi mum t ol erat ed s ys t emi c dos ages s houl d be gi ven even at t he end of t he t reat ment cours e (us ual l y a t ot al of 2 weeks ).

TABLE 8-2 Examination of Cerebrospinal Fluid in Suspected Meningitis W B C (c Gl

el

u P ls c r / o ot m s ei L e n ) B L In 1 a o cr 0 ct w e 0 e

a to

ri

s >

Pa g e 1 6 8 4


al

e 1 d 0 0 0 wi th n e ut ro p hi l d o m in a nc

e F L N 1 u o or â n w m €“ g t o al 5 al n t o 0 or i n 0 m cr al e a s e d T L In 5 B o cr â T w e €“

Pa g e 1 6 8 5


u

a 1

b

s 0

e

e 0

rc

d

ul a r Vi N N 5 r or or â al m m €“ al al 3 0 0 wi th ly m p h oc yt e pr e d o m in a nc e W BC, whi t e bl ood cel l . 

P.345

Pa g e 1 6 8 6


TABLE 8-3 Organisms in Bacterial Meningitis Pr edi sp Im osi po Or

ng rta

ga

Fa nt

nis Ag cto Poi m e rs nts Nei Chi Fat s s e l dr

al

ri a en

if

me an

not

ni n d

t re

gi t i you

at e

di s ng

d

ad

ear

ul t

l y,

s

di ff us e pur pur ic ras h, req ui r es pro phy

Pa g e 1 6 8 7


l ax is for exp os e d con t ac ts Gro Ne Ma up on t er B

at e nal

St r s

i nf

ept

ect

oc o

i on

ccu s, Es c her ich ia c ol i Li s Ne Im t eri on mu a

at e nos

mo s ,

up

noc el d pre yt o erl s s i ge y

on

nes St r Al l Chr Mo ept ag oni s t oc o es , c

co

c c u el d i l l n mm s

erl es s on

Pa g e 1 6 8 8


pn y

,

cau

eu

as p s e

mo

l en i n

ni a

ia

ad

e

ul t

Ha Ad

s Pre

em ul t

do

op s

mi

hi l

nat

us

ed

i nfl

in

ue

chi l

nza

dre

e

n unt il uni ver s al vac ci n at i on

St a Al l Bac phy ag t er l oc es em oc c

i a,

us

for

aur

ei g

eus

n bo dy, en doc

Pa g e 1 6 8 9


ard itis Gra Al l Se m- ag ps i ne es , s , gat el d ne i ve erl uro rod y

s ur

s

ger y 



(i) In adul t s , i ni t i al t herapy wi t h a combi nat i on of a broad-s pect rum cephal os pori n and vancomyci n i s us ed i ni t i al l y. Frequent l y, t hi s can be s i mpl i fi ed once t he res ul t s of cul t ures and s ens i t i vi t i es have been obt ai ned. Ampi ci l l i n i s s t i l l us ual l y effect i ve agai ns t S. pneumoni ae and vi rt ual l y al ways effect i ve agai ns t N. meni ngi t i di s and Li s t eri a.





(ii) If res i s t ant organi s ms are found, t he appropri at e drug (e.g., cefot axi me or vancomyci n) i s begun or cont i nued, and ot her agent s are s t opped. S. pneumoni ae res i s t ant t o peni ci l l i n (and s omet i mes cephal os pori ns ) i s bei ng i s ol at ed more frequent l y. In cri t i cal l y i l l pat i ent s wi t h s us pect ed or es t abl i s hed pneumococcal meni ngi t i s , vancomyci n s houl d be

Pa g e 1 6 9 0


added t o t he regi men unt i l s us cept i bi l i t y i nformat i on i s avai l abl e. 



(iii) If pyogeni c meni ngi t i s i s pres ent , a s hort cours e of cort i cos t eroi ds s uch as dexamet has one s t art i ng before or with t he ant i bi ot i cs can prevent deat h and s ubs t ant i al morbi di t y i n adul t s or chi l dren.





(b) Aseptic meningitis. There i s no specific chemotherapy for t hi s condi t i on. Any underl yi ng di s eas e s houl d be t reat ed. If drug hypers ens i t i vi t y i s s us pect ed, t he offendi ng agent s houl d be s t opped.

o

o

b. Chronic meningitis 



(1) Etiology. The mos t common caus es of chroni c meni ngi t i s are t ubercul os i s , crypt ococcal di s eas e, mal i gnancy, and s arcoi dos i s .





(2) Clinical features. Chroni c meni ngi t i s may have an i ndol ent pres ent at i on, wi t h s ympt oms s i mi l ar t o t hos e of acut e meni ngi t i s or wi t h al t ered ment at i on wi t h or wi t hout fever. CSF abnormal i t i es may progres s i f t he underl yi ng di s eas e i s unt reat ed. In many of t hes e

Pa g e 1 6 9 1


di s eas es , t he CSF gl ucos e l evel i s l ow. Chroni c meni ngi t i s s houl d be cons i dered when a l ow CSF gl ucos e l evel i s not ed i n pat i ent s who are found not t o have acut e bact eri al meni ngi t i s . 



(3) T herapy. Treat ment i s di rect ed at t he underl yi ng di s eas e. [See VII C 3 and VIII G 1 (1) (c) for TB and crypt ococcal t reat ment .]

o

o

2. Encephalitis 



a. Etiology. Mos t encephal i t i des are caus ed by vi rus es , s everal of whi ch are t rans mi t t ed by t he bi t es of i nfect i ve mos qui t oes .





b. Clinical features. Pat i ent s wi t h encephal i t i s us ual l y pres ent wi t h al t ered ment at i on, s ei zures , or bot h. The CSF may be normal or have an as ept i c pat t ern.





c. Diagnosis. Di agnos i s i nvol ves meas uri ng ri s i ng t i t ers of ant i body t o one of t he encephal i t i s vi rus es i n pat i ent s wi t h a compat i bl e cl i ni cal s yndrome. W hen herpes simplex encephalitis i s s us pect ed, earl y ant i vi ral t reat ment i s recommended. Meas urement of herpes s i mpl ex vi rus â €“s peci fi c nucl ei c aci d i n CSF has l argel y s uppl ant ed brai n bi ops y for di agnos i s . Succes s ful t reat ment of herpes encephal i t i s depends on i ni t i at i on of medi cat i ons before

Pa g e 1 6 9 2


neurol ogi c det eri orat i on becomes ext ens i ve. W es t Ni l e vi rus was fi rs t des cri bed as a caus e of encephal i t i s i n New Y ork i n 1999, but s i nce t hen t hi s mos qui t o-borne i nfect i on has been found t hrough much of Nort h Ameri ca. Pat i ent s wi t h W es t Ni l e encephal i t i s can have a P.346

compl et e recovery of funct i on, but many pat i ent s have s evere weaknes s duri ng t he i nfect i on and may recover onl y part i al l y i f at al l . 



d. Differential diagnosis. T oxopl as ma gondi i can caus e encephal i t i s i n pat i ent s wi t h di mi ni s hed T-cel l funct i on (e.g., due t o AIDS or pos t t rans pl ant at i on i mmunos uppres s i ve t herapy). Some i nt oxi cat i ons and i mmune di s eas es [e.g., s ys t emi c l upus eryt hemat os us (SLE)] may have a pres ent at i on i ndi s t i ngui s habl e from encephal i t i s . Endocardi t i s al s o s houl d be cons i dered. Ot her vi rus es t o cons i der i ncl ude CMV, Eps t ei n-Barr vi rus (EBV), HIV, and t he zoonot i c encephal i c vi rus es s uch as W es t ern equi ne encephal i t i s and St . Loui s encephal i t i s vi rus . Syphi l i s , dug t oxi ci t y, and SLE s houl d al s o be cons i dered i n an i ndi vi dual wi t h acut e encephal i t i s .





e. T herapy. Treat ment of vi ral encephal i t i s i s supportive, wi t h t he except i on of acycl ovi r for herpes s i mpl ex encephal i t i s . Drug i nt oxi cat i on and i mmune di s eas es are

Pa g e 1 6 9 3


t reat abl e, and pat i ent s wi t h as s oci at ed encephal i t i s us ual l y res pond. o

o

3. Intracranial abscess. Suppurat i ve i nfect i ons can i nvol ve t he cont ent s of t he cal vari um, us ual l y by di rect s pread from an i nfect ed s i nus or ear. 



a. Etiology. The bact eri ol ogy of i nt racrani al i nfect i ons refl ect s t he t ypes of organi s ms t hat caus e di s eas e i n more s uperfi ci al cont i guous s t ruct ures s uch as s t rept ococci and anaerobi c bact eri a. Abs ces s es can be l ocal i zed t o t he ext radural (al s o cal l ed epi dural ) or s ubdural s paces or i n t he brai n parenchyma. Rarel y, hemat ogenous s pread of bact eri a can gi ve ri s e t o i nt racrani al abs ces s es . Les s common agent s are T oxopl as ma, Noc ardi a, and Crypt oc oc c us s peci es , whi ch us ual l y are s een i n i mmunocompromi s ed pat i ent s wi t h reduced hel per T-cel l numbers or funct i on.





b. Diagnosis. Magnetic resonance imaging (MRI) (more s ens i t i ve) or CT (more wi del y avai l abl e and l es s expens i ve) of t he brai n i s hel pful i n maki ng t he di agnos i s . Earl y s cans may be equi vocal , but s t udi es repeat ed wi t hi n a few days are al mos t al ways pos i t i ve, es peci al l y wi t h t he us e of cont ras t . Defi ni t i ve di agnos i s requi res as pi rat i on for s t ai n and cul t ure.





c. T herapy. Bact eri al abs ces s es are t reat ed wi t h appropri at e antibiotics t hat penet rat e

Pa g e 1 6 9 4


brai n t i s s ue wel l . Thes e may i ncl ude peni ci l l i n, chl orampheni col , and met roni dazol e. The us ual t reat ment i s gi ven for i nfect i on by T oxopl as ma (e.g., pyri met hami ne, s ul fadi azi ne), Crypt oc oc c us (e.g., amphot eri ci n B, fl ucyt os i ne), or Noc ardi a (e.g., a s ul fa drug wi t h or wi t hout t ri met hopri m). Surgi cal exci s i on or decompres s i on i s not al ways needed, but s ome pat i ent s , es peci al l y t hos e wi t h l arge l es i ons or s l ow res pons e t o t reat ment , requi re serial aspirations or more aggres s i ve s urgi cal dÃ©bri dement .

B. Head and neck infections 



1. Otitis. Infect i ons of t he ear can i nvol ve any of t he ear's t hree major anat omi c areas â€”t he out er, mi ddl e, or i nner ear. o

o

a. Outer ear infections t end t o be mi nor i rri t at i ons of t he ext ernal audi t ory canal . Topi cal ant i bi ot i c t reat ment i s us ed for ext ernal ot i t i s . An except i on i s malignant otitis externa, a des t ruct i ve proces s mos t commonl y found i n di abet i c pat i ent s (s ee IV A 4 a). Mal i gnant ot i t i s ext erna requi res ant i bi ot i cs t hat are effect i ve agai ns t P. aerugi nos a i nfect i on pl us s urgi cal dÃ©bri dement and drai nage.

o

o

b. Middle ear infection, or otitis media, t ypi cal l y i s a di s eas e of chi l dren and mani fes t s as ear pai n and reduced audi t ory acui t y. Ot os copy s hows a dul l , poorl y mobi l e t ympani c membrane wi t h or

Pa g e 1 6 9 5


wi t hout pus behi nd i t . The mos t common caus es are pneumococci , St rept oc oc c us pyogenes , Moraxel l a c at arrhal i s , and H. i nfl uenzae. In chroni c cas es , es peci al l y i f mul t i pl e cours es of ant i bi ot i cs have been gi ven, ent eri c Gram-negat i ve rods and anaerobes may be i nvol ved. Therapy for acut e ot i t i s medi a i s amoxi ci l l i n, amoxi ci l l i n wi t h cl avul ani c aci d, t ri met hopri m wi t h s ul famet hoxaz ol e, a macrol i de s uch as azi t hromyci n or cl ari t hromyci n, or an oral cephal os pori n. Cul t ures and appropri at e t herapy are s ugges t ed for chroni c ot i t i s medi a. o

o

c. Inner ear infections rarel y are caus ed by bact eri a. However, s everal vi rus es may be as s oci at ed wi t h a s yndrome of vertigo wi t h or wi t hout tinnitus. No t reat ment i s hel pful .





2. Sinusitis. (Fi gure 8-2) The paranas al s i nus es have cont i nuous expos ure t o t he ext ernal envi ronment vi a t he os t i a i n t he nos e. Under normal condi t i ons , hos t defens es mai nt ai n t he s t eri l e envi ronment of t he s i nus es . However, when mucoci l i ary cl earance i s i nt errupt ed becaus e of s t ruct ural or funct i onal abnormal i t i es , i nfect i on can s upervene. In addi t i on, pat i ent s wi t h mi d- t o l at e-s t age HIV i nfect i on are prone t o recurrent or chroni c s i nus i t i s . P.347

Pa g e 1 6 9 6


FIGURE 8-2 Si nus i t i s . o

o

a. Etiology. As i n mi ddl e ear i nfect i ons , virulent bacteria s uch as pneumococci and H. i nfl uenzae are mos t l i kel y t o caus e acut e di s eas e, and anaerobi c or ent eri c organi s ms are as s oci at ed wi t h more chroni c i nfect i ons . Bact eri al s i nus i t i s may fol l ow and mi mi c vi ral upper res pi rat ory i nfect i ons ; however, onl y t he bact eri al i nfect i ons go on t o devel op s uppurat i ve compl i cat i ons of t he CNS.

o

o

b. Diagnosis. Sinus radiography s hows mucos al t hi ckeni ng or opaci fi cat i on or ai râ€“fl ui d l evel s i n s i nus i t i s . Tendernes s and edema hel p l ocal i ze di s eas e t o t he s i nus es but are not pres ent i n al l pat i ent s . CT scanning i s more s ens i t i ve t han s i nus radi ography, but i t s houl d not be performed i n t he earl y s t ages of â€œcol ds ,â€• becaus e mi nor s i nus abnormal i t i es are commonl y s een on CT s can i n pat i ent s wi t hout s i gni fi cant ongoi ng s i nus i t i s . Mos t cas es of s i nus i t i s are di agnos ed cl i ni cal l y, and i magi ng i s res erved for pat i ent s wi t h refract ory or

Pa g e 1 6 9 7


recurrent di s eas e. o

o

c. T herapy 



(1) In mi l d cas es deconges t ant s al one are adequat e.





(2) Funct i onal endoscopic sinus surgery can be us eful i n pat i ent s wi t h repeat ed or pers i s t ent i nfect i on.





3. Odontogenic infections, t he mos t common i nfect i ons occurri ng i n t he oral cavi t y, us ual l y are l ocal and res pond t o s i mpl e meas ures s uch as drai ni ng abs ces s es , res t ori ng cari ous t eet h, and mai nt ai ni ng good oral hygi ene. Somet i mes , however, s oft t i s s ue i nfect i ons i n t he mout h can di s s ect t hrough t i s s ue pl anes and i nvol ve deeper s t ruct ures of t he face or neck. Exampl es are Ludwig' s angina, whi ch i s an i nfect i on ext endi ng t o t he fl oor of t he mout h, and retropharyngeal abscess, whi ch can t rack down t o t he medi as t i num. The i nvol ved bact eri a are s t rept ococci and i ndi genous oral anaerobes .





4. Eye infections. Normal l y, t he eyes are res i s t ant t o i nfect i ons . o

o

a. Conjunctivitis. Superfi ci al i nfect i ons of t he conjunct i va us ual l y are bact eri al or vi ral and res ol ve s pont aneous l y. An except i on i s gonorrheal conjunctivitis, a rare adul t di s eas e t hat mus t be t reat ed vi gorous l y.

Pa g e 1 6 9 8


o

b. Keratitis. Becaus e t he t rans parency of t he cornea i s cruci al for vi s i on, di agnos t i c t es t s s uch as bact eri al and vi ral s mears and cul t ures are warrant ed. Ini t i al t herapy i s gui ded by t he cl i ni cal pi ct ure, becaus e a vari et y of organi s ms can caus e kerat i t i s , i ncl udi ng S. aureus , P. aerugi nos a, s t rept ococci , numerous fungi , and herpes s i mpl ex and vari cel l a-zos t er vi rus es . It i s i mport ant t o recogni ze kerat i t i s caus ed by herpes simplex virus s o t hat appropri at e ant i vi ral t herapy t o prevent bl i ndnes s can be i ns t i t ut ed.

o

o

c. Endophthalmitis. Bact eri a mos t commonl y caus e t hi s i nfect i on of t he i nt ernal s t ruct ures of t he eye, whi ch may fol l ow eye s urgery or i nfect i on el s ewhere i n t he body. Sys t emi c and t opi cal ant i bi ot i cs , s el ect ed on t he bas i s of cl i ni cal fi ndi ngs and Gram s t ai n of ocul ar mat eri al , are admi ni s t ered t o prevent i rrevers i bl e des t ruct i on of t he eye. However, t he prognos i s for normal vi s ual acui t y aft er endopht hal mi t i s i s poor.

P.348

C. Respiratory tract infections 



1. Upper respiratory infections. Infect i ons i nvol vi ng t he nos e, t hroat , l arynx, ai rways , and adjacent s t ruct ures are t he mos t common caus es of morbi di t y i n t he Uni t ed St at es . o

Pa g e 1 6 9 9


o

a. Etiology. Upper res pi rat ory i nfect i ons al mos t i nvari abl y are vi ral .

o

o

b. Clinical features. Thes e â€œcol ds â€• and â€œfl us â€• i nvol ve rhi norrhea, coryz a, cough, a s l i ght fever, and, s omet i mes , s ore t hroat . Duri ng s eas ons when i nfl uenz a i s epi demi c i n a communi t y, headache, cough, myal gi a, and a more marked t emperat ure el evat i on may s ugges t t he di agnos i s .

o

o

c. T herapy. Treat ment for â€œcol ds â€• i s s ympt omat i c. Infl uenz a A vi rus i nfect i ons may res ol ve more qui ckl y when an ant i vi ral s uch as amant adi ne, ri mant adi ne, os el t ami vi r, or zanami vi r i s admi ni s t ered wi t hi n 24â€“48 hours . Thes e medi cat i ons can be us eful i n prevent i ng i nfl uenz a i n hi gh-ri s k pat i ent s when i mmuni zat i on i s not feas i bl e or i s performed t oo l at e t o offer meani ngful prot ect i on.

o

d.

Prevention. Becaus e of t he ubi qui t y and ext reme i nfect i vi t y of

mos t epi demi c vi rus es , prevent i on of mos t upper res pi rat ory di s eas e i s di ffi cul t . Careful handwas hi ng i s a s i mpl e meas ure t o prevent t he s pread of upper res pi rat ory i nfect i ons . In many cas es , t i mel y admi ni s t rat i on of vacci ne devel oped agai ns t t he epi demi c s t rai ns t hat exi s t duri ng a part i cul ar s eas on al s o may prevent i nfl uenz a. Immuni zat i on s houl d be di rect ed at i ndi vi dual s who are at great es t ri s k for compl i cat i ons of upper res pi rat ory i nfect i on s uch as el derl y or chroni cal l y i l l i ndi vi dual s . Y earl y i mmuni zat i on has a favorabl e i mpact on i nfl uenz a morbi di t y and mort al i t y. In addi t i on, i mmuni z at i on of heal t hy adul t s may reduce abs ent eei s m at work, and vacci nat i on of heal t h care provi ders may prevent or s l ow

Pa g e 1 7 0 0


epi demi cs of i nfl uenz a i n nurs i ng homes and hos pi t al s . 



2. Pharyngitis o

o

a. Etiology. The major et i ol ogi c agent s of pharyngi t i s , a common i l l nes s , are vi rus es , and S. pyogenes (group A s t rept ococci ).

o

o

b. Clinical features. Sore throat t hat occurs wi t h or wi t hout object i ve fi ndi ngs of eryt hema or exudat e on t he oropharynx or t ons i l s i s charact eri s t i c.

o

o

c. T herapy 



(1) Treat ment for group A s t rept ococcal pharyngi t i s may accel erat e heal i ng and reduce s ympt oms , but t he major purpos e of t reat i ng t hi s di s order i s prevention of subsequent rheumatic fever, a rare s equel a.





(2) Vi ral pharyngi t i s does not i mprove wi t h any known chemot herapy.





(3) W het her t reat ment of mycopl as mal or chl amydi al pharyngi t i s i s benefi ci al i s not known.





3. T racheobronchitis i s an i nfect i on of t he ai rways . o

Pa g e 1 7 0 1


o

a. Etiology. Mos t cas es of t racheobronchi t i s are as s oci at ed wi t h i nfect i on by mycopl as ma or by viruses, s uch as i nfl uenz a or parai nfl uenz a vi rus (i n adul t s ) or res pi rat ory s yncyt i al vi rus (i n young chi l dren). However, bact eri a may pl ay a rol e i n pat i ent s wi t h chroni c obs t ruct i ve pul monary di s eas e (COPD) and cys t i c fi bros i s . H. i nfl uenzae, S. aureus , and P. aerugi nos a are bel i eved t o be pat hogeni c i n t hos e wi t h cys t i c fi bros i s (s ee Chapt er 2 IV B).

o

o

b. Clinical features and laboratory findings. Cough wi t h abundant , t hi ck s put um i s charact eri s t i c of t racheobronchi t i s . Fever, ches t pai n, and wheez i ng al s o may occur. If ral es or cons ol i dat i on i s found, pneumoni a i s s ugges t ed. The W BC count and ches t radi ograph are unchanged from bas el i ne i n uncompl i cat ed t racheobronchi t i s .

o

o

c. T herapy. Si mpl e s upport i ve meas ures us ual l y s uffi ce. Ant i bi ot i cs us ual l y are gi ven t o pat i ent s wi t h COPD exacerbat i on, al t hough t he benefi t of s uch t herapy i s modes t and mos t pronounced when al l t hree el ement s of exacerbat i on are pres ent : dys pnea, i ncreas ed vol ume of s put um, and i ncreas ed purul ence of s put um. Pat i ent s wi t h cys t i c fi bros i s undergo ches t phys i cal t herapy and recei ve ant i mi crobi al agent s accordi ng t o s put um bact eri ol ogy (s ee Chapt er 2 IV B 6 b).





4. Pneumonia o

o

a. Etiology. Caus es i ncl ude bact eri a, vi rus es , fungi ,

Pa g e 1 7 0 2


and paras i t es . Al t hough i dent i fi cat i on of t he s peci fi c caus e of pneumoni a i s i deal , many pat i ent s can be t reat ed i ni t i al l y on t he bas i s of cl i ni cal and demographi c feat ures . o

o

b. Clinical features and diagnosis 



(1) Patient history may i ndi cat e an underl yi ng condi t i on. For exampl e, t he i nci dence of bact eri al pneumoni a i s i ncreas ed i n as s oci at i on wi t h COPD or al cohol i s m. Fever i s us ual l y, but not i nvari abl y, pres ent . Evi dence of ext ra fl ui d i n t he l ungs i s not ed as ral es or cons ol i dat i on on phys i cal exami nat i on and i nfi l t rat e on ches t radi ograph. In addi t i on, t he appearance of t he s put um can be us eful for maki ng t he appropri at e di agnos i s .





(2) Becaus e of t he vast differential diagnosis, i t i s hel pful t o cons i der pneumoni a i n t wo ways (recogni zi ng t hat a cons i derabl e overl ap i s pos s i bl e): 



(a) W het her i t devel oped at home (community-acquired) or i n a hos pi t al or i ns t i t ut i on (hospital-acquired or nosocomial)





(b) W het her i t had a rapi d ons et wi t h chi l l s , fever, and cough (classical) or a more i ndol ent ons et (atypical)

Pa g e 1 7 0 3


P.349

o

o

c. Pneumonia syndromes (Tabl e 8-4) 



(1) Classical community-acquired (CAP) pneumonia 



(a) Etiology. Thi s s yndrome mos t frequent l y i s caus ed by S. pneumoni ae. However, H. i nfl uenzae, M. c at arrhal i s , and ent eri c Gram-negat i ve baci l l i al s o can caus e t hi s cl i ni cal pi ct ure.





(b) Diagnosis. Gram s t ai ni ng of expect orat ed s put um s hows l arge numbers of neut rophi l s (i .e., >25 per l ow-power fi el d) and few s quamous cel l s (10 /mL. 



2. Centrifuged sediment us ual l y reveal s

Pa g e 1 7 3 6


l eukocyt uri a (neut rophi l s ) and bact eri uri a. 



3. Gram stain may charact eri ze t he offendi ng organi s m, al l owi ng more s peci fi c t herapy.

o

o

b. Routine urine culture is the definite method of 5

diagnosis. More t han 10 col oni es /mL s i gni fi es an i nfect i on t hat needs t reat ment . o

o

c. Examining the patient. W hen t o exami ne pat i ent s for anat omi c abnormal i t i es t o expl ai n UTIs i s cont rovers i al . Mos t evi dence s ugges t s t hat cys t os copy and urography s el dom s how t reat abl e caus es of i nfect i on; us e onl y for pat i ent s wi t h frequent recurrences and jeopardi zed ki dney funct i on. Men have a hi gher rat e of anat omi c compl i cat i ons (us ual l y pros t at e-rel at ed) t han women. Rect al exami nat i on may i ndi cat e enl argement or t endernes s of t he pros t at e, and purul ent di s charge may be expres s ed from t he uret hra aft er pros t at i c exami nat i on.

o

o

d. W hen bl ood cul t ures are pos i t i ve i n t he cont ext of a UTI, i nvol vement of t he ki dneys or pros t at e gl and i s i mpl i ed. Fever al s o s ugges t s renal i nvol vement .





6. T herapy. Ant i bi ot i c t reat ment i s us ual l y di rect ed at t he agent mos t l i kel y t o be res pons i bl e for t he i nfect i on. Correct i ve s urgery i s i ndi cat ed t o remove cal cul i or repai r obs t ruct i ve anat omi c l es i ons . o

Pa g e 1 7 3 7


o

a. E. coliâ€“caused infections. E. c ol i has a propens i t y for caus i ng i nfect i ons i n ot herwi s e heal t hy i ndi vi dual s , s o admi ni s t er ant i bi ot i cs effect i ve agai ns t E. c ol i i n t he abs ence of cul t ures . Oral t ri met hopri m and s ul famet hoxaz ol e can be us ed al one or t oget her, as wel l as qui nol ones , t et racycl i nes , and s ome peni ci l l i n preparat i ons s uch as amoxi ci l l i n wi t h cl avul ani c aci d. Ampi ci l l i n al one i s l i kel y t o be i neffect i ve becaus e of t he l arge number of ampi ci l l i n-res i s t ant E. c ol i . 



(1) A 3-day cours e of t herapy i s adequat e t o cure mos t i nfect i ons (es peci al l y cys t i t i s ) where uri ne drug l evel s s eem t o be t he mos t i mport ant det ermi nant of effect i venes s .





(2) Fai l ure t o cure i nfect i ons rapi dl y does not al t er t he effi cacy of fut ure t herapy. In rare i ns t ances , refract ory i nfect i on may requi re a l ong cours e of t herapyâ€”s omet i mes up t o s everal mont hs â€”al t hough bri efer cours es (i .e., 2 weeks ) oft en are s ucces s ful .

o

o

b. Uncomplicated lower tract infection. Three-day t reat ment of t ri met hopri mâ€“s ul famet hoxaz ol e (TMP-SMX) i s effect i ve and i nexpens i ve. Be aware of l ocal pat t erns of bact eri al s us cept i bi l i t y. Al t ernat i ves i ncl ude ni t rofurant oi n, and Î²-l act am ant i bi ot i cs , s uch as amoxi ci l l i n or cephal exi n.

o

o

c. Treat relapsing UT I and pyelonephritis for 14 days wi t h TMP-SMX, i f s t abl e; al t ernat i ves i ncl ude

Pa g e 1 7 3 8


fl uoroqui nol ones and amoxi ci l l i n or amoxi ci l l i n/cl avul ani c aci d. In t he pres ence of hi gh fever, hi gh whi t e bl ood cel l count , vomi t i ng, dehydrat i on, or evi dence of s eps i s , t he pat i ent s houl d be admi t t ed and t reat ed wi t h i nt ravenous ant i bi ot i cs unt i l s t abl e, and t hen can compl et e t herapy wi t h oral agent s as an out pat i ent . o

o

d. Asymptomatic bacteriuria. Treat ment i s i ndi cat ed for pat i ent s wi t h a known s t ruct ural or funct i onal abnormal i t y of t he ki dneys (i ncl udi ng renal t rans pl ant ) and t hos e who are pregnant .

o

o

e. Catheter-related bacteriuria may occur i n acut el y cat het eri zed pat i ent s and us ual l y res ol ves when t he cat het er i s removed. If not , or s ympt oms devel op wi t hi n 12â€“24 hours , t reat wi t h t he P.357

appropri at e ant i bi ot i c. Frequent bl adder cat het eri zat i ons (s everal t i mes dai l y) rat her t han us e of an i ndwel l i ng cat het er may l es s en t he ri s k of t hi s i nfect i on. o

o

f. Prostate infections. Us e ant i bi ot i cs t hat penet rat e and remai n act i ve i n pros t at e t i s s ue and fl ui d (e.g., t ri met hopri m, carbeni ci l l i n). Treat for at l eas t 14 days .

o

o

g. Recurrent UT I t ypi cal l y requi re TMP-SMX, met henami ne mandel at e, and s ul fi s oxazol e. Us i ng ci profl oxaci n may res ul t i n s t eri l e uri ne.

Pa g e 1 7 3 9


G. Skin and soft tissue infections Bact eri al , fungal , and vi ral i nfect i ons of t he s ki n and rel at ed s t ruct ures (e.g., hai r fol l i cl es , s weat gl ands ) are common. (See al s o Chapt er 12 XI.) 



1. Bacterial skin infections us ual l y s t art i n areas of t rauma or previ ous di s eas e. o

o

a. Etiology. In ot herwi s e heal t hy i ndi vi dual s , Gram-pos i t i ve cocci s uch as S. pyogenes and S. aureus caus e mos t s ki n i nfect i ons . Immunocompromi s ed i ndi vi dual s are s ubject t o t he us ual Gram-pos i t i ve fl ora as wel l as a wi der vari et y of pat hogens , i ncl udi ng ent eri c Gram-negat i ve baci l l i and P. aerugi nos a.

o

o




(1) Cellulitis i s charact eri zed by rednes s , warmt h, and t endernes s of t he s ki n. It may i nvol ve a l i mi t ed area or may s pread wi del y and rapi dl y. Fever and l eukocyt os i s are common. [In s ome pat i ent s , a rapi dl y progres s i ve cut aneous i nfect i on (s t rept ococcal TSS) caus ed by group A s t rept ococci and charact eri zed by s i gni fi cant s ys t emi c feat ures can caus e s evere s ki n damage and even deat h.]





(2) Abscesses repres ent deeper, ci rcums cri bed i nfect i ons , whi ch oft en s t art i n

Pa g e 1 7 4 0


acces s ory s t ruct ures s uch as hai r fol l i cl es . They may be warm or of normal s ki n t emperat ure and frequent l y cont ai n pus . Fever i s mos t l i kel y t o be pres ent i n i ndi vi dual s wi t h l arge, mul t i pl e, or deep abs ces s es . Hi dradeni t i s occurs from i nfl ammat i on of s weat gl ands wi t h res ul t ant abs ces s ; oft en i t can be t reat ed wi t h warm compres s i on. 



(3) Ulcers are not us ual l y t he res ul t of bact eri al i nfect i on al one but refl ect t i s s ue damage from i s chemi a or t rauma. Invari abl y, ul cers are col oni zed by bact eri a and may l ead t o deep s oft t i s s ue or bone i nfect i on. They us ual l y occur i n dependent areas (e.g., t he s acrum) or i n areas of poor bl ood fl ow or decreas ed s ens at i on (e.g., i n t he feet of a pat i ent wi t h di abet es ).

o

o

c. T herapy 



(1) Cellulitis requires antibiotic management. Agent s act i ve agai ns t s t rept ococci and s t aphyl ococci us ual l y are effect i ve, i ncl udi ng s emi s ynt het i c peni ci l l i ns (e.g., nafci l l i n), cephal os pori ns , vancomyci n, cl i ndamyci n, and l i nezol i d.





(2) Abscesses should be drained, al t hough s ome rupt ure s pont aneous l y. Ant i bi ot i cs are s el dom needed unl es s t here i s accompanyi ng cel l ul i t i s .



Pa g e 1 7 4 1




(3) Ulcers us ual l y are managed by dÃ©bridement and antibiotic therapy wi t h broad-s pect rum agent s act i ve agai ns t ent eri c Gram-negat i ve rods , Gram-pos i t i ve cocci , and anaerobes . Ski n graft i ng may be benefi ci al .





2. Fungal skin infections us ual l y are acqui red by expos ure of t he s ki n t o pat hogeni c fungi . Except i ons are cut aneous mani fes t at i ons of bl as t omycos i s or candi dal fungemi a. o

o

a. Clinical features. Fungal i nfect i ons t hat s t art i n t he s ki n fal l i nt o t hree groups . 



(1) Dermatophytosis i s a s uperfi ci al i nfect i on of t he epi dermi s due t o dermat ophyt i c fungi (e.g., T ri c hophyt on, Mi c ros porum, and Epi dermophyt on s peci es ). At hl et e's foot and ri ngworm are exampl es . The s ki n us ual l y i s fl aky and may be s l i ght l y di s col ored but i s not frankl y pai nful .





(2) Candidiasis i s a red, t ender edemat ous ras h occurri ng i n moi s t body part s and caus ed by C. al bi c ans , oft en s een i n di abet i cs and i mmunos uppres s ed pat i ent s . Int ert ri go i n t he axi l l ary or i nframammary area i s an exampl e.





(3) Mixed bacterial flora and fungi (us ual l y Candi da s peci es ) can be i nvol ved i n s uperfi ci al i nfect i on. Thi s may be evi dent duri ng or aft er

Pa g e 1 7 4 2


admi ni s t rat i on of ant i bact eri al t herapy. o

o

b. Diagnosis. Pot as s i um hydroxi de preparat i ons and fungal cul t ures are t he foundat i on of di agnos i s .

o

o

c. T herapy 



(1) Dermat ophyt os i s i s t reat ed wi t h t opi cal t herapy for l i mi t ed di s eas e or wi t h oral t herapy for ext ens i ve i nfect i on. Azoles (e.g., ket oconazol e, fl uconazol e) are mos t commonl y us ed. P.358





(2) Candi di as i s i s t reat ed t opi cal l y, but s peci al at t ent i on s houl d be gi ven t o keepi ng t he affect ed area cl ean and dry. Rarel y, s ys t emi c azol e t herapy i s requi red.





(3) Mi xed bact eri al and fungal i nfect i ons us ual l y do not requi re s peci fi c ant i fungal t herapy.





3. Viral skin infections may be cut aneous l y i nocul at ed, as i n t he cas e of herpes s i mpl ex, but more commonl y are a mani fes t at i on of s ys t emi c vi ral i nfect i on or an i mmune res pons e t o i nfect i on. An exampl e of t hi s i s varicella (chickenpox), i n whi ch t he vi rus i s acqui red

Pa g e 1 7 4 3


vi a t he res pi rat ory t ract and s preads t o t he s ki n aft er a vi remi a. 



4. Deep soft tissue infections are rare but s eri ous i nfect i ons us ual l y caus ed by s t rept ococci , anaerobes , and Gram-negat i ve rods . There may be comparat i vel y l i t t l e abnormal i t y of t he s ki n i n s ome of t hes e i nfect i ons (e.g., fasciitis). Combi nat i ons of medi cal and s urgi cal t herapy us ual l y are us ed, but even s o, many pat i ent s s uccumb t o t hes e i nfect i ons . o

o

a. Gangrene i s an i nfect i on of t he s ki n and s oft t i s s ues caus ed by a mi xed anaerobi c and aerobi c bact eri al fl ora t hat us ual l y i ncl udes C. perfri ngens . It i s charact eri zed by cel l ul i t i s and gas i n t he s oft t i s s ues . Therapy i nvol ves s urgi cal dÃ©bri dement and ant i bi ot i c t herapy (e.g., wi t h peni ci l l i n).

o

o

b. Fasciitis i s a rare i nfect i on bet ween t i s s ue pl anes . It us ual l y occurs pos t operat i vel y, aft er rupt ure of an abdomi nal vi s cus , or i n di abet i c pat i ent s . Pat hogeni c bact eri a i ncl ude mi xed anaerobes , s t rept ococci , and, occas i onal l y, Gram-negat i ve baci l l i .

H. Osteomyelitis Bone i nfect i ons can be cl as s i fi ed accordi ng t o t hei r pat hogenes i s . In general , bone i nfect i ons devel op i n t hree ways : by ext ens i on from a cont i guous i nfect i on, by di rect i nocul at i on duri ng s urgery or as a res ul t of t rauma, and by hemat ogenous s pread. 



1. Osteomyelitis due to contiguous infection or inoculation. Bone i nfect i on s houl d be s us pect ed i n

Pa g e 1 7 4 4


pat i ent s wi t h a hi s t ory of trauma or surgery or wi t h obvi ous soft tissue infection overl yi ng bone, al t hough t he bone i nvol vement may be di ffi cul t t o prove. o

o

a. Etiology. Al mos t any bact eri um can be res pons i bl e, i ncl udi ng S. aureus , P. aerugi nos a, or anaerobes .

o

o

b. Clinical features. Sympt oms and s i gns may s i mpl y be t hos e of t he adjacent i nfect i on. Pai n i s common, and fever i s vari abl e.

o

o

c. Diagnosis. Thi s proces s may be di ffi cul t . Radi ographi c evi dence of os t eomyel i t i s l ags behi nd t he s ympt oms and pat hol ogi c changes by approxi mat el y 7â€“10 days . Al t hough bone s canni ng i s s ens i t i ve for os t eomyel i t i s , i t may not di s t i ngui s h bone i nfect i on from more s uperfi ci al s oft t i s s ue i nfect i on. The defi ni t i ve di agnos i s res t s on bone bi ops y and bact eri al cul t ure. An expens i ve but us eful t es t i s t he MRI s can, whi ch s hows changes i n t he bone marrow t hat can be det ect ed wel l before change i n pl ai n x-rays (Fi gure 8-4).

o

o

d. Clinical course and therapy. The cl i ni cal cours e gui des t he l engt h of t reat ment , but , general l y, long courses of antibiotics are neces s ary. Devi t al i zed bone, poor bl ood s uppl y, and adjacent i nfect i on may be reas ons for ext ended (mont hs ) t herapy and/or s urgi cal dÃ©bri dement .





2. Hematogenous osteomyelitis. Thi s t ype of di s eas e

Pa g e 1 7 4 5


s houl d be s us pect ed i n febri l e pat i ent s who experi ence pai n and s wel l i ng over a bone but have no obvi ous s ource of i nfect i on. o

o

a. Etiology. The bact eri ol ogy i nvol ves l argel y S. aureus . However, Sal monel l a s peci es s eem t o be more i mport ant i n pat i ent s wi t h s i ckl e cel l di s eas e. Vert ebral os t eomyel i t i s al s o i s s omewhat di fferent i n t hat Gram-negat i ve baci l l i may be i nt roduced from t he uri nary t ract t hrough venous channel s .

o

o

b. Diagnosis. Radi ography and bone s canni ng are hel pful . The eryt hrocyt e s edi ment at i on rat e us ual l y i s el evat ed but t hi s i s qui t e a nons peci fi c fi ndi ng. Bone as pi rat i on and cul t ure are recommended for mi crobi ol ogi c di agnos i s . Bl ood cul t ures al s o s houl d be obt ai ned.

o

o

c. T herapy. Treat ment i s a prol onged cours e of antibiotics. Nonvi abl e bone may need t o be removed s urgi cal l y becaus e i t provi des a s i t e for pot ent i al rel aps e.

I. Intravascular infections and endocarditis Int ravas cul ar i nfect i ons mani fes t as bacteremia, or fungemia, dependi ng on t he t ype of i nfect i ve organi s m demons t rat ed i n t he bl ood. Such i nfect i ons may refl ect invasion or failure of containment at a localized site (e.g., bowel or l ung) or a primary infection of the blood vessels or the heart (e.g., endocardi t i s ). 



1. Local infections l ead t o pos i t i ve bl ood cul t ures , wi t h a frequency dependent on t he s i t e and s everi t y of t he i nfect i on and on t he organi s m or organi s ms res pons i bl e

Pa g e 1 7 4 6


for t he i nfect i on. P.359

FIGURE 8-4 Magnet i c res onance i magi ng (MRI) s can of os t eomyel i t i s i n t he t horaci c s pi ne. In t he T1 i mage (l eft ), l os s of bony s t ruct ure i n a vert ebra i s s een (arrow). In t he T2 i mage (ri ght ), t he hi gh s i gnal i nt ens i t y due t o wat er mol ecul es s hows edema and i nfi l t rat e i n t he s ame vert ebra. (From Engl eberg NC, Dermody T, Di Ri t a V. Sc haec ht er's Mec hani s ms of Mi c robi al Di s eas e. 4t h ed. Bal t i more: Li ppi ncot t W i l l i ams & W i l ki ns , 2006. ) o

o

a. For exampl e, among hos pi t al i zed pat i ent s wi t h pneumococcal pneumoni a, 10%â€“25% have bact eremi a. The prognos i s for t hes e pat i ent s i s wors e t han for t hos e wi t hout bact eremi a becaus e

Pa g e 1 7 4 7


t hos e wi t h bact eremi a t end t o have more di ffus e l ung i nvol vement and more vi rul ent organi s ms . o

o

b. Even when bl ood cul t ures do not demons t rat e a part i cul ar organi s m, met as t at i c i nfect i on or di s s emi nat i on (e.g., crypt ococcal meni ngi t i s or mi l i ary t ubercul os i s ) s t rongl y s ugges t s bl ood-borne s pread.





2. Sepsis i s recogni zed as a s ys t emi c i nfl ammat ory res pons e s yndrome (SIRS) i n t he s et t i ng of an i nfect i on. SIRS i s defi ned i n a pat i ent wi t h t wo of t he fol l owi ng cri t eri a: o

o

1. Temperat ure >38Â°C or 90 bpm

o

o

3. Res pi rat i ons >20/mi n or PaCO 2 12,000/mi n , 10% i mmat ure (band) cel l s .

o

o

a. Etiology. Seps i s can progres s t o s ept i c s hock, whi ch i ncl udes organ dys funct i on s econdary t o hyperfus i on. Sept i c s hock can be mul t i fact ori al , but one i dent i fi ed caus e i s endot oxi n (t he l i popol ys acchari de coat of Gram-negat i ve

Pa g e 1 7 4 8


organi s ms ). However, an i ndi s t i ngui s habl e cl i ni cal di s eas e can be caus ed by Gram-pos i t i ve bact eri a, vi rus es , and yeas t . o

o

b. T herapy. Antibiotic treatment i s cri t i cal for pat i ent recovery. Hi gh-dos e cort i cos t eroi d t herapy t o s uppl ement us ual s upport i ve meas ures does not i mprove s urvi val . Vari ous i mmunomodul at ors s uch as TNF i nhi bi t ors and ant i body t o endot oxi n have fai l ed t o i mprove t he prognos i s of s ept i c s hock. Act i vat ed prot ei n C (drot recogi n) has ant i coagul ant propert i es but al s o s eems t o bl ock s ome of t he des t ruct i ve pos i t i ve feedback l oops t hat promot e organ damage i n s hock. It i s us eful i n t he mos t s everel y i l l pat i ent s .





3. Catheter-related infections are s eri ous probl ems as s oci at ed wi t h hos pi t al i zat i on. Infect i on s el dom i s caus ed by t he i nfus i on of cont ami nat ed fl ui d. Rat her, t hes e i nfect i ons mos t commonl y occur at t he site of cannulation. o

o

a. Diagnosis. Di agnos i s i nvol ves demons t rat i on of ei t her l ocal s ki n i nfect i on at t he cannul at i on s i t e or pos i t i ve bl ood cul t ures and t he pres ence of t he s ame bact eri a i n s i gni fi cant numbers on P.360

a s emi quant i t at i ve cul t ure of t he cat het er. Somet i mes a vei n i nfect i on may not be apparent unt i l aft er t he cat het er has been removed. Infect ed vei ns are al mos t al ways cl ot t ed at t he s i t e of t he i nfect i on.

Pa g e 1 7 4 9


o

b. T herapy. Removal of t he cat het er when l ocal i nfect i on i s pres ent i s neces s ary. W hen vas cul ar acces s i s cruci al and t he cat het er has been as ept i cal l y i ns ert ed i nt o t he vena cava (e.g., a Hickman catheterâ€”a wi de-bore s i l as t i c cat het er us ed for chemot herapy, hyperal i ment at i on, or drawi ng bl ood), cons ervat i ve t herapy wi t h ant i bi ot i cs al one may cure t he i nfect i on. Fungal i nf ect i ons or t hos e caus ed by hi ghl y res i s t ant bact eri a us ual l y cannot be cured wi t hout removal of t he cat het er. Tunnel ed cat het ers t hat exhi bi t eryt hema and ot her s i gns of i nfl ammat i on al ong t he cat het er t ract al s o need t o be removed. Rarel y, an i nfect ed peri pheral vei n wi l l requi re s urgi cal management becaus e pus needs t o be drai ned.





4. Endocarditis us ual l y res ul t s from i nfect i on of t he cus p of a heart val ve, al t hough any part of t he endocardi um or any pros t het i c mat eri al i ns ert ed i nt o t he heart may be i nvol ved. o

o

a. Etiology. A vari et y of organi s ms may caus e endocardi t i s , al t hough bact eri a account for al mos t al l cas es . The s peci fi c agent of endocardi t i s depends on whi ch cardi ac s t ruct ures are affect ed. 



(1) Infection of normal valves, whi ch i s rare, i s us ual l y as s oci at ed wi t h i nt ravenous drug us e. S. aureus i s t he mos t common pat hogen.





(2) Infection of previously damaged valves,

Pa g e 1 7 5 0


oft en from rheumat i c heart di s eas e, us ual l y i s at t ri but abl e t o vi ri dans s t rept ococci . Ot her agent s of endocardi t i s i n t hi s s et t i ng are ent erococci , S. aureus , and vari ous s mal l Gram-negat i ve rods cons t i t ut i ng part of t he normal oral fl ora known as t he Haemophi l us parai nfl uenzae, Haemophi l us aphrophi l us , Ac t i nobac i l l us ac t i nomyc et emc omi t ans , Cardi obac t eri um homi ni s , Ei kenel l a c orrodens , and Ki ngel l a ki ngae (HACEK) organi s ms . 



(3) Infection of prosthetic valves i nvol ves s t aphyl ococci (bot h coagul as e-pos i t i ve and coagul as e-negat i ve) as t he mos t common agent s of earl y ons et di s eas e (occurri ng < 2 mont hs pos t operat i vel y). St rept ococci are t he mos t common agent s of l at e-ons et di s eas e (occurri ng >2 mont hs pos t operat i vel y).

o

o

b. Clinical features. Si gns and s ympt oms vary wi del y. 



(1) Fever i s al mos t uni vers al . A new heart murmur i s hi ghl y s ugges t i ve but not al ways pres ent . Endocardi t i s i s one of t he mos t common caus es of fever of unknown ori gi n.





(2) Les s commonl y, embolic disease s uch as s t roke or s pl eni c art ery embol i s m and i nfarct i on i s evi dent . Mos t embol i are s mal l and may gi ve ri s e t o uncommon but di agnos t i cal l y hel pful phys i cal fi ndi ngs i ncl udi ng Roth' s spots, Osler' s nodes,

Pa g e 1 7 5 1


Janeway lesions, and conjunctival hemorrhage. 



(3) A vari et y of cons t i t ut i onal s ympt oms s uch as myal gi a, back pai n, confus i on, or fat i gue may occur.

o

o

c. Diagnosis 



(1) Blood cultures are cri t i cal and are pos i t i ve i n more t han 90% of cas es of endocardi t i s . (Previ ous us e of ant i bi ot i cs may l ower t hi s val ue.) Becaus e of t he cont i nuous bact eremi a of endocardi t i s , vi rt ual l y al l cul t ures are pos i t i ve, and i t i s rarel y neces s ary t o obt ai n more t han t hree or four cul t ures .





(2) For pat i ent s wi t h cul t ure-negat i ve endocardi t i s , t here i s l i t t l e i ncrement al val ue i n col l ect i ng s everal addi t i onal bl ood s ampl es for cul t ure. Somet i mes , t he mi crobi ol ogy l aborat ory can enhance i s ol at i on by us i ng special culture techniques, s uch as prol onged i ncubat i on t o i s ol at e s l ow-growi ng organi s ms (e.g., HACEK).





(3) Echocardi ography s houl d be performed i n s us pect ed endocardi t i s . t rans t horaci c echocardi ography (TTE) may reveal veget at i on or val vul ar i ns uffi ci ency s ugges t i ve of endocardi t i s , but t rans es ophageal

Pa g e 1 7 5 2


echocardi ography (TEE) has hi gher s ens i t i vi t y. 



(4) Immune compl exes may caus e a glomerulonephritis, whi ch i s charact eri zed by el evat ed s erum creat i ni ne, hemat uri a, and cas t s i n t he uri ne, or rheumat ol ogi c mani fes t at i ons s uch as s t eri l e art hri t i s . The rol e of i mmune compl exes i n ot her as pect s of endocardi t i s i s not wel l unders t ood.





(5) Moderate anemia i s as s oci at ed wi t h endocardi t i s t hat has been pres ent for more t han 2 weeks .

P.361

o

o

d. T herapy. Treat ment has been careful l y s t udi ed. W hen endocardi t i s i s unt reat ed, i t i s al mos t uni forml y fat al . In general , pros t het i c val ve di s eas e i s more di ffi cul t t o t reat medi cal l y or s urgi cal l y. 



(1) Antibiotic therapy al one provi des an excel l ent chance of cure for s t rept ococcal di s eas e on a nat i ve val ve and for s t aphyl ococcal di s eas e on t he t ri cus pi d val ve. The key i s t o provi de an adequat e dos e for a l ong enough peri od, us ual l y 4â€“8 weeks , dependi ng on t he organi s m.





(2) In medi cal fai l ures , valve replacement

Pa g e 1 7 5 3


may be a neces s ary adjunct t o ant i bi ot i c t herapy. Ot her i ndi cat i ons for val ve s urgery i ncl ude: 



(a) Fungal endocardi t i s (an abs ol ut e i ndi cat i on)





(b) Conges t i ve heart fai l ure (CHF)





(c) Recurrent major embol i





(d) Inabi l i t y t o s t eri l i ze t he bl ood aft er 10â€“14 days

VI. Sexually Transmitted Diseases (STDs) A. Modes of transmission STDs us ual l y affect heal t hy adul t s . Mul t i pl e STDs can be pres ent at once. Mi croorgani s ms may be t rans mi t t ed duri ng i nt i mat e s exual rel at i ons i n t hree ways . 



1. Cutaneous inoculation i s t he mos t common rout e for t he fi ve â€œcl as s i cal â€• STDs (i .e., s yphi l i s , gonorrhea, chancroi d, l ymphogranul oma venereum, and granul oma i ngui nal e) as wel l as for herpes s i mpl ex. Appos i t i on of an i nfect ed s i t e t o a s us cept i bl e s i t e i n a part ner res ul t s i n a phys i cal t rans fer of mi croorgani s ms . Abras i on or t rauma may faci l i t at e t he i nfect i on of s ki n.





2. Blood-borne infection can be t rans mi t t ed by s exual act i vi t y. HBV, HCV, CMV, and HIV are al l t rans mi t t ed by i nocul at i on of mi cros copi c amount s of bl ood or s erum.

Pa g e 1 7 5 4




3. Enterically acquired infection may occur wi t h s exual act i vi t y becaus e t he anal area i s cl os e t o t he geni t al s or i s al s o us ed for s exual i nt eract i on. Shi gel l a, Ent amoeba, and HAV are exampl es of s exual l y t rans mi s s i bl e ent eri c di s eas es .

B. Urethritis 



1. Etiology. Uret hri t i s i s cl as s i fi ed as gonococcal or nongonococcal. o

o

a. Gonococcal urethritis i s caus ed by N. gonorrhoeae. In al mos t al l cas es of gonococcal uret hri t i s , Gram s t ai n of t he uret hral di s charge s hows Gram-negat i ve i nt racel l ul ar di pl ococci .

o

o

b. Nongonococcal urethritis i s caus ed by C. t rac homat i s , Ureapl as ma ureal yt i c um, or s ome ot her, yet uni dent i fi ed, agent . (In 25% of cas es of gonococcal uret hri t i s , one of t hes e organi s ms al s o i s pres ent , and pat i ent s may have recurrent s ympt oms aft er t herapy for gonorrhea.)






o

a. Dysuria i s obs erved i n mos t cas es of uret hri t i s , whet her gonococcal or nongonococcal .

o

o

b. Urethral discharge i s obs erved more frequent l y

Pa g e 1 7 5 5


i n men t han women and may be purul ent (us ual l y i n gonococcal di s eas e) or cl oudy and mucoi d (us ual l y i n nongonococcal di s eas e). 



3. T herapy o

o

a. A vari et y of antibiotic regimens can be us ed t o t reat gonorrhea. However, res i s t ance pat t erns change, and up-t o-dat e recommendat i ons s houl d be s ought .

o

o

b. Many cl i ni ci ans recommend t hat t reat ment wi t h a t et racycl i ne or macrol i de fol l ow gonococcal t herapy t o el i mi nat e pos s i bl e s i mul t aneous nongonococcal uret hri t i s . A 7-day cours e of a t et racycl i ne or eryt hromyci n or a s i ngl e dos e of azi t hromyci n i s us ual l y s uffi ci ent , al t hough s ome pat i ent s experi ence a rel aps e wi t hi n a few weeks . Thes e pat i ent s us ual l y res pond t o anot her cours e of ant i bi ot i cs .

C. Pelvic inflammatory disease (PID) PID refers t o a compl ex of i nfect i ons i nvol vi ng t he ut erus , fal l opi an t ubes , or l i gament s of t he ut erus . 



1. Etiology o

o

a. N. gonorrhoeae, C. t rac homat i s , or a mi xt ure of pel vi c anaerobes may be i nvol ved, al t hough i t i s di ffi cul t t o det ermi ne whi ch of t hes e i s res pons i bl e when i ns t i t ut i ng t herapy.

o

Pa g e 1 7 5 6


o

b. The pres ence of an i nt raut eri ne devi ce (IUD) may predi s pos e pat i ent s t o PID.

P.362





2. Clinical features and laboratory findings. The s ympt oms may be cont emporaneous wi t h mens t ruat i on and us ual l y cons i s t of l ower abdomi nal or pel vi c pai n and t endernes s on pal pat i on of t he cervi x, ut erus , or adnexa. Fever i s not neces s ari l y a s i gni fi cant feat ure. A cervi cal di s charge or pel vi c mas s may be pres ent , and t he W BC count may be normal or el evat ed.





3. Diagnosis o

o

a. It i s i mport ant t o obt ai n cul t ures or ot her di agnos t i c t es t s for N. gonorrhoeae and Chl amydi a.

o

o

b. Ul t ras onography of t he pel vi s may demons t rat e an adnexal mas s or abs ces s , whi ch s houl d be fol l owed careful l y.





4. T herapy. No s i mpl e t herapy i s effect i ve i n al l cas es of PID. Hos pi t al i zat i on i s s ugges t ed when pai n i s i ncapaci t at i ng or when parent eral t herapy i s gi ven. Combi nat i ons of ant i bi ot i cs are us ual l y needed t o cover t he t hree major cat egori es of pos s i bl e pat hogens .





5. Complications. The mos t s eri ous l ong-t erm

Pa g e 1 7 5 7


compl i cat i ons of PID are i nfert i l i t y, ect opi c pregnancy, and t he need for hys t erect omy.

D. Infectious proctitis 



1. Etiology. Infect i ous proct i t i s can be caus ed by a vari et y of mi croorgani s ms . W hen anal s ex i s pract i ced, gonorrhea, s yphi l i s , chl amydi al i nfect i on, and herpes s houl d be cons i dered.





2. Clinical features and diagnosis. Proct al gi a (rect al pai n), a change i n bowel habi t s , and a mucoi d or bl oody anal di s charge bet ween bowel movement s s ugges t i nfect i ous proct i t i s . A s exual hi s t ory s houl d be obt ai ned t o ai d i n t he di agnos i s , and appropri at e di agnos t i c s t udi es (e.g., s i gmoi dos copy, cul t ure and Gram s t ai n of t he di s charge, bi ops y) s houl d be performed.





3. T herapy. W hen s peci fi c agent s of i nfect i ous proct i t i s can be i dent i fi ed, appropri at e ant i bi ot i c t reat ment s houl d be admi ni s t ered. In general , t he s ame regi mens us ed t o t reat t hes e pat hogens i n ot her body s i t es are effect i ve i n proct i t i s . However, for gonorrheal proct i t i s , cure rat es are l ower t han for gonorrheal uret hri t i s , and pos t -t herapy cul t ures s houl d be obt ai ned.

E. Syndromes of genital ulcers and lymphadenopathy 



1. Incidence. Ul cerat i ve l es i ons of t he geni t al i a are common out pat i ent probl ems .



Pa g e 1 7 5 8




2. Etiology. There are many caus es , whi ch vary i n di fferent part s of t he worl d. In t he Uni t ed St at es , genital herpes i s t he mos t common caus e of geni t al ul cers , fol l owed by syphilis. Ot her caus es i ncl ude lymphogranuloma venereum, chancroid, and granuloma inguinale (donovanosis), al l of whi ch are uncommon i n t he Uni t ed St at es . P.363



3. Clinical features (Tabl e 8-5)

See Onl i ne Fi gures 8-5, 8-6, 8-7,

8-8, 8-9, 8-10 and 8-11 for col or phot os of t hes e condi t i ons . 

ONLINE FIGURE 8-5 Geni t al herpes . (From Faro S. Sexual l y T rans mi t t ed Di s eas es i n Women. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2003:CP14-A ).

Pa g e 1 7 5 9


ONLINE FIGURE 8-6 Pri mary s yphi l i s , peni l e chancre. (From Hal l JC. Sauer's Manual of Ski n Di s eas es . 8t h ed. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 1999:16-2A. ) 

ONLINE FIGURE 8-7 Secondary s yphi l i s . Macul opapul ar ras h on t he s ol e of t he foot of a pat i ent wi t h s econdary s yphi l i s . (From Faro S. Sexual l y T rans mi t t ed Di s eas es i n Women. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2003:CP25 ).

Pa g e 1 7 6 0


ONLINE FIGURE 8-8 Lymphogranul oma venereum. (From Faro S. Sexual l y T rans mi t t ed Di s eas es i n Women. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2003:CP22 ). 

ONLINE FIGURE 8-9 Chancroi d. (From Kaufman RH, Faro S, Fri edri ch FG, et al . Beni gn Di s eas es of t he Vul va and Vagi na. St . Loui s : Mos by, 1994. )

Pa g e 1 7 6 1


ONLINE FIGURE 8-10 Granul oma i ngui nal e. (From Faro S. Sexual l y T rans mi t t ed Di s eas es i n Women. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2003:CP3 ). 

ONLINE FIGURE 8-11 Granul oma i ngui nal e. Donovan bodi es are vi s i bl e wi t hi n vacuol es of a mononucl ear cel l . Not e t he bi pol ar s t ai ni ng, whi ch i s at ypi cal . (From Faro S. Sexual l y T rans mi t t ed Di s eas es i n Women. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2003:CP5. ) o

o

a. Genital herpes i ni t i al l y mani fes t s as i t chi ng and s orenes s fol l owed by t he appearance of eryt hema

Pa g e 1 7 6 2


and, event ual l y, t he devel opment of herpet i c ves i cl es . In i mmunocompromi s ed pat i ent s (e.g., t rans pl ant reci pi ent s , pat i ent s wi t h HIV), ves i cl es may be confl uent and l ead t o l arge ul cers . o

o

b. Syphilis, i n i t s pri mary form, mani fes t s as a pai nl es s , oft en s ol i t ary, chancre (ul cer) wi t h a hard, i ndurat ed bas e. Oral and vul var l es i ons may be s ubt l e, and oral l es i ons may be pai nful .

o

o

c. Lymphogranuloma venereum mani fes t s as nodes t hat are di s proport i onat el y l arge compared wi t h t he ul cers charact eri zed by a depres s i on bet ween t he i ngui nal and femoral nodes (groove sign).

o

o

d. Chancroid i s charact eri zed by mul t i pl e, pai nful ul cers wi t h ragged, undermi ned edges and s uppurat i ve i ngui nal nodes .

o

o

e. Granuloma inguinale i s a more i ndol ent i nfect i on charact eri zed by a pai nl es s , beefy-red l es i on wi t h ragged edges and l es s promi nent adenopat hy. It i s rare i n t he Uni t ed St at es . The cl i ni cal charact eri s t i cs and cours e of i l l nes s are more l i ke geni t al cancer t han ot her STDs .





4. Diagnosis (s ee Tabl e 8-5) o

o

a. W hen a genital ulcer i s not ed, a T zanck smear for herpes can hel p make a di agnos i s . However,

Pa g e 1 7 6 3


many l abs us e s hel l vi al s , whi ch produce res ul t s i n 1 day. Vi ral cul t ures are hel pful es peci al l y wi t h res i s t ant vi rus es . o

b. In al l cas es of geni t al ul cers , s erol ogi c t es t i ng

o

for s yphi l i s s houl d be performed. o

c. Di agnos i s of lymphogranuloma venereum i s

o

di ffi cul t .

TABLE 8-5 Sexually Transmitted Diseases C a u s Di at a Cl iv g in e n ic O o al Di r st Fi s g ic n e a T di a ni e n s s st g e m s s G H Di L e er re e ni p ct s i ta e i l

o

s mn

h si m â

Pa g e 1 7 6 4


er m u €” p pl n m e e of ul s x lu ti vi or pl ru e e, s sc v e e nc s i e; cu vi l o ra p l

u

cu s t l t ul ur ar e ; p ai nf ul S TrD L y e ar e p p kf s i hi o i e o li n ld n s e mâ m i c €” a ro u p sc s al o u l i p al d y; l y u R s m P ol

Pa g e 1 7 6 5


R it t e ar s t y; in d ur at e d; p ai nl e ss N o d e s â €” ru b b er y; n ot fl uc tu a nt Ly C C L m hl ul e

Pa g e 1 7 6 6


p a tu si h m re o o y ; n gr di s s a a er â n t r ol €” ul a o s o c gi m m h c al a o e l v mx p e at a a n is m p er

i n ul

e

at e

u

i o or

m

n v e si cl e N o d e s â €” la rg e; s u p p

Pa g e 1 7 6 7


ur at iv e C H Gr L h a a e a e m si nc m s t o ro o ai n i d p n; â hi cu €” l u l t ra s ur g d e g u (s e c r p d; e ec s yi i a of l

t;

m di e rt di y a lo n o e ki e n d g e N d) o d e s â €” te

Pa g e 1 7 6 8


n d er ; s u p p ur at iv e Gr C Bi L T a al o e et n y p s i ra ul m s y o cy o m wi n cl m at t h â i n a o Gi €” e; in b e la tr g a m rg i ui c t s e; m n er a s l et al i u or o h e m W wl o gr ri y pr a g a i n ht d m ul 's v â o s t a €“ m ai nc s at n i n ul is

g; fa ro m l l et

Pa g e 1 7 6 9


e h d o e x d a g z e ol s; e n ot in d ur at e d N o d e s â €” n ot pr o m in e nt RPR, rapi d pl as ma reagi n. o

o

d. Di agnos i s of chancroid i nvol ves el i mi nat i ng

Pa g e 1 7 7 0


ot her caus es of geni t al ul cers and i s ol at i ng Haemophi l us duc reyi from t he ul cers or s uppurat i ve nodes . o

o

e. Di agnos i s of granuloma inguinale i s confi rmed by demons t rat i on of Donovan bodi es i n edge s crapi ngs prepared wi t h Gi ems a or W ri ght 's s t ai n.





5. T herapy. Ident i fi cat i on and t reat ment of s exual cont act s i s al ways des i rabl e. o

o

a. Herpes infections are s el f-l i mi t ed but recurrent . Acycl ovi r, famci cl ovi r, or val acycl ovi r may s hort en t he cours e and reduce s ympt oms but do not affect t he nat ural hi s t ory of t hes e i nfect i ons . Pat i ent s wi t h frequent recurrences can us e l ower dos es of t hes e s ame medi ci nes as prophyl axi s .

o

o

b. Syphilis i s t reat ed wi t h varyi ng s chedul es of peni ci l l i n, dependi ng on t he s t age. Tet racycl i ne may be us eful for pat i ent s wi t h peni ci l l i n i nt ol erance or ot her s peci al requi rement s , but peni ci l l i n i s cl earl y preferred even i f i t requi res des ens i t i zat i on.

o

o

c. Lymphogranuloma venereum i s t reat ed wi t h a t et racycl i ne or a macrol i de.

o

o

d. Chancroid i s t reat ed wi t h azi t hromyci n, ceft ri axone, fl uoroqui nol ones , or eryt hromyci n. However, res i s t ance pat t erns of H. duc reyi are

Pa g e 1 7 7 1


vari abl e, and cul t ure s ens i t i vi t i es s houl d be obt ai ned i f pos s i bl e. o

o

e. Granuloma inguinale i s t reat ed wi t h a t et racycl i ne or t ri met hopri mâ€“s ul famet hoxaz ol e.





6. Late complications o

o

a. Herpes simplex recurrences t end t o be mos t common earl y aft er acqui s i t i on but may cont i nue t o occur for many years and may become s evere i n i mmunocompromi s ed pat i ent s . Herpes al s o can compl i cat e part uri t i on and caus e devas t at i ng i nfect i on i n neonat es .

o

o

b. Syphilitic chancres heal s pont aneous l y aft er 1â€“2 weeks . However, i n t he s econdary phas e, s yphi l i s can mani fes t as a mul t i s ys t em di s eas e i ncl udi ng, but not l i mi t ed t o, l ymphadenopat hy, ras h (es peci al l y on t he pal ms and s ol es ), fever, pharyngi t i s , and meni ngi t i s . The mul t i s ys t em di s eas e res ol ves s pont aneous l y, and a l at ent , noni nfect i ve phas e ens ues . Mos t pat i ent s remai n s eropos i t i ve. In t ert i ary s yphi l i s , approxi mat el y 10% of pat i ent s devel op s eri ous l at e compl i cat i ons of t he aort a or t he CNS. The neurol ogi c l es i ons are vari ed but i ncl ude pupi l l ary di s t urbances , pos t eri or s pi nal col umn probl ems , and major cogni t i ve i mpai rment . Treat ment may hal t progres s i on but i s unl i kel y t o revers e damage, maki ng earl y di agnos i s and t reat ment cri t i cal .

o

Pa g e 1 7 7 2


o

c. Lymphogranuloma venereum may rarel y l ead t o geni t al or rect al s carri ng.

P.364

VII. Other Infectious Diseases and Syndromes A. Infections associated with adenopathy and splenomegaly Syndromes of adenopat hy (bot h l ocal and general ), s pl enomegal y, and fever are common medical probl ems . The di fferent i al di agnos i s s houl d i ncl ude t umors , rheumat i c di s eas es , and vas cul i t i s as wel l as s peci fi c i nfect i ous proces s es . 



1. Generalized lymphadenopathy and fatigue are t he cl as s i c s i gns of infectious mononucleosis. o

o

a. Mononucl eos i s mos t commonl y i s caus ed by t he Epstein-Barr virus (EBV) and i s as s oci at ed wi t h s pl enomegal y, pharyngi t i s , and an at ypi cal l ymphocyt os i s .

o

o

b. CMV caus es a mononucl eos i s s yndrome t hat i s vi rt ual l y i ndi s t i ngui s habl e from EBV-i nduced mononucl eos i s .

o

o

c. Bot h i nfect i ons t end t o occur i n adol es cent s and young adul t s and may be s ubcl i ni cal . 

Pa g e 1 7 7 3




(1) They are di s t i ngui s hed by s erol ogi c t es t s s uch as t he Monospot test, whi ch us ual l y demons t rat es t he pres ence of het erophi l e ant i body i n EBV i nfect i on and t he abs ence of het erophi l e ant i body i n CMV i nfect i on.





(2) Speci fi c ant i body t es t i ng for t he t wo vi rus es can confi rm t he di agnos i s i n equi vocal cas es .





(3) Bot h vi rus es can be t rans mi t t ed by i nt i mat e cont act i ncl udi ng, but not l i mi t ed t o, s exual i nt ercours e.

o

o

d. Some cas es of mononucl eos i s are caus ed by T oxopl as ma gondi i , but t hi s i nfect i on us ual l y i s s ubcl i ni cal or pres ent s as a mi l d â€œvi ral -t ype s yndromeâ€• i n heal t hy adul t s .

o

o

e. Early HIV infection may mani fes t as fever, l ymphadenopat hy, and fat i gue, as wel l as ras h, neck s t i ffnes s , or ot her feat ures of a â€œvi ral i nfect i on.â€• Thi s s et of s ympt oms occurs i n 30%â€“60% of pat i ent s who experi ence acut e HIV i nfect i on. (Thi s i s s omet i mes cal l ed s eroconvers i on i l l nes s , becaus e ant i bodi es t o HIV become apparent at t he end of t hi s peri od.) Lymphadenopat hy al one or wi t h a vari et y of cons t i t ut i onal probl ems al s o occurs i n mi d t o l at e s t ages of HIV i nfect i on.



Pa g e 1 7 7 4


2. Fever, adenopat hy, and fat i gue al s o may be manifestations of secondary syphilis.





3. Splenomegaly out of proportion to adenopathy o

o

a. Thi s cl i ni cal pres ent at i on i s charact eri s t i c of onl y a few i nfect i ons s uch as mal ari a, s chi s t os omi as i s , and kal a-azar (vi s ceral l ei s hmani as i s ).

o

o

b. Thi s s yndrome al s o s houl d s ugges t a malignancy s uch as l ymphoma or Hodgki n's di s eas e, an infiltrative disease s uch as Gaucher's di s eas e, a congestive disease s uch as hepat i c ci rrhos i s , or a connective tissue disease s uch as SLE.

o

o

c. Local infections s uch as s pl eni c abs ces s and l eft -s i ded s ubphreni c abs ces s may mani fes t as a pal pabl e s pl een.





4. Localized adenopathy hel ps pi npoi nt a pot ent i al infection or tumor. o

o

a. A few s mal l ( T able of Cont ent s > Chapt er 9 - Endoc rine and Met abolic Diseases

Chapter 9 Endocrine and Metabolic Diseases Sonia Blome Daniel Lender

I. Disorders of the Pituitary Gland A. Anterior pituitary disease Anterior pituitary disease res ul t s from i ns uffi ci ent product i on of pi t ui t ary hormones (hypopi t ui t ari s m), exces s i ve product i on of pi t ui t ary hormones (acromegal y, Cus hi ng's di s eas e, or hyperprol act i nemi a), or t he l ocal effect s of pi t ui t ary t umors . 



1. Pituitary tumors make up 10% of i nt racrani al t umors . Mos t are beni gn, but t hei r cont i nued s l ow growt h i n t he confi ned s el l ar and s upras el l ar areas may caus e s eri ous neurol ogi c damage. o

o

a. T ypes 



(1) Pituitary adenomas are cl as s i fi ed by cel l t ype, bas ed on el ect ron mi cros copy and i mmunohi s t ochemi cal s t ai ni ng. Lactotroph tumors produce prol act i n, somatotroph tumors produce growt h hormone (GH), and corticotroph tumors produce adrenocort i cot ropi c hormone (ACTH).



Pa g e 1 8 5 5


(2) Craniopharyngiomas, t he mos t common t umors of t he hypot hal ami câ€“pi t ui t ary area i n chi l dren, ari s e from remnant s of cel l s from Rat hke's pouch. 



(a) Thes e t umors us ual l y are l ocat ed above t he s el l a t urci ca, but t hey may produce changes wi t hi n t he s el l a i t s el f.





(b) They may be s ol i d or cys t i c, may cont ai n chol es t erol -ri ch fl ui d, and oft en cont ai n areas of cal ci fi cat i on.





(3) Meningiomas and metastatic tumors may i nvol ve t he hypot hal ami câ€“pi t ui t ary area.

o

o




(1) Excess hormone production by pi t ui t ary adenomas may l ead t o acromegaly (s ee I A 4), Cushing' s disease (s ee V B 1 a), or hyperprolactinemia (s ee I A 3). 



(a) In rare cas es t hes e t umors may produce exces s t hyroi d-s t i mul at i ng hormone (TSH), caus i ng hypert hyroi di s m.





(b) Fol l i cl e-s t i mul at i ng hormone (FSH) and l ut ei ni zi ng hormone (LH) are frequent l y produced i n exces s by

Pa g e 1 8 5 6


pi t ui t ary t umors , but t hi s us ual l y does not res ul t i n a cl ear-cut cl i ni cal s yndrome. 



(2) Insufficient hormone production, due t o compres s i on or des t ruct i on of pi t ui t ary and hypot hal ami c cel l s , produces t he s yndrome of hypopituitarism (s ee I A 2).





(3) Neurologic effects 



(a) Optic nerve compression may occur. Pi t ui t ary t umors may pres s upward on t he i nferi or s urface of t he opt i c chi as m. Vi s i on l os s t ends t o occur fi rs t i n t he s uperi or t emporal quadrant s , wi t h bi t emporal hemi anopi a i n more advanced cas es .





(b) Headache i s common.





(c) Ot her neurol ogi c mani fes t at i ons s uch as ment al s t at us changes , crani al nerve abnormal i t i es , vomi t i ng, and papi l l edema are l es s common.





(4) Sens i t i ve i magi ng t echni ques [e.g., magnet i c res onance i magi ng (MRI)] can s how pi t ui t ary microadenomas (t umors 1 mg /dL ab ove nor ma l ran ge Ag e

Pa g e 1 9 5 0


4 00 mg /dL Bo ne mi ner al de ns i ty >2. 5 SD s bel ow pe ak bo ne ma ss (t s co re) Pat i en t pre fer enc e

Pa g e 1 9 5 2


for s ur ger y or un wi l l i ng nes s /i na bi l i ty to un der go pro l on ge d fol l ow -up SD, sta nd ard dev i at i on. o

P.404

o



Pa g e 1 9 5 3




b. Sarcoidosis may caus e hypercal cemi a becaus e of product i on of 1,25-di hydroxyvi t ami n D 3 by granul omat ous t i s s ue. If no ot her fi ndi ngs i ndi cat e t he pres ence of s arcoi dos i s and t he PTH concent rat i on i s not el evat ed, a t herapeut i c t ri al may be hel pful . Serum cal ci um l evel s decl i ne wi t hi n 1 week of t he s t art of gl ucocort i coi d admi ni s t rat i on (e.g., 40 mg predni s one dai l y) i n mos t cas es of s arcoi dos i s , but are unaffect ed i n mos t cas es of pri mary hyperparat hyroi di s m.





c. Benign familial hypercalcemia (fami l i al hypocal ci uri c hypercal cemi a) i s an aut os omal domi nant di s order caus ed by an i nact i vat i ng mut at i on of t he gene encodi ng t he cal ci um-s ens i ng recept or. The parat hyroi d gl ands and t he renal t ubul es fai l t o recogni ze t he t rue concent rat i on of ext racel l ul ar cal ci um, l eadi ng t o overproduct i on of PTH and i ncreas ed renal reabs orpt i on of cal ci um. 



(1) The res ul t i ng s yndrome cons i s t s of mi l d-t o-moderat e hypercal cemi a wi t h normal or s l i ght l y el evat ed s erum PTH l evel s and hypocal ci uri a. Pat i ent s remai n as ympt omat i c, wi t hout renal cal cul i , renal parenchymal damage, or bone di s eas e.





(2) Di agnos t i c cl ues are t he fami l i al occurrence and t he l ow (rat her t han hi gh)

Pa g e 1 9 5 4


uri nary cal ci um excret i on. 



(3) Becaus e s urgi cal t reat ment i s not benefi ci al and i s not recommended, t hi s condi t i on s houl d be rul ed out i n pat i ent s wi t h apparent pri mary hyperparat hyroi di s m.





d. Vitamin D intoxication, whi ch i s us ual l y s een i n pat i ent s recei vi ng pharmacol ogi c dos es of t he vi t ami n for t he t reat ment of hypoparat hyroi di s m, res ul t s i n hypercal cemi a. 



(1) The di agnos i s s houl d be apparent from t he pat i ent 's hi s t ory.





(2) If a s uffi ci ent l y rapi d fal l i n s erum cal ci um l evel s does not res ul t when vi t ami n D i nges t i on i s s t opped, gl ucocort i coi ds s houl d be gi ven. Gl ucocort i coi ds i nhi bi t t he act i on of vi t ami n D on i nt es t i nal cal ci um abs orpt i on and rapi dl y l ower s erum cal ci um l evel s .





e. Milkâ€“alkali syndrome i s caus ed by t he i nges t i on of l arge quant i t i es of cal ci um and abs orbabl e al kal i . It i s charact eri zed by hypercal cemi a, s ys t emi c al kal os i s , and renal damage due t o nephrocal ci nos i s . Thi s s yndrome i s unl i kel y t o devel op unl es s cal ci um i nt ake exceeds 5 g cal ci um carbonat e

Pa g e 1 9 5 5


(2 g el ement al cal ci um) dai l y, whi ch i s approxi mat el y doubl e t he dos e us ual l y recommended for t he prevent i on or t reat ment of os t eoporos i s . 



f. Other causes of hypercalcemia 



(1) Hyperthyroidism. Thi s condi t i on may caus e hypercal cemi a becaus e of i ncreas ed bone t urnover. The di agnos i s i s us ual l y evi dent becaus e t he hypert hyroi di s m, not t he hypercal cemi a, i s t he pres ent i ng s yndrome.





(2) T hiazide diuretics. Thes e agent s decreas e uri nary cal ci um excret i on but rarel y caus e hypercal cemi a; t hey s houl d be avoi ded, however, i n pat i ent s wi t h hyperparat hyroi di s m.





(3) Prolonged immobilization. Becaus e of cont i nui ng bone res orpt i on i n t he abs ence of normal pos t ural s t i mul i for bone format i on, hypercal cemi a may occur. Thi s probl em i s part i cul arl y common i n chi l dren who are confi ned t o bed for l ong peri ods (e.g., i n a t ot al body cas t for t reat ment of mul t i pl e t raumat i c fract ures ).





(4) Paget' s disease. Increas ed bone t urnover and l ocal i zed bone t umors due

Pa g e 1 9 5 6


t o defect i ve regul at i on of bone met abol i s m may produce hypercal cemi a, es peci al l y duri ng peri ods of i mmobi l i zat i on. 



(5) Recovery from acute renal failure. A s yndrome of hypercal cemi a may devel op duri ng t he recovery peri od aft er rhabdomyol ys i s and acut e renal fai l ure. Duri ng t he fi rs t 2â€“3 days aft er mus cl e i njury, t he i ni t i al mus cl e damage l eads t o l ocal cal ci um and phos phat e depos i t i on. W hen renal funct i on ret urns t o normal , cal ci um and phos phat e exi t from s i t es of mus cl e damage and ent er t he ci rcul at i on t o produce hypercal cemi a. Thi s defect t ypi cal l y occurs 2â€“3 weeks aft er t he acut e mus cl e i njury.

o

o

7. T herapy of primary hyperparathyroidism 



a. Surgery 



(1) Indications. As ympt omat i c pat i ent s wi t h mi ni mal el evat i on i n s erum cal ci um and no compl i cat i ons oft en have no progres s i on of t he di s eas e for 10 years or l onger. Such pat i ent s may be fol l owed cl os el y and cons i dered for s urgery onl y i f t hey devel op s peci fi c i ndi cat i ons (Tabl e 9-10).



Pa g e 1 9 5 7


(2) Initial surgical exploration. In mos t cas es , a single adenoma i s found and removed. If parathyroid hyperplasia i s found, t he s urgeon may remove t hree gl ands and part of t he fourt h, or al l parat hyroi d t i s s ue and t rans pl ant a port i on t o t he mus cl es of t he forearm or neck. The removal of addi t i onal parat hyroi d t i s s ue from t he t rans pl ant ed port i on may be accompl i s hed eas i l y i f neces s ary.





(3) Repeat surgical exploration. Approxi mat el y 10% of i ni t i al neck expl orat i ons fai l t o i ndi cat e abnormal parat hyroi d t i s s ue or cure t he di s eas e. Aft er t he pat i ent i s re-eval uat ed, addi t i onal i nvas i ve and noni nvas i ve l ocal i zi ng procedures are cons i dered before a s econd operat i on i s performed.





(4) Postoperative course. Trans i ent hypocal cemi a i s common aft er t he removal of a parat hyroi d adenoma becaus e t he remai ni ng normal gl ands are l i kel y t o have been s uppres s ed by l ong-s t andi ng hypercal cemi a. 



(a) Pat i ent s us ual l y recover wi t hi n a few weeks .





(b) In t he occas i onal pat i ent wi t h s evere bone di s eas e, marked

Pa g e 1 9 5 8


i nt ract abl e hypocal cemi a may pers i s t for s everal mont hs , becaus e, when t he exces s PTH s t i mul us i s s uddenl y removed, t he demi neral i zed bone becomes avi d for cal ci um (t he â€œhungry bones â€ • s yndrome). 



b. Medical therapy may be us ed i f no i ndi cat i ons for s urgery are pres ent (s ee Tabl e 9-10), i f ot her i l l nes s cont rai ndi cat es s urgery, or i f t he pat i ent refus es s urgery. 



(1) Increased fluid intake and act i vi t y hel p t o mi ni mi ze hypercal cemi a.





(2) Oral phosphate i n dos es of 1â€“2 g dai l y oft en l owers t he s erum cal ci um l evel . The mai n compl i cat i on, ext ras kel et al cal ci fi cat i on, i s uncommon i f t hi s dos e i s not exceeded.





(3) Estrogen may l ower mi l dl y el evat ed s erum cal ci um l evel s t o normal , apparent l y by decreas i ng bone res orpt i on. Thi s t reat ment may be cons i dered i n pos t menopaus al women, who make up t wo-t hi rds of t he cas es of pri mary hyperparat hyroi di s m.





c. Emergency treatment i s neces s ary i f t he cal ci um l evel i ncreas es above 13â€“15 mg/dL

Pa g e 1 9 5 9


before t he adenoma can be removed or i f s urgi cal t reat ment i s refus ed or i s uns ucces s ful . Hypercal cemi a caus ed by di s eas es ot her t han hyperparat hyroi di s m (e.g., hypercal cemi a due t o mal i gnancy) al s o may be t reat ed by t he fol l owi ng met hods . 



(1) Hydration with sodium diuresis. Four t o s i x l i t ers or more of i nt ravenous s al i ne dai l y, wi t h l arge dos es of furos emi de, i ncreas e renal cal ci um excret i on and reduce s erum cal ci um l evel s .





(2) Bisphosphonates s uch as pamidronate and z ol endri c aci d (Zomet a) bi nd t o hydroxyapat i t e i n bone and bl ock di s s ol ut i on of t hi s mi neral ; t hey al s o i nhi bi t os t eocl as t act i vi t y. The res ul t i ng i nhi bi t i on of bone res orpt i on produces a decl i ne i n s erum cal ci um l evel s over 1â€“7 days . Pami dronat e (60â€“90 mg) i s gi ven i nt ravenous l y i n a s i ngl e dos e over 24 hours ; t hi s can be repeat ed i n 7 days i f neces s ary.





(3) Plicamycin (formerl y cal l ed mi t hramyci n) i s an ant i neopl as t i c agent t hat l owers s erum cal ci um l evel s by i nhi bi t i ng os t eocl as t i c bone res orpt i on. A s i ngl e i nt ravenous dos e of 25 Âµg/kg admi ni s t ered over 4â€“6 hours may l ower t he s erum cal ci um l evel s for s everal

Pa g e 1 9 6 0


days . Thi s drug i s commonl y us ed i n t reat i ng hypercal cemi a due t o mal i gnancy. 



(4) Gallium nitrate i s a pot ent i nhi bi t or of bone res orpt i on. It i s gi ven i n a dos e 2

of 200 mg/m /day by cont i nuous i nfus i on for 5 days . Pot ent i al nephrot oxi ci t y l i mi t s i t s us e t o pat i ent s wi t hout renal fai l ure. 



(5) Calcitonin l owers s erum cal ci um l evel s by i nhi bi t i ng os t eocl as t i c bone res orpt i on. It i s t he fas t es t act i ng hypocal cemi c agent and i s very s afe, but i t i s l es s pot ent t han pl i camyci n, gal l i um ni t rat e, or pami dronat e, and i t s effect t ends t o decreas e aft er s everal days . Sal mon cal ci t oni n, 4 U/kg, i s gi ven i nt ramus cul arl y or s ubcut aneous l y every 12 hours .





(6) Glucocorticoids l ower s erum cal ci um l evel s i n pat i ent s wi t h s arcoi dos i s and vi t ami n D i nt oxi cat i on, and s omet i mes i n t hos e pat i ent s wi t h myel oma and hemat ol ogi c mal i gnancy. However, gl ucocort i coi ds do not l ower s erum cal ci um l evel s i n pat i ent s wi t h hyperparat hyroi di s m.

B. Hypoparathyroidism and hypocalcemia 

Pa g e 1 9 6 1




1. Etiology o

o

a. Surgical removal of the parathyroid glands i s t he mos t common caus e of hypoparat hyroi di s m. 



(1) Thi s may be an unavoi dabl e res ul t of radi cal neck di s s ect i on for cancer or a rare compl i cat i on of s ubt ot al t hyroi dect omy.





(2) T emporary hypoparathyroidism aft er neck s urgery i s not uncommon and may be due t o i s chemi c i njury t o t he gl ands . Recovery us ual l y occurs i n a few weeks or mont hs .

o

o

b. Idiopathic hypoparathyroidism of aut oi mmune et i ol ogy i s much l es s common. It us ual l y i s di agnos ed i n chi l dhood, may be fami l i al , and s omet i mes i s as s oci at ed wi t h adrenal i ns uffi ci ency and mucocut aneous candi di as i s .





2. Pathophysiology. PT H deficiency leads to hypocalcemia, the hallmark of hypoparathyroidism, t hrough t he s ame mechani s ms by whi ch i ncreas ed s ecret i on of PTH caus es hypercal cemi a P.405

(s ee III A 3). In addi t i on, t he decreas ed renal phos phat e cl earance l eads t o hyperphosphatemia, whi ch i s pres ent i n mos t cas es of hypoparat hyroi di s m. 

Pa g e 1 9 6 2




3. Clinical features and diagnosis. Hypocal cemi a produces acut e s ympt oms rel at ed t o i ncreas ed neuromus cul ar i rri t abi l i t y. In addi t i on, l ong-t erm changes may occur as a res ul t of effect s on ect odermal t i s s ues and ect opi c cal ci um depos i t i on. o

o

a. Symptoms and signs 



(1) Latent tetany 



(a) Mi l d hypocal cemi a may caus e muscular fatigue and weakness as wel l as numbness and t i ngl i ng around t he mout h and i n t he hands and feet .





(b) Chvostek' s sign may be pos i t i ve (i .e., a t ap over t he faci al nerve i n front of t he ear el i ci t s a cont ract i on of t he faci al mus cl es and upper l i p). However, Chvos t ek's s i gn may be pos i t i ve i n 10% of normal i ndi vi dual s .





(c) T rousseau' s sign may be pos i t i ve; t hat i s , i nfl at i on of a bl ood pres s ure cuff on t he arm t o a pres s ure hi gher t han t he pat i ent 's s ys t ol i c pres s ure for 3 mi nut es el i ci t s carpal s pas m [fl exi on of t he met acarpophal angeal (MCP) joi nt s and ext ens i on of t he i nt erphal angeal joi nt s , wi t h drawi ng t oget her of t he fi ngers and adduct i on of t he t humb].

Pa g e 1 9 6 3




(2) Overt tetany. Severe hypocal cemi a caus es twitching and cramps of the muscles with carpopedal spasm. Laryngeal stridor and seizures may occur i n s evere cas es .





(3) Long-term effects of hypocalcemia 



(a) Ectodermal changes i ncl ude at rophy, bri t t l enes s , and ri dgi ng of t he nai l s ; drynes s and s cal i ng of t he s ki n; and enamel defect s and hypopl as i a of t he t eet h.





(b) Calcification of the basal ganglia may occur and i s occas i onal l y as s oci at ed wi t h parki ns oni an s i gns and s ympt oms .





(c) Calcification of the optic lens may lead to cataract formation.

o

o

b. Laboratory abnormalities. Hypocalcemia and hyperphosphatemia are cons i s t ent l y pres ent i n hypoparat hyroi di s m. PTH l evel s , of cours e, are l ow, but cl i ni cal as s ays may not be s uffi ci ent l y s ens i t i ve t o di s t i ngui s h bet ween l ow and normal l evel s . An al bumi n l evel s houl d al ways be checked and t he s erum cal ci um correct ed for a l ow al bumi n. The correct i on formul a i s [4.0 â€“ meas ured al bumi n] 0.8 + s erum cal ci um.



Pa g e 1 9 6 4




4. Differential diagnosis o

o

a. Pseudohypoparathyroidism 



(1) Ps eudohypoparat hyroi di s m i s a heredi t ary di s eas e wi t h t wo di s t i nct areas of cl i ni cal expres s i on. 



(a) Calcium metabolism is abnormal becaus e of end-organ res i s t ance t o t he act i on of PTH; t hat i s , t he ki dney and bone cannot res pond t o PTH, even t hough i t s concent rat i on i n t he s erum i s normal or i ncreas ed. The res ul t i s hypocal cemi a and hyperphos phat emi a, as are s een i n t rue hypoparat hyroi di s m.





(b) Developmental and skeletal abnormalities (Albright' s hereditary osteodystrophy) are pres ent . 



(i) The mos t common abnormal i t i es are s hort s t at ure, s hort eni ng of t he met acarpal and met at ars al bones , and ment al defi ci ency.





(ii) The s kel et al abnormal i t i es s omet i mes occur i n t he abs ence of any di s order of cal ci um met abol i s m; t hi s has been cal l ed

Pa g e 1 9 6 5


â€œps eudops eudohypoparat hyroi di s m.â€• 



(2) If Al bri ght 's heredi t ary os t eodys t rophy i s not pres ent and i f hypocal cemi a i s not cl earl y pos t s urgi cal i n i t s ons et , t he di fferent i at i on bet ween t rue hypoparat hyroi di s m and ps eudohypoparat hyroi di s m may depend on l aborat ory t es t s . 



(a) PTH l evel s may be s uffi ci ent l y el evat ed i n ps eudohypoparat hyroi di s m t o di s t i ngui s h t he s yndrome cl earl y from hypoparat hyroi di s m.





(b) Inject i on of PTH i s fol l owed prompt l y by i ncreas ed uri ne concent rat i ons of phos phat e and cAMP and, wi t hi n 1 or 2 days , by an i ncreas e i n s erum cal ci um i n pat i ent s wi t h hypoparat hyroi di s m. No res pons e occurs i n pat i ent s wi t h ps eudohypoparat hyroi di s m.

o

o

b. Hypoalbuminemia caus es a decreas e i n t he fract i on of s erum cal ci um t hat i s bound t o prot ei n and, t herefore, a decreas e i n t ot al s erum cal ci um; becaus e t he i oni zed fract i on of s erum cal ci um remai ns normal , however, t here are no cl i ni cal mani fes t at i ons of cal ci um defi ci ency. Thi s s houl d not be cons i dered a form of t rue hypocal cemi a. For each decrement i n s erum al bumi n of 1 g/L, t he s erum cal ci um i s expect ed t o decl i ne by approxi mat el y 0.8 mg/dL.

Pa g e 1 9 6 6


o

c. Hypocal cemi a i n renal failure i s caus ed by many fact ors . Thes e i ncl ude renal phos phat e ret ent i on (wi t h res ul t ant hyperphos phat emi a), reduced product i on of 1,25-di hydroxyvi t ami n D 3 by t he di s eas ed ki dneys , and bone res i s t ance t o t he cal cemi c act i on of PTH.

o

o

d. Malabsorption as s oci at ed wi t h gas t roi nt es t i nal di s eas e may l ead t o i nadequat e cal ci um or vi t ami n D abs orpt i on and cons equent hypocal cemi a.

o

o

e. Vitamin D deficiency or res i s t ance t o t he act i ons of vi t ami n D may caus e hypocal cemi a t hrough decreas ed gas t roi nt es t i nal abs orpt i on of cal ci um.

o

o

f. Acute pancreatitis may l ead t o i nt ra-abdomi nal preci pi t at i on of cal ci um s oaps i n areas of fat necros i s . W het her t hi s expl ai ns why hypocal cemi a i s s omet i mes s een i n pat i ent s wi t h acut e pancreat i t i s i s uncert ai n.

o

o

g. Osteoblastic metastasis of pros t at e, breas t , or l ung cancer may produce hypocalcemi a, pres umabl y becaus e of rapi d bone upt ake of cal ci um.

o

o

h. Hypomagnesemia decreas es product i on of PTH and i nhi bi t s t he act i ons of PTH and vi t ami n D on bone, l eadi ng t o hypocal cemi a.



Pa g e 1 9 6 7




5. T herapy o

o

a. Hypoparathyroidism. PTH, whi ch mus t be i nject ed t wi ce dai l y, i s not commonl y us ed for l ong-t erm t herapy. Ins t ead, t reat ment wi t h supplemental calcium, combi ned wi t h vitamin D t o enhance i t s abs orpt i on, i s effect i ve i n correct i ng t he hypocal cemi a and hyperphos phat emi a of hypoparat hyroi di s m, even i n cas es caus ed by end-organ unres pons i venes s t o PTH (e.g., ps eudohypoparat hyroi di s m). 



(1) Calcium supplementation. Us ual l y 1â€“2 g el ement al cal ci um i s gi ven dai l y. 



(a) Commonl y us ed preparat i ons i ncl ude cal ci um gl uconat e (each 1-g t abl et cont ai ns 90 mg el ement al cal ci um), cal ci um carbonat e (each t abl et of Os -Cal 500 cont ai ns 500 mg cal ci um), and cal ci um gl ubi onat e (each t abl es poon of Neo-Cal gl ucon cont ai ns 345 mg cal ci um).





(b) The cal ci um i s gi ven i n t hree or four di vi ded dos es . The dos e can eas i l y be rai s ed or l owered t o regul at e s erum cal ci um l evel s .





(2) Vitamin D. Vitamin D 2 (ergocalciferol) has been us ed for years i n t he t reat ment of hypoparat hyroi di s m, but calcitriol has l argel y

Pa g e 1 9 6 8


repl aced i t . 



(a) Calciferol 



(i) Becaus e vi t ami n D 2 mus t be convert ed t o 1,25-di hydroxyvi t ami n D 3 t o be ful l y effect i ve (a convers i on t hat i s great l y i nhi bi t ed i n t he abs ence of PTH), l arge dos es are neces s ary. The average dai l y dos e i s 50,000 U, wi t h a range of 25,000â€“150,000 U, al t hough t he recommended di et ary al l owance i n normal pers ons i s onl y 400 U.





(ii) The ons et of act i on i s s l ow (1â€“2 weeks ), but t he effect may pers i s t for mont hs aft er admi ni s t rat i on i s s t opped.





(b) Calcitriol (1,25-dihydroxyvitamin D 3 ). The mai n advant age of cal ci t ri ol over vi t ami n D 2 i s t he fas t er ons et and ces s at i on of act i on, whi ch may l ead t o more preci s e cont rol of bl ood cal ci um l evel s . Cal ci t ri ol i s gi ven i n dos es of 0.25â€“2.0 Âµg/day.

P.406

o

o

b. Acute hypocalcemia. Treat ment of t hi s

Pa g e 1 9 6 9


condi t i on, whi ch may occur s hort l y aft er parat hyroi d res ect i on and may caus e s evere t et ani c s ympt oms , cons i s t s of i nt ravenous admi ni s t rat i on of cal ci um. Cal ci um gl uconat e (10%) i n a dos e of 1â€“2 g i s gi ven i nt ravenous l y i n approxi mat el y 10 mi nut es fol l owed by s l ow i nfus i on of 1 g cal ci um gl uconat e over t he next 6â€“8 hours .

IV. Disorders of Glucose Homeostasis A. Diabetes mellitus Thi s condi t i on i s characterized by hyperglycemia and ot her met abol i c derangement s t hat are caused by inadequate action of insulin on body t i s s ues , becaus e of ei t her reduced ci rcul at i ng l evel s of i ns ul i n or res i s t ance of t arget t i s s ues t o i t s act i ons . 



1. Classification (Tabl e 9-11). Di abet es mel l i t us i s di vi ded i nt o t wo cat egori es â€”type 1 diabetes (formerl y cal l ed i ns ul i n-dependent di abet es ) and type 2 diabetes (formerl y cal l ed noni ns ul i n-dependent di abet es ). Syndromes wi t h feat ures from ei t her of t hes e cat egori es may be rel at ed t o t he s t age or s everi t y of t he di s eas e or t o ot her condi t i ons . Thes e s yndromes i ncl ude i mpai red fas t i ng gl ucos e, i mpai red gl ucos e t ol erance, ges t at i onal di abet es , previ ous abnormal i t y of gl ucos e t ol erance, pot ent i al abnormal i t y of gl ucos e t ol erance, and di abet es as s oci at ed wi t h cert ai n ot her di s eas es . o

o

a. T ype 1 diabetes affect s 5%â€“10% of di abet i c pat i ent s . 



(1) In t ype 1 di abet es , not onl y i s i ns ul i n needed for opt i mal cont rol of bl ood gl ucos e, whi ch al s o may be t rue for pat i ent s wi t h t ype

Pa g e 1 9 7 0


2 di s eas e, but without exogenous insulin, patients are prone to the development of ketoacidosis. Thi s i s t hought t o refl ect a compl et e or al mos t compl et e abs ence of i ns ul i n i n pat i ent s wi t h t ype 1 di abet es , i n cont ras t t o t he part i al l ack of i ns ul i n and t he res i s t ance t o i ns ul i n charact eri s t i c of pat i ent s wi t h t ype 2 di abet es . 



(2) Ot her key feat ures of t ype 1 di abet es are i t s occurrence i n chi l dren and young adul t s and i t s occurrence i n i ndi vi dual s who are l ean rat her t han obes e.

o

o

b. T ype 2 diabetes commonl y affect s overwei ght i ndi vi dual s ol der t han 40 years of age, al t hough wi t h t he ri s i ng preval ence of obes i t y i t i s i ncreas i ngl y bei ng di agnos ed i n chi l dren. 



(1) Becaus e s ome i ns ul i n i s produced by t hes e pat i ent s , ketoacidosis does not occur.





(2) However, i ns ul i n t herapy may be neces s ary t o prevent s evere hypergl ycemi a.

TABLE 9-11 Major Types of Primary Diabetes Mellitus

Pa g e 1 9 7 1


T T y y p p e e 1 2 Di Di a a b b et et e e s s M M el el lit lit u u s s P 0. 2 re 2 % v %â al â €“ e €“ 4 n 0. % c 5 ; e %w ; o m m e e n n = > w m o e m n e n A U U

Pa g e 1 9 7 2


g susu e al al at l y l y o < > n 2 4 s 5 0 et ye ye ar ar s s G < > e 1 2 n 0 0 et % % ic of of s fi r fi r st st -d -d e e gr gr e e e e re re la la ti ti ve ve s s af af fe fe ct ct e e d; d; 5 9 0 0 %% co â

Pa g e 1 9 7 3


nc €“ or 1 d 0 a 0 nc % e co i n nc i d or e d nt a i c nc al e t in wi i d ns e nt ic al t wi ns H A N L ss o A oc n ia e te d wi th H L AD R 3,

Pa g e 1 9 7 4


H L AD R 4, H L AD Q A In N ut cr o oi e n m as e me u d ni pr ty ev al e nc e of a ut o a nt ib o di es to is

Pa g e 1 9 7 5


le t ce ll s a n d ot h er ti ss u es B U U o susu d al al y ly ly b le o ui a b ld n es e M K K et et et a os os b is is ol pr -r is o es m n is e; t a i n nt su; li in n su

Pa g e 1 9 7 6


pr l i o n d le uc ve ti ls o m n ay a b bs e e hi nt g h, n or m al , or lo w T In W re s u ei at l i g m n ht e

lo

nt

ss ; or al a g e nt s (e

Pa g e 1 9 7 7


.g ., su lf o ny lu re as , m et fo r m in , th ia zo li di n e di o n es ) or in su li n HLA,

Pa g e 1 9 7 8


human l eukoc yt e ant i ge n.

o

P.407

o

Online TABLE 9-12. Major Risk Factors for Type 2 Diabetes Fa mi l y hi s t or y of di a bet es (i .e ., par ent s or sib

Pa g e 1 9 7 9


lin gs wi t h di a bet es ) Ov erw ei g ht (B MI â ‰ ¥2 5 kg/ m2 ) Ha bi t ual phy sic al i na ct i vi t y Rac e/e t hn i ci t y

Pa g e 1 9 8 0


(e. g., Afri can Am eri can , Hi s pa ni c Am eri can , Nat i ve Am eri can , As i an Am eri can , an d Pac i fi c Is l an der )

Pa g e 1 9 8 1


Pre vi o us l y i de nt i f i ed IFG or IGT Hy per t en sio n â ‰ ¥1 40/ 90 mm Hg in ad ul t s) HD L cho l es t er ol â ‰ ¤3

Pa g e 1 9 8 2


5 mg /dL (0. 09 mm ol / L) an d/o r a t ri g l yc eri de l ev el â ‰ ¥2 50 mg /dL (2. 82 mm ol / L) Hi s t or y of GD M or

Pa g e 1 9 8 3


del i ve ry of a ba by wei ghi ng >9 lb Pol ycy sti c ova ry s yn dro me BM I, bo dy ma ss i nd ex; GD M, ges t at i on al

Pa g e 1 9 8 4


di a bet es me llit us ; HD L, hi g h-d ens ity lip opr ot e i n; IFG , im pai red fas tin g gl u cos e; IGT , im pai red gl u cos e

Pa g e 1 9 8 5


t ol er anc e. Us ed wi t h per mi s sio n fro m Scr ee ni n g for di a bet es . Di a bet es Car e 20 02; 25: 21 â€“ 24. o

Pa g e 1 9 8 6


c. Related syndromes 



(1) Impaired fasting glucose or impaired glucose tolerance (see T able 9-13). Thi s i s a di s order of gl ucos e met abol i s m i n whi ch bl ood gl ucos e l evel s are hi gher t han t hos e of normal i ndi vi dual s but l ower t han t hos e of pat i ent s wi t h di abet es . The ri s k of devel opment of di abet es i s i ncreas ed i n affect ed i ndi vi dual s .

TABLE 9-13 Glucose Levels as Diagnostic Criteria for Diabetes Mellitus An y on e of the foll ow ing thr ee crit eri a mu st be me t to

Pa g e 1 9 8 7


ma ke a di a gn os i s of di a bet es me llit us . Th e di a gn os i s s ho ul d be con fi r me d by obt ai n i ng t he sa me res

Pa g e 1 9 8 8


ul t s (or fi n di n g an ot h er a bn or ma lity ) on a di ff ere nt day . Fas tin g pl a sm a gl u cos e l ev el â ‰

Pa g e 1 9 8 9


¥1 26 mg /dL (pr efe rre d t es t )* Pl a sm a gl u cos e l ev el â ‰ ¥2 00 mg /dL 2 ho urs aft er a 75g gl u cos e

Pa g e 1 9 9 0


l oa d (or al gl u cos e t ol era nce t es t)

â€

Ca s ua l pl a sm a gl u cos e l ev el (i .e ., wi t ho ut reg ard to foo d i nt ake

Pa g e 1 9 9 1


) 20 0 mg /dL or gre at e r (va lid onl y if sy mp to ms s uc h as pol yur i a, pol ydi ps i a, or wei ght l os s are pre s en

Pa g e 1 9 9 2


t) *A fas tin g pl a sm a gl u cos e l ev el >1 10 mg /dL but 9 pounds ), t he pres ence of di abet es i n an i dent i cal t wi n, or s i mi l ar fact ors .





(5) Di abet es or i mpai red gl ucos e t ol erance may occur secondary t o cert ai n di s eas es t hat affect t he product i on or act i on of i ns ul i n, s uch as chronic pancreatitis, Cushing' s syndrome, acromegaly, insulin receptor abnormalities, and ot hers .





(6) T he metabolic syndrome (i ns ul i n res i s t ance s yndrome, s yndrome X). Some met abol i c and pat hophys i ol ogi c abnormal i t i es t end t o cl us t er i n cert ai n pat i ent s . Ins ul i n res i s t ance may be a common abnormal i t y, perhaps t he pri mary one. Component s of t hi s s yndrome i ncl ude di abet es mel l i t us , obes i t y, hypert ens i on, dys l i pi demi a, and at heros cl eros i s .



Pa g e 1 9 9 6




2. Etiology (Onl i ne Tabl e 9-12). The caus e of di abet es mel l i t us i s unknown. Many et i ol ogi c fact ors are s us pect ed, wi t h major di fferences bet ween t hos e fact ors t hat are et i ol ogi c for t ype 1 and t ype 2 di abet es . o

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a. T ype 1 diabetes. How t he fol l owi ng fact ors i nt eract t o caus e di abet es i s s pecul at i ve. For exampl e, a vi ral i nfect i on may t ri gger Î²-cel l des t ruct i on i n an i ndi vi dual wi t h genet i cal l y det ermi ned s us cept i bi l i t y t o s uch an i nfect i on and t o aut oi mmune react i vi t y t o i s l et -cel l ant i gens . 



(1) Genetic factors 



(a) Fi ft y percent of i dent i cal t wi ns of pat i ent s wi t h t ype 1 di abet es are di abet i c.

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(b) There i s a s t rong as s oci at i on bet ween t ype 1 di abet es and cert ai n human l eukocyt e ant i gens (HLAs ) (s ee Tabl e 9-11).

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(2) Autoimmune factors 



(a) Ant i bodi es t o i s l et -cel l ant i gens (i ns ul i n, gl ut ami c aci d decarboxyl as e, and i ns ul i n-as s oci at ed prot ei n 2) can precede i t s ons et and are commonl y pres ent i n di abet i c pat i ent s s hort l y aft er

Pa g e 1 9 9 7


t he di s eas e i s di agnos ed, al t hough t hey us ual l y di s appear wi t hi n a few years . 



(b) Ant i bodi es agai ns t ot her t i s s ues s uch as ant i t hyroi d ant i bodi es al s o are i ncreas ed.

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(3) Environmental factors 



(a) The concordance rat e for di abet es i n i dent i cal t wi ns i s 50% rat her t han 100%, whi ch woul d be t he rat e predi ct ed i f t he di s eas e were t ot al l y genet i c.

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(b) Seas onal occurrence has been obs erved, wi t h an i ncreas ed di agnos i s of new cas es i n t he fal l and wi nt er.

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b. T ype 2 diabetes 



(1) Genetic factors are even more i mport ant et i ol ogi cal l y i n t ype 2 t han i n t ype 1 di abet es . The concordance rat e for di abet es i n i dent i cal t wi ns i s 90%â€“100%.

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(2) Obesity i s a s i gni fi cant fact orâ€”80% of pat i ent s wi t h t ype 2 di abet es are more t han 15% above t hei r i deal wei ght . Obes i t y i s as s oci at ed wi t h res i s t ance t o t he act i on of i ns ul i n bot h i n di abet i c and nondi abet i c

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i ndi vi dual s ; t hi s res i s t ance i s caus ed mai nl y by abnormal i ns ul i n act i on beyond t he recept or. 

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(3) Genet i cal l y s us cept i bl e i ndi vi dual s may be unabl e t o s us t ai n t he i ncreas ed i ns ul i n product i on needed t o mai nt ai n carbohydrat e homeos t as i s i n t he face of i ns ul i n res i s t ance, wi t h res ul t i ng di abet es . Online T able 9-12 l i s t s ri s k fact ors for t ype 2 di abet es .

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(4) Genetic defects of beta-cell function. 

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(a) Type 2 di abet es can be pres ent at a young age. It has been es t i mat ed t o repres ent 2% of pat i ent s wi t h t ype 2 di abet es . Thi s i s a di s t i nct group of i ndi vi dual s , not rel at ed t o t he epi demi c of obes i t y and di abet es , but t o an aut os omal domi nant t rans mi s s i on. They us ual l y have mi l d di s eas e. It has been cal l ed mat uri t y-ons et di abet es of t he young (MODY ). Thes e pat i ent s are qui t e het erogenous . There are members of t he fami l y t hat have t he defect but who do not devel op di abet es .

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(b) Several genet i c abnormal i t i es have been i dent i fi ed; t ypes 3 and 2 account for 65% and 15% of cas es , res pect i vel y. Ot her s ubt ypes of t ype 1 and t ype 2

Pa g e 1 9 9 9


di abet es wi l l probabl y become more cl earl y defi ned i n t he fut ure. 

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(c) There i s a group of i ndi vi dual s who are di agnos ed wi t h aut oi mmune di abet es when t hey are adul t s and mi ght not requi re i ns ul i n i ni t i al l y. Phenot ypi cal l y t hey l ook l i ke pat i ent s wi t h t ype 2 di abet es . Thi s t ype of di abet es has been named l at ent aut oi mmune di abet es of adul t s , or LADA. It al s o has been cal l ed s l owl y progres s i ng i ns ul i n-dependent di abet es or 1.5 di abet es . It i s pres ent i n about 10% of newl y di agnos ed nonâ€“i ns ul i n-requi ri ng di abet i cs i n t he Uni t ed St at es . The pres ence of gl ut ami c aci d decarboxyl as e (GAD)-ant i bodi es hel ps t o make t he di agnos i s .

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3. Pathophysiology 



a. Levels of insulin 



(1) In type 1 diabetes, s ome i ns ul i n may be produced for a few years aft er t he di s eas e i s di agnos ed, but i ns ul i n product i on event ual l y ceas es t ot al l y.

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(2) In type 2 diabetes, i ns ul i n l evel s vary and oft en are s i mi l ar t o t he l evel s i n nondi abet i c i ndi vi dual s of s i mi l ar wei ght . However, t hes e i ns ul i n l evel s are

Pa g e 2 0 0 0


l ow when cons i dered i n rel at i on t o t he el evat ed bl ood gl ucos e concent rat i ons of di abet i c pat i ent s , and t hes e l evel s refl ect a decreas e i n Î²-cel l res pons i venes s t o gl ucos e. 



b. Consequences of impaired insulin action. Impai red i ns ul i n act i on may be caus ed by i nadequat e i ns ul i n s ecret i on, by t arget -t i s s ue res i s t ance t o t he act i on of i ns ul i n, or bot h. 



(1) Hyperglycemia. Ins ul i n i ncreas es t he s ynt hes i s of gl ycogen i n t he l i ver and i n mus cl e and i ncreas es t he upt ake of gl ucos e i n mus cl e and adi pos e t i s s ue. In t he abs ence of adequat e P.408

i ns ul i n act i on, hepat i c gl ucos e product i on i ncreas es (wi t h i ncreas ed gl ycogenol ys i s and i ncreas ed gl uconeogenes i s ) and peri pheral gl ucos e us e decreas es . The res ul t i s hypergl ycemi a. 



(2) â€œ Glucose toxicity.â€• Hypergl ycemi a i s t hought t o i ni t i at e a s el f-perpet uat i ng cycl e i n whi ch el evat ed gl ucos e l evel s furt her i mpai r bot h t he abi l i t y of t he Î² cel l s t o produce i ns ul i n and t he act i on of i ns ul i n on peri pheral t i s s ues , l eadi ng t o a furt her ri s e i n s erum gl ucos e l evel s .

Pa g e 2 0 0 1


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(3) Other metabolic derangements 

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(a) Ins ul i n normal l y act s as an anabol i c, energy s t orageâ€“promot i ng agent . In addi t i on t o t he s t orage of gl ucos e as gl ycogen, i ns ul i n s t i mul at es t he format i on of fat t y aci ds from gl ucos e, t he es t eri fi cat i on of fat t y aci ds t o form t ri gl yceri des , and t he s t orage of ami no aci ds as prot ei n.

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(b) Inadequat e i ns ul i n act i on on t arget t i s s ues caus es i nadequat e di s pos al of i nges t ed nut ri ent s and exces s i ve cons umpt i on of endogenous met abol i c fuel s . Bl ood fat t y aci ds and l i pi ds are i ncreas ed becaus e of decreas ed l i pogenes i s and i ncreas ed l i pol ys i s ; bl ood ami no aci ds are i ncreas ed becaus e of decreas ed prot ei n s ynt hes i s and i ncreas ed cat abol i s m of mus cl e prot ei n.

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

c. Levels of other hormones 

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(1) Glucagon l evel s are oft en el evat ed i n pat i ent s wi t h t ype 2 di abet es . Thi s may cont ri but e t o hypergl ycemi a t hrough t he act i on of gl ucagon i n s t i mul at i ng

Pa g e 2 0 0 2


gl ycogenol ys i s . 



(2) Epinephrine, cortisol, and GH l evel s may be i ncreas ed duri ng peri ods of s t res s or poor di abet i c cont rol . Thi s may cont ri but e t o hypergl ycemi a t hrough t he ant i -i ns ul i n effect and di abet ogeni c act i on of t hes e hormones .

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4. Clinical features 



a. Polyuria and polydipsia us ual l y occur. The mos t common s ympt om of hypergl ycemi a i s i ncreas ed uri ne vol ume, whi ch i s caus ed by gl ucos e-i nduced os mot i c di ures i s . Increas ed fl ui d i nt ake i s a res pons e t o t he res ul t i ng dehydrat i on and t hi rs t .

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

b. Weight loss res ul t s from t he l os s of gl ucos e i n uri ne and t he cat abol i c effect s of t he decreas e i n i ns ul i n act i on, des pi t e i ncreas ed food i nt ake. General i zed weaknes s al s o refl ect s t he met abol i c derangement s .

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

c. Infections of the skin, vulva, and urinary tract are es peci al l y common i n uncont rol l ed di abet es , becaus e hypergl ycemi a decreas es res i s t ance t o i nfect i on.

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

d. Blurring of vision i s caus ed by changes i n t he s hape and refract i ve qual i t i es of t he opt i c

Pa g e 2 0 0 3


l ens t hat res ul t from hypergl ycemi a-i nduced os mot i c al t erat i ons . o

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5. Diagnosis. Di abet es mel l i t us i s oft en s us pect ed becaus e of t ypi cal cl i ni cal mani fes t at i ons s uch as pol yuri a and unexpl ai ned wei ght l os s ; however, a defi ni t i ve di agnos i s i s bas ed on elevated glucose levels. 



a. Glucose levels. Di abet es mel l i t us i s di agnos ed i f any one of t he t hree abnormal i t i es des cri bed i n Tabl e 9-13 i s pres ent . The di agnos i s s houl d be confi rmed by repeat i ng t he fas t i ng gl ucos e on a di fferent day.





b. Urine glucose levels. Gl ucos e appears i n t he uri ne onl y when t he renal t hres hol d of approxi mat el y 180 mg/dL i s exceeded. 



(1) Thi s t hres hol d vari es wi del y and t ends t o i ncreas e wi t h age. Therefore, uri ne gl ucos e meas urement i s an i ns ens i t i ve and unrel i abl e t es t for di abet es .

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(2) However, uri ne gl ucos e l evel s can be a rough gui de t o t he pres ence or abs ence of marked hypergl ycemi a and current l y i s not bei ng us ed t o manage pat i ent s .



Pa g e 2 0 0 4


c. Hemoglobin A1c i s not recommended for di agnos i s , but i s t he mos t effect i ve met hod for moni t ori ng t he t reat ment .

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6. Acute complications of diabetes. 



a. Diabetic ketoacidosis occurs i n pat i ent s wi t h t ype 1 di abet es whos e ci rcul at i ng i ns ul i n i s i ns uffi ci ent t o al l ow gl ucos e us e by peri pheral t i s s ue and t o i nhi bi t gl ucos e product i on and t i s s ue cat abol i s m. Increas ed l evel s of gl ucagon and hormones t hat i ncreas e i n res pons e t o s t res s (i .e., epi nephri ne, norepi nephri ne, cort i s ol , and GH) cont ri but e t o t he met abol i c derangement s . It can rarel y occur i n t ype 2 di abet es . 



(1) Precipitating factors. Ket oaci dos i s may occur aft er s everal days of wors eni ng di abet i c cont rol or may appear s uddenl y wi t hi n a few hours . P.409





(a) Preci pi t at i ng fact ors i ncl ude any event t hat decreas es i ns ul i n avai l abi l i t y or caus es s t res s t hat i ncreas es t he need for i ns ul i n.

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(b) Common fact ors are t he

Pa g e 2 0 0 5


omi s s i on of i ns ul i n dos es , i nfect i ons , i njuri es , emot i onal s t res s , exces s i ve al cohol i nges t i on, and i nt ercurrent i l l nes s . 



(2) Pathophysiology (Fi gure 9-5) 



(a) Hyperglycemia. Ins uffi ci ent i ns ul i n reduces peri pheral gl ucos e ut i l i zat i on and, t oget her wi t h gl ucagon exces s , i ncreas es hepat i c product i on of gl ucos e t hrough t he s t i mul at i on of gl uconeogenes i s and gl ycogenol ys i s and t he i nhi bi t i on of gl ycol ys i s . Prot ei n breakdown i n peri pheral t i s s ues provi des a fl ow of ami no aci ds t o t he l i ver as s ubs t rat e for gl uconeogenes i s . Hypergl ycemi a i s t he res ul t .



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(b) Osmotic diuresis. Thi s condi t i on, whi ch res ul t s from t he el evat ed s erum gl ucos e (and ket one) l evel s , produces hypovolemia, dehydration, and loss of sodium, potassium, phosphate, and other substances in the urine. Vol ume depl et i on s t i mul at es cat echol ami ne rel eas e, whi ch furt her oppos es i ns ul i n act i on i n t he l i ver and cont ri but es t o l i pol ys i s .



Pa g e 2 0 0 6


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(c) Ketogenesis. The l i pol ys i s t hat res ul t s from i ns ul i n l ack and cat echol ami ne exces s mobi l i zes free fat t y aci ds from t hei r s t ores i n adi pos e t i s s ue. Ins t ead of re-es t eri fyi ng t he i ncomi ng fat t y aci ds t o form t ri gl yceri des , t he l i ver s hi ft s i t s met abol i c pat hways t oward t he product i on of ket one bodi es . 



(i) Gl ucagon i ncreas es t he hepat i c l evel of carni t i ne, whi ch enabl es fat t y aci ds t o ent er t he mi t ochondri a where t hey undergo Î²-oxi dat i on t o ket one bodi es .

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(ii) Gl ucagon decreas es t he hepat i c cont ent of mal onyl coenzyme A, an i nhi bi t or of fat t y aci d oxi dat i on.

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(d) Acidosis. The i ncreas ed hepat i c product i on of ket one bodi es (acet oacet at e and Î²-hydroxybut yrat e) exceeds t he body's abi l i t y t o met abol i ze or excret e t hem. 



(i) The hydrogen i ons of t he ket one bodi es are buffered by

Pa g e 2 0 0 7


bi carbonat e, l eadi ng t o a decreas e i n s erum bi carbonat e and pH. 



(ii) Art eri al carbon di oxi de t ens i on (PaCO 2 ) al s o decreas es becaus e of vent i l at ory compens at i on.

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(iii) The ani on gap i ncreas es becaus e of t he el evat ed pl as ma l evel s of acet oacet at e and Î²-hydroxybut yrat e.

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(iv) The res ul t i s met abol i c aci dos i s t hat i s as s oci at ed wi t h an i ncreas ed ani on gap.

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(3) Clinical features and diagnosis 



(a) Physical findings 



(i) Rapid, deep breathing (Kussmaul' s respirations) occurs as t he body t ri es t o compens at e for met abol i c aci dos i s by i ncreas i ng carbon di oxi de excret i on.

Pa g e 2 0 0 8


FIGURE 9-5 Pat hogenes i s of di abet i c ket oaci dos i s . (From Adl i n EV. Endoc ri nol ogy Sc i enc e and Medi c i ne. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2001:80. ) 

P.410





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(ii) An odor of acetone i s oft en det ect ed on t he breat h.

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(iii) Marked dehydrat i on i s common, wi t h dry skin and mucous membranes and poor skin turgor. Orthostatic hypotension may be pres ent becaus e of i nt ravas cul ar vol ume depl et i on.





(iv) Clouding of consciousness i s pres ent i n mos t cas es , and approxi mat el y 10% of pat i ent s are

Pa g e 2 0 0 9


comatose. 



(b) Laboratory abnormalities 



(i) Hyperglycemia. Serum gl ucos e l evel s i n ket oaci dos i s may be onl y s l i ght l y i ncreas ed, but more oft en t hey are markedl y el evat ed, averagi ng approxi mat el y 500 mg/dL. Renal funct i on affect s t he degree of hypergl ycemi a; gl ucos e l evel s are great l y el evat ed onl y when uri nary excret i on of gl ucos e i s l i mi t ed by vol ume depl et i on or renal abnormal i t i es .

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(ii) Hyperketonemia. Serum l evel s of acet oacet at e, acet one, and Î²-hydroxybut yrat e are great l y i ncreas ed. The agent ni t roprus s i de, i n t he form of t abl et s or reagent s t ri ps , i s commonl y us ed t o meas ure s erum and uri ne ket one bodi es . It react s onl y wi t h acet oacet at e. If t he ot her ket one bodi es are i ncreas ed t o a much great er or much l es s er ext ent t han acet oacet at e, t he res ul t s of t he t es t may be

Pa g e 2 0 1 0


mi s l eadi ng. 



(iii) Metabolic acidosis. T he serum bicarbonate level is low (us ual l y < N or o ‰ 3 2 5 2. 2 o m

¥

al

4

â€

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7 5

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0 In Y â â â â â â N s

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m

0

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a F Y â â < < â â N ac e ‰‰ 2 5 ‰‰ o ti s ¤ ¥ 0

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ti

4 3 0

2. 2

o

5 *

7 5

u s h y p o gl yc e m ia fr o m in s ul in

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S Y â â â â â â Y ul e ‰‰‰‰‰‰ e fo s ¤ ¥ ¥ ¥ ¤ ¥ s n

4 3 2 5 2. 2

yl

5

ur

0

7 5

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e ain d uc e d h y p o gl yc e m ia H Y â â < > â â N y e ‰‰ 2 5 ‰‰ o p

s ¤ ¤ 0

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4 3 0

2. 2

gl

5

7 5

yc e m ia m e di

Pa g e 2 0 7 1


at e d b y in s ul in -l i k e gr o w th fa ct or N Y â < < < > < N o e ‰ 3 2 5 2. 2 o n s ¤

0

â

4

0

€“

5

7 5

in s ul in m e di at e d

Pa g e 2 0 7 2


h y p o gl yc e m ia In N â < < < â â N a o ‰ 3 2 5 ‰‰ o d

¥

0

¤ ¥

v

4

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er

5

7 5

te nt fe e di n g d ur in g th e fa st N Y â < < < > < N o e ‰ 3 2 5 2. 2 o n s ¥

0

h

4

0

y

0

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p

Pa g e 2 0 7 3


o gl yc e m ic di s or d er Meas urement s are made at t he t i me t he deci s i on i s made t o end t he fas t . Sequent i al s erum gl ucos e meas urement s i n t he hypogl ycemi c range fl uct uat e. Serum gl ucos e concent rat i ons 45 mg/dL at t he t i me a deci s i on i n made t o end t he fas t may ri s e t o as much as 56 mg/dL when t he fas t i s act ual l y ended approxi mat el y 1 hour l at er. Serum gl ucos e concent rat i on may be as l ow as 40

Pa g e 2 0 7 4


mg/dL duri ng prol onged fas t i ng i n normal women. To convert s erum gl ucos e val ues t o mmol /L, mul t i pl y by 0.056. To convert i ns ul i n val ues t o pmol /L, mul t i pl y by 6.0. Serum C-pept i de and proi ns ul i n were meas ured by i mmunomet ri c as s ay. In normal s ubject s l evel s of s erum i ns ul i n, C-pept i de, and proi ns ul i n concent rat i ons may be hi gher i f t he s erum gl ucos e concent rat i on i s 60 mg/dL. *Refers t o t he change i n s erum gl ucos e aft er t he admi ni s t rat i on of i nt ravenous gl ucagon. â€

Serum i ns ul i n

concent rat i ons may be very hi gh (>100 ÂµU/mL) i n fact i t i ous

Pa g e 2 0 7 5


hypogl ycemi a from i ns ul i n. Reproduced wi t h permi s s i on from Servi ce FJ. Hypogl ycemi c di s orders . N Engl J Med 1995;332:1144. Copyri ght Â© 1995 Mas s achus et t s Medi cal Soci et y. 



(3) Proinsulin, t he l arge precurs or mol ecul e of i ns ul i n, i s produced i n i ncreas ed amount s by i ns ul i nomas . Proi ns ul i n normal l y makes up 5%â€“20% of t he t ot al i ns ul i n i n bl ood t hat i s meas ured by radi oi mmunoas s ay; i n pat i ent s wi t h an i ns ul i noma, proi ns ul i n us ual l y exceeds 25%.



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(4) Diagnostic imaging wi t h MRI, CT, ul t ras onography (i ncl udi ng endos copi c or i nt raoperat i ve ul t ras ound), and s el ect i ve art eri ography may be us ed t o i dent i fy and l ocal i ze an i ns ul i noma. Thes e t umors may be s mal l , however, averagi ng 1â€“2 cm, and t hey oft en cannot be vi s ual i zed.

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c. T herapy 



(1) Surgical removal of an adenoma or part i al pancreat ect omy for mul t i pl e adenomas

Pa g e 2 0 7 6


or Î²-cel l hyperpl as i a i s t he t reat ment of choi ce. 



(2) Medical therapy i s res erved for pat i ent s whos e t umors cannot be compl et el y removed becaus e met as t at i c di s eas e exi s t s , previ ous s urgi cal at t empt s have fai l ed, or i l l nes s or pat i ent refus al makes s urgery i nfeas i bl e. 



(a) Diazoxide i nhi bi t s t he rel eas e of i ns ul i n from Î² cel l s . A dos e of 200 mg dai l y, whi ch can be rai s ed as hi gh as 800 mg i f neces s ary, can prevent hypogl ycemi a i n pat i ent s wi t h an i noperabl e i ns ul i noma.





(b) Octreotide i nhi bi t s i ns ul i n and gl ucagon. Streptozocin i s an ant i bi ot i c t hat s peci fi cal l y des t roys Î² cel l s . It i s us ed t o t reat mal i gnant Î²-cel l t umors . Sys t emi c chemot herapy, i nt erferon-Î±, or chemoembol i zat i on coul d be t ri ed for mal i gnant t umors .

P.420

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2. Factitious hypoglycemia i s caus ed by t he s urrept i t i ous s el f-admi ni s t rat i on of i ns ul i n or an oral hypogl ycemi c drug, mos t oft en by an i ndi vi dual who i s fami l i ar wi t h heal t h care, s uch as a nurs e or medi cal t echnol ogi s t , or by a di abet i c or rel at i ve of a di abet i c. Di fferent i at i on from hypogl ycemi a

Pa g e 2 0 7 7


caus ed by an i ns ul i noma may depend on s peci al s t udi es . 



a. Serum C-peptide measurement i ndi cat es t he s ource of i ns ul i n s ecret i on [s ee IV B 1 b (3); Tabl e 9-17]. The l ow gl ucos e and hi gh i ns ul i n l evel s t hat are pat hognomoni c of an i ns ul i noma s houl d be accompani ed by i ncreas ed C-pept i de l evel s ; i f t he l at t er are l ow, i ndi cat i ng an exogenous s ource of t he hi gh i ns ul i n concent rat i on, t he di s eas e i s fact i t i ous .





b. Inges t i on of a s ul fonyl urea, however, s t i mul at es endogenous i ns ul i n product i on and t he C-pept i de l evel i s hi gh; t herefore, screening of blood or urine for sulfonylureas i s al s o neces s ary t o rul e out fact i t i ous di s eas e.

o

o

3. Extrapancreatic tumors may caus e hypogl ycemi a. Thes e us ual l y are l arge, i nt ra-abdomi nal t umors , mos t oft en of mes enchymal ori gi n (e.g., fi bros arcoma), al t hough t hey may be hepat i c carci nomas or ot her t umors . The mechani s m of hypogl ycemi a i s poorl y unders t ood; i ncreas ed us e of gl ucos e by s ome t umors and product i on by ot hers of an i ns ul i n-l i ke growt h fact or II (IGF-II) have been obs erved.

o

o

4. Ethanol-induced hypoglycemia occurs i n pat i ent s whos e gl ycogen s t ores are depl et ed becaus e of i nadequat e recent food i nt ake, us ual l y

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12â€“24 hours aft er a bout of heavy dri nki ng. 



a. The oxi dat i on of et hanol t o acet al dehyde and acet at e generat es reduced ni cot i nami de-adeni ne di nucl eot i de (NADH) and decreas es t he avai l abi l i t y of ni cot i nami de-adeni ne di nucl eot i de (NAD), whi ch i s needed for gl uconeogenes i s . W hen nei t her gl ycogenol ys i s nor gl uconeogenes i s i s avai l abl e t o mai nt ai n hepat i c gl ucos e product i on i n t he fas t i ng s t at e, hypogl ycemi a res ul t s .





b. Prompt recogni t i on and gl ucos e admi ni s t rat i on are es s ent i al becaus e t he mort al i t y rat e i s hi gher t han 10%.

o

o

5. Liver disease may res ul t i n i mpai rment of gl ycogenol ys i s and gl uconeogenes i s s uffi ci ent t o caus e fas t i ng hypogl ycemi a. Thi s i s s een i n ful mi nant vi ral hepat i t i s or acut e t oxi c l i ver di s eas e but not i n t he us ual , l es s s evere cas es of ci rrhos i s or hepat i t i s .

o

o

6. Other causes of fasting hypoglycemia i ncl ude cort i s ol defi ci ency, GH defi ci ency, or bot h, whi ch may occur i n adrenal insufficiency or hypopituitarism. Hypogl ycemi a may occur i n pat i ent s wi t h renal failure and heart failure; however, t he caus es are poorl y unders t ood.

o

o

7. â€œ Reactive hypoglycemiaâ€• may occur as a

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res ul t of anot her, s mal l er group of di s orders , whi ch caus e hypogl ycemi a a few hours aft er t he i nges t i on of carbohydrat es . Ins ul i noma and t he ot her condi t i ons di s cus s ed previ ous l y mos t commonl y produce hypogl ycemi a i n t he fas t i ng s t at e. 



a. Alimentary hypoglycemia occurs i n pat i ent s who have had a gas t rect omy or ot her s urgi cal procedure t hat l eads t o abnormal l y rapi d movement of food i nt o t he s mal l bowel . Rapi d abs orpt i on of carbohydrat e s t i mul at es exces s i ve i ns ul i n s ecret i on, caus i ng hypogl ycemi a s everal hours aft er a meal .





b. Reactive hypoglycemia of diabetes occurs i n an occas i onal pat i ent wi t h earl y di abet es who may have a l at e but exces s i ve rel eas e of i ns ul i n aft er a carbohydrat e-cont ai ni ng meal . The gl ucos e l evel i s el evat ed aft er 2 hours but t hen decreas es t o hypogl ycemi c l evel s 3â€“5 hours aft er t he meal .





c. â€œ Functionalâ€• hypoglycemia, al t hough commonl y di agnos ed i n pat i ent s wi t h chroni c fat i gue and anxi et y, i s probabl y a rare condi t i on. Hypogl ycemi a i s not a caus e of chroni c fat i gue, depres s i on, and l ack of energy. 



(1) Clinical features. Hypogl ycemi a, wi t h adrenergi c s ympt oms s uch as s weat i ng and pal pi t at i ons , occurs 2â€“5 hours aft er a carbohydrat e-ri ch meal ,

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pres umabl y becaus e of i ncreas ed i ns ul i n product i on or i ns ul i n s ens i t i vi t y. 



(2) Diagnosis 



(a) The overdi agnos i s of funct i onal hypogl ycemi a s t ems i n part from mi s i nt erpret at i on of t he 5-hour gl ucos e t ol erance t es t . One i n four normal i ndi vi dual s has a s erum gl ucos e l evel l es s t han 50 mg/dL 3â€“5 hours aft er t he nonphys i ol ogi c s t i mul us of 75â€“100 g gl ucos e, and s ome normal i ndi vi dual s have l evel s l es s t han 35 mg/dL, wi t hout P.421

s ympt oms . Thes e res pons es do not prove funct i onal hypogl ycemi a, and t he t es t s houl d not be done t o make t he di agnos i s of hypogl ycemi a. 



(b) The di agnos i s depends on fi ndi ng hypogl ycemi a t hat coi nci des wi t h t he pat i ent 's t ypi cal s ympt oms and on fi ndi ng rel i ef of s ympt oms by carbohydrat e i nges t i on.





(3) T herapy cons i s t s of eat i ng four t o s i x s mal l meal s dai l y t hat are l ow i n carbohydrat e and hi gh i n prot ei n.

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V. Disorders of the Adrenal Gland A. General considerations 



1. Di s eas es of t he adrenal cortex are caus ed by t he exces s i ve product i on of cort i s ol (Cushing' s syndrome), al dos t erone (primary aldosteronism), and adrenal androgens (congenital adrenal hyperplasia), as wel l as by i nadequat e product i on of cort i s ol and al dos t erone (Addison' s disease).





2. Los s of t he adrenal medulla does not caus e i l l nes s , but catecholamine overproduction by a pheochromocytoma (a t umor of t he adrenal medul l a) caus es a charact eri s t i c hypert ens i ve s yndrome.

B. Cushing's syndrome Cushing' s syndrome i s caus ed by exces s i ve concent rat i ons of cort i s ol or ot her gl ucocort i coi d hormones i n t he ci rcul at i on. 



1. Etiology o

o

a. The mos t common caus e of s pont aneous Cus hi ng's s yndrome i s bilateral adrenal hyperplasia (al s o known as Cushing' s disease). Bi l at eral adrenal hyperpl as i a i s caus ed by i ncreas ed s ecret i on of ACTH by a cort i cot roph adenoma of t he pi t ui t ary gl and. Exces s product i on of ACTH by t he pi t ui t ary gl and i s Cus hi ng's di s eas e. Cus hi ng's s yndrome i s a nons peci fi c des i gnat i on t hat refers t o i ncreas ed gl ucocort i coi d l evel s from any ori gi n.

o

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o

b. Adrenal adenomas and adrenal carcinomas may caus e Cus hi ng's s yndrome.

o

o

c. Ectopic ACT H product i on by t umors s uch as oat cel l carci noma of t he l ung, carci noma of t he pancreas , bronchi al carci noi d t umors , and ot hers caus es adrenal hyperpl as i a and Cus hi ng's s yndrome.

o

o

d. Iatrogenic Cushing' s syndrome i s s een more oft en t han t he s pont aneous l y occurri ng s yndrome. It i s an expect ed compl i cat i on i n pat i ent s recei vi ng l ong-t erm gl ucocort i coi d t reat ment for as t hma, art hri t i s , and ot her condi t i ons .






o

a. Central obesity i s caus ed by t he effect of exces s gl ucocort i coi d l evel s on fat di s t ri but i on. Fat accumul at es i n t he face, neck, and t runk, whereas t he l i mbs remai n t hi n. The â€œ moon face,â€• â€œ buffalo humpâ€• (cervi cal fat pad), and supraclavicular fat pads cont ri but e t o t he â€œcus hi ngoi dâ€• appearance of affect ed i ndi vi dual s .

o

o

b. Hypertension res ul t s from t he vas cul ar effect s of cort i s ol as wel l as ot her act i ons of t he hormone, i ncl udi ng s odi um ret ent i on.

o

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c. Decreased glucose tolerance i s common; 20% of pat i ent s have overt di abet es . Thi s i s a res ul t of t he i ncreas ed hepat i c gl uconeogenes i s and decreas ed peri pheral gl ucos e ut i l i zat i on caus ed by el evat ed l evel s of gl ucocort i coi d.

o

o

d. Symptoms of androgen excess (e.g., ol i gomenorrhea, hi rs ut i s m, and acne) may occur i n women wi t h Cus hi ng's di s eas e becaus e of s t i mul at i on by ACTH of adrenal androgen product i on.

o

o

e. Purple striae are l i near marks on t he abdomen, where t he t hi n, was t ed s ki n i s s t ret ched by underl yi ng fat .

o

o

f. Muscle wasting and weakness refl ect t he cat abol i c effect s of cort i s ol on mus cl e prot ei n.

o

o

g. Osteoporosis i s a frequent res ul t of cort i s ol exces s . It i s caus ed by i ncreas ed bone cat abol i s m and perhaps by t he i nhi bi t ory effect s of cort i s ol on col l agen s ynt hes i s and cal ci um abs orpt i on.

o

o

h. Susceptibility to bruising i s probabl y caus ed by enhanced capi l l ary fragi l i t y.

o

o

i. Psychiatric disturbances, es peci al l y depres s i on, are frequent res ul t s of cort i s ol exces s .

o

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j. Growth retardation i n chi l dren may be s evere.





3. Diagnosis. Serum and uri ne cort i s ol l evel s are el evat ed i n Cus hi ng's di s eas e and Cus hi ng's s yndrome, but overl ap wi t h normal val ues i s common, and el evat ed l evel s are s een i n normal pers ons at t i mes of s t res s . Therefore, t es t s of t he s uppres s i bi l i t y of cort i s ol and ot her s peci al t es t s are P.422

neces s ary. Fi gure 9-9 s hows a s cheme for t he di agnos i s of Cus hi ng's s yndrome t hat pos es t wo ques t i ons . Is Cus hi ng's s yndrome pres ent (Fi gure 9-9A)? If i t i s pres ent , what caus es i t s occurrence (Fi gure 9-9B)?

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FIGURE 9-9 Al gori t hms t o det ermi ne t he di agnos i s and et i ol ogy of Cus hi ng's s yndrome. (A) St eps t o t ake t o det ermi ne whet her a pat i ent has Cus hi ng's s yndrome (of any caus e). (B) St eps t o t ake t o i dent i fy t he caus e of Cus hi ng's s yndrome (once t he di agnos i s has been made). ACTH, adrenocort i cot ropi c hormone; CRH,

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cort i cot ropi n-rel eas i ng hormone; CT, comput ed t omography; MRI, magnet i c res onance i magi ng. o

o

a. Nonspecific laboratory abnormalities i ncl ude l eukocyt os i s , wi t h a rel at i vel y l ow percent age of l ymphocyt es and eos i nophi l s , and an el evat i on i n t he s erum gl ucos e l evel . P.423

o

o

b. The serum cortisol l evel i n normal i ndi vi dual s i s hi ghes t i n earl y morni ng and decreas es t hroughout t he day, reachi ng a l ow poi nt at about mi dni ght . Al t hough t he morni ng l evel may be i ncreas ed i n pat i ent s wi t h Cus hi ng's s yndrome, a l os s of t he normal di urnal vari at i on and an i ncreas e i n t he eveni ng l evel are more cons i s t ent fi ndi ngs . Sal i vary cort i s ol can be meas ured at ni ght .

o

o

c. The 24-hour urinary free cortisol excretion rate i s i ncreas ed i n mos t pat i ent s wi t h Cus hi ng's s yndrome. Thi s t es t i s t he mos t us eful i ndi cat or of dai l y cort i s ol s ecret i on.

o

o

d. ACT H measurement may hel p di fferent i at e t he caus es of Cus hi ng's s yndrome. 



(1) ACTH l evel s are us ual l y hi gh-normal or s l i ght l y el evat ed i n pat i ent s wi t h Cus hi ng's di s eas e and may be markedl y el evat ed i n pat i ent s wi t h ect opi c ACTH product i on.

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

(2) W hen an aut onomous l y funct i oni ng adrenal t umor i s t he s ource of exces s cort i s ol s ecret i on, pi t ui t ary s ecret i on of ACTH i s s uppres s ed becaus e of t he hi gh l evel s of ci rcul at i ng cort i s ol , and t he ACTH l evel i s ext remel y l ow or undet ect abl e.

o

o

e. Low-dose dexamethasone suppression tests 



(1) The overnight low-dose dexamethasone suppression test i s recommended as an i ni t i al s creeni ng procedure for any pat i ent s us pect ed of havi ng Cus hi ng's s yndrome. The pat i ent t akes 1 mg dexamet has one oral l y at 11:00 PM, and t he pl as ma cort i s ol l evel i s meas ured at 8:00 AM t he fol l owi ng day. 



(a) The pl as ma cort i s ol l evel i s l es s t han 2 Âµg/dL i n mos t i ndi vi dual s , i ndi cat i ng normal s uppres s i on of ACTH and cort i s ol by t he dexamet has one. Becaus e t hi s t es t i s very s ens i t i ve, t he di agnos i s of Cus hi ng's s yndrome i s unl i kel y i n pat i ent s wi t h a normal res pons e.





(b) Pat i ent s wi t h Cus hi ng's s yndrome have cort i s ol l evel s great er t han 3 Âµg/dL; t he l evel s us ual l y exceed 10 Âµg/dL. Thi s res ul t i ndi cat es t hat furt her s t udy i s needed. (The t es t i s not very

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s peci fi c; ment al or phys i cal s t res s may produce a fal s e-pos i t i ve res ul t .) 



(2) In t he standard low-dose dexamethasone suppression test, t he pat i ent t akes dexamet has one 0.5 mg every 6 hours for 48 hours , s t art i ng at 8:00 AM (ei ght dos es ). The morni ng pl as ma cort i s ol drawn aft er 48 hours i s normal l y s uppres s ed t o l es s t han 2 Âµg/dL.

o

o

f. High-dose dexamethasone suppression tests 



(1) In t he overnight high-dose dexamethasone suppression test, pl as ma cort i s ol i s meas ured at 8:00 AM on t wo cons ecut i ve days , and dexamet has one 8 mg i s t aken at 11:00 PM on t he fi rs t day. A decreas e i n t he pl as ma cort i s ol l evel of l es s t han 50% on t he s econd day i ndi cat es fai l ure of s uppres s i on. The hi gh-dos e t es t i s des i gned t o di s t i ngui s h bet ween t he t wo pri mary caus es of ACTH-dependent Cus hi ng's s yndrome. 



(a) Pat i ent s wi t h Cus hi ng's di s eas e behave as t hough t hei r feedback res pons e t o gl ucocort i coi ds i s i nt act but s et at a hi gher-t han-normal l evel ; t hey res pond t o hi gh but not t o l ow dos es of dexamet has one.





(b) Pat i ent s wi t h ect opi c ACTH s ecret i on

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produce ACTH aut onomous l y; t hei r cort i s ol l evel s are not s uppres s ed even by hi gh dos es of dexamet has one. 



(2) In t he standard high-dose dexamethasone suppression test, 2 mg of dexamet has one i s t aken every 6 hours for 48 hours (ei ght dos es ). A fal l of 50% or more i n t he morni ng pl as ma cort i s ol at 48 hours i ndi cat es s uppres s i on.

o

o

g. In inferior petrosal sinus sampling, ACTH concent rat i ons are meas ured i n venous bl ood obt ai ned by cat het eri zat i on of t he i nferi or pet ros al s i nus es . Cort i cot ropi n-rel eas i ng hormone (CRH) may be i nject ed t o s t i mul at e ACTH s ecret i on. A hi gh concent rat i on of ACTH compared wi t h t hat i n peri pheral bl ood i ndi cat es t hat a pi t ui t ary adenoma i s t he caus e of ACTH exces s ; i f one s uperi or pet ros al s i nus has a hi gh ACTH concent rat i on whi l e t he ot her has a concent rat i on s i mi l ar t o peri pheral bl ood, t he adenoma i s more l i kel y t o be on t he s i de of t he pi t ui t ary corres pondi ng t o t he hi gher concent rat i on.

o

o

h. A combined standard low-dose dexamethasone suppression test and CRH test may be us ed when ot her t es t s have fai l ed t o di s t i ngui s h bet ween t rue Cus hi ng's s yndrome and t he â€œps eudo-Cus hi ng's s yndromeâ€• s omet i mes s een wi t h al cohol i s m or depres s i on. 



(1) Aft er t he admi ni s t rat i on of 0.5 mg

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dexamet has one every 6 hours for 48 hours , CRH i s i nject ed i nt ravenous l y, and pl as ma cort i s ol i s meas ured 15 mi nut es l at er. Pat i ent s wi t h Cus hi ng's s yndrome have cort i s ol l evel s great er t han 1.4 Âµg/dL, whereas pat i ent s wi t h â€œps eudo-Cus hi ng's s yndromeâ€• have l evel s l es s t han 1.4 Âµg/dL. P.424





(2) Thi s combi ned t es t makes us e of t he fol l owi ng obs ervat i ons : pat i ent s wi t h adrenal t umors or ect opi c ACTH product i on are res i s t ant t o s uppres s i on of cort i s ol by dexamet has one, whereas pat i ent s wi t h Cus hi ng's di s eas e have exaggerat ed res pons es t o CRH. By combi ni ng t hes e t es t s , i t i s pos s i bl e t o obt ai n a great er s eparat i on bet ween t he res ul t s s een i n Cus hi ng's s yndrome and t hos e s een i n ps eudo-Cus hi ng's s yndrome.

o

o

i. Radiographic findings 



(1) Skull radiographs s how enl argement of t he s el l a t urci ca i n t he 10% of pat i ent s wi t h Cus hi ng's s yndrome who have macroadenomas, but t hey do not reveal mos t of t hes e t umors , whi ch are microadenomas averagi ng 5â€“6 mm i n di amet er.



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

(2) CT scans with injection of contrast medium det ect approxi mat el y 50% of t he pi t ui t ary adenomas t hat caus e Cus hi ng's di s eas e. MRI with gadolinium contrast, however, reveal s approxi mat el y 75% of t hes e t umors and i s t he met hod of choi ce.





(3) CT scans of the adrenal gland s how mos t adrenal t umors . Uni form enl argement of bot h adrenal gl ands s ugges t s an ACTH-dependent form of Cus hi ng's s yndrome, ei t her Cus hi ng's di s eas e or t he ect opi c ACTH s yndrome.





4. T herapy o

o

a. Adrenal adenomas can us ual l y be res ect ed compl et el y, oft en l aparos copi cal l y, wi t h cure of t he di s eas e. Cort i s ol repl acement may be needed for s everal mont hs t o a year pos t operat i vel y, unt i l t he remai ni ng normal adrenal t i s s ue (s uppres s ed by t he previ ous hi gh cort i s ol l evel s ) regai ns i t s abi l i t y t o produce cort i s ol .

o

o

b. Adrenal carcinoma i s oft en i noperabl e when fi rs t di agnos ed becaus e of met as t as es , us ual l y t o t he l i ver and t he l ungs . Mi t ot ane, met yrapone, and ami nogl ut et hi mi de are drugs t hat bl ock adrenal s t eroi d product i on, and t hey may rel i eve t he mani fes t at i ons of exces s cort i s ol product i on i n pat i ent s wi t h i noperabl e adrenal carci noma. Prol onged s urvi val of t hes e pat i ent s i s uncommon.

o

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o

c. The ectopic ACT H syndrome can be cured by removal of t he t umor, but t hi s i s not pos s i bl e i n many cas es . The t umor caus i ng t he s yndrome, rat her t han t he Cus hi ng's s yndrome i t s el f, i s us ual l y t he pri mary probl em.

o

o

d. Cushing' s disease may be t reat ed i n s everal ways . 



(1) T ranssphenoidal pituitary surgery is the treatment of choice. Even when t umors cannot be s een on CT s can or MRI, t rans s phenoi dal expl orat i on may di s cl os e a mi croadenoma. Surgery i s s ucces s ful i n 50%â€“95% of cas es and i s fol l owed by normal pi t ui t ary and adrenal funct i on as wel l as cure of Cus hi ng's di s eas e.





(2) Pituitary irradiation i s effect i ve i n many chi l dren, but i t cures fewer t han one-t hi rd of affect ed adul t s ; t he reas on for t he di fference i n res pons e bet ween chi l dren and adul t s i s uncl ear.





(3) Bilateral adrenalectomy cures Cus hi ng's di s eas e but l eaves t he pat i ent wi t h Addison' s disease and t he need for l i fel ong s t eroi d repl acement . In addi t i on, adrenal ect omy i s s omet i mes fol l owed by t he devel opment of Nelson' s syndrome, i n whi ch a pi t ui t ary adenoma undergoes rapi d growt h, perhaps becaus e i t i s no l onger i nhi bi t ed by

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above-normal l evel s of cort i s ol . 



(4) Medical therapy can be t ri ed i n a s el ect group of pat i ent s . Ket oconazol e, mi t ot ane, or ami nogl ut et hi mi de (t he l at t er t wo are more t oxi c) coul d be us ed.

C. Adrenal insufficiency 



1. Etiology o

o

a. Primary adrenal insufficiency(Addison' s disease) 



(1) Idiopathic atrophy of the adrenal cortex due t o an aut oi mmune proces s i s t he mos t common caus e of adrenal i ns uffi ci ency.





(2) T uberculosis may i nvol ve t he adrenal gl ands , wi t h des t ruct i on of bot h t he adrenal cort ex and medul l a.





(3) Iatrogenic causes 



(a) Bilateral adrenalectomy for Cus hi ng's di s eas e res ul t s i n adrenal i ns uffi ci ency.





(b) Adrenal suppression following

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prolonged steroid therapy may pers i s t for up t o 1 year or l onger. 



(4) Acquired immunodeficiency syndrome (AIDS) s omet i mes l eads t o adrenal i ns uffi ci ency t hrough cyt omegal ovi rus (CMV) i nfect i on and ot her i nfect i ons of t he adrenal gl ands . P.425





(5) Adrenoleukodystrophy i s an X-l i nked di s order caus ed by a defi ci ency of very-l ong-chai n acyl CoA s ynt het as e. Thi s l eads t o an accumul at i on of very-l ong-chai n fat t y aci ds i n t he adrenal gl ands , caus i ng adrenal i ns uffi ci ency, and i n t he CNS, caus i ng a demyel i nat i ng s yndrome.





(6) Less common causes of adrenal des t ruct i on i ncl ude amyloidosis, fungal infections, syphilis, bilateral adrenal hemorrhage (es peci al l y i n pat i ent s recei vi ng ant i coagul ant s ), and metastatic malignancy.

o

o

b. Secondary adrenal insufficiency i s due t o pi t ui t ary di s eas e and res ul t s from any of t he caus es of hypopi t ui t ari s m (s ee I A 2 a).





2. Clinical features. The s ympt oms of adrenal i ns uffi ci ency are caus ed by bot h cort i s ol and al dos t erone

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defi ci enci es . o

o

a. Cortisol deficiency 



(1) Hyperpigmentation of the skin i s caus ed by i ncreas ed MSH act i vi t y t hat accompani es t he i ncreas ed pi t ui t ary s ecret i on of ACTH. The l at t er i s a feedback res pons e t o t he cort i s ol defi ci ency. 



(a) Hyperpi gment at i on i s mos t not i ceabl e over expos ed areas , on mucous membranes , and i n s ki n creas es and s cars .





(b) In s econdary adrenal i ns uffi ci ency (whi ch i s caus ed by pi t ui t ary di s eas e), ACTH l evel s are l ow rat her t han el evat ed, and hyperpi gment at i on i s abs ent .





(2) Hypotension, oft en ort hos t at i c, i s caus ed by t he abs ence of t he pres s or effect of cort i s ol on vas cul ar t one and by a decreas e i n cardi ac out put . In Addi s on's di s eas e al dos t erone defi ci ency al s o pl ays a rol e.





(3) Gastrointestinal symptoms i ncl ude anorexi a, naus ea and vomi t i ng, and wei ght l os s .



Pa g e 2 0 9 6




(4) Hypoglycemia i s rel at ed t o decreas ed cort i s ol -i nduced gl uconeogenes i s .





(5) Mental symptoms may i ncl ude l et hargy and confus i on. Ps ychot i c mani fes t at i ons occur on occas i on.





(6) Intolerance to stress may occur. Pat i ent s who cannot i ncreas e t hei r cort i s ol out put i n res pons e t o s evere s t res s ri s k an acut e exacerbat i on of t he s ympt oms di s cus s ed above, wi t h l i fe-t hreat eni ng vas cul ar col l aps e.

o

o

b. Aldosterone deficiency 



(1) Sodium loss res ul t s from reduced al dos t erone-medi at ed reabs orpt i on of s odi um i n t he di s t al renal t ubul es . Hypovolemia, decreased cardiac output, and decreased renal blood flow with azotemia as wel l as weaknes s , hypot ens i on, and wei ght l os s may be rel at ed t o s odi um depl et i on.





(2) Potassium retention caus ed by al dos t erone defi ci ency may l ead t o hyperkalemia and cardiac arrhythmias.





(3) Becaus e angiotensin II, rat her t han ACT H, has pri mary cont rol of al dos t erone p roduct i on, and t he reni nâ€“angi ot ens i n s ys t em

Pa g e 2 0 9 7


i s not affect ed by ACTH defi ci ency, t here i s us ual l y no defi ci ency of al dos t erone i n s econdary adrenal i ns uffi ci ency. o

o

3. Diagnosis 



a. ACT H response 



(1) The normal adrenal gl and s harpl y i ncreas es i t s out put of cort i s ol when s t i mul at ed by ACTH; abs ence of t hi s res pons e i ndi cat es adrenal i ns uffi ci ency.





(2) ACT H test. The s erum l evel of cort i s ol i s meas ured before and 1 hour aft er an i nt ravenous or i nt ramus cul ar i nject i on of 0.25 mg (25 U) cos ynt ropi n, a s ynt het i c form of ACTH. The pl as ma cort i s ol s houl d reach a l evel of 20 Âµg/dL or hi gher.

o

o




(1) Nons peci fi c l aborat ory abnormal i t i es may i ncl ude hyponatremia, hyperkalemia, hypoglycemia, and an increased eosinophil count (gl ucocort i coi ds l ower t he eos i nophi l count ). Ches t radi ography may s how a small heart.



Pa g e 2 0 9 8


(2) Plasma cortisol, urinary free cortisol, and urinary 17-hydroxycorticosteroid levels are low. Bas el i ne l evel s , however, may overl ap wi t h t he val ues i n normal i ndi vi dual s , whi ch i s why ACTH t es t i ng i s neces s ary for a defi ni t i ve di agnos i s .

o

o

4. T herapy 



a. Glucocorticoid replacement is needed in all patients. 



(1) The us ual dos e of cort i s ol i s 10â€“30 mg dai l y. A hi gher dos e i s us ual l y gi ven i n t he morni ng and a s mal l er dos e i n t he eveni ng, t o mi mi c t he normal di urnal vari at i on. To avoi d t he P.426

pot ent i al harmful effect s of exces s cort i s ol , s uch as os t eoporos i s , t he dos e s houl d be no more t han i s neces s ary t o rel i eve t he mani fes t at i ons of cort i s ol defi ci ency. 



(2) The dos e mus t be i ncreas ed duri ng t i mes of s t res s . Typi cal dos es woul d be t wi ce t he us ual dos e duri ng mi nor s t res s (e.g., common col d or dent al ext ract i on), 3â€“5 t i mes t he us ual dos e duri ng moderat e s t res s (e.g., i nfl uenz a or mi nor s urgery), and â€œs t res s dos es â€• of 200â€“300 mg duri ng s evere s t res s (e.g.,

Pa g e 2 0 9 9


major s urgery or a s eri ous i nfect i on or i njury). 



b. Mineralocorticoid replacement i s needed i n pat i ent s wi t h Addi s on's di s eas e. Fludrocortisone (Fl ori nef) i s gi ven i n a dai l y dos e of 0.05â€“0.2 mg. Pers i s t ence of l ow bl ood pres s ure, weaknes s , and l ow s erum s odi um and hi gh s erum pot as s i um l evel s s ugges t t hat a hi gher dos e of mi neral ocort i coi d i s needed; hypert ens i on, edema, or hypokal emi a s ugges t t hat t he dos e s houl d be decreas ed.

o

o

5. Adrenal crisis (addisonian crisis) i s an acut e, l i fe-t hreat eni ng compl i cat i on of Addi s on's di s eas e i n whi ch t he mani fes t at i ons of adrenal i ns uffi ci ency are great l y exaggerat ed. 



a. Clinical features. Fever, vomiting, abdominal pain, altered mental status, and vascular collapse may occur i f Addi s on's di s eas e remai ns unt reat ed, or i t may occur i n a t reat ed pat i ent duri ng acut e s t res s i f addi t i onal gl ucocort i coi d repl acement i s not provi ded.





b. T herapy. Immedi at e i nt ravenous admi ni s t rat i on of 100 mg cort i s ol over 5â€“10 mi nut es s houl d be fol l owed by an addi t i onal 300 mg i n t he next 24 hours . Int ravenous s al i ne i s al s o needed, and mi neral ocort i coi d repl acement s houl d be provi ded i f hypot ens i on

Pa g e 2 1 0 0


and vol ume depl et i on pers i s t .

D. Primary aldosteronism 



1. Etiology. Exces s i ve adrenal product i on of al dos t erone i s us ual l y caus ed by a s i ngl e small (0.5â€“3.0 cm) adrenal adenoma. Les s oft en (i .e., i n 20%â€“40% of cas es ), t here i s bi l at eral hyperpl as i a of t he adrenal cort ex.





2. Clinical features. Al dos t erone i ncreas es t he reabs orpt i on of s odi um and t he excret i on of pot as s i um and hydrogen i ons i n t he di s t al renal t ubul es . o

o

a. Sodium retention causes blood pressure elevation, whi ch i s t he chi ef cl i ni cal mani fes t at i on of t hi s s yndrome. 



(1) The amount of s odi um and wat er t hat are ret ai ned i s l i mi t ed by compens at ory mechani s ms t hat i ncreas e renal s odi um excret i on i n res pons e t o ext racel l ul ar fl ui d vol ume expans i on; s odi um bal ance i s res t ored aft er 1â€“2 kg of fl ui d have accumul at ed.





(2) Al t hough t hi s amount of vol ume expans i on does not caus e edema, t he l ong-t erm i ncreas e i n cardi ac out put and, perhaps , ot her effect s of mi neral ocort i coi d exces s l ead t o hypert ens i on.

o

Pa g e 2 1 0 1


b. Potassium loss causes hypokalemia, whi ch may produce muscle weakness, paresthesias, and tetany i n s evere cas es . 



(1) Hypokalemic nephropathy may caus e pol yuri a.





(2) Metabolic alkalosis i s a res ul t of t he renal l os s of pot as s i um and hydrogen i ons .





3. Diagnosis o

o

a. Laboratory diagnosis 



(1) Hypokalemia i n a hypert ens i ve pat i ent i s oft en t he cl ue t hat t ri ggers t he s earch for pri mary al dos t eroni s m, al t hough not al l pat i ent s wi t h al dos t eroni s m have a l ow s erum l evel of pot as s i um.





(2) Aldosterone mus t be meas ured under s t andardi zed condi t i ons becaus e i t i s affect ed by s odi um bal ance, di uret i cs , and ot her fact ors . 



(a) Di uret i cs , ACE i nhi bi t ors , and vas odi l at ors s houl d be di s cont i nued at l eas t 2 weeks before s t udi es of al dos t erone (and reni n) are undert aken.



Pa g e 2 1 0 2




(b) Random al dos t erone meas urement s i n pat i ent s wi t h pri mary al dos t eroni s m may overl ap t hos e of normal i ndi vi dual s ; s odi um l oadi ng may be neces s ary t o di fferent i at e t he al dos t erone l evel s i n affect ed pat i ent s (whi ch are not s uppres s ed by a s odi um l oad) from t he l evel s i n normal i ndi vi dual s (whi ch are s uppres s ed by a s odi um l oad). Two of t he many ways t hat t hi s procedure can be performed are as fol l ows . 



(i) The 24-hour urinary aldosterone excretion rate can be meas ured aft er t he pat i ent has i nges t ed more t han 250 mEq of s odi um dai l y for at l eas t 3 days . (Thi s can be ens ured by gi vi ng s odi um chl ori de t abl et s .) Sodi um l oadi ng may furt her l ower s erum l evel s of pot as s i um; t herefore, caut i on i s neces s ary i f t he pat i ent is P.427

hypokal emi c. An el evat ed al dos t erone l evel i n a 24-hour uri ne s ampl e t hat cont ai ns more t han 250 mEq of s odi um i ndi cat es hyperal dos t eroni s m. 



(ii) Plasma levels of aldosterone can be meas ured aft er 2000 mL of

Pa g e 2 1 0 3


normal s al i ne have been i nfus ed over 4 hours . A val ue above 10 ng/dL i s cons i s t ent wi t h pri mary al dos t eroni s m. An eas i er, and maybe s afer t es t can be done by gi ve s odi um oral l y for 3 days aft er whi ch a 24-hour uri ne col l ect i on s houl d be done t o meas ure al dos t erne s ecret i on. A l evel great er t han 10 t o 14 mcg/day t oget her wi t h an uri nary s odi um of 250 mmol /day i s di agnos t i c of pri mary al dos t eroni s m. Severe hypert ens i on and conges t i ve heart fai l ure (CHF) are cont rai ndi cat i ons t o s al i ne i nfus i on. 



(3) Plasma renin activity i s t he mos t us eful i ndi cat or of whet her el evat ed al dos t erone product i on i s pri mary or s econdary. 



(a) Secondary aldosteronism i s caus ed by condi t i ons t hat ori gi nat e out s i de t he adrenal gl and and t hat reduce t he effect i ve art eri al bl ood vol ume, t hereby di mi ni s hi ng t he pres s ure or t ens i on s ens ed by t he juxt agl omerul ar cel l s . 



(i) Such condi t i ons i ncl ude heart fai l ure, nephros i s , ci rrhos i s , vol ume depl et i on caus ed by di uret i cs , and renovas cul ar di s eas e.



Pa g e 2 1 0 4




(ii) Decreas ed pres s ure on t he juxt agl omerul ar cel l s s t i mul at es reni n rel eas e, whi ch i ncreas es angi ot ens i n II and, i n t urn, al dos t erone. Thus , the high aldosterone level is accompanied by increased renin activity.





(b) In primary aldosteronism, t he enhanced al dos t erone product i on i s caus ed by an adrenal abnormal i t y, not by i ncreas ed reni n act i vi t y; t he res ul t i ng vol ume expans i on s uppres s es reni n product i on. Thi s combi nat i on of increased aldosterone production and reduced renin activity can be caused only by primary aldosteronism, and i t i s a rel i abl e i ndi cat or of t hi s di agnos i s .





(c) Suppres s i on of reni n act i vi t y i s di agnos ed wi t h cert ai nt y onl y i f l evel s remai n l ow aft er mani pul at i ons t hat are known t o s t i mul at e reni n i n normal i ndi vi dual s s uch as di et ary s odi um res t ri ct i on, s everal hours of upri ght pos t ure, or furos emi de admi ni s t rat i on.





(4) The best screening test for primary aldosteronism i s meas urement of t he rat i o of pl as ma al dos t erone (ng/dL) t o pl as ma reni n act i vi t y (ng of angi ot ens i n I/mL/hr) i n a bl ood s ampl e drawn wi t h t he pat i ent i n an upri ght pos i t i on. Thi s rat i o i s i ncreas ed bot h by t he

Pa g e 2 1 0 5


el evat ed al dos t erone l evel and t he s uppres s ed reni n l evel charact eri s t i c of t he di s eas e. An al dos t erone-t o-reni n rat i o great er t han 25 i ndi cat es need for furt her s t udy. o

o

b. Adenoma versus hyperplasia. Pri mary al dos t eroni s m due t o an adenoma mus t be di s t i ngui s hed from pri mary al dos t eroni s m due t o hyperpl as i a, becaus e t he di s t i nct i on affect s t reat ment , whi ch i s us ual l y s urgi cal i n cas es of adrenal adenoma and medi cal i n bi l at eral hyperpl as i a. 



(1) The bi ochemi cal changes of pri mary al dos t eroni s mâ€”t he hypokal emi a, t he i ncreas ed al dos t erone l evel , and t he l ow reni n act i vi t yâ€”are more pronounced i n cas es caus ed by a uni l at eral adenoma t han i n cas es caus ed by hyperpl as i a.





(2) The pl as ma al dos t erone concent rat i on may be meas ured at 8:00 AM, aft er 8 hours of recumbency, and agai n at noon, aft er 4 hours of ambul at i on. 



(a) Level s are hi gher aft er ambul at i on i n normal s ubject s and i n pat i ent s wi t h bi l at eral hyperpl as i a, becaus e reni n and angi ot ens i n are s t i mul at ed by t he upri ght pos t ure and s ympat het i c out fl ow.





(b) However, pat i ent s wi t h uni l at eral

Pa g e 2 1 0 6


adrenal adenomas have a paradoxi cal fal l i n pl as ma al dos t erone l evel s , pres umabl y becaus e when reni n i s profoundl y s uppres s ed, al dos t erone i s i nfl uenced mai nl y by t he di urnal fal l i n ACTH. 



(3) Adrenal vein aldosterone concentrations may be meas ured i n bl ood s ampl es obt ai ned by s el ect i ve cat het eri zat i on. A very hi gh l evel on one s i de i ndi cat es an adenoma; hi gh l evel s on bot h s i des i ndi cat e bi l at eral hyperpl as i a.





(4) CT scans and MRI s omet i mes s how al dos t erone-produci ng adenomas , but t hes e t umors may be s mal l and oft en cannot be vi s ual i zed.





(5) An al gori t hm for t he di agnos i s of pri mary al dos t eroni s m i s s hown i n Fi gure 9-10.

o

o

c. Ingestion of large amounts of natural black licorice s houl d be cons i dered i n t he di fferent i al di agnos i s .





4. T herapy o

o

a. Surgery 



(1) Removal of a uni l at eral adenoma res ul t s i n cure of t he hypert ens i on i n approxi mat el y

Pa g e 2 1 0 7


60% of cas es and i mprovement i n anot her 25%. P.428

FIGURE 9-10 Al gori t hm for t he di agnos i s of pri mary al dos t eroni s m. CT, comput ed t omography; MRI, magnet i c res onance i magi ng. (From Adl i n EV, Endoc ri nol ogy Sc i enc e and Medi c i ne. Phi l adel phi a: Li ppi ncot t W i l l i ams & W i l ki ns , 2001:123. ) 

Pa g e 2 1 0 8


(2) In cont ras t , onl y 20%â€“50% of pat i ent s wi t h bi l at eral hyperpl as i a are i mproved by s urgery, even i f bi l at eral adrenal ect omy i s performed. Medi cal t herapy i s preferabl e. Epl erenone 50â€“100 mg dai l y can be us ed i n pat i ent s who devel op gynecomas t i a on s pi ronol act one.

o

o

b. Medical therapy. Spironolactone i nhi bi t s t he effect s of al dos t erone on t he renal t ubul e. A dos age of 200â€“400 mg dai l y correct s t he hypokal emi a and oft en correct s t he hypert ens i on.

E. Congenital adrenal hyperplasia 



1. Etiology and pathophysiology. Congeni t al adrenal hyperpl as i a i s caus ed by a defect i n one of t he enzymes t hat are neces s ary for t he s ynt hes i s of cort i s ol . Cort i s ol defi ci ency s t i mul at es ACTH, whi ch caus es hyperpl as i a of t he adrenal cort ex and overproduct i on of what ever ACTH-dependent s t eroi ds are not affect ed by t he enz yme defi ci ency (mai nl y adrenal androgens ).






o

a. Androgen excess i s caus ed by i ncreas ed adrenal product i on of dehydroepi andros t erone, andros t enedi one, and t es t os t erone. 



(1) If pres ent duri ng fet al devel opment , t hi s di s order may caus e ambiguous genitalia i n femal e i nfant s . If androgen exces s i s

Pa g e 2 1 0 9


mani fes t ed i n t he pos t nat al peri od, i t may caus e virilization i n prepubert al gi rl s or i n young women. P.429





(2) In mal e i nfant s , t he cons equence of androgen exces s duri ng fet al devel opment i s macrogeni t os omi a. In t he pos t nat al peri od, t he cons equence i s precocious puberty.

o

o

b. The cort i s ol defi ci t us ual l y does not caus e major cl i ni cal mani fes t at i ons becaus e t he ACTH s t i mul at i on and adrenal hyperpl as i a mai nt ai n cort i s ol l evel s i n t he l ow-normal range, des pi t e t he enzyme defi ci ency.

o

o

c. Ot her mani fes t at i ons occas i onal l y occur, dependi ng on t he s peci fi c enzyme affect ed. 



(1) 21-Hydroxylase deficiency account s for 95% of cas es of adrenal hyperpl as i a. 



(a) In t he mi l d (s i mpl e vi ri l i zi ng) form, onl y t he androgen-exces s s ympt oms are of i mport ance.





(b) In t he s evere (s al t -l os i ng) form, t he product i on of al dos t erone i s i mpai red as wel l as t hat of cort i s ol ; mi neral ocort i coi d

Pa g e 2 1 1 0


defi ci ency l eads t o hyponat remi a, hyperkal emi a, dehydrat i on, and hypot ens i on. 



(2) In 11-hydroxylase deficiency, deoxycort i cos t erone, a mi neral ocort i coi d, and adrenal androgens are overproduced. Thi s caus es hypert ens i on t hrough mechani s ms t hat are s i mi l ar t o t hos e caus i ng hypert ens i on i n pri mary al dos t eroni s m.





(3) In 17-hydroxylase deficiency, deoxycort i cos t erone i s overproduced, res ul t i ng i n hypert ens i on. However, becaus e 17-hydroxyl as e i s neces s ary for s ex s t eroi d s ynt hes i s , t here i s androgen defi ci ency as wel l as es t rogen defi ci ency. Thi s caus es t he devel opment of ambi guous geni t al i a i n mal e i nfant s and pri mary amenorrhea i n women.





3. Diagnosis. Concent rat i ons of adrenal androgens and precurs ors of cort i s ol are i ncreas ed i n bl ood and uri ne. The mos t us eful meas urement s are of blood testosterone, androstenedione, dehydroepiandrosterone, and 17-hydroxyprogesterone (a cort i s ol precurs or) as wel l as urinary 17-ketosteroids and pregnanetriol (a met abol i t e of 17-hydroxyproges t erone).





4. T herapy o

o

a. Medical therapy. Cortisol admi ni s t rat i on

Pa g e 2 1 1 1


s uppres s es t he overproduct i on of ACTH and adrenal androgens . In t he s al t -l os i ng s yndrome, mi neral ocort i coi d repl acement wi t h fl udrocort i s one may be neces s ary. o

o

b. Surgery. Recons t ruct i ve s urgery of t he ext ernal geni t al i a i n femal e i nfant s i s done i n t he fi rs t few years of l i fe.

F. Pheochromocytoma Thi s t umor i s deri ved from chromaffin cells, t he cel l s t hat s ynt hes i z e and s t ore cat echol ami nes . Locat ed pri mari l y i n t he adrenal medul l a, t hey al s o are l ocat ed i n s ympat het i c gangl i a and el s ewhere. The cel l s i n t he adrenal medul l a produce epi nephri ne and norepi nephri ne; t he ext ra-adrenal chromaffi n cel l s make onl y norepi nephri ne. 



1. Epidemiology o

o

a. Incidence. Pheochromocyt oma i s found i n approxi mat el y 0.5% of pat i ent s wi t h s evere hypert ens i on and i n l es s t han 0.05% of al l hypert ens i ve pat i ent s . However, becaus e t hi s t umor may caus e a dramat i c and debi l i t at i ng s yndrome, oft en wi t h fat al compl i cat i ons i f undet ect ed, di agnos t i c effort s and awarenes s are requi red out of proport i on t o t he frequency of occurrence.

o

o

b. Familial occurrence. Pheochromocyt omas may occur s poradi cal l y or may occur as part of one of s everal fami l i al s yndromes . 

Pa g e 2 1 1 2




(1) Multiple endocrine neoplasia type II (Sipple' s syndrome) i s charact eri zed by mul t i pl e pheochromocyt omas and medul l ary carci noma of t he t hyroi d; hyperparat hyroi di s m i s oft en pres ent .





(2) Neurofibromatosis and von Hippel-Lindau disease may be as s oci at ed wi t h pheochromocyt oma.





2. Pathology. Mos t pheochromocyt omas are s i ngl e t umors of t he adrenal medul l a. However, 10%â€“20% are l ocat ed out s i de of t he adrenal gl and, and 1%â€“3% are i n t he ches t or neck. Approxi mat el y 20% are mul t i pl e and 10% are mal i gnant .





3. Clinical features. The mani fes t at i ons of pheochromocyt oma (Tabl e 9-18) are caus ed by i ncreas ed l evel s of ci rcul at i ng cat echol ami nes . o

o

a. Hypertension i s paroxys mal i n approxi mat el y 50% of cas es and i s s us t ai ned i n t he remai nder. The di agnos i s i s oft en s ugges t ed by t he paroxysmal nature of the symptoms, caus ed by vari at i ons i n t he funct i on of t he t umor. At t acks t ypi cal l y l as t l es s t han 1 hour and may be preci pi t at ed by P.430

exerci s e, i nduct i on of anes t hes i a, uri nat i on (s ugges t i ng a pheochromocyt oma of t he bl adder), or pal pat i on of t he

Pa g e 2 1 1 3


abdomen.

TABLE 9-18 Manifestations of Pheochromocytoma Hy Pal per pi t t en at i s i o ons n He Ner ad vou ach s ne e

ss an d t re mo r

Sw W e eat i gh i ng t l os s o

o

b. Other features t hat s ugges t t he pres ence of a pheochromocyt oma are hyperglycemia, hypermetabolism, and postural hypotension i n a hypert ens i ve pat i ent .





4. Diagnosis. Pheochromocyt oma i s s us pect ed far more oft en t han i t i s di agnos ed. Many pat i ent s wi t h s ympt oms

Pa g e 2 1 1 4


of cat echol ami ne exces s prove t o have normal hormone l evel s . W i t h t he i ncreas ed us e of comput ed i magi ng, an i ncreas i ng number of as ympt omat i c pat i ent s wi t h pheochromocyt omas have been di agnos ed. o

o

a. The l evel s of urine catecholamines and t hei r met abol i t es are el evat ed i n mos t confi rmed cas es . 



(1) The 24-hour urinary metanephrine excretion rate may be t he mos t us eful s creeni ng t es t , but t es t s of urinary free catecholamines (i .e., epi nephri ne and norepi nephri ne) and vanillylmandelic acid concent rat i ons are al s o of val ue. Cert ai n medi cat i ons and s t res s can gi ve fal s e-pos i t i ve res ul t s .





(2) St res s ful i l l nes s can rai s e cat echol ami ne l evel s t wofol d; great er t han t wofol d el evat i ons are more s ugges t i ve of pheochromocyt oma.

o

o

b. Serum catecholamine levels are vari abl e and are more di ffi cul t t o i nt erpret t han t he 24-hour uri ne meas urement s . Level s of plasma free metanephrines may prove t o be a s ens i t i ve i ndi cat or of a pheochromocyt oma.

o

o

c. The clonidine suppression test i s us eful i n pat i ent s wi t h mi l d cat echol ami ne el evat i on. Three hours aft er an oral dos e of 0.3 mg cl oni di ne, t he pl as ma l evel of norepi nephri ne i s l owered i nt o t he

Pa g e 2 1 1 5


normal range i n mos t normal i ndi vi dual s , but i t remai ns el evat ed i n pat i ent s wi t h pheochromocyt oma. o

o

d. CT scans or MRI of t he abdomen det ect as many as 90% of t hes e t umors becaus e t hey us ual l y are great er t han 1 cm i n di amet er.

o

o

e. Adrenal scanning wi t h

131

I i odobenzyl guani di ne

(MIBG) i s es peci al l y us eful for l ocal i zi ng ext ra-adrenal t umors . 



5. T herapy o

o

a. Medical therapy 



(1) The Î±- and Î²-adrenergi c bl ocki ng agent s are us eful for i noperabl e t umors and for preparat i on for s urgery. 



(a) Î±-Adrenergic blocking agents rel i eve t he hypert ens i on and adrenergi c s ympt oms . 



(i) Phenoxybenzamine i s gi ven oral l y, s t art i ng wi t h 10 mg t wi ce dai l y and i ncreas i ng t o 40 mg t wi ce dai l y, i f neces s ary.



Pa g e 2 1 1 6


(ii) Phentolamine can be gi ven i nt ravenous l y t o t reat acut e s evere el evat i ons i n bl ood pres s ure.





(iii) Prazosin, terazosin, or doxazosin al s o can be gi ven t o produce s us t ai ned Î±-adrenergi c bl ockade.





(b) Î²-Adrenergic blocking agents s houl d not be us ed al one, becaus e unoppos ed Î±-adrenergi c s t i mul at i on may l ead t o exacerbat i on of t he hypert ens i on. Î²-Bl ockers are s omet i mes us eful i n conjunct i on wi t h Î±-bl ockers .





(2) Metyrosine, whi ch i s an i nhi bi t or of t yros i ne hydroxyl as e, bl ocks t he format i on of norepi nephri ne and epi nephri ne and i s an al t ernat i ve agent for t he rel i ef of t he s ympt oms of pheochromocyt oma. It may be us ed when pat i ent s are i nt ol erant of t he adrenergi c-bl ocki ng agent s .

o

o

b. Surgery. Surgical removal of the pheochromocytoma is the treatment of choice. Careful expl orat i on of t he adrenal gl ands and t he peri aort i c s ympat het i c chai n s houl d be performed. 



(1) Complications t hat frequent l y occur duri ng and aft er s urgery are ext reme s wi ngs i n bl ood pres s ure, cardi ac arrhyt hmi as , and

Pa g e 2 1 1 7


s hock. Thes e are caus ed by t he s udden removal P.431

of t he s ource of exces s cat echol ami ne product i on and by t he l ow bl ood vol ume t hat res ul t s from l ong-t erm cons t ri ct i on of t he vas cul ar compart ment . 



(2) To prevent vas cul ar i ns t abi l i t y duri ng removal of a pheochromocyt oma, pat i ent s are t reat ed wi t h Î±-bl ockers t o mai nt ai n normal bl ood pres s ure for at l eas t 1 week before s urgery. Î²-Bl ockers may be added for a few days before s urgery, es peci al l y i f t achycardi a or anot her arrhyt hmi a i s pres ent .

VI. Female Reproductive Disorders Endocri ne di s orders t hat affect t he femal e reproduct i ve s ys t em us ual l y caus e mens t rual abnormal i t i es and i ncl ude t hos e di s orders i n whi ch menarche does not occur (primary amenorrhea) and t hos e di s orders t hat caus e ces s at i on of mens t rual peri ods aft er menarche (secondary amenorrhea). Androgen-exces s s yndromes are a common caus e of reproduct i ve abnormal i t i es t hat al s o are cons i dered i n t hi s s ect i on.

A. Primary amenorrhea (Table 9-19) 



1. Gonadal dysgenesis (T urner' s syndrome). Thi s condi t i on occurs i n 1 i n 2500 l i ve femal e bi rt hs . o

o

a. Etiology and pathophysiology. Gonadal dys genes i s i s caus ed by a chromosomal abnormality t hat i s not fami l i al and i s not rel at ed

Pa g e 2 1 1 8


t o t he mot her's age. Pat i ent s have a chromat i n-negat i ve buccal s mear and a 45,X karyot ype. o

o




(1) Ovaries fail to develop; onl y bi l at eral s t reaks of connect i ve t i s s ue are pres ent , wi t hout germ cel l s . Es t rogen defi ci ency, caus ed by t he abs ence of ovari an t i s s ue, res ul t s i n sexual infantilism, wi t h abs ence of breas t devel opment and ot her s econdary s exual charact eri s t i cs , and i ncreas ed l evel s of LH and FSH.





(2) Somatic abnormalities are as s oci at ed wi t h gonadal dys genes i s . 



(a) Mos t pat i ent s are s hort , bet ween 48 and 58 i nches i n hei ght .





(b) Ot her feat ures , pres ent i n varyi ng numbers of pat i ent s , i ncl ude a s hort , webbed neck, epi cant hal fol ds , l ow-s et ears , a s hi el d-l i ke ches t wi t h wi del y s paced ni ppl es , cubi t us val gus (wi de carryi ng angl e), and renal and cardi ac abnormal i t i es .

o

o

c. T herapy 

Pa g e 2 1 1 9




(1) Estrogen therapy i nduces t he devel opment of s econdary s exual charact eri s t i cs . If es t rogen i s gi ven cycl i cal l y wi t h proges t erone, regul ar mens t rual bl eedi ng occurs , but fert i l i t y i s not pos s i bl e becaus e of t he abs ence of ovari es .





(2) GH therapy, i f s t art ed earl y enough, may add 2â€“4 i nches t o t he adul t hei ght .





(3) Removal of streak gonads may be neces s ary. Gonadal dys genes i s may occur i n pat i ent s wi t h s ex chromos ome mos ai ci s m i n whi ch one or more cel l l i nes bear a Y chromos ome. The frequency of gonadobl as t oma and ot her gonadal t umors i s i ncreas ed i n pat i ent s wi t h t hes e gonads , and t hei r prophyl act i c removal i s recommended.





2. T esticular feminization syndrome. Indi vi dual s wi t h t hi s s yndrome are genet i c mal es wi t h a 46,XY karyot ype, but t hey have normal femal e ext ernal geni t al i a and are rai s ed as gi rl s . o

o

a. Pathogenesis. The bas i c defect i s res i s t ance of t arget t i s s ues t o t he act i on of androgens . The fet al t es t es produce t es t os t erone, but becaus e t he wol ffi an duct s and geni t al t i s s ues cannot res pond t o t es t os t erone, femal e di fferent i at i on of t he ext ernal geni t al i a t akes pl ace. The fet al P.432

Pa g e 2 1 2 0


t es t es al s o produce mÃ¼l l eri an duct â€“i nhi bi t i ng fact or, whi ch has i t s normal effect i n i nhi bi t i ng t he mÃ¼l l eri an anl age, and s o t he fal l opi an t ubes , ut erus , and upper vagi na do not devel op.

TABLE 9-19 Causes of Primary Amenorrhea Ext ra Go go na na dal dal ca ca us us es es Go Hy na po dal pi t dys ui t ge ari nes s m is

Hy

(Tu po rne go r's na s yn dot dro rop me i c )

hyp

Tes og t i c on ul a adi r

sm

Pa g e 2 1 2 1


fe

Del

mi aye ni z d at i me on nar s yn che dro

C

me on Re ge s i s ni t t an al t

adr

ova en ry

al

s yn hyp dro erp me l as ia Ab nor ma liti es of t he ut e rus or vag i na o

o

b. Clinical features. The res ul t i s a phenot ypi c woman wi t h a vagi na t hat ends i n a bl i nd pouch, hypopl as t i c mal e duct s i ns t ead of t he fal l opi an

Pa g e 2 1 2 2


t ubes and ut erus , and t es t es l ocat ed i n t he abdomen, i ngui nal canal , or l abi a majora. Endogenous es t rogen s t i mul at es normal breas t devel opment at pubert y. The condi t i on i s s us pect ed when menarche fai l s t o occur or when a t es t i s i s fel t as an abdomi nal mas s , whi ch i s expl ored. o

o

c. T herapy. The t es t es are prone t o mal i gnant degenerat i on and s houl d be removed. Es t rogen t reat ment i s t hen gi ven t o mai nt ai n s econdary s exual charact eri s t i cs .





3. Resistant ovary syndrome. Inabi l i t y of t he ovari es t o res pond t o normal or i ncreas ed s t i mul at i on by gonadot ropi ns may be a res ul t of aut oi mmune des t ruct i on of t he ovari es or ot her condi t i ons .





4. Hypogonadotropic hypogonadism o

o

a. Panhypopituitarism due t o des t ruct i ve l es i ons of t he hypot hal ami câ€“pi t ui t ary area (s ee I A 2 a) caus es pri mary or s econdary amenorrhea, dependi ng on whet her t he probl em i s prepubert al or pos t pubert al i n ons et .

o

o

b. Isolated gonadotropin deficiency i s mos t oft en caus ed by defect i ve hypot hal ami c product i on of GnRH, us ual l y of unknown et i ol ogy. In Kallmann' s syndrome, t hi s defect i s as s oci at ed wi t h anos mi a.





5. Delayed menarche. Thi s di agnos i s s houl d be

Pa g e 2 1 2 3


cons i dered when mens t rual peri ods have not begun by 16 years of age. o

o

a. A di agnos i s of del ayed menarche, as oppos ed t o t hat of pri mary amenorrhea, can onl y be made i n ret ros pect , aft er s pont aneous mens t rual peri ods have begun. A fami l y hi s t ory of l at e pubert al devel opment s ugges t s t hat s pont aneous menarche may yet be expect ed.

o

o

b. If s evere ps ychol ogi cal s t res s i s caus ed by t he abs ence of s exual devel opment , i t may be neces s ary t o gi ve one or more 6-mont h cours es of es t rogen t herapy, wi t h l ong t reat ment -free peri ods t o obs erve whet her s pont aneous pubert y wi l l occur.

B. Secondary amenorrhea (Table 9-20) 



1. Hypothalamic (al s o cal l ed â€œ psychogenic,â€• â€œ functional,â€• and â€œ idiopathicâ€•) amenorrhea is t he most common form of nonphysiologic secondary amenorrhea. Obvi ous ps ychol ogi cal s t res s may or may not be pres ent . LH and FSH l evel s are l ow i n s ome cas es and normal i n ot hers . If t he hypot hal ami c-rel eas i ng hormone GnRH i s i nfus ed i n a phys i ol ogi c fas hi on (pul s e dos es every 90â€“120 mi nut es ), al l abnormal i t i es may be correct edâ€”ovari an fol l i cl es mat ure, ovul at i on t akes pl ace, a corpus l ut eum devel ops and funct i ons , and pregnancy may occur. Thi s s upport s t he cl i ni cal i mpres s i on t hat mos t cas es of funct i onal or i di opat hi c amenorrhea are caus ed by abnormal hypot hal ami c GnRH product i on.

Pa g e 2 1 2 4


TABLE 9-20 Causes of Secondary Amenorrhea Pre Ov gn ari anc an y

cau

Me s es no Pri pa ma us e ry Ut e ova ri n ri a e

n

cau fai l s es ure Int (â€ rau œp t eri re ne ma s yn t ur ech e i ae me (As no her pa ma us e n's â€ s yn •) dro Oo me ph )

ore

Hy ct o s t e my rec Ra

Pa g e 2 1 2 5


t o di a my t i o Hy n pot t he hal rap am y, i câ che €“p mo i t ui t he t ar rap y

y

cau Es t s es rog Hy en po exc pi t es s ui t Ov ari ari s m an Hy t u pot mo hal rs am Pro ic

l ac

(â€ t i n œp exc s yc es s ho Pi t ge ui t ni c ary â€ t u •) mo am rs en An orr dro

Pa g e 2 1 2 6


he ge a

n

Mal exc nut es s ri t i Pol on, ycy chr s t i oni c c

ova

i l l n ry es s s yn Exe dro rci s me e

Ov

Di s erp con rod t i n uct uat i on i on of of

adr

ora en l

al

con an t ra dro cep ge tiv n es Ov ari an tu mo rs P.433

Pa g e 2 1 2 7




2. Malnutrition may pl ay a rol e. Menarche s eems t o occur when a cri t i cal body wei ght i s reached, and mens t ruat i on oft en ceas es when t he wei ght of a woman whos e mens t rual cycl e was previ ous l y normal fal l s bel ow t hi s cri t i cal wei ght , whet her becaus e of food depri vat i on, chroni c i l l nes s , exces s i ve di et i ng, or anorexi a nervos a.





3. Exercise may be a fact or. Amenorrhea i s pres ent i n up t o 50% of femal e bal l et dancers , runners , and at hl et es . Exerci s e-rel at ed wei ght l os s i s at l eas t part i al l y res pons i bl e; t he ri s k of amenorrhea i s much hi gher i n women who have l os t more t han 10%â€“15% of t hei r body wei ght . Level s of LH, FSH, and es t rogen t end t o be l ow, s ugges t i ng a hypot hal ami c abnormal i t y.





4. â€œ Post-pill amenorrheaâ€• refers t o a del ay of more t han 6 mont hs i n t he ret urn of mens es aft er t he di s cont i nuat i on of oral cont racept i ve us e. It occurs i n fewer t han 1% of oral cont racept i ve us ers . Ot her caus es of amenorrhea mus t be excl uded before cont racept i ve us e i s det ermi ned t o be t he caus e.





5. Primary ovarian failure (â€œ premature menopauseâ€•) i s s i mi l ar t o normal menopaus e; t hat i s , ovari an funct i on decl i nes , es t rogen l evel s decreas e, and gonadot ropi n l evel s i ncreas e. However, pri mary ovari an fai l ure occurs before 40 years of age. Aut oant i bodi es agai ns t ovari an ant i gens have been found i n s ome cas es .



Pa g e 2 1 2 8


6. Ovarian tumors (e.g., granul os aâ€“t heca cel l t umors ) may i nhi bi t normal mens t rual cycl i ng by produci ng exces s i ve quant i t i es of es t rogen.





7. Prolactin excess i s a common caus e of s econdary amenorrhea (s ee I A 3 b).





8. Menopause o

o

a. Manifestations 



(1) Menopaus e, or t ot al ces s at i on of mens t rual peri ods , occurs i n al l women when t he ovari es are depl et ed of fol l i cl es and ovul at ory funct i on and es t rogen product i on ceas e. The average age of menopaus e i n t he Uni t ed St at es i s 51 years .





(2) As fol l i cul ar s ecret i on of es t radi ol and i nhi bi n (a s uppres s or of gonadot ropi ns ) fal l s at menopaus e, FSH and LH l evel s ri s e. Es t radi ol l evel s remai n l ow, al t hough s ome es t radi ol i s formed by peri pheral convers i on of andros t enedi one produced by t he adrenal s and ovari es .





(3) The mos t promi nent s ympt oms of t he menopaus e i s t he hot flash, a s ens at i on of warmt h t hat may l as t up t o 5 mi nut es , s omet i mes fol l owed by s weat i ng and a col d s ens at i on. Headache, pal pi t at i ons , di zzi nes s ,

Pa g e 2 1 2 9


and weaknes s may accompany t he hot fl as h. Thes e epi s odes occur i rregul arl y and may i nt erfere wi t h s l eep. Hot fl as hes us ual l y di s appear wi t hi n a few years of menopaus e. 



(a) The hot fl as h s eems t o be rel at ed t o a fal l i n es t rogen l evel s . Feedback s t i mul at i on of GnRH-produci ng cel l s i n t he hypot hal amus may affect nearby t hermoregul at ory cent ers .





(b) Es t rogen t herapy i s very effect i ve i n decreas i ng t he frequency and s everi t y of hot fl as hes .





(4) Ot her s ympt oms as s oci at ed wi t h t he menopaus e i ncl ude geni t ouri nary at rophy, vagi nal drynes s , uri nary s ympt oms , i ns omni a, and depres s i on.

o

o

b. Postmenopausal hormone replacement therapy. For many years i t was wi del y accept ed t hat repl acement of es t rogen aft er menopaus e had benefi t s t hat great l y out wei ghed i t s drawbacks . Recent s t udi es have changed t hi s percept i on, and t he i ndi cat i ons for pos t menopaus al hormone repl acement t herapy are bei ng recons i dered. 



(1) Effects of estrogen on cardiovascular disease 

Pa g e 2 1 3 0


(a) Many obs ervat i onal s t udi es have s hown t hat women who t ake es t rogen aft er menopaus e have l ower rat es of cardi ovas cul ar di s eas e. But l arge randomi zed cont rol l ed t ri al s have recent l y s hown t hat es t rogen does not prevent cardi ovas cul ar di s eas e, and may even, at t he begi nni ng of t reat ment , have s l i ght l y harmful effect s i n women who al ready have cardi ovas cul ar di s eas e.





(b) It appears t hat t he earl i er s t udi es di d not adequat el y account for s oci oeconomi c and educat i onal fact ors : t he women who t ook es t rogen al s o engaged i n ot her heal t h-promot i ng behavi ors s uch as s moki ng ces s at i on, exerci s e, bl ood pres s ure cont rol , and heal t hi er eat i ng. Thus es t rogen t herapy was as s oci at ed wi t h, but not t he caus e of, cardi ovas cul ar benefi t .





(2) Benefits of estrogen therapy In addi t i on t o rel i evi ng t he s ympt oms of hot fl as hes and geni t ouri nary at rophy, es t rogen repl acement i ncreas es bone mi neral dens i t y and reduces t he ri s k of os t eoporot i c fract ures . It al s o reduces t he ri s k of col orect al cancer. A very l arge s t udy, t he W omen's Heal t h Ini t i at i ve, found 5 fewer hi p fract ures and 6 fewer cas es of col orect al cancer per 10,000 women per year among t hos e t aki ng es t rogen.



Pa g e 2 1 3 1


(3) Risks of estrogen therapy Es t rogen i s known t o i ncreas e t he ri s k of breas t cancer, and t o affect t he cl ot t i ng mechani s m, t hereby i ncreas i ng t he ri s k of t hromboembol i c event s . The W omen's Heal t h Ini t i at i ve found 8 addi t i onal cas es of breas t cancer, 10 addi t i onal cas es of deep vei n t hrombos i s , and 8 addi t i onal cas es of pul monary embol i s m per 10,000 women per year i n t hos e t aki ng es t rogen. In ol der pat i ent s , es t rogen t herapy s eems t o i ncreas e t he ri s k for cardi ovas cul ar event s .





(4) Indications for hormone replacement therapy 



(a) Becaus e t he pos s i bl e l ong-t erm harmful effect s of es t rogen repl acement now appear t o out wei gh i t s benefi t s , l ong-t erm hormone repl acement t herapy i s no l onger recommended i n mos t cas es .





(b) Es t rogen repl acement t herapy i s i ndi cat ed for s hort -t erm t reat ment of hot fl as hes i n t he peri menopaus al peri od, but t he s mal l es t dos e t hat rel i eves t hes e s ympt oms s houl d be us ed.





(5) Estrogen administration 



(a) Es t rogen t herapy aft er menopaus e i ncreas es t he ri s k of ut eri ne cancer; t hi s

Pa g e 2 1 3 2


ri s k i s mi ni mi zed i f proges t erone i s gi ven al ong wi t h t he es t rogen. 



(b) Es t rogenâ€“proges t erone combi nat i ons can be gi ven cycl i cal l y or cont i nuous l y. A t ypi cal cycl i c regi men woul d be conjugat ed es t rogens 0.625 mg dai l y from day 1 t o day 25 each mont h, wi t h 5 or 10 mg medroxyproges t erone acet at e from day 16 t o day 25. Bl eedi ng i s expect ed a few days aft er t he hormones are s t opped.





(c) Combi ned t herapy al s o can be gi ven dai l y. A t ypi cal regi men woul d be conjugat ed es t rogens 0.625 mg and medroxyproges t erone acet at e 2.5 mg once dai l y. Thi s regi men has t he advant age of caus i ng amenorrhea aft er 6 mont hs or more i n a majori t y of women, but s ome women may cont i nue t o have unpredi ct abl e s pot t i ng.





(d) Ot her es t rogen preparat i ons i ncl ude oral es t radi ol and et hi nyl es t radi ol , and t rans dermal preparat i ons of es t radi ol . Many ot her proges t at i onal agent s are al s o avai l abl e.





(e) In women who have had a hys t erect omy, es t rogen can be gi ven dai l y wi t hout proges t erone, becaus e t here i s no ri s k of endomet ri al cancer.

Pa g e 2 1 3 3


C. Androgen excess syndromes 



1. Polycystic ovary syndrome, a di s order of unknown et i ol ogy, i s charact eri zed by a chroni c l ack of ovul at i on, as s oci at ed wi t h s ympt oms of androgen exces s and oft en wi t h obes i t y. It i s pres ent i n 5%â€“10% of reproduct i ve-age women and i s one of t he mos t common caus es of i nfert i l i t y. P.434

TABLE 9-21 Diagnostic Criteria for Polycystic Ovary Syndrome Na tio nal Ins tit ute s of He alt h crit eri a (1 99 0)

Pa g e 2 1 3 4


Me ns t rua l i rre gul ari t y du e to an ovu l at i on or ol i goovu l at i on Evi de nce of cl i n i cal or bi o che mi c al hyp era ndr

Pa g e 2 1 3 5


og eni sm Cl i ni c al : hi r s ut ism , acn e, or ma l epat t er n bal di n g Bi och em i cal : hi g h s er um an dro ge n con

Pa g e 2 1 3 6


cen t ra tio ns Exc l us i on of ot h er cau s es of hyp era ndr og eni sm an d me ns t rua l i rre gul ari t y, s uc h as con ge ni t

Pa g e 2 1 3 7


al adr en al hyp erp l as i a, an dro ge n-s ecr et i ng tu mo rs , an d hyp erp rol act i ne mi a Ro tte rd am Cri ter ia by

Pa g e 2 1 3 8


the Eu ro pe an So cie ty of Hu ma n Re pr od uct ion an d Em bry olo gy /A me ric an So cie ty of Re pr od uct

Pa g e 2 1 3 9


ive Me dici ne (2 20 3) Tw o of t hr ee of t he fol l owi ng fi n di n gs are req ui r ed for di a gn os i s: Me ns t rua l i rre gul

Pa g e 2 1 4 0


ari t y du e to an ovu l at i on or ol i goovu l at i on Evi de nce of cl i n i cal or bi o che mi c al hyp era ndr og eni sm Cl i ni c al :

Pa g e 2 1 4 1


hi r s ut ism , acn e, or ma l epat t er n bal di n g Bi och em i cal : hi g h s er um an dro ge n con cen t ra tio ns Pol ycy

Pa g e 2 1 4 2


sti c ova ri e s (by ul t r as o un d) o

o

a. Pathophysiology (Online Figure 9-11). In t he cycl e s hown i n Onl i ne Fi gure 9-11, t he i ni t i at i ng event i s uncert ai n, and i t probabl y i s not t he s ame i n al l cas es . Propos ed pri mary defect s i ncl ude i ns ul i n res i s t ance, pri mary ovari an di s eas e, abnormal s ecret i on of LH by t he hypot hal ami câ€“pi t ui t ary axi s , and adrenal di s eas e.

Pa g e 2 1 4 3


ONLINE FIGURE 9-11 Propos ed pat hogenes i s of t he pol ycys t i c ovary s yndrome. The oval -s haped bl ocks repres ent cont ri but i ng fact ors ; t he rect angul ar bl ocks , key el ement s ; and t he unout l i ned words , i nt ermedi at e s t eps . FSH, fol l i cl e-s t i mul at i ng hormone; LH, l ut ei ni z i ng hormone. 



(1) The ovary produces exces s androgeni c s t eroi ds , es peci al l y androstenedione. The andros t enedi one i s convert ed t o es t rone, an es t rogen, i n fat and ot her peri pheral t i s s ues . The i ncreas ed ci rcul at i ng and i nt raovari an l evel s of andros t enedi one and ot her androgens prevent t he mat urat i on of graafi an fol l i cl es , caus i ng anovulation.





(2) The i ncreas ed ci rcul at i ng l evel of es t rone has a pos i t i ve feedback effect on pi t ui t ary product i on of LH and a negat i ve effect on product i on of FSH. The increased LH level caus es hyperpl as i a of ovari an t hecal cel l s and s t roma and i ncreas ed androgen product i on. The decreased FSH level cont ri but es t o t he l ack of fol l i cl e mat urat i on.





(3) Obesity may enhance t he el evat ed l evel s of s ex s t eroi ds by decreas i ng s ex hormoneâ€“bi ndi ng gl obul i n (t hereby i ncreas i ng t he l evel of free t es t os t erone) and by i ncreas i ng t he peri pheral convers i on of andros t enedi one t o es t rone.





(4) As a res ul t of t he arrested follicle development, t he ovari es are enl arged, wi t h

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t hi ckened caps ul es and many s mal l fol l i cul ar cys t s . St romal and t hecal hyperpl as i a are s een on mi cros copi c exami nat i on. 



(5) Insulin resistance i s pres ent i n many women wi t h t he pol ycys t i c ovary s yndrome; obes i t y account s for s ome but not al l of t he i ns ul i n res i s t ance. Ins ul i n l evel s are el evat ed becaus e of t he t i s s ue res i s t ance t o i t s act i on. That t he hyperi ns ul i nemi a may be a pri mary caus e (or at l eas t a cont ri but i ng caus e) of t he i ncreas ed ovari an product i on of androgens i s s ugges t ed by t he cl i ni cal i mprovement t hat fol l ows t reat ment wi t h drugs t hat i ncreas e i ns ul i n s ens i t i vi t y and t hus ret urn s erum i ns ul i n l evel s t o normal .





(6) Abnormal i t i es of adrenal androgen production may be pres ent ; di s appearance of t he pol ycys t i c ovary s yndrome has fol l owed removal of an androgen-s ecret i ng adrenal adenoma i n s ome cas es .

o

o

b. Clinical features (T able 9-21) 



(1) Infertility and menstrual abnormalities are t he res ul t of chroni c anovul at i on. Mos t pat i ent s have amenorrhea or ol i gomenorrhea. The prol onged, noncycl i c, unoppos ed es t rogeni c s t i mul at i on of t he endomet ri um may caus e funct i onal bl eedi ng and an i ncreas ed ri s k of endomet ri al carci noma.



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

(2) Androgen excess caus es oi l i nes s of t he s ki n, acne, and hi rs ut i s m i n mos t women wi t h t hi s s yndrome. Si gns of t rue vi ri l i zat i on (e.g., deepeni ng of t he voi ce, enl argement of t he cl i t ori s ) are rare.





(3) Obesity i s pres ent i n approxi mat el y 40% of pat i ent s .

o

o

c. Laboratory findings 



(1) An increased LH-to-FSH ratio (â‰¥2) i s a us eful di agnos t i c fi ndi ng. The LH l evel i s us ual l y el evat ed, and t he FSH l evel i s at t he l ow end of t he normal range (or t he l ow-normal range).





(2) Serum testosterone and androstenedione levels are us ual l y el evat ed. Increas ed l evel s of t he androgens of predomi nant l y adrenal ori gi n (i .e., dehydroepi andros t erone, dehydroepi andros t erone s ul fat e) are found l es s oft en.





(3) Serum estrone levels are us ual l y hi gh, and es t radi ol l evel s are normal .





(4) Prolactin l evel can be hi gh.



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

(5) In pat i ent s wi t h abnormal fasting glucose, an oral gl ucos e t ol erance t es t can be cons i dered.

o

o

d. T herapy. The goals of treatment are the relief of symptoms of androgen excess, the induction of ovulation and fertility, and the prevention of endometrial hyperplasia due t o exces s noncycl i c es t rogen s t i mul at i on. 



(1) Androgen excess 



(a) Metformin and thiazolidinediones, drugs t hat i ncreas e t he s ens i t i vi t y of t i s s ues t o i ns ul i n, have l owered t es t os t erone l evel s and i mproved t he s ympt oms of hyperandrogeni s m and mens t rual dys funct i on i n i ndi vi dual s wi t h pol ycys t i c ovary s yndrome. The effi cacy of metformin i n t hi s s yndrome makes i t a reas onabl e choi ce for i ni t i al t herapy, al t hough i t does not caus e i mprovement i n al l cas es .





(b) Spironolactone, an al dos t erone ant agoni s t t hat i s us ed pri mari l y for i t s di uret i c and ant i hypert ens i ve propert i es , has addi t i onal act i ons t hat make i t us eful i n t he t reat ment of hi rs ut i s m. Thi s agent decreas es ovari an and adrenal s ynt hes i s of androgens and i nhi bi t s androgen bi ndi ng t o recept ors i n hai r

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fol l i cl es and ot her t arget t i s s ues . A dos e of 100 mg once or t wi ce dai l y i s oft en effect i ve. P.435





(c) Estrogenâ€“progestin combinations may decreas e androgen l evel s by feedback i nhi bi t i on of pi t ui t ary LH product i on and by s t i mul at i on of hepat i c s ynt hes i s of s ex hormoneâ€“bi ndi ng gl obul i n, whi ch decreas es t he unbound fract i on of t es t os t erone.





(d) Glucocorticoids (e.g., predni s one 5.0â€“7.5 mg dai l y) may decreas e adrenal androgen product i on by s uppres s i ng ACTH. Thes e agent s may al s o l ower ovari an androgen s ecret i on, al t hough t he mechani s m i s unknown.





(e) The effect s of medi cal t herapy i n di mi ni s hi ng t he growt h of unwant ed faci al and body hai r are s el dom dramat i c and us ual l y t ake pl ace over a peri od of 3â€“6 mont hs . Mechanical methods of hair removal are us ual l y needed as wel l (e.g., s havi ng, el ect rol ys i s , l as er t reat ment , bl eachi ng, chemi cal depi l at ori es , and wax t reat ment s ). Vaniqa cream (efl orni t hi ne hydrochl ori de) i nhi bi t s an enz yme i n

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s ki n, orni t hi ne decarboxyl as e, and may s l ow t he rat e of hai r growt h. 



(2) Infertility. If met formi n does not res t ore normal ovul at ory mens t rual cycl es , ot her drugs may be us ed t o t reat i nfert i l i t y. 



(a) Clomiphene citrate bl ocks t he bi ndi ng of es t rogen t o recept ors i n t arget t i s s ues . By bl ocki ng t he negat i ve feedback effect s of es t rogen on t he hypot hal amus and pi t ui t ary gl and, t hi s drug s t i mul at es LH and FSH product i on. 



(i) If gi ven on t he fi ft h day t hrough t he ni nt h day aft er a mens t rual peri od i nduced by proges t erone, cl omi phene ci t rat e oft en s t i mul at es fol l i cl e mat urat i on and ovul at i on.





(ii) Ovul at i on can be i nduced wi t h cl omi phene ci t rat e i n approxi mat el y 80% of pat i ent s .





(b) Human menopausal gonadotropin has bot h FSH and LH bi oact i vi t y. 



(i) It i s i nject ed dai l y unt i l i ncreas i ng s erum es t rogen l evel s and ul t ras onography of t he ovary i ndi cat e t hat fol l i cl e mat urat i on has

Pa g e 2 1 4 9


occurred. 



(ii) Then human chori oni c gonadot ropi n (hCG), whi ch has pri mari l y LH act i vi t y, i s i nject ed t o i nduce ovul at i on. Becaus e t he ri s k of ovari an hypers t i mul at i on and of mul t i pl e ges t at i on i s hi gh, t hi s t herapy s houl d be res erved for res i s t ant cas es of i nfert i l i t y.





(c) GnRH, when gi ven i nt ravenous l y or s ubcut aneous l y i n pul s e dos es every 90â€“120 mi nut es , may i nduce ovul at i on wi t hout caus i ng ovari an hypers t i mul at i on.





(3) Chronic anovulation and abnormal menstrual bleeding. Unoppos ed noncycl i c s t i mul at i on of t he endomet ri um by es t rogen may caus e funct i onal bl eedi ng and may i ncreas e t he ri s k of endomet ri al cancer. Pers i s t ent endomet ri al prol i ferat i on can be i nt errupt ed ei t her wi t h proges t i n t reat ment (e.g., 10 mg dai l y of medroxyproges t erone acet at e for 10 days every 1â€“3 mont hs ) or wi t h cycl i c es t rogenâ€“proges t i n t herapy.





2. Androgen-producing ovarian tumors are rare. Arrhenobl as t oma, t he mos t common of t hes e t umors , makes up l es s t han 1% of s ol i d ovari an t umors ; ot hers are hi l ar cel l t umors , adrenal res t t umors , and granul os a cel l t umors .

Pa g e 2 1 5 0


o

a. Tes t os t erone l evel s t end t o be hi gher t han t hos e i n t he pol ycys t i c ovary s yndrome, and vi ri l i zat i on occurs more frequent l y.

o

o

b. Androgen l evel s are not s uppres s ed by t reat ment wi t h gl ucocort i coi ds or es t rogenâ€“proges t i n combi nat i ons , as t hey oft en are i n t he pol ycys t i c ovary s yndrome.

o

o

c. Di agnos i s depends on det ect i on of t he t umor by pel vi c exami nat i on (t he majori t y are pal pabl e) and on di agnos t i c i magi ng t echni ques .





3. Hyperthecosis of t he ovary i s probabl y a s evere form of t he pol ycys t i c ovary s yndrome, but t he androgen exces s i s more evi dent . o

o

a. Diagnosis depends on t he hi s t ol ogi c fi ndi ng of l ut ei ni zed t hecal and s t romal cel l s .

o

o

b. Medical therapy i s not effect i ve, and oophorect omy may be neces s ary.





4. Adrenal tumors, ei t her adenomas or carci nomas , may produce exces s androgens wi t h or wi t hout exces s cort i s ol . Hi gh l evel s of adrenal androgens (uri nary 17-ket os t eroi ds , s erum dehydroepi andros t erone) t hat cannot be s uppres s ed by dexamet has one s ugges t t hi s di agnos i s ; 24-hour uri nary 17-ket os t eroi d l evel s great er

Pa g e 2 1 5 1


t han 50â€“100 mg s t rongl y s ugges t adrenal carci noma. 



5. Congenital adrenal hyperplasia i s di s cus s ed i n t he s ect i on on di s orders of t he adrenal gl and (s ee V E). P.436





6. Idiopathic hirsutism i s a poorl y unders t ood but common condi t i on i n whi ch hi rs ut i s m occurs i n t he abs ence of marked hormone abnormal i t i es or mens t rual dys funct i on. o

o

a. The caus e of i di opat hi c hi rs ut i s m i s not known. It may have a fami l i al occurrence, and i t i s more common i n women of Medi t erranean ances t ry.

o

o

b. Increas ed res pons e of hai r fol l i cl es t o normal l evel s of t es t os t erone i s s us pect ed.

VII. Male Reproductive Disorders and Gynecomastia A. Hypogonadism Hypogonadism i n men affect s t wo s eparat e funct i ons â€”t he product i on of s permat ozoa by t he s emi ni ferous t ubul es and t he s ecret i on of t es t os t erone by t he Leydi g cel l s . The s emi ni ferous t ubul e defect caus es i nfert i l i t y; t he t es t os t erone defi ci ency l eads t o i nadequat e devel opment and mai nt enance of s econdary s exual charact eri s t i cs . 



1. Physical and developmental effects

Pa g e 2 1 5 2


o

a. Before puberty, t es t i cul ar fai l ure prevent s normal s exual devel opment . 



(1) The peni s and t es t es remai n s mal l , and s permat ozoa are abs ent .





(2) Faci al and body hai r are s pars e.





(3) The voi ce remai ns hi gh-pi t ched, and mus cl e mas s and s t rengt h are di mi ni s hed.





(4) Increas ed growt h of l ong bones (becaus e of del ayed epi phys eal cl os ure) produces t he â€œeunuchoi dal habi t us ,â€• i n whi ch t he arm s pan i s more t han 2 i nches great er t han t he hei ght , and t he fl oor-t o-pubi c s ymphys i s di s t ance i s more t han 2 i nches great er t han t he s ymphys i s -t o-crown di s t ance.

o

o

b. After puberty, l os s of l i bi do and s exual pot ency may be t he fi rs t s ympt oms of t es t i cul ar fai l ure. Part i al regres s i on of s econdary s ex charact eri s t i cs may occur gradual l y, wi t h s l owi ng of faci al and body hai r growt h and decreas ed mus cl e mas s and bone dens i t y.





2. Clinical syndromes o

Pa g e 2 1 5 3


a. Hypogonadotropic syndromes (Tabl e 9-22). The caus es of hypogonadi s m are di vi ded i nt o disorders of the hypothalamicâ€“pituitary axis (hypogonadotropic hypogonadism) and disorders that originate with testicular damage, wi t h cons equent feedback s t i mul at i on of LH and FSH (hypergonadotropic hypogonadism). 



(1) Hypogonadotropic (secondary) hypogonadism i s charact eri zed by defi ci ency of LH and FSH, wi t h res ul t i ng t es t os t erone defi ci ency and eunuchoi di s m. Kallmann' s syndrome i s a form of hypogonadot ropi c hypogonadi s m t hat i s as s oci at ed wi t h mi dl i ne defect s s uch as agenes i s of t he ol fact ory l obes , anos mi a, and cl eft pal at e. It i s more common i n men t han i n women. The bas i c hormonal defect i s i n t he hypot hal amus , rat her t han i n t he pi t ui t ary gl and; t hi s has been demons t rat ed by LH and FSH res pons e t o GnRH admi ni s t rat i on.

TABLE 9-22 Causes of Hypogonadism in Men

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Hy Hy pe po rg go on na ad dot otr ro opi pic c sy sy nd nd ro ro me me s s Hy Kl i po nef pi t el t ui t er' ari s s m s yn Hy dro po me go Tes na t i c dot ul a rop r ic

ag

eu en nuc es i hoi s di s Tes m

tic

Kal ul a lm r an i nj n's ury

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s yn Mu dro mp me s Del orc aye hi t i d

s

pu Ot ber her t y i nf ect i on s (e. g., go nor rhe a) Tra um a Sur ger y Ra di a tio n t he rap y Ca nce r che

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mo t he rap y Cry pt o rch i di sm My ot o ni c dys t ro phy *Exces s produc t i on of ACTH by t he pi t ui t a ry gl and is Cus hi n g's di s eas e. Cus hi n g's s yndro me i s a nons pe

Pa g e 2 1 5 7


ci fi c des i gn at i on t hat refers to i ncreas ed gl ucoc ort i coi d l evel s from any ori gi n. o

P.437

o





(2) Delayed puberty i s a ret ros pect i ve di agnos i s . Pubert y may occur s pont aneous l y up t o about 20 years of age; unt i l t hi s age, t rue hypogonadot ropi c hypogonadi s m cannot be di agnos ed wi t h cert ai nt y unl es s as s oci at ed abnormal i t i es s uch as anos mi a are pres ent . The di agnos i s of del ayed pubert y i s s ugges t ed by a fami l y hi s t ory of l at e mat urat i on. 



(a) If del ayed pubert y i s s us pect ed, a cours e of t herapy wi t h l ow dos es of t es t os t erone can be i ni t i at ed t o i nduce pubert al changes ; t rue pubert y may be i nduced by t hi s t reat ment .

Pa g e 2 1 5 8




(b) Tes t os t erone s houl d be gi ven for no more t han 6 mont hs at a t i me, wi t h 6 mont hs bet ween cours es , t o avoi d caus i ng epi phys eal cl os ure and l i mi t at i on of ul t i mat e hei ght and t o al l ow recogni t i on of t he ons et of s pont aneous pubert y, i f i t s houl d occur.

o

o

b. Hypergonadotropic syndromes (primary hypogonadism) 



(1) Klinefelter' s syndrome, i n whi ch t he pres ence of t wo or more X chromos omes caus es congeni t al t es t i cul ar damage, occurs i n approxi mat el y 1 i n 400 mal e bi rt hs . 



(a) Approxi mat el y 80% of pat i ent s have a 47,XXY karyotype.





(b) The t es t es are s mal l (1 hour) morning stiffness. Pain in involved joints t ypi cal l y i s wors e i n t he morni ng. Constitutional complaints (wei ght l os s , anorexi a, and fat i gue) are common.



2. Physical examination. Cl as s i cal l y i nvol ved joi nt s are t he wrists and t he MCP and PIP joints of the hand; DIP joi nt s are t ypi cal l y s pared, as i s t he axi al s kel et on except for t he cervi cal s pi ne. Soft tissue swelling, rat her t han bony enl argement , i s t ypi cal around i nvol ved joi nt s , unl es s s econdary degenerat i ve changes have occurred; l i mi t at i on of joi nt mot i on and warmt h may be not ed. Rheumatoid nodules oft en are pres ent i n hi ghl y expres s ed di s eas e; t hey can be found over ext ens or promi nences , es peci al l y near t he ol ecranon. (

Onl i ne Fi gure 10-4



Page 2263


ONLINE FIGURE 10-4 Rheumat oi d art hri t i s . Severe ul nar devi at i on and met acarpophal angeal joi nt s ubl uxat i on i s charact eri s t i c of RA. (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:9105040.) 



3. Laboratory findings. The compl et e bl ood count (CBC) may reveal a normocytic, normochromic anemia of chroni c di s eas e, l eukocyt os i s , and t hrombocyt os i s . Thes e fi ndi ngs al ong wi t h an i ncreas ed ESR refl ect chroni c i nfl ammat i on. Rheumatoid factor and anti-CCP antibody (s ee onl i ne I B 2). Synovi al fl ui d fi ndi ngs refl ect mi l d-t o-moderat e i nfl ammat i on; l eukocyt e count s 3

are 5000â€“25,000/mm and cons i s t mai nl y of neut rophi l s . 

4. Radiographic findings. Earl y charact eri s t i cs i ncl ude soft tissue swelling and l os s of bone i n peri art i cul ar areas (periarticular osteopenia). Si gns of s us t ai ned i nfl ammat i on i ncl ude l os s of bone at joi nt margi ns (erosions) and joint space narrowing as a res ul t of cart i l age l os s .

Onl i ne Fi gure 10-5

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ONLINE FIGURE 10-5 Rheumat oi d art hri t i s . Thi s x-ray of t he wri s t s hows advanced res orpt i on of t he di s t al ul na and di ffus e des t ruct i ve art hri t i s of t he carpus . Thi s i s t ypi cal of s evere rheumat oi d art hri t i s . (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:3505070.) 



5. Differential diagnosis (s ee Fi gure 10-1). Becaus e rheumat oi d art hri t i s i s one of many i l l nes s es charact eri zed by chroni c pol yart i cul ar i nfl ammat i on, di agnos i s rel i es on excl udi ng ot her s uch P.455

i l l nes s es and s earchi ng for s ymmet ri cal peri art i cul ar s oft t i s s ue s wel l i ng and i nfl ammat ory charact eri s t i cs of rheumat oi d art hri t i s . o

o

a. Nonarticular disorders. Fi bromyal gi a i s a s yndrome of general i zed achi ng and t endernes s i n

Pa g e 2 2 6 5


s peci fi c s oft t i s s ue areas , wi t hout joi nt i nvol vement or i nfl ammat i on. Tendon, neurol ogi c, and vas cul ar compl ai nt s al s o may mi mi c joi nt pai n. o

o

b. Noninflammatory disorders 



(1) Osteoarthritis us ual l y caus es bony rat her t han s oft t i s s ue s wel l i ng, and t he i nvol ved joi nt s t ypi cal l y are t he DIP and PIP joi nt s of t he hand, t he hi ps , and t he knees . The l umbar and cervi cal s pi ne can be i nvol ved as wel l . Cons t i t ut i onal and i nfl ammat ory compl ai nt s are abs ent , and s ynovi al fl ui d l eukocyt e 3

count s are l es s t han 2000/mm . 



(2) Metabolic disorders (e.g., CPPD, hemochromat os i s , and W i l s on's di s eas e) caus e bony degenerat i ve change i n at ypi cal joi nt s (e.g., MCP joi nt s ).

o

o

c. Axial joint inflammation. Infl ammat i on of t he axi al s pi ne (es peci al l y t he s acroi l i ac joi nt s ) i s charact eri s t i c of t he s pondyl oart hropat hi es , and i nfl ammat ory back pai n due t o sacroiliitis s houl d be s ought . Infl ammat ory back pai n i s i ns i di ous , day-aft er-day pai n s t art i ng i n t he s acroi l i ac area and t ypi cal l y as s oci at ed wi t h prol onged morni ng s t i ffnes s . It i s wors ened wi t h res t and i mproved by exerci s e, t he oppos i t e of mechani cal l ow back pai n. The abs ence of s acroi l i ac joi nt i nvol vement does not rul e out t hes e di s orders , but i t s pres ence makes s pondyl oart hropat hy l i kel y.

o

Pa g e 2 2 6 6


o

d. Oligoarticular presentations. Cert ai n i l l nes s es mus t be cons i dered more s t rongl y when t he i ni t i al i nfl ammat ory pres ent at i on i nvol ves four or fewer joi nt s and i s as ymmet ri cal . Thes e di s orders i ncl ude crys t al di s eas es , i nfect i ous art hri t i s (e.g., Lyme di s eas e, gonococcemi a, endocardi t i s , and rheumat i c fever), and s pondyl oart hropat hi es (e.g., react i ve art hri t i s , ps ori at i c art hri t i s ).

o

o

e. Polyarticular presentations. It al s o i s i mport ant t o cons i der i nfl ammat ory di s orders t hat i ni t i al l y i nvol ve four or more joi nt s and are fai rl y s ymmet ri cal . Al t hough rheumat oi d art hri t i s i s t he prot ot ype, many ot her i l l nes s es mus t be di s t i ngui s hed, bas ed on cl i ni cal feat ures or organ i nvol vement not t ypi cal of rheumat oi d art hri t i s . Det ai l ed hi s t ory and phys i cal exami nat i on wi t h bas i c l aborat ory dat a are cri t i cal i n di s t i ngui s hi ng among di s orders t hat feat ure pol yart hri t i s . 



(1) Other rheumatic diseases (e.g., l upus , s cl eroderma, pol ymyos i t i s /dermat omyos i t i s , PMR, and vas cul i t i s ) are di s t i ngui s hed by t he feat ures of t he pri mary i l l nes s .





(2) Viral disorders (e.g., rubel l a, HBV, and parvovi rus i nfect i on) are di s t i ngui s hed by a t ypi cal ras h, s erol ogi c markers , or organ i nvol vement .





(3) Malignancies may mani fes t as l ong bone pai n, di gi t al cl ubbi ng, and peri os t i t i s

Pa g e 2 2 6 7


mi mi cki ng pol yart hri t i s (hypert rophi c os t eoart hropat hy) or as paraneopl as t i c pol yart hri t i s . 



(4) Sarcoidosis exhi bi t s medi as t i nal adenopat hy on ches t radi ograph and us ual l y eryt hema nodos um when i t i ncl udes a pol yart hri t i s .





(5) Amyloidosis i s as s oci at ed wi t h Congo redâ€“pos i t i ve depos i t s i n t ypi cal organs , s ubcut aneous t i s s ue, and joi nt s .

G. Therapy In al l pat i ent s wi t h rheumat oi d art hri t i s , an at t empt i s made t o cont rol pai n and reduce i nfl ammat i on wi t hout caus i ng undes i rabl e s i de effect s . Pres ervat i on of joi nt funct i on and t he abi l i t y t o mai nt ai n l i fes t yl e are i mport ant l ong-t erm goal s . 



1. Nonpharmacologic therapy o

o

a. Patient education. Educat i ng pat i ent s about t he di s eas e proces s i s part i cul arl y i mport ant i n chroni c di s eas es s uch as rheumat oi d art hri t i s , i n whi ch compl i ance wi t h i ns t ruct i ons and drug t reat ment i s cri t i cal t o t he out come. 



(1) Description of the illness. The vari ous di s eas e cours es of rheumat oi d art hri t i s mus t be des cri bed, emphas i zi ng t hat mos t pat i ent s do wel l i f t hey are t reat ed appropri at el y. The chroni ci t y and i nt ermi t t ency of s ympt oms

Pa g e 2 2 6 8


mus t be di s cus s ed s o t hat pat i ent s unders t and t hat s pont aneous fl uct uat i ons i n an ext ended di s eas e cours e are normal . Pat i ent s mus t be educat ed about t he s ys t emi c nat ure of t he di s eas e proces s , s o t hat bot h t hey and t hei r fami l i es unders t and t hat fat i gue, mal ai s e, and wei ght l os s oft en accompany t hi s i l l nes s . 



(2) Rest and exercise. Pat i ent s s houl d be advi s ed t o res t or s pl i nt acut el y i nvol ved joi nt s t o reduce i nfl ammat i on. Bri ef peri ods of bed res t may be us eful i n pat i ent s wi t h s evere P.456

pol yart i cul ar exacerbat i ons , and regul ar naps may hel p pat i ent s deal wi t h t he fat i gue of rheumat oi d art hri t i s . Convers el y, exerci s es t o s t rengt hen mus cl es s urroundi ng i nvol ved joi nt s s houl d be encouraged when t he art hri t i s i s under good cont rol . Al l joi nt s s houl d be put t hrough a ful l range of mot i on once dai l y t o prevent cont ract ures . o

o

b. Physical medicine 



(1) Pat i ent s may benefi t from coordi nat i on of t hei r nonpharmacol ogi c t reat ment by physiatrists.





(2) Physical therapists can hel p pat i ent s s t rengt hen weakened mus cl e groups t o prot ect

Pa g e 2 2 6 9


damaged joi nt s . They can s how pat i ent s range-of-mot i on exerci s es t hat prevent joi nt cont ract ures . 



(3) Occupational therapists can hel p pat i ent s obt ai n devi ces t o as s i s t t hem, can cons t ruct s pl i nt s for i nvol ved joi nt s , and can ai d i n rehabi l i t at i ng pat i ent s for act i vi t i es of dai l y l i vi ng and empl oyment .





2. Pharmacologic therapy. Nons t eroi dal ant i -i nfl ammat ory drugs (NSAIDs ) and cort i cos t eroi ds are oft en us ed t o provi de rel at i vel y prompt cont rol of pai n and i nfl ammat i on, but t hes e drugs do not al t er di s eas e progres s i on. Al t hough t he cours e of rheumat oi d art hri t i s can be vari abl e, mos t pat i ent s undergo a rel ent l es s progres s i ve cours e requi ri ng t he us e of di s eas e-modi fyi ng ant i rheumat i c drugs (DMARDs ). Cort i cos t eroi ds , whi ch are not vi ewed as fi rs t - or s econd-l i ne t herapi es , oft en are us ed i nt ra-art i cul arl y for di s eas e fl are-ups or oral l y t o hel p pat i ent s who are wai t i ng for a DMARD t o t ake effect . o

o

a. NSAIDs. As pi ri n i s t he prot ot ypi c drug of t hi s cl as s . Nonacet yl at ed s al i cyl at es al s o have been devel oped, whi ch caus e l es s s uppres s i on of pros t agl andi n s ynt hes i s . 



(1) Mechanism of action. The pri mary mechani s m of act i on i s t he i nhi bi t i on of cycl ooxygenas e, wi t h a res ul t ant decreas e i n pros t agl andi n product i on. More recent dat a have s hown t hat cycl ooxygenas e exi s t s i n t wo

Pa g e 2 2 7 0


i s oforms : COX-1 and COX-2. COX-1 i s expres s ed cons t i t ut i vel y i n monocyt es /macrophages , t he cent ral nervous s ys t em (CNS), gas t ri c mucos a, ki dneys , and pl at el et s , where i t i s res pons i bl e for many of t he â€œhous ekeepi ngâ€• act i vi t i es . However, COX-2 i s t i ght l y regul at ed and produced duri ng i nfl ammat i on. Mos t of t he avai l abl e t radi t i onal NSAIDs i nhi bi t bot h COX-1 and COX-2. 



(2) Use. NSAIDs are us ed t o cont rol pai n and i nfl ammat i on by t he mechani s ms expl ai ned previ ous l y. Mos t pat i ent s us e t hem i n combi nat i on wi t h DMARDs .





(3) T oxicity. Becaus e t he majori t y of NSAIDs i nhi bi t bot h COX-1 and COX-2, t hey are more l i kel y t o produce gas t roi nt es t i nal ul cerat i on. Typi cal t oxi ci t i es i ncl ude dys peps i a, pept i c ul cers (pri mari l y of t he s t omach), hypert ens i on, renal dys funct i on, and bl eedi ng. Some pat i ent s are pl aced on mi s opros t ol or omeprazol e t o reduce t he ri s k of ul cers . Cl i ni cal hepat i t i s and bone marrow t oxi ci t y are very rare. The COX-2 agent s have been s hown t o have a l ower i nci dence of pept i c ul cerat i on and do not i nhi bi t pl at el et funct i on.





(4) COX-2 inhibitors. Cel ecoxi b i s a COX-2â€“s peci fi c i nhi bi t or. Thi s agent i s purport ed t o have a l ower i nci dence of gas t roi nt es t i nal ul cerat i on compared wi t h

Pa g e 2 2 7 1


t radi t i onal NSAIDs , and, becaus e of t he l ack of effect on pl at el et s , can be us ed i n pat i ent s on ant i coagul at i on. Cel ecoxi b mus t be us ed wi t h caut i on i n pat i ent s wi t h renal i ns uffi ci ency and i t al s o may caus e i ncreas ed fl ui d ret ent i on. Recent dat a have s ugges t ed an i ncreas ed cardi ovas cul ar mort al i t y i n pat i ent s recei vi ng rofecoxi b and val decoxi b, l eadi ng t o t he wi t hdrawal of t hes e agent s from t he market by t he U.S. Food and Drug Admi ni s t rat i on (FDA). Sul fa-al l ergi c pat i ent s s houl d not t ake cel ecoxi b. o

o

b. Corticosteroids. Thes e drugs have pot ent ant i -i nfl ammat ory effect s but equal l y pot ent and predi ct abl e t oxi ci t i es . They are us ed mos t commonl y i n rheumat oi d art hri t i s t o cont rol s eri ous ext ra-art i cul ar mani fes t at i ons (e.g., vas cul i t i s ). 



(1) Systemic administration. In rare s i t uat i ons s uch as s evere progres s i ve di s eas e, predni s one dos es no hi gher t han 5â€“10 mg once dai l y i n t he morni ng may be us ed t o al l ow cont i nued funct i oni ng. Cont i nual at t empt s t o t aper t he dos age s houl d be made.





(2) Local instillation. Inject abl e cort i cos t eroi d preparat i ons can be i ns t i l l ed i nt o one or t wo joi nt s i nfl amed â€œout of phas eâ€• wi t h ot her i nvol ved joi nt s . Thes e i nject i ons s houl d be performed onl y occas i onal l y, becaus e cart i l age l os s may res ul t from frequent i nject i ons i nt o t he s ame joi nt .

Pa g e 2 2 7 2


P.457

o

c. T raditional DMARDs. Di s eas e-modi fyi ng

o

ant i rheumat i c drugs are cri t i cal i n t he armament ari um i n t he t reat ment of rheumat oi d art hri t i s . Thes e agent s need t o be s t art ed earl y i n t he cours e of di s eas e (i deal l y wi t hi n 3 mont hs ). The hal l mark of t hes e agent s i s t hei r abi l i t y t o hal t progres s i on of di s eas e, s uch as t he devel opment of eros i ons . Commonl y us ed DMARDs i n t he t reat ment of rheumat oi d art hri t i s are l i s t ed i n Tabl e 10-6. Al t hough s i de effect s of many of t hes e medi cat i ons may be s eri ous , i n mos t i ns t ances t hey are mi l d, predi ct abl e, and can be managed. In mos t cas es , t he ri s k of ongoi ng progres s i ve di s eas e out wei ghs t he pot ent i al ri s k of medi cat i on t oxi ci t y. Each of t he agent s may be us ed al one or i n combi nat i on.

TABLE 10-6 DMARDS Used in the Treatment of Rheumatoid Arthritis M Si e d c e h Ef a fe M ni ct o s s ni A m / to g of P ri e A ot n nt ct e g

Pa g e 2 2 7 3


nt ia l T o xi io ci n ty H U M E y n ac y d k ul e r n ar e o o d x x w a a y n, m m c b a in hl ut g at o li e io r k

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m e s a n d m ac ro p h a g e fu nc ti o n M In M C et hi y B h bi el C, ot t s o A r di s S e h u T, x y p A at dr pr L e of e T, ol s s cr at i o e e n, at re h i n d e in uc p e, t a at al

Pa g e 2 2 7 5


s ic b e, fi u t h br m er o i n e si e b s/ v y ci er i n rr y hi h m bi o o t i s i nt n s, h g p fo p ul r ur m 6 in o m e n o ( ar nt D y h N in s A) fl t h sya e nt m n h me e at v s i i o er s n/ y fi 6 br â o €“ si 8 s, w st e o e m ks

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at . iti B s a s el in e C X R a n d h e p at iti s pr of il e L In Di S ef hi ar a lu bi rh m n ts e e o di a, a m h el s id y e M e dr v T o- at X or e b ot d ut at l i n

Pa g e 2 2 7 7


e v o d er b e e a h n s y z y el dr m i n o e e g s, C e al X n o R a p s ec e, i a th , er t e e ra b to y g in e hi ni bi ci ti ty n re g q p ui yr ri i

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Pa g e 2 2 7 8


s y pr nt ot h oc e ol s i wi s th ch ol e st yr a m in e S In G C ul hi a B fa bi s t C s t s ro e al pr i n v a o t e er zi s t s t y n a in 2 e gl al â a i n €“ n to 4 di l e w n ra e s nc e a e, ks n h fo d e r ch m fi r e at s t m ol 3

Pa g e 2 2 7 9


ot o m a gi o xi c nt s cy h to s p th e e ni n a e s, v h er e y p 3 at m ot o o nt xi h ci s ty B , a co s nt el ra i n in e di G ca 6 te P d D if te s st ul i n fa g al le rg

Pa g e 2 2 8 0


ic A A M C z pr y B at o el C hi dr o e o u s v p g u er ri co p y n n pr 1 e v e â er s s €“ te io 2 d n, w to h e 6- e e m p ks er at wi ca ot t h pt o ch o xi a p ci n ur t y g in , e e ly s (6 m i n M p d P) h o s o s u pr e b ol a s if n e er d q at e u iv v e e er

Pa g e 2 2 8 1


nt di y ly s 1 co or â n d €“ v er 3 er s ; m t e ca o d ut nt in io h to n s t h wi t h i o t h er p co e ur nc af i n ur t e e re r n nt uc u le s ot e i d of e al s lo d p ec ur re i n a ol si n g d e n o v

Pa g e 2 2 8 2


o sy nt h e si s of p ur in e s C In R Cr y hi e e cl bi n at o t s al i n s T- i n i n p ce s e o l l uf e ri ac fi v n t i ci er e v e y at nc 2 i o y, w n a e n e e ks mu i a nt , il h st y a p bl er e

Pa g e 2 2 8 3


te th n e si n o m n o h nt y hl p y, er p t r er ic io h di o c si C s, B p C, ar LF e T st s h e si a s, gi n gi v al h y p er tr o

Pa g e 2 2 8 4


p h y; ca ut io n â €” m ul ti pl e m e di ca ti o n in te ra ct io n s DMARDs , di s eas emodi fyi n g ant i rheu mat i c drugs ;

Pa g e 2 2 8 5


ALT. al ani ne ami not ra ns feras e ; AST, as part at e ami not ra ns feras e ; CBC, compl et e bl ood count ; CXR, ches t x-ray; LFTs , l i ver funct i on t es t s ; MTX, met hot re xat e. 



(1) Monotherapy 



(a) Methotrexate i s cons i dered t he gol d s t andard for t he t reat ment of rheumat oi d art hri t i s , us ual l y gi ven as a weekl y oral dos e. At hi gher dos es , s ubcut aneous i nject i ons of met hot rexat e may be gi ven t o i mprove abs orpt i on and di mi ni s h s i de effect s . Concurrent dai l y fol i c aci d

Pa g e 2 2 8 6


admi ni s t rat i on hel ps prevent common s i de effect s , i ncl udi ng mucos al ul cers , dys peps i a, and cyt openi as . The us e of l eucovori n may be neces s ary i f t he s i de effect s do not res pond t o t he fol i c aci d. The s t art i ng dos e of met hot rexat e i s 7.5â€“10 mg weekl y, es cal at i ng t o a maxi mum of 25 mg weekl y. If a pat i ent has underl yi ng l i ver di s eas e or pul monary di s eas e or us es al cohol , met hot rexat e may not be appropri at e t o us e. 



(b) Leflunomide act s s i mi l arl y t o met hot rexat e and requi res es s ent i al l y t he s ame moni t ori ng s t rat egy except t here i s no ri s k of pul monary t oxi ci t y; t hus , i t i s oft en P.458

us ed when met hot rexat e cannot be us ed, s uch as i n a pat i ent wi t h underl yi ng pul monary di s eas e. 



(c) Sulfasalazine, al t hough not approved by t he FDA for us e i n rheumat oi d art hri t i s , has been us ed becaus e of i t s modes t effect i venes s and rat her l ow i nci dence of t oxi ci t y. In Europe i t i s t ypi cal l y us ed as a fi rs t -l i ne agent .





(d) Les s commonl y us ed agent s as

Pa g e 2 2 8 7


monot herapy i n t he t reat ment of RA i ncl ude gold, azathioprine, and hydroxychloroquine sulfate. 



(2) Combination therapy i s us ed i f pat i ent s have had a s ubopt i mal res pons e t o monot herapy. Commonl y us ed combi nat i ons are l i s t ed bel ow. 



(a) Methotrexate and hydroxychloroquine sulfate





(b) Methotrexate and hydroxychloroquine sulfate and sulfasalazine





(c) Methotrexate and leflunomide





(d) Methotrexate and cyclosporine





d. Biologic DMARDs. As t he pat hogenes i s of rheumat oi d art hri t i s and t he vari ous i mmune and i nfl ammat ory medi at ors have been i dent i fi ed, novel agent s i n t he t reat ment of RA have been devel oped. Thes e i ncl ude t he devel opment of t umor necros i s fact or (TNF) ant agoni s t s , ant i -cyt oki ne t herapy, and B-cel l modul at ors . The common bi ol ogi c DMARDs avai l abl e for us e are l i s t ed i n Tabl e 10-7.

Pa g e 2 2 8 8


TABLE 10-7 Biologic DMARDs Used in the Treatment of Rheumatoid Arthritis D o s e M a e n Si c d d h R e A a o Ef g ni ut fe e s in ct nt m e s Et R 2 Fl a ec 5 un o m li er m g k ce bi S e pt n Q s y a t m nt wi pt fu ce o si w m o e s, n e in pr kl je ot y ct ei or i o n 5 n bi 0 s i n m te d g re

Pa g e 2 2 8 9


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Pa g e 2 2 9 1


u n e p h e n o m e n a In C 3 In fl i hi m fu xi m g/ s i m er k o a ic g n b m IV m o o a n v y oc er b lo 2 e n h a al o s s a ur oc nt s i a ib e te o v d d er wi y y th t h 8 fe at w v bi e er n e , d ks n

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CHF, conges t i ve heart fai l ure; IV, i nt raven ous ; SQ, s ubcut an eous l y; TNF, t umor necros i s fact or. 



(1) T NF inhibitors. TNF i s a pro-i nfl ammat ory cyt oki ne t hat i s s ynt hes i zed by a vari et y of cel l t ypes . Normal l y, s mal l amount s of TNF are pres ent , but overproduct i on t ri ggers a cas cade of i nfl ammat ory react i ons . Etanercept, infliximab, and adalimumab are FDA-approved for t he t reat ment of RA. Each of t hes e agent s has been s hown t o be effect i ve i n reduci ng s i gns and s ympt oms and i nhi bi t i ng t he progres s i on of s t ruct ural damage i n rheumat oi d art hri t i s . 



(a) Use. TNF i nhi bi t ors may be us ed al one or i n combi nat i on (us ual l y wi t h met hot rexat e). P.459

Pa g e 2 3 0 1






(b) Safety considerations. Seri ous i nfect i ous and opport uni s t i c i nfect i ons (t ubercul os i s ) have been s een wi t h al l of t he TNF ant agoni s t s . TNF has been s hown t o be neces s ary i n granul oma format i on t hat i s cri t i cal i n t he cont rol of TB. Thus , i nhi bi t i on of TNF has been as s oci at ed wi t h react i vat i on of TB. Screeni ng for TB i s recommended before ini t i at i ng t reat ment wi t h t hes e agent s .





(2) Anti-cytokine therapy. IL-1RA (anakinra) cont rol s RA t hrough a mechani s m di fferent from t hat of t he TNF bl ocki ng agent s but has s i mi l ar s afet y concerns , i ncl udi ng i ncreas ed ri s k of i nfect i ons (not TB), neut ropeni a, and t he pot ent i al devel opment of mal i gnanci es . No dat a as yet s ugges t hi gher ri s k of demyel i nat i on or devel opment of conges t i ve heart fai l ure.





(3) Anti B-cell therapy. B cel l s pl ay a key rol e i n t he devel opment of i nfl ammat i on i n RA, i n addi t i on t o t he des t ruct i ve T cel l s . Therefore, an agent t hat can cont rol t he effect s of B cel l s may be benefi ci al t o t hes e pat i ent s . Ri t uxi mab i s a chi meri cal monocl onal

Pa g e 2 3 0 2


ant i body t hat bi nds CD20, a B-cel l s urface ant i gen. Thi s l eads t o a decreas e i n t he B-cel l popul at i on and has s hown benefi ci al effect s at cont rol l i ng i nfl ammat i on i n RA. 



(4) T -Cell targeted therapy. CTLA4 Ig (abat acept ) prevent s CD28 from bi ndi ng t o i t s count er recept or CD80/CD86, caus i ng i nact i vat i on of pat hogeni c T cel l s .





e. Assessment of response. The effect i venes s of drug t herapy i s judged by as s es s i ng t he reduct i on i n a number of fact ors : morni ng s t i ffnes s , cons t i t ut i onal compl ai nt s , number of s wol l en and t ender joi nt s , and ESR. Somet i mes i mprovement i n anemi a of chroni c di s eas e and res ol ut i on of t hrombocyt os i s occurs . Indi ces t hat meas ure a pat i ent 's abi l i t y t o perform act i vi t i es of dai l y l i vi ng (heal t h as s es s ment ques t i onnai res ) al s o are us ed.





f. As new t herapi es are bei ng i nt roduced, t he t reat ment s t rat egy has been evol vi ng. In 2002, t he Ameri can Col l ege of Rheumat ol ogy revi s ed t he management gui del i nes .

o

o

3. Surgery. Art hropl as t i es or t ot al joi nt repl acement s may be appropri at e t o rel i eve pai n or hel p res t ore funct i on i n s t ruct ural l y damaged joi nt s .

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H. Prognosis 

1. Prognostic factors (Tabl e 10-8). Inabi l i t y t o cont rol



di s eas e act i vi t y and t he pres ence of s everal of t hes e i ndi cat ors s ugges t a poor prognos i s and t he need for more aggres s i ve t herapy, perhaps i ncl udi ng combi nat i ons of s econd-l i ne agent s and l ow-dos e oral gl ucocort i coi ds .

TABLE 10-8 Indicators of Poor Prognosis in Patients with Rheumatoid Arthritis Ma ny per sis t en tly i nfl am ed joi nt s Po or fun ct i on al sta t us (as cer

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t ai ne d fro m he al t h-a sse ss me nt qu es t i on nai res ) Lo w for ma l ed uca tio n l ev el Rh eu ma t oi d fac

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t or pos itiv ity HL ADR 4 pos itiv ity Ext raart i cul ar di s eas e Per sis t en tly el e vat ed acu te ph as e rea ct a nt s (e. g.,

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ery t hr ocy te s ed im ent at i on rat e) Ra di o gra phi c evi de nce of ero sio ns HL A, hu ma n l eu koc yt e ant i ge n. 

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2. Mortality. Many pat i ent s wi t h rheumat oi d art hri t i s have a reas onabl y good prognos i s i f t hey res pond wel l t o t reat ment . Adequat e earl y res pons e t o t he us e of NSAIDs or ant i mal ari al s , wi t h or wi t hout cort i cos t eroi ds , i s a favorabl e prognos t i c s i gn. However, recent epi demi ol ogi c s t udi es s ugges t t hat pat i ent s wi t h s evere and pers i s t ent di s eas e have i ncreas ed mort al i t y rat es . In t hos e wi t h t he mos t hi ghl y expres s ed forms of rheumat oi d art hri t i s , mort al i t y rat es approach t hos e found i n s t age IV conges t i ve heart fai l ure (CHF) or s t age IV Hodgki n's di s eas e. The i ncreas e i n mort al i t y appears t o be t he res ul t of organ compromi s e caus ed by ext ra-art i cul ar feat ures (e.g., i nt ers t i t i al l ung di s eas e, cardi ac compl i cat i ons , and vas cul i t i s ), compl i cat i ons of drug t herapy, and i nfect i on.

P.460

IV. Spondyloarthropathies A. Unifying characteristics (Table 10-9) The s pondyl oart hropat hi es are a group of i nfl ammat ory art hri t i des di s t i nct from rheumat oi d art hri t i s , i ncl udi ng ankyl os i ng s pondyl i t i s , react i ve art hri t i s , ps ori at i c art hri t i s , and art hri t i s as s oci at ed wi t h i nfl ammat ory bowel di s eas e. Typi cal di s t i ngui s hi ng feat ures i ncl ude:

TABLE 10-9 Distinguishing Characteristics of Spondyloarthropathies

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Axi al s ke l et on i nfl am ma tio n Ent hes is i nfl am ma tio n, oft en as y mm et ri c Ch ara ct e ri s t ic ext ras kel et a l fea

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t ur es Uv ei t i s or con jun ct i vi t i s Ure t hri tis I nfl am ma t or y bo wel l es i on s P s or i as i s -l i ke ras hes As s

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oci at i on wi t h HL Aâ €“B 27 Ab s en ce of rhe um at o id fac t or HL A, hu ma n l eu koc yt e ant i ge n. 

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a. Skeletal

Pa g e 2 3 1 1


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(1) Axial. As a group, t he s pondyl oart hropat hi es promi nent l y i nvol ve t he axi al s kel et on, part i cul arl y t he sacroiliac joints. W i t h t he except i on of t he cervi cal s pi ne, t he axi al s kel et on i s not commonl y i nvol ved i n rheumat oi d art hri t i s .

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(2) Appendicular. Infl ammat ory art hri t i s of t he appendi cul ar s kel et on al s o occurs i n t hes e di s orders , but t he i nvol vement t ends t o be ol i goart i cul ar and as ymmet ri cal . In cont ras t , rheumat oi d art hri t i s us ual l y i s pol yart i cul ar and s ymmet ri cal .

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(3) Enthesis. In bot h t he axi al and appendi cul ar s kel et ons , i nfl ammat i on of t endon and l i gament s i t es of at t achment t o bone i s common (e.g., cos t ochondri t i s , Achi l l es t endi ni t i s , and pl ant ar fas ci i t i s ). Tendon i nfl ammat i on i s l es s promi nent i n rheumat oi d art hri t i s .

o

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b. Extraskeletal 



(1) Nodules. Rheumat oi d nodul es are not found i n t he s pondyl oart hropat hi es .



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(2) Internal organ involvement. The t ypi cal eye i nvol vement i n t he s pondyl oart hropat hi es (conjunct i vi t i s and ant eri or uvei t i s ), cardi ac

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i nvol vement (aort i t i s ), and geni t ouri nary i nvol vement (uret hri t i s and pros t at i t i s ) are much di fferent from t he us ual ext ra-art i cul ar feat ures of rheumat oi d art hri t i s . o

o

c. Laboratory findings. Several cardi nal l aborat ory feat ures of chroni c i nfl ammat i on (i .e., anemi a, t hrombocyt os i s , and el evat ed gamma gl obul i n l evel s ) are not commonl y pres ent i n t he s pondyl oart hropat hi es as t hey are i n rheumat oi d art hri t i s . Al t hough t he ESR may be i ncreas ed, i t i s not a good meas ure of di s eas e act i vi t y. Rheumat oi d fact or t ypi cal l y i s abs ent .

o

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d. Radiographic findings. The charact eri s t i c changes s een radi ographi cal l y are t hos e of peri os t eal new bone format i on at t he s i t e of t he ent hes opat hi c l es i ons (s ee IV A 3), bot h at axi al l ocat i ons (i n t he form of syndesmophytes) and appendi cul ar l ocat i ons . Al t hough eros i ve changes can occur, t hey occur mos t t ypi cal l y i n t he axi al s kel et on (i n t he hi ps , s acroi l i ac joi nt s , and s houl ders ).

o

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e. T herapeutic response. Several s econd-l i ne agent s commonl y us ed i n t reat i ng rheumat oi d art hri t i s (e.g., gol d and hydroxychl oroqui ne) have no proven rol e i n t he t reat ment of s pondyl oart hropat hy, wi t h t he except i on of ps ori at i c peri pheral art hropat hy. Sul fas al azi ne and met hot rexat e are us ed for bot h rheumat oi d art hri t i s and t he appendi cul ar art hri t i s of t he s pondyl oart hropat hi es . TNF-i nhi bi t ors (et anercept ,

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i nfl i xi mab, and adal i mumab) are now FDA-approved for t he t reat ment of ankyl os i ng s pondyl i t i s . 



2. Genetic factors. The s t rong as s oci at i on of t he hi s t ocompat i bi l i t y ant i gen HLA-B27 wi t h cl i ni cal expres s i on of t he s pondyl oart hropat hi es provi des evi dence for genet i c t rans mi s s i on of t hes e di s orders . However, HLA-B27 i s found i n 8% of Caucas i ans , 3% of Afri can Ameri cans , and l es s t han P.461

1% of As i ans , and al l of t hes e i ndi vi dual s do not devel op s pondyl oart hropat hi es . Convers el y, s pondyl oart hropat hi es are found i n pat i ent s who are HLA-B27 negat i ve (10%â€“20%). o

o

a. Thi s rel at i ons hi p al s o i s a major reas on for groupi ng t hes e di s orders . The i ndependent correl at i on of HLA-B27 wi t h s peci fi c feat ures of s pondyl oart hropat hi es (e.g., s acroi l i i t i s , aort i t i s , and ant eri or uvei t i s ) expl ai ns bot h t he cl i ni cal overl ap among t hes e di s eas es and t hei r fami l i al cl us t eri ng.

o

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b. The rol e of t he ant i gen i n di s eas e caus at i on i s not unders t ood. However, t rans geni c rat s can expres s HLA-B27 on cel l s urfaces and devel op cl i ni cal feat ures of s pondyl oart hropat hi es , s o t hi s gene product i s cl earl y i nvol ved i n di s eas e caus at i on or perpet uat i on.

o

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c. Di s eas e s us cept i bi l i t y i s al s o as s oci at ed wi t h

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ot her unknown genes , perhaps T-cel l recept or genes , account i ng for t he 10-fol d i ncreas e i n ri s k as s oci at ed wi t h HLA-B27 pos i t i vi t y i n s pondyl i t i s fami l i es . 



3. Pathology o

o

a. The bas i c pat hol ogi c l es i on i n t he s pondyl oart hropat hi es i s an enthesopathyâ€”an i nfl ammat i on occurri ng at t he s i t e where l i gament s and t endons at t ach t o bone. Thi s t ype of i nfl ammat i on expl ai ns t he frequency of s acroi l i i t i s , as cendi ng s pi nal l es i ons , and peri pheral t endon l e s i ons (e.g., Achi l l es t endi ni t i s ).

o

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b. Al t hough i nfl ammat ory s ynovi t i s t hat i s i ndi s t i ngui s habl e from rheumat oi d s ynovi t i s can be s een i n t hes e i l l nes s es , i t i s not t ypi cal l y as wi des pread, chroni cal l y act i ve, and pot ent i al l y des t ruct i ve as i t i s i n rheumat oi d art hri t i s (ps ori at i c art hri t i s mut i l ans i s a not abl e except i on).

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4. HIV-related spondyloarthropathic disease. Some HIV-pos i t i ve pat i ent s have s pondyl oart hropat hi c i l l nes s oft en wi t h feat ures of reactive arthritis or psoriatic arthritis. However, mos t commonl y, t hey have s ki n, joi nt , and t endon feat ures t hat prevent eas y cl as s i fi cat i on i nt o one i l l nes s or t he ot her, s ugges t i ng t hat t hes e s pondyl oart hropat hi c i l l nes s es have a common pat hogenes i s (s ee XIV A 1).

B. Specific disorders

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1. Ankylosing spondylitis o

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a. Definition. Ankyl os i ng s pondyl i t i s i s t he s pondyl oart hropat hy t hat i s mos t cl os el y as s oci at ed wi t h i nfl ammat i on of t he axi al s kel et on. Back pain and limited spinal mobility caus ed by sacroiliitis and vari abl e as cent of t he i nfl ammat i on up t he s pi ne domi nat e t he cl i ni cal expres s i on of t hi s di s eas e.

o

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b. Epidemiology 

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(1) Prevalence. Ankyl os i ng s pondyl i t i s may be as common as 1 i n 1000 Caucas i an i ndi vi dual s , becaus e t he frequency of di s eas e paral l el s t he preval ence of t he HLA-B27 ant i gen i n t he popul at i on (s ee IV A 2). The frequency of ankyl os i ng s pondyl i t i s i s l ower i n Afri can Ameri can and As i an popul at i ons , paral l el i ng t he preval ence of t he ant i gen i n t hes e groups .

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(2) Gender distribution. Ankyl os i ng s pondyl i t i s may be as preval ent i n women as i n men i f radi ographi c fi ndi ngs of s acroi l i i t i s are cons i dered t o be di agnos t i c of t he di s eas e. However, women t end t o have s omewhat mi l der di s eas e wi t h more peri pheral joi nt mani fes t at i ons .

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(3) Familial aggregation. The ri s k of ankyl os i ng s pondyl i t i s i n an HLA-B27â€“pos i t i ve fami l y member of an affect ed proband i s 20%, as compared t o 1%â€“2% for t he general popul at i on of t hos e wi t h HLA-B27.

o

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c. Etiology 



(1) The major hi s t ocompat i bi l i t y ant i gen HLA-B27 occurs i n 90%â€“95% of whi t e pat i ent s wi t h ankyl os i ng s pondyl i t i s , but t he as s oci at i on i s l es s marked i n nonwhi t e popul at i ons (40%â€“50% of Afri can Ameri cans wi t h ankyl os i ng s pondyl i t i s have HLA-B27).

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(2) Becaus e t he gene codi ng for t he expres s i on of HLA-B27 res i des on chromos ome 6, aut os omal t rans mi s s i on occurs . Thus , chi l dren of a proband who i s het eroz ygous for t he gene cont rol l i ng HLA-B27 product i on have a 50% probabi l i t y of event ual expres s i on of t he ant i gen on cel l s urfaces .

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(3) The presence of HLA-B27 on cell membranes i s t hought t o be i mport ant i n t he caus at i on of ankyl os i ng s pondyl i t i s . The di s eas e i s s omehow caus ed or perpet uat ed by t he P.462

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pres ence of a s hort ami no aci d s equence i n t he pept i de-bi ndi ng cl eft of t he HLA-B27 mol ecul e t hat i s abl e t o bi nd a uni que art hri t i s -caus i ng pept i de. 

(a) Receptor theory

(Onl i ne Fi gure 10-6A). One current t heory

i s t hat t hi s marker i s a recept or for an envi ronment al fact or (e.g., bact eri al pept i de ant i gen, vi rus ), whi ch t hen can caus e di s eas e. The arthritogenic peptide theory i s a vari at i on i n whi ch an i mmune res pons e t o a bact eri al pept i de i s i ncreas ed becaus e t he pept i de (aft er i nt racel l ul ar proces s i ng) i s part i cul arl y wel l pres ent ed by HLA-B27. 

ONLINE FIGURE 10-6 Human l eukocyt e ant i gen B27 (HLA-B27) as t he caus e of ankyl os i ng s pondyl i t i s . (A) Recept or t heory. A bact eri al pept i de or vi rus forms a compl ex ext ernal l y wi t h HLA-B27. The art hri t ogeni c pept i de t heory, a vari at i on of t he recept or t heory,

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mai nt ai ns t hat t he bact eri al or vi ral pept i de i s proces s ed i nt racel l ul arl y and onl y pres ent ed on t he cel l s urface i n as s oci at i on wi t h t he HLA-B27 mol ecul e. (B) Mol ecul ar mi mi cry t heory. An i mmune res pons e i s mount ed agai ns t HLA-B27 (aut oi mmuni t y) or s uppres s ed agai ns t t he di s eas e-caus i ng pept i de (t ol erance) becaus e t he i mmune s ys t em cannot di s t i ngui s h bet ween t hei r s i mi l ar ami no aci d s equences . 

(b) Molecular mimicry theory

(Onl i ne Fi gure 10-6B). A bact eri al

or ot her envi ronment al ant i gen pres ent ed on t he cel l s urface wi t h a di fferent HLA mol ecul e mi ght s hare s i mi l ar s equences wi t h t he HLA-B27 mol ecul e. If t hi s cl as s I compl ex (nonâ€“HLA-B27 pl us +

pept i de) i s recogni zed by t he cyt ot oxi c CD8 T cel l as HLA-B27, an i mmune res pons e can be mount ed agai ns t HLA-B27 (autoimmunity) or s uppres s ed agai ns t t he di s eas e-caus i ng pept i de (tolerance). Ei t her condi t i on coul d l ead t o cl i ni cal di s eas e expres s i on.  

(c) T hymic selection theory.

HLA-B27 may funct i on at t he l evel

of t he t hymus by al l owi ng s el ect i on of arthritogenic T cells. o

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d. Clinical features 

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(1) Disease onset. The di s eas e us ual l y devel ops i n t he s econd or t hi rd decade of l i fe.

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(2) Disease course. The di s eas e begi ns wi t h t he gradual ons et of chroni c s acral backache, whi ch i s as s oci at ed wi t h prol onged morni ng s t i ffnes s and whi ch i mproves wi t h exerci s e. Mos t pat i ent s have prol onged, unremi t t i ng l ow back pai n for years . The di s eas e may be mi l d and caus e mi ni mal i nt erference wi t h funct i on,

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or i t may be s evere and deformi ng. 

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(3) Manifestations of disease 

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(a) Axial skeletal involvement. Symmet ri cal i nfl ammat i on of t he s acroi l i ac joi nt s (s acroi l i i t i s ) i s t he mos t common pres ent at i on. Infl ammat i on and cons equent cal ci fi cat i on of t he s pi nal l i gament s and t he i nt ervert ebral zygapophys eal joi nt s can caus e l i mi t ed s pi nal mobi l i t y, and i nt ercos t al l i gament ent hes opat hy can caus e l i mi t at i on of ches t wal l expans i on.

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(b) Peripheral joint involvement. Thi s feat ure i s t ypi cal of more s evere ankyl os i ng s pondyl i t i s . Eros i ve hi p and s houl der i nvol vement i s not uncommon and may be s evere. More di s t al s ynovi t i s i s l es s common, al t hough 35% of pat i ent s wi t h ankyl os i ng s pondyl i t i s have s ome evi dence of peri pheral joi nt di s eas e.

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(c) Extraskeletal features. Cons t i t ut i onal compl ai nt s , fat i gue, and wei ght l os s are not as common i n ankyl os i ng s pondyl i t i s as i n rheumat oi d art hri t i s , but t hey may occur. Ant eri or uvei t i s occurs i n 25% of pat i ent s wi t h ankyl os i ng s pondyl i t i s , and s omet i mes occurs as an i s ol at ed cl i ni cal as s oci at i on

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of HLA-B27. Aort i c root i nfl ammat i on can occur, us ual l y i n pat i ent s wi t h l ong-s t andi ng di s eas e; t hi s proces s can l ead t o aort i c val ve i ns uffi ci ency or, i f i t ext ends i nt o t he conduct i on s ys t em, compl et e heart bl ock. Upper l obe pul monary fi bros i s and chroni c pros t at i t i s are ot her uncommon ext ras kel et al feat ures . o

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e. Diagnosis. Combi ni ng hi s t ori cal , phys i cal , and radi ographi c evi dence as wel l as excl udi ng mechani cal l ow back pai n, ot her s pondyl oart hropat hi es , and ot her i nfl ammat ory art hri t i des , al l ows for di agnos i s . 

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(1) Historical information 

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(a) Inflammatory versus mechanical low back pain. Infl ammat ory s acroi l i i t i s has a gradual ons et , i n earl y adul t hood, and i s pers i s t ent for more t han 3 mont hs ; t he pai n i s as s oci at ed wi t h prol onged earl y morni ng back s t i ffnes s and i s rel i eved by exerci s e and wors ened by res t . In cont ras t , t he ons et of mechani cal l ow back pai n us ual l y occurs l at er i n l i fe, wi t h s udden, s el f-l i mi t ed epi s odes t hat are wors ened by exerci s e and i mproved by bed res t .

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(b) Familial association. Pat i ent s wi t h ankyl os i ng s pondyl i t i s oft en have ot her

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affect ed fami l y members . 

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(c) Associated complaints. Evi dence of pri or i nfl ammat ory eye s ympt oms , recurrent ol i goart hri t i s , and i nfl ammat ory t endi ni t i s s houl d be s ought .

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(2) Physical findings 

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(a) Musculoskeletal examination. Each s acroi l i ac joi nt s houl d be eval uat ed for t endernes s , l umbar s pi nal mobi l i t y s houl d be as s es s ed i n al l di rect i ons , and ches t expans i on s houl d be eval uat ed t o as s es s s everi t y of ches t wal l ent hes opat hi c l es i ons .

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(b) General physical examination. Evi dence of as s oci at ed abnormal i t i es s houl d be s ought , i ncl udi ng ocul ar eryt hema, aort i c i ns uffi ci ency murmurs , and peri pheral art hri t i s and t endi ni t i s .

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(3) Laboratory findings. The onl y charact eri s t i c l aborat ory abnormal i t y i n ankyl os i ng s pondyl i t i s i s t he vari abl e pres ence of HLA-B27 i n di fferent popul at i on groups . In general , t es t i ng for t hi s ant i gen i s not neces s ary for t he di agnos i s .

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(4) Radiographic findings. Sacroi l i ac

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i nvol vement i s bes t s een on an ant eropos t eri or radi ograph of t he pel vi s . Bl urred joi nt margi ns , peri art i cul ar s cl eros i s , eros i ons , and P.463

joi nt -s pace wi deni ng are charact eri s t i c, but t ot al joi nt obl i t erat i on i s t ypi cal of l ong-s t andi ng di s eas e. If t he i l l nes s i s more s evere or l ong-s t andi ng, as cendi ng s pi nal i nvol vement can occur, wi t h del i cat e fl owi ng cal ci fi cat i ons (s yndes mophyt es ) t hat bri dge t he i nt ervert ebral di s k, cul mi nat i ng i n a bamboo-spine appearance on a radi ograph. 

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(5) Differential diagnosis 



(a) Nature of low back pain. As ment i oned previ ous l y, mechani cal l ow back pai n mus t be di fferent i at ed from i nfl ammat ory l ow back pai n [s ee IV B 1 e (1) (a)].

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(b) Other disorders. Sacroi l i i t i s i s hi ghl y unus ual i n nons pondyl i t i c di s eas es . Charact eri s t i c s ki n l es i ons may s ugges t t hat a pat i ent wi t h s acroi l i i t i s has ps ori as i s or react i ve art hri t i s . Promi nent uret hri t i s i n as s oci at i on wi t h s acroi l i i t i s may al s o s ugges t react i ve art hri t i s , and promi nent bowel compl ai nt s wi t h s acroi l i i t i s may s ugges t

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i nfl ammat ory bowel di s eas e. o

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f. T herapy. Pat i ent educat i on and mul t i di s ci pl i nary t reat ment are i mport ant t herapeut i c component s i n ankyl os i ng s pondyl i t i s , jus t as t hey are i n rheumat oi d art hri t i s . Short -t erm goal s i nvol ve cont rol of pai n and reduct i on of i nfl ammat i on wi t hout caus i ng drug t oxi ci t y, and l ong-t erm goal s are prevent i on of pos t ural deformi t y and ret ent i on of empl oyment . 

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(1) Education 

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(a) Cigarette smoking. Indi vi dual s wi t h ent hes opat hi c ches t wal l res t ri ct i on or fi brot i c l ung di s eas e s houl d be di s couraged from s moki ng.

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(b) Genetic counseling. Pat i ent s s houl d be made aware of t he fami l i al i nci dence of t he i l l nes s s o t hat i t can be di agnos ed earl y i n chi l dren and t reat ment of s pondyl i t i c s ympt oms begun.

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(c) Protection of brittle spine. Pat i ent s wi t h ext ens i ve s pi nal i nvol vement mus t unders t and t hat mi ni mal t rauma can caus e a s pi nal fract ure. W eari ng a hard or s oft col l ar s houl d be recommended for aut omobi l e dri vi ng.

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(2) Exercise. Spi nal ext ens i on exerci s es and correct pos t ure are i mport ant for prevent i on of deformi t y. Hard mat t res s es and s mal l cervi cal pi l l ows hel p prevent exces s i ve s pi nal fl exi on duri ng s l eep.

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(2) Drug therapy. Al t hough many pat i ent s requi re DMARDS, NSAIDs are t he mai ns t ay of t reat ment . For pers i s t ent di s eas e act i vi t y, TNF i nhi bi t ors (et anercept , i nfl i xi mab, and adal i mumab) are now FDA-approved for t he t reat ment of ankyl os i ng s pondyl i t i s . They al l evi at e s ympt oms , i mprove funct i on, and may i mpact t he nat ural progres s i on of t he di s eas e. Local joi nt or peri t endi nous i ns t i l l at i on of a cort i cos t eroi d s omet i mes i s benefi ci al i n pat i ent s wi t h promi nent peri pheral di s eas e mani fes t at i ons not cont rol l ed by NSAIDs .

o

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g. Prognosis. Mos t pat i ent s wi t h ankyl os i ng s pondyl i t i s remai n empl oyabl e and cont i nue t o funct i on wel l i n s oci et y. The progres s i on t o s evere, deformi ng di s eas e cannot be predi ct ed on t he bas i s of HLA-B27 s t at us or ot her cri t eri a. Pat i ent s wi t h s evere s pondyl i t i s t end t o have bri t t l e s pi nes , more cardi opul monary di s eas e, and ot her ext ras pi nal compl i cat i ons ; t hes e pat i ent s may have s hort ened l i fe s pans .

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2. Reactive arthritis o

o

a. Definition. React i ve art hri t i s i s anot her

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s pondyl oart hropat hy t hat i s s t rongl y as s oci at ed wi t h HLA-B27. 



(1) React i ve art hri t i s i ni t i al l y referred t o t he cl as s i c t ri ad of nongonococcal uret hri t i s , conjunct i vi t i s , and art hri t i s t hat occurred aft er a di arrheal i l l nes s or geni t ouri nary i nfect i on, us ual l y wi t h Chl amydi a t rac homat i s . Many pat i ent s s t i l l have t he cl as s i c di s eas e t ri ad, but t he us e of HLA-B27 t ypi ng has al l owed â€œi ncompl et eâ€• forms (wi t hout t he uret hri t i s or conjunct i vi t i s ) t o be i dent i fi ed.

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(2) React i ve art hri t i s i s a predomi nant l y l ower ext remi t y ol i goart hri t i s t ri ggered by urethritis, cervicitis, or dysenteric infection. The vari abl e feat ures of t he t ypi cal s yndrome i ncl ude mucocutaneous lesions, inflammatory eye lesions, and sacroiliitis or peripheral arthritis.

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b. Epidemiology 

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(1) Incidence. React i ve art hri t i s occurs i n 1%â€“3% of pat i ent s aft er nons peci fi c uret hri t i s and 0.2% of pat i ent s aft er dys ent ery out breaks caus ed by Shi gel l a fl exneri . HLA-B27 i s pres ent P.464

i n 75%â€“80% of cas es . Pat i ent s wi t h t he marker who devel op nons peci fi c uret hri t i s or S. fl exneri

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dys ent ery have a 20%â€“25% chance of devel opi ng react i ve art hri t i s . 

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(2) Gender distribution. React i ve art hri t i s i s di agnos ed i n men much more oft en t han i n women, i n part becaus e cervi ci t i s i s l es s s ympt omat i c t han uret hri t i s . However, t he art hri t i s t ends t o be l es s s evere i n women as wel l .

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c. Etiology and pathogenesis. Speci fi c i nfect i ons t ri gger t he cl i ni cal expres s i on of art hri t i s i n s us cept i bl e pat i ent s , i ncl udi ng chl amydi al and mycopl as mal uret hri t i s as wel l as dys ent eri c i nfect i ons caus ed by cert ai n s erot ypes of Shi gel l a, Sal monel l a, and Y ers i ni a. The pres ence of t he organi s m may not be neces s ary for l at er exacerbat i ons or chroni c act i vi t y of t he di s eas e, al t hough s ome pol ymeras e chai n react i on (PCR) and el ect ron mi cros copi c s t udi es of i nfl amed s ynovi um s ugges t t he pers i s t ence of chl amydi al organi s ms or fragment s i n react i ve art hri t i s . The unus ual s everi t y of react i ve art hri t i s i n pat i ent s wi t h acqui red i mmunodefi ci ency s yndrome (AIDS) s ugges t s t hat t he i nfl ammat ory res pons e does not +

requi re funct i oni ng CD4 cel l s . 

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(1) Exaggerated immune response. Concei vabl y, i nfect i ous ant i gens cros s -react wi t h s el f ant i gens s uch as HLA-B27 and s t i mul at e an exaggerat ed i mmune res pons e t hat can i ncl ude a noni nfect i ous art hri t i s .

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(2) Suppressed immune response. It i s al s o concei vabl e t hat mol ecul ar mi mi cry bet ween HLA-B27 and bact eri al pept i des prevent s t he hos t i mmune s ys t em from recogni zi ng t he pat hogen, t hus al l owi ng di s s emi nat i on and product i on of di s eas e at wi del y vari ed s i t es . Evi dence t hat s ugges t s pers i s t ence of organi s ms or fragment s at s i t es of chroni c i nfl ammat i on s upport s t hi s t heory.

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(2) Protected site of infection. Pers i s t ent s ubcl i ni cal geni t ouri nary or gas t roi nt es t i nal i nfect i ons (e.g., Chl amydi a, Shi gel l a) coul d caus e recurrent s heddi ng of organi s ms or bact eri al ant i gens t o joi nt s . Pers i s t ent s peci fi c IgA res pons es t o caus at i ve organi s ms and i mprovement wi t h s urgi cal s t ri ppi ng of t he uret hra i n venereal ons et of react i ve art hri t i s s upport t hi s t heory.

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(1) Disease onset. React i ve art hri t i s begi ns mos t oft en i n young adul t hood. One t o t hree weeks aft er an epi s ode of uret hri t i s or dys ent ery, any of t he t ypi cal cl i ni cal feat ures of t he s yndrome can occur. The di s eas e oft en i s mi s di agnos ed becaus e t hes e feat ures t end t o occur s eri al l y rat her t han s i mul t aneous l y.

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(2) Manifestations of disease 

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(a) Musculoskeletal 

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(i) Arthritis. A l ower ext remi t y ol i goart hri t i s i s t he mos t common joi nt pres ent at i on. The art hri t i s may be acut e and s el f-l i mi t ed, but i t i s more commonl y rel aps i ng or chroni c.

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(ii) Enthesopathy. Infl ammat i on of t he t endons and l i gament s are as much a part of react i ve art hri t i s as t hey are of ankyl os i ng s pondyl i t i s . Pl ant ar fas ci i t i s and Achi l l es t endi ni t i s are mos t t ypi cal . Dactylitis (s aus age t oe), a l es i on i nvol vi ng bot h joi nt and t endon i nfl ammat i on i n t he s ame di gi t , i s al s o a common feat ure.

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(iii) Sacroiliitis. As ymmet ri cal i nvol vement of s acroi l i ac joi nt s occurs i n approxi mat el y 20% of pat i ent s . Les s frequent l y, as ymmet ri cal as cendi ng s pi nal di s eas e occurs . The cons equent back pai n has t ypi cal i nfl ammat ory charact eri s t i cs , but onl y rarel y does t he as cendi ng s pi nal di s eas e l i mi t t horaci c or cervi cal s pi nal mobi l i t y.

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(b) Genitourinary. Sympt omat i c or

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as ympt omat i c urethritis i s ext remel y common. Chroni c prostatitis al s o i s common, affect i ng as many as 80% of pat i ent s i n s ome s eri es . 



(c) Ocular. Bot h conjunctivitis and anterior uveitis oft en occur. The conjunct i val i nfl ammat i on i s an acut e, us ual l y s el f-l i mi t ed mani fes t at i on, whi ch may be recurrent . Ant eri or uvei t i s occurs i n more es t abl i s hed forms of di s eas e; i t may be chroni c and requi re t opi cal or s ys t emi c cort i cos t eroi ds t o prevent vi s ual det eri orat i on.

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(d) Mucocutaneous. Fl eet i ng and pai nl es s oral ul cers are t he t ypi cal mucous membrane feat ures . Keratoderma blennorrhagica i s t he charact eri s t i c s cal i ng, pl aque-l i ke l es i on found anywhere on t he body, i ncl udi ng t he pal ms and s ol es . Thi s l es i on res embl es pus t ul ar ps ori as i s cl i ni cal l y and pat hol ogi cal l y. Circinate balanitis i s a pai nl es s , P.465

eryt hemat ous eros i on of t he gl ans peni s t hat may expand t o s urround t he uret hral ori fi ce. Each of t hes e s ki n l es i ons occurs i n approxi mat el y 20%â€“30% of pat i ent s wi t h react i ve art hri t i s , al t hough ci rci nat e bal ani t i s i s t he mos t common.

Pa g e 2 3 3 0


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(e) Cardiovascular. Earl y cardi ovas cul ar changes i ncl ude t rans i ent pericardial rubs or first-degree heart block. In more s evere, l ong-s t andi ng di s eas e, an aortitis i dent i cal t o t hat s een i n ankyl os i ng s pondyl i t i s can caus e val vul ar i ns uffi ci ency or conduct i on s ys t em l es i ons .

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e. Diagnosis 



(1) General considerations. React i ve art hri t i s can be di ffi cul t t o di agnos e when t he ons et of vari ous cl i ni cal feat ures i s wi del y s eparat ed over t i me, but i t i s qui t e eas y i f arthritis, dysentery or urethritis, conjunctivitis, and mucocutaneous lesions appear s i mul t aneous l y. A t ent at i ve di agnos i s can be made when a s eronegat i ve as ymmet ri cal ol i goart hri t i s i s as s oci at ed wi t h any of t hes e ext ra-art i cul ar feat ures . Becaus e t hi s form of art hri t i s i s , s t ri ct l y s peaki ng, a â€œreact i veâ€• art hri t i s , t he t emporal appearance of art hri t i s aft er uret hri t i s or a dys ent eri c i l l nes s i s es peci al l y convi nci ng. The mucocut aneous l es i ons , uret hri t i s , and cervi ci t i s , whi ch oft en are as ympt omat i c, mus t be s ought s peci fi cal l y whi l e t aki ng t he pat i ent hi s t ory and duri ng t he phys i cal exami nat i on.

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(2) Laboratory findings. Ei ght y percent of whi t es wi t h react i ve art hri t i s have HLA-B27.

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The s ynovi al fl ui d t ypi cal l y i s mi l dl y t o moderat el y i nfl ammat ory, wi t h neut rophi l predomi nance and no i mport ant di s t i ngui s hi ng charact eri s t i cs . 



(3) Radiographic findings. As ymmet ri cal , ol i goart i cul ar eros i ons , joi nt s pace narrowi ng, and peri art i cul ar os t eopeni a can be s een radi ographi cal l y i n es t abl i s hed di s eas e. Peri os t eal new bone format i on i s a charact eri s t i c feat ure of react i ve art hri t i s , es peci al l y adjacent t o t he i ns ert i ons of t he Achi l l es t endon and pl ant ar fas ci a. Sacroi l i i t i s , i f i t occurs , t ypi cal l y i s as ymmet ri cal , and t he occas i onal pat i ent wi t h s pondyl oart hropat hy has as ymmet ri cal , l arge s yndes mophyt es at s cat t ered vert ebral l evel s .

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(a) Diseases most likely to mimic acute reactive arthritis are gonococcal art hri t i s and ot her i nfect i ous art hropat hi es , even Lyme di s eas e. Thus , appropri at e t i s s ues s houl d be cul t ured and s erol ogi es obt ai ned. Crys t al -medi at ed art hri t i s (i .e., gout and ps eudogout ) and t he art hri t i s of rheumat i c fever s houl d be excl uded.

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(b) Diseases most likely to mimic chronic recurring reactive arthritis i ncl ude ot her s pondyl oart hropat hi es ,

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es peci al l y ps ori at i c art hri t i s and ankyl os i ng s pondyl i t i s . Cl os e at t ent i on t o t he s ymmet ry and s everi t y of s acroi l i ac and s pi nal i nvol vement , t o ext ras kel et al feat ures , and t o t he pres ence or abs ence of i nfect i ous t ri ggers may hel p di fferent i at e t hes e i l l nes s es . Many cas es of s o-cal l ed seronegative rheumatoid arthritis may act ual l y be cas es of react i ve art hri t i s . Typi cal cl i ni cal feat ures as wel l as radi ographi c evi dence of s acroi l i ac joi nt and peri os t i t i s s houl d be s ought . The pres ence or abs ence of HLA-B27 may be hel pful i n di agnos i ng part i cul arl y di ffi cul t cas es . o

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f. T herapy 

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(1) Goals of treatment are es s ent i al l y t he s ame as i n ankyl os i ng s pondyl i t i s [s ee IV B 1 f (1)].

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(2) Exercise. Pat i ent s s houl d be advi s ed t o res t t o l es s en i nfl ammat i on and t o perform appropri at e exerci s es t hat al l ow pres ervat i on of joi nt funct i on and prevent i on of cont ract ures .

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(3) Drug therapy 

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(a) NSAIDs. Thes e agent s are t he

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mai ns t ay of t reat ment . However, as pi ri n i s rel at i vel y i neffect i ve. 



(b) Corticosteroids. Occas i onal i nt ra-art i cul ar i ns t i l l at i on may be us eful i n t he management of part i cul ar joi nt s t hat do not res pond t o t reat ment wi t h NSAIDs .

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(c) Second-line agents. Bot h azat hi opri ne and met hot rexat e have been us ed t o cont rol part i cul arl y s evere and chroni c di s eas e, and s ul fas al azi ne i s us ed for art hri t i s unres pons i ve t o NSAIDs . The effect s of t hes e medi cat i ons on di s eas e cours e are not yet known. HIV t es t i ng s houl d be cons i dered for pat i ent s wi t h react i ve art hri t i s s uffi ci ent l y s evere t o requi re i mmunos uppres s i ve medi cat i ons .

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(d) Antibiotics. Tri al s of t et racycl i ne-l i ke drugs , us ed for 3-mont h peri ods earl y i n di s eas e as s oci at ed wi t h uret hri t i s , s ugges t t hat ant i bi ot i c t reat ment may l es s en t he s everi t y and chroni ci t y of art hri t i s .

P.466

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g. Prognosis. Chroni c or recurrent di s eas e appears t o be common. In 60%â€“80% of pat i ent s wi t h

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react i ve art hri t i s , s kel et al compl ai nt s , ext ras kel et al compl ai nt s , or bot h, recur or become chroni c. Perhaps as many as 25% of pat i ent s are funct i onal l y di s abl ed by t hei r i l l nes s . Long-t erm probl ems wi t h aort i c regurgi t at i on and conduct i on di s t urbances are unus ual but i ncreas e wi t h t he durat i on of t he di s eas e. Pat i ent s who have HLA-B27 ant i gen have more s acroi l i i t i s and are more l i kel y t o have recurrent or chroni c di s eas e. 

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3. Psoriatic arthritis o

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a. Definition. Any form of i nfl ammat ory art hri t i s as s oci at ed wi t h ps ori as i s i s cal l ed ps ori at i c art hri t i s . Rheumat oi d fact or general l y i s abs ent .

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b. Epidemiology 

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(1) Ps ori at i c art hri t i s occurs much more commonl y i n pat i ent s who have a fi rs t -degree rel at i ve wi t h t he di s order.

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(2) Ps ori as i s occurs t wo t o t hree t i mes more commonl y i n pat i ent s wi t h art hri t i s t han i n t he normal popul at i on. Convers el y, as many as 10%â€“20% of pat i ent s wi t h ps ori as i s may have an i nfl ammat ory art hri t i s .

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c. Etiology. Al t hough a heredi t ary et i ol ogy i s apparent i n ps ori at i c art hri t i s , i t s charact eri s t i cs are not ful l y unders t ood. HLA-B27 i s hi ghl y

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as s oci at ed wi t h s acroi l i i t i s i n ps ori as i s , and HLA-B27, -B13, and -DR7 are i ndependent l y as s oci at ed wi t h art hri t i s and ps ori as i s at an i ncreas ed frequency. Unknown environment al fact ors al s o may be i mport ant i n di s eas e expres s i on. o

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(1) Disease onset. Mos t pat i ent s wi t h ps ori at i c art hri t i s devel op t he di s eas e i n t hei r l at e t hi rt i es t o earl y fort i es . Mos t pat i ent s devel op s ki n l es i ons before t he art hri t i s , but as many as 16% devel op i nfl ammat ory art hri t i s before t he ps ori as i s .

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(2) Patterns of arthritis. Fi ve pat t erns of ps ori at i c art hropat hy have been di s t i ngui s hed, al t hough t he t ypi cal pat i ent oft en has t he s kel et al mani fes t at i ons of s everal of t hes e pat t erns . Peri pheral joi nt and t endon i nvol vement may be more s evere i n t he upper t han i n t he l ower ext remi t i es . 

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(a) DIP arthritis i s t he cl as s i c form of ps ori at i c art hri t i s . It i s s t rongl y as s oci at ed wi t h t ypi cal fi ngernai l abnormal i t i es as wel l as DIP joi nt rednes s , s oft t i s s ue s wel l i ng, and eros i ve changes s een radi ographi cal l y i n a cl i ni cal pi ct ure res embl i ng pri mary eros i ve os t eoart hri t i s .

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(b) Asymmetrical oligoarthritis. Large and s mal l joi nt ol i goart hri t i s i s anot her cl i ni cal form of ps ori at i c art hri t i s . Sausage digits are common i n t hi s form as a mani fes t at i on of joi nt and ent hes i s i nvol vement of a s i ngl e phal anx.

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(c) Symmetrical polyarthropathy. A fai rl y s ymmet ri cal pol yart hropat hy can occur i n conjunct i on wi t h ps ori as i s , and i t can be di ffi cul t t o di s t i ngui s h from rheumat oi d art hri t i s . As much as 25% of t hes e pat i ent s may be s eropos i t i ve for rheumat oi d fact or.

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(d) Arthritis mutilans i s an unus ual l y des t ruct i ve form of ps ori at i c art hri t i s becaus e of t he s evere peri art i cul ar bone res orpt i on t hat occurs i n t he s mal l fi nger joi nt s . â€œTel es copi ng di gi t s â€• charact eri ze t he end s t age of t hi s uncommon form of art hri t i s . W i des pread joi nt ankyl os i s al s o can occur.

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(e) Sacroiliitis. As many as 20% of pat i ent s wi t h ps ori at i c art hri t i s can have cl i ni cal or radi ographi c evi dence of s acroi l i i t i s , us ual l y as ymmet ri cal . As cendi ng s pi nal s yndes mophyt es occur i n an as ymmet ri cal and pat chy fas hi on.

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(3) Extra-articular features

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(a) Skin. Art hri t i s i s more l i kel y t o occur i n pat i ent s wi t h s evere s ki n i nvol vement t han i n t hos e wi t h mi l d ps ori as i s , al t hough i t can occur i n t he pres ence of l ocal i zed cut aneous l es i ons . Ski n and joi nt fl ares of di s eas e can occur i n as s oci at i on wi t h each ot her or i ndependent l y i n i ndi vi dual pat i ent s .

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(b) Nails. Nai l abnormal i t i es mos t commonl y occur i n conjunct i on wi t h DIP joi nt l es i ons ; however, nai l changes are not ed more frequent l y i n al l of t he peri pheral forms of ps ori at i c art hri t i s i n compari s on t o ps ori as i s uncompl i cat ed by art hri t i s . Mul t i pl e pitting, t rans vers e depres s i ons , and onycholysis are t he charact eri s t i c abnormal i t i es found.

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(c) Ocular. The onl y ot her ext ra-art i cul ar feat ures t hat occur commonl y i n pat i ent s wi t h ps ori at i c art hri t i s are conjunct i vi t i s (i n 20% of cas es ) and ant eri or uvei t i s (i n 10% of cas es ).

P.467

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e. Diagnosis 



(1) Clinical considerations. An as s oci at i on

Pa g e 2 3 3 8


s houl d be made bet ween t he t ypi cal s ki n and nai l l es i ons and t he joi nt and s pi nal i nvol vement t o di agnos e ps ori at i c art hri t i s . The s ki n mani fes t at i ons may be s ubt l e, s o part i cul ar care mus t be t aken t o check t he el bows , s cal p, groi n, navel , and but t ock cl eft . 

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(2) Laboratory findings. Laborat ory i ndi cat ors of chroni c di s eas e (e.g., anemi a, t hrombocyt os i s ) t ypi cal l y are abs ent . Pat i ent s us ual l y are s eronegat i ve for rheumat oi d fact or, al t hough 25% of pat i ent s wi t h s ymmet ri cal pol yart hri t i s are s eropos i t i ve.

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(3) Radiographic findings 



(a) DIP joint erosions can l ead t o joi nt -s pace narrowi ng, and proxi mal phal angeal bone res orpt i on can l ead t o a â€œpenci l -i n-cupâ€• abnormal i t y s een i n art hri t i s mut i l ans . Thi s s evere des t ruct i on al s o can occur i n more proxi mal joi nt s .

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(b) Spinal involvement. As ymmet ri cal s acroi l i i t i s and as ymmet ri cal pat chy s yndes mophyt es are s een and are s i mi l ar t o t hos e s een i n react i ve art hri t i s .

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(c) Enthesopathy. Cal ci fi cat i ons at t endon and l i gament i ns ert i ons occur.

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Pa g e 2 3 3 9


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(a) Reactive arthritis i s di s t i ngui s hed from ps ori at i c art hri t i s by i t s charact eri s t i c ext ra-art i cul ar feat ures and i t s t endency t o i nvol ve t he l ower ext remi t i es more t han t he upper ext remi t i es . In ps ori at i c art hri t i s , upper ext remi t y peri pheral joi nt i nvol vement i s more common.

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(b) Rheumatoid arthritis. Pat i ent s wi t h ps ori as i s who pres ent wi t h s ymmet ri cal pol yart hri t i s , s eropos i t i vi t y for rheumat oi d fact or, and rheumat oi d nodul es may be di agnos ed wi t h rheumat oi d art hri t i s . Ot her overl appi ng pres ent at i ons of t he t wo di s eas es may be di ffi cul t t o di agnos e.

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f. T herapy. Drug t reat ment for ps ori at i c art hri t i s i s s i mi l ar t o t hat for t he ot her s pondyl oart hropat hi es i n t hat NSAIDs are t he corners t one of t herapy. An i mport ant di fference: Gol d can be admi ni s t ered i nt ramus cul arl y t o t reat s us t ai ned mani fes t at i ons of peri pheral art hri t i s . Sul fas al azi ne al s o i s effect i ve. Met hot rexat e i s oft en t he fi rs t agent us ed i f NSAIDs are not s uffi ci ent ; i t has been part i cul arl y s ucces s ful i n cont rol l i ng bot h t he s ki n di s eas e and refract ory art hri t i s . Ot her cyt ot oxi c drugs (e.g., azat hi opri ne) al s o have been us ed i n t reat ment of s evere s ki n and joi nt di s eas e. Bi ol ogi cal agent s (TNF i nhi bi t ors ) are now

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FDA-approved for t he t reat ment of ps ori at i c art hri t i s and pl aque art hri t i s . o

o

g. Prognosis. Mos t pat i ent s wi t h ps ori at i c art hri t i s , except for t he 5% or s o who devel op art hri t i s mut i l ans , can avoi d s i gni fi cant deformi t y and remai n empl oyed.





4. Enteropathic arthropathies o

o

a. Definition. Infl ammat ory art hri t i s as s oci at ed wi t h ei t her Crohn's di s eas e or ul cerat i ve col i t i s i s t ypi fi ed by a s eronegat i ve, mi grat ory pol yart i cul ar i nvol vement t hat waxes and wanes wi t h t he act i vi t y of t he bowel di s eas e. Sacroi l i i t i s and s pondyl i t i s al s o can occur i n affect ed i ndi vi dual s .

o

o

b. Clinical syndromes 



(1) Peripheral arthritis. In 10%â€“20% of pat i ent s wi t h s evere ul cerat i ve col i t i s or Crohn's di s eas eâ€”us ual l y t hos e wi t h ot her ext ra-i nt es t i nal mani fes t at i ons â€”a predomi nant l y l ower ext remi t y art hri t i s or t endi ni t i s occurs i n as s oci at i on wi t h fl are-ups of bowel di s eas e. The art hri t i s oft en occurs abrupt l y and us ual l y remi t s compl et el y wi t hi n weeks . There i s no as s oci at i on wi t h HLA-B27 i n t hi s peri pheral art hri t i s . Treat ment i s di rect ed at cont rol of t he bowel di s eas e, al t hough NSAIDs or l ocal or s ys t emi c cort i cos t eroi ds may hel p cont rol t he art i cul ar

Pa g e 2 3 4 1


compl ai nt s . 



(2) Spondylitis. The s pondyl i t i s of i nfl ammat ory bowel di s eas e i s as s oci at ed wi t h HLA-B27 i n about 50% of pat i ent s . The radi ographi c fi ndi ngs are t ypi cal of t hos e found i n pri mary ankyl os i ng s pondyl i t i s (i .e., s ymmet ri cal s acroi l i ac joi nt changes and, l es s commonl y, as cendi ng s ymmet ri cal s pondyl i t i s wi t hout s ki n l es i ons ). Approxi mat el y 5% of pat i ent s wi t h i nfl ammat ory bowel di s eas e devel op s acroi l i i t i s or s pondyl i t i s , but t he act i vi t y of t hes e l es i ons and t hat of t he bowel di s eas e are i ndependent of one anot her. NSAIDs us ual l y are effect i ve i n cont rol l i ng s ympt oms but can caus e i ncreas ed bowel compl ai nt s ; s omet i mes onl y nonacet yl at ed s al i cyl at es can be t ol erat ed by t hes e pat i ent s .

P.468

o

o

c. Differential diagnosis. W hi ppl e's di s eas e can be confus ed wi t h ent eropat hi c art hropat hi es , becaus e mos t pat i ent s mani fes t promi nent bowel and joi nt compl ai nt s . In fact , s acroi l i i t i s occurs i n about 20% of cas es . However, W hi ppl e's di s eas e i s qui t e rare and mos t commonl y mani fes t s i n mi ddl e-aged men as wei ght l os s , s ki n hyperpi gment at i on, l ymphadenopat hy, fever, and s ympt oms of mal abs orpt i on.

V. Crystal-Related Joint Diseases A. Gout

Pa g e 2 3 4 2






1. Definition. Gout i s a di s order of puri ne met abol i s m t hat i s charact eri zed by serum uric acid elevation (hyperuri cemi a) and urate deposition i n art i cul ar or ext ra-art i cul ar t i s s ues . El evat i on of s erum uri c aci d al one i s not s uffi ci ent for t he di agnos i s of gout ; i n fact , onl y 10% of pat i ent s wi t h hyperuri cemi a devel op gout . Some unknown fact or predi s pos es pat i ent s t o urat e depos i t i on and art i cul ar i nfl ammat i on i n t he s et t i ng of s us t ai ned hyperuri cemi a.





2. Etiologic classification of hyperuricemia. Gout i s charact eri zed by ei t her epi s odi c or cons t ant elevation of serum uric acid concent rat i on above 7 mg/dL. Pat i ent s wi t h el evat ed s erum uri c aci d can be cl as s i fi ed as overproducers or underexcreters of uri c aci d, dependi ng on t he amount of uri c aci d excret ed duri ng a 24-hour peri od. Exces s i ve di et ary i nt ake of puri nes can cont ri but e t o hyperuri cemi a i n bot h t ypes of pat i ent s . o

o

a. Overproducers, who make up approxi mat el y 10% of t he gout popul at i on, excret e more than 750â€“1000 mg uri c aci d per day on an unres t ri ct ed di et . Thes e pat i ent s s ynt hes i ze great er t han normal amount s of uri c aci d de novo from i nt ermedi at es or vi a breakdown of puri ne bas es from nucl ei c aci ds . The defect caus i ng uri c aci d overproduct i on can be primary (as s oci at ed wi t h puri ne pat hway enzymat i c defect s ) or secondary (i ncreas ed cel l t urnover as s oci at ed wi t h al cohol us e, hemat ol ogi c mal i gnanci es , chroni c hemol ys i s , or cancer chemot herapy).

o

Pa g e 2 3 4 3


o

b. Underexcreters, who cons t i t ut e approxi mat el y 90% of t he gout popul at i on, excret e less than 700 mg uri c aci d per day. 



(1) The mos t common caus es of decreas ed uri c aci d excret i on are drug effects (e.g., di uret i cs , al cohol , and l ow-dos e as pi ri n i nt erference wi t h t ubul ar handl i ng of urat e) and renal disease (e.g., chroni c renal fai l ure and l ead nephropat hy) [s ee Chapt er 6, Part I: XII B 2a]. Subt l e renal t ubul ar defect s i n urat e handl i ng al s o may be inherited and predi s pos e t o underexcret i on.





(2) Thi s group includes patients with combined defects, becaus e overproducers of uri c aci d al s o may be underexcret ers . The decreas ed renal excret i on of uri c aci d i s t he bas i s for hyperuri cemi a i n t hes e i ndi vi dual s .





(3) Mul t i pl e fact ors cont ri but e t o t he occurrence of gout i n cardiac, renal, and liver transplant recipients. Underl yi ng renal i ns uffi ci ency, us e of di uret i cs , and cycl os pori ne i mmunos uppres s i ve t herapy are t he mos t common predi s pos i ng fact ors . Affect ed pat i ent s t end t o have a rapi dl y progres s i ve form of gout wi t h t he format i on of ext ens i ve t ophi .





3. Associated conditions. The fol l owi ng condi t i ons occur more commonl y i n pat i ent s wi t h gout but are not known

Pa g e 2 3 4 4


t o be caus al . o

o

a. Obesity. Serum uri c aci d l evel ri s es wi t h body wei ght . Gout i s s i gni fi cant l y more common i n i ndi vi dual s who are more t han 15% overwei ght , part l y becaus e of decreas es i n urat e excret i on.

o

o

b. Diabetes mellitus. Impai red gl ucos e t ol erance i s common i n gout and may be a funct i on of obes i t y.

o

o

c. Hypertension. Al t hough hypert ens i on i s common i n pat i ent s wi t h gout , no i ndependent correl at i on exi s t s bet ween bl ood pres s ure and s erum uri c aci d l evel . Obes i t y probabl y i s res pons i bl e for a hi gh rat e of hypert ens i on i n pat i ent s wi t h gout .

o

o

d. Hyperlipidemias (t ypes II and IV). Increas ed pl as ma concent rat i ons of s ome l i pi ds are common i n pat i ent s wi t h gout ; however, di et , al cohol i nt ake, and body wei ght s eem t o be more i mport ant as s oci at i ons .

o

o

e. Atherosclerosis. Deat h i n pat i ent s wi t h gout i s commonl y at t ri but abl e t o cardi ovas cul ar or cerebrovas cul ar di s eas es . However, t he previ ous l y ment i oned ri s k fact ors t hat commonl y occur i n pat i ent s wi t h gout s eem t o expl ai n t he t endency for accel erat ed at herogenes i s .

P.469



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

4. Clinical stages of gout o

o

a. Asymptomatic hyperuricemia i s charact eri zed by an i ncreas ed s erum uri c aci d l evel i n t he abs ence of cl i ni cal evi dence of depos i t i on di s eas e (i .e., art hri t i s , t ophi , nephropat hy, or uri c aci d s t ones ). 



(1) Hyperuricemia. The ri s k of acut e gout y art hri t i s or nephrol i t hi as i s i ncreas es as t he s erum uri c aci d concent rat i on i ncreas es . However, mos t pat i ent s do not devel op ei t her of t hes e condi t i ons .





(2) Hyperuricosuria. The ri s k of uri c aci d s t one format i on i n pat i ent s wi t h hyperuri cemi a i s mos t cl os el y rel at ed t o a uri nary uri c aci d excret i on exceedi ng 1000 mg/day. Thes e pat i ent s al s o are at ri s k for acute obstructive uropathy, a form of acut e renal fai l ure occurri ng mos t oft en fol l owi ng combi nat i on chemot herapy for cancer. Large puri ne l oads l ead t o s udden i ncreas es i n s erum uri c aci d l evel s , wi t h s ubs equent preci pi t at i on of uri c aci d crys t al s i n t he col l ect i ng t ubul es and uret ers .

o

o

b. Acute gouty arthritis, t he s econd s t age and pri mary mani fes t at i on of gout , i s an ext remel y pai nful , acut e-ons et art hri t i s . 

Pa g e 2 3 4 6

ABC Amber CHM Converter Trial version, http://www.processtext.com/abcchm.html 

(1) T ypical patient. Mos t pat i ent s (80%â€“90%) are mi ddl e-aged or el derl y men who have had s us t ai ned as ympt omat i c hyperuri cemi a for 20â€“30 years before t he fi rs t at t ack. W omen s eem t o be s pared unt i l menopaus e, perhaps vi a an es t rogen effect on uri c aci d cl earance. Ons et of acut e gout y art hri t i s i n t he t eens or t went i es i s unus ual and mos t oft en as s oci at ed wi t h a pri mary or s econdary caus e of uri c aci d overproduct i on.





(2) T ypical attack 

(a) Presentation. A monoart i cul ar, l ower ext remi t y pres ent at i on i s mos t common wi t h 50% of pat i ent s experi enci ng t hei r fi rs t at t ack i n t he fi rs t met at ars ophal angeal (MTP) joi nt (cal l ed podagra) ( Onl i ne Fi gure 10-7). Many at t acks occur s uddenl y at ni ght , wi t h rapi d evol ut i on of joi nt eryt hema, s wel l i ng, t endernes s , and warmt h. Int ens e joi nt i nfl ammat i on can ext end i nt o t he s oft t i s s ues and mi mi c cel l ul i t i s or phl ebi t i s . Fever can occur i n s evere at t acks . 

Page 2347


ONLINE FIGURE 10-7 Gout . Podagra i s t he cl as s i c pres ent at i on of gout , i nvol vi ng eryt hema and s wel l i ng of met at ars ophal angeal joi nt . (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:9114040.) 



(b) Course. At t acks us ual l y res ol ve i n a few days , al t hough s ome can ext end over s everal weeks . The joi nt us ual l y ret urns t o normal bet ween at t acks . Pol yart i cul ar i nvol vement can occur i n s ome cas es , and a t ypi cal progres s i on from monoart i cul ar t o pol yart i cul ar i nvol vement occurs by ext ens i on t o adjacent joi nt s .





(3) Pathogenesis of acute attacks (Onl i ne Fi gure 10-8)

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ONLINE FIGURE 10-8 Pos t ul at ed pat hogenes i s of crys t al -i nduced joi nt i nfl ammat i on. Ig, i mmunogl obul i n; C3 and C4, compl ement component s C3 and C4; LP, l i poprot ei n. 



(a) Sus t ai ned hyperuri cemi a or a rapi d fl uct uat i on i n t he l evel of s erum uri c aci d (as occurs i n t he s et t i ng of dehydrat i on, rapi d rehydrat i on, or wi t h t he i ni t i at i on of uri cos uri c t herapy), may l ead t o t he devel opment of microtophi (i .e., s mal l crys t al aggregat es ) i n t he s ynovi al membrane and cart i l age.



Pa g e 2 3 4 9




(b) Through s everal mechani s ms , mi crot ophi are di s rupt ed and crys t al s are rel eas ed i nt o t he joi nt s pace. Spont aneous urat e crys t al l i zat i on can al s o occur i n condi t i ons of urat e s upers at urat i on of joi nt fl ui d. (Trauma, joi nt t emperat ure changes , and fl uct uat i ons i n s erum or s ynovi al fl ui d uri c aci d concent rat i on are pot ent i al i ni t i at ors of t hes e proces s es .)





(c) Urat e crys t al s are coat ed by immunoglobulins and complement components. Thes e adherent prot ei ns enhance phagocyt os i s by neut rophi l s .





(d) Phagos omes i n t he crys t al -cont ai ni ng neut rophi l s fus e wi t h l ys os omes , and t he l ys os omal enzymes di ges t t he prot ei n coat i ng of t he crys t al s . The naked crys t al s t hen apparent l y di s rupt t he phagos omal membranes .





(e) Neut rophi l s are damaged by t he crys t al s , and l ys os omal enzymes are rel eas ed i nt o s ynovi al fl ui d, pot ent i at i ng i nfl ammat i on.





(f) Inflammatory mediators (e.g., IL-6) can be rel eas ed from s ynovi al macrophages expos ed t o uri c aci d crys t al s and may be res pons i bl e for

Pa g e 2 3 5 0


ext ens i on of i nfl ammat i on t o ot her joi nt s and i nt o s oft t i s s ues . 



(g) Lipoproteins can ent er i nfl amed s ynovi al membranes and at t ach t o t he crys t al s , downregul at i ng t he i nfl ammat ory proces s .

o

o

c. Intercritical gout, t he t hi rd s t age of gout , i s an as ympt omat i c peri od aft er t he i ni t i al at t ack. Thi s s t age may be i nt errupt ed by new acut e at t acks . 



(1) Recurrence of monoarticular attacks. About 7% of pat i ent s never experi ence a new at t ack of acut e gout y art hri t i s aft er t he fi rs t epi s ode. However, 62% experi ence a recurrence wi t hi n 1 year. Typi cal l y, pat i ent s are as ympt omat i c bet ween at t acks , but at t acks event ual l y become more frequent and abat e more gradual l y i f urat e depos i t i on remai ns unt reat ed over t i me.





(2) Disease progression. At t acks t end t o become pol yart i cul ar and more s evere over t i me. Some pat i ent s devel op a chroni c i nfl ammat ory art hri t i s wi t hout as ympt omat i c i nt erval s â€”a condi t i on t hat may be di ffi cul t t o di s t i ngui s h from rheumat oi d art hri t i s . Tophaceous gout t ypi cal l y occurs over a 10- t o 20-year peri od of unt reat ed urat e depos i t i on.

o

o

d. Chronic tophaceous gout, whi ch devel ops i n

Pa g e 2 3 5 1


unt reat ed pat i ent s , i s t he fi nal s t age of gout . The t ophus i s a col l ect i on of urat e crys t al mas s es s urrounded by i nfl ammat ory cel l s and vari abl e fi bros i s . Tophi t end t o devel op i n areas t hat are l ower i n t emperat ure, whi ch di mi ni s hes t he s ol ubi l i t y of t he crys t al s . 



(1) T ypical locations of tophaceous deposits 



(a) The pinna of the external ear i s a pot ent i al s i t e of t ophus devel opment , al t hough depos i t i on here i s uncommon.





(b) Other common locations are t he s urfaces of chroni cal l y i nvol ved joi nt s and s ubchondral bone as wel l as ext ens or s urfaces of t he forearms , ol ecranon burs ae, and t he i nfrapat el l ar and Achi l l es t endons .





(2) Pathogenesis of tophaceous gout 



(a) Al t hough mi crot ophi may form i n joi nt s earl y i n t he urat e depos i t i on phas e, aggregat es t hat are l arge enough t o be pal pabl e or t o caus e anat omi c deformi t i es t ake years t o devel op. The rat e of t ophus format i on i s di rect l y rel at ed t o t he s everi t y and durat i on of hyperuri cemi a i n pat i ent s wi t h gout . Tophi do not occur i n pat i ent s wi t h as ympt omat i c hyperuri cemi a.

Pa g e 2 3 5 2




(b) Eros i on of cart i l age and adjacent s ubchondral bone occurs due t o di s pl acement of normal t i s s ue by t he t ophus and by t he i nfl ammat ory react i on to it.





5. Renal complications may ari s e at any s t age of gout , but nephrol i t hi as i s i s t he onl y common cl i ni cal pres ent at i on of renal i nvol vement . Prot ei nuri a and i mpai red abi l i t y t o concent rat e uri ne P.470

rel at ed t o urat e depos i t i on i n t he renal i nt ers t i t i um have been des cri bed i n gout pat i ent s (s ee Chapt er 6, Part I: XII B 3). 



6. Diagnosis o

o

a. Acute gouty arthritisâ€”laboratory findings 



(1) Serum findings. The s erum uri c aci d val ue oft en i s not hel pful i n t he cl i ni cal di agnos i s of acut e gout . Serum uri c aci d concent rat i on i s normal i n at l eas t 10% of pat i ent s at t he t i me of an acut e at t ack, and an el evat ed s erum uri c aci d l evel i s not s peci fi c for acut e gout .





(2) Synovial fluid findings. The demons t rat i on of urate crystals, es peci al l y i nt racel l ul ar crys t al s , i n s ynovi al fl ui d i s

Pa g e 2 3 5 3


di agnos t i c. Thes e crystals characteristically are needle-shaped and negatively birefringent i n red-compens at ed, pol ari z ed l i ght , and t hey may be pres ent i n neut rophi l s duri ng an acut e at t ack. Synovi al fl ui d whi t e bl ood cel l (W BC) count s of 3

10,000â€“60,000/mm (predomi nant l y neut rophi l s ) al s o are common i n acut e at t acks . o

o

b. Chronic tophaceous gout 



(1) Physical appearance. Tophi are fi rm, movabl e, and cream-col ored or yel l owi s h i f s uperfi ci al l y l ocat ed. If t hey ul cerat e, a chal ky mat eri al i s ext ruded.





(2) Radiographic findings. Tophaceous depos i t s appear as wel l -defi ned, l arge eros i ons (punched-out eros i ons ) of t he s ubchondral bone. Thes e eros i ons are mos t common at t he fi rs t MTP joi nt and at t he bas es and heads of phal anges ; however, any art i cul at i on can be affect ed. Typi cal gout y eros i ons have an overhanging edge of s ubchondral new bone format i on. Peri art i cul ar os t eopeni a i s abs ent .





(3) Aspiration. Tophi can be as pi rat ed and crys t al s demons t rat ed by pol ari zed mi cros copy.



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7. T herapy. In al l s t ages of gout , s econdary caus es of hyperuri cemi a (e.g., medi cat i ons , obes i t y, exces s di et ary puri ne i nt ake, al cohol i nt ake, ot her di s eas e) s houl d be al t ered i f pos s i bl e. o

o

a. Asymptomatic hyperuricemia. In general , pat i ent s wi t hout evi dence of urat e depos i t i on do not requi re t reat ment ot her t han correct i on of underl yi ng caus es . Pat i ent s wi t h uri c aci d el evat i ons t hat chroni cal l y exceed 10 mg/dL have a great er t han 90% chance of developi ng acut e gout at s ome t i me, but mos t phys i ci ans wai t for an acut e at t ack t o begi n t reat ment .

o

o

b. Acute gouty arthritis. Drug t reat ment of t he acut e at t ack i s mos t effect i ve when s t art ed very earl y aft er s ympt oms begi n. As wi t h any i nfl ammat ory art hri t i s , res t or i mmobi l i zat i on of t he i nvol ved joi nt i s an i mport ant adjunct t o t reat ment . 



(1) Colchicine, whi ch i nhi bi t s neut rophi l chemot axi s and i nfl ammat ory medi at or rel eas e by s uppres s i ng phos phol i pas e A 2 , has been us ed i nt ravenous l y t o t reat acut e at t acks . However, i t i s rarel y us ed t oday, as i t has been as s oci at ed wi t h i rrevers i bl e bone marrow s uppres s i on. Caut i on i s neces s ary i n el derl y pat i ent s and i n t hos e wi t h renal or hepat i c i mpai rment due t o i ncreas ed bone marrow t oxi ci t y and neuromyot oxi ci t y. Col chi ci ne can be us ed oral l y for acut e at t acks , but naus ea, vomi t i ng, and di arrhea oft en appear before t herapy i s s ucces s ful , s o t hat NSAIDs and

Pa g e 2 3 5 5


cort i cos t eroi ds are us ual l y preferred. 



(2) NSAIDs oft en are us ed i n hi gh but qui ckl y t apered dos es t o t reat acut e at t acks . Any of t hes e agent s can be us ed, al t hough drugs t hat affect uri c aci d cl earance (e.g., s al i cyl at es , di fl uni s al ) s houl d be avoi ded, becaus e any fl uct uat i on i n s erum urat e can prol ong acut e at t acks . Caut i on i s warrant ed when us i ng NSAIDs i n t he pres ence of gas t roi nt es t i nal , hepat i c, or renal di s eas e. Indomet haci n, i f t ol erat ed, appears t o be t he mos t acut el y effi caci ous agent .





(3) Corticosteroids, oral and i nt ra-art i cul ar, can be us ed t o t reat acut e at t acks , part i cul arl y when NSAIDs are cont rai ndi cat ed.





(4) Drugs that alter serum uric acid concentrations (e.g., allopurinol, probenecid ) s houl d be avoi ded duri ng acut e at t acks becaus e rai s i ng or l oweri ng s erum uri c aci d can prol ong at t acks . In pat i ent s al ready t aki ng s uch drugs , t he dos age s houl d not be al t ered.

o

o

c. Intercritical gout. Prophyl act i c t reat ment wi t h s mal l dos es of col chi ci ne (0.6 mg once or t wi ce dai l y) or s mal l dos es of an NSAID can be us ed t o fores t al l new at t acks .

o

o

d. Chronic or tophaceous gout. Therapy for

Pa g e 2 3 5 6


chroni c gout cent ers on cont rol of hyperuri cemi a. Drugs t hat i ncreas e renal uri c aci d excret i on (uri cos uri c drugs ) or t hat decreas e uri c aci d product i on (xant hi ne oxi das e i nhi bi t ors ) are avai l abl e. The ai m of t hi s t reat ment i s t o reduce s erum urat e bel ow 6 mg/dL, t o al l ow reduct i on i n s erum s upers at urat i on by urat e and P.471

mobi l i zat i on of t i s s ue uri c aci d depos i t s . Pat i ent s who have had a recent acut e at t ack s houl d recei ve l ow-dos e col chi ci ne or an NSAID t o prevent new at t acks caus ed by fl uct uat i on i n s erum urat e. 



(1) Uricosuric drugs (e.g., probenecid, sulfinpyrazone) can be us ed i n pat i ent s who excret e l es s t han 700 mg uri c aci d dai l y, who have normal renal funct i on, and who have no hi s t ory of uri nary s t ones .





(2) Xanthine oxidase inhibitors i ncl ude allopurinol, whi ch i s an anal og of hypoxant hi ne. Thi s drug i nhi bi t s de novo uri c aci d s ynt hes i s and compet i t i vel y i nhi bi t s xant hi ne oxi das e vi a enzymat i c convers i on t o oxypuri nol . Inhi bi t i on of uri c aci d s ynt hes i s wi t h xant hi ne oxi das e i nhi bi t ors i s preferred i n pat i ent s wi t h urat e excret i on great er t han 1000 mg/day, creat i ni ne cl earance l es s t han 30 mL/mi nut e, t ophaceous gout , or a hi s t ory of nephrol i t hi as i s . Dos ages are reduced i n t he pres ence of renal fai l ure t o avoi d t oxi ci t y. The mos t common s i de effect s of al l opuri nol are

Pa g e 2 3 5 7


dys peps i a, di arrhea, and ras h, whi ch occur i n 3%â€“10% of pat i ent s . A ful l -bl own hypers ens i t i vi t y s yndrome can occur rarel y, wi t h a mort al i t y rat e around 20%â€“30%. 



(3) Import ant t reat ment i s s ues : 



(a) It i s i mport ant t o us e col chi ci ne, NSAIDs , or s t eroi ds whi l e i ns t i t ut i ng al l opuri nol t herapy t o avoi d an acut e at t ack of gout i nduced by fl uct uat i on i n s erum urat e l evel s .





(b) Can us e col chi ci ne chroni cal l y i n pat i ent s unabl e t o t ol erat e al l opuri nol .





(c) Beware of us e of col chi ci ne i n pat i ent s wi t h renal i ns uffi ci ency, becaus e s ecret i on i s reduced and s evere t oxi ci t y may occur.





(d) May us e chroni c l ow-dos e s t eroi d t reat ment i n pat i ent s wi t h chroni c gout and chroni c renal i ns uffi ci ency.

B. Calcium pyrophosphate dihydrate (CPPD) deposition disease 



1. Definition. Depos i t i on of CPPD crys t al s i n cart i l age and peri art i cul ar connect i ve t i s s ues can caus e a gamut

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of art i cul ar mani fes t at i ons , rangi ng from as ympt omat i c depos i t i on t o acut e and chroni c i nfl ammat ory art hri t i s . The acut e form of CPPD depos i t i on di s eas e i s commonl y cal l ed pseudogout. 



2. Etiologic classification o

o

a. Hereditary CPPD disease. A hi gh preval ence of CPPD di s eas e has been not ed i n many fami l i es , wi t h aut os omal domi nant t rans mi s s i on t he t ypi cal pat t ern. Secondary met abol i c as s oci at i ons wi t h CPPD di s eas e t ypi cal l y are not pres ent i n t hes e fami l i es .

o

o

b. Osteoarthritis. Chondrocal ci nos i s and CPPD crys t al s can occur as a res ul t of s evere os t eoart hri t i s . CPPD di s eas e al s o can caus e os t eoart hri t i s by damagi ng cart i l age.

o

o

c. CPPD disease associated with metabolic disorders. Correct i on of underl yi ng met abol i c di s orders , i f pos s i bl e, does not s eem t o al t er t he progres s i on of CPPD di s eas e. CPPD di s eas e occurs at a hi gher-t han-expect ed frequency i n as s oci at i on wi t h cert ai n di s eas es and condi t i ons . Pot ent i al abnormal i t i es of cal ci um, phos phorus , or cart i l age met abol i s m can expl ai n t he as s oci at i ons , whi ch i ncl ude: 



(1) Hyperparat hyroi di s m

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Pa g e 2 3 5 9


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(2) Hemochromat os i s

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(3) Hypot hyroi di s m

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(4) Hypophos phat as i a

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(5) Hypomagnes emi a

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(6) W i l s on's di s eas e





3. Pathogenesis (s ee Onl i ne Fi gure 10-8) o

a.

Crystal deposition 



(1) Site. The i ni t i al s i t e of CPPD depos i t i on appears t o be art i cul ar cart i l age s urroundi ng l acunae i n t he mi dzone. Lat er, depos i t i on occurs i n cl eft s of degenerat ed cart i l age and i n s cat t ered foci i n t he cart i l age mat ri x and s ynovi al membrane, event ual l y formi ng l arge crys t al l i ne mas s es .





(2) Process. An al t erat i on of cart i l age ground s ubs t ance, t he i oni c compos i t i on of t he mat ri x (i .e., cal ci um and pyrophos phat e), or a combi nat i on of bot h i s requi red for crys t al l i zat i on. Pos s i bl y, an al t ered condi t i on of t he mat ri x (e.g., removal of an i nhi bi t i ng agent or addi t i on of a nucl eat i ng agent )

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al l ows crys t al s t o form i n t he mi croenvi ronment around t he chondrocyt e as pyrophos phat e i s rel eas ed from t he cel l . A cel l s urface ect oenzyme, nucl eos i de t ri phos phat e pyrophos phohydrol as e (NTP-PPH), generat es pyrophos phat e i n t he proces s of s cavengi ng ext racel l ul ar adenos i ne t ri phos phat e (ATP); t he i ncreas ed energy requi rement of great er prot eogl ycan s ynt hes i s i n os t eoart hri t i s t hus may l ead t o CPPD product i on. o

b.

Crystal-mediated joint damage. CPPD depos i t s s t i ffen t he

cart i l age, i mpai ri ng i t s wei ght -beari ng propert i es and accel erat i ng os t eoart hri t i c change. The acut e art hri t i c at t acks are bel i eved t o be i nduced by t he rel eas e of crys t al s from t he cart i l age i nt o t he joi nt s pace. 



(1) Factors mediating crystal release 



(a) Matrix loosening. CPPD crys t al s i n cart i l age exi s t i n equi l i bri um wi t h s ynovi al fl ui d cal ci um and pyrophos phat e concent rat i ons . Decreas es i n s erum cal ci um concent rat i on can l ead t o decreas es i n s ynovi al fl ui d pyrophos phat e l evel s and s ol ubi l i zat i on of joi nt CPPD crys t al s as equi l i bri um i s res t ored. Los s of margi nal CPPD depos i t s may caus e t he ent i re depos i t t o l oos en i n t he mat ri x, wi t h s ubs equent rel eas e of abundant CPPD crys t al s i nt o t he joi nt s pace. Thus , fl uct uat i ons of s erum cal ci um concent rat i on i n t he s et t i ng of acut e medi cal i l l nes s or duri ng t he

Pa g e 2 3 6 1


peri operat i ve peri od may i ni t i at e acut e crys t al rel eas e. 



(b) Loss of matrix. Enzymat i c eros i on of cart i l age due t o an as s oci at ed i nfl ammat ory art hri t i s (e.g., i nfect i ous art hri t i s ) al s o may caus e crys t al rel eas e.





(c) Biomechanical forces. Impai red di s s i pat i on of wei ght -beari ng forces on cart i l age al s o may l ead t o crys t al l oos eni ng and rel eas e i nt o t he joi nt s pace.





(2) Factors affecting acute attacks 



(a) Inflammatory response. Neut rophi l s are at t ract ed t o crys t al s coat ed wi t h IgG, compl ement , fi bronect i n, fi bri nogen, or ki ni nogen. Crys t al s are i nges t ed, caus i ng t he rel eas e of i nfl ammat ory medi at ors s uch as pros t agl andi ns and col l agenas e.





(b) Degree of response. CPPD crys t al s are s omewhat l es s i nfl ammat ory t han urat e crys t al s . General l y, fewer are rel eas ed i n t he acut e at t ack, t he crys t al s ads orb i nfl ammat ory prot ei ns l es s wel l , and CPPD crys t al s are not membranol yt i c.

o

Pa g e 2 3 6 2


4. Clinical syndromes 



a. Pseudogout account s for 25% of cas es of CPPD di s eas e. Acut e s wel l i ng, pai n, s t i ffnes s , and eryt hema devel op i n previ ous l y as ympt omat i c joi nt s . The knee i s mos t commonl y i nvol ved (50% of cas es ), but al mos t any s ynovi al joi nt , i ncl udi ng t he fi rs t MTP joi nt , can be i nvol ved. Spread t o adjacent joi nt s can occur, and preci pi t at i on of at t acks by acut e medi cal or s urgi cal i l l nes s i s P.472

common, occurri ng i n 10%â€“20% of cas es . Sys t emi c fi ndi ngs s uch as fever and l eukocyt os i s may be pres ent , es peci al l y i n el derl y pat i ent s . Joi nt s t ypi cal l y ret urn t o normal bet ween at t acks . 



b. Pseudoâ€“rheumatoid arthritis account s for 5% of cas es of CPPD di s eas e. In s ome pat i ent s , a s mol deri ng chroni c art hropat hy can occur. Subacut e epi s odes of pai n and s wel l i ng i n one or more joi nt s can be s uperi mpos ed on a more chroni c pi ct ure of prol onged morni ng s t i ffnes s , fat i gue, s ynovi al t hi ckeni ng, and progres s i ve deformi t i es .





c. Pseudo-osteoarthritis account s for 50% of cas es of CPPD di s eas e. Affect ed pat i ent s pres ent wi t h a cl i ni cal and radi ographi c pi ct ure s i mi l ar t o t hat of degenerat i ve joi nt di s eas e, al t hough about hal f have

Pa g e 2 3 6 3


s uperi mpos ed acut e at t acks of ps eudogout . Fl exi on cont ract ures are more common t han i n t ypi cal os t eoart hri t i s , and bi l at eral knee varus deformi t i es or i s ol at ed pat el l ofemoral art hri t i s may occur more commonl y t han i n os t eoart hri t i s . A s mal l percent age of t hes e pat i ent s may have s uch s evere joi nt des t ruct i on (e.g., of t he s houl ders or knees ) t hat t he cl i ni cal and radi ographi c appearance i s t hat of a neuropathic joint disorder, even i n t he abs ence of underl yi ng neurol ogi c di s eas e or apparent propri ocept i ve defi ci t . 



d. Asymptomatic CPPD di s eas e occurs i n 20% of cas es . Thes e pat i ent s do not have joi nt pai n; t he di s eas e t ypi cal l y i s uncovered by t he fi ndi ng of as ympt omat i c chondrocal ci nos i s on radi ography. The preval ence of t hi s as ympt omat i c di s eas e, as wel l as ot her cl i ni cal l y evi dent forms of CPPD di s eas e, i ncreas es wi t h age.

o

o

5. Diagnosis. The fi ndi ng of t ypi cal crys t al s on s ynovi al fl ui d anal ys i s i s di agnos t i c of ps eudogout . Chondrocal ci nos i s s een on radi ography i s evi dence for a di agnos i s of CPPD depos i t i on. However, chondrocal ci nos i s may be pres ent i n pat i ent s who never devel op acut e ps eudogout . 



a. Synovial fluid findings. Chunky, rhomboi d crystals that exhibit weakly positive birefringence i n red-compens at ed, pol ari z ed l i ght are t he hal l mark of t he acut e art hri t i s

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s yndromes as s oci at ed wi t h CPPD di s eas e. Thes e may be i nt racel l ul ar (i n neut rophi l s ) or ext racel l ul ar, but t hey us ual l y are much l es s preval ent t han i n a t ypi cal gout -i nvol ved joi nt . Synovi al fl ui d l eukocyt os i s of 3

10,000â€“20,000 cel l s /mm (mos t l y neut rophi l s ) i s t ypi cal . 



b. Radiographic findings 



(1) Chondrocalcinosis. Cal ci fi cat i on of art i cul ar hyal i ne cart i l age, fi brocart i l age (mos t commonl y i n t he knee meni s ci , i nt ervert ebral di s k annul i , s ymphys i s pubi s , and wri s t t ri angul ar fi brocart i l age), s ynovi al membrane, t endons , and burs ae can occur, us ual l y i n a s t i ppl ed, l i near fas hi on.

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(2) Osteoarthritis. Os t eoart hri t i c changes i n at ypi cal joi nt s (e.g., wri s t , el bow, and s houl der and MCP joi nt s ) s ugges t CPPD di s eas e. Subchondral bone cys t s may be more ext ens i ve i n radi ographs of joi nt s affect ed by CPPD di s eas e, and hook-s haped os t eophyt es charact eri s t i cal l y are pres ent wi t h MCP i nvol vement .

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(3) Pseudoneuropathic joint. Radi ographi c fi ndi ngs t ypi cal of neuropat hi c joi nt di s orders , i ncl udi ng ext reme joi nt di s organi zat i on and bone

Pa g e 2 3 6 5


fragment s , can be found i n s evere cas es of CPPD di s eas e. 



c. When to suspect CPPD 



(1) Clinical or radiographic evidence of osteoarthritis i n joi nt s not us ual l y i nvol ved by os t eoart hri t i s s houl d s ugges t CPPD di s eas e as an al t ernat i ve di agnos i s .

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(2) Attacks of acute inflammatory arthritis i n a s et t i ng of apparent os t eoart hri t i s s houl d s ugges t CPPD di s eas e.

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(3) Acute arthritis occurring shortly after a medical illness or surgical procedure s houl d s ugges t a crys t al -medi at ed art hri t i s s uch as gout or ps eudogout .

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(4) Radiographic changes more typical of osteoarthritis i n pat i ent s t hought t o have rheumat oi d art hri t i s s houl d s ugges t CPPD di s eas e as an al t ernat i ve di agnos i s .

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(5) The presence of diseases commonly associated with CPPD disease (e.g., hyperparat hyroi di s m,

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hemochromat os i s ) s houl d s ugges t CPPD di s eas e as a pos s i bl e caus e of any joi nt mani fes t at i ons . In peopl e younger t han 55 years of age, or i n t hos e wi t h recurrent , pol yart i cul ar di s eas e, an as s oci at ed met abol i c di s eas e i s more l i kel y. In t hes e pat i ent s , det ermi nat i ons of cal ci um, magnes i um, al kal i ne phos phat as e, cerul opl as mi n, and ferri t i n l evel s as wel l as l i ver and t hyroi d funct i on t es t s s houl d be cons i dered. 

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(6) Neuropathic joint presentations s houl d prompt i nves t i gat i on for CPPD di s eas e as wel l as pot ent i al l y as s oci at ed neurol ogi c di s orders .

P.473

o

o

6. T herapy 



a. Acute attacks. Typi cal t reat ment i nvol ves as pi rat i on of i nfl ammat ory joi nt fl ui d, i nt ra-art i cul ar i nject i on of cort i cos t eroi d, and us e of NSAIDs .



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b. Prophylaxis. No cl earl y effect i ve regi men i s avai l abl e, al t hough NSAIDs and, rarel y, l ow-dos e col chi ci ne are us ed.

C. Hydroxyapatite arthritis Hydroxyapat i t e crys t al s , t he t ypi cal compl exed form of cal ci um i n

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bone, al s o can caus e s everal rheumat i c s yndromes . 



1. Clinical syndromes o

o

a. Crystal deposition in osteoarthritis. Mi neral format i on i n cart i l age may be a res ul t of abnormal cart i l age met abol i s m i n more s evere forms of os t eoart hri t i s . Joi nt effus i ons i n t hes e pat i ent s cont ai n crys t al s of hydroxyapat i t e as oft en as t hey cont ai n CPPD crys t al s .

o

o

b. Calcific periarthritis. Hydroxyapat i t e depos i t i on i n burs ae and t endon s heat hs can caus e epi s odes of acut e i nfl ammat i on (i .e., peri art hri t i s and peri t endi ni t i s ), wi t h acut e at t acks of pai n, s wel l i ng, and eryt hema. Di s cret e cl umped depos i t s can be found radi ographi cal l y around t he s houl ders , great er t rochant ers , wri s t s , el bows , and di gi t s and i n ot her peri art i cul ar areas . Thes e depos i t s can be s hown t o di s i nt egrat e gradual l y on radi ographs t aken s everal weeks aft er t he acut e peri art hri t i s .

o

o

c. Destructive arthritis. Hydroxyapat i t e crys t al s can be as s oci at ed wi t h a chroni c des t ruct i ve art hropat hy, whi ch i s charact eri zed by eros i ve radi ographi c changes , l arge (us ual l y noni nfl ammat ory) effus i ons , prol i ferat i ve s ynovi t i s , s ynovi al mi neral depos i t i on, and peri art i cul ar l i gament ous i ns t abi l i t y. Thi s s yndrome occurs mos t oft en i n t he knee and s houl der (â€œ Milwaukee shoulderâ€•) of el derl y pat i ent s . Synovi al fl ui d 3

anal ys i s s hows few W BCs (500â€“1000/mm ), wi t h

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monocyt es predomi nat i ng. Hi gh concent rat i ons of neut ral prot eas es and col l agenas es s omet i mes are pres ent . 



2. Diagnosis. Li ght mi cros copi c exami nat i on of s ynovi al fl ui d occas i onal l y reveal s browni s h gl obul es t hat are l arge cl umps of hydroxyapat i t e crys t al s . Is ol at ed crys t al s are t oo s mal l t o be s een wi t h ordi nary l i ght or pol ari zed l i ght mi cros copy. A cal ci um s t ai n, alizarin red S, can be us ed as a s creeni ng t es t for t he pres ence of hydroxyapat i t e or CPPD crys t al s i n effus i ons . As pi rat es from burs ae or t endon s heat hs may yi el d mi l ky or pas t y mat eri al t hat cont ai ns hi gh concent rat i ons of t hes e hydroxyapat i t e crys t al s .

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3. Associated conditions. Di s orders of cal ci um and phos phorous met abol i s m s houl d be s ought i f mul t i pl e depos i t s are found.

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4. T herapy. Mechani cal s pl i nt i ng and NSAIDs are us ed t o t reat acut e epi s odes of peri art hri t i s . NSAIDs oft en are us ed i n t he chroni c hydroxyapat i t e art hropat hy as wel l . Peri odi c as pi rat i on of t he l arge s ynovi al effus i ons t hat occur i n t he Mi l waukee s houl der may hel p pres erve l i gament ous i nt egri t y and remove des t ruct i ve enz ymes . Cort i cos t eroi d i nject i ons may hel p t reat acut el y s ympt omat i c joi nt s .

VI. Osteoarthritis A. Definition Os t eoart hri t i s i s t radi t i onal l y defi ned as a noni nfl ammat ory joi nt di s order charact eri zed by det eri orat i on of art i cul ar cart i l age and format i on of new bone at t he joi nt s urfaces and margi ns . Emergi ng

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evi dence recogni zes t he i mport ance of bi omechani cal , bi ochemi cal , and cyt oki ne-medi at ed changes i n t he pat hogenes i s of os t eoart hri t i s .

B. Etiology Bot h s ys t emi c and l ocal fact ors cont ri but e t o t he devel opment of os t eoart hri t i s . Sys t emi c fact ors i ncl ude age, s ex, genet i cs , bone dens i t y, and nut ri t i onal el ement s , whi ch may make t he cart i l age more vul nerabl e t o i njury and l es s effi ci ent at repai r. Local bi omechani cal component s , i n combi nat i on wi t h s ys t emi c fact ors , have a s ynergi s t i c effect on t he proces s of cart i l age breakdown. 



1. Age. The preval ence and i nci dence of os t eoart hri t i s i n al l joi nt s correl at es wi t h i ncreas i ng age. Agi ng i s as s oci at ed wi t h t he fol l owi ng changes : o

o

a. Decreas ed res pons i venes s of chondrocyt es t o growt h fact ors t hat s t i mul at e repai r

o

o

b. Increas ed l axi t y of l i gament s , whi ch makes t he joi nt s more uns t abl e and s us cept i bl e t o i njury P.474

o

o

c. Fai l ure of s hock abs orbers or prot ect ors of t he joi nt , whi ch i ncl udes decreas es i n mus cl e s t rengt h and neurol ogi c res pons es

o

o

d. Devel opment of a t hi nner ri m of noncal ci fi ed cart i l age, whi ch l eads t o an i ncreas ed s hear s t res s at t he bas al cart i l age l evel

Pa g e 2 3 7 0




2. Race. No cl ear raci al predi l ect i on has been document ed.





3. Sex. Gender appears t o be part i cul arl y i mport ant i n t he devel opment of erosive osteoarthritis of t he DIP and PIP joi nt s . Thi s vari ant i s 10 t i mes more common i n women t han men; i t i s aut os omal domi nant i n women and reces s i ve i n men.





4. Genetics. Res earchers have di s covered a defect i n t he gene codi ng for type II collagen synthesis, whi ch al l ows for earl y degenerat i on of t he t ype II col l agen. The pres ence of t hi s abnormal gene i s as s oci at ed wi t h a t ype of premat ure pol yart i cul ar os t eoart hri t i s and mi l d epi phys eal dys pl as i a s een i n s everal fami l i es .





5. Inflammation. Des pi t e t he noni nfl ammat ory nat ure of t he s ynovi al membrane and s ynovi al fl ui d i n os t eoart hri t i s , evi dence i ndi cat es t hat i nfl ammat ory medi at ors produced by s ynovi al t i s s ues and cart i l age pl ay a s i gni fi cant rol e. Cyt oki nes s uch as IL-1 as wel l as ot her i nfl ammat ory medi at ors s uch as ni t ri c oxi de and pros t agl andi ns are i mport ant i n t he aut odes t ruct i ve proces s es t hat promot e cart i l age degenerat i on. Thes e medi at ors , s eques t ered wi t hi n avas cul ar and aneural hyal i ne cart i l age, do not provoke t he cl as s i cal s i gns of i nfl ammat i on.

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

6. Obesity and abnormal stresses. An as s oci at i on exi s t s bet ween obes i t y and os t eoart hri t i s of t he knee, but i nt eres t i ngl y, t he s ame as s oci at i on does not exi s t

Pa g e 2 3 7 1


wi t h os t eoart hri t i s of t he hi p. Abnormal mechani cal l oadi ng cont ri but es t o di s eas e progres s i on by al t eri ng t he met abol i s m of os t eocyt es wi t hi n s ubchondral bone and chondrocyt es wi t hi n art i cul ar cart i l age. In addi t i on, abnormal bi omechani cal forces can i ncreas e t he expres s i on of mechanores pons i ve genes , wi t h t he res ul t ant rel eas e of prot eol yt i c enzymes , growt h fact ors , and medi at ors . 



7. Neuropathy. Mus cl e t one around a joi nt modul at es t he forces of joi nt i mpact l oadi ng. If propri ocept i ve i nput t o t he joi nt i s i mpai red, abnormal mus cl e t one may res ul t i n os t eoart hri t i s by t rans ferri ng abnormal forces t o t he joi nt .





8. Deposition diseases (e.g., hemochromat os i s , ochronos i s , W i l s on's di s eas e, crys t al depos i t i on di s eas es ). Thes e condi t i ons , whi ch caus e depos i t i on of s ubs t ances i n t he cart i l age mat ri x, can res ul t i n di rect chondrocyt e i njury and premat ure os t eoart hri t i s .

C. Pathogenesis Os t eoart hri t i s i s a met abol i cal l y act i ve condi t i on, not a degenerat i ve one. Repai r and s ynt hes i s count eract t he des t ruct i ve proces s es unt i l t he repai r proces s es are overwhel med l at e i n t he di s eas e cours e. 



1. Initial insult. Chondrocyt es i n hyal i ne cart i l age are res pons i bl e for mai nt ai ni ng t he ext racel l ul ar mat ri x by bal anci ng cat abol i c and anabol i c funct i ons . Synt hes i s of t he mat ri x i s s ynchroni zed wi t h t hei r degradat i on by prot eol yt i c enzymes . Two fact ors may cont ri but e t o t he i ni t i at i on of os t eoart hri t i s . o

Pa g e 2 3 7 2


o

a. A regi on of hi ghl y focal mechani cal s t res s

o

o

b. An i nt ri ns i c defect i n t he cart i l age mat ri x, as s i ngl e-bas e mut at i on i n t he t ype II procol l agen gene (COL2A1) renders col l agen fi bri l s prone t o fragment at i on and t hus earl y os t eoart hri t i s (s ee VI B 4)





2. Progression o

o

a. Early. Synt hes i s of prot eogl ycan and col l agen i s i ncreas ed, wi t h s ome degree of degradat i on.

o

o

b. Late. As os t eoart hri t i s devel ops furt her, prot eogl ycan s ynt hes i s decreas es , res ul t i ng i n a net l os s of mat ri x prot ei n. St ruct ural changes i n t he prot eogl ycan mol ecul es i ncl ude degradat i on of t he core prot ei n, reduct i on i n t he s i ze of t he prot eogl ycan aggregat es , and reduct i on i n t he hyal uroni c aci d cont ent . In addi t i on, s ynt hes i s of di fferent col l agen gene product s , whi ch al t er t he col l agen fi ber net work, charact eri zes t hi s l at e phas e.



3.

Factors involved o

o

a. Proteolytic enzymes. Chondrocyt es s ecret e degradat i ve enzymes (e.g., met al l oprot ei nas es ). Met al l oprot ei nas e act i vi t y i s cont rol l ed by i nhi bi t ors and act i vat ors . In os t eoart hri t i s , t he product i on of met al l oprot ei nas es exceeds t he

Pa g e 2 3 7 3


amount of s o-cal l ed t i s s ue i nhi bi t ors of met al l oprot ei nas e (TIMPs ). o

o

b. Cytokines and inflammatory mediators 



(1) Catabolic: IL-1, IL-6, and IL-8; TNF; ni t ri c oxi de; and pros t agl andi n E 2 (PGE 2 ). IL-1 s t i mul at es t he product i on of prot eas es whi l e s uppres s i ng t he s ynt hes i s of prot eogl ycan and t ype II col l agen. In addi t i on, IL-1 i nduces chondrocyt e product i on of ot her det ri ment al cyt oki nes as wel l as ni t ri c oxi de and PGE 2 .





(2) Anabolic: growt h fact ors s uch as TGF-Î² and i ns ul i n-l i ke growt h fact or (IGF-1). TGF-Î² ant agoni zes t he act i on of IL-1, and IGF-1 i s t he major regul at or of prot eogl ycan s ynt hes i s .

D. Pathology 



1. Cartilage changes o

o

a. Earl y i n os t eoart hri t i s , cart i l age changes i n color from bl ue t o yel l ow due t o l os s of prot eogl ycan.

o

o

b. Local i zed areas of softening are t he earl i es t pat hol ogi c changes i n os t eoart hri t i s .

o

o

c. Superfi ci al chipping and flaking of cart i l age

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s i gni fi es more advanced di s eas e. o

o

d. Vert i cal fibrillations i n t he cart i l age i ndi cat e furt her progres s i on.

o

o

e. If t he heal i ng forces are overwhel med by des t ruct i ve forces , confl uent erosions event ual l y progres s t o ful l -t hi cknes s cart i l age l os s .





2. Bone changes o

o

a. New bone formation can occur under t he cart i l age (s een as eburnat i on on a radi ograph) or at t he joi nt margi n (s een as os t eophyt i c s purs on a radi ograph).

o

o

b. Subchondral cysts. Large ps eudocys t i c areas can form i n t he juxt a-art i cul ar bone due t o t rans mi s s i on of i ncreas ed mechani cal forces t o bone; pres umabl y, t hes e cys t s fai l t o heal becaus e of i mpai red perfus i on from s ubchondral mi crofract ures .

E. Classification (Table 10-10) 



1. Primary osteoarthritis has no underl yi ng caus e for joi nt damage. It t ypi cal l y i nvol ves t he DIP and PIP joi nt s and t he fi rs t carpomet acarpal joi nt s . Knees , hi ps , and fi rs t MTP joi nt s oft en are i nvol ved as wel l as cervi cal and l umbar s pi ne facet joi nt s . The joi nt i nvol vement may be generalized or i t may occur i n an

Pa g e 2 3 7 5


i s ol at ed, sporadic fas hi on. Erosive os t eoart hri t i s i s a uni que s ubs et t hat occurs predomi nant l y i n mi ddl e-aged women and has aut os omal domi nant , s ex-i nfl uenced charact eri s t i cs . Epi s odi c eryt hema, s wel l i ng, and t endernes s occur i n i nvol ved joi nt s , es peci al l y t he DIP and PIP joi nt s of t he hands . Charact eri s t i c radi ographi c abnormal i t i es i ncl ude bone eros i ons and ankyl os i s , whi ch are unus ual i n t ypi cal os t eoart hri t i s . Diffuse idiopathic skeletal hyperostosis i s noni nfl ammat ory axi al and peri pheral ent hes i s hyperos t os i s mani fes t ed by radi ographi c â€œwhi s keri ngâ€• at t endon or l i gament i ns ert i on and fl owi ng os t eophyt es adjacent t o vert ebral di s ks . 



2. Secondary osteoarthritis exhi bi t s an underl yi ng caus e for degenerat i ve joi nt di s eas e and may i nvol ve joi nt s not t ypi cal l y affect ed by pri mary os t eoart hri t i s (e.g., el bow, wri s t ). A pri mary met abol i c, i nfl ammat ory, or mechani cal proces s l eads s econdari l y t o os t eoart hri t i s (s ee Tabl e 10-10). P.475

TABLE 10-10 Classification of Osteoarthritis

Pa g e 2 3 7 6


Pri ma ry ost eo art hri tis (m ulti ple sit es) He ber de n's no des Ge ner al i z ed os t eo art hri t is â€ œE ros i ve â€ • os t

Pa g e 2 3 7 7


eo art hri t is Di f fus e i di op at h ic s ke l et al hyp ero sto sis Pri ma ry ost eo art hri tis (lo cal ) Cer vi c al s pi ne Hi p

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Fi r st car po me t ac arp al joi nt Di s t al i nt erp hal an ge al joi nt s Lu mb ar s pi ne Kn ee Fi r st me t at ars op hal an

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ge al joi nt Pro xi m al i nt erp hal an ge al joi nt s Se co nd ary ost eo art hri tis Co ng eni t al (e. g., hi p dys pl a sia )

Pa g e 2 3 8 0


De pos itio n di s eas e Oc hro nos is W il s on 's di s eas e He mo chr om at o sis Go ut Cal ci u m pyr op

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hos ph at e de pos itio n di s eas e Ne uro pat hi c joi nt (e. g., di a bet es me llit us , s yp hi l i s) En doc ri n e/ me t ab ol i c (e.

Pa g e 2 3 8 2


g., acr om eg al y ) Os t eo nec ros is (es pec i al l y hi p s, kne es ) Inf ect i on (t u ber cul os i s) Infl am ma tio n (rh eu ma

Pa g e 2 3 8 3


t oi d art hri t is)

F. Clinical features 



1. Symptoms vary wi t h t he joi nt i nvol ved and t he s everi t y of t he di s eas e. o

o

a. Pain. Mos t pat i ent s experi ence t he gradual ons et of a deep, achi ng pai n, whi ch wors ens wi t h act i vi t y and i s rel i eved by res t . W i t h more s evere di s eas e, pai n can occur even at res t and i nt erfere wi t h s l eep.

o

o

b. Morning stiffness i s bri ef (1000/mm ) and severe myalgia found i n t he abs ence of ot her pos s i bl e caus es . Vari abl e feat ures i ncl ude s ki n ras hes and i ndurat i on, i nt ers t i t i al pul monary i nfi l t rat es , and pol yneuropat hy. El evat i on of mus cl e enzymes [al dol as e, not creat i ne ki nas e (CK)] and hepat i c enzymes al s o can occur.

H. Therapy 



1. General. Di s eas e expres s i on i n i ndi vi dual pat i ent s i s ext remel y het erogenous . Speci fi c t herapy s houl d focus on ext ent of organ damage and rat e of progres s i on of di s eas e.





2. Specific disease features o

o

a. Skin involvement. D-Peni ci l l ami ne and col chi ci ne are l argel y s el ect i ve t herapi es of t he pas t . Mycophenolate mofetil and methotrexate may be us eful i n rapi dl y progres s i ng s ki n di s eas e.

o

o

b. Raynaud' s phenomenon. Pat i ent s s houl d unders t and t he need t o cover t hei r head, ears , hands , feet , and t runk i n col d weat her t o mi ni mi ze refl ex vas ocons t ri ct i on, and s moki ng s houl d be di s couraged. Calcium channel blocking agents are us eful vas odi l at i ng agent s i n t he t reat ment of s cl eroderma. Pat i ent s s houl d avoi d nons el ect i ve

Pa g e 2 4 7 5


Î²-bl ockers t hat can al s o cont ri but e t o vas ocons t ri ct i on. Intravenous prostaglandin infusions (epopros t enol ) have been us ed wi t h s ucces s for t reat i ng refract ory vas os pas t i c epi s odes and for heal i ng s ki n ul cerat i ons . o

o

c. Esophageal involvement. Refl ux es ophagi t i s , oft en s evere, requi res t he us e of prot on-pump i nhi bi t ors (e.g., omepraz ol e, l ans oprazol e). Ant i refl ux meas ures (e.g., head-of-bed el evat i on, frequent s mal l feedi ngs ) are hel pful as wel l .

o

o

d. Pulmonary involvement. For i nt ers t i t i al pul monary di s eas e, dai l y oral cyclophosphamide may be t he mos t effect i ve t herapy for al veol i t i s and progres s i ve pul monary fi bros i s . Tobacco s moki ng may be s ynergi s t i c i n pul monary i njury. Treat ment for t he pri mary pul monary hypert ens i on-l i ke s yndrome i ncl ude t he endot hel i n-1 recept or ant agoni s t , bos ent an; t he phos phodi es t eras e-5 i nhi bi t or, s i l denafi l ; and vari ous pros t agl andi n anal ogs (e.g., i l opros t , epopros t enol ). Ant i coagul at i on i n combi nat i on wi t h vas odi l at ors i mproves s urvi val , whi ch probabl y rel at es t o t he hi gh i nci dence of i n s i t u mi crot hrombi or pul monary embol i .

o

o

e. Lower gastrointestinal involvement. Bact eri al overgrowt h mal abs orpt i on may be i mproved by i nt ermi t t ent t reat ment wi t h broad-spectrum antibiotics (e.g., t et racycl i ne). Prokinetic agents (e.g., oct reot i de, ci s apri de) hel p cons t i pat i on and bl oat i ng rel at ed t o l ower gas t roi nt es t i nal mot i l i t y

Pa g e 2 4 7 6


dys funct i on. P.491

o

o

f. Muscle involvement. W hen i nfl ammat ory myos i t i s occurs i n overl ap s yndromes , corticosteroids are us ed, as i n pol ymyos i t i s . Met hot rexat e may be hel pful i n t reat i ng myos i t i s and joi nt di s eas e. NSAIDs may be us ed i n t reat i ng art i cul ar s ympt oms , as wel l , t aki ng care t o moni t or renal funct i on cl os el y.

o

o

g. Renal involvement. Aggres s i ve cont rol of hypert ens i on i s bes t . The angiotensin-converting enzyme (ACE) inhibitors (e.g., capt opri l and enal apri l ) are major advances i n cont rol l i ng bl ood pres s ure i n pat i ent s wi t h s cl eroderma and may hel p revers e t he angi ot ens i n-dependent vas ocons t ri ct i ve s t at e of s cl eroderma renal cri s i s . The avoi dance of hypovol emi a i n di ures i s and i n t he peri operat i ve s t at e i s i mport ant .

o

o

h. Cardiac involvement. Medi cat i ons us eful for cont rol of angi na, CHF, and arrhyt hmi as are us ed when t hes e compl i cat i ons occur.

X. Inflammatory Myopathies (Polymyositis and Dermatomyositis) A. Definition Pol ymyos i t i s i s an i di opat hi c i nfl ammat ory mus cl e di s eas e as s oci at ed wi t h promi nent proxi mal mus cl e weaknes s , mus cl e

Pa g e 2 4 7 7


enz yme el evat i ons , charact eri s t i c myopat hi c el ect romyogram (EMG) pat t erns , and i nfl ammat ory i nfi l t rat es on mus cl e bi ops y. W hen t hi s compl ex i s accompani ed by a charact eri s t i c ras h i t i s cal l ed dermatomyositis. Dermat omyos i t i s i s much more common t han pol ymyos i t i s i n chi l dren.

B. Epidemiology Pol ymyos i t i s i s a rare di s eas e, occurri ng i n approxi mat el y 1 i n 200,000 i ndi vi dual s , wi t h a peak i nci dence i n chi l dhood and i n l at e adul t hood. It i s t wi ce as common i n femal es as i n mal es and may be as s oci at ed wi t h mal i gnancy i n t he adul t -ons et form.

C. Etiology The bas i c caus e of pol ymyos i t i s i s unknown. However, i t i s bel i eved t hat an i ni t i at i ng vi ral i nfect i on and al t ered i mmune res pons es are pot ent i al l y i mport ant i n caus at i on and pat hogenes i s . Lymphocyt e-medi at ed mus cl e cel l damage i s t hought t o be t he cent ral pat hogenet i c fact or i n t hi s di s eas e, al t hough s mal l ves s el damage i s al s o an i mport ant fact or i n dermat omyos i t i s . 



1. Infections can caus e acut e myos i t i s . o

o

a. Elevated titers of antibodies to picornaviruses (e.g., coxs acki evi rus B) have been found i n s ome juveni l e dermat omyos i t i s pat i ent s , and hi gh t i t ers of ant i bodi es t o T oxopl as ma gondi i have been found i n s ome adul t pol ymyos i t i s pat i ent s .

o

o

b. Is ol at i on of t hes e organi s ms from mus cl e of pat i ent s wi t h pol ymyos i t i s or dermat omyos i t i s has not been accompl i s hed, and ant i bi ot i c t reat ment for t oxopl as mos i s has not i mproved myos i t i s i n pat i ent s wi t h hi gh t i t ers of ant i body t o T . gondi i .



Pa g e 2 4 7 8




2. Autoimmunity o

o

a. Humoral. Mos t pat i ent s wi t h i nfl ammat ory myopat hi es demons t rat e aut oant i bodi es when human t umor cel l l i nes [i .e., human epi t hel i al cel l s (HEp-2)] are us ed as t es t i ng s ubs t rat e, but i t i s not known whet her t hes e ant i bodi es i nt erfere wi t h t he normal phys i ol ogi c funct i on of t hei r ant i gens . Molecular mimicry may be i mport ant i n pol ymyos i t i s /dermat omyos i t i s , becaus e aut oant i bodi es di rect ed agai ns t t RNA s ynt het as es are found i n s ome pat i ent s , perhaps res ul t i ng from mi mi cry bet ween a vi rus and an epi t ope on t he i nt racel l ul ar enzyme. Vas cul ar depos i t s of i mmune compl exes and compl ement are as s oci at ed wi t h endot hel i al cel l i njury and s mal l ves s el obs t ruct i on i n dermat omyos i t i s , es peci al l y i n juveni l e dermat omyos i t i s .

o

o

b. Cellular 



(1) Polymyositis. Peri pheral bl ood l ymphocyt es from pol ymyos i t i s pat i ent s produce a l ymphot oxi n t hat i s cyt ot oxi c t o +

mus cl e cel l s . In addi t i on, cyt ot oxi c CD8 T cel l s are t he predomi nant cel l t ype found i n t he i nfl ammat ory i nfi l t rat e i n mus cl e, apparent l y at t acki ng mus cl e cel l s expres s i ng i ncreas ed numbers of cl as s I MHC-res t ri ct ed markers . 



(2) Dermatomyositis. Some s t udi es s ugges t

Pa g e 2 4 7 9

ABC Ambe r CHM Conve rte r Tria l ve rsion, http://w w w .proce sste x t.com/a bcchm.html +

t hat CD4 T cel l s and B cel l s are predomi nant i n dermat omyos i t i s i nfi l t rat es , i n cont ras t t o +

t he predomi nant l y CD8 T-cel l i nfi l t rat es i n pol ymyos i t i s . Perhaps humoral mechani s ms are rel at i vel y more i mport ant i n dermat omyos i t i s t han i n pol ymyos i t i s .

D. Pathology The major s i t es of i nfl ammat i on are s kel et al mus cl e and, l es s commonl y, cardi ac mus cl e. Ski n i nvol vement i s a mi nor pat hol ogi c feat ure. 



1. Inflammatory infiltrate. Lymphocyt es and pl as ma cel l s are t he predomi nant i nfl ammat ory cel l s , al t hough macrophages , eos i nophi l s , and neut rophi l s al s o can be +

s een i n mus cl e t i s s ue. CD8 cel l s i nfi l t rat e mus cl e fi bers +

i n pol ymyos i t i s . In dermat omyos i t i s , CD4 cel l s and B cel l s oft en are cl us t ered around s mal l bl ood ves s el s wi t hi n t he mus cl e. 



2. Muscle fiber damage. Spot t y mus cl e fi ber necros i s and degenerat i on occur, wi t h l os s of cros s s t ri at i ons and vari at i on i n t he s i ze of s urvi vi ng fi bers . Increas ed numbers of mus cl e nucl ei and enhanced bas ophi l i c s t ai ni ng of fi bers i ndi cat e regenerat i on i n t he mi ds t of cel l deat h. Int ers t i t i al fi brot i c i nfi l t rat es occur i n chroni c cas es .

E. Clinical features and laboratory findings Infl ammat ory myopat hi es are cl i ni cal l y grouped i nt o s peci fi c s yndromes , dependi ng on s peci fi c organ mani fes t at i ons and res ul t s of l aborat ory t es t s . 



1. Organ involvement

Pa g e 2 4 8 0


o

a. Skin. The ras h of dermat omyos i t i s cons i s t s of eryt hemat ous pat ches , whi ch s omet i mes are s cal i ng or at rophi c and are di s t ri but ed over t he face, neck, upper ches t , and ext ens or s urfaces . Onl y s cat t ered i nfl ammat ory i nfi l t rat es i n t he dermi s are evi dent on bi ops y. 

(1) Pat hognomoni c s ki n fi ndi ngs i ncl ude heliotrope rash (a vi ol et di s col orat i on and s wel l i ng of t he eyel i ds ) and Gottron' s sign (heaped-up eryt hemat ous papul es over t he MCP or PIP joi nt s ) (Onl i ne Fi gure 10-12). 

ONLINE FIGURE 10-12 Dermat omyos i t i s . Thi s pat i ent has a hel i ot rope ras h i nvol vi ng t he eyel i ds . (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:9109010) 

(2) Ot her s i gni fi cant fi ndi ngs i ncl ude mechanic' s hands (roughened eryt hemat ous s ki n and hypert rophi c changes of t he pal ms and fi ngers ) as wel l as t he eryt hemat ous V sign (ant eri or ches t ) and shawl sign (neck and upper back)

(Onl i ne Fi gure

Pa g e 2 4 8 1


10-13). 

P.492



ONLINE FIGURE 10-13 Dermat omyos i t i s . â€œMechani c's hands â€• i s charact eri s t i c of t hi s di s order. Demons t rat ed i s t he cracki ng of t he fi nger pads . (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:9109060.) o

o

b. Lung. Chroni c i nt ers t i t i al l ung di s eas e can occur, es peci al l y i n as s oci at i on wi t h ant i s ynt het as e ant i bodi es . As pi rat i on pneumoni t i s and vent i l at ory i ns uffi ci ency al s o can occur [See d (1) bel ow].

o

o

c. Joint. A mi l d, s ymmet ri cal i nfl ammat ory art hri t i s occurs uncommonl y and rarel y i s des t ruct i ve; i t i s s een mos t oft en i n pat i ent s wi t h t he s ynt het as e ant i bodi es [s ee X E 2 b (2) (a)].

o

o

d. Muscle. Mos t pat i ent s have gradual but s t eady progres s i on of mus cl e weaknes s ; however, s ome

Pa g e 2 4 8 2


pat i ent s have s uch ful mi nant cours es t hat acute respiratory failure or myoglobinuric renal failure can ens ue. 



(1) Skeletal muscle weakness i s t he pri mary mani fes t at i on of pol ymyos i t i s . 



(a) Symmetrical, proximal, and upper and lower extremity weakness occurs , caus i ng di ffi cul t y wi t h ri s i ng from a chai r, s i t t i ng up i n bed, or combi ng hai r.





(b) Pharyngeal muscle involvement can l ead t o s wal l owi ng di ffi cul t i es and as pi rat i on, and res pi rat ory mus cl e dys funct i on can l ead t o res pi rat ory fai l ure.





(2) Cardiac muscle involvement i s not as common, but when i t occurs i t mani fes t s as cardi omyopat hy wi t h CHF, arrhyt hmi as , and conduct i on di s t urbances .





2. Laboratory findings o

o

a. Muscle enzymes. An i ncreas ed concent rat i on of enzymes t ypi cal l y pres ent i n s kel et al mus cl e i s promi nent i n pol ymyos i t i s . CK and aldolase are rout i nel y meas ured, and CK fract i onat i on may s ugges t myocardi al i nvol vement i f t he MB fraction (i .e., t he CK i s oenzyme found mai nl y i n

Pa g e 2 4 8 3


myocardi um but al s o i n regenerat i ng s kel et al mus cl e) i s i ncreas ed. However, i n mos t pat i ent s , CK el evat i on i s caus ed by t he MM band (i .e., t he fract i on mos t preval ent i n s kel et al mus cl e). Serum myoglobin l evel s are al s o el evat ed i n mos t pat i ent s and may be more s ens i t i ve t han CK l evel s i n s ome myos i t i s pat i ent s . Enzyme el evat i ons us ual l y correl at e wi t h act i vi t y of t he mus cl e di s eas e and are us ed as a paramet er t o eval uat e t reat ment res pons e. o

o

b. Autoantibodies. Mos t pat i ent s wi t h pol ymyos i t i s /dermat omyos i t i s (80%â€“90%) have ant i bodi es t o nucl ear or cyt opl as mi c ant i gens . Rout i ne ANA t es t i ng agai ns t HEp-2 cel l s i s performed; ot her myos i t i s -s peci fi c ant i bodi es requi re s peci al i zed t es t i ng (e.g., i mmunopreci pi t at i on). 



(1) Nonspecific autoantibodies. ANAs , part i cul arl y speckled-pattern ANAs, are t he mos t common aut oant i bodi es i n t he i nfl ammat ory myopat hi es , occurri ng i n more t han 50% of pat i ent s . Ot her ant i bodi es al s o can be s een, i ncl udi ng Ro antibodies, La antibodies, PM/Scl antibodies, and Ku antibodies.





(2) Specific autoantibodies. Several aut oant i bodi es are formed onl y i n i nfl ammat ory myopat hi es ; t hey t arget cyt opl as mi c or nucl ear cons t i t uent s of myocyt es . The appearance of t hes e

Pa g e 2 4 8 4


ant i bodi es , whi ch s eem t o correl at e wi t h cl i ni cal pat t erns of i nvol vement , may be more us eful i n cl as s i fyi ng pat i ent s . 



(a) Synthetase antibodies (anti-aminoacylâ€“tRNA synthetases) are di rect ed agai ns t cyt opl as mi c enzymes i nvol ved i n s peci fi c ami no aci d at t achment t o t RNA. Jo-1 antibody, found i n 20% of myos i t i s pat i ent s , i s t he mos t common, di rect ed agai ns t hi s t i dyl â€“t RNA s ynt het as e. Pat i ent s wi t h t hes e ant i bodi es may be cons i dered t o have t he â€œant i s ynt het as e s yndrome,â€• whi ch i s as s oci at ed wi t h DR3 and DRw52 hapl ot ypes . Thi s condi t i on, whi ch us ual l y occurs i n t he s pri ng, i s charact eri zed by acut e ons et of art hri t i s , i nt ers t i t i al l ung di s eas e, fever, mechani c hands , and Raynaud's phenomenon. Affect ed pat i ent s have a 5-year s urvi val rat e of 70%.





(b) Signal recognition particle antibodies (SRP antibodies) recogni ze one of t he component s of t he SRP, a cyt opl as mi c prot ei n compl ex i nvol ved i n pol ypept i de t rans fer acros s t he endopl as mi c ret i cul um. Immunogenet i c dat a i ndi cat e a DR5 and DRw52 as s oci at i on. Pat i ent s t end t o have an acut e ons et of s evere myal gi a and s i gni fi cant cardi ac probl ems s uch as pal pi t at i ons . Prognos i s i s very poor, wi t h

Pa g e 2 4 8 5


a 5-year s urvi val rat e of onl y 25%. 



(c) Mi-2 antibodies t arget a nucl ear prot ei n of unknown funct i on, i n cont ras t t o t he cyt opl as mi c prot ei ns of t he ot her myos i t i s -s peci fi c ant i bodi es . Thi s ant i body pat t ern i s found i n pat i ent s wi t h cl as s i c dermat omyos i t i s . The 5-year s urvi val i s nearl y 100%.





3. Clinical syndromes. The t radi t i onal cl as s i fi cat i on s cheme i s gi ven bel ow. o

o

a. Polymyositis. Charact eri s t i c feat ures i ncl ude upper and l ower ext remi t y proxi mal mus cul ar weaknes s and el evat ed mus cl e enzymes . Al l organ mani fes t at i ons l i s t ed i n X E 1 can occur, except t he s ki n fi ndi ngs . Pat i ent s wi t h pol ymyos i t i s t end t o have di s eas e t hat i s l es s res pons i ve P.493

t han dermat omyos i t i s t o t herapy. The t reat ment -res i s t ant , acut el y s evere di s eas e i s oft en as s oci at ed wi t h cardi ac mus cl e i nvol vement , a fi ndi ng more promi nent i n pat i ent s wi t h SRP antibodies. Pat i ent s wi t h pol ymyos i t i s who have PM/Scl antibodies t end t o do rel at i vel y wel l . o

o

b. Dermatomyositis. Charact eri s t i c feat ures i ncl ude t he mus cl e weaknes s , el evat ed mus cl e enzymes , and organ mani fes t at i ons s een i n pol ymyos i t i s , but t he di s t i nct feat ure of t hi s

Pa g e 2 4 8 6


s yndrome i s t he pres ence of skin involvement. In general , dermat omyos i t i s pat i ent s res pond reas onabl y wel l t o t herapy. o

o

c. Polymyositis or dermatomyositis associated with malignancy. Vi s ceral mal i gnanci es occur i n approxi mat el y 10%â€“25% of cas es , es peci al l y i n el derl y i ndi vi dual s wi t h l at e-ons et i nfl ammat ory myopat hy. The i nci dence of mal i gnancy i s t hought t o be hi gher i n pat i ent s wi t h dermat omyos i t i s t han i n t hos e wi t h pol ymyos i t i s . The mos t common mal i gnanci es are t hos e t hat are t ypi cal i n mi ddl e-aged or el derl y i ndi vi dual s (i .e., cancers of t he l ung, gas t roi nt es t i nal t ract , breas t , ut erus , and ovari es ). Removal of t he mal i gnancy occas i onal l y res ul t s i n remi s s i on of t he mus cl e di s eas e, but t he prognos i s i n general for t hes e pat i ent s i s poor; t hey di e of t hei r mal i gnancy or uncont rol l abl e mus cl e di s eas e.

o

o

d. Juvenile dermatomyositis. Mos t chi l dren have dermat omyos i t i s rat her t han pol ymyos i t i s . Lat e i n t he di s eas e cours e, young pat i ent s may devel op mus cl e cont ract ures from cal ci fi c depos i t s i n t he chroni cal l y damaged mus cl e. A wi des pread s mal l art ery and capi l l ary vas cul i t i s may l ead t o s ki n, mus cl e, and bowel i s chemi c l es i ons . Ot herwi s e, prognos i s i s s i mi l ar t o t hat i n adul t forms of i nfl ammat ory myopat hy.

o

o

e. Overlap syndromes. Mus cl e di s eas e t hat i s i dent i cal t o pol ymyos i t i s can occur i n SLE, rheumat oi d art hri t i s , s ys t emi c s cl eros i s , and

Pa g e 2 4 8 7


SjÃ¶gren's s yndrome. Pat i ent s oft en have mi l der mus cl e di s eas e t hat i s res pons i ve t o t herapy, and prognos i s i s det ermi ned by t he feat ures of t he underl yi ng di s eas e more t han t he mus cl e fi ndi ngs . o

o

f. Inclusion body myositis. Thi s s yndrome i s cons i dered a s ubs et of i nfl ammat ory myopat hi es +

becaus e of t he as s oci at ed CD8 -cel l cyt ot oxi ci t y di rect ed agai ns t mus cl e fi bers . The s yndrome t ends t o affect older men and has a gradual di s eas e ons et and progres s i on. Al t hough pat i ent s have mus cl e weaknes s , CK el evat i ons , and myopat hi c EMGs , t hey are di s t i ngui s hed from t ypi cal pol ymyos i t i s pat i ent s by havi ng distal as well as proximal weakness, t ypi cal absence of autoantibodies, and a characteristic muscle biopsy s howi ng vacuol ar changes and di s t i nct i ve el ect ron mi cros copi c fi ndi ngs . The cl i ni cal feat ures oft en are poorl y res pons i ve t o i mmunos uppres s i ve t herapy, but pat i ent s have an excel l ent 5-year s urvi val rat e becaus e of t he s l ow progres s i on of t he di s eas e.

F. Diagnosis 



1. Approach o

o

a. Distinctive muscle findings. A cl i ni cal di agnos i s of i nfl ammat ory myopat hy t ypi cal l y i s cons i dered when pat i ent s pres ent wi t h proximal muscle weakness or increased muscle enzymes (e.g., CK, al dol as e). True proxi mal mus cl e weaknes s mus t be di s t i ngui s hed from general i zed fat i gue, di s t al

Pa g e 2 4 8 8


weaknes s more t ypi cal of neuropat hy, and pai n-rel at ed weaknes s (i .e., joi nt or t endon pai n t hat prevent s ful l mus cl e cont ract i on). Pat i ent s wi t h t rue proxi mal mus cl e weaknes s compl ai n of bei ng unabl e t o comb t hei r hai r or t o ri s e from a s quat t i ng or s i t t i ng pos i t i on. If t rue proxi mal weaknes s appears l i kel y from t he hi s t ory and phys i cal exami nat i on, CK t es t i ng i s performed and EMG and bi ops y of s ympt omat i c del t oi d or quadri ceps mus cl e s houl d be cons i dered. MRI may al s o be us eful i n l ocal i zi ng t he bes t bi ops y s i t e. The di agnos i s of pol ymyos i t i s i s l i kel y i f a pat i ent has t hree of t he fol l owi ng mus cl e cri t eri a: 



(1) Charact eri s t i c proxi mal mus cl e weaknes s





(2) Infl ammat ory cel l i nfi l t rat e and myofi bri l degenerat i on on mus cl e bi ops y





(3) Increas ed mus cl e enzyme l evel s





(4) Myopat hi c EMG changes

o

o

b. Supportive findings 



(1) The characteristic skin findings, i f found, are s upport i ve evi dence and s omet i mes precede cl i ni cal evi dence of mus cl e i nvol vement .



Pa g e 2 4 8 9


(2) Becaus e 90% of pol ymyos i t i s pat i ent s have aut oant i bodi es when t hei r s erum i s t es t ed agai ns t HEp-2 cel l s , t he pres ence of a pos i t i ve t es t for aut oant i bodi es al s o i s s upport i ve evi dence for t he di s eas e, part i cul arl y i f a myositis-specific antibody i s found.

P.494





2. Consideration of malignancy. A s earch for a mal i gnancy i s warrant ed i n mi ddl e-aged or el derl y pol ymyos i t i s /dermat omyos i t i s pat i ent s . Thorough phys i cal exami nat i on, i ncl udi ng a careful pel vi c eval uat i on i n women, ches t radi ograph, rout i ne hemat ol ogi c and bi ochemi cal t es t i ng, uri nal ys i s , and s t ool t es t i ng for occul t bl ood s houl d be performed. Abnormal i t i es found s houl d be purs ued t hrough addi t i onal t es t i ng.





3. Differential diagnosis. Ot her ent i t i es s houl d be cons i dered i n maki ng a di agnos i s of i nfl ammat ory myopat hy, es peci al l y when t he pres ent at i on i s s omewhat at ypi cal . Some di s orders can be el i mi nat ed on cl i ni cal grounds ; ot hers requi re l aborat ory t es t i ng, EMG, or mus cl e bi ops y. o

o

a. Endocrine disorders 



(1) Hypothyroidism can mani fes t as proxi mal mus cl e achi ng, weaknes s , and mi l d-t o-moderat e CK el evat i on.

Pa g e 2 4 9 0




(2) Hyperthyroidism can mani fes t as di ffus e weaknes s ; CK l evel s t ypi cal l y are normal .





(3) Patients with Cushing' s syndrome may have l ower more t han upper ext remi t y proxi mal mus cl e weaknes s ; mus cl e enzymes are normal .

o

o

b. Drugs. Numerous drugs and t oxi ns can caus e mus cl e weaknes s and s omet i mes CK el evat i on; t hes e effect s us ual l y res ol ve when t he agent i s removed. Some of t he mos t common of t hes e agent s i ncl ude al cohol , chol es t erol -l oweri ng drugs (e.g., cl ofi brat e, gemfi broz i l , and l ovas t at i n), col chi ci ne, chl oroqui ne, cort i cos t eroi ds , D-peni ci l l ami ne, and zi dovudi ne.

o

o

c. Muscle diseases. Mus cul ar dys t rophi es and met abol i c mus cl e di s eas es can be di s t i ngui s hed by careful fami l y hi s t ory, di s t i ngui s hi ng pat t erns of weaknes s , and l ack of i nfl ammat i on on mus cl e bi ops y. Some requi re exerci s e t es t i ng wi t h venous l act at e det ermi nat i ons or el ect ron mi cros copi c exami nat i on of mus cl e.

o

o

d. Neurologic diseases. Earl y i n t he di s eas e cours e, i l l nes s es s uch as myas t heni a gravi s or amyot rophi c l at eral s cl eros i s (ALS) can mi mi c i nfl ammat ory myopat hy. The pres ence of ocul ar mus cl e i nvol vement or charact eri s t i c EMG or nerve conduct i on vel oci t y (NCV) fi ndi ngs can hel p i n

Pa g e 2 4 9 1


di agnos i ng t hes e di s eas es . o

o

e. Infections 



(1) Bacterial. Some cas es of Lyme di s eas e are as s oci at ed wi t h myopat hy.





(2) Viral. Acut e and conval es cent s erol ogi es can di s t i ngui s h vi ral i l l nes s . Common caus es i ncl ude coxs acki evi rus , echovi rus , i nfl uenz a vi rus , and HIV.





(3) Parasitic. Serol ogi c t es t i ng can hel p di s t i ngui s h t oxopl as mos i s or t ri chi nos i s from pol ymyos i t i s .

o

o

f. Sarcoidosis. Infl ammat ory mus cl e i nvol vement , whi ch can be di s t i ngui s hed by charact eri s t i c organ i nvol vement and fi ndi ng noncas eat i ng granul omas on mus cl e bi ops y, may occur.

G. Therapy 



1. Corticosteroids. Large dos es of cort i cos t eroi ds appear t o be effect i ve i n cont rol l i ng t he mus cl e di s eas e i n mos t pat i ent s . Predni s one us ual l y i s begun at a dos e of 60 mg/day and i s reduced gradual l y over s everal mont hs as mus cl e s t rengt h i mproves and CK l evel fal l s . Al t ernat e-day regi mens can be us ed t o prevent s t eroi d t oxi ci t y, but onl y aft er t he normal i zat i on of CK l evel and ret urn of mus cl e s t rengt h.

Pa g e 2 4 9 2




2. Immunosuppressive agents. Pat i ent s who do not res pond t o t he previ ous l y ment i oned cort i cos t eroi d s chedul es wi t hi n 3 mont hs are cons i dered t o be nonres ponders t o t reat ment . Frequent l y, t he addi t i on of met hot rexat e or az at hi opri ne al l ows cont rol of t he mus cl e di s eas e and gradual t aperi ng of t he s t eroi ds . The +

CD4 cel l -s peci fi c drug cycl os pori ne al s o has been effect i ve i n s ome pat i ent s who do not res pond t o general i mmunos uppres s i on. Tacrol i mus and mycophenol at e mofet i l may be effect i ve i n t reat i ng i nt ers t i t i al di s eas e and mus cl e i nfl ammat i on. 



3. Physical therapy. W hen t he di s eas e proces s has been cl i ni cal l y cont rol l ed (i .e., CK l evel s normal i zed and mus cl e s t rengt h i mproved), mus cl e s t rengt heni ng exerci s e and aerobi c t rai ni ng can be i ni t i at ed. Mi l d exerci s e and pas s i ve s t ret chi ng t o prevent cont ract ures s houl d be us ed i n act i ve di s eas e.





4. Hydroxychloroquine. Thi s agent may hel p cont rol t he ras h of dermat omyos i t i s . P.495





5. Intravenous immunoglobulin. Thi s agent has been hel pful i n s ome s t eroi d-res i s t ant pat i ent s and i n pat i ent s pres ent i ng wi t h earl y, s evere di s eas e i ncl udi ng res pi rat ory i nvol vement /res pi rat ory fai l ure.

XI. SjÃ¶gren's Syndrome (SS) A. Definition

Pa g e 2 4 9 3


SjÃ¶gren's s yndrome (al s o cal l ed sicca syndrome) i s an i di opat hi c, aut oi mmune di s order charact eri zed by dry mout h (xerostomia) and dry eyes (keratoconjunctivitis sicca). Vari abl e lacrimal or salivary gland enlargement can occur (rel at ed t o l ymphocyt i c i nfi l t rat i on of l acri mal and s al i vary gl ands ).

B. Classification SjÃ¶gren's s yndrome i s di vi ded i nt o pri mary and s econdary forms . The t wo forms can be di s t i ngui s hed on t he bas i s of cl i ni cal feat ures and HLA as s oci at i ons . 



1. Primary SjÃ¶gren' s syndrome has charact eri s t i c organ and exocri ne gl andul ar feat ures and a s i gni fi cant l y i ncreas ed as s oci at i on wi t h HLA-DR3. Pat i ent s can pres ent wi t h a vari et y of cl i ni cal mani fes t at i ons t hat are uncommon i n t he s econdary form, mai nl y due t o a wi der at t ack on exocri ne gl ands i n t he pri mary form. Speci fi c organ i nvol vement i s as fol l ows : o

o

a. Skin: dry s ki n and vagi na, Raynaud's phenomenon, and purpura (vas cul i t i s )

o

o

b. Lung: recurrent i nfect i ons and i nt ers t i t i al fi bros i s

o

o

c. Gastrointestinal tract: angul ar chei l i t i s , oral candi di as i s , beefy red t ongue, recurrent parot i t i s , dys phagi a, at rophi c gas t ri t i s , chroni c act i ve hepat i t i s , bi l i ary ci rrhos i s , and pancreat i t i s

o

o

d. Kidney: renal t ubul ar aci dos i s and i nt ers t i t i al nephri t i s

Pa g e 2 4 9 4


o

e. Muscle: i ndol ent myos i t i s

o

o

f. Nerve: CNS i nvol vement (pos s i bl y vas cul i t i s , wi t h cl i ni cal mani fes t at i ons s i mi l ar t o CNS l upus ) and peri pheral neuropat hy

o

o

g. Hematologic system: s pl enomegal y wi t h neut ropeni a, l ymphomas , and ps eudol ymphomas

o

o

h. Joint: art hral gi as or mi l d i nfl ammat ory art hri t i s

o

o

i. Endocrine system: chroni c t hyroi di t i s [i ncreas ed t hyroi d-s t i mul at i ng hormone (TSH) l evel s and ant i t hyroi d ant i bodi es , perhaps i n as many as 50% of pat i ent s ]

o

o

j. Vasculitis (pol yart eri t i s -l i ke)





2. Secondary SjÃ¶gren' s syndrome occurs i n t he s et t i ng of anot her rheumat i c di s eas e (e.g., rheumat oi d art hri t i s , SLE, and s cl eroderma) and has an i ncreas ed as s oci at i on wi t h HLA-DR4. Pat i ent s us ual l y have s ympt oms t hat are l i mi t ed t o l acri mal and s al i vary gl and abnormal i t i es , al t hough t hey al s o have t ypi cal feat ures of a pri mary rheumat i c di s eas e.

C. Diagnosis 

Pa g e 2 4 9 5


1. Clinical approach. Pat i ent s are mos t commonl y eval uat ed for SjÃ¶gren's s yndrome when t hey have compl ai nt s of dry eyes, dry mouth, or salivary gland enlargement. Pri mary SjÃ¶gren's s yndrome al s o s houl d be cons i dered i n t he s et t i ng of cutaneous vasculitis (purpura), CNS dysfunction s i mi l ar t o t hat whi ch occurs i n SLE (ei t her focal neurol ogi c abnormal i t i es or di ffus e feat ures s uch as depres s i on, ps ychos i s , or cogni t i ve dys funct i on), or t he cons pi cuous pres ence of ot her cl i ni cal feat ures l i s t ed i n XI B 1. o

o

a. Compl ai nt s of gritty eyes and dry mouth can be i nves t i gat ed i n t he fol l owi ng way: 



(1) Ophthalmologic slit-lamp examination wi t h fl uores cei n or Ros e Bengal s t ai ni ng can be us ed t o exami ne for t he punct at e s t ai ni ng of kerat oconjunct i vi t i s . The Schirmer test, whi ch meas ures t he degree of t ear wet t i ng on fi l t er paper, i s a s upport i ve t es t ; l i mi t ed wet t i ng s ugges t s t hat kerat oconjunct i vi t i s found on s t ai ni ng i s s i cca-rel at ed.





(2) Lip biopsy of t he l ower l i p mucos a can be us ed t o s earch for charact eri s t i c l ymphocyt i c i nfi l t rat i on of t he mi nor s al i vary gl ands i n t hat l ocat i on.

o

o

b. Salivary gland enlargement can be eval uat ed wi t h an MRI of t he parot i d gl and. A nonhomogeneous dens i t y, whi ch can be di s t i ngui s hed from parot i t i s , t umor, and normal gl andul ar t i s s ue, may be evi dent .

Pa g e 2 4 9 6


o

c. Salivary flow rate tests (sialometry) and radiographic studies (sialography) are s ens i t i ve but nons peci fi c t es t s and are not oft en us ed.

o

o

d. Many laboratory abnormalities occur and may offer s ugges t i ve evi dence; however, no s peci fi c l aborat ory t es t i s di agnos t i c. P.496





(1) T ests suggesting chronic inflammation. Anemi a of chroni c di s eas e, el evat ed ESR, hypergammagl obul i nemi a, and rheumat oi d fact or oft en are found i n SjÃ¶gren's s yndrome, whet her pri mary or s econdary.





(2) Autoantibody findings. ANAs are s een frequent l y i n SjÃ¶gren's s yndrome; ant i bodi es t o t he s mal l RNA prot ei n Ro are found i n 70% of pat i ent s and ant i bodi es t o t he prot ei n La are found i n 40% of pat i ent s . La ant i bodi es rarel y are found wi t hout Ro ant i bodi es , and t he pres ence of bot h i s rel at i vel y s peci fi c for SjÃ¶gren's s yndrome. Sal i vary duct ant i bodi es are common onl y i n t he s econdary form.






Pa g e 2 4 9 7


a. Salivary gland enlargement al s o may be caus ed by a l ymphoi d or parot i d gl and neopl as m, granul omat ous i nfi l t rat i on (s arcoi dos i s ), al cohol us e, ci rrhos i s , s t arvat i on, di abet es , amyl oi dos i s , graft -vers us -hos t di s eas e (GVHD), hyperl i pi demi as , or i nfect i on (e.g., bact eri al i nfect i ons , mumps , HIV).

o

o

b. Dry mouth may be caus ed by t he us e of cert ai n drugs , i ncl udi ng t ri cycl i c ant i depres s ant s , phenot hi azi nes , and ant i hi s t ami nes .

o

o

c. Dry mouth and dry eyes are common i n t he geri at ri c popul at i on, and t hey oft en are pres ent wi t hout any ot her feat ures of SjÃ¶gren's s yndrome.

D. Therapy 



1. General considerations o

o

a. Scrupulous oral hygiene i s i mport ant t o prevent rampant dent al cari es .

o

o

b. Pat i ent s wi t h pri mary SjÃ¶gren's s yndrome who demons t rat e s al i vary gl and or l ymphoi d t i s s ue enl argement mus t be cons i dered at risk for lymphoma, becaus e non-Hodgki n's l ymphomas occur at 40 t i mes t he normal rat e i n t hes e pat i ent s .





2. Symptomatic treatment

Pa g e 2 4 9 8


o

a. Xerostomia. Avoi dance of drugs t hat dry out t he mout h and frequent dri nks of wat er or ot her l i qui ds t o keep t he mout h wet are t he us ual s ympt omat i c meas ures for t hi s condi t i on. Art i fi ci al s al i vas are commerci al l y avai l abl e, whi ch may hel p wi t h mout h wet t i ng and prevent i on of dent al cari es . Pi l ocarpi ne hydrochl ori de, a chol i nergi c agoni s t , i s avai l abl e for oral us e and can i ncreas e s ecret i on by t he exocri ne gl ands i ncreas i ng s al i vary fl ow.

o

o

b. Keratoconjunctivitis sicca. Art i fi ci al t ears (met hyl cel l ul os e) are us ed as oft en as needed t o keep t he eyes l ubri cat ed. Refract ory s ympt oms may res pond t o punct al i ns ert i on of s i l i cone pl ugs .

o

o

c. Features of severe disease. Progressive pneumonitis, vasculitis, neuropathy, and CNS involvement may requi re ant i -i nfl ammat ory t reat ment wi t h cort i cos t eroi ds and i mmunos uppres s i ve drugs .

E. Prognosis Out come for pat i ent s wi t h pri mary SjÃ¶gren's s yndrome depends on t he s everi t y of i nvol vement of organs ot her t han t he s al i vary gl ands , part i cul arl y t he CNS. Al s o, t he ri s k of l ymphoma i s hi gher i n more s evere cas es . Feat ures of t he pri mary rheumat i c di s eas e det ermi ne t he prognos i s for pat i ent s wi t h s econdary SjÃ¶gren's s yndrome.

XII. Vasculitis A. Definition Vas cul i t i c s yndromes are a group of cl i ni cal l y di s parat e di s orders

Pa g e 2 4 9 9


charact eri zed by necrosis and inflammation of blood vessel walls. Vas cul i t i s can exi s t as t he pri mary feat ure of an i di opat hi c condi t i on or as a s econdary mani fes t at i on of i nfect i ous , mal i gnant , or rheumat i c di s eas e.

B. Etiology Mos t of t he vas cul i t i c s yndromes are i di opat hi c. Hepat i t i s B s urface ant i gen (HBs Ag) and HCV have been found i n i mmune compl exes of s everal di fferent s yndromes , i ncl udi ng s ome cas es of pol yart eri t i s nodos a and es s ent i al mi xed cryogl obul i nemi a. HIV, parvovi rus , and cyt omegal ovi rus (CMV) have been as s oci at ed wi t h vas cul i t i c di s eas es , part i cul arl y pol yart eri t i s .

C. Pathogenesis Indi vi dual s yndromes oft en demons t rat e feat ures of di s ordered humoral and cel l ul ar i mmuni t y. 



1. Disordered humoral immune response. In s ome vas cul i t i c s yndromes (e.g., l eukocyt ocl as t i c vas cul i t i s perhaps pol yart eri t i s nodos a), s ol ubl e i mmune compl exes form and depos i t i n ves s el wal l s , fi x compl ement , and at t ract i nfl ammat ory cel l s , whi ch caus e damage. Ant i bodi es may al s o react di rect l y wi t h neut rophi l s or endot hel i al cel l s t o caus e ves s el damage (e.g., W egener's granul omat os i s and ANCAs ). The s i t e and degree of damage are det ermi ned by many vari abl es , i ncl udi ng: o

o

a. Phys i cal and bi ochemi cal charact eri s t i cs of t he i mmune compl exes

o

o

b. Vari at i ons i n bl ood pres s ure (hydros t at i c forces )

o

Pa g e 2 5 0 0


c. Changes i n bl ood ves s el s i ze and permeabi l i t y

o

o

d. Endot hel i al cel l adhes i ve propert i es

o

o

e. Effect i venes s of ret i cul oendot hel i al s ys t em removal of i mmune compl exes

o

o

f. Degree of t urbul ence i n ves s el s (e.g., i mmune compl exes depos i t at branch poi nt s )

o

o

g. Degree of pers i s t ence or recurrence of ant i gen expos ure (e.g., t oxi n vers us HBV)

o

o

h. Vari at i ons i n hos t i mmune res pons e (e.g., ANCA i n pat i ent s wi t h W egener's granul omat os i s ). An i nhal ed ant i gen or ot her i mmune s ys t em chal l enge may act i vat e neut rophi l s , whi ch i n t he pres ence of ANCA, degranul at e, recrui t T cel l s and monocyt es , and damage ves s el wal l s .





2. Disordered cellular immune response. Di s orders i nvol vi ng granul oma format i on are t he bes t exampl es of t he cont ri but i ons of t he cel l ul ar i mmune res pons e t o vas cul i t i c proces s es . Int eract i ons bet ween macrophages +

and CD4 T cel l s i n res pons e t o unknown ant i gens l ead t o granul oma format i on i n and around ves s el wal l s . In gi ant cel l art eri t i s , age-rel at ed ves s el degenerat i on i n l arge art eri es may expos e ant i gens t ypi cal l y hi dden t o t he i mmune s ys t em, whi ch t hen el i ci t a cel l ul ar i mmune res pons e; t here al s o may be an HLA-DR4 as s oci at i on wi t h t hi s di s eas e and prol i ferat i on of s peci fi c T-cel l

Pa g e 2 5 0 1


cl ones i n ves s el l es i ons .

D. Classification The current s ys t ems for cl as s i fyi ng vas cul i t i c s yndromes us e cl i ni cal feat ures , s i ze of t he i nvol ved ves s el , and t ype of cel l ul ar i nfi l t rat e t o s eparat e t he s yndromes (Tabl e 10-14). P.497

TABLE 10-14 Major Vasculitic Syndromes: Clinicopathologic Distinctions P at h ol o g Cl

y

in

c

ic

el

S al

lu

y F v la Di n e e r a d at ss in g r u el fil n o r si tr o m e z at si e s e e s H S S L S y ki m e ki p n al u n e in l

k bi

Pa g e 2 5 0 2


rs v (c oc o e ol a yt p n v pi oc s y si e l l l a ti m ar s t vi e i e i c ty nt s ; v v pr v a a e e sc sc d n ul ul o ul i t i iti m e s s i n s ; wi (s a ar t h er nt t e al u Vi ri l m s c ol l e s i er e s i ck al s ) o n in

n

e v

s

s s ol

at

; v

th

dr e

e

u m

s

g e

a

re nt

m

ac t y

e

t i pi

d

o ca

e

n ll

v

s; y

el

H m

o

e in

p

n i

m

Pa g e 2 5 0 3


oc m

e

h- al

nt

Sc a

al

h n

st

Ã d

a

¶ s

g

nl el

e

ei fn li p m ur i t p e ur d a; m ix e d e ss e nt ia l cr y o gl o b ul in e m ia

Pa g e 2 5 0 4


) P M S N Bi C ol ul m ec o or y t i al ro p t i a syl

t i s y co

rt s t a zi of s t e e n n i n er ri m d g v oi ti i l l m ar ol d s n e te v s; n e di ri e cy o ss u ti d to d M m s or t o o aj -s at g xi s or i z v a c a ar e e n a t e d s s Vi g ri ar el s c e al t e br er nt i s ri a al s ch e nc a a e s h n d m

p gi d

ic

oi o e

le

nt gr d

si

s a if

o

Si p n

n

mh o

s

ul y re

th

ta

s

at

n

p

s

e

o

p

o

n

ar

u

s

e

s

e

Pa g e 2 5 0 5


lu

le

n

si

g

o

s

n

a

s

n

at

d

v

s

ar

pl

io

e

u

e

s

n

st

N

a

o

g

d

e

o

s

s e sk in le si o n s u nc o m m o n Al Pr V Gr Bi le o ar a o r m yi n p

Pa g e 2 5 0 6


gi i n n ul s y c e g o of a nt (c m i n n al a at v gi l e pi o ol iti rg l l u v s i c ar s e (C , i e i n d h a s ; fi l or ur s t v t r g g- h e at a St m n e n, ra at ul s t y u i c e wi pi s s hi s ; t h ca di s t s e l l s or m o y e y al s i l u a L l

n n

s u ar o g e) n t e p g ri hi in e ls v s) ol v e m e nt Bl o o d e

Pa g e 2 5 0 7


o si n o p hi li a co m m o n WU S N L e p m ec u g p al ro n e er l

ti g

n a (a zi bi e n rt n o r' d er g p s l o i e gr s y g w s ; a (s r er v n i n a re ei ul u n s n o s ul pi s ) m bi o ra

a o

m to

s p

at ry

in sy

o tr

u u

si ac

p s

s t

p u

in

er al

v

a ly

ol

n n

Pa g e 2 5 0 8


v

d o

e

lo n

m

w di

e

er a

nt

ai g

Pr

r n

o

w o

m

a st

in

ys i c

e

F )

nt

oc c-

re

al A

n

n N

al

ec C

a

ro A

b

ti

n

zi

or

n

m

g

al

ar

iti

te

e

ri

s

ti s in lu n g s N ec ro ti zi n

Pa g e 2 5 0 9


g gl o m er ul o n e p hr iti s in ki d n e ys Gi P L Gi T a ol ar a e nt y g nt m c m e ce p el y ar l l or l al t e a al a gi ri n ar rt a e d t e e rh s ch ry ri e (e ro bi ti u s ni o s mp c p (t at ec m s y e ic ia o m a ll n p in y o

Pa g e 2 5 1 0


o 5 te n r 0 m uc al % p l e a O or ar rt cc al i n e ur ar fi l ri s t e t r ti i n ry at s) p ) e at

s

ie

in

nt

v

s

e

ol

ss

d

el

er

w

th

al

a

ls

n 5 0 Si g n s a n d sy m pt o m s of

Pa g e 2 5 1 1


cr a ni al ar te ry in v ol v e m e nt Hi g h er yt hr oc yt e s e di m e nt at io n ra te

Pa g e 2 5 1 2


T L L Gi A a ar ar a n k g g nt gi a e e ce o y v ar l l gr a e te a a s s s ri n p u' el e d h s cl s ch y a a (a ro C rt u or ni h e di t i c e ri ca c m s t ti t i ar o M s o ch n RI n ) o N O

n ec

cc

uc k

ur

l e ul

s

ar t r

in

in a

y

fi l s

o

tr o

u

at n

n

e o

g

s gr

(o

in a

ft

v p

e

e h

n

ss y

A

el

si

w

a

al

n)

ls

w

Pa g e 2 5 1 3


o m e n ANCA, ant i neut rophi l cyt opl as mi c ant i body; c-ANCA, cyt opl as mi c ANCA; MRI, magnet i c res onance i magi ng. P.498





1. Pat hol ogi c cl as s i fi cat i on by ves s el s i ze may be t he mos t cl i ni cal l y us eful : o

o

a. Large ves s el : 



(1) Gi ant cel l (t emporal ) art eri t i s (GCA)





(2) Takayas u's art eri t i s

o

o

b. Medi um ves s el : 



(1) Pol yart eri t i s nodos a (PAN)



Pa g e 2 5 1 4




(2) Kawas aki 's di s eas e

o

o

c. Smal l ves s el : 



(1) Immune-compl ex medi at ed 



(a) Hypers ens i t i vi t y vas cul i t i s





(b) Serum s i cknes s





(c) Mi xed es s ent i al cryogl obul i nemi a





(d) Henoch-SchÃ¶nl ei n purpura (HSP)





(e) Urt i cari al vas cul i t i s





(2) ANCA-as s oci at ed (para-i mmune) 



(a) W egener's granul omat os i s





(b) Churg-St raus s





(c) Mi cros copi c pol yangi i t i s (MPA)





2. Nons peci fi c hemat ol ogi c and i mmunol ogi c abnormal i t i es (e.g., anemi a, l eukocyt os i s , el evat ed ESR,

Pa g e 2 5 1 5


and hypocompl ement emi a) oft en exi s t i n many of t hes e s yndromes , but t hes e are not not ed i n Tabl e 10-14 unl es s t hey are s peci fi cal l y i mport ant for t he di agnos i s of a part i cul ar s yndrome. It i s i mport ant t o unders t and t hat t hes e s yndromes oft en bl ur and overl ap i n act ual pat i ent s .

E. Vasculitic syndromes 

1. Hypersensitivity vasculitis (

onl i ne Fi gures 10-14 and 10-15



ONLINE FIGURE 10-14 Vas cul i t i s . Di gi t al i nfarct s can be caus ed by i nfl ammat i on and s ubs equent occl us i on of t he s mal l art eri es . Thi s can be caus ed by any s mal l ves s el vas cul i t i s . (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:9105220.)

Pa g e 2 5 1 6


ONLINE FIGURE 10-15 Vas cul i t i s . Pal pabl e purpura, as i s s een here, can be pres ent i n s mal l ves s el vas cul i t i s from any caus e. (ACR Sl i de Col l ect i on of t he Rheumat i c Di s eas es , 3rd ed., 2004:9112120.) o

o

a. T ypical hypersensitivity vasculitis syndrome. Hypers ens i t i vi t y vas cul i t i s (al s o cal l ed leukocytoclastic vasculitis or cutaneous vasculitis ) i s i mmune compl exâ€“medi at ed i nfl ammat i on of s mal l ves s el s (art eri ol es , capi l l ari es , and venul es ). The caus e oft en i s uncl ear. In many cas es , hypers ens i t i vi t y vas cul i t i s s eems t o occur as an exaggerat ed i mmune res pons e t o a drug (e.g., peni ci l l i n) or infection (vi ral or bact eri al ant i gen), caus i ng a s el f-l i mi t ed i mmune compl ex vas cul i t i s . The s ki n al mos t al ways i s i nvol ved, wi t h pal pabl e purpura, urt i cari a, or ul cers . Pol yart i cul ar art hri t i s i s common. Di s t i nct organ i nvol vement may al l ow furt her cl as s i fi cat i on.

o

Pa g e 2 5 1 7


b. Distinctive subsets 



(1) Henoch-SchÃ¶nlein purpura i s a s ys t emi c, s mal l ves s el vas cul i t i s t hat occurs pri mari l y i n chi l dren, oft en fol l owi ng a s t rept ococcal pharyngi t i s . 



(a) Clinical features. Pal pabl e purpura, pol yart i cul ar art hral gi as or i nfl ammat ory art hri t i s , abdomi nal pai n or gas t roi nt es t i nal bl eedi ng due t o mes ent eri c ves s el i nvol vement , and i mmune compl exâ€“medi at ed gl omerul onephri t i s t ypi cal l y occur. A di s t i nct i ve feat ure i s IgA deposition i n t he vas cul ar l es i ons .





(b) Course. Mos t cas es of Henoch-SchÃ¶nl ei n purpura res ol ve s pont aneous l y over a peri od of days t o weeks . Pat i ent s wi t h s evere renal or gas t roi nt es t i nal i nvol vement may requi re s t eroi ds .





(2) Serum sickness i s an i mmune compl ex vas cul i t i s t hat oft en fol l ows a drug (e.g., peni ci l l i n or s ul fonami de) or forei gn prot ei n expos ure by 7â€“10 days . Ant i l ymphocyt e gl obul i n now i s one of t he mos t common caus es . HBV art hri t i s â€“dermat i t i s s yndrome i s a s erum s i cknes s â€“l i ke res pons e t o Hbs Ag. 

Pa g e 2 5 1 8


(a) Clinical features. Urt i cari a, purpura, art hri t i s , and art hral gi as are charact eri s t i c, and l ymphadenopat hy and i mmune compl ex gl omerul onephri t i s are common.





(b) Course. Res ol ut i on i s t ypi cal fol l owi ng removal of t he i nci t i ng agent .





(2) Hypocomplementemic urticarial vasculitis 



(a) Clinical features. Pat i ent s wi t h t hi s form of vas cul i t i s exhi bi t urt i cari a, t ypi cal l y l as t i ng l onger t han 24 hours and, s omet i mes , art hri t i s , gl omerul onephri t i s , or gas t roi nt es t i nal i nvol vement . Hypocomplementemia i s a cons i s t ent feat ure, apparent l y rel at ed t o ant i bodi es di rect ed agai ns t C1q; t he degree of compl ement depres s i on t ypi cal l y paral l el s di s eas e act i vi t y. P.499





(b) Course. The di s eas e fol l ows a rel aps i ng, remi t t i ng cours e and may requi re cort i cos t eroi ds for t he more di s abl i ng mani fes t at i ons .





(4) Mixed essential cryoglobulinemia i s an

Pa g e 2 5 1 9


i di opat hi c di s order caus ed by col d-preci pi t at ed i mmunogl obul i n (cryogl obul i n) compl exes , whi ch produce a vas o-occl us i ve or i nfl ammat ory i njury. The s yndrome t ypi cal l y occurs i n pat i ent s who have t ype II (mi xed) cryogl obul i n. Many pat i ent s have been found t o have HCV or l es s oft en, HBV, i n t he i mmune compl exes . 



(a) Clinical features. Recurrent at t acks of pal pabl e purpura, Raynaud's phenomenon, art hral gi a, and i mmune compl ex gl omerul onephri t i s may occur. Gas t roi nt es t i nal , hepat i c, and pul monary dys funct i on are occas i onal feat ures .





(b) Course. Severe renal i nvol vement i s t he mos t common reas on for t reat ment , whi ch may i ncl ude cort i cos t eroi ds , cyt ot oxi c agent s , or removal of t he cryo gl obul i n by apheres i s . IFN-Î± may hel p when t he di s eas e i s as s oci at ed wi t h HBV or HCV.





2. Polyarteritis nodosa i s a necrot i zi ng vas cul i t i s of s mal l and medi um-s i zed art eri es , whi ch mani fes t s as a mul t i s ys t em i l l nes s . Is chemi c art eri al l es i ons are caus ed by ves s el wal l i nfl ammat i on, i n s ome cas es as s oci at ed wi t h i mmune compl ex depos i t i on. HBs Ag i s pos i t i ve i n up t o 50% of pat i ent s . o

o

a. Clinical features. Constitutional complaints (e.g., fever, wei ght l os s , and anorexi a) are

Pa g e 2 5 2 0


common, and multiorgan ischemic dysfunction i s t he rul e. The l ungs and s pl een t ypi cal l y are s pared. 



(1) Renal involvement i s mos t common and mani fes t s as s evere hypert ens i on, prot ei nuri a and act i ve s edi ment from gl omerul onephri t i s , or renal i ns uffi ci ency.





(2) Other common features i ncl ude art hral gi as , myal gi as , peri pheral nervous s ys t em abnormal i t i es (s ens ory pol yneuropat hi es , mononeuri t i s mul t i pl ex), and s ki n l es i ons (i nfarct i ons , nodos e l es i ons ). Ins i di ous CHF, di ffus e or focal CNS dys funct i on, and gas t roi nt es t i nal i nvol vement al s o can occur, dependi ng on t he s i ze of t he i s chemi c l es i ons .





(3) Microscopic polyarteritis i s a cl i ni cal vari ant t ypi fi ed by promi nent l ung i nvol vement and s egment al gl omerul onephri t i s , s omet i mes rapi dl y progres s i ve. The ves s el s i nvol ved t end t o be s mal l er (capi l l ari es , art eri ol es , and s mal l art eri es ). p-ANCA i s commonl y found (50%â€“80% of pat i ent s ) and abdomi nal angi ography i s t ypi cal l y negat i ve (becaus e t he s mal l er ves s el s are i nvol ved).

o

o

b. Course. Treat ment wi t h cort i cos t eroi ds , cyt ot oxi c agent s , or bot h i s neces s ary; t he i l l nes s t ypi cal l y i s fat al i f unt reat ed. IFN-Î± may hel p i n HBV-as s oci at ed cas es .



Pa g e 2 5 2 1




3. Allergic angiitis (Churg-Strauss disease) i s a granul omat ous vas cul i t i s t hat t ypi cal l y occurs i n pat i ent s wi t h as t hma. o

o

a. Clinical features. Al l ergi c angi i t i s i s t ypi cal l y a t ri phas i c di s eas e. Asthma occurs fi rs t , oft en as s oci at ed wi t h blood eosinophilia. T issue infiltrates, es peci al l y pulmonary ones , occur next ; eos i nophi l s are oft en pres ent i n t hes e l es i ons , s omet i mes i n granul omas . Vasculitis of s mal l or medi um-s i zed ves s el s occurs l as t , commonl y i nvol vi ng s ki n, nerve, or mus cl e l es i ons .

o

o

b. Course. The fart her apart i n t i me t he t hree phas es of i l l nes s occur, t he mi l der t he di s eas e; t he cl os er t oget her, t he more expl os i ve. Cat as t rophi c l ung, gas t roi nt es t i nal t ract , cardi ac, or nerve l es i ons may mandat e aggres s i ve i nt ravenous cort i cos t eroi d and cyt ot oxi c t herapy, but more i ndol ent forms are oft en eas i l y cont rol l ed wi t h moderat e cort i cos t eroi d dos es .





4. Wegener' s granulomatosis i s a granul omat ous , s mal l ves s el vas cul i t i s t hat t ypi cal l y i nvol ves t he upper and l ower res pi rat ory t ract and ki dney. o

o

a. Clinical features 



(1) Respiratory tract. Pul monary feat ures t ypi cal l y i ncl ude upper ai rway compl ai nt s (e.g., s i nus i t i s , rhi ni t i s ) as wel l as l ower

Pa g e 2 5 2 2


ai rway s ympt oms (e.g., cough, s hort nes s of breat h, hemopt ys i s ). Cavi t ary or mul t i pl e i nfi l t rat es may be s een on ches t radi ography. 



(2) Kidney. Renal i nvol vement i s charact eri zed by abnormal s edi ment or renal funct i onal i mpai rment .





(3) Organs. Ot her, l es s cl as s i cal feat ures i ncl ude s ki n l es i ons (pal pabl e purpura), art hri t i s , ocul ar or orbi t al i nfl ammat i on (t ypi cal l y wi t h propt os i s ), cardi ac l es i ons , and CNS or peri pheral nervous s ys t em i nvol vement . P.500





(4) Presence of c-ANCA. c-ANCA i s oft en found i n pat i ent s wi t h act i ve, mul t i organ di s eas e. In t hes e pat i ent s , t he pres ence of c-ANCA may be a rel at i vel y s peci fi c di agnos t i c t es t and may hel p moni t or di s eas e act i vi t y.

o

o

b. Course. Al t hough cort i cos t eroi ds may be us ed i ni t i al l y, cyt ot oxi c agent s s uch as cycl ophos phami de are uni forml y requi red t o prevent deat h. Met hot rexat e may pl ay a rol e i n mai nt ai ni ng di s eas e remi s s i on or i n l i mi t ed forms of t he di s eas e.





5. Giant cell (temporal) arteritis us ual l y i s a

Pa g e 2 5 2 3


granul omat ous i nfl ammat i on of t he carot i d art ery and i t s branches , but i t s omet i mes can i nvol ve t he vert ebral art ery or ot her aort i c branches . The pat hol ogy i s i ndi s t i ngui s habl e from t hat of Takayas u's art eri t i s . o

o

a. Clinical features. The di s eas e rarel y occurs i n pat i ent s younger t han age 50. 



(1) Approxi mat el y 50% of pat i ent s have PMR (i .e., achi ng and s t i ffnes s of s houl der and hi p gi rdl es as s oci at ed wi t h an ESR >50 mm/hour, age >50 years , and cons t i t ut i onal compl ai nt s s uch as fever, mal ai s e, and wei ght l os s ), and mos t pat i ent s have feat ures rel at ed t o i s chemi a i n t he carot i d art ery regi on (i .e., headache, vi s ual s ympt oms , jaw cl audi cat i on, s cal p t endernes s , and neurol ogi c compl ai nt s ).





(2) Superficial temporal artery involvement i s common but oft en i s cl i ni cal l y s i l ent . Pot ent i al cl i ni cal feat ures i ncl ude t endernes s , nodul es , or eryt hema. Even when t he art ery i s cl i ni cal l y normal , t emporal art ery bi ops y t ypi cal l y reveal s pat hol ogy.

o

o

b. Course. Pat i ent s requi re s t eroi ds earl y and i n hi gh dos es t o prevent blindness, t he mos t s eri ous compl i cat i on of t hi s i l l nes s . Pat i ent s s houl d be s t art ed i mmedi at el y on at l eas t 1 mg/kg predni s one t o prevent bl i ndnes s . A t emporal art ery bi ops y may s t i l l be di agnos t i c up t o 1 week aft er t he i ni t i at i on of s t eroi ds . A cont ral at eral t emporal art ery i s neces s ary for di agnos i s i f t he ori gi nal

Pa g e 2 5 2 4


bi ops y s peci men i s negat i ve. 



6. T akayasu' s arteritis i s a granul omat ous i nfl ammat i on of t he ves s el s of t he aort i c arch t hat i s charact eri zed pat hol ogi cal l y by a panart eri t i s cont ai ni ng mononucl ear and gi ant cel l s . Y oung, oft en As i an, women are at hi ghes t ri s k for t hi s di s order. o

o




(1) Generalized aching s i mi l ar t o PMR oft en occurs earl y i n t he i l l nes s . Feat ures of large artery ischemia devel op weeks t o mont hs l at er and may i ncl ude upper ext remi t y cl audi cat i on, angi na, and CHF from cardi ac or aort i c i nvol vement . Pul monary and mes ent eri c ves s el s al s o can be i nvol ved.





(2) Findings on physical examination i ncl ude art eri al brui t s , pul s e defi ci t s , and bl ood pres s ure di fferences bet ween ext remi t i es .

o

o

b. Course. Pat i ent s may requi re s t eroi ds earl y i n t he cours e of t he i l l nes s ; l at er, vas cul ar recons t ruct i on may be requi red for occl us i ve l es i ons . Cyt ot oxi c agent s are t ypi cal l y added i f s t eroi ds do not cont rol i nfl ammat ory di s eas e.





7. Other vasculitic syndromes do not fi t i nt o t he major cat egori es of vas cul i t i s due t o di s t i nct cl i ni cal or overl appi ng pat hol ogi c feat ures .

Pa g e 2 5 2 5


o

a. Vasculitis as a secondary feature of a primary disease. Cert ai n di s eas es can exhi bi t vas cul i t i c i nfl ammat i on as a s econdary feat ure. The vas cul i t i s t ypi cal l y i s s mal l ves s el , cut aneous vas cul i t i s but s omet i mes can overl ap wi t h pol yart eri t i s -l i ke ves s el i nvol vement , es peci al l y i n rheumatoid arthritis and lupus. Dermal and CNS vas cul i t i c l es i ons are recent l y recogni zed s econdary feat ures of SjÃ¶gren' s syndrome. Hematologic malignancies and bact eri al and vi ral infections al s o can i ncl ude vas cul i t i c feat ures , us ual l y wi t h t he s ki n t he predomi nant organ i nvol ved.

o

o

b. BehÃ§et' s syndrome. The pres ence of recurrent oral and geni t al ul cers defi nes t hi s s yndrome. Pat i ent s al s o may have eye i nfl ammat i on, pathergic skin lesions (l es i ons occurri ng at s i t es of s ki n i njury), and vas cul i t i s of t he CNS or ot her organs .

o

o

c. Kawasaki disease (mucocutaneous lymph node syndrome). Thi s febri l e i l l nes s of i nfant s and young chi l dren i s charact eri zed by conjunct i val i nject i on; di ffus e macul opapul ar ras h wi t h as s oci at ed edema, eryt hema, and event ual des quamat i on of t he hands and feet ; cracked l i ps ; â€œs t rawberry t ongueâ€•; and cervi cal adenopat hy. Coronary vas cul i t i s can devel op i n 25% of pat i ent s and l ead t o aneurys m, MI, and s udden deat h. However, t he i nci dence of t hi s vas cul i t i s has great l y decreas ed s i nce t he advent of i nt ravenous i mmunogl obul i n t herapy, whi ch,

Pa g e 2 5 2 6


al ong wi t h as pi ri n, i s t he t reat ment of choi ce i n t hi s di s eas e. P.501

o

o

d. Isolated CNS vasculitis. Thi s condi t i on i s a granul omat ous i nfl ammat i on of s mal l or medi um-s i zed art eri es of t he brai n. Typi cal l y, pat i ent s do not have cl i ni cal or l aborat ory evi dence of i nfl ammat i on el s ewhere. Pres ent i ng feat ures oft en are combi nat i ons of di ffus e CNS compl ai nt s (headache, al t ered ment al s t at us , poor memory) and more focal ones (crani al nerve defect s , hemi pares i s ). A chroni c meni ngi t i s pi ct ure, wi t h pl eocyt os i s and i ncreas ed prot ei n, t ypi cal l y i s found on LP. An enhanced MRI s can of t he brai n i s a s ens i t i ve but nons peci fi c i ndi cat i on of pos s i bl e i nvol vement .

F. Diagnosis 



1. Why suspect an underlying vasculitic process? Combi nat i ons of cl i ni cal feat ures s ugges t t he pos s i bi l i t y of a vas cul i t i s . o

o

a. Evi dence of a mul t i s ys t em di s eas e

o

o

b. Infect i ous et i ol ogi es t horoughl y excl uded

o

o

c. Laborat ory dat a may s ugges t an i nfl ammat ory

Pa g e 2 5 2 7


proces s o

o

d. Di s t i nct i ve cl i ni cal feat ures or pat t erns (Tabl e 10-15)

TABLE 10-15 Clinical Data Suggesting Vasculitis P h L ys a ic b al or E at x or a y m St Hi in u st at di or io e y n s C V N o e o n ss n st el s it fi p ut n e io di ci n n fi al g c c s te o Bl st mo s pl o (c

Pa g e 2 5 2 8


ai d hr nt pr o s es ni M suc al re i n ai /p fl s e ul a A se m n d m or ef at ex i ci i o i a t s n) Fe H A ve yp n r er e W te m ei ns i a g i o (c ht n hr l o (s o s s u ni D d c ru d di g e se e n as x o e) p ns T o et hr s ) o ur V m e es b (p s e oc re l

yt

s c t e os ri n i s

Pa g e 2 5 2 9


b d In e er cr d n e or es as ill s, e i ci n d t ) o er In d yt fe ul hr ct es oc io ,

yt

n br e H ui s e u t s di m S m a ki e n n nt i

fi at

m n io m di n u n ra n g te o s In d P cr ef al e i ci p as e a e nc bl d y e g vi p a ru ur m s p m (H ur a IV a gl ) In o

Pa g e 2 5 3 0


H fa b e rc ul p ti in at o s i t i ns T s Ul e B ce st or rs in C M di vi u c ru sc at s le in O fi g rg n p a di ot n n e is g nt c s ia h T l e e is mn c ic d h c er e o n m m es ia pl s , A ai cr b nt a n s m or A pi m n n al gi g re n N n a er al Ex v fu

Pa g e 2 5 3 1


t r e nc e fi t i m n o i t di n y n (â or g †‘ ja s cr w S e cl e at a ns i n u or i n di y/ e, ca m B t i ot U o or N) n n A Vi e b s u ur n al o or co p m m at al pl hi m ai es us nt Fo cl s ca e/ Tr l / l i a di ve ns ff r i e us e nt e nz is C y ch N m e S es m dy (â i c s f †‘

Pa g e 2 5 3 2


at u C t a nc K, ck t i A s o S St n T, ro T A ke e LT st ) is El T ec e tr n oc d ar er di n o es gr s a m T e st s p oi nt in g to w ar d s p e ci

Pa g e 2 5 3 3


fi c di a g n o s e s HI V (s ev er al sy n dr o m es ) H B s A g (2 0 % â €“ 3 0

Pa g e 2 5 3 4


% of p ol ya rt er iti s p at ie nt s) H e p at iti s C R N A A N A (S LE m or e li ke ly

Pa g e 2 5 3 5


) cA N C A ( W e g e n er 's gr a n ul o m at os is ) pA N C A ( m ic ro sc o

Pa g e 2 5 3 6


pi c p ol ya rt er iti s) Cr yo gl o b ul in s ( m ix e d es se nt ia l cr yo gl o b ul in e

Pa g e 2 5 3 7


m ia ) A nt iR o (S jÃ ¶ gr e n' s sy n dr o m e, SL E) ALT, al ani n e ami not rans fer as e; ANCA, ant i ne ut rophi l cyt opl as mi c

Pa g e 2 5 3 8


ant i bo dy; ANA, ant i nu cl ear ant i bo dy; AST, as part at e ami not rans fer as e; BUN, bl ood urea ni t roge n; CK, creat i n e ki nas e ; CNS, cent ral nervou s s ys t em ; SLE, s ys t em ic l upus eryt he mat os us 

Pa g e 2 5 3 9


2. Confirming the diagnosis. If t he cl i ni cal eval uat i on s ugges t s a reas onabl e chance of vas cul i t i s , t he appropri at e approach t o maki ng a di agnos i s us ual l y l i es i n bi ops y of i nvol ved t i s s ue or vi s ceral angi ography; ANCA t es t i ng may be hel pful when mi cros copi c pol yart eri t i s or W egener's granul omat os i s are s us pect ed. o

o

a. Biopsy of a fresh lesion. Bi ops y from cl i ni cal l y i nvol ved t i s s ues i s t he preferred met hod of di agnos i ng vas cul i t i s ; i f i nvol ved, t he s ki n oft en i s t he eas i es t t i s s ue t o obt ai n. 



(1) Di agnos i s of Wegener' s granulomatosis oft en rel i es on open l ung bi ops y demons t rat i on of granul omat ous vas cul i t i s , becaus e paranas al s i nus t i s s ue t ypi cal l y s hows nons peci fi c i nfl ammat i on and renal t i s s ue s hows onl y gl omerul onephri t i s .





(2) Di agnos i s of temporal arteritis requi res exami nat i on of a 3- t o 6-cm s egment of t he s uperfi ci al t emporal art ery i n mul t i pl e s ect i ons ; bi ops y of t he cont ral at eral s i de may be needed i f t he fi rs t bi ops y i s negat i ve and cl i ni cal s us pi ci on remai ns hi gh. P.502





(3) Bi ops y of l ept omeni nges and cl i ni cal l y i nvol ved brai n t i s s ue may be needed when isolated CNS vasculitis i s s t rongl y s us pect ed.

o

Pa g e 2 5 4 0


o

b. Visceral angiography. W hen pol yart eri t i s i s s us pect ed and appropri at e t i s s ue cannot be obt ai ned for bi ops y or when t he bi ops y i s unreveal i ng, abdomi nal t hree-ves s el angi ography may s how aneurys ms or art eri opat hy (di s cret e narrowi ng) s ugges t i ve of s mal l t o medi um-s i zed art ery vas cul i t i s . Aort i c arch and l arge ves s el angi ograms , carot i d ul t ras onography, and MRI s t udi es of t he ches t are us eful i n Takayas u's art eri t i s and gi ant cel l art eri t i s , becaus e t he i nvol ved ves s el s oft en cannot be s afel y s ubject ed t o bi ops y. CNS angi ograms may be warrant ed when i s ol at ed CNS vas cul i t i s i s s us pect ed.

o

o

c. Presence of ANCA. ANCA are t ypi cal l y IgG ant i bodi es di rect ed agai ns t cyt opl as mi c component s of neut rophi l s and monocyt es (s ee onl i ne I B 5).





3. Differential diagnosis. Numerous condi t i ons s houl d be cons i dered i n t he di fferent i al di agnos i s of vas cul i t i s . Import ant di s orders and t he t es t s us ed t o el i mi nat e t hem i ncl ude: o

o

a. Bacterial endocarditis (bl ood cul t ure)

o

o

b. Left atrial myxoma (t wo-di mens i onal or t rans es ophageal echocardi ogram)

o

o

c. Cholesterol embolism s yndrome (bi ops y s howi ng refract i l e crys t al s )

Pa g e 2 5 4 1


d. T hrombotic diseases s uch as antiphospholipid

o

syndrome (ant i phos phol i pi d ant i body) and disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP) [PT, PTT, pl at el et count , fi bri nogen, and fi bri n s pl i t product s ]

G. Therapy The management of pat i ent s wi t h vas cul i t i s i s compl ex. In al l pat i ent s wi t h known vas cul i t i c di s eas e, i t i s i mport ant t o record t he ext ent of di s eas e i ni t i al l y and t o moni t or organ i nvol vement (i n t erms of cl i ni cal , bi ops y, and angi ographi c evi dence). The t empo of di s eas e progres s i on al s o s houl d be gauged t o det ermi ne t he bes t t reat ment . 



1. Antigen removal. Drugs t hat may be caus i ng vas cul i t i c proces s es s houl d be s t opped; pl as mapheres i s has been us ed i n at t empt t o remove known ant i gens (Hbs Ag and HCV) and unknown ant i gens (cryogl obul i n).





2. T reatment of primary disease. Cont rol of any pri mary rheumat ol ogi c, i nfect i ous , or mal i gnant proces s general l y i s t he mos t effect i ve way t o cont rol vas cul i t i s t hat i s a s econdary feat ure.





3. Immunosuppressive treatment. Vas cul i t i c s yndromes t hat are not rel at ed t o a removabl e ant i gen or t reat abl e pri mary di s order oft en s houl d be cont rol l ed wi t h i mmunos uppres s i ve agent s â€”ei t her corticosteroids, cytotoxic drugs, or a combi nat i on of bot h. Cyclosporine, worki ng s peci fi cal l y on act i vat ed +

CD4 T cel l s , has been us ed i n s ome vas cul i t i s di s eas es ,

Pa g e 2 5 4 2


part i cul arl y t o count eract eye i nvol vement i n BehÃ§et 's s yndrome and s ome cas es of refract ory s mal l ves s el vas cul i t i s . o

o

a. Corticosteroids al one s houl d be at t empt ed as fi rs t -l i ne pharmacol ogi c t reat ment i n al l pat i ent s who requi re concomi t ant cyt ot oxi c t herapy, except t hos e wi t h W egener's granul omat os i s . Dai l y dos i ng us ual l y i s requi red, al t hough al t ernat e-day dos i ng may be s uffi ci ent once s ys t emi c feat ures of t he i l l nes s are cont rol l ed. Low-dose aspirin therapy i s oft en added t o t reat ment of vas cul i t i c di s orders t o count eract t he pot ent i al vaso-occlusive effect s of gl ucocort i coi ds .

o

o

b. Cytotoxic drugs (e.g., cycl ophos phami de) 



(1) Wegener' s granulomatosis al mos t al ways i s fat al wi t hout cyt ot oxi c t herapy; t herefore, pat i ent s s houl d be s t art ed on a combi nat i on of one of t hes e agent s and cort i cos t eroi ds .





(2) Polyarteritis nodosa and allergic angiitis al s o oft en requi re cyt ot oxi c drugs i n addi t i on t o s t eroi ds for cont rol of di s eas e mani fes t at i ons , al t hough recent pros pect i ve s t udi es have s hown benefi t i n decreas i ng di s eas e recurrences but not i n prevent i ng mort al i t y.





(3) In ot her di s orders , cyt ot oxi c drugs

Pa g e 2 5 4 3


t ypi cal l y are added t o cort i cos t eroi d t herapy i f t he s t eroi d dos es cannot be eas i l y l owered wi t hout t he di s eas e fl ari ng. 



4. Other drugs s uch as daps one, col chi ci ne, NSAIDs , hydroxychl oroqui ne, and H 1 - or H 2 -bl ocki ng ant i hi s t ami ni c agent s have been us ed, part i cul arl y i n refract ory s mal l ves s el vas cul i t i s .





5. Plasmapheresis, whi ch removes ant i bodi es and i mmune compl exes from pl as ma, has not been s hown t o i mprove out comes i n s ys t emi c necrot i zi ng vas cul i t i s (e.g., pol yart eri t i s and al l ergi c angi i t i s ). In mixed cryoglobulinemia, whet her or not i t i s rel at ed t o HBV or HCV i nfect i on, pl as mapheres i s may i mprove di s eas e feat ures , at l eas t t emporari l y.

P.503

XIII. Juvenile Idiopathic Arthritis (JIA) A. Definition Juveni l e i di opat hi c art hri t i s (JIA) i s a chronic inflammatory arthritis t hat begi ns before age 16 years . Before cons i deri ng a di agnos i s of JIA, art hri t i s s houl d be pres ent i n one or more joi nt s for more t han 6 weeks , and ot her rheumat i c di s eas es s houl d be excl uded.

B. Epidemiology Annual i nci dence may be as hi gh as 0.01%. Al t hough t he apparent HLA as s oci at i ons s ugges t t hat t he al t ered i mmune res pons es are genet i cal l y t rans ferabl e, fami l i al aggregat i on of cas es i s uncommon.

C. Etiology and pathogenesis

Pa g e 2 5 4 4


The s ame fact ors i mport ant i n t he devel opment of adul t rheumat oi d art hri t i s al s o appl y t o JIA (s ee III C and onl i ne D). Et i ol ogi c fact ors are unknown but may i ncl ude i nfect i ous agent s . Immune system dysfunction i s apparent i n t he prol ongat i on and mai nt enance of s ynovi t i s . A s ubs et of pat i ent s wi t h JIA have s el ect i ve IgA defi ci ency whi ch may be i mport ant i n di s eas e pat hogenes i s .

D. Pathology The synovial lesions cannot be di s t i ngui s hed hi s t ol ogi cal l y from t hos e i n adul t rheumat oi d art hri t i s . Infl ammat ory changes cont i guous t o t he growt h pl at e may l ead t o premat ure epi phys eal cl os ure and s hort ened l i mbs or di gi t s . Chroni cal l y i nvol ved joi nt s exhi bi t fibrous ankylosis more oft en t han i n adul t rheumat oi d art hri t i s . Pannus formation can occur, al t hough t ypi cal l y l at er i n t he di s eas e cours e t han i n adul t s wi t h rheumat oi d art hri t i s . As a cons equence, des t ruct i ve joi nt di s eas e al s o i s much l es s common i n JIA.

E. Classification Three pri mary s ubt ypes of JIA (i .e., s ys t emi c-ons et juveni l e art hri t i s , pauci art i cul ar art hri t i s , and pol yart i cul ar art hri t i s ) can be di s t i ngui s hed i n t he fi rs t 6 mont hs of i l l nes s . It i s i mport ant prognos t i cal l y and t herapeut i cal l y t o di s t i ngui s h bet ween s ubt ypes of i l l nes s . Import ant cl as s i fi cat i on feat ures are t he presence or absence of prominent systemic features and t he total number of involved joints. 



1. Systemic-onset juvenile arthritis, al s o cal l ed Still' s disease, occurs i n approxi mat el y 10%â€“20% of pat i ent s and i s charact eri zed by an earl y pat t ern of prominent systemic complaints and extra-articular involvement. Boys are affect ed as commonl y as gi rl s , and a peak age of i nci dence i s not evi dent . o

o

a. Clinical features

Pa g e 2 5 4 5




(1) T ypical features of the early disease course are high spiking fevers and marked constitutional complaints. Overt art hri t i s may not be part of t he earl y cours e but devel ops wi t hi n weeks t o mont hs of t he ons et of i l l nes s . A charact eri s t i c nonpruritic, fleeting, maculopapular rash occurs i n 90% of pat i ent s and i s mos t apparent wi t h fever s pi kes .





(2) Common features of active disease i ncl ude l ymphadenopat hy, hepat os pl enomegal y, and peri cardi t i s . Accompanyi ng myocardi t i s i s rare.





(3) The mos t s eri ous mani fes t at i on of s ys t emi c-ons et juveni l e art hri t i s i s macrophage act i vat i on s yndrome. Act i vat ed macrophages i n mul t i pl e organs l eads t o l eukopeni a, t hrombocyt openi a, CNS and l i ver dys funct i on, and pos s i bl e mul t i organ fai l ure and deat h.

o

o




(1) Hematologic findings i ncl ude a s t ri ki ngl y el evat ed ESR, promi nent l eukocyt os i s , and t hrombocyt os i s , and moderat e-t o-s evere anemi a of chroni c di s eas e, al t hough t here oft en i s s t ri ki ng mi crocyt os i s .



Pa g e 2 5 4 6




(2) Serologic findings onl y rarel y i ncl ude rheumat oi d fact or and ANAs .

o

o

c. Disease course. Di s eas e fl are-ups are punct uat ed by rel at i vel y s ympt om-free i nt erval s . Pol yart i cul ar art hri t i s becomes evi dent at s ome poi nt i n t he fi rs t 6 mont hs of i l l nes s . Sys t emi c s ympt oms mos t oft en decreas e wi t hi n 9 mont hs aft er ons et . 



(1) Approxi mat el y 50% of pat i ent s may begi n t o devel op s ympt oms of di s eas e t hat res embl e t he pol yart i cul ar art hri t i s s ubs et , wi t h progres s i ve joi nt i nvol vement det ermi ni ng di s eas e out come.





(2) The remai ni ng 50% of pat i ent s event ual l y recover compl et el y.





2. Polyarticular arthritis occurs i n approxi mat el y 30%â€“40% of pat i ent s and involves five or more joints i n t he fi rs t 6 mont hs of i l l nes s . Systemic features are not present. Gi rl s are affect ed P.504

much more oft en t han boys . Pol yart i cul ar art hri t i s can be furt her s eparat ed i nt o rheumatoid factorâ€“positive or â€“negative subsets. Pat i ent s who are pos i t i ve for rheumat oi d fact or pres ent mos t oft en i n l at e chi l dhood; a peak age of i nci dence i s not evi dent for pat i ent s who are negat i ve for rheumat oi d fact or.

Pa g e 2 5 4 7


o




(1) Typi cal l y, i nfl ammat ory pol yart i cul ar art hri t i s may have an acut e or a gradual ons et s i mi l ar t o t he pres ent at i on of adul t rheumat oi d art hri t i s . Symmet ri cal l arge and s mal l joi nt i nvol vement al s o i s t ypi cal . Promi nent feat ures may i ncl ude cervi cal s pi ne, and t emporomandi bul ar joi nt (TMJ) di s eas e.





(2) Rarel y, pat i ent s have s ympt oms and s i gns of ant eri or uvei t i s .





(3) Pat i ent s who are pos i t i ve for rheumat oi d fact or can have s ubcut aneous nodul es as i n adul t -ons et rheumat oi d art hri t i s .

o

o




(1) Hematologic findings frequent l y i ncl ude moderat e el evat i on of eryt hrocyt e s edi ment at i on rat e, l eukocyt e count , and pl at el et count . Pat i ent s us ual l y devel op a mi l d normochromi c, normocyt i c anemi a of chroni c di s eas e.





(2) Serologic findings i ncl ude rheumat oi d fact or i n 10%â€“20% and ANAs i n 20%â€“40% of pat i ent s .

Pa g e 2 5 4 8


P.505

o

o

c. Disease course. Pol yart i cul ar art hri t i s can be chroni c and pers i s t ent or can purs ue a more i nt ermi t t ent , rel aps i ng cours e. 



(1) Pat i ent s who are pos i t i ve for rheumat oi d fact or are at great es t ri s k for chroni c, eros i ve, and s evere art hri t i s and s i gni fi cant di s abi l i t y. Thes e pat i ent s have di s eas e t hat i s very s i mi l ar t o adul t -ons et rheumat oi d art hri t i s .





(2) Pat i ent s who are negat i ve for rheumat oi d fact or l es s oft en have s evere di s eas e or di s eas e t hat l as t s i nt o adul t hood.





3. Pauciarticular arthritis occurs i n approxi mat el y 50% of pat i ent s and i nvol ves four or fewer joints i n t he fi rs t 6 mont hs of i l l nes s . Thi s pat i ent group i s compos ed of t hree s ubs et s . o

o

a. Oligoarthritis and anterior uveitis affect gi rl s more oft en t han boys , and peak i nci dence i s i n earl y chi l dhood. 






(a) Typi cal l y, t he art hri t i s i s

Pa g e 2 5 4 9


as ymmet ri cal , mi l d, and i nvol ves t he knee. Ot her peri pheral joi nt s al s o can be i nvol ved, but t he axi al s kel et on us ual l y i s s pared. 



(b) Sys t emi c s ympt oms and s i gns are mi l d or abs ent .





(c) Pot ent i al l y s eri ous anterior uveitis unrel at ed t o art hri t i s act i vi t y can devel op i n up t o 25% of pat i ent s . Thi s us ual l y chroni c eye l es i on can be as ympt omat i c and can l ead t o blindness i f unrecogni zed or i nadequat el y t reat ed.





(2) Laboratory findings 



(a) Hematologic findings us ual l y do not i ncl ude anemi a, t hrombocyt os i s , and l eukocyt os i s . The ESR i s normal or onl y mi ni mal l y el evat ed.





(b) Serologic findings i ncl ude ANA pos i t i vi t y i n 60% of pat i ent s , whi ch i dent i fi es t hos e at hi gher ri s k for chroni c uvei t i s . Rheumat oi d fact or t ypi cal l y i s not pres ent .



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(3) Disease course. Mos t pat i ent s have pauci art i cul ar i nvol vement t hat i s manageabl e and not di s abl i ng. In approxi mat el y one-t hi rd

Pa g e 2 5 5 0


of pat i ent s , t he di s eas e event ual l y i nvol ves more t han four joi nt s , and i s furt her s ubdi vi ded as ext ended pauci -art i cul ar art hri t i s . o

o

b. Axial skeleton oligoarthritis predomi nant l y affect s boys , wi t h di s eas e ons et us ual l y begi nni ng i n l at e chi l dhood. 



(1) Clinical features. As ymmet ri cal knee, ankl e, or mi d-t ars al art hri t i s i s mos t common, fol l owed by t he s acroi l i ac hi p joi nt s . Acut e ant eri or uvei t i s can occur as i n adul t s pondyl oart hropat hi es , but t hi s feat ure i s not t he chroni c and s i ght -t hreat eni ng form s een i n t he ot her pauci art i cul ar s ubs et .





(2) Laboratory findings 



(a) Hematologic findings are not di s t i nct .





(b) Serologic findings i ndi cat e t hat 50% of t hes e pat i ent s have HLA-B27, but few have rheumat oi d fact or.





(2) Disease course. Many of t hes e pat i ent s devel op feat ures of ankyl os i ng s pondyl i t i s , ps ori at i c art hri t i s , or react i ve art hri t i s i n l at er l i fe.

o

Pa g e 2 5 5 1


o

c. Oligoarthritis with prominent dactylitis i s a t hi rd pres ent at i on s een mos t frequent l y i n gi rl s of any age. Psoriasis commonl y affect s t hes e pat i ent s and t hei r fami l i es .

F. Diagnosis 



1. Difficulties in diagnosis. Di agnos i ng art hri t i s i n chi l dren may be di ffi cul t . Chi l dren may avoi d us i ng an i nvol ved joi nt i ns t ead of compl ai ni ng of pai n. They may res pond t o t he pai n of an i nfl amed joi nt by di s pl ayi ng i rri t abi l i t y, regres s i ve behavi or, or emot i onal wi t hdrawal . Once joi nt i nvol vement has been di s covered, di s eas e s houl d be pres ent for at l eas t 6 weeks before a di agnos i s of JIA i s s eri ous l y cons i dered. W i t hi n t he fi rs t 6 mont hs , an at t empt s houl d be made t o cl as s i fy pat i ent s i nt o a cl i ni cal s ubs et . o

o

a. The synovial fluid us ual l y i s mi l dl y i nfl ammat ory 3

(i .e., a W BC count of 10,000â€“20,000/mm ); however, t he number of W BCs pres ent may not paral l el di s eas e act i vi t y. Joi nt fl ui d cul t ure and anal ys i s are es peci al l y i mport ant i n more acut e pauci -art i cul ar forms t o excl ude i nfect i on (bact eri al or mycobact eri al ). o

o

b. Radiographic findings are nons peci fi c. 



(1) Early findings may i ncl ude onl y s oft t i s s ue s wel l i ng and peri -art i cul ar demi neral i zat i on.



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

(2) Late findings i ncl ude epi phys eal changes (ei t her premat ure cl os ure or overgrowt h, dependi ng on epi phys eal act i vi t y at t he t i me of i nvol vement ) and art i cul ar eros i on or joi nt -s pace narrowi ng.





(3) Distinctive long bone periosteal elevation in leukemia may al l ow di fferent i at i on from JIA. Local i zed joi nt abnormal i t i es (e.g., os t eonecros i s and os t eochondri t i s ) may have di s t i nct radi ographi c pres ent at i ons .





(4) Cervical spine involvement, part i cul arl y wi t h ankyl os i s at C2â€“C3, i s common i n JIA.






o

a. A vari et y of genetic or inborn metabolic disorders as wel l as nonrheumat i c condi t i ons can s uperfi ci al l y res embl e JIA. It i s s peci fi cal l y i mport ant t o rul e out infectious etiologies (e.g., Lyme di s eas e and TB) and malignancies (e.g., l eukemi a) as caus es of chi l dhood art hri t i s .

o

o

b. Other rheumatic diseases (e.g., rheumat i c fever, SLE, and undi fferent i at ed connect i ve t i s s ue di s eas e) may requi re a peri od of obs ervat i on for charact eri s t i c ext ra-art i cul ar feat ures t o evol ve.

G. Therapeutic approach

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



1. Education of patients and parents about i nfl ammat ory art hri t i s i s i mport ant , and t he general l y favorabl e cours e of JIA s houl d be emphas i zed. Long-t erm goal s of s uppres s i on of di s eas e act i vi t y and prevent i on of deformi t y s houl d be i ns t i t ut ed, and chi l dren's ps ychol ogi cal and emot i onal devel opment s houl d not be negl ect ed.





2. The us e of appropri at e therapy i s i mport ant i n rel i evi ng pai n and mai nt ai ni ng funct i on. Parent s s houl d be urged t o perform act i ve rol es i n gi vi ng phys i cal t herapy and medi cat i ons , encouragi ng s chool at t endance, and mai nt ai ni ng chi l dren's abi l i t y t o be s el f-s uffi ci ent . o

o

a. Pharmacologic therapy 



(1) Salicylates. Thes e agent s are no l onger t he pri mary drugs us ed i n t he t reat ment of JIA becaus e of concerns about t he pot ent i al preci pi t at i on of Reye's s yndrome by as pi ri n.





(2) Other NSAIDs. Current l y, naproxen and i buprofen are mos t oft en pres cri bed as i ni t i al t reat ment . Al t hough i ndomet haci n and nabumet one are not FDA-approved for chi l dren, t hey are al s o effect i ve.





(3) Second-line agents. Met hot rexat e, t he

Pa g e 2 5 5 4


mos t commonl y us ed s econd-l i ne agent , i s effect i ve. Oral gol d, hydroxychl oroqui ne, and D-peni ci l l ami ne al s o are now rarel y us ed i n t he t reat ment of juveni l e rheumat oi d art hri t i s . Sul fas al azi ne i s al s o us ed becaus e i t has rapi d ons et of effect , i nfrequent s eri ous t oxi ci t y, and rel at i vel y good effi cacy. A recent t ri al of l efl unomi de s howed t he agent t o be effect i ve. 



(4) Biologic agents. Et anercept , a genet i cal l y engi neered fus i on prot ei n of recombi nant TNF and human IgG, i s approved for us e i n chi l dren. Thi s agent i s mos t oft en i ndi cat ed i n juveni l e rheumat oi d art hri t i s of a pol yart i cul ar cours e t hat i s unres pons i ve t o met hot rexat e.





(5) Corticosteroids 



(a) In patients with systemic complaints who have life-threatening manifestations (e.g., peri cardi t i s ), moderat e-t o-hi gh-dos e s ys t emi c cort i cos t eroi ds may be requi red. P.506





(b) In nonambulatory children with polyarticular disease, a s mal l , every-ot her-day dos e of cort i cos t eroi ds may promot e wei ght beari ng. The cons equences of bei ng nonambul at ory i n

Pa g e 2 5 5 5


chi l dhood out wei gh pos s i bl e cort i cos t eroi d compl i cat i ons i n t hi s cl i ni cal s i t uat i on. 



(c) Local cort i cos t eroi d i nject i ons oft en are effect i ve i n managi ng pauci-articular disease or more severely involved joints in polyarticular disease. In s ome chi l dren wi t h l i mi t ed pauci -art i cul ar di s eas e, i nt ra-art i cul ar s t eroi d t herapy at ons et may l ead t o compl et e remi s s i on.





(d) In t he t reat ment of chronic uveitis, s ys t emi c cort i cos t eroi ds may be needed i f i ni t i al t reat ment wi t h t opi cal or l ocal cort i cos t eroi ds and di l at i ng agent s i s not effect i ve. Recent cl i ni cal t ri al s wi t h i nfl i xi mab are very encouragi ng. Pat i ent s at hi gh ri s k for chroni c uvei t i s (ol i goart i cul ar s ubgroup) s houl d be eval uat ed every 3 mont hs t o det ermi ne t reat ment effect i venes s .





(6) Intravenous infusions of gamma globulin. Thi s agent has been us ed t o cont rol s evere s ys t emi c-ons et or pol yart i cul ar di s eas e.

o

o

b. Surgery. Correct i on of deformi t i es and t ot al joi nt repl acement s may be needed i n chroni c, s evere di s eas e. Jaw i mpl ant s have been us ed for mi crognat hi a.

o

Pa g e 2 5 5 6


o

c. Physical and occupational therapy. Such t reat ment i s es peci al l y i mport ant i n JIA. Chi l dren mus t l earn and pract i ce exerci s es t hat mai nt ai n mus cl e t one and prevent joi nt cont ract ures . Ni ght s pl i nt s may hel p mi ni mi ze t he evol ut i on of joi nt cont ract ures ; s eri al s pl i nt i ng may i mprove exi s t i ng joi nt cont ract ures .

H. Prognosis 



1. Disability. Bet ween 50% and 75% of pat i ent s recover compl et el y by adul t hood. Approxi mat el y 10% devel op s evere funct i onal deformi t i es .





2. Specific complications o

o

a. Joint deformities. Pat i ent s wi t h pol yart i cul ar art hri t i s are mos t l i kel y t o devel op chroni c, eros i ve art hri t i s and s ubs equent joi nt deformi t i es , es peci al l y t hos e chi l dren wi t h rheumat oi d fact or, who res embl e pat i ent s wi t h adul t rheumat oi d art hri t i s .

o

o

b. Chronic uveitis. As much as 15% of pat i ent s wi t h ol i goart i cul ar di s eas e who have chroni c uvei t i s devel op s ome vi s ual i mpai rment , even i f t he probl em i s careful l y t reat ed.

o

o

c. Growth retardation 

Pa g e 2 5 5 7


(1) General growth retardation can occur i n pat i ent s wi t h pers i s t ent , wi des pread i nfl ammat ory act i vi t y and i n t hos e t reat ed wi t h s ys t emi c cort i cos t eroi ds .





(2) Local growth abnormalities from t he i nfl ammat ory proces s can l ead t o micrognathia as wel l as t o leg and finger length discrepancies i n s ome pat i ent s .





3. Death. Macrophage act i vat i on s yndrome may be l i fe-t hreat eni ng, and, i n rare cas es , pat i ent s wi t h part i cul arl y s evere and prot ract ed di s eas e devel op progres s i ve amyloidosis or di e of s econdary i nfect i on. Rarel y, overwhel mi ng myocarditis i n s ys t emi c-ons et juveni l e rheumat oi d art hri t i s can l ead t o CHF and deat h.

XIV. Miscellaneous Syndromes A. Rheumatic manifestations of human immunodeficiency virus (HIV) Mus cul os kel et al compl ai nt s are rel at i vel y common duri ng t he cours e of HIV i nfect i on. The cl i ni cal s pect rum i s vari ed, rangi ng from art hral gi as t o di s t i nct rheumat i c di s orders . Art hral gi a and myal gi as , t he mos t common rheumat i c mani fes t at i ons , occur i n 10%â€“20% of pat i ent s , us ual l y wi t h t he i ni t i al i nfect i on. Ot her mani fes t at i ons can be cl as s i fi ed i nt o t he fol l owi ng groups : 



1. Spondyloarthropathy (react i ve art hri t i s , ps ori at i c art hri t i s , and undi fferent i at ed s pondyl oart hropat hy). In young pers ons wi t h s eronegat i ve art hri t i s , i t i s i mport ant t o cons i der HIV.



Pa g e 2 5 5 8


2. HIV-associated arthritis. The us ual pres ent at i on i s an ol i goart i cul ar as ymmet ri c peri pheral art hri t i s affect i ng t he knees and ankl es . A s ymmet ri cal pol yart i cul ar eros i ve form, whi ch can al s o occur, may be di ffi cul t t o di s t i ngui s h from rheumat oi d art hri t i s . Thi s form i s us ual l y res pons i ve t o t reat ment wi t h NSAIDs .





3. Painful articular syndrome. Thi s poorl y unders t ood s yndrome, whi ch affect s 10% of HIV-i nfect ed pat i ent s , i s charact eri zed by s evere joi nt pai n of abrupt ons et t hat l as t s a few hours t o 2 days . Laborat ory s t udi es and i magi ng res ul t s us ual l y are normal . P.507





4. Septic arthritis. Thi s condi t i on i s us ual l y s een more frequent l y i n pat i ent s wi t h a hi s t ory of i nt ravenous drug abus e and i n hemophi l i acs . Bot h t he us ual and opport uni s t i c organi s ms are i mpl i cat ed. In i nt ravenous drug abus ers , t he mos t common pat hogens are S. aureus and St rept oc oc c us pneumoni ae. Of t he opport uni s t i c organi s ms , Candi da al bi c ans i s t he mos t common. Axi al joi nt s are affect ed more frequent l y t han peri pheral joi nt s .





5. Diffuse infiltrative lymphocytosis syndrome (DILS). Thi s s yndrome cons i s t s of dry eyes and mout h wi t h a pos i t i ve Schi rmer t es t and s al i vary gl and enl argement . DILS di ffers from cl as s i c SjÃ¶gren's s yndrome i n t hat i t us ual l y affect s mal es and i s not charact eri zed by art hri t i s or aut oant i body product i on (SS-A, SS-B, and rheumat oi d fact or).

Pa g e 2 5 5 9




6. Myopathies. Si gni fi cant mus cl e weaknes s may be t he pres ent i ng compl ai nt . Such condi t i ons may be t he res ul t of HIV myopat hy, z i dovudi ne myopat hy, HIV was t i ng s yndrome, rhabdomyol ys i s , or pyomyos i t i s .





7. Avascular necrosis and osteopenia/osteoporosis. Recent l y, avas cul ar necros i s has been report ed i n HIV pat i ent s . The et i ol ogy i s uncl ear. Os t eopeni a and os t eoporos i s l i kewi s e are newer fi ndi ngs i n t hi s pat i ent group. HIV t herapy may be i mpl i cat ed.

B. Hepatitis and cryoglobulinemia Bot h HBV and HCV can be l i nked wi t h art hri t i s . HBV i s as s oci at ed wi t h s udden-ons et s ymmet ri c art hri t i s occas i onal l y found wi t h urt i cari a. HCV i s oft en as s oci at ed wi t h t ype II cryogl obul i nemi a and can mani fes t as a combi nat i on of art hri t i s , pal pabl e purpura, and cryogl obul i nemi a.

C. Acute rheumatic fever (ARF) The di s order occurs fol l owi ng a group A s t rept ococcus (S. pyogenes ) pharyngeal i nfect i on. In one-t hi rd of pat i ent s , t he t ri ggeri ng i nfect i on i s s i l ent , but i t can be i dent i fi ed s erol ogi cal l y. The i ncubat i on peri od from pharyngi t i s t o i nfect i on i s 2â€“3 weeks . Accordi ng t o t he revi s ed Jones Cri t eri a (1992) for t he di agnos i s of ARF, i f a pat i ent has s upport i ve evi dence of precedi ng i nfect i on, t he pres ence of t wo major or one major and t wo mi nor mani f es t at i ons s ugges t s a hi gh probabi l i t y of ARF. 



1. Major manifestations are cardi t i s , pol yart hri t i s , chorea, eryt hema margi nat um, and s ubcut aneous nodul es . The art hri t i s i s us ual l y mi grat ory, preferent i al l y affect i ng t he l arge joi nt s of t he l ower ext remi t i es . Pai n i n affect ed joi nt s may be out of proport i on t o phys i cal

Pa g e 2 5 6 0


exami nat i on fi ndi ngs of i nfl ammat i on. 



2. Minor manifestations are art hral gi as , fever, el evat ed ESR, and a prol onged P-R i nt erval .





3. Supporting evidence of preceding group A streptococcal infection i ncl udes a pos i t i ve t hroat cul t ure, el evat ed or ri s i ng ant i s t rept ol ys i n-O t i t er, or rapi d s t rept ococcal ant i gen t es t .

D. Avascular necrosis Thi s condi t i on, whi ch i s al s o referred t o as osteonecrosis, i s us ed t o des cri be t he deat h of cel l ul ar component s of bone as t he res ul t of di mi ni s hed art eri al bl ood s uppl y. It may be i di opat hi c or occur i n a vari et y of s et t i ngs as s oci at ed wi t h cert ai n medi cat i ons (s t eroi ds and cyt ot oxi c agent s ), underl yi ng connect i ve t i s s ue di s eas es , hemat ol ogi c di s orders , i nfi l t rat i ve di s orders , embol i s m, al cohol , and t rauma. Invol vement of t he epi phys i s of l ong bones s uch as t he femoral heads i s us ual l y charact eri s t i c, but ot her bones can be affect ed. In t he earl i es t s t ages , di agnos i s can be made by MRI, but at l at er s t ages , fi ndi ngs can be i dent i fi ed on pl ai n fi l ms . Bl ood s t as i s , hypercoagul abi l i t y, and damage t o endot hel i al cel l s are i mport ant .

E. Fibromyalgia Thi s common noni nfl ammat ory condi t i on i s charact eri zed by di ffus e pai n. The et i ol ogy remai ns uncl ear, but affect ed pat i ent s t end t o have di s rupt i on of nonâ€“rapi d-eye movement (REM) s t age IV s l eep. In addi t i on t o di ffus e pai n, pat i ent s oft en report probl ems wi t h i ns omni a, i rri t abl e bowel , t ens i on headaches , mi grai nes , and depres s i on. Exami nat i on reveal s mul t i pl e t ender poi nt s (pai n on pal pat i on) over t he fol l owi ng mus cl e regi ons : s ubocci pi t al mus cl e i ns ert i on; t rapezi us ; s upras pi nat us ; gl ut eal ; great er t rochant er; l ow ant eri or cervi cal ; s econd cos t ochondral junct i on, 2 cm di s t al t o t he l at eral epi condyl es ; and t he medi al fat pad of t he knees , proxi mal

Pa g e 2 5 6 1


t o t he joi nt l i ne. Laborat ory i nves t i gat i on s houl d i ncl ude s t udi es t o rul e out met abol i c di s orders (e.g., hypot hyroi di s m and hypert hyroi di s m); el ect rol yt e di s t urbances (e.g., l ow magnes i um, cal ci um, or phos phorus ); l i ver di s eas e (e.g., vi ral hepat i t i s ); connect i ve t i s s ue di s eas e (e.g., PMR and SLE); and pri mary myopat hy as cl i ni cal l y i ndi cat ed. Treat ment i s ai med at i mprovi ng t he qual i t y of s l eep. Ami t ri pt yl i ne or l ow-dos e mus cl e rel axant s , i n addi t i on t o regul ar phys i cal exerci s e, are commonl y us ed. If depres s i on i s a major component , referral for ps ychi at ri c cons ul t at i on i s i ndi cat ed. P.508

F. Amyloidosis The t hree mai n forms of amyl oi d depos i t i on di s orders t hat pres ent wi t h an art hropat hy are AL amyl oi d, B2 mi crogl obul i n amyl oi d, and AA amyl oi d. 



1. AL amyloid us ual l y mani fes t s as prot ei nuri a/renal fai l ure, a cardi omyopat hy, or a vari et y of neuropat hi c s ympt oms . Ot her fi ndi ngs i ncl ude edema, hepat omegal y, macrogl os s i a, and purpura. Peri -art i cul ar amyl oi d depos i t i on can pres ent as a ps eudoart hri t i s , but joi nt effus i ons wi t h amyl oi d fi bri l s may al s o be found. The charact eri s t i c fi ndi ng may be a s oft t i s s ue â€œs houl der pad s i gn.â€•





2. B2 microglobulin amyl oi d i s t he s econd mos t common form of amyl oi d depos i t i on. Mos t pat i ent s who devel op t hi s form of amyl oi dos i s have been on renal di al ys i s for prol onged peri ods and pres ent wi t h joi nt pai n, carpal t unnel s yndrome, and os t eonecros i s .



Pa g e 2 5 6 2


3. AA amyloid i s found i n pat i ent s wi t h rheumat oi d art hri t i s and fami l i al Medi t erranean fever. It i s al s o referred t o as a s econdary (react i ve) amyl oi d, becaus e i t can occur i n any chroni c i nfl ammat ory di s order, i ncl udi ng i nfect i ons , neopl as i a, or ot her rheumat i c condi t i ons .

G. Parvovirus B19 infection Parvovi rus or Fi ft h's di s eas e i s endemi c i n s chool -age chi l dren. It mani fes t s as fever, cons t i t ut i onal s ympt oms , and a â€œs l apped cheekâ€• appearance wi t h s t ri ki ng eryt hema on t he chi l d's face. Adul t s t ypi cal l y pres ent wi t h art hral gi as or a s ymmet ri cal art hri t i s t hat may mi mi c rheumat oi d art hri t i s . Tes t i ng for Parvovi rus s erol ogy earl y i n t he cours e of t he di s eas e can be di agnos t i c (pos i t i ve IgM ant i body). The cours e i s s el f-l i mi t ed and res ponds t o ant i -i nfl ammat ory pai n medi cat i ons .

H. Relapsing polychondritis H. Rel aps i ng pol ychondri t i s i s a condi t i on charact eri zed by i nfl ammat i on of cart i l age. It can affect any cart i l age i n t he body, but mos t commonl y affect s t he cart i l agi nous port i on of t he nos e and ext ernal ear, pres ent i ng as s udden pai n, rednes s , and s wel l i ng wi t h event ual des t ruct i on i f unt reat ed. The et i ol ogy i s uncl ear, but aut oi mmune mechani s ms may be i nvol ved. It i s s omet i mes as s oci at ed wi t h ot her connect i ve t i s s ue di s orders as wel l as mal i gnanci es .

I. Auto-inflammatory diseases Thes e di s orders are del i neat ed mos t oft en by cycl es of cl i ni cal i nfl ammat i on wi t hout t he pres ence of ant i gen-s peci fi c T cel l s or charact eri s t i c aut oant i bodi es . Several of t hes e di s eas es previ ous l y have been cat egori zed as peri odi c fever s yndromes . Over t he l as t 5 years , t he genet i c bas i s for mos t of t hes e di s orders has been det ermi ned, and DNA s equenci ng t o det ect s peci fi c mut at i ons i s avai l abl e i n commerci al l aborat ori es (s ee onl i ne Tabl e 10-16).

ONLINE TABLE 10-16 AutoInflammatory

Pa g e 2 5 6 3


Diseases F e at

T

N

u

R H F

O

r F A I C MM e M P D AW I s F S S S S D M Je Sc D N N N aj wi ot ut o o o o s t i ch p p p r h, s , at at at A T h, Fr t e t e t e n ur Ir e rn rn rn c ki i s nc e s h h st h, ry Ar a b, Ar m e ni a n G A A A A A R e ut ut ut ut ut ar n o o o o o el et s s s s s y ic o o o o o a P m m m m m ut at al al al al al o te R D R d d s

Pa g e 2 5 6 4


r ec o ec o o o n e me mmm s s i n s s i n i n al iv a iv a a d e nt e nt nt o m in a nt C 1 1 1 1 1 1 h 6 2 2 q q q r p p q 4 4 4 o 1 1 2 4 4 4 m3 3 4 o s o m al L o c at io n G M T M CI CI CI e E N e A A A n F F v S S S e V R al 1 1 1 I

S o

n

FI n

v

A at

ol

(t e

v

y ki

e

p n

Pa g e 2 5 6 5


d

e a I s T e N F re ce pt or

) A 9 1 6 9 8 M g 0 0 m5 5 o e % 0 o % % st at b % nt < < wi O y b h 6 2 th n a y s m 0 in s g a m et e g e

Y 6 m

2 e di 0 2 a 0 n D 1 D 3 < 2 C u â a â 2 â o r €“ ys €“ 4 €“ nt at 3 t o 7 h 3 i n io d w d o d u n a e a ur a o of ys e ys s ys u A

ks

s

tt a c k s A P P P N N N b er ai ai o o o

Pa g e 2 5 6 6


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Pa g e 2 5 6 7


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Pa g e 2 5 6 8


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Pa g e 2 5 7 1


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Pa g e 2 5 7 2


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oi s d s ESR, eryt hrocyt e s edi ment at i on rat e; IgD, i mmunogl obul i n D; IL-1, i nt erl euki n-1; NSAIDs , nons t eroi dal ant i -i nfl ammat ory drugs ; TNF, t umor necros i s fact or; W BC, whi t e bl ood cel l . 



1. Familial Mediterranean Fever (FMF). Thi s di s order us ual l y pres ent s before age 20 wi t h peri odi c 1- t o 3-day epi s odes of fever, pl euro-peri t oneal pai n, and art hri t i s . A majori t y of pat i ent s , part i cul arl y t hos e not t reat ed

Pa g e 2 5 7 3


wi t h col chi ci ne, devel op amyl oi dos i s . 



2. T umor Necrosis Factorâ€“Associated Periodic Syndrome (T RAPS). Thi s s yndrome al s o pres ent s pri mari l y before age 20, but pat i ent s experi ence l onger and l es s regul ar epi s odes of fever and al s o devel op t ender deep eryt hemat ous pat ches and pai nful conjunct i val i nject i on.





3. Hyper IgD Syndrome (HIDS). Cl i ni cal s ympt oms us ual l y s t art wi t hi n t he fi rs t 6 mont hs of l i fe. Al ong wi t h fever, t here i s s i gni fi cant abdomi nal pai n, oft en wi t h di arrhea, cervi cal l ymphadenopat hy, macul opapul ar ras h, and ol i goart hri t i s .





4. Familial Cold Auto-inflammatory Syndrome (FCAS). Sympt oms s t art duri ng i nfancy wi t h a s hort -l i ved ( Chapt er 11 - Neurologic Disorders

Chapter 11

Neurologic Disorders Kerri Kissel Neil Porter

I. Approach to the Patient with a Neurologic Complaint A. Patient history The pat i ent hi s t ory i s t he corners t one of neurol ogi c as s es s ment . 



1. Key questions. Ques t i ons t hat may hel p di rect t he pat i ent i nt ervi ew i ncl ude: o

o

a. W as t he ons et of s ympt oms gradual or s udden?

o

o

b. Are t he s ympt oms s t at i c, i nt ermi t t ent , or progres s i ve?

o

o

c. Has t he probl em remai ned l i mi t ed i n s cope, or have new feat ures been i nt roduced over t i me?

o

o

d. W hat concurrent probl ems does t he pat i ent have, and what medi cat i ons or drugs are bei ng us ed?

o

o

e. Is t here a fami l y hi s t ory of t he di s order or

Pa g e 2 5 8 9


predi s pos i ng condi t i ons ? o

o

f. W hat habi t s and t oxi n expos ures mi ght t he pat i ent have?





2. Review of symptoms. Dependi ng on t he cl i ni cal compl ai nt , a pat i ent s houl d be as ked whet her t here i s any hi s t ory of: o

o

a. Headache or t rauma t o t he head, neck, or s pi ne

o

o

b. Los s of cons ci ous nes s , convul s i ve act i vi t y, mood al t erat i ons , confus i on, or memory di s t urbances

o

o

c. Impai red or doubl e vi s i on, faci al numbnes s or weaknes s , i mpai red heari ng or s wal l owi ng, or abnormal s peech

o

o

d. Arm or l eg weaknes s or heavi nes s , s l ownes s of movement , al t ered l i mb s ens at i on, di s comfort or t i ngl i ng i n t he ext remi t i es

o

o

e. Cl ums i nes s , fal l i ng, or di zzi nes s

o

o

f. Bowel or bl adder di s t urbances or s exual dys funct i on

B. Neurologic examination From t he pat i ent hi s t ory, t he phys i ci an can generat e a s eri es of

Pa g e 2 5 9 0


di agnos t i c hypot hes es t hat can be t es t ed wi t h a focus ed neurol ogi c exami nat i on. Anat omi c l ocal i zat i on of t he pat hol ogy wi t hi n t he nervous s ys t em i s es s ent i al t o t hi s proces s (Fi gure 11-1). 



1. Mental status. If t he pat i ent 's ment al s t at us i s abnormal , t he hi s t ory and t hos e component s of t he phys i cal exami nat i on t hat depend on pat i ent cooperat i on mus t be approached wi t hi n t he proper cont ext . For exampl e, i f t he pat i ent i s confus ed, t he s ens ory exami nat i on may be unrel i abl e. o

o

a. The pat i ent 's l evel of arous al , ori ent at i on, s hort - and l ong-t erm memory, affect (i .e., mood), concent rat i on and at t ent i on, fund of knowl edge, i ns i ght , judgment , and cons t ruct i onal abi l i t y s houl d be as s es s ed.

o

o

b. Li ngui s t i c abi l i t i es are eval uat ed by exami ni ng comprehens i on, repet i t i on, fl uency, nami ng, readi ng, and wri t i ng.

o

o

c. The i nt egri t y of ot her cort i cal funct i ons (e.g., graphes t hes i a, s t ereognos i s , t wo-poi nt di s cri mi nat i on, ri ght â€“l eft ori ent at i on, and negl ect ) s houl d be exami ned i f pari et al l obe dys funct i on i s s us pect ed.





2. Cranial nerves. Exami nat i on of crani al nerves IIâ€“XII i s neces s ary (Tabl e 11-1). o

o

a. In part i cul ar, vi s ual acui t y and fi el ds s houl d be

Pa g e 2 5 9 1


checked; t he opt i c nerve s houl d be exami ned; and abnormal i t i es of ocul ar mot i l i t y, i ncl udi ng nys t agmus and dys met ri a, s houl d be document ed (Tabl e 11-2). o

o

b. Abnormal i t i es of faci al s ens at i on (i ncl udi ng t he corneal refl ex) and movement al s o s houl d be i nves t i gat ed.

P.517

Pa g e 2 5 9 2


FIGURE 11-1 Summary of s ome of t he out s t andi ng neurol ogi c s i gns and s ympt oms t hat occur wi t h focal des t ruct i ve l es i ons i n t he ri ght or l eft cerebral hemi s phere as det ect ed on neurol ogi c exami nat i on. (A) Lat eral vi ew of t he l eft cerebral hemi s phere. (B ) Lat eral vi ew of t he ri ght cerebral hemi s phere. (Repri nt ed from NMS Neuroanat omy. Mal vern, PA: Harwal Publ i s hi ng, 1988:314 ).

TABLE 11-1 Twelve Cranial Nerves C N F N er u v n e ct io n I Ol S fa m ct el or l y II O Vi pt s i ic o n II O Ey I cu e lo m m ov ot e or m

Page 2593


e nt s IV Tr Ey oc e hl d e e ar pr es si o n ( w h e n a d d uc te d) V Tr Fa i g ci e al m se i n ns al at io n VI A Ey b e d a uc b e d

Pa g e 2 5 9 4


ns uc ti o n VI Fa Fa I ci ci al al m ov e m e nt VI V H II es e t i ar b in ul g oc oc hl e ar IX Gl P os al s o at p al h se ar ns yn at g io e n al X V P a al g at us al

Pa g e 2 5 9 5


m ov e m e nt XI S S pi h n o al ul ac d ce er ss sh or ru y g XI H T I yp o o n gl g os u sa e l

pr ot ru si o n

CN, crani al nerve. P.518

TABLE 11-2 Innervation of the Eye by

Pa g e 2 5 9 6


Its Six Nerves N In Cl u n in m er ic b v al er at Ef a io fe n n ct d

s

N

of

a

In

m

te

e

rr

of

u

N

pt

er

io

v

n

e

of N er v

e Effere nt C St Di N ri pl II at o I e pi (o d a, cu m ey l o us e m cl a ot e: b or s u d

Pa g e 2 5 9 7


n p uc er er t e ve i o d ) r, a m n e d di t u al rn ,

e

a d n d d o in w fe n ri Pt or os re i s ct (p i ; ar i n al fe ys ri i s or of o vo bl l i t iq io u n e al Le l i va d t o el r ev p at al i o p n)

Pa g e 2 5 9 8


e P br u a pi e l S di m la o te ot d h a m n us d cl fi e: xe p d u to pi l i ll g oc ht o Lo ns s s t ri of ct l e or ns Ci t h li ic ar ke y ni m n us g cl e C St Di N ri pl IV at o (t e pi

Pa g e 2 5 9 9


ro d a, ch m m l e us os ar cl t n e: s e er s u ve ve p re ) er o io n r lo o ok bl i n iq g u d e o w n a n d in ; ey e ex to rt e d; h e a d til te

Pa g e 2 6 0 0


d to si d e o p p os it e p ar al yz e d ey e C St Di N ri pl VI at o (a e pi b d a, d m m uc us os e cl t ns e: s e n l a ve er t e re ve ra o ) l

n

re l o ct ok u in

Pa g e 2 6 0 1


us g to si d e of p ar al ys is ; ey e tu rn e d in (a d d uc te d) C S H ar m or ot o n i d ot er s y h 's m m sy p us n at cl dr h e; o et s u m

Pa g e 2 6 0 2


ic p e n er (p er i o t o ve r s i ta s, rs m al i o a si n s, d h p e u m pi i f l l ac o ia di l la a to n r hi dr os is , va so di la ti o n) Affere nt C Fr Bl N o in II m d

Pa g e 2 6 0 3


(o re n pt t i es ic n s n a er ve ) C C A N or n V n es (t e t h ri al es g /c i a e o of m nj co i n u rn al nc e n ti a er va wi ve l

th

) af l o fe s s re of nt co s rn e al re fl ex Adapt e d from NMS Neuroa nat om

Pa g e 2 6 0 4


y. Mal ver n, PA: Harwal Publ i s hi ng, 1988:2 19.





3. Sensory system. Regi ons of abnormal t ouch, pai n (es t i mat ed by pi npri ck), t emperat ure, vi brat i on, and propri ocept i on s houl d be defi ned. o

o

a. Are t he fi ndi ngs confi ned t o one s i de of t he body, t he di s t ri but i on of one or more dermat omes , or t he t erri t ory of one or more peri pheral nerves ?

o

o

b. Are t he s ens ory changes found i n a â€œs t ocki ngâ€“gl oveâ€• di s t ri but i on?





4. Motor system o

o

a. The pat i ent 's strength s houl d be defi ned as i t pert ai ns t o i ndi vi dual mus cl es or groups of mus cl es . One convent i onal met hod of gradi ng mus cl e s t rengt h for purpos es of compari s on and des cri pt i on i s s hown i n Tabl e 11-3.

o

Pa g e 2 6 0 5


b. A pronat or dri ft can be as s es s ed by havi ng pat i ent s ext end t hei r arms (pal m upward) wi t h t hei r eyes cl os ed. Any depres s i on or pronat i on i s s i gni fi cant .

o

o

c. The pres ence of atrophy, fasciculations, spasticity, and rigidity s houl d be not ed.

o

o

d. The pat i ent 's abi l i t y t o perform rapid alternating and other complex maneuvers s houl d be det ermi ned.

o

o

e. The pat i ent 's stance and gait s houl d be eval uat ed.





5. Coordination. Fi nger-t o-nos e and heel -t o-s hi n t es t i ng s houl d be performed. The phys i ci an s houl d l ook for Romberg' s sign (i .e., s wayi ng or fal l i ng when s t andi ng wi t h eyes cl os ed and feet cl os e t oget her).





6. Muscle stretch reflexes. The act i vi t y and s ymmet ry of t he brachi oradi al i s (C5, C6), bi ceps (C5, C6), t ri ceps (C7, C8), knee (L3, L4), and ankl e (S1, S2) refl exes s houl d be det ermi ned. The pres ence of t he Babinski response s houl d be as s es s ed wi t h pl ant ar s t i mul at i on.

TABLE 11-3 Medical Research Council of Great Britain Muscle Strength Grading Scale

Pa g e 2 6 0 6


Gr Eq ad uiv e ale nt Pa tie nt Abi lity 5/5 Nor ma l abi lity 4/5 Abi lity to ove rco me gra vi t y an d so me res ist anc e im pos ed by

Pa g e 2 6 0 7


t he exa mi ner 3/5 Abi lity to ove rco me gra vi t y onl y 2/5 Abi lity to mo ve wi t h gra vi t y el i mi nat ed 1/5 Onl y a fl i c ker of mo ve

Pa g e 2 6 0 8


me nt 0/5 Co mp l et e i na bi l i ty to mo ve P.519

C. Neurodiagnostic studies 



1. Cerebrospinal fluid (CSF) evaluation o

o

a. Indications. St udy of t he CSF can provi de i nformat i on about i nt racrani al pres s ure (ICP) and i nfect i on, bl eedi ng, mal i gnancy, and s t eri l e i nfl ammat i on wi t hi n t he cent ral nervous s ys t em (CNS).

o

o

b. Specific measurements and assays 



(1) Pressure. The openi ng pres s ure s houl d be det ermi ned. Pres s ure exceedi ng 180â€“200 mm H 2 O i s abnormal when a pat i ent i s rel axed and i n a l at eral decubi t us pos i t i on.

Pa g e 2 6 0 9




(2) Protein. An el evat ed CSF prot ei n l evel i s a nons peci fi c i ndi cat or of i nfl ammat i on or breakdown of t he bl oodâ€“brai n barri er.





(3) Glucose. Hypoglycorrhachia (i .e., CSF gl ucos e 185 mm Hg or a di as t ol i c bl ood pres s ure >110 mm Hg





(iv) A medi cat i on-i nduced or di s eas e-rel at ed coagul opat hy





(v) A hi s t ory of hemorrhagi c s t oke, recent s urgery, or anot her i nvas i ve procedure





(2) Al t hough not yet â€œs t andard of care,â€ • t here i s i ncreas i ng experi ence wi t h i nt ra-art eri al t hrombol ys i s and s everal

Pa g e 2 6 9 3


mechani cal approaches t o i nt ra-art eri al cl ot l ys i s for pat i ent s acut el y pres ent i ng wi t h l arge art ery t hromboembol i c occl us i ons . A vari et y of i magi ng t echni ques , i ncl udi ng CT and MR perfus i on s cans , MR di ffus i on, and CT or MR angi ography may as s i s t i n pat i ent s el ect i on. 



2. T ransient ischemic attacks (T IAs) are s hort -l i ved neurol ogi c defi ci t s , t ypi cal l y l as t i ng mi nut es . A recent recommendat i on i s t hat t he maxi mal durat i on of a TIA be revi s ed downward t o 1 hour, i n cont radi s t i nct i on t o t he cl as s i c defi ni t i on of up t o 24 hours . Sympt oms are at t ri but abl e t o i s chemi a i n t he carot i d or vert ebrobas i l ar art eri al di s t ri but i ons . The di s t i nct i on bet ween a TIA and a s t roke i s arbi t rary, and even a bri ef s ympt omat i c epi s ode of cerebral i s chemi a, i n conjunct i on wi t h an abnormal di ffus i on wei ght ed i magi ng (DW I) s can, mi ght be cons t rued as repres ent i ng a s t roke. Bot h warrant compl et e eval uat i on t o det ermi ne t he underl yi ng pat hophys i ol ogy and decreas e t he ri s k of s ubs equent i s chemi c event s . o

o

a. Etiology. Al t hough TIAs oft en res ul t from at heros cl erot i c l arge ves s el di s eas e, ot her di agnos t i c pos s i bi l i t i es des erve cons i derat i on, i ncl udi ng cardi ogeni c embol i , aort i c arch at herot hrombot i c embol i , ot her l arge art ery di s orders s uch as di s s ect i on and fi bromus cul ar dys pl as i a, s mal l art ery di s eas e, hemat ol ogi c di s orders , and mi grai ne. Ot her di s eas e ent i t i es s uch as s ei zures , t umors , s ubdural hemat omas , and MS s omet i mes mas querade as a TIA.

o

Pa g e 2 6 9 4


o

b. Diagnosis. Di agnos t i c s t udi es s houl d i ncl ude a CBC, s yphi l i s s erol ogy, a coagul at i on profi l e, and a CT s can or MRI. A t rans t horaci c or t rans es ophageal echocardi ogram and 24-hour ambul at ory el ect rocardi ography (ECG) moni t ori ng may be i ndi cat ed. 



(1) A dupl ex exami nat i on of t he ext racrani al carot i d art ery t erri t ory i s oft en i nformat i ve.





(2) TCD s t udi es , MRA, and CTA can provi de i ns i ght i nt o t he ext racrani al and i nt racrani al art eri al ci rcul at i on.





(3) Convent i onal i nt ervent i onal angi ography i s t he defi ni t i ve t es t t o out l i ne t he vas cul ar anat omy.





(4) Pat i ent s wi t h an unreveal i ng cardi ac eval uat i on who are t hought t o have an embol us may benefi t from a t rans es ophageal echocardi ogram.





(5) If cl i ni cal s us pi ci on exi s t s , an LP can be us ed t o eval uat e t he pos s i bi l i t y of CNS i nfl ammat i on.

o

o

c. T herapy. If at heros cl eros i s i s s us pect ed as t he caus e of t rans i ent cerebral i s chemi a, cont rol of ri s k fact ors for at heros cl eros i s i s es s ent i al (s ee Chapt er

Pa g e 2 6 9 5


1 III A 2). An eval uat i on for coronary art ery di s eas e i s al s o appropri at e. 



(1) Extracranial carotid artery disease. Carot i d endart erect omy i s s uperi or t o medi cal t herapy i n t he prevent i on of i s chemi c s t roke i n pat i ent s experi enci ng a TIA i ps i l at eral t o an angi ographi cal l y demons t rat ed 50%â€“99% s t enos i s at t he i nt ernal carot i d art ery ori gi n. 



(a) Pat i ent s wi t h l es s s evere s t enos i s s houl d be t reat ed wi t h as pi ri n. Cl opi dogrel or as pi ri n combi ned wi t h s l ow-rel eas e di pyri damol e are al s o effect i ve i n prevent i ng s t roke.





(b) Ri s k fact or management pert i nent t o at heros cl eros i s i s appropri at e.





(2) Intracranial large artery disease. A TIA can res ul t from l arge art ery s t enos i s or occl us i on. Recent evi dence s ugges t s t hat as pi ri n t herapy i s s afer t han, and as effect i ve as , ant i coagul at i on t herapy for s ympt omat i c i nt racrani al l arge art ery s t enos i s . P.538





(3) Other causes of T IA. Therapy s houl d be di rect ed at t he appropri at e pat hophys i ol ogi c proces s . For i ns t ance, ant i coagul ant s are

Pa g e 2 6 9 6


frequent l y us ed i n pat i ent s wi t h a s ource of cardi ogeni c embol i . 



3. Cardiogenic embolic stroke o

o

a. Etiology. The mos t common caus e of embol i c s t roke i s nonval vul ar at ri al fi bri l l at i on. 



(1) Ot her condi t i ons as s oci at ed wi t h cardi ogeni c embol i i ncl ude recent myocardi al i nfarct i on (MI), an aki net i c vent ri cul ar s egment , di l at ed cardi omyopat hy, a pros t het i c heart val ve, i nfect i ve and nonbact eri al t hrombot i c endocardi t i s , l eft heart myxoma, l eft at ri al s pont aneous cont ras t echo, and at ri al s ept al aneurys m.





(2) A pat ent foramen oval e (PFO) or at ri al s ept al defect predi s pos es pat i ent s t o paradoxi cal embol i , es peci al l y i f t here i s a document ed venous t hrombos i s . Pat i ent s younger t han 55 years of age wi t h a PFO and an as s oci at ed at ri al s ept al aneurys m may be at part i cul arl y hi gh ri s k for embol i c s t roke.





(3) Ot her cardi ac condi t i ons s uch as mi t ral val ve prol aps e or a hypoki net i c vent ri cul ar s egment are rarel y as s oci at ed wi t h a cardi ogeni c embol us .

o

o

b. Diagnosis. The di agnos i s i s mos t cert ai n i f t here

Pa g e 2 6 9 7


i s an abrupt ons et of neurol ogi c dys funct i on, an underl yi ng cardi ac condi t i on known t o predi s pos e t o embol i , s t rokes i n mul t i pl e vas cul ar t erri t ori es , hemorrhagi c art eri al i nfarct i on, s ys t emi c embol i , an abs ence of concurrent condi t i ons known t o caus e s t roke, and angi ography demons t rat i ng (pot ent i al l y t rans i ent ) ves s el occl us i ons i n t he abs ence of an i nt ri ns i c vas cul opat hy. Pat i ent s who have a cardi ac embol i s m rarel y pres ent wi t h al l of t hes e condi t i ons . o

o

c. T herapy. An i s chemi c i nfarct i on caus ed by a cardi ogeni c embol us may devel op i nt o a hemorrhagi c i nfarct i on, es peci al l y i f reperfus i on occurs or t he i nfarct i on i s l arge. Therefore, care mus t be t aken t o l es s en t he ri s k of parenchymal hemorrhage i n acut el y i l l pat i ent s whi l e s i mul t aneous l y t aki ng meas ures t o prot ect t hem from anot her embol i c s t roke. 



(1) If t he pat i ent has had a rel at i vel y s mal l i s chemi c embol i c i nfarct i on, a CT s can s houl d be obt ai ned. If no bl ood i s pres ent , a cont i nuous i nfus i on of hepari n i s admi ni s t ered. A part i al t hrombopl as t i n t i me (PTT) great er t han t wi ce t he cont rol val ue s houl d be avoi ded t o mi ni mi ze t he ri s k of hemorrhagi c convers i on of t he i s chemi c i nfarct i on and cl i ni cal wors eni ng.





(2) If t he pat i ent has had a l arge i s chemi c embol i c i nfarct i on, ant i coagul at i on t herapy s houl d be wi t hhel d for 5â€“7 days . If t he

Pa g e 2 6 9 8


pat i ent i s recoveri ng and a s ubs equent CT s can reveal s no bl ood, hepari n may be admi ni s t ered. 



(3) Subs equent t reat ment wi t h oral ant i coagul ant s depends on t he underl yi ng di s eas e proces s and t he pat i ent 's general condi t i on.





4. Large artery disease o

o

a. Aortic arch atheromas. or thrombi. Thes e t hrombi , whi ch are vi s ual i zed by t rans es ophageal echocardi ography, can embol i ze t o t he cerebral ci rcul at i on and caus e s t roke. Opt i mal management i s yet t o be defi ned but us ual l y i nvol ves ant i pl at el et or ant i coagul at i on t herapy, wi t h t he l at t er bei ng us ed for mobi l e, peduncul at ed t hrombi .

o

o

b. Asymptomatic cervical bruit and carotid stenosis. The combi nat i on of an i nt ernal carot i d art ery brui t and at heros cl eros i s at t he i nt ernal carot i d art ery ori gi n i s a marker for coronary art ery di s eas e as wel l as cerebrovas cul ar di s eas e. Approxi mat el y 2% of t hes e pat i ent s wi l l have an i s chemi c s t roke each year. Pat i ent s wi t h a hemodynami cal l y s i gni fi cant or progres s i ve s t enos i s are at i ncreas ed ri s k for cerebral i nfarct i on. 



(1) Etiology. A mi dcervi cal brui t can be caus ed by a hyperdynami c ci rcul at i on (e.g., as i n anemi a, pregnancy, and t hyrot oxi cos i s ), an

Pa g e 2 6 9 9


ext ernal carot i d art ery s t enos i s , an i nt ernal carot i d art ery s t enos i s , or a venous hum. 



(2) Diagnosis. Noni nvas i ve vas cul ar t es t i ng (s ee I C 3 d) i s hel pful i n det ermi ni ng whet her t he brui t ori gi nat es from at heros cl erot i c i nt ernal carot i d art ery di s eas e and whet her t he l es i on i s hemodynami cal l y s i gni fi cant . Angi ography i s us ual l y us ed i f t he pat i ent i s a s urgi cal candi dat e.





(3) T herapy 



(a) Control of risk factors for atherosclerosis (s ee Chapt er 1 III A 2). Ant i pl at el et t herapy (as pi ri n, cl opi dogrel , or as pi ri n combi ned wi t h s l ow-rel eas e di pyri damol e) i s oft en pres cri bed, and a careful coronary art ery eval uat i on i s warrant ed. P.539





(b) Medical treatment. Pat i ent s wi t h l es s t han a 50% i nt ernal carot i d art ery s t enos i s s houl d be managed medi cal l y.





(c) Carotid endarterectomy 



(i) Pat i ent s wi t h a 50%â€“99%

Pa g e 2 7 0 0


s t enos i s who undergo carotid endarterectomy have l es s of a ri s k of i ps i l at eral s t roke t han pat i ent s managed medi cal l y i f s urgery can be achi eved wi t h l es s t han a 3% ri s k of compl i cat i ons . 



(ii) Prophylactic carotid endarterectomy for uni l at eral , s l i ght l y or moderat el y s t enot i c, as ympt omat i c i nt ernal carot i d art ery di s eas e before major cardi ac or vas cul ar s urgery i s usually inadvisable.

o

o

c. Ischemic infarction. An unders t andi ng of neuroanat omy i s es s ent i al t o l ocal i ze t he compromi s ed area of t he brai n and t o correl at e t hi s i nformat i on wi t h a l i kel y s i t e of vas cul ar di s eas e. 



(1) Etiology 



(a) Large artery occlusive disease can caus e i s chemi c i nfarct i on, ei t her by bei ng a s ource of art ery-t o-art ery embol i or by caus i ng hypoperfus i on di s t al t o a hemodynami cal l y s i gni fi cant vas cul ar s t enos i s . Large art ery di s eas e can i nvol ve t he ext racrani al or i nt racrani al port i ons of t he cerebrovas cul ar ci rcul at i on.



Pa g e 2 7 0 1


(b) Vas cul ar condi t i ons ot her t han at heros cl eros i s (e.g., arterial dissection, arteritis, T akayasu' s syndrome, fibromuscular dysplasia, and radiation-induced vasculopathy) s houl d be cons i dered.





(2) Diagnosis. Di agnos t i c s t udi es are purs ued t o defi ne t he vas cul ar anat omy. CTA, MRA, carot i d dupl ex, TCD, and convent i onal angi ography can be us ed. The s cope of t es t i ng i s det ermi ned, i n part , by t he cl i ni cal condi t i on of t he pat i ent and whet her carot i d endart erect omy or ant i t hrombot i c t herapy are pri mary t herapeut i c cons i derat i ons . The more accurat e t he defi ni t i on of t he underl yi ng caus e of t he i nfarct i on, t he more preci s e t he det ermi nat i on of prognos i s and t reat ment .





(3) T herapy 



(a) Extracranial carotid artery disease. If t he pat i ent has s us t ai ned a mi nor i nfarct i on wi t h a funct i onal recovery and has a 50%â€“99% at heros cl erot i c s t enos i s of t he i ps i l at eral ori gi n of t he i nt ernal carot i d art ery, carot i d endart erect omy i s s uperi or t o medi cal t herapy for prevent i on of s ubs equent s t roke. If t he s t enos i s i s l es s t han 50%, t herapy wi t h ant i pl at el et drugs i s appropri at e.



Pa g e 2 7 0 2




(b) Intracranial large artery disease 



(i) If t he i nfarct i on i s caus ed by a s evere s t enos i s or occl us i on of a l arge i nt racrani al art ery, recent evi dence s ugges t s t hat as pi ri n t herapy i s s afer t han, and equal l y effect i ve as , ant i coagul at i on t herapy.





(ii) Some phys i ci ans us e ant i coagul at i on agent s i f t he pat i ent has new s ympt oms .





5. Small artery disease. The i nfarct i ons res ul t i ng from s mal l art ery di s eas e t ypi cal l y are deep i n t he hemi s pheres or t he pont omes encephal i c regi on and are known as lacunae. The l es i ons are l es s t han or equal t o 15 mm i n di amet er. o

o

a. Etiology. The underl yi ng vas cul ar l es i on i s us ual l y hypert ens i on-as s oci at ed l i pohyal i nos i s . Di abet es mel l i t us i s al s o as s oci at ed wi t h l acunar i nfarct s . A s mal l at heromat ous pl aque bl ocki ng t he os t i um of an art eri ol e may, on occas i on, be t he caus e of s ome occl us i ons , as may i nfect i ous or s t eri l e i nfl ammat i on, cardi ogeni c embol i , and l arge art ery occl us i ve di s eas e.

o

o

b. Diagnosis 

Pa g e 2 7 0 3




(1) Is chemi c event s from s mal l art ery di s eas e caus e s t ereot ypi c s yndromes s uch as pure mot or or s ens ory s t roke, s ens ori mot or s t roke, cl ums y handâ€“dys art hri a s yndrome, and at axi c hemi pares i s .





(2) Pat i ent s s houl d be s creened for t he pos s i bi l i t y of cardi ogeni c embol i , l arge art ery occl us i ve di s eas e, and hemat ol ogi c and i nfl ammat ory di s orders (s ee VIII B) i f t hey are not hypert ens i ve or i f t hei r hi s t ory, exami nat i on, or rout i ne di agnos t i c t es t s s ugges t a caus e ot her t han hypert ens i on.

o

o

c. T herapy i s di rect ed at cont rol l i ng hypert ens i on. If anot her condi t i on i s defi ned as t he caus e of t he i nfarct i on, appropri at e i nt ervent i on s houl d be purs ued. Ant i pl at el et t herapy may be admi ni s t ered t o decreas e t he l i kel i hood of s ubs equent i s chemi c s t roke.





6. Hematologic and systemic conditions. Thes e di s t urbances are as s oci at ed wi t h i s chemi c i nfarct i on. P.540

o

o

a. Associated conditions. Si ckl e cel l di s eas e, hypervi s cos i t y as s oci at ed wi t h pol ycyt hemi a and paraprot ei nemi as , and hypercoagul abi l i t y are condi t i ons as s oci at ed wi t h i s chemi c s t roke.

Pa g e 2 7 0 4


o

b. Etiology. Hypercoagul abi l i t y i s as s oci at ed wi t h ant i phos phol i pi d ant i bodi es (i ncl udi ng ant i cardi ol i pi ns and t he l upus ant i coagul ant s yndrome), hyperhomocys t ei nemi a, defi ci ency of prot ei ns C and S, act i vat ed prot ei n C res i s t ance, ant i t hrombi n III defi ci ency, mal i gnancy, nephrot i c s yndrome, and pregnancy, as wel l as s everal ot her condi t i ons .





7. T he young ischemic stroke patient. Pat i ent s younger t han 45 years of age who pres ent wi t h s t roke are oft en di agnos t i c chal l enges . The pot ent i al et i ol ogi es are vas t and i ncl ude, but are not l i mi t ed t o, t he fol l owi ng condi t i ons : o

o

a. Drug (es peci al l y cocai ne) and al cohol abus e

o

o

b. Hypercoagul abl e s t at es

o

o

c. Cardi ogeni c embol i

o

o

d. Mi grai ne

o

o

e. Vas cul i t i s and ot her rare art eri al l es i ons

o

o

f. CNS i nfect i on, i ncl udi ng HIV-as s oci at ed condi t i ons

o

Pa g e 2 7 0 5


o

g. Cancer

o

o

h. Di s orders of homocys t ei ne met abol i s m

o

o

i. Fami l i al condi t i ons [e.g., neurofi bromat os i s (NF), von Hi ppel -Li ndau di s eas e)]

o

o

j. Pregnancy and t he pos t part um s t at e





8. T he deteriorating ischemic stroke patient o

o

a. Pathophysiology. 



(1) The pat i ent 's condi t i on may det eri orat e as a res ul t of progres s i ve occl us i on of art eri es from cl ot propagat i on or art ery-t o-art ery embol i or becaus e of s ubs equent cardi ogeni c embol i . Det eri orat i on al s o may res ul t from exces s i ve l oweri ng of bl ood pres s ure or i nadequat e ant i coagul at i on t herapy.





(2) Hemorrhagi c i nfarct i on or a parenchymal hemat oma can occur s pont aneous l y or as a res ul t of t hrombol yt i c or ant i coagul at i on t herapy.





(3) If hepari n i s bei ng us ed as t reat ment , t he pos s i bi l i t y of hepari n-i nduced t hrombos i s

Pa g e 2 7 0 6


(wi t h as s oci at ed t hrombocyt openi a) s houl d be cons i dered. 



(4) Cerebral edema can devel op, caus i ng s hi ft i ng of brai n s t ruct ures and an i ncreas e i n t he ICP.

o

o

b. Approach to the patient. Ideal l y, cont i nui ng effort s s houl d be made t o defi ne t he pat hophys i ol ogy of t he s t roke. 



(1) The bl ood pres s ure and degree of hydrat i on s houl d be checked.





(2) A CT s can s houl d be obt ai ned t o defi ne mas s effect and hemorrhagi c compl i cat i ons .





(3) A hemat ocri t , pl at el et count , and cl ot t i ng profi l e s houl d be obt ai ned as appropri at e.

o

o

c. T herapy. Pat i ent s s houl d be confi ned t o bed, and ext remes of bl ood pres s ure s houl d be avoi ded. 



(1) Appropri at e hydrat i on s houl d be mai nt ai ned wi t h normal s al i ne, and i ncreas es i n ICP s houl d be t reat ed as neces s ary.





(2) Cons i derat i on can be gi ven t o novel , i nt ervent i onal neuroradi ol ogi c t echni ques s uch

Pa g e 2 7 0 7


as i nt ra-art eri al t hrombol ys i s and angi opl as t y, dependi ng on t he degree of neurol ogi c i mpai rment , t he t i me cours e of t he i l l nes s , and t he avai l abi l i t y of res ources .

C. Hemorrhagic disorders 



1. Subarachnoid hemorrhage (SAH) o

o

a. Etiology. The mos t common caus es of SAH are trauma and ruptured berry aneurysms. 



(1) Ot her caus es i ncl ude coagul opat hi es , mycot i c aneurys m, art eri ovenous mal format i on, vas cul i t i s , and s ympat homi met i c drugs .





(2) Aneurysms may be fami l i al and are as s oci at ed wi t h pol ycys t i c ki dney di s eas e, coarct at i on of t he aort a, fi bromus cul ar dys pl as i a, moyamoya di s eas e, pol yart eri t i s nodos a, ps eudoxant homa el as t i cum, and Marfan and Ehl ers -Danl os s yndromes .

o

o

b. Diagnosis 



(1) Clinical signs. Pat i ent s who have a rupt ured berry aneurys m compl ai n of â€œt he wors t headache of my l i fe,â€• but exami nat i on may not reveal many object i ve fi ndi ngs . Ot her

Pa g e 2 7 0 8


P.541

pat i ent s can pres ent wi t h meni ngi s mus , al t ered s t at es of arous al , and focal neurol ogi c fi ndi ngs . A part i al t hi rd nerve pal s y wi t h pupi l l ary di l at i on i s s ugges t i ve of a pos t eri or communi cat i ng art ery aneurys m. 



(2) Diagnostic studies. A CT scan reveal s t he pres ence of s ubarachnoi d bl ood i n mos t pat i ent s (Fi gure 11-3). If t he i ndex of s us pi ci on for an SAH i s hi gh, but a CT s can i s unreveal i ng, an LP provi des t he proper di agnos i s . Convent i onal i nt ervent i onal angi ography i s neces s ary t o charact eri ze t he aneurys m.

o

o

c. T herapy. Treat ment of aneurys mal SAH i s ai med at controlling complications, whi ch i ncl ude re-bl eedi ng, vas os pas m l eadi ng t o del ayed i s chemi c s t roke, hyponat remi a, acut e or chroni c hydrocephal us , i nt raparenchymal and i nt ravent ri cul ar hemat oma, and cardi ac arrhyt hmi as . Unfort unat el y, t he mort al i t y rat e from aneurys mal rupt ure approaches 50%, al t hough recent s t udi es s ugges t i mproved out comes . Int ervent i onal neuroradi ol ogi c t echni ques are pl ayi ng a l arger rol e i n t he management of aneurys ms . 



(1) Re-bleeding mos t frequent l y occurs i n t he fi rs t 48 hours aft er aneurys mal rupt ure. Early

Pa g e 2 7 0 9


intervention t o i s ol at e t he aneurys m s houl d be performed when pos s i bl e t o el i mi nat e t he t hreat of rebl eedi ng. Surgi cal â€œcl i ppi ngâ€• or endovas cul ar t herapy, whi ch i nvol ves pl aci ng t hrombogeni c â€œcoi l s â€• i n t he aneurys m, can be us ed t o i s ol at e t he aneurys m. 



(2) The cours e of vasospasm can be fol l owed wi t h TCD and CTA s t udi es , and t reat ed accordi ngl y. 



(a) The devel opment of i s chemi c s t roke from vas os pas m i s l es s l i kel y when nimodipine, a cal ci um channel bl ocker t hat may decreas e s mal l art ery vas ocons t ri ct i on or provi de neuronal prot ect i on from i s chemi a, i s admi ni s t ered.





(b) Prophyl axi s agai ns t s ympt omat i c vas os pas m al s o i ncl udes mai nt ai ni ng pat i ent s i n a euvol emi c s t at e and avoi di ng hypot ens i on.





(c) If t he aneurys m has been i s ol at ed from t he ci rcul at ory s ys t em, s ympt omat i c vas os pas m may be t reat ed wi t h hypervolemic therapy, coupl ed wi t h a moderat e i ncreas e i n bl ood pres s ure.





(d) Refract ory vas os pas m may be

Pa g e 2 7 1 0


amenabl e t o angi opl as t y or s el ect i ve i nt ra-art eri al papaveri ne or cal ci um ant agoni s t i nfus i on.

FIGURE 11-3 A nonenhanced comput ed t omography (CT) s can demons t rat i ng a s ubarachnoi d hemorrhage (SAH). Not e t he bl ood i n t he bas al ci s t erns and t he s yl vi an fi s s ures . o

P.542

o





(3) Symptomatic hydrocephalus can be t reat ed wi t h a vent ri cul ar drai n, repeat ed LPs , or vent ri cul operi t oneal s hunt i ng, as di ct at ed by cl i ni cal ci rcums t ances .





2. Intraparenchymal hematoma o

Pa g e 2 7 1 1


o

a. Diagnostic considerations. Chroni c hypert ens i on i s oft en, but not i nvari abl y, as s oci at ed wi t h hemorrhage i n t he regi on of t he put amen, t hal amus , cerebel l um, and pons . 



(1) An i nt raparenchymal hemorrhage t hat i s not accompani ed by a hi s t ory of hypert ens i on s houl d prompt a s earch for an underl yi ng caus e of bl eedi ng (e.g., coagul opat hy, aneurys m, art eri ovenous mal format i on, or t umor), part i cul arl y i f t he hemorrhage i s not l ocat ed i n a regi on of t he brai n t ypi cal l y as s oci at ed wi t h hypert ens i ve bl eedi ng.





(2) In el derl y pat i ent s , l obar hemat omas , es peci al l y i f mul t i pl e, may be i ndi cat i ve of amyl oi d angi opat hy. The APOE4 al l el e may be a ri s k fact or for amyl oi d angi opat hy and amyl oi d angi opat hy-rel at ed hemorrhage.





(3) Coagul opat hi es (es peci al l y when i nduced by t hrombol yt i c t herapy) and t he us e of drugs s uch as cocai ne and s ympat homi met i cs are as s oci at ed wi t h i nt raparenchymal hemat oma.

o

o

b. Diagnosis 



(1) Clinical signs 



(a) A large putaminal hematoma

Pa g e 2 7 1 2


caus es i mpai red cons ci ous nes s , cont ral at eral hemi pares i s and s ens ory l os s , and gaz e preference t o t he s i de of t he hemorrhage. 



(b) T halamic hemorrhage can l ead t o i mpai red cons ci ous nes s ; cont ral at eral weaknes s and s ens ory l os s ; di mi ni s hed vert i cal gaz e; and s mal l , poorl y react i ve pupi l s (i .e., Pari naud's s yndrome).





(c) Pat i ent s wi t h cerebellar hemorrhage may pres ent wi t h di zzi nes s , i mpai red gai t and s t ance and l i mb at axi a. If t he hemat oma i s l arge, i mpai red cons ci ous nes s , crani al nerve pal s i es (i ncl udi ng eye movement abnormal i t i es ), and weaknes s can devel op.





(d) The cl as s i c s i gns of pontine hemorrhage i ncl ude coma, pi npoi nt react i ve pupi l s , i mpai red l at eral ocul ar mot i l i t y, and quadri pl egi a wi t h decerebrat e pos t uri ng. Smal l pont i ne hemorrhages caus e more res t ri ct ed pont i ne s yndromes .





(2) Diagnostic studies. A CT s can i s cent ral t o di agnos i s . A coagul at i on profi l e and drug t oxi col ogy s creen s houl d be performed. Angi ography may be appropri at e i n normot ens i ve pat i ent s and i n t hos e wi t h

Pa g e 2 7 1 3


hemorrhage at at ypi cal s i t es . o

o

c. T herapy 



(1) Taki ng meas ures t o l ower t he el evat ed ICP as s oci at ed wi t h parenchymal hemat oma can i mprove out come.





(2) W i t h cerebel l ar hemat omas , s urgi cal res ect i on i s a l i fes avi ng meas ure. Surgi cal res ect i on of hemat omas at ot her s i t es i s recei vi ng i ncreas i ng at t ent i on.





(3) A coagul opat hy s houl d be t reat ed appropri at el y.





3. Arteriovenous malformation. Headaches , s ei zures , and i nt raparenchymal or, occas i onal l y, SAHs may res ul t . Therapeut i c i nt ervent i on may i ncorporat e mul t i pl e modal i t i es , i ncl udi ng s urgery, i nt ervent i onal radi ol ogy wi t h embol i zat i on, and s t ereot act i c radi os urgery.

IX. Seizures and Epilepsy A s ei z ure i nvol ves a sudden abnormality of brain electrical activity. Mani fes t at i ons of a s ei zure can i ncl ude i mpai rment or l os s of cons ci ous nes s and s ens ory, mot or, or behavi oral abnormal i t i es . The t erm epilepsy des cri bes a s yndrome charact eri zed by recurrent s ei z ures .

A. Classification Opt i mal management of s ei zure pat i ent s depends on proper cl as s i fi cat i on of t he s ei zure t ype. Sei zures can be cat egori zed as generalized or partial (focal).

Pa g e 2 7 1 4




1. Generalized seizures are charact eri zed by a s udden l os s of cons ci ous nes s . o

o

a. Generalized convulsive seizures. cons i s t of t oni c, cl oni c, or t oni câ€“cl oni c (grand mal ) mot or act i vi t y. General i zed convul s i ons can res ul t from a focal s ei zure di s order t hat has s pread, i nvol vi ng t he ent i re brai n. Postictal obtundation and confusion commonl y l as t mi nut es , and occas i onal l y, hours . The EEG oft en s hows general i zed s pi kes or s pi kes and as s oci at ed s l ow waves .

o

o

b. Aabsence seizures are charact eri zed by a bri ef, s t ari ng s pel l s wi t hout a pos t -i ct al s t at e. Typi cal l y, t he EEG demons t rat es general i zed 3-Hz s pi kes and as s oci at ed s l ow waves .

P.543





2. Simple partial (focal) seizures are not accompani ed by an i mpai rment of cons ci ous nes s . General i zed mot or s ei z ures may devel op s econdari l y. o

o

a. There may be i s ol at ed cl oni c or t oni c act i vi t y of a l i mb or t rans i ent al t ered s ens ory percept i ons .

o

o

b. The s ei zure act i vi t y may s pread over one s i de of t he body i n a Jacksonian march (e.g., t he

Pa g e 2 7 1 5


convul s i ve act i vi t y can s t art i n t he face, move t o t he i ps i l at eral arm and t hen t o t he l eg, and may evol ve i nt o a general i zed s ei zure). o

o

c. The EEG may s how a focal rhyt hmi c di s charge at t he ons et of a s i mpl e part i al s ei zure, but occas i onal l y, no i ct al act i vi t y i s det ect ed. Int eri ct al l y, focal s pi kes wi t h as s oci at ed s l ow waves are frequent l y pres ent .





3. Complex partial (focal) seizures are oft en charact eri zed by an aura fol l owed by impaired awareness. The EEG oft en s hows i nt eri ct al s pi kes or s pi kes wi t h as s oci at ed s l ow waves i n t he t emporal or front ot emporal areas and i ct al focal rhyt hmi c di s charges . General i zed mot or s ei zures may devel op s econdari l y. o

o

a. The aura may i nvol ve hallucinations (e.g., ol fact ory, vi s ual , audi t ory, or gus t at ory) and compl ex illusions (e.g., of havi ng experi enced a new event or of never havi ng experi enced a commonpl ace event ). However, pat i ent s frequent l y do not recal l t hei r aura.

o

o

b. Naus ea or vomi t i ng, focal s ens ory percept i ons , and focal t oni c or cl oni c act i vi t y may accompany a compl ex s ei zure.

o

o

c. Aft er t he aura, t here may be an epi s ode of i mpai red cons ci ous nes s , l as t i ng s econds t o s everal mi nut es , duri ng whi ch t i me aut omat i s ms may be obs erved. Ret urn t o bas el i ne cogni t i ve abi l i t i es can

Pa g e 2 7 1 6


t ake s everal mi nut es . 



4. St at us epi l ept i cus i s defi ned as an epi s ode of repeat ed or ongoi ng s ei zure act i vi t y wi t h i mpai red arous al l as t i ng at l eas t 30 mi nut es . St at us epi l ept i cus may i nvol ve bot h convulsive (general i zed t oni câ€“cl oni c act i vi t y) and nonconvulsive (abs ence or compl ex part i al ) s ei zures . o

o

a. Pat i ent s experi enci ng convul s i ve s ei zures are at ri s k for hypoxi a, as pi rat i on, aci dos i s , hypot ens i on, hypert hermi a, myogl obi nuri a, hypogl ycemi a, and mul t i pl e phys i cal i njuri es .

o

o

b. Pat i ent s experi enci ng nonconvul s i ve s ei zures can appear del i ri ous . A fl uct uat i ng s ens ori um and s ubt l e aut omat i s ms or myocl oni c jerks are cl ues t o t he di agnos i s , and t he EEG i s confi rmat ory.

B. Etiology Tabl e 11-6 out l i nes s ome of t he many caus es of s ei zures . Several s ei z ure t ypes have a defi ned genet i c bas i s : aut os omal domi nant front al l obe epi l eps y (neuronal ni cot i ni c acet yl chol i ne recept or mut at i on) and aut os omal domi nant t emporal l obe epi l eps y wi t h audi t ory feat ures .

TABLE 11-6 Selected Causes of Seizures

Pa g e 2 7 1 7


Idi op at h ic Ge net ic pre di s pos itio n Me sia l te mp ora l s cl ero sis Me t ab ol i c ab nor ma liti es Hy po nat re

Pa g e 2 7 1 8


mi a Hy poor hyp erg l yc em ia Hy poc al c em ia Hy po ma gn es e mi a Ure mi a Va s cu l ar di s eas e

Pa g e 2 7 1 9


an d str oke I nfa rct i on, es p eci al l y cor tic al Va s cu l ar ma l for ma tio n Va s cu liti s Infl am ma t or y cau

Pa g e 2 7 2 0


s es S ys t em ic l up us ery t he ma t os us (SL E) Ne opl as i a Me t as t at ic an d pri ma ry bra in tu mo rs Inf ect

Pa g e 2 7 2 1


i on Me ni n gi t i s, abs ces s, an d enc ep hal itis De ge ner at i ve di s eas es Al z hei me r's di s eas e Tra um a Ecl

Pa g e 2 7 2 2


am ps i a Dru gs T he op hyl lin e L i do cai ne Coc ai n e Dru g an d s ub sta nce wi t hdr aw al Ant i co nvu lsa

Pa g e 2 7 2 3


nt me di c at i ons Be nz o di a z ep i ne s Al c oh ol Ps y cho ge ni c cau s es P.544

C. Diagnosis 



1. Patient history and physical examination can ai d i n t he det ermi nat i on of whet her a s ei zure or s ome ot her t rans i ent event was res pons i bl e for t he pat i ent 's s ympt oms . o

Pa g e 2 7 2 4


a. A family history of epilepsy or a history of febrile convulsions i s rel evant .

o

o

b. An accurate description of the event by an observer i s hel pful i n defi ni ng t he probl em.

o

o

c. Urinary incontinence, back pain (from a vert ebral compres s i on fract ure), myalgias, and oral lacerations are cl ues t o proper di agnos i s .

o

o

d. Fever, fatigue, stress, alcohol withdrawal, medications, and menses can provoke s ei zures .





2. Differential diagnosis. Ot her condi t i ons t hat may produce s udden l os s of cons ci ous nes s are di s cus s ed i n II A. Ps ychogeni c s ei zures s houl d be cons i dered i f pat i ent s exhi bi t nons t ereot ypi c event s , have an unexpect ed res i s t ance t o ant i epi l ept i c drugs , or have a ps ychi at ri c di s order.





3. Diagnostic studies o

o

a. The EEG i s cent ral t o t he eval uat i on of s ei zure pat i ent s . The bes t t echni que for ful l y charact eri zi ng a s ei zure di s order i s cont i nuous vi deo EEG moni t ori ng, but t hi s i s not us ual l y us ed as an i ni t i al di agnos t i c t es t . A normal EEG does not excl ude t he di agnos i s of epi l eps y.

o

o

b. An MRI s can i s t he mos t us eful modal i t y for

Pa g e 2 7 2 5


det ect i ng l es i ons t hat may caus e s ei zures . o

o

c. SPECT and positron emission tomography (PET ) can provi de addi t i onal i nformat i on t o hel p l ocal i ze a s ei zure focus .

o

o

d. Laboratory studies are i ndi cat ed t o eval uat e pot ent i al met abol i c or t oxi c caus es , i ncl udi ng gl ucos e, s odi um, cal ci um, bl ood urea ni t rogen (BUN), creat i ni ne (Cr), l i ver fucnt i on t es t s (LFTs ), and t oxi n s creen.

D. Therapy 



1. General considerations. If a s ei zure i s t he s us pect ed di agnos i s , deci s i ons about t herapy depend on t he underl yi ng caus e. o

o

a. Correct i on of hyponat remi a, hypogl ycemi a, or drug i nt oxi cat i on may be al l t hat i s neces s ary.

o

o

b. Pat i ent s wi t h a neurol ogi c condi t i on known t o be as s oci at ed wi t h recurrent s ei zures oft en requi re medi cat i on.

o

o

c. Ant i convul s ant t herapy i s oft en not i ni t i at ed i n pat i ent s wi t h a s i ngl e, unprovoked convul s i on; a normal neurol ogi c exami nat i on; and a normal brai n i magi ng s t udy and EEG unl es s t hey experi ence a s econd s ei zure.



Pa g e 2 7 2 6




2. Medical therapy o

o

a. General principles. An at t empt i s us ual l y made t o prevent s ubs equent s ei zures by us i ng a single agent, t o l i mi t t oxi c effect s . The drug s houl d be admi ni s t ered i n progressive doses unt i l s ei zure cont rol has been achi eved or unt i l drug t oxi ci t y occurs . Onl y i f monot herapy fai l s s houl d a s econd drug be added. If cont rol i s t hen obt ai ned, t he fi rs t agent mi ght be careful l y wi t hdrawn.

o

o

b. Specific agents. The choi ce of medi cat i on s houl d be bas ed on t he s ei zure t ype, beari ng i n mi nd pos s i bl e cont rai ndi cat i ons and s i de effect s . 



(1) Typi cal l y, general i zed convul s i ve, s i mpl e part i al , and compl ex part i al s ei zures are t reat ed wi t h carbamaz epi ne, phenyt oi n, val proi c aci d, t opi ramat e, l evet i racet am, l amot ri gi ne, or zoni s ami de.





(2) Val proi c aci d or et hos uxi mi de i s us ed for general i zed nonconvul s i ve s pel l s (abs ence s ei zures ).





(3) Val proi c aci d i s part i cul arl y effect i ve for cont rol l i ng juveni l e myocl oni c epi l eps y (a di s order charact eri zed by myocl oni c s ei zures ).





(4) Lamotrigine, gabapentin, tiagabine,

Pa g e 2 7 2 7


oxcarbazepine, and topiramate are adjunct i ve medi cat i ons for t he t reat ment of pat i ent s wi t h refract ory part i al s ei zures . 



3. Surgical therapy. Pat i ent s refract ory t o medi cal cont rol of s ei zures may be candi dat es for s urgery t o cont rol t he epi l eps y. T emporal lobe resection, ablation of a cortical seizure focus, and corpus callosum sectioning are abl e t o reduce s ei zure frequency i n s ome pat i ent s who meet s peci fi c cri t eri a. Vagus nerve stimulation may hel p cont rol s ei zures .





4. Control of status epilepticus. General i zed convul s i ve s t at us epi l ept i cus i s a l i fe-t hreat eni ng condi t i on; t herefore, management of convul s i ve s t at us epi l ept i cus requi res maki ng cert ai n t hat t he P.545

ai rway i s unobs t ruct ed and mai nt ai ni ng adequat e oxygenat i on, bl ood pres s ure, and hydrat i on. Defi ni t i on of t he underl yi ng probl em i s es s ent i al . o

o

a. Glucose. and thiamine s houl d be admi ni s t ered aft er bl ood s ampl es for gl ucos e, el ect rol yt es , renal funct i on, ant i convul s ant drug l evel s , and t oxi col ogy have been obt ai ned.

o

o

b. Oft en, intravenous diazepam or lorazepam i s gi ven t o s t op t he convul s i ons . Loraz epam carri es l es s of a ri s k of res pi rat ory depres s i on or arres t and remai ns effect i ve for l onger peri ods .

Pa g e 2 7 2 8


o

c. Admi ni s t rat i on of a benzodi azepi ne i s fol l owed by admi ni s t rat i on of phenytoin, fosphenytoin, or phenobarbital.

o

o

d. If convul s i ons cont i nue aft er l oadi ng dos es of phenyt oi n or fos phenyt oi n or phenobarbi t al have been admi ni s t ered, i nt ravenous midazolam, propofol, or pentobarbital can be gi ven i n a careful l y s upervi s ed s et t i ng, wi t h cont i nuous EEG moni t ori ng, unt i l t he s ei zure di s charges are el i mi nat ed from t he EEG.

o

o

e. Di mi ni s hed cardi ac out put , bradycardi a, and hypot ens i on oft en l i mi t t he dos e of i nt ravenous ant i convul s ant s . Fluid resuscitation and vasopressors may be us ed.





5. Psychosocial issues. The fol l owi ng i s s ues are i mport ant t o cons i der when managi ng epi l eps y. o

o

a. Pat i ent s may be depres s ed, have behavi oral di s t urbances , and oft en requi re vocat i onal s upport s ervi ces . Frequent l y, communi t y s upport s ervi ces are avai l abl e.

o

o

b. Revi ew of t he pat i ent 's driving status and work and pl ay envi ronment are neces s ary.

o

o

c. Fami l y and fri ends need t o be couns el ed as t o

Pa g e 2 7 2 9


how t o manage a convul s i on. o

o

d. W omen of chi l dbeari ng age s houl d be couns el ed about i s s ues rel at i ng t o pregnancy.

o

o

e. Pregnant women s houl d be mai nt ai ned on monot herapy at t he l owes t effect i ve dos e, gi ven t hat s ei zures may harm t he fet us , and t he ri s k of bi rt h defect s i ncreas es wi t h pol ypharmacy.

X. Movement Disorders A. Parkinson's disease 



1. Pathogenesis o

o

a. Parki ns on's di s eas e i s charact eri zed by a degenerat i on of cel l s i n t he s ubs t ant i a ni gra, whi ch caus es a defi ci ency of dopami ne (a neurot rans mi t t er) i n t he CNS, l eadi ng t o a s eri es of changes i n mot or cont rol pat hways . The mechani s m behi nd t he degenerat i on of t hes e cel l s i s unknown, al t hough hypot hes es cent er about free radi cal damage and i mpai red mi t ochondri al oxi dat i ve funct i on.

o

o

b and c. Genet i cs . Major i ns i ght s i nt o t he genet i cs of Parki ns on's di s eas e are emergi ng. The SNCA gene codes for Î±-s ynucl ei n, t he PRKN gene codes for parki n, and t he UCHL1 gene codes for a ubi qui t i n hydroxyl as e. Several ot her chromos ome l oci have been as s oci at ed wi t h Parki ns on's di s eas e.

Pa g e 2 7 3 0


o

c. A common feat ure emergi ng from t he genet i cs s t udi es i s t hat t he pat hophys i ol ogy of Parki ns on's di s eas e, as wel l as t hat of ot her neurodegenerat i ve di s eas es , may i nvol ve abnormal i t i es i n pat hways as s oci at ed wi t h ubi qui t i n-as s oci at ed prot ei n degradat i on.





2. Diagnosis o

o

a. Clinical symptoms and signs. 



(1) Parki ns on's di s eas e pat i ent s oft en compl ai n of â€œs l owi ng downâ€•; t hey have t roubl e dres s i ng, ari s i ng from a s eat ed pos i t i on, cl i mbi ng or des cendi ng s t ai rs , wri t i ng, and t urni ng over i n bed.





(2) On exami nat i on, rigidity and akinesia or bradykinesia are pres ent and a 3-Hz resting tremor and postural instability are oft en evi dent . Si gns are oft en as ymmet ri cal earl y i n t he di s eas e.





(3) Cogni t i ve i mpai rment devel ops i n more t han 50% of pat i ent s over t i me.

o

o

b. Differential diagnosis. The di agnos i s i s a cl i ni cal det ermi nat i on, al t hough, at t i mes , t es t i ng t o excl ude ot her ent i t i es pres ent i ng as

Pa g e 2 7 3 1


parki ns oni s m i s i ndi cat ed. 



(1) Somet i mes serial observations are neces s ary t o det ermi ne whet her t he parki ns oni an s t at e i s t he harbi nger of anot her neurol ogi c i l l nes s ; t hi s i s of s peci al concern i n pat i ent s who do not have t he characteristic â€œ pill-rollingâ€• or resting tremor of Parkinson' s disease or fai l t o res pond t o l evodopa t herapy.





(2) Condi t i ons t hat may produce parki ns oni an s ympt oms s i mi l ar t o t hos e found i n pat i ent s wi t h Parki ns on's di s eas e i ncl ude NPH, mul t i pl e s t rokes , hypot hyroi di s m, drug effect s [e.g., neurol ept i cs (dopami ne-bl ocki ng agent s ), met ocl oprami de, di l t i azem, and res erpi ne], W i l s on's di s eas e, anoxi c encephal opat hy, and i nt oxi cat i on [e.g., by carbon monoxi de, manganes e, or n-met hyl -4-phenyl -1,2,3,6-t et rahydropyri di ne (MPTP)].



(3) Rare neurol ogi c di s orders t hat may have parki ns oni an feat ures are s ummari zed i n o

Onl i ne Tabl e 11-7.

P.546

o

ONLINE TABLE 11-7 Key Features of Selected Conditions Causing Parkinsonism

Pa g e 2 7 3 2


Dis Dis or tin de gui r

shi ng Cli nic al Ch ar act eri sti

cs Pro Im gre pai s s i red ve ver s up t i c ran al ucl gaz ear e; pal ear sy ly (â€ axi œt al au ri gi op di t at h y yâ€ wi t •) h pos t ur al i ns

Pa g e 2 7 3 3


t ab ilit y Mul Aut t i pl on e

om

s ys i c t e i ns ms uffi at r ci e op ncy hy ; (Sh cer y-D eb rag el l er ar s yn dys dro fun me ct i )

on; up per an d l ow er mo t or ne uro n dys fun ct i on

Pa g e 2 7 3 4


Di f De fus me e

nt i

Le a wy ear bo l y dy i n di s i l l n eas es s e

,

(â€ fl u œD ct u em at i ent ng ia

cog

wi t ni t i h

on,

Le vi s wy ual bo hal di e l uci s â€ nat •) i on s Cor As y t i c mm al - et ri bas c al

fi n

ga di n ngl gs i on on ic

exa

de mi ge nat

Pa g e 2 7 3 5


ner i on at i of on s en (â€ s or œt y au l os op s at h an yâ€ d •) apr axi a; uni l at era l ri gi di t y; uni l at era l sti mu l us -s e ns i tiv e my ocl on us ; dys

Pa g e 2 7 3 6


t on ia Fro Ap nt o at h t e y, mp di s ora i nh l

i bi t

l ob i on ar , de an ge om ner i a, at i eff on ort (â€ ful œt s pe au ech op at h yâ€ •) Hu Par nt i ki n ngt s on on' i an s

fea

di s t ur eas es e

pro mi ne nt in you

Pa g e 2 7 3 7


ng pat i en ts; fa mi l y hi s t or y, cho reo at h et o sis Ol i Cer vop eb ont el l oce ar reb dys el l fun ar ct i at r on; op aut hy* on om ic dys fun ct i on Ba Cal s al ci fi ga cat ngl i on

Pa g e 2 7 3 8


ia

vi s i

cal bl e ci fi on cat co i on mp ut e d to mo gra phy (CT ) s ca n Ne Aca uro nt h aca ocy nt h t es ocy i n t os we is

t per i ph era l bl o od sm

ear *May be t he s ame as mul t i pl

Pa g e 2 7 3 9


e s ys t em s at roph y.





3. T herapy. Parki ns on's di s eas e i s a progres s i ve di s eas e. Therefore, management prot ocol s vary dependi ng on t he pat i ent 's s ympt oms and t he ext ent of funct i onal i mpai rment . o

o

a. Early therapy. Several medi cat i ons are avai l abl e t o t reat Parki ns on's di s eas e. 



(1) Carbidopa/levodopa combinations are t he mai ns t ay of t reat ment for Parki ns on's di s eas e. Thi s t reat ment s houl d begi n when t he di s eas e i mpai rs t he pat i ent 's funct i onal s t at us . A s us t ai ned rel eas e formul at i on of carbi dopa/l evodopa i s avai l abl e and provi des a more uni form cl i ni cal res pons e t han convent i onal dos i ng. 



(a) Levodopa i s convert ed t o dopami ne by t he pres ynapt i c neuron and t herefore i ncreas es t he amount of neurot rans mi t t er avai l abl e t o t he pos t s ynapt i c dopami ne

Pa g e 2 7 4 0


recept or. 



(b) Carbidopa bl ocks s ys t emi c convers i on of l evodopa t o dopami ne, t hereby decreas i ng t he undes i rabl e s ys t emi c effect s of l evodopa.





(2) Dopamine agonists are i ncreas i ngl y bei ng us ed at i ni t i al t herapy, es peci al l y i n younger pat i ent s . They may have s ome neuroprot ect i ve benefi t s . Drugs i ncl ude pramipexole, ropinirole, pergolide, and bromocriptine.





(3) Anticholinergics, whi ch i mprove t he chol i nergi câ€“dopami nergi c bal ance i n t he bas al gangl i a, are part i cul arl y hel pful i n t reat i ng t remor. However, t hey may cont ri but e t o cogni t i ve i mpai rment .





(4) Amantadine, whi ch i ncreas es t he avai l abi l i t y of dopami ne t o t he pos t s ynapt i c neuron, can be effect i ve earl y i n t he cours e of t he di s eas e or as an adjunct i ve t herapy l at er i n t he di s eas e cours e t o hel p â€œs moot h out â€• mot or funct i on.

o

o

b. Advanced therapy. In t he l at er s t ages of t he di s eas e, t herapy i s di rect ed at opt i mi zi ng t he pat i ent 's funct i onal s t at us and avoi di ng advers e effect s of medi cat i on. 

Pa g e 2 7 4 1


(1) Dopamine agonists. If t he t herapeut i c res pons e t o carbi dopa/l evodopa t herapy i s i nadequat e, or i f t he pat i ent cannot t ol erat e t he medi cat i on, pramipexole, ropinirole, pergolide, or bromocriptine may be admi ni s t ered. 



(a) Thes e drugs are direct postsynaptic dopamine-receptor agonists.





(b) A combi nat i on of carbi dopa/l evodopa and a dopami ne agoni s t s eems t o be part i cul arl y effect i ve and i s oft en wel l t ol erat ed. Dopami ne agoni s t s hel p decreas e mot or fl uct uat i ons when us ed i n conjunct i on wi t h carbi dopa/l evodopa.





(2) Management with disease progression. Management of Parki ns on's di s eas e becomes i ncreas i ngl y di ffi cul t as t he di s eas e progres s es . â€œ Wearing offâ€• effect s , dyskinesias, and wi de, random s wi ngs i n pat i ent mobi l i t y (â€œ onâ€“offâ€• phenomena) devel op. A s us t ai ned-rel eas e form of carbi dopa/l evodopa (al one or i n combi nat i on wi t h a dopami ne agoni s t ) can be us ed. Catechol O-methyltransferase inhibitors, whi ch i ncreas e t he s ynapt i c avai l abi l i t y of l evodopa by bl ocki ng i t s degradat i on, al s o can be us ed t o manage uns t abl e pat i ent s .

o

o

c. Ancillary therapy

Pa g e 2 7 4 2




(1) Ot her t herapeut i c maneuvers i ncl ude t he strategic reduction of medication i f pat i ent s are experi enci ng dys ki nes i a and judicious use of psychotropic agents t o t reat t he vari ous unt oward behavi oral cons equences of Parki ns on's di s eas e (e.g., i ns omni a, hal l uci nat i ons , agi t at i on).





(2) Dietary manipulations t hat redistribute or limit protein i nt ake duri ng t he day may i mprove t he effi cacy of l evodopa.





(3) Physical therapy and an exercise program hel p opt i mi ze mobi l i t y.





(4) Pallidotomy and deep brain stimulation offer new t herapeut i c opt i ons for refract ory Parki ns on's di s eas e pat i ent s .





(5) The rol e of s urgi cal i mpl ant s of dopami ne-cont ai ni ng cel l s for t he t reat ment of Parki ns on's di s eas e remai ns experi ment al .

B. Hyperkinetic disorders 



1. T remor o

o

a. Benign essential tremor. i s charact eri zed by a pos t ure-rel at ed 5â€“9-Hz os ci l l at i on of t he hands

Pa g e 2 7 4 3


and forearms t hat i mpai rs performance of fi ne mot or t as ks . 



(1) Thi s t ype of t remor i s oft en familial and may be accompani ed by titubation (head tremor).





(2) Cons umpt i on of al cohol may t emporari l y s uppres s t he t remor; s t res s , caffei ne, or s l eep depri vat i on may exacerbat e t he condi t i on.





(3) Î²-Adrenergic blocking agents and primidone are effect i ve t reat ment s .

P.547

o

o

b. An action (kinetic) tremor i s evi dent when pat i ent s move t hei r arms ; t here may be a rel at i vel y mi l d accompanyi ng pos t ural and i nt ent i on component . Treat ment wi t h clonazepam may be us eful .





2. Chorea des cri bes rapid, â€œ dance-likeâ€• distal limb and facial movements. Caus es i ncl ude hypert hyroi di s m, drugs (e.g., bi rt h cont rol pi l l s and l evodopa), Sydenham's chorea, pregnancy, SLE, ant i phos phol i pi d s yndrome, s t roke, porphyri a, W i l s on's di s eas e, Lyme di s eas e, Hunt i ngt on's di s eas e, and neuroacant hocyt os i s .



Pa g e 2 7 4 4


3. Athetosis general l y refers t o involuntary, slow, writhing, â€œ snake-likeâ€• limb movements. Caus es i ncl ude W i l s on's di s eas e, Hunt i ngt on's di s eas e, anoxi c encephal opat hy, t rauma, bi rt h cont rol pi l l s , and s everal rare heredi t ary di s orders .





4. Dystonia des cri bes slow, writhing, sustained and involuntary contractions of the proximal limb, trunk, and neck musculature. Dys t oni a i s as s oci at ed wi t h W i l s on's di s eas e, Parki ns on's di s eas e, Hunt i ngt on's di s eas e, t rauma, neuronal s t orage di s orders , encephal i t i s , drugs (e.g., neurol ept i cs , l evodopa), and ot her rare heredi t ary condi t i ons . o

o

a and b. Genet i cs . The T OR1A gene for aut os omal domi nant general i zed t ors i on dys t oni a codes for t ors i n A, an ATP-bi ndi ng and heat s hock prot ei n. Pat i ent s may res pond t o hi gh dos es of t ri hexypheni dyl .

o

o

b. Some pat i ent s wi t h aut os omal domi nant i di opat hi c dys t oni a are part i cul arl y res pons i ve t o carbi dopa/l evodopa t herapy. Thi s condi t i on i s as s oci at ed wi t h t he DY T 5 gene on chromos ome 14 t hat codes for guani ne t ri phos phat e (GTP) cycl ohydrol as e I; a defi ci ency of t hi s enzyme caus es l os s of dopami ne s ynt hes i s .

o

o

c. Focal dys t oni as s uch as wri t er's cramp, bl epharos pas m, s pas t i c dys phoni a, and t ort i col l i s can occur. Treat ment wi t h l ocal bot ul i num t oxi n i nfi l t rat i on can be benefi ci al .

Pa g e 2 7 4 5


o

d. Some pat i ent s wi t h dys t oni a may exhi bi t chorea and at het os i s .





5. Hemiballismus des cri bes wild, flinging, principally proximal movements of t he arms or legs. It i s oft en caus ed by an i nfarct i n t he s ubt hal ami c nucl eus . Hal operi dol can decreas e t he i nvol unt ary movement s .





6. Blepharospasm can occur i n i s ol at i on or as part of a more wi des pread di s order s uch as Parki ns on's di s eas e, s t roke, or Mei ge's s yndrome (orofaci al dys t oni a). Bl epharos pas m can be of s uch s everi t y as t o caus e funct i onal bl i ndnes s . o

o

a. Many drugs have been t ri ed i n an at t empt t o cont rol t he probl em wi t h modes t effect .

o

o

b. Infi l t rat i on of bot ul i num t oxi n about t he eyes can provi de rel i ef by decreas i ng neuromus cul ar t rans mi s s i ons .





7. Neuroleptic-associated movement disorders repres ent a s pect rum of di s orders rel at ed t o t he acut e or chroni c admi ni s t rat i on of neurol ept i c medi cat i ons (al t hough for s el ect ed condi t i ons , ot her drugs are i mpl i cat ed as wel l ). o

o

a. Acute dystonia. t ypi cal l y occurs s hort l y aft er t he fi rs t few dos es of a neurol ept i c agent .

Pa g e 2 7 4 6




(1) Clinical signs i ncl ude uncont rol l abl e face, neck, t ongue, and eye mus cl e (ocul ogyri c cri s i s ) s pas ms .





(2) T herapy cons i s t s of t he admi ni s t rat i on of ant i chol i nergi cs or di phenhydrami ne.

o

o

b. Parkinsonism can devel op wi t h neurol ept i c us e. Therapy cons i s t s of decreas i ng t he dos e of t he neurol ept i c agent ; changi ng t o anot her neurol ept i c drug; admi ni s t eri ng an ant i chol i nergi c agent ; or us i ng amant adi ne, a carbi dopa/l evodopa preparat i on, or an â€œat ypi cal â€• neurol ept i c s uch as cl ozapi ne, ri s peri done, or ol anzapi ne.

o

o

c. T ardive dyskinesia i s an al mos t cons t ant wri t hi ng movement of t he t ongue and oromandi bul ar area, whi ch may be accompani ed by bl epharos pas m, res pi rat ory grunt s , choreo-at het os i s , and t runcal hyperact i vi t y. Il l -fi t t i ng dent ures or an edent ul ous s t at e can caus e mout hi ng movement s t hat are mi s t aken for t ardi ve dys ki nes i a. 



(1) Tardi ve dys ki nes i a i s us ual l y an advers e s i de effect of l ong-t erm us e of neurol ept i c agent s ; occas i onal l y ot her drugs s uch as amphet ami nes , ant i hi s t ami nes , and carbamazepi ne are caus al l y i mpl i cat ed.



Pa g e 2 7 4 7


(2) If a medi cat i on i s i mpl i cat ed as t he caus e of t he probl em, t he offendi ng agent s houl d be di s cont i nued i f pos s i bl e. Cl onaz epam, res erpi ne, t et rabenazi ne, and ot her drugs have been us ed t o t reat t ardi ve dys ki nes i a wi t h vari abl e s ucces s . Us e of an â€œat ypi cal â€• neurol ept i c s uch as cl ozapi ne i s anot her opt i on.

o

o

d. Other neuroleptic-associated movement disorders i ncl ude t ardi ve dys t oni a, akat hi s i a (mot or res t l es s nes s ), and t he rabbi t s yndrome (rhyt hmi c l i p movement s ).

o

o

e. Neuroleptic malignant syndrome (NMS) i s an i di os yncrat i c react i on t o neurol ept i c agent s . It can al s o occur i n Parki ns on's di s eas e pat i ent s aft er t he abrupt di s cont i nuat i on of ant i parki ns oni an medi cat i ons . Dopami ne recept or bl ockade i s t hought t o be t he caus e of NMS. P.548





(1) Clinical signs i ncl ude al t ered ment at i on, hi gh fever, ri gi di t y, aut onomi c i ns t abi l i t y, hi gh creat i ne ki nas e (CK) l evel s , and myogl obi nuri a.





(2) T herapy for t hi s pot ent i al l y l et hal condi t i on i ncl udes hydrat i on, cool i ng bl anket s , ant i pyret i cs , dant rol ene, and

Pa g e 2 7 4 8


l evodopa/carbi dopa preparat i ons or bromocri pt i ne, al t hough t he us e of ant i parki ns oni an drugs i s cont rovers i al . 



8. Meige' s syndrome (orofacial dystonia) i s an i di opat hi c condi t i on t hat has feat ures of dys t oni a and t ardi ve dys ki nes i a, part i cul arl y bl epharos pas m. o

o

a. Thi s di agnos i s cannot be made i f t he pat i ent has recent l y t aken neurol ept i c agent s or ot her drugs i mpl i cat ed as a caus e of t ardi ve dys ki nes i a.

o

o

b. No s i ngl e medi cat i on i s cons i s t ent l y effect i ve i n t reat i ng t hi s condi t i on; cl onaz epam i s a reas onabl e fi rs t -l i ne agent . Bot ul i num t oxi n i nfi l t rat i on can be us ed t o t reat t he bl epharos pas m.





9. Hemifacial spasm des cri bes l i ght ni ng-qui ck s pas ms of mus cl es i nnervat ed by t he faci al nerve. o

o

a. The condi t i on i s mos t oft en caus ed by i rri t at i on of t he faci al nerve by a vas cul ar â€œl oop.â€•

o

o

b. Rarel y, i t occurs aft er faci al nerve paral ys i s or i s as s oci at ed wi t h t umors , MS, or ot her i rri t at i ve proces s es .

o

o

c. Botulinum toxin infiltration, clonazepam, and carbamazepine have been us ed t o t reat hemifacial spasm; mi cros urgi cal decompres s i on

Pa g e 2 7 4 9


may be s ucces s ful . 



10. T ics are bri ef, s t ereot ypi cal , i nvol unt ary movement s , s ounds , or s ens at i ons t hat occur wi t hi n t he cont ext of normal neurol ogi c funct i on. o

o

a. T ypes of tics. 



(1) Simple motor tics are i s ol at ed movement s s uch as an eyebl i nk, s houl der s hrug, or faci al gri mace. Complex motor tics i ncl ude t ouchi ng, s mel l i ng, and jumpi ng.





(2) Simple phonic tics i ncl ude t hroat cl eari ng, s ni ffl i ng, and grunt i ng. Complex phonic tics i ncl ude t he repet i t i on of words and coprol al i a.





(3) Sensory tics oft en accompany mot or and phoni c t i cs and are charact eri zed by focal s ens at i ons of pres s ure, t i ckl e, warmt h, or col d.

o

o

b. T ourette' s syndrome 



(1) Characteristics 



(a) Mul t i pl e mot or and one or more phoni c t i cs (t hat has been pres ent at s ome t i me over t he cours e of t he i l l nes s )

Pa g e 2 7 5 0




(b) Ti cs t hat occur many t i mes a day, nearl y every day, for more t han 1 year





(c) Ti cs t hat change over t i me i n t hei r anat omi c l ocat i on, number, frequency, compl exi t y, t ype, and s everi t y





(d) Ons et of i l l nes s before age 21





(e) Abs ence of ot her condi t i ons t hat can caus e s i mi l ar, but i s ol at ed, s ympt oms (e.g., neurol ept i c drug effect s , s ei zures , and chorea)





(2) Etiology. Touret t e's s yndrome i s t hought t o be i nheri t ed i n a pol ygeni c manner. St ri at al dopami ne recept or s upers ens i t i vi t y may be res pons i bl e for t he cl i ni cal mani fes t at i ons .





(3) Associated behavioral disturbances. Obsessiveâ€“compulsive disorder and attention deficit hyperactivity disorder may occur.





(4) T herapy. Treat ment cons i s t s of educat i on and couns el i ng of t he pat i ent , fami l y, and ot her appropri at e part i es . Cl oni di ne, pi mozi de, or hal operi dol can be us ed t o manage di s abl i ng t i cs . Behavi oral

Pa g e 2 7 5 1


di s t urbances s houl d res pond t o appropri at e ps ychoact i ve medi cat i ons .

XI. Demyelinating Diseases A. Multiple sclerosis (MS) Mul t i pl e s cl eros i s (MS) i s charact eri zed by mul t i pl e foci of CNS demyel i nat i on. Pat i ent s ei t her experi ence cl i ni cal remi s s i ons (oft en fol l owed by rel aps es ) or chroni c, progres s i ve s ympt oms . 



1. Pathophysiology. Al t hough t he caus e of MS remai ns unknown, a predomi nant t heory cont ends t hat MS i s an i mmunol ogi c di s order as s oci at ed wi t h CNS i mmunogl obul i n product i on and al t erat i on of T and B l ymphocyt es . The pathologic hallmark of MS i s i nfl ammat i on as s oci at ed wi t h areas of demyelination scattered about CNS white matter. Recent fi ndi ngs have al s o document ed axonal disruption.





2. Diagnosis o

o

a. Clinical signs. 



(1) The di agnos i s i s mos t cert ai n i f neurol ogi c probl ems occur over an ext ended peri od and i nvol ve s everal whi t e mat t er pat hways . MRI fi ndi ngs can be us ed as evi dence of di s eas e di s s emi nat i on over t i me and anat omi c s pace.





(2) Several pat t erns emerge t hat are s ugges t i ve of MS, i ncl udi ng optic neuritis (a s i gn of whi ch i s t he Marcus -Gunn pupi l or afferent pupi l l ary defect ) and internuclear

Pa g e 2 7 5 2


ophthalmoplegia, ei t her i n i s ol at i on or i n as s oci at i on wi t h cort i cos pi nal t ract or cerebel l ar s i gns . Long-t erm fol l ow-up i ndi cat es t hat 74% of women and 34% of men who pres ent wi t h i s ol at ed opt i c neuri t i s ul t i mat el y devel op MS. 



(3) Neurol ogi c s i gns t hat can be l ocal i zed t o a s i ngl e di s cret e area i n t he CNS s uch as t he brai ns t em or crani ocervi cal junct i on s houl d s ugges t an al t ernat e di agnos i s s uch as a t umor or art eri ovenous mal format i on.

o

o

b. Differential diagnosis. There i s no s peci fi c di agnos t i c marker for MS; t he phys i ci an needs t o excl ude ot her condi t i ons t hat can mas querade as MS. Among t hes e di s orders are s omat i zat i on di s order, SLE, brai ns t em or s pi nal vas cul ar mal format i on, SjÃ¶gren's s yndrome, Lyme di s eas e, HIV i nfect i on, vi t ami n B 1 2 defi ci ency, brai ns t em neopl as m, vas cul i t i s , s arcoi dos i s , and adrenomyel ol eukodys t rophy.

o

o

c. Diagnostic studies 



(1) MRI i s an excel l ent t echni que for vi s ual i zi ng whi t e mat t er l es i ons . Al t hough i t s di agnos t i c s peci fi ci t y i s poor, t he cont ras t agent gadolinium-DT PA i ndi cat es areas of breakdown of t he bl oodâ€“brai n barri er. Seri al MRI s t udi es s how whi t e mat t er l es i ons t hat may come and go wi t hout cl i ni cal mani fes t at i ons .

Pa g e 2 7 5 3




(2) Examination of the CSF can i ndi cat e a s t eri l e i nfl ammat i on wi t h a mi l d prot ei n el evat i on; modes t , predomi nant l y mononucl ear pl eocyt os i s ; an el evat ed IgG i ndex; ol i gocl onal bands ; and i ncreas ed myel i n bas i c prot ei n. Onl y occas i onal l y do al l of t hes e abnormal i t i es occur i n a s i ngl e pat i ent .





(3) Visual, brain stemâ€“auditory, and somatosensory EPs and central motor conduction studies can demons t rat e cl i ni cal l y s i l ent di s rupt i on of whi t e mat t er t ract s .





3. T herapy. There i s no cure for MS. o

o

a. Corticosteroid therapy. may has t en maxi mal recovery from an acut e exacerbat i on. If opt i c neuri t i s i s t reat ed, hi gh dos es of i nt ravenous cort i cos t eroi ds are preferabl e t o l ower, oral dos es .

o

o

b. Interferon-Î² (IFN-Î²) t herapy decreas es t he frequency of rel aps es , es peci al l y moderat e and s evere at t acks . As judged by s eri al MRI s t udi es , di s eas e act i vi t y i s l es s ened wi t h IFN-Î² t reat ment . P.549

o

o

c. Glatiramer acetate al s o decreas es t he

Pa g e 2 7 5 4


frequency of rel aps es , es peci al l y for pat i ent s wi t h mi l d di s eas e. o

o

d. Ot herwi s e, t reat ment i s di rect ed at symptoms. 



(1) Modafinil, amantadine, and pemoline can i mprove fatigue.





(2) Baclofen, tizanidine, and diazepam i mprove spasticity.





(3) A variety of agents may hel p urologic dysfunction, dependi ng on t he s peci fi c probl em.

o

o

e. Pat i ent s wi t h s evere di s eas e may res pond t o i mmunos uppres s i ve t herapy.

B. Central pontine myelinolysis 



1. Etiology. Demyel i nat i on of t he pons and deep cerebral whi t e mat t er has been as s oci at ed wi t h t he excessively rapid correction of severe hyponatremia. Cent ral pont i ne myel i nol ys i s has been s een i n al cohol i cs , mal nouri s hed pat i ent s , and i n as s oci at i on wi t h di uret i c us e.





2. Diagnosis. Pat i ent s devel op impaired arousal, quadriparesis, and pseudobulbar signs. MRI or CT scan confi rms t he di agnos i s .

Pa g e 2 7 5 5


3. T herapy. Cons i s t s of s upport i ve meas ures .



Hyponat remi a s houl d be correct ed slowly, and hypernat remi a s houl d be avoi ded.

XII. Myelopathy and Other Spinal Cord Disorders A. Definition Myel opat hy refers t o a di s order of t he s pi nal cord. Speci fi c s yndromes occur i n rel at i on t o t he vari ous mot or and s ens ory t ract s affect ed by t he di fferent di s eas e proces s es (Fi gure 11-4).

B. Etiology Sel ect ed caus es of myel opat hy are l i s t ed i n

Onl i ne Tabl e 11-8.

ONLINE TABLE 11-8 Selected Causes of Myelopathy Ver t eb ral col um n di s ord ers T rau ma Cer vi c

Pa g e 2 7 5 6


al ste nos is Di s k pro t ru sio n Od ont oi d s ub l ux at i on Rh eu ma t oi d art hri t is Do wn s yn dro me Ne

Pa g e 2 7 5 7


opl as i a E pi d ura l s pi nal cor d co mp res sio n I nt r ad ura l ext ra me dul l ar y ma ss I nt r am ed ul l ary

Pa g e 2 7 5 8


ma ss Inf ect i on S pi n al epi dur al abs ces s Hu ma n im mu no def i ci e ncy vi r us (HI V) Hu ma n T-c el l l ym

Pa g e 2 7 5 9


ph ot r op hi c vi r us t yp e I (HT LVI) Mul t i pl e s cl ero sis Va s cu l ar di s eas e I nfa rct i on Va s cu l ar ma l for ma tio

Pa g e 2 7 6 0


n Me t ab ol i c di s eas es Vi t am in B12 def i ci e ncy (s u bac ut e co mb i ne d de ge ner at i on) Vi t am in E def i ci e ncy

Pa g e 2 7 6 1


Adr en om yel on eur op at h y Ra di a tio n eff ect s Syr i ng om yel ia Spi noc ere bel l ar de ge ner at i on

C. Clinical signs Di s eas e affect i ng t he s pi nal cord can pres ent wi t h pri nci pal l y â€œ long tract signsâ€• or a combi nat i on of l ong t ract s i gns and

Pa g e 2 7 6 2


local radicular features. 



1. Long tract motor signs res ul t from t he di s rupt i on of des cendi ng cort i cos pi nal fi bers , whi ch caus es weakness, spasticity, and hyperreflexia.





2. Impaired sensation res ul t s from di s ordered funct i on of as cendi ng s pi not hal ami c (pai n and t emperat ure) and dors al col umn pat hways (vi brat i on and propri ocept i on) (s ee Fi gure 11-4).





3. Bowel, bladder, and erectile function may be compromised.





4. Local radicular symptoms and signs include radiating pain, weakness, and sensory loss referabl e t o one or s everal myot omes and dermat omes . Thes e fi ndi ngs hel p defi ne t he ros t ral â€“caudal ext ent of a l es i on (Fi gure 11-5).

D. Selected conditions 



1. Syringomyelia o

o

a. Definition. Syri ngomyel i a i s a condi t i on of unknown caus e res ul t i ng i n cavitation of the spinal cord. Syri ngomyel i a can occur i n i s ol at i on or i n as s oci at i on wi t h t he Arnold-Chiari malformation (i .e., des cent of t he cerebel l ar t ons i l s i nt o t he cervi cal s pi nal canal ).

Pa g e 2 7 6 3


FIGURE 11-4 Cros s s ect i on of t he s pi nal cord at C1. CST, cort i cos pi nal t ract ; DC, dors al col umn; STT, s pi not hal ami c t ract . o P.550 o

Pa g e 2 7 6 4


FIGURE 11-5 Topographi c rel at i ons hi p among nerve root s , s pi nal cord s egment s , and t he bodi es and s pi nous proces s es of t he vert ebrae, whi ch are i ndi cat ed by Roman numeral s . o

o

b. Diagnosis 



(1) Signs of lower motor neuron dysfunction devel op on a s egment al bas i s and are accompani ed by upper motor neuron signs caudal t o t he cavi t y.

Pa g e 2 7 6 5




(2) Dermatomal loss of pain and temperature sensibility res ul t s from l ocal di s rupt i on of t he cros s i ng s pi not hal ami c fi bers by t he cavi t y (s yri nx). Impai red as cendi ng dors al col umn s ens i bi l i t y occas i onal l y occurs caudal t o t he cavi t y.



(3) MR I of t he s pi ne is t he opt im al dia gn ost ic tes t (

Onl i ne Fi g ure 116).

Pa g e 2 7 6 6


ONLINE FIGURE 11-6 Nonenhanced T 1 -wei ght ed magnet i c res onance i magi ng (MRI) s can demons t rat i ng s yri ngomyel i a and an as s oci at ed Arnol d-Chi ari mal format i on. o

o

c. T herapy. Surgery i s occas i onal l y i ndi cat ed t o decompres s t he fl ui d-fi l l ed s pi nal cord cavi t y and t o perform a bi ops y of t he wal l t o eval uat e t he pos s i bi l i t y of a cavi t ary neopl as m. Otherwise, treatment is supportive.





2. T ransverse myelitis. Infl ammat i on of t he s pi nal cord can caus e an acut e myel opat hy. o

Pa g e 2 7 6 7


a. Etiology. Al t hough many cas es of s egment al t rans vers e i nfl ammat i on are i di opat hi c, MS, SLE, and vari ous i nfect i ous agent s may caus e t rans vers e myel i t i s .

o

o

b. Diagnosis. Pat i ent s may experi ence l ocal i zed back or radi cul ar pai n, fol l owed by pri ckl i ng or burni ng s ens at i ons and progres s i ve weaknes s i n t he l egs . Bowel and bl adder di s t urbances are us ual l y pres ent .

o

o

c. T herapy. Corticosteroid treatment i s oft en advocat ed but i s of unproven val ue.

P.551





3. The Brown-SÃ©quard syndrome i s caus ed by a l es i on of one s i de of t he s pi nal cord at a di s cret e l evel . There i s caudal i ps i l at eral upper mot or neuron weaknes s , upper mot or neuron s i gns , and l os s of propri ocept i on and vi brat ory s ens at i on as wel l as cont ral at eral l os s of pai n and t emperat ure s ens at i on.





4. Anterior spinal artery occlusion o

o

a. Etiology. Bl ockage of a radi cul ar art ery t o t he s pi nal cord can caus e an i s chemi c i nfarct i on. 



(1) In many cas es , t he artery of Adamkiewicz, a branch of t he aort a s uppl yi ng

Pa g e 2 7 6 8


t he ant eri or t wo-t hi rds of t he l umbar s pi nal cord, i s compromi s ed. 



(2) Thrombos i s can be caus ed by aort i c di s s ect i on, l ocal at heros cl eros i s , vas cul i t i s , and hypervi s cos i t y.

o

o

b. Diagnosis. Pat i ent s pres ent wi t h fl acci d, hyporefl exi c parapl egi a; i mpai red l ower ext remi t y pai n and t emperat ure s ens at i on; and compromi s ed bl adder and bowel funct i on. However, pos i t i on and vi brat i on s ens es are us ual l y pres erved.

o

o

c. T herapy. Treat ment of t he di s eas e res pons i bl e for t he s pi nal cord i nfarct i on.

XIII. Neuropathy A. Classification Neuropat hi es may be cl as s i fi ed by: 



1. Course (acut e, s ubacut e, or chroni c)





2. T ype of symptoms and signs (s ens ory, mot or, aut onomi c, or any combi nat i on of t he t hree)





3. Presence of pain (hyperes t hes i a or dys es t hes i a)





4. Distribution (general i zed, focal , or mul t i focal )



Pa g e 2 7 6 9


5. NCV/EMG features (axonal or demyel i nat i ng)

B. Etiology Sel ect ed caus es of neuropat hy are l i s t ed i n Tabl es 11-9A and 11-9B.

C. Therapy Cont rol of t he underl yi ng di s eas e proces s i s cri t i cal . 



1. If i mpai red s ens at i on renders t he pat i ent prone t o i njury, prot ect i ve meas ures s houl d be t aken.





2. W eaknes s (e.g., wri s t or foot drops ) cal l s for appropri at e s pl i nt i ng and phys i cal t herapy.





3. Aut onomi c i ns uffi ci ency i s di ffi cul t t o manage; ort hos t at i c hypot ens i on can be t reat ed wi t h agent s t hat expand bl ood vol ume (e.g., fl udrocort i s one) and i ncreas e vas cul ar t one (e.g., mi dodri ne).





4. Tri cycl i c ant i depres s ant s , carbamaz epi ne, phenyt oi n, and gabapent i n, can hel p pat i ent s wi t h pai n.

D. Selected syndromes 



1. Compression neuropathies o

o

a. Pathophysiology. 



(1) Nerves can be damaged by repeat ed wear agai ns t fi rm s urfaces , t ypi cal l y bone or fi brous

Pa g e 2 7 7 0


t i s s ue. Mot or and s ens ory l os s devel op, referent t o t he affect ed nerve. 



(2) Common s i t es of compres s i on l eadi ng t o focal nerve dys funct i on i ncl ude t he median nerve at t he wri s t (carpal t unnel ), t he ulnar nerve at t he el bow, and t he peroneal nerve at t he fi bul ar head.

o

o

b. Etiology. The carpal tunnel syndrome can res ul t from repet i t i ve wri s t movement s , t rauma, carpal t unnel s t enos i s , art hri t i des (rheumat oi d art hri t i s and crys t al -i nduced s ynovi t i s ), di abet es mel l i t us , myxedema, pregnancy, birt h cont rol pi l l s , acromegal y, and i nfi l t rat i ve proces s es s uch as amyl oi dos i s .

o

o

c. Diagnosis. A pos i t i ve Ti nel 's s i gn (el i ci t i ng pares t hes i as by percus s i ng t he nerve at t he s i t e of compres s i on) may be s een cl i ni cal l y. An NCV s t udy reveal s evi dence of focal demyel i nat i on. If compres s i on i s s evere, evi dence of axonal i njury may appear (e.g., mus cl e was t i ng, denervat i on on t he EMG).

o

o

d. T herapy. T reatment of underlying conditions i s i mport ant . Spl i nt i ng oft en al l evi at es t he condi t i on, es peci al l y i f aggravat i ng maneuvers can be el i mi nat ed. Local cort i cos t eroi d i nject i ons may be benefi ci al . Surgical decompression of t he nerve i s neces s ary at t i mes .

P.552

Pa g e 2 7 7 1


TABLE 11-9A Selected Types and Causes of Neuropathy Cause s a s c c u h ut b r e a o c ni ut c e o r c Ne

h

ur

r

op

o

ath

ni

y Se

c Di T

ns o

a o

ry

b xi

ne

et n

uro

e s

pat

s Vi

hy

m ta el m lit in u B6 s in Ur t o e

Pa g e 2 7 7 2


m xi i a ca Al t i co o h n ol Sj a Ã b ¶ u gr s e e n' D s ef s y ic n i e dr nc o ie m s e Vi * ta P m ar in a s n B1 e , o B 6 pl , a B st 12

, ic

ni (a ac nt in iH H IV u H a

Pa g e 2 7 7 3


er nt e ib di o ta d ry y) n * e P ur ar o a p pr at ot hi ei e n s e Dr m u ia g Cr s y Vi o nc gl a o al b k ul al i n oi e d m s ia Ci A s m pl yl at oi in d P o h si e s

Pa g e 2 7 7 4


n L yt e oi pr n o 2 sy â € ², 3 â € ²Di d e o xy cy ti di n e Mo G CI t or ui D ne l l P uro ai L pat n- e hy B a ar d rÃ i n © to s y xi n ca dr t i o o

Pa g e 2 7 7 5


mn e M Di ul a ti b fo et ca e l s m m ot el or lit n u e s ur (p o ro p xi at mh al y is A ch nt e ib mo i c di n e e s ur t o o G p M1 at C h h y) ar Cr co iti tca M l

ar

Pa g e 2 7 7 6


ill ie n -T e o s s ot p h ol di y s n e e a ur s o e p at h y P or p h yr ia Se

Di CI

ns o

a D

ri m

b P/

ot o

et D

r

e A

ne

s D

uro

mS

pat

el

hy

lit u s Ur e m

â€

C h ar co tM

Pa g e 2 7 7 7


i a ar Cr i e i t i -T ca o l

ot

ill h n di e s ss e p a ol s y e n O e th ur er o h p er at e h di y ta V ry a n sc e ul ur iti o s p H at y hi p e ot s h M yr et oi ac di hr s o

Pa g e 2 7 7 8


mm Ly at m ic e le di u s k e o a d s ys e tr P o ar p a h pr y ot R ei ef n s e u mm i a di â€

Cr y o gl o b ul in e m ia P ar a

s e a s e A dr e n o m y el o n

Pa g e 2 7 7 9


n e e ur o o pl p a at st h ic y Dr Li u p g o s pr T ot o ei xi n n d s ef ic ie nc ie s S ar co id o si s Aut G Di H on ui a IV om l l b Vi ic

ai et nc

ne n- e ri uro B s s t pat ar m i n

Pa g e 2 7 8 0


hy rÃ el e © lit syu n s dr A o m m yl e oi P d or o p si h s yr F ia a m ili al d ys a ut o n o m ia HIV, human i mmunode fi ci ency vi rus ; CIDP, chroni c i nfl ammat ory

Pa g e 2 7 8 1


demyel i na t i ng pol yneuro pat hy; DADS, di s t al acqui red demyel i na t i ng s ymmet ri c neuropat h y. *Al s o, s ens ory neuronopa t hy. â€

Incl udi ng myel i n-as s oci at ed gl ycoprot e i n (MAG) ant i body and monocl on al gammopat hy. 



2. Guillain-BarrÃ© syndrome o

o

a. Definition and etiology. Gui l l ai n-BarrÃ© s yndrome i s a predomi nant l y demyel i nat i ng mot or pol yneuropat hy t hat us ual l y occurs i n ot herwi s e

Pa g e 2 7 8 2


heal t hy i ndi vi dual s . The i l l nes s can fol l ow a nons peci fi c vi ral s yndrome or be as s oci at ed wi t h HIV i nfect i on, Campyl obac t er jejuni i nfect i on, hepat i t i s , i nfect i ous mononucl eos i s , Myc opl as ma pneumoni ae i nfect i on, vacci nat i on, s urgery, l ymphoma, or SLE. o

o

b. Diagnosis 



(1) Clinical signs 



(a) Cl as s i cal l y, pat i ent s pres ent wi t h progres s i ve weaknes s and arefl exi a. Progres s i on of t he di s eas e s houl d not ext end beyond 4â€“6 weeks .





(b) Generalized paralysis can devel op gradual l y or rel at i vel y acut el y, i mpedi ng res pi rat ory funct i on.





(c) Rel at i vel y mi nor s ens ory s i gns and s ympt oms occur; however, pat i ent s may compl ai n of pai nful ext remi t i es .





(d) The autonomic nervous system i s oft en i nvol ved. Invol vement of t he aut onomi c nervous s ys t em can l ead t o earl y mort al i t y as a res ul t of cardiac arrhythmias and wide swings in blood pressure.

P.553

Pa g e 2 7 8 3


TABLE 11-9B Selected Types and Causes of Neuropathy Classified by Other Features Ne Ca ur us op es ath y Dy Di a s es bet t he es t i c me ne l l i t uro us pat Al c hy oh ol ab us e HI V 2â €², 3â €²Di d eox ycy t i di ne Va

Pa g e 2 7 8 4


s cu liti s Ax Di a on bet al

es

ne me uro l l i t pat us hy Ure mi a Dru gs an d t ox i ns Cri tic al illn es s pol yne uro pat hy Va s cu liti s Par apr ot e

Pa g e 2 7 8 5


i ne mi a Cry ogl ob ul i ne mi a Vi t am in B12 def i ci e ncy Her edi t ar y ne uro pat hi e s De Gui my l l ai el i n-B nat arr i ng Ã© ne s yn uro dro pat me hy CI

Pa g e 2 7 8 6


DP Par apr ot e i ne mi a* Her edi t ar y ne uro pat hi e s Mul Di a t i fo bet cal es (m me on l l i t on us eur Va i t i s s cu mu l i t i ltip s l ex Ly )

me

ne di s uro eas pat e hy Lep ros y Sar

Pa g e 2 7 8 7


coi dos is Her edi t ar y lia bi l i ty to pre ssu re pal sy Mal i gn ant i nfi l t ra t es HIV, human i mmun odefi ci ency vi rus ; CIDP, chroni c i nfl am mat ory demyel i nat i ng pol yne

Pa g e 2 7 8 8


uropat hy. *Incl u di ng myel i n -as s oci at ed gl ycopr ot ei n (MAG) ant i bo dy and monocl onal gammo pat hy. 



(2) Diagnostic studies 



(a) Exami nat i on of t he CSF s hows an el evat ed prot ei n and l es s t han 50 3

mononucl ear cel l s /mm ( albuminocytologic dissociation). 



(b) The mot or nerve conduct i on vel oci t i es are t ypi cal l y s l owed.





(c) An abnormal l y s mal l compound mus cl e act i on pot ent i al ampl i t ude obt ai ned wi t h di s t al s t i mul at i on of a peri pheral nerve (a meas ure of t he i nt egri t y of t he mos t di s t al part s of t he

Pa g e 2 7 8 9


axonal port i on of t he nerve) i s as s oci at ed wi t h a poor prognos i s . o

o

c. T herapy 



(1) Plasmapheresis can s hort en t he l engt h of t i me t hat pat i ent s are dependent on a res pi rat or and unabl e t o ambul at e. Cri t eri a t o i ni t i at e pl as mapheres i s i ncl ude t he i nabi l i t y t o wal k or rapi d progres s i on of t he di s eas e.





(2) Intravenous immunoglobulin treatment i s al s o effi caci ous and i s bet t er t ol erat ed t han pl as mapheres i s .





3. Diabetic neuropathy (s ee al s o Chapt er 9 IV A 7 d). Di abet es mel l i t us caus es s everal neuropat hi c s yndromes . The nerve i njury may be s econdary t o chroni c hypoxi a (rel at ed t o mi crovas cul ar di s eas e) t hat l eads t o axonal damage. o

o

a. T ypes. 



(1) A predomi nant l y s ens ory, di s t al , s ymmet ri c, s mal l fi ber pol yneuropat hy can be dys es t het i c and i nvol ve pai n and t emperat ure modal i t i es more t han vi brat i on and pos i t i on s ens es .





(2) A predomi nant l y s ens ory, di s t al ,

Pa g e 2 7 9 0


s ymmet ri c, l arge-fi ber pol yneuropat hy may occur, affect i ng vi brat i on and pos i t i on modal i t i es . 



(3) A s ens ori mot or neuropat hy can devel op.





(4) An aut onomi c neuropat hy or a mononeuropat hy or mononeuri t i s mul t i pl ex can occur. P.554





(5) Proxi mal di abet i c neuropat hy repres ent s i njury t o l arge nerves t hat caus es weaknes s and pai n; i t commonl y i nvol ves t he l umbos acral pl exus .

o

o

b. T herapy. As a group, pat i ent s wi t h bet t er bl ood gl ucos e cont rol have a l es s s evere pol yneuropat hy. However, i n i ndi vi dual pat i ent s , s ympt oms us ual l y do not res pond t o t i ght er bl ood gl ucos e cont rol .





4. Chronic inflammatory demyelinating polyneuropathy (CIDP). Thi s condi t i on, whi ch can be i di opat hi c or as s oci at ed wi t h a monocl onal gammopat hy, caus es s ens ori mot or neuropat hy. Ant i myel i n-as s oci at ed gl ycoprot ei n ant i bodi es may be det ect ed or t here may be an IgM monocl onal gammopat hy. Several vari ant s of CIDP have been defi ned bas ed on charact eri s t i c cl i ni cal pres ent at i ons , as s oci at ed monocl onal prot ei ns or ant i bodi es , and res pons e t o t herapy.

Pa g e 2 7 9 1


o

a. Diagnosis. NCV s t udi es i ndi cat e s l owi ng, and t he CSF t ot al prot ei n i s el evat ed.

o

o

b. T herapy. CIDP i s res pons i ve t o cort i cos t eroi d t herapy, pl as mapheres i s , and i nt ravenous i mmunogl obul i n admi ni s t rat i on, as wel l as s everal i mmunos uppres s ant drugs .

XIV. Disorders of the Neuromuscular Junction A. Myasthenia gravis 



1. Etiology. Ant i bodi es di rect ed agai ns t t he acet yl chol i ne recept or on t he mus cl e s urface caus e an i ncreas ed rat e of recept or des t ruct i on and l ead t o weaknes s .





2. Diagnosis o

o

a. Clinical signs. Pat i ent s are oft en young women or ol der men. Compl ai nt s of doubl e vi s i on, di ffi cul t y s wal l owi ng and s peaki ng, and l i mb weaknes s and fat i gue are common. On exami nat i on, pt os i s , eye movement abnormal i t i es , and proxi mal weaknes s may be s een. A t hymoma i s pres ent i n 10%â€“25% of pat i ent s .

o

o

b. Diagnostic studies

Pa g e 2 7 9 2




(1) Admi ni s t rat i on of intravenous edrophonium (a s hort -act i ng chol i nes t eras e i nhi bi t or) us ual l y produces a t rans i ent i mprovement i n s t rengt h i n pat i ent s s ufferi ng from myas t heni a gravi s . Pat i ent s wi t h res pi rat ory compromi s e or exces s i ve oral s ecret i ons s houl d not be gi ven edrophoni um becaus e t hey may be unabl e t o compens at e for t he i ncreas e i n s ecret i ons t hat occurs aft er admi ni s t rat i on of t hi s agent .





(2) Repetitive nerve stimulation studies can demons t rat e a decrement al res pons e of t he compound mus cl e act i on pot ent i al .





(3) Acetylcholine receptor antibodies can be det ect ed i n t he bl ood of 80%â€“90% of pat i ent s .





(4) A thoracic CT or MRI scan s hows a t hymoma, i f pres ent .





3. T herapy o

o

a. The mai ns t ay of t herapy i s admi ni s t rat i on of a cholinesterase inhibitor (e.g., pyri dos t i gmi ne).

o

o

b. T hymectomy can oft en l ead t o i mprovement ; t he pres ence of a t hymoma i s a defi ni t e i ndi cat i on

Pa g e 2 7 9 3


for s urgery. o

o

c. Corticosteroids, immunosuppressive agents, intravenous immunoglobulin, or plasmapheresis are effect i ve i n pat i ent s wi t h refract ory di s eas e.

B. Eaton-Lambert myasthenic syndrome 



1. Pathophysiology. Thi s s yndrome res ul t s when ant i bodi es di rect ed agai ns t t he cal ci um channel s on t he pres ynapt i c membrane of t he neuromus cul ar junct i on i nt erfere wi t h t he cal ci um-medi at ed rel eas e of acet yl chol i ne ves i cl es i n res pons e t o nerve s t i mul at i on. Thi s s yndrome i s oft en as s oci at ed wi t h an underl yi ng mal i gnancy, es peci al l y small cell carcinoma of the lung, and aut oi mmune di s eas es .





2. Diagnosis o

o

a. Clinical signs. Pat i ent s compl ai n of weaknes s and fat i gue, have di mi ni s hed mus cl e s t ret ch refl exes , and may have i mpai red aut onomi c funct i on, l eadi ng t o dry mout h and poor vi s ual accommodat i on. Unl i ke myas t heni a, s t rengt h i mproves wi t h act i vi t y.

o

o

b. Diagnostic studies. Repet i t i ve nerve s t i mul at i on s t udi es s how an i ncrement al res pons e of t he compound mus cl e act i on pot ent i al .





3. T herapy. Di ami nopyri di ne, pl as mapheres i s ,

Pa g e 2 7 9 4


i nt ravenous i mmunogl obul i n, or i mmunos uppres s i ve t herapy may be hel pful . P.555

XV. Disorders of Muscle A. Muscular dystrophies 



1. T ypes of muscular dystrophies o

o

a. Duchenne muscular dystrophy (DMD). i s an X-l i nked reces s i ve di s order caus ed by a defect i n t he dys t rophi n gene, whi ch codes for a mus cl e membrane prot ei n, dys t rophi n, t hat i s not det ect abl e i n pat i ent s wi t h DMD. 



(1) Al t hough di s t al mus cl es are event ual l y affect ed as wel l , pat i ent s experi ence i ni t i al progres s i ve proxi mal mus cul ar weaknes s .





(2) Prednisone treatment s l ows progres s i on of weaknes s .





(3) Death us ual l y occurs i n t he t hi rd decade of l i fe, oft en as a res ul t of pneumoni a.

o

o

b. Becker' s muscular dystrophy (BMD) i s an X-l i nked reces s i ve di s order of mus cl e caus ed by a defect i n t he dys t rophi n gene, whi ch codes for a

Pa g e 2 7 9 5


mus cl e prot ei n, dys t rophi n, t hat i s al t ered or pres ent i n reduced quant i t y i n BMD. Pat i ent s wi t h BMD have a more benign course than those with DMD, with a 50% s urvi val rat e beyond age 50. o

o

c. Myotonic muscular dystrophy i s an aut os omal domi nant di s order l ocal i zed t o a gene, myot oni n-prot ei n ki nas e, l ocat ed on chromos ome 19. Pat i ent s wi t h myot oni c dys t rophy have an i ncreas ed number of CTG t ri nucl eot i de repeat s i n t he ki nas e gene. The s everi t y of t he di s eas e can i ncreas e i n s ucces s i ve generat i ons , and t he CTG repeat s i ncreas e proport i onat el y (a phenomenon known as â€œant i ci pat i onâ€•). 



(1) Clinical signs i ncl ude a charact eri s t i c mus cl e myot oni a (i .e., pers i s t ent mus cl e act i vi t y i n res pons e t o cont ract i on or percus s i on), di s t al weaknes s , cat aract s , front al bal di ng, i mpai red i nt el l ect , hypers omni a, t es t i cul ar at rophy, cardi omyopat hy, mi t ral val ve prol aps e, and cardi ac conduct i on defect s .





(2) Death occurs i n t he fi ft h or s i xt h decade and t ypi cal l y i s at t ri but abl e t o res pi rat ory compromi s e or cardi ac arrhyt hmi a.

o

o

d. Facioscapulohumeral muscular dystrophy i s an aut os omal domi nant di s order charact eri zed by progres s i ve weaknes s about t he face, neck, upper t ors o, and proxi mal arms . The res pons i bl e gene i s l ocat ed on chromos ome 4.

Pa g e 2 7 9 6


o

e. Limb-girdle muscular dystrophy i s act ual l y a group of aut os omal domi nant and reces s i ve di s orders charact eri zed by progres s i ve l os s of mot or s t rengt h of t he t runk and proxi mal l i mbs . 



(1) The di s order repres ent s a group of condi t i ons wi t h di fferent genot ypi c ori gi ns and s i mi l ar phenot ype.





(2) Pat i ent s may have defect s i n t hei r dys t rophi n-as s oci at ed prot ei ns (e.g. members of t he dys t rophi nâ€“gl ycoprot ei n compl ex) or ot her membrane-as s oci at ed prot ei ns .





2. Diagnosis. Pat i ent s t ypi cal l y have an elevated serum CK level. EMG demons t rat es a â€œmyopat hi câ€• pat t ern (i .e., bri ef, s mal l ampl i t ude mus cl e pot ent i al s ). A muscle biopsy i s oft en i nformat i ve. Genetic studies are i ncreas i ngl y purs ued.

B. Acquired myopathy 



1. Etiology. Mus cl e di s eas e can be caus ed by i nfl ammat ory, t oxi c, or met abol i c proces s es (Tabl e 11-10).





2. Diagnosis o

o

a. Clinical signs. A pat i ent hi s t ory and exami nat i on

Pa g e 2 7 9 7


may provi de cl ues t o t he di agnos i s . 



(1) W eaknes s i s us ual l y proxi mal and s ymmet ri c. Di s eas e ons et can be acut e, s ubacut e, or chroni c.





(2) Swal l owi ng and breat hi ng can be compromi s ed, and myogl obi nuri a may res ul t from rapi d mus cl e des t ruct i on, l eadi ng t o renal i ns uffi ci ency.

o

o

b. Diagnostic studies. The s erum CK l evel may be el evat ed. The EMG reveal s a â€œmyopat hi câ€• pat t ern. A mus cl e bi ops y i s oft en i nformat i ve.





3. Selected syndromes o

o

a. Corticosteroid myopathy. i s us ual l y caus ed by chroni c cort i cos t eroi d t herapy and i s as s oci at ed wi t h proxi mal mus cl e weaknes s and was t i ng. The s erum CK l evel i s normal , and t he EMG i s us ual l y unremarkabl e.

o

o

b. W i t h polymyositis, t he as s oci at ed i nfi l t rat i on of l ymphocyt es des t roys mus cl e fi ber (s ee Chapt er 10 IX D). P.556

Pa g e 2 7 9 8


TABLE 11-10 Selected Causes of Acquired Myopathy Pol ym yos itis I di o pat hi c As s oci at e d wi t h ot h er con nec tiv e tis s ue di s eas es , i nf ect i ou s ag

Pa g e 2 7 9 9


ent s (i n cl u di n g HI V), an d dru gs Der ma to my os i tis As s oci at e d wi t h ma lig na ncy Inc l us i on bo dy my

Pa g e 2 8 0 0


os i tis El e ct r ol y te di s ord ers Hy pok al e mi a Hy per kal em ia Hy per cal ce mi a Hy po ma gn es e mi

Pa g e 2 8 0 1


a Hy po ph os p hat em ia En doc ri n e di s ord ers Hy pot hyr oi d ism Hy per t hy roi di s m Cu s hi ng' s di s

Pa g e 2 8 0 2


eas e an d i at r og eni c cor tic os t ero id ad mi ni s t ra tio n Ad di s on' s di s eas e Acr om eg al y Dru gs (e.

Pa g e 2 8 0 3


g., â€ œs t at i ns â€ • Îµam i no cap roi c aci d, pro cai na mi de, zid ovu di n e, ph enc ycl i di n e, L-t ryp t op ha n) HI

Pa g e 2 8 0 4


V, hu ma n im mu no def i ci e ncy vi r us . o

o

c. Inclusion body myositis i s an i nfl ammat ory myopat hy charact eri zed by a res i s t ance t o cort i cos t eroi d t herapy and by di s t al and proxi mal weaknes s t hat may be as ymmet ri c. 



(1) Diagnosis. Mus cl e bi ops y demons t rat es i nfl ammat i on and i ncl us i on bodi es (i ncl udi ng â€œri mmed vacuol es â€•) t hat cont ai n amyl oi d. Cyt ot oxi c T (Tc) cel l s are act i ve agai ns t a mus cl e ant i gen.





(2) T herapy. There i s no accepted treatment.

o

o

d. Polymyalgia rheumatica (PMR) i s not a myopat hy but can mas querade as one. 



(1) Clinical signs

Pa g e 2 8 0 5




(a) Pat i ent s oft en appear weak, but t he major s ympt om i s painful (tender, aching, and stiff) muscles.





(b) Act i vi t i es s uch as as cendi ng s t ai rs may be di ffi cul t t o perform. On formal s t rengt h t es t i ng, pat i ent s may appear s l i ght l y weak, pres umabl y becaus e t he pai n prevent s maxi mal effort . It has been found t hat i f t he pai n can be rel i eved, s t rengt h i s pres erved.





(c) T emporal (giant cell) arteritis i s pres ent i n 15%â€“20% of pat i ent s .





(2) Diagnostic studies. The eryt hrocyt e s edi ment at i on rat e us ual l y i s s i gni fi cant l y el evat ed but may be normal . The s erum CK l evel i s normal , and t he EMG i s unremarkabl e. Mus cl e hi s t ol ogy i s normal ; bi ops y i s us ual l y not performed.





(3) T herapy. NSAID or corticosteroid therapy s houl d bri ng about a rapi d res ol ut i on of s ympt oms .

C. Nondystrophic myotonias (channelopathies) Nondystrophic myotonias (channelopathies) are charact eri zed by prol onged mus cl e rel axat i on aft er vol unt ary cont ract i on or mechani cal s t i mul at i on.

Pa g e 2 8 0 6


1. Clinical signs.

Onl i ne Tabl e 11-11 s ummari zes t he cl i ni cal

feat ures of t he nondys t rophi c myot oni as . 

ONLINE TABLE 11-11 Clinical Features of the Nondystrophic Myotonias Sodi Chl um orid Cha

e

nnel Cha Dise nnel ase Dise s

ase

s H P Myo y a toni p r

a

e a Con rk m geni al y

ta

e ot m o ic ni a P C T B e o h e ri n o c o g m k F di e p e e c ni s r' at P ta e s n' u a r r e al

s

Pa g e 2 8 0 7


y si s P Y Y N Y er e e o e io s s

s

di c p ar al ys is P Y In N N ot e s o o a s o ss

m

iu

e

m

fa

-i

m

n

ili

d

e

uc

s

e d w e a k n e ss C N Y N N ol o e o o d-

s

in

Pa g e 2 8 0 8


d uc e d w e a k n e ss P O Y N N ar cc e o o a a s d si o o xi n ca al l m y ot o ni a Pr V V N R o ar ar o ar gr i a i a

e

e bl bl ss e e iv e w e a k

Pa g e 2 8 0 9


n e ss S N N N N ys o o o o te m ic in v ol v e m e nt G A A A A e D D D R/ n /1 /1 /7 7 et 7 7 ic tr a n s m is si o n/ ch ro m o s o

Pa g e 2 8 1 0


m e lo cu s Adapt ed from Pt acek LJ, Johns on KJ, Gri ggs RC: Genet i cs and phys i ol ogy of t he myot oni c mus cl e di s orders . N Engl J Med 1993;328(7 ):483. AD = aut os omal domi nant ; AR = aut os omal reces s i ve. 



2. T herapy. Treat ment i ncl udes t he us e of qui ni ne, procai nami de, and phenyt oi n.

D. Metabolic myopathies Metabolic myopathies i ncl ude di s orders of carbohydrat e and l i pi d met abol i s m.

Pa g e 2 8 1 1


E. Myoglobinuria Myoglobinuria can be caus ed by crus h i njuri es , vas cul ar occl us i ons , i nfect i on, t oxi ns , drugs , met abol i c myopat hi es , hypert hermi a, and s evere i nfl ammat i on. 



1. Diagnosis i s ai ded by document i ng an el evat ed s erum CK l evel and uri nary myogl obi n. The l at t er can be s us pect ed on t he fi ndi ng of dark (browni s h) uri ne and a pos i t i ve di ps t i ck for bl ood al ong wi t h a paradoxi cal abs ence of RBCs i n t he uri ne.





2. T herapy s houl d be di rect ed at t he underl yi ng caus e. Pat i ent s mus t be kept vi gorous l y hydrat ed t o prevent ki dney damage.

P.557

F. Acute quadriplegic myopathy Acute quadriplegic myopathy can devel op as a compl i cat i on of cri t i cal i l l nes s and t he s ys t emi c i nfl ammat ory res pons e s yndrome. There i s an as s oci at i on wi t h t he us e of cort i cos t eroi ds and nondepol ari zi ng neuromus cul ar bl ocki ng agent s . Treat ment i s s upport i ve.

XVI. Infection A. Meningitis, encephalitis, and neurologic complaints associated with HIV infection A. Meningitis, encephalitis, and neurologic complaints associated with HIV infection are di s cus s ed i n Chapt er 8.

B. Brain abscess 

Pa g e 2 8 1 2




1. Etiology. An abs ces s can occur aft er neuros urgery or penet rat i ng head t rauma, i n as s oci at i on wi t h ot i t i s medi a or poor oral hygi ene, i n pat i ent s wi t h a bact eremi a, and i n i ndi vi dual s wi t h a pul monary art eri ovenous mal format i on or cardi ac ri ght -t o-l eft s hunt .





2. Diagnosis o

o

a. Clinical signs. Pat i ent s may pres ent wi t h headache, s ei zures , an al t ered s ens ori um, and focal neurol ogi c s ympt oms and s i gns .

o

o

b. Diagnostic studies. CT or MRI scanning can eas i l y det ect a brai n abs ces s , al t hough di fferent i at i on from a neopl as t i c l es i on can be di ffi cul t .





3. T herapy. Empi ri c t reat ment s houl d be di rect ed agai ns t aerobi c and mi croaerophi l i c gram-pos i t i ve s t rept ococci and anaerobes , i ncl udi ng Bac t eroi des fragi l i s . o

o

a. Antibiotic therapy. oft en i ncl udes peni ci l l i n, chl orampheni col , met roni dazol e, and cefot axi me or t ri met hopri mâ€“s ul famet hoxaz ol e. The cl i ni cal s et t i ng can hel p defi ne t he mos t l i kel y pat hogen.

o

o

b. Therapy i s moni t ored by s eri al brai n i magi ng t echni ques .

Pa g e 2 8 1 3


o

c. Oft en, surgical excision of t he abs ces s can be avoided. Stereotactic biopsy and drainage of an abscess occas i onal l y i s requi red.

C. A spinal epidural abscess A spinal epidural abscess i s us ual l y caus ed by hemat ogenous s eedi ng of an i nfect i ve organi s m and i s charact eri zed by l ocal pai n and t endernes s , fever, and neurol ogi c s i gns and s ympt oms appropri at e t o t he s i t e of t he i nfect i on. 



1. Diagnosis can be ai ded by spinal MRI or CT scans and myelography.





2. Surgical drainage i s i ndi cat ed al ong wi t h antibiotic therapy.

D. Neurosyphilis 



1. Stages and clinical signs o

o

a. Asymptomatic disease. CSF abnormal i t i es may be t he onl y s i gn of i nfect i on.

o

o

b. Acute syphilitic meningitis us ual l y devel ops wi t hi n 2 years of pri mary i nfect i on. Headache, meni ngi s mus , hydrocephal us , and crani al nerve pal s i es can occur.

o

o

c. Cerebrovascular (meningovascular) syphilis

Pa g e 2 8 1 4


mani fes t s mont hs t o years aft er pri mary i nfect i on. Affect ed pat i ent s pres ent wi t h i s chemi c s t rokes (oft en as s oci at ed wi t h headache) and behavi oral abnormal i t i es . o

o

d. General paresis devel ops one t o t wo decades aft er pri mary i nfect i on and i s charact eri zed by a progres s i ve dement i a.

o

o

e. T abes dorsalis al s o mani fes t s 10â€“20 years aft er pri mary i nfect i on wi t h l i ght ni ng pai ns , pares t hes i as , bl adder dys funct i on, gai t i ns t abi l i t y, Argyl l Robert s on pupi l s (i .e., i mpai red pupi l l ary l i ght react i on wi t h pres erved pupi l l ary cons t ri ct i on t o accommodat i on, perhaps as a res ul t of a mi dbrai n t egment al l es i on), arefl exi a (es peci al l y at t he ankl es ), and l os s of pos i t i on and vi brat i on s ens i bi l i t y.





2. Diagnostic studies. Pat i ent s wi t h HIV i nfect i on are at part i cul ar ri s k for neuros yphi l i s . o

o

a. Al mos t al l pat i ent s wi t h neuros yphi l i s have a reactive serum fluorescent treponemal antibody (FT A-ABS) test. Pat i ent s wi t h a nonreact i ve CSF FTA-ABS t es t do not have neuros yphi l i s .

o

o

b. The CSF VDRL t es t i s oft en react i ve i n neuros yphi l i s , but a nonreact i ve CSF VDRL t es t i s found i n 25-75% of pat i ent s wi t h neurol ogi c di s eas e years removed from t he pri mary i nfect i on. P.558

Pa g e 2 8 1 5


o

o

c. Other CSF findings i ncl ude a predomi nant l y mononucl ear pl eocyt os i s and an el evat ed prot ei n and IgG i ndex.





3. T herapy. Peni ci l l i n i s t he t reat ment of choi ce for neuros yphi l i s . Pat i ent s wi t h concurrent HIV i nfect i on devel op neuros yphi l i s earl i er and may be more res i s t ant t o t herapy t han i mmunocompet ent pat i ent s .

XVII. Primary CNS Tumors Al t hough t hes e t umors are rel at i vel y uncommon, t hey s eem t o be i ncreas i ng i n i nci dence.

A. Astrocytic neoplasms 



1. As t rocyt omas are neopl as ms wi t h s l i ght hypercel l ul ari t y and pl eomorphi s m. Anaplastic astrocytomas are charact eri zed as havi ng moderat e cel l ul ari t y and pl eomorphi s m and s ome vas cul ar prol i ferat i on. o

o

a. Clinical signs. Pat i ent s wi t h as t rocyt omas and anapl as t i c as t rocyt omas t ypi cal l y pres ent wi t h focal hemi s pheri c neurol ogi c dys funct i on, convul s i ons , or headache.

o

o

b. T herapy. Anapl as t i c as t rocyt omas can be t reat ed wi t h surgery and radiotherapy. Chemotherapy may be hel pful .

Pa g e 2 8 1 6


o

c. Prognosis. Out come i s i nvers el y rel at ed t o t he pat i ent 's age and t he pres ence of t umor necros i s . The s urvi val rat e aft er 2 years i s 38%â€“50%. Ot her predi ct ors of out come i ncl ude t he pat i ent 's funct i onal s t at us and t he amount of res i dual t umor aft er i ni t i al s urgery.





2. Glioblastoma multiforme has moderat e-t o-marked hypercel l ul ari t y, pl eomorphi s m, and necros i s ; vas cul ar prol i ferat i on may be pres ent . o

a. Clinical signs. Cl i ni cal feat ures are s i mi l ar t o t hos e of l es s aggres s i ve t umors . CT or MRI s cans t ypi cal l y s how an enhanci ng, i rregul ar mas s (

Onl i ne Fi gure 11-7).

o

ONLINE FIGURE 11-7 An enhanced T 1 -wei ght ed magnet i c

Pa g e 2 8 1 7


res onance i magi ng (MRI) s can demons t rat i ng a gl i obl as t oma mul t i forme. o

o

b. T herapy. Treat ment i ncl udes corticosteroid therapy (for edema reduct i on), surgical debulking, radiation therapy, and chemotherapy, bot h s ys t emi cal l y or l ocal l y admi ni s t ered.

o

o

c. Prognosis. The prognos i s of gl i obl as t oma mul t i forme i s poor, wi t h a s urvi val rat e of 10% aft er 24 mont hs .

B. Oligodendrogliomas 



1. Clinical signs. Pat i ent s wi t h t hes e i nfi l t rat i ng t umors commonl y pres ent wi t h headache and convul s i ons ; focal neurol ogi c defi ci t s can devel op.





2. T herapy. Anapl as t i c ol i godendrogl i omas s eem t o be res pons i ve t o radiation therapy and chemotherapy. Surgery i s t he mai ns t ay of t reat ment .





3. Prognosis. The overal l medi an l engt h of s urvi val i s 53 mont hs .

C. Meningiomas Meningiomas are t umors t hat ari s e from t he meni nges and s l owl y enl arge, caus i ng a mas s effect t hat di s pl aces normal s t ruct ures . Angi obl as t i c meni ngi omas are l ocal l y i nvas i ve. 



1. Clinical signs. Headache, s ei zures , and focal neurol ogi c s i gns can occur.

Pa g e 2 8 1 8




2. T herapy. Treat ment i s surgical resection; radiation therapy can be us ed for i nvas i ve t umors .





3. Prognosis. If t he ent i re t umor can be s urgi cal l y res ect ed, t he majori t y of pat i ent s do wel l . If t he ent i re t umor cannot be removed, t he pat i ent may experi ence recurrence of s ympt oms .

D. Schwannomas Schwannomas of t he ei ght h crani al nerve (acous t i c neuroma) t ypi cal l y ari s e from t he ves t i bul ar component of t he nerve. They can enl arge and di s pl ace s t ruct ures about t he cerebel l opont i ne angl e. 



1. Clinical signs. Pat i ent s devel op di zzi nes s , heari ng l os s , and t i nni t us . A di mi ni s hed corneal refl ex may be a s i gn of t ri gemi nal nerve compromi s e by an enl argi ng mas s .





2. Diagnostic studies. Di agnos i s i s bes t made wi t h an enhanced MRI.





3. T herapy. Treat ment opt i ons i ncl ude surgical resection or stereotactic radiation therapy.





4. Prognosis. Smal l t umors can be s urgi cal l y cured. If res i dual t umor remai ns , recurrent s ympt oms can devel op, us ual l y years l at er.

P.559

Pa g e 2 8 1 9


E. Primary CNS lymphoma Primary CNS lymphoma i s i ncreas i ng i n i nci dence, es peci al l y i n i mmunocompromi s ed pat i ent s . Occas i onal l y, pri mary CNS l ymphoma pres ent s as meni ngeal l ymphomat os i s . 



1. Diagnostic studies. Imaging studies s how one or more i nt ens el y enhanci ng l es i ons , t ypi cal l y i n a peri vent ri cul ar di s t ri but i on. The di agnos i s can be es t abl i s hed wi t h s t ereot act i c bi ops y.





2. T herapy. Al t hough i ni t i al t reat ment wi t h cort i cos t eroi ds can l ead t o a rapi d decreas e i n t he s i ze of t he mas s , ul t i mat e s urvi val depends on radi at i on t herapy and chemot herapy.





3. Prognosis. The devel opment of mul t i modal i t y t reat ment prot ocol s has ext ended pat i ent s urvi val for years , es peci al l y i n i mmunocompet ent pat i ent s .

XVIII. Hereditary Disorders

A. Wilson's disease (hepatolenticular degeneration) Thi s aut os omal reces s i ve di s eas e i s l ocal i zed t o an abnormal i t y of t he AT P7B gene on chromos ome 13. It may be as s oci at ed wi t h t he accumul at i on of copper i n t he brai n, l i ver, and ot her t i s s ues . Abnormal i t i es i n t he copper-bi ndi ng prot ei n cerul opl as mi n are us ual l y found. 

Pa g e 2 8 2 0




1. Clinical signs. Pres ent i ng s i gns may i ncl ude hepat i c di s eas e; Kays er-Fl ei s cher ri ngs i n Des cemet 's membrane of t he cornea; or neurol ogi c s ympt oms : behavi oral probl ems (i ncl udi ng ps ychos i s ), movement di s orders (e.g., i ncoordi nat i on, t remor, mas ked faci es , dys t oni a, and at het os i s ); and hemol yt i c anemi a. There are al s o â€œpres ympt omat i câ€• pat i ent s who may pres ent wi t hout t hes e s ympt oms .





2. Diagnosis o

o

a. Di agnos i s i s made by fi ndi ng a l ow s erum cerul opl as mi n l evel (us ual l y), exces s i ve 24-hour uri ne copper excret i on, Kays er-Fl ei s cher ri ngs on eye exami nat i on wi t h a s l i t l amp, or i ncreas ed l evel s of hepat i c copper (by bi ops y).

o

o

b. MRI may reveal at rophy of t he caudat e and put amen wi t h i ncreas ed s i gnal i nt ens i t y on T 2 -wei ght ed i mages .





3. T herapy. Treat ment cons i s t s of copper chelation wi t h t ri ent i ne or D-peni ci l l ami ne, i f copper l evel s are hi gh enough. Zi nc may be us ed bot h as a mai nt enance t herapy or for pres ympt omat i c pat i ent s .

B. Neurofibromatosis (NF) 



1. Neurofibromatosis type 1 (NF 1, von

Pa g e 2 8 2 1


Recklinghausen' s disease) i s an aut os omal domi nant di s order. The res pons i bl e gene i s l ocat ed on chromos ome 17, and t he gene product i s neurofi bromi n. o

o

a. Pat i ent s who meet t wo or more of t he fol l owi ng cri t eri a can be di agnos ed as s ufferi ng from NF 1. 



(1) Neurofibromas (t wo or more, or one pl exi form neurofi broma)





(2) CafÃ©-au-lait macules (s i x or more meas uri ng 1.5 cm i n t hei r great es t di mens i on)





(3) Freckling i n t he axillary or inguinal areas





(4) Optic glioma





(5) Two or more iris hamartomas (Lisch nodules)





(6) Sphenoid dysplasia or thinning of the cortex of the long bones





(7) An immediate relative wi t h NF 1

o

o

b. Complications of NF 1 i ncl ude as t rocyt i c t umors , opt i c gl i oma, neurofi bros arcoma, compres s i ve peri pheral neuropat hi es , compres s i ve myel opat hy,

Pa g e 2 8 2 2


pheochromocyt oma, and s col i os i s . o

o

c. T herapy i s di rect ed at t he compl i cat i ons of t he di s eas e.





2. Neurofibromatosis type 2 (NF 2) i s an aut os omal domi nant di s order l ocal i zed t o chromos ome 22 and charact eri zed by bi l at eral acous t i c neurofi bromas .

C. von Hippel-Lindau disease Thi s aut os omal domi nant di s order i s l ocal i zed t o chromos ome 3. Cerebellar and retinal hemangioblastomas are charact eri s t i c. 



1. Hemangi obl as t omas al s o may be found t hroughout t he CNS. The ki dneys , pancreas , and l i ver can harbor hemangi omas . Pheochromocyt omas may devel op.





2. Pol ycyt hemi a i s as s oci at ed wi t h cerebel l ar hemangi obl as t oma.

D. Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) Thi s aut os omal domi nant di s order i s as s oci at ed wi t h t wo genes ( HHT 1 and HHT 2). It i s charact eri zed by t el angi ect at i c s ki n l es i ons , CNS vas cul ar mal format i ons , and pul monary art eri ovenous fi s t ul ae. Brai n abs ces s es may occur, as may i s chemi c s t roke, s econdary t o a paradoxi cal embol us vi a a pul monary art eri ovenous fi s t ul a.

Pa g e 2 8 2 3


E. Tuberous sclerosis Thi s aut os omal domi nant di s order i s as s oci at ed wi t h t wo abnormal genes , T SC1 and T SC2. 



1. Criteria for diagnosis i ncl ude mul t i pl e faci al angi ofi bromas , ungual fi bromas , ret i nal hamart oma, cort i cal t ubers , s ubependymal gl i al nodul es (oft en cal ci fi ed), and mul t i pl e renal angi omyol i pomas .





2. Some associated features are hypomel anot i c macul es , a s hagreen pat ch, mul t i cys t i c ki dneys , s ei z ures , and ment al ret ardat i on. Beni gn gi ant cel l as t rocyt omas can devel op, oft en near t he foramen of Monro.

F. Down syndrome (trisomy 21) Thi s genet i c di s order i s charact eri zed by ment al ret ardat i on, epi cant hal fol ds , Brus hfi el d s pot s on t he i ri s , a t rans vers e pal mar creas e, and cardi ac mal format i ons . By age 50, mos t pat i ent s devel op Al zhei mer's di s eas e. Myel opat hy may devel op becaus e of at l ant oaxi al di s l ocat i on.

G. Huntington's disease The gene t hat i s res pons i bl e for t hi s aut os omal domi nant di s order, whi ch i s l ocal i zed t o chromos ome 4, has an exces s of t ri nucl eot i de repeat s and encodes t he prot ei n hunt i ngt i n. Pat i ent s devel op a progres s i ve cogni t i ve decl i ne and choreoat het os i s bet ween 30 and 50 years of age. Depres s i on frequent l y occurs . At rophy of t he caudat e nucl eus i s charact eri s t i c.

Pa g e 2 8 2 4


H. Cerebellar atrophies Thes e condi t i ons are as s oci at ed wi t h mul t i s ys t em degenerat i ve proces s es i ncl udi ng abnormal ocul omot or funct i on, bul bar was t i ng and fas ci cul at i ons , upper mot or neuron s i gns , ext rapyrami dal dys funct i on, cogni t i ve decl i ne, vi s ual l os s , and peri pheral neuropat hy. 



1. Etiology. Thes e di s eas es can be t rans mi t t ed as aut os omal domi nant or reces s i ve di s orders , or t hey may be s poradi c and pres umabl y rel at ed t o a new mut at i on.





2. T ypes. Numerous aut os omal domi nant s pi nocerebel l ar at axi as have been genet i cal l y i dent i fi ed. Mos t of t hes e at axi as are charact eri zed by an exces s number of t ri nucl eot i de repeat s and are i dent i fi ed as s pi nocerebel l ar at rophy t ype 1 (SCA-1), SCA-2, and s o on. o

o

a. The phenot ypi câ€“genot ypi c correl at i ons are oft en poor, maki ng i t di ffi cul t t o accurat el y predi ct a pat i ent 's genot ype from cl i ni cal eval uat i on al one.

o

o

b. Mol ecul ar genet i cs wi l l al l ow furt her genot ypi c cl as s i fi cat i on of t hes e di s orders .





3. Associated conditions. Cerebel l ar at rophi es have been as s oci at ed phenot ypi cal l y wi t h defi ci enci es of gl ut amat e dehydrogenas e, pyruvat e dehydrogenas e compl ex, and hexos ami ni das e; vi t ami n E defi ci ency; mi t ochondri al di s orders ; and el evat ed very l ongâ€“chai n fat t y aci ds .

Pa g e 2 8 2 5


I. Peroxisome disorders The peroxi s ome i s a cel l ul ar organel l e t hat i s i nvol ved wi t h fat t y aci d oxi dat i on. 



1. Adrenoleukodystrophy i s an X-l i nked di s order charact eri zed by progres s i ve i nt el l ect ual decl i ne, s pas t i ci t y, and vi s ual l os s . Adrenomyeloneuropathy, al s o an X-l i nked di s order, i s charact eri zed by a progres s i ve myel opat hy and neuropat hy. o

o

a. W hi t e mat t er changes are vi s i bl e on CT and MRI s cans i n adrenol eukodys t rophy.

o

o

b. Bot h condi t i ons res ul t i n exces s i ve l evel s of very l ongâ€“chai n fat t y aci ds i n t he bl ood, perhaps as a res ul t of defect i ve Î²-oxi dat i on.





2. Refsum disease i s an aut os omal reces s i ve di s order charact eri zed by a s ens ori mot or neuropat hy, pi gment ary ret i nopat hy, at axi a, anos mi a, heari ng l os s , s ki n l es i ons , and el evat ed CSF prot ei n. o

o

a. Pathophysiology. There i s an exces s of phyt ani c aci d i n t he bl ood becaus e of a defect i n al pha-oxi dat i on of t hi s fat t y aci d.

o

o

b. T herapy. Di et ary cont rol of phyt ani c aci d i nt ake and pl as mapheres i s can hel p cont rol t he neurol ogi c

Pa g e 2 8 2 6


probl ems .

J. Mitochondrial disorders Mi t ochondri al DNA codes for component s of t he mi t ochondri al res pi rat ory chai n and oxi dat i ve phos phoryl at i on enzymat i c compl exes . Di s orders of mi t ochondri al DNA are t rans mi t t ed by nonmendel i an, mat ernal i nheri t ance. The mi t ochondri al encephal opat hi es and myopat hi es have ragged red fi bers i n mus cl e. The ragged red fi bers repres ent abundant abnormal mi t ochondri a t hat are demons t rat ed by us i ng a modi fi ed Gomori t ri chrome s t ai n. Pat i ent s may have s ens ori neural heari ng l os s , s hort s t at ure, or di abet es mel l i t us , and t hey oft en have el evat ed bl ood l act i c aci d l evel s . 



1. Kearns-Sayre syndrome i s charact eri zed by progres s i ve ext ernal opht hal mopl egi a, pi gment ary ret i nopat hy, compl et e heart bl ock, CSF prot ei n l evel s great er t han 100 mg/dL, at axi a, and myopat hy. Del et i ons i n t he mi t ochondri al DNA are found.





2. Myoclonic epilepsy with ragged red fibers (MERRF) pres ent s wi t h myocl onus , epi l eps y, and at axi a. There i s a poi nt mut at i on i n t he mi t ochondri al genome.





3. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like events (MELAS) i s charact eri zed by i nt ermi t t ent vomi t i ng and headaches , recurrent i s chemi c s t rokes , and s ei zures . Poi nt mut at i ons are pres ent i n t he mi t ochondri al DNA.





4. Leber' s hereditary optic neuropathy mani fes t s as

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s ubacut e bi l at eral cent ral vi s i on l os s wi t h ret i nal mi croangi opat hy. It i s caus ed by s everal poi nt mut at i ons i n t he mi t ochondri al genome.

XIX. Toxic and Metabolic Disorders A. Vitamin B 12 deficiency Thi s vi t ami n defi ci ency res ul t s i n s ubacut e combi ned degenerat i on or SCD. 



1. Pathophysiology. Depri vat i on of vi t ami n B 1 2 l eads t o demyel i nat i on and axonal degenerat i on, affect i ng t he peri pheral nerves , t he s pi nal cord (where t he pos t eri or and l at eral col umns are demyel i nat ed), and t he cerebrum.





2. Diagnosis o

o

a. Clinical signs. Neurol ogi c mani fes t at i ons i ncl ude cogni t i ve i mpai rment , di mi ni s hed pos i t i on and vi brat ory s ens at i on, upper mot or neuron s i gns wi t h abnormal gai t , and s ens ory peri pheral neuropat hy.

o

o

b. Diagnosis. Pat i ent s t ypi cal l y have anemi a, macrocyt os i s , and a l ow vi t ami n B 1 2 l evel . However, neurol ogi c di s eas e can occur wi t hout anemi a or macrocyt os i s . If t he di agnos i s remai ns s us pect i n a pat i ent wi t h a normal or margi nal l y decreas ed s erum vi t ami n B 1 2 l evel , t he fi ndi ng of el evat ed s erum met hyl mal oni c aci d and t ot al homocys t ei ne can confi rm t he pres ence of vi t ami n B 1 2 defi ci ency.



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3. T herapy. Treat ment i s admi ni s t rat i on of cobalamin.

B. Acute intermittent porphyria 



1. Pathophysiology. Thi s aut os omal domi nant di s order i s caus ed by a defect i n t he act i vi t y of uroporphyri nogen I s ynt het as e, whi ch l eads t o i ncreas ed act i vi t y of Î”-ami nol evul i ni c aci d s ynt het as e and el evat ed l evel s of Î”-ami nol evul i ni c aci d.





2. Diagnosis. Acut e i nt ermi t t ent porphyri a caus es del i ri u m; s ei zures ; and aut onomi c, s ens ory, and mot or neuropat hi es ; a Gui l l ai n-BarrÃ©â€“l i ke i l l nes s can devel op. Duri ng an acut e at t ack, t he Watson-Schwartz test i ndi cat es el evat ed l evel s of uri nary porphobi l i nogen.





3. T herapy. Hematin administration can decreas e cl i ni cal mani fes t at i ons . Preci pi t ant s s uch as barbi t urat es , phenyt oi n, s t arvat i on, and i nfect i on s houl d be avoi ded i n s us cept i bl e i ndi vi dual s .

C. Complications of alcohol abuse Al cohol may affect t he nervous s ys t em by i t s el f (i .e., al cohol i nt oxi cat i on, addi ct i on, or wi t hdrawal ) or i n t andem wi t h a nut ri t i onal defi ci ency. P.560





1. Complications from intoxication, addiction, and

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withdrawal o

o

a. Acute alcohol intoxication. caus es del i ri um and i ncoordi nat i on. 



(1) Severe i nt oxi cat i on can l ead t o met abol i c coma wi t h res pi rat ory depres s i on.





(2) Al cohol i c â€œ blackoutsâ€• are charact eri zed by t he i nabi l i t y t o form new memori es i n s pi t e of pres ervat i on of cons ci ous nes s .

o

o

b. Alcohol withdrawal caus es earl y s ympt oms of t remul ous nes s and hal l uci nos i s . Del i ri um t remens i s s een duri ng l at e wi t hdrawal from al cohol . Benzodi azepi nes may be us ed t o t reat al cohol wi t hdrawal s ympt oms .

o

o

c. Alcohol-related seizures (â€œ rum fitsâ€•) are bri ef, general i zed t oni câ€“cl oni c convul s i ons t hat frequent l y occur i n cl us t ers . 



(1) Cl as s i cal l y, al cohol -rel at ed s ei zures were t hought t o occur pri mari l y i n t he 48 hours aft er wi t hdrawal from chroni c al cohol i nt ake. However, al cohol -rel at ed s ei zures al s o may be caus ed by chroni c al cohol i nt oxi cat i on and repres ent a t oxi c effect of al cohol on t he brai n, not a wi t hdrawal phenomenon.



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

(2) Typi cal l y, pat i ent s are al ert s hort l y aft er t he s ei zure. They do not have s ei zure di s charges on an i nt eri ct al EEG.





(3) T herapy s houl d be di rect ed at t he underl yi ng al cohol abus e. Ant i convul s ant medi cat i ons are not i ndi cat ed for t ypi cal al cohol -rel at ed s ei zures .

o

o

d. Al cohol abus e i s as s oci at ed wi t h cerebral atrophy and cognitive impairments and may predispose patients to stroke.

o

o

e. Al cohol i c pat i ent s may devel op a myopathy t hat i s acut e or chroni c and predomi nant l y affect s t he proxi mal mus cl es . Rhabdomyolysis can compl i cat e t he acut e di s order.





2. Complications related to nutritional deficiencies o

o

a. Wernicke' s encephalopathy. i s s een i n mal nouri s hed al cohol i c pat i ent s who have a thiamine deficiency. Ot her condi t i ons (e.g., hyperemes i s , renal di al ys i s , and mal nut ri t i on) are as s oci at ed wi t h t hi ami ne defi ci ency and can l ead t o W erni cke's encephal opat hy, even i n pat i ent s who do not abus e al cohol . 



(1) Clinical signs. Pat i ent s t ypi cal l y are del i ri ous and have nys t agmus , eye movement

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abnormal i t i es , and at axi a. Di s orders of cons ci ous nes s and hypot hermi a can occur. 



(2) T herapy. Thi ami ne admi ni s t rat i on can res ol ve t he acut e i l l nes s .

o

o

b. Korsakoff psychosis i s a chroni c encephal opat hy t hat i s s een i n al cohol i c pat i ent s wi t h a t hi ami ne defi ci ency. 



(1) Clinical signs. Feat ures i ncl ude ret rograde and ant erograde memory defi ci t s , apat hy, and i mpai red probl em-s ol vi ng abi l i t i es .





(2) T herapy. Pat i ent s may not i mprove wi t h abs t i nence from al cohol or t hi ami ne admi ni s t rat i on.

o

o

c. Sensory neuropathy i s caus ed by al cohol and oft en l eads t o dys es t hes i a. Al t hough t hi s axonal (al t hough s ome aut hors s ugges t demyel i nat i ve) neuropat hy i s probabl y rel at ed t o concurrent mal nut ri t i on, al cohol i t s el f may be t oxi c t o nerves .

o

o

d. Cerebellar degeneration may occur i n al cohol i cs . The ant eri or and s uperi or vermi s are part i cul arl y affect ed. Pat i ent s have di ffi cul t y wi t h gai t and s t ance; nys t agmus and arm at axi a are not promi nent .

D. Drug abuse

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



1. Us e of cocaine or â€œ crackâ€• can res ul t i n s ei z ures , i s chemi c s t roke, s ubarachnoi d and i nt raparenchymal hemorrhage, and rhabdomyol ys i s . Hemorrhagi c s t rokes may be as s oci at ed wi t h an underl yi ng vas cul ar l es i on; defi ni t i on of t he vas cul ar anat omy i s us ual l y i ndi cat ed t o s earch for an aneurys m or art eri ovenous mal format i on.





2. Us e of heroin can caus e a met abol i c coma; mi os i s i s a charact eri s t i c fi ndi ng i n heroi n us ers . Heroi n has been as s oci at ed wi t h rhabdomyol ys i s , chroni c myopat hy, t rans vers e myel i t i s , and peri pheral neuropat hi es .





3. Inges t i on of phencyclidine (PCP) can caus e a wi de range of neurol ogi c di s t urbances rangi ng from acut e ps ychos i s t o coma. Nys t agmus , mi os i s , at axi a, myocl onus , dys t oni c pos t uri ng, general i zed ri gi di t y, dys ki nes i as , and s ei zures can occur.





4. Inges t i on of â€œ ecstasyâ€• (an amphet ami ne anal og) can caus e del i ri um, hypert hermi a, and rhabdomyol ys i s . Thi s drug s el ect i vel y damages s erot oni nergi c neurons .

P.561

XX. Sleep Disorders A. Narcolepsy Narcolepsy i s charact eri zed by hypers omni a wi t h s hort l at ency peri ods for t he ons et of dayt i me s l eep and t he earl y devel opment

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of rapi d eye movement (REM) s l eep. Pat i ent s awaken refres hed from s l eep at t acks . 



1. Etiology. Narcol eps y i s probabl y an aut os omal domi nant di s order wi t h vari abl e penet rance; i t has been mapped t o chromos ome 6. The vas t majori t y of pat i ent s have ant i gens for HLA-DR2 and HLA-DQB1.





2. Clinical signs. Feat ures i ncl ude cataplexy (i .e., t rans i ent epi s odes of di mi ni s hed mus cl e t one), sleep paralysis, and vivid dreams at t he begi nni ng and end of s l eep.





3. T herapy. Met hyl pheni dat e, pemol i ne, or modafi ni l can di mi ni s h t he hypers omni a, and prot ri pt yl i ne or i mi prami ne can decreas e cat apl exy.

B. Sleep apnea Sleep apnea, or hypovent i l at i on duri ng s l eep, can be at t ri but abl e t o obs t ruct i ve caus es (e.g., obes i t y, a s mal l oropharynx) or t o nonobs t ruct i ve (CNS) caus es . Sl eep apnea i s commonl y â€œmi xedâ€ • and repres ent s bot h CNS and obs t ruct i ve probl ems . 



1. Clinical signs. Pat i ent s have dayt i me hypers omni a and can devel op noct urnal hypoxi a, pul monary hypert ens i on, and cardi ac arrhyt hmi as .





2. T herapy. Treat ment opt i ons i ncl ude wei ght l os s , cont i nuous pos i t i ve ai rway pres s ure (CPAP), uvul opal at opharyngopl as t y (UPPP), t racheos t omy, and s everal new, mi ni mal l y i nvas i ve s urgi cal t echni ques .

C. Periodic movements in sleep

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Periodic movements in sleep i nvol ve fl exor cont ract i ons i n t he l egs . Pat i ent s can al s o experi ence s l eep myocl onus and dys t oni a and res t l es s l egs s yndrome whi l e awake. 



1. Clinical signs. Pat i ent s are moment ari l y arous ed, and t herefore noct urnal s l eep qual i t y i s poor, l eadi ng t o dayt i me hypers omni a.





2. T herapy. Treat ment opt i ons i ncl ude carbi dopa/l evodopa combi nat i ons , dopami ne agoni s t s , gabapent i n, opi at es , and cl onaz epam.

XXI. Trauma A. Brain injury 



1. A concussion i s a moment ary di s rupt i on of brai n funct i on aft er head i njury t hat res ul t s i n a bri ef l os s of cons ci ous nes s . o

o

a. Clinical signs. Aft er awakeni ng, pat i ent s compl ai n of headache, i mpai red memory, poor concent rat i on, bl urred vi s i on, t i nni t us , di zzi nes s , and naus ea.

o

o

b. Duration of symptoms. Sympt oms can pers i s t for days or weeks as t he postconcussion syndrome. Posttraumatic migraine can devel op but may be al l evi at ed by us i ng ant i mi grai ne agent s .



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2. Severe head trauma can caus e brai n cont us i on, epi dural and s ubdural hemat oma, penet rat i ng brai n i njuri es , SAH, and CSF l eaks . o

o

a. Clinical signs. Progres s i ve ment al s t at us changes l eadi ng t o coma and focal neurol ogi c s i gns can devel op.

o

o

b. Diagnostic studies. Emergent CT s canni ng can hel p del i neat e t he ext ent of t he probl em.

o

o

c. T herapy. Cont rol of ICP and neuros urgi cal eval uat i on are i ndi cat ed as appropri at e.





3. A subdural hematoma can res ul t from acut e head t rauma. Pat i ent s pres ent wi t h an al t ered s ens ori um and focal neurol ogi c fi ndi ngs (e.g., hemi pares i s ). A s ubdural hemat oma i s al s o as s oci at ed wi t h mi nor t rauma and can pres ent wi t h s ubt l e s ubacut e or chroni c behavi oral changes and mi l d focal defi ci t s . At t i mes , no hi s t ory of t rauma i s el i ci t ed; t hi s i s es peci al l y t rue i n el derl y pat i ent s . o

a. Diagnostic studies. A CT s can i s very hel pful i n document i ng t he pres ence of a s ubdural hemat oma (

Onl i ne Fi gure 11-8).

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ONLINE FIGURE 11-8 A nonenhanced comput ed t omography (CT) s can s howi ng a chroni c s ubdural hemat oma. Not e t he mas s effect on t he l at eral vent ri cl e and t he abs ence of s ul ci .  P.562 

o

o

b. T herapy. Neuros urgi cal i nt ervent i on i s us ual l y i ndi cat ed for an acut e s ubdural hemat oma; a chroni c s ubdural hemat oma may not requi re s urgery.

B. Spinal cord injury Spinal cord injury can res ul t i n an acut e parapares i s or quadri pares i s . A cent ral cord s yndrome, whi ch can fol l ow a hyperext ens i on i njury t o t he cervi cal s pi nal cord, i s charact eri zed by l ower mot or neuron dys funct i on affect i ng t he cervi cal myot omes , mi l d s ens ory l os s i n t he arms , and a myel opat hy.

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

1. Diagnostic studies. Becaus e t he vert ebral col umn may not be s t abl e, pat i ent s s houl d be i mmobi l i zed whi l e a radi ographi c as s es s ment i s made.





2. T herapy. Hi gh-dos e met hyl predni s ol one t herapy gi ven wi t hi n 8 hours of i njury can i mprove out come.

P.563

Study Questions/Answers and Explanations 1. A 70-year-old man, a retired professor, complains of weakness and fatigue. Any physical activity is an effort, and he cannot find a comfortable position at rest. He has lost 5 pounds over the past month. Physical examination is normal. Which of the following diagnoses is most likely? A. Depres s i on B. Hypokal emi a C. Temporal (gi ant cel l ) art eri t i s D. Pol ymyal gi a rheumat i ca (PMR) E. Pol ymyos i t i s Vi ew Ans wer 1. T he answer is D [IV B 5 a; XV B 3 d (1)â€“(2)]. Pol ymyal gi a rheumat i ca (PMR) i s charact eri zed by mus cl e di s comfort , and pat i ent s oft en pres ent wi t h vague compl ai nt s , as i n t hi s cas e. By defi ni t i on, t he res ul t s of t he neuromus cul ar exami nat i on are normal . Depres s i on can caus e fat i gue and di mi ni s hed act i vi t y, but di s comfort i s l es s frequent l y a compl ai nt . A normal eryt hrocyt e s edi ment at i on rat e, whi ch i s el evat ed i n t he pres ence of PMR, woul d s upport a di agnos i s of depres s i on. Hypokal emi a can caus e mus cl e weaknes s , but di s comfort i s not a t ypi cal feat ure. Temporal (gi ant cel l ) art eri t i s can occur wi t h PMR, but t hi s pat i ent has no

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compl ai nt of headache or s ympt oms referabl e t o vi s i on. Pol ymyos i t i s can caus e mus cl e di s comfort , but t here s houl d be accompanyi ng weaknes s . The s erum creat i ne ki nas e (CK) l evel i s oft en el evat ed. 2. A 29-year-old woman suddenly develops a left hemiparesis. T he patient experienced a deep venous thrombosis in her right leg 3 years ago. Which of the following conditions is the most likely cause of this patient' s deficit? A. Nonval vul ar at ri al fi bri l l at i on B. Lupus ant i coagul ant C. Mi t ral val ve prol aps e D. Mul t i pl e s cl eros i s (MS) E. As t rocyt oma Vi ew Ans wer 2. T he answer is B [VIII B 6 b]. The l upus ant i coagul ant (an ant i phos phol i pi d ant i body) i s as s oci at ed wi t h peri pheral venous t hrombos i s and i s chemi c (art eri al ) s t roke. In pat i ent s wi t h a hi s t ory of deep venous t hrombos i s , t he pos s i bi l i t y of a paradoxi cal embol us caus i ng a s t roke (vi a a ri ght -t o-l eft cardi ac s hunt ) s houl d al s o be cons i dered. Nonval vul ar at ri al fi bri l l at i on i s a common caus e of s t roke i n t he el derl y, but t here i s no reas on t o s us pect a rhyt hm di s t urbance i n t hi s pat i ent . Mi t ral val ve prol aps e has been as s oci at ed wi t h cardi ogeni c embol i and s t roke. However, a s earch for ot her caus es of s t roke s houl d al ways be made, becaus e mi t ral val ve prol aps e i s a rel at i vel y common ent i t y, and t he as s oci at i on wi t h s t roke i s weak. Mul t i pl e s cl eros i s (MS) and an as t rocyt oma can caus e neurol ogi c defi ci t s i n young pat i ent s ; however, t hes e condi t i ons are not as s oci at ed wi t h deep venous t hrombos i s unl es s t he pat i ent i s i mmobi l i z ed. Thes e di agnos es s houl d be cons i dered i n t he eval uat i on of pat i ent s wi t h hemi pares i s , but t he pat i ent 's hi s t ory can oft en s erve as a cl ue t o gui de di agnos t i c t hi nki ng. 3. An assembly-line worker complains of awakening at night with right-hand discomfort that resolves after several minutes. After 3 weeks of continuing symptoms, he seeks medical advice.

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Examination discloses mild weakness of thumb abduction and diminished pain sensibility on the palmar aspect of the thumb and index finger. Which of the following diagnoses is most likely? A. Carpal t unnel s yndrome B. Cervi cal radi cul opat hy C. Refl ex s ympat het i c dys t rophy D. Tendi ni t i s E. Left mi ddl e cerebral art ery i s chemi c at t acks Vi ew Ans wer 3. T he answer is A [XIII D 1 aâ€“b]. Peopl e s uch as as s embl y-l i ne workers and t ypi s t s are part i cul arl y prone t o carpal t unnel s yndrome becaus e t hei r dai l y act i vi t i es requi re repet i t i ve wri s t movement s , whi ch may, i n t i me, compres s t he medi an nerve, caus i ng neuropat hy. Awakeni ng at ni ght wi t h hand di s comfort i s a common compl ai nt , and t he fi ndi ngs on exami nat i on s upport t he di agnos i s . A cervi cal radi cul opat hy can caus e s ome of t hes e fi ndi ngs . However, t he hi s t ory i s more s ugges t i ve of carpal t unnel s yndrome. Pat i ent s wi t h a cervi cal radi cul opat hy oft en have a concurrent carpal t unnel s yndrome and vi ce vers a. The hi s t ory and exami nat i on are not s upport i ve of a di agnos i s of t endi ni t i s or refl ex s ympat het i c dys t rophy. Trans i ent i s chemi c at t acks (TIAs ) rarel y caus e di s comfort and are not as s oci at ed wi t h neurol ogi c defi ci t s aft er 24 hours have el aps ed. 4. A 73-year-old woman presents with a 6-month history of deteriorating gait and low back discomfort, which is exacerbated by walking. Examination is unremarkable except for hypoactive muscle stretch reflexes in the legs. Radiographs of the lumbosacral area show the expected degenerative changes associated with a woman of her age. Which of the following diagnoses is most likely? A. Acut e l umbar di s k herni at i on B. Lumbar s t enos i s C. Myopat hy D. Normal pres s ure hydrocephal us (NPH) E. Cervi cal s t enos i s

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Vi ew Ans wer 4. T he answer is B [VII A 2 b]. Lumbar s t enos i s i s caus ed by degenerat i ve changes i n t he l umbos acral s pi ne, oft en i n as s oci at i on wi t h a congeni t al l y s mal l l umbos acral i nt ras pi nal s pace. The hi s t ory i s oft en t hat of vague l ow back di s comfort as s oci at ed wi t h s ubt l e fi ndi ngs on exami nat i on referabl e t o i mpi ngement on mot or and s ens ory root s . Di agnos i s can be made by t he charact eri s t i c fi ndi ng of an â€œhourgl as s â€• appearance on magnet i c res onance i magi ng (MRI) s cans . An acut e di s k herni at i on i s charact eri zed by l ow back di s comfort and pai n ext endi ng i n a radi cul ar fas hi on down one or bot h l egs . Exami nat i on i s oft en cons i s t ent wi t h i mpi ngement on a s i ngl e s ens ory or mot or root . A myopat hy can caus e an i mpai red gai t ; l ow back di s comfort becaus e of weaknes s ; and hypoact i ve mus cl e s t ret ch refl exes , t ypi cal l y at t he knees . However, t hi s condi t i on i s much l es s common t han l umbar s t enos i s and t herefore i s not t he mos t l i kel y di agnos i s . Normal pres s ure hydrocephal us (NPH) caus es an apract i c gai t (i .e., di ffi cul t y i n wal ki ng i n s pi t e of an i nt act mot or, s ens ory, and cerebel l ar exami nat i on), cogni t i ve i mpai rment , and uri nary i ncont i nence. The cl i ni cal pi ct ure i s not cons i s t ent wi t h t hi s di agnos i s . Cervi cal s t enos i s can caus e a myel opat hy and res ul t ant gai t probl em. Becaus e t he pat i ent does not exhi bi t s i gns of a myel opat hy, t hi s di agnos i s i s unl i kel y. 5. A 45-year-old right-handed man complains that he has had difficulty holding and using a writing instrument for the past year. He notes the development of right-hand and forearm spasms only when writing. Physical examination is unremarkable. Which of the following diagnoses is most likely? A. Parki ns on's di s eas e B. Focal dys t oni a C. Carpal t unnel s yndrome D. Cervi cal radi cul opat hy E. Beni gn es s ent i al t remor Vi ew Ans wer 5. T he answer is B [X B 1; X B 4 XIII D 1 aâ€“b]. W ri t er's cramp i s

Pa g e 2 8 4 1


a focal dys t oni a of unknown caus e. Pat i ent s devel op s ympt oms of cramps or s pas ms wi t h al t ered hand and arm pos t ure when at t empt i ng t he s peci fi c t as k of wri t i ng. Exami nat i on of t he pat i ent i s ot herwi s e normal . Mi crographi a i s a s ympt om of Parki ns on's di s eas e but i s us ual l y accompani ed by s i gns of ri gi di t y and bradyki nes i a, and oft en t remor. Carpal t unnel s yndrome i s caus ed by pres s ure on t he medi an nerve as i t ent ers t he hand vi a t he carpal t unnel . Medi an nerve dys funct i on l eads t o hand weaknes s and l os s of s ens i bi l i t y, whi ch can affect wri t i ng. A cervi cal radi cul opat hy can l ead t o hand numbnes s and weaknes s and hyporefl exi a. The exact di s t ri but i on of fi ndi ngs depends on t he nerve root s i nvol ved. A beni gn es s ent i al t remor i s charact eri zed by a di s t al upper ext remi t y t remor duri ng a t as k. There i s no accompanyi ng ri gi di t y or bradyki nes i a. Handwri t i ng i n part i cul ar may s uffer. Carpal t unnel s yndrome, cervi cal radi cul opat hy, and beni gn es s ent i al t remor are al l unl i kel y becaus e t he pat i ent 's exami nat i on s hows no s i gns or s ympt oms ot her t han di ffi cul t y wi t h wri t i ng. 6. A 24-year-old construction worker with a 2-year history of low back pain complains of an acute onset of bilateral leg weakness and incontinence. Which of the following treatments would be the best management tactic? A. Admi ni s t rat i on of nons t eroi dal ant i -i nfl ammat ory drugs (NSAIDs ) B. Emergency s urgery P.564

C. St ri ct bed res t D. Lumbar t ract i on E. Back exerci s es Vi ew Ans wer 6. T he answer is B [VII A 2 a (2)â€“(3)]. The pat i ent probabl y has an acut e di s k herni at i on caus i ng a cauda equi na s yndrome, an i ndi cat i on for emergency s urgery. Surgery s houl d be cons i dered as an el ect i ve i nt ervent i on for t hos e pat i ent s wi t h s ci at i ca,

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non-di s abl i ng neurol ogi c defi ci t s , and di s k herni at i on (as demons t rat ed by appropri at e i magi ng t echni ques ) who fai l t o res pond t o 6 weeks of cons ervat i ve management . Nons t eroi dal ant i -i nfl ammat ory drugs (NSAIDs ) can be hel pful i n t he t reat ment of acut e, and pos s i bl y chroni c, l ow back pai n; however, t hey are not i ndi cat ed as pri mary t herapy for pat i ent s wi t h acut e, s evere neurol ogi c di s abi l i t y. Avoi dance of s t renuous act i vi t y i s very hel pful for t he t reat ment of acut e back pai n, but t hi s t herapy i s not appropri at e for t hi s pat i ent . Lumbar t ract i on i s probabl y not effect i ve for t he t reat ment of l ow back pai n. Pat i ent s t ypi cal l y cannot exerci s e duri ng t he fi rs t few days of acut e back pai n. However, as t he acut e pai n s ubs i des , an exerci s e program may hel p prevent fut ure probl ems . 7. A 32-year-old man presents with repetitive generalized motor convulsions that continue for 35 minutes until 2 mg of lorazepam are administered intravenously. T he next course of action should be to administer which of the following? A. Phenyt oi n i nt ravenous l y B. Carbamazepi ne oral l y C. Pent obarbi t al i nt ravenous l y D. Et hos uxi mi de oral l y E. Di az epam rect al l y Vi ew Ans wer 7. T he answer is A [IX D 2 b (1)â€“(2), 4 b, c]. Admini s t rat i on of i nt ravenous l orazepam s houl d be fol l owed by t he admi ni s t rat i on of phenyt oi n (or fos phenyt oi n) t o cont rol s t at us epi l ept i cus becaus e t he durat i on of act i on of l orazepam i s l i mi t ed. Therefore, unl es s t here i s a cont rai ndi cat i on, t he pat i ent s houl d recei ve a l oadi ng dos e of phenyt oi n (or fos phenyt oi n) i nt ravenous l y. Carbamazepi ne i s an effect i ve ant i convul s ant , but i t cannot be gi ven i nt ravenous l y or i nt ramus cul arl y. Therefore, a t herapeut i c l evel cannot be rapi dl y achi eved gi ven a drug hal f-l i fe of 8â€“12 hours . Int ravenous pent obarbi t al can be us ed t o cont rol repet i t i ve s ei z ures . However, becaus e t he pat i ent i s not current l y convul s i ng, i nduct i on of barbi t urat e coma i s not i ndi cat ed. Et hos uxi mi de i s

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i ndi cat ed for t he t reat ment of abs ence s ei zures . Therefore, t hi s i s not an appropri at e t herapy for general i zed mot or convul s i ons . Rect al di azepam i s us ed t o abort s ei zures t emporari l y, es peci al l y i n chi l dren. 8. A 78-year-old woman complains of experiencing headaches and progressive confusion for the past month. She has a left hemianopia and cannot dress herself. A computed tomography (CT ) scan demonstrates a large, irregularly enhancing mass in the right parietal lobe. T here is no obvious systemic disease. Which of the following diagnoses is most likely? A. Brai n abs ces s B. Gl i obl as t oma mul t i forme C. Meni ngi oma D. Met as t as i s E. Cent ral nervous s ys t em (CNS) l ymphoma Vi ew Ans wer 8. T he answer is B [XVII A 2]. A l arge, i rregul arl y enhanci ng cent ral nervous s ys t em (CNS) mas s i n an el derl y pat i ent wi t hout s ys t emi c cancer i s hi ghl y s ugges t i ve of a gl i obl as t oma mul t i forme. However, a bi ops y i s neces s ary before a defi ni t i ve di agnos i s can be made. The pat i ent has no predi s pos i ng condi t i on for a brai n abs ces s s uch as poor dent i t i on or i nt ravenous drug abus e. A meni ngi oma can occur i n t he pari et al area and di s t ort t he brai n; however, a â€œconvexi t yâ€• meni ngi oma i s t ypi cal l y a homogeneous l y enhanci ng l es i on. In t he abs ence of s ys t emi c cancer, a brai n met as t as i s i s an unl i kel y caus e of t he pat i ent 's probl em. However, wi t hout a bi ops y, t he di agnos i s of met as t at i c di s eas e cannot be excl uded. CNS l ymphoma t ypi cal l y mani fes t s as a homogeneous l y enhanci ng mas s l es i on. Pat i ent s wi t h human i mmunodefi ci ency vi rus (HIV) and ot her i mmunocompromi s ed pat i ent s are prone t o CNS l ymphoma; i n ot her popul at i ons , CNS l ymphoma i s rare. 9. A 63-year-old woman develops intermittent dizziness. Examination shows a diminished right corneal reflex and mild hearing loss in the right ear. Which of the following diagnoses is

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most likely? A. Cerebel l opont i ne angl e t umor B. Beni gn paroxys mal pos i t i onal vert i go (BPPV) C. Lat eral medul l ary s yndrome D. MÃ©ni Ã¨re's di s eas e E. Pont i ne i nfarct i on Vi ew Ans wer 9. T he answer is A [XVII D 1â€“3]. A cerebel l opont i ne angl e t umor s uch as a s chwannoma can caus e i nt ermi t t ent di zzi nes s . The t umor can ari s e from t he ei ght h crani al nerve, t hereby al s o affect i ng heari ng, and can pres s on t he t ri gemi nal nerve, caus i ng i mpai rment of t he corneal refl ex. Beni gn paroxys mal pos i t i onal vert i go (BPPV) caus es i nt ermi t t ent bri ef di z z i nes s t hat i s dependent on pos t ural changes . Nys t agmus i s charact eri s t i c, but t here are no ot her neurol ogi c defi ci t s . A l at eral medul l ary s yndrome us ual l y caus es cons t ant di zzi nes s t hat i s exacerbat ed wi t h movement . Al t hough t he corneal refl ex can be depres s ed, heari ng i s normal . Meni ere's di s eas e caus es i nt ermi t t ent di z z i nes s and heari ng l os s , but t he corneal refl ex i s not di mi ni s hed. A pont i ne i nfarct i on does not caus e i nt ermi t t ent s ympt oms ; heari ng l os s i s not expect ed as a res ul t . 10. A previously vigorous 80-year-old woman collapses when getting out of bed. Examination of her legs indicates bilateral weakness, loss of pain and temperature sensation, and areflexia. Her bladder is distended. T he remainder of the examination is unremarkable. Which of the following diagnoses is most likely? A. Gui l l ai n-BarrÃ© s yndrome B. Ant eri or cerebral art ery occl us i on C. Cauda equi na s yndrome D. Ant eri or s pi nal art ery occl us i on E. Thoraci c s pi nal cord compres s i on Vi ew Ans wer 10. T he answer is D [XII D 4 b]. Thrombos i s of t he caudal ant eri or s pi nal art ery l eads t o a fl acci d parapl egi a, l os s of pai n and

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t emperat ure s ens at i on, and bowel and bl adder dys funct i on. The bl ood s uppl y t o t he caudal s pi nal cord ari s es from t he aort a vi a t he l umbar Art ery of Adamki ewi cz. The perfus i on t erri t ory of t he ant eri or s pi nal art ery i nvol ves t he ant eri or horn cel l s and t he pai n and t emperat ure pat hways . In t he Gui l l ai n-BarrÃ© s yndrome, whi ch rarel y devel ops s uddenl y, l os s of t emperat ure and pai n s ens at i on can occur but rarel y wi t hout a concurrent l os s of pos i t i on and vi brat i on s ens e. Sens ory l os s i s us ual l y l es s s evere t han mot or l os s . General i zed arefl exi a i s common. An ant eri or cerebral art ery t hrombos i s , es peci al l y when bi l at eral , caus es l eg weaknes s , but s ens ory l os s , when pres ent , i nvol ves al l modal i t i es . Upper mot or neuron s i gns are pres ent i n t he l eg. A cauda equi na s yndrome [VII A 2 (3) a] can caus e a fl acci d parapl egi a, but al l s ens ory modal i t i es may be compromi s ed becaus e s ens ory nerve root s , whi ch carry s ens ory fi bers of al l t ypes , are i nvol ved i n t he di s eas e proces s . Thoraci c s pi nal cord compres s i on i s oft en as s oci at ed wi t h back pai n and produces upper mot or neuron dys funct i on i n t he l egs . In t he acut e condi t i on, t he bl adder may be di s t ended, but wi t h t i me, i t s capaci t y i s t ypi cal l y reduced. 11. A 70-year-old man reports that over the past 2 months he has had progressive difficulty walking. Examination indicates distal (greater than proximal) weakness in the arms and legs and the absence of muscle stretch reflexes. Motor nerve conduction velocities (NCVs) are slowed. Which of the following diagnoses is most likely? A. Gui l l ai n-BarrÃ© s yndrome B. Lead poi s oni ng C. Chroni c i nfl ammat ory demyel i nat i ng pol yneuropat hy (CIDP) D. Amyot rophi c l at eral s cl eros i s (ALS) E. Pol ymyos i t i s Vi ew Ans wer 11. T he answer is C [XIII D D 4; Tabl es 11-9A and 11-9B]. Chroni c i nfl ammat ory demyel i nat i ng pol yneuropat hy (CIDP) i s charact eri zed by progres s i ve weaknes s t hat occurs over an ext ended t i me (e.g.,

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>4 weeks ), abs ent mus cl e s t ret ch refl exes , and s l owed mot or nerve conduct i on vel oci t i es (NCVs ). Gui l l ai n-BarrÃ© s yndrome s houl d not caus e progres s i ve wors eni ng of s t rengt h beyond 4 weeks . Typi cal l y, onl y s ome mot or nerves demons t rat e s l owi ng, us ual l y i n a s egment al , rat her t han a general i z ed, fas hi on. Lead poi s oni ng can caus e a mot or neuropat hy i n chi l dren but onl y rarel y i n adul t s . Amyot rophi c l at eral s cl eros i s (ALS) caus es progres s i ve weaknes s , but mot or NCVs are unremarkabl e and mus cl e s t ret ch refl exes are oft en hyperact i ve. Pol ymyos i t i s caus es progres s i ve proxi mal (great er t han di s t al ) weaknes s and i s not as s oci at ed wi t h i mpai red mot or NCVs . Mus cl e s t ret ch refl exes are oft en pres erved i n proport i on t o t he mus cl e s t rengt h. 12. A 56-year-old man presents with a 2-year history of impotence and not feeling â€œ right.â€• Examination reveals masked facies, bradykinesia, rigidity, mild ataxia, and postural hypotension. T he diagnosis is which of the following? A. Parki ns on's di s eas e B. Subacut e combi ned degenerat i on P.565

C. Mul t i pl e s ys t ems at rophy D. Spi nocerebel l ar degenerat i on E. Vi t ami n E defi ci ency Vi ew Ans wer 12. T he answer is C [VI A 1 b; X A 2 a (2); XIX A 2 a; onl i ne Tabl e 11-7]. The s i gns and s ympt oms are mos t cons i s t ent wi t h mul t i pl e s ys t ems at rophy (Shy-Drager s yndrome). The earl y appearance of aut onomi c dys funct i on (i mpot ence and pos t ural hypot ens i on) and at axi a do not s upport t he di agnos i s of Parki ns on's di s eas e. Combi ned s ys t ems degenerat i on i s due t o vi t ami n B 1 2 defi ci ency. Parki ns oni an feat ures are not a feat ure of t he di s eas e. Spi nocerebel l ar degenerat i on i s charact eri zed by cerebel l ar dys funct i on and an accompanyi ng upper mot or neuron

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s yndrome. Ext rapyrami dal and aut onomi c dys funct i on are not promi nent feat ures . Vi t ami n E defi ci ency can mas querade as s pi nocerebel l ar degenerat i on. 13. A patient with a subarachnoid hemorrhage (SAH) caused by a right anterior communicating artery aneurysm undergoes successful surgery 2 days after the hemorrhage. T hree days later, right arm weakness develops. Which of the following diagnoses is most likely? A. Hydrocephal us B. Meni ngi t i s C. Repeat hemorrhage D. Vas os pas m E. Hyponat remi a Vi ew Ans wer 13. T he answer is D [VIII C 1 c (2)]. Vas os pas m can devel op s everal days aft er an aneurys mal s ubarachnoi d hemorrhage (SAH). Pat i ent s pres ent wi t h progres s i ve weaknes s and al t erat i ons i n cons ci ous nes s . Earl y i n t he cours e, a comput ed t omography (CT) s can may not reveal an i s chemi c i nfarct i on. Hydrocephal us can occur i mmedi at el y aft er an SAH or weeks t o mont hs l at er. Sympt oms are t ypi cal l y nonfocal and, i f t he hydrocephal us devel ops acut el y, i t i s oft en accompani ed by a depres s ed l evel of cons ci ous nes s . Bact eri al meni ngi t i s can devel op aft er a crani ot omy. Typi cal l y, t here i s fever and i mpai red arous al . Focal s i gns can devel op but are rarel y t he pres ent i ng feat ure. Al t hough a repeat hemorrhage can occur aft er cl i ppi ng of an aneurys m i f t he aneurys m i s not compl et el y i s ol at ed from t he ci rcul at i on, i t i s unus ual for t hi s t o happen and pres ent wi t h a focal defi ci t , as oppos ed t o depres s ed cons ci ous nes s . Hyponat remi a, whi ch can devel op aft er SAH, can caus e an al t ered s ens ori um and s ei z ures but not uni l at eral weaknes s . 14. A 17-year-old high school varsity diver develops a headache, dizziness, left-sided arm and leg clumsiness, and loss of pain and temperature sensation in the left facial and right body areas after a practice session. Which of the following diagnoses is

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most likely? A. Beni gn paroxys mal pos i t i onal vert i go (BPPV) B. Mul t i pl e s cl eros i s (MS) C. Vert ebral art ery di s s ect i on D. As t rocyt oma E. Labyri nt hi t i s F. Mi grai ne wi t h aura Vi ew Ans wer 14. T he answer is C [VI B 2 f]. The pat i ent has mani fes t at i ons of a l at eral medul l ary s yndrome. In a young pat i ent , who has s ubject ed hi ms el f t o s t renuous neck movement s , t he mos t l i kel y et i ol ogy i s vert ebral art ery di s s ect i on. Beni gn paroxys mal pos i t i onal vert i go (BPPV) caus es s udden epi s odes of di zzi nes s , t ypi cal l y wi t h changes i n pos i t i on. However, t here are no as s oci at ed neurol ogi c s ympt oms or s i gns ot her t han nys t agmus . Mul t i pl e s cl eros i s (MS) can caus e di zzi nes s and cl ums i nes s . However, t he cons t el l at i on of fi ndi ngs i n t hi s pat i ent , whi ch are referabl e t o a s i ngl e s i t e wi t hi n t he brai n and are of s udden ons et , make t he di agnos i s of MS l es s l i kel y. An as t rocyt oma can caus e di zzi nes s and uns t eadi nes s . Oft en t here i s a headache. The ons et i s t ypi cal l y i ns i di ous , and t he s ympt oms progres s i ve. Labyri nt hi t i s caus es s evere vert i go. Pat i ent s fi nd i t di ffi cul t t o move about and prefer t o remai n s t i l l . Gai t i ns t abi l i t y can occur becaus e of t he profound di z zi nes s i n t he abs ence of cerebel l ar defi ci t s . There are no neurol ogi c s i gns ot her t han nys t agmus . Mi grai ne wi t h aura i s as s oci at ed wi t h headache and focal neurol ogi c s ympt oms and s i gns . Unl es s pat i ent s have a hi s t ory s i mi l ar t o t hat des cri bed, t hey s houl d be eval uat ed for al t ernat i ve di agnos es s uch as art eri al di s s ect i on. Pat i ent s wi t h mi grai ne as s oci at ed wi t h focal neurol ogi c defi ci t s s houl d be eval uat ed for al t ernat e di agnos es before t he probl em i s at t ri but ed t o mi grai ne wi t h aura. 15. A 26-year-old woman presents with recurrent throbbing headaches accompanied by nausea, emesis, photophobia, and phonophobia. She has been treating herself with acetaminophen and ice packs to her forehead. A reasonable therapeutic

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intervention might be to prescribe: A. Bacl ofen B. Ami t ri pt yl i ne C. Indomet haci n D. Cort i cos t eroi ds E. Sumat ri pt an Vi ew Ans wer 15. T he answer is B [IV B 1 d (1)â€“(2) (a)]. Migrai ne headaches res pond wel l t o t reat ment wi t h t ri cycl i c ant i depres s ant s s uch as ami t ri pt yl i ne. Thi s pat i ent has been unres pons i ve t o o ver-t he-count er acet ami nophen. As s umi ng s he i s havi ng frequent headaches t hat are i nt erferi ng wi t h her l i fes t yl e, i t i s reas onabl e t o begi n t reat ment wi t h a prophyl act i c mi grai ne medi cat i on. Bacl ofen i s not effect i ve for mi grai ne. Indomet haci n i s not commonl y pres cri bed for mi grai ne; t hough i t may benefi t an acut e headache epi s ode, i t i s not cons i dered a prophyl act i c medi cat i on. Cort i cos t eroi ds can be hel pful i n t he t reat ment of a s evere, acut e mi grai ne headache. However, cort i cos t eroi ds are not commonl y pres cri bed for mi grai ne prophyl axi s . Sumat ri pt an i s an effect i ve t reat ment for an acut e mi grai ne headache but i t i s not i ndi cat ed as a prophyl act i c mi grai ne t herapy. 16. A 76-year-old woman has been experiencing left temporal headaches for the prior 3 weeks. Over the prior 2 days she has had several brief episodes of cloudy vision in her left eye. On questioning, she notes a 5-pound weight loss over the past 2 weeks, which she attributes to discomfort when chewing. T herapy should be initiated with: A. Bacl ofen B. Ami t ri pt yl i ne C. Indomet haci n D. Cort i cos t eroi ds E. Sumat ri pt an Vi ew Ans wer 16. T he answer is D [IV B 5 c]. Thi s pat i ent l i kel y has gi ant cel l (t emporal ) art eri t i s . The t reat ment of choi ce for gi ant cel l art eri t i s

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i s cort i cos t eroi ds . An eryt hrocyt e s edi ment at i on rat e and C-react i ve prot ei n as s ay s houl d be obt ai ned before begi nni ng cort i cos t eroi d t herapy, but wai t i ng for a t emporal art ery bi ops y s houl d not del ay i ni t i at i on of t herapy. Nei t her bacl ofen, ami t ri pt yl ene, i ndomet haci n, or s umat ri pt an are i ndi cat ed for gi ant cel l art eri t i s . 17. A 57-year-old man has a 2-month history of severe, daily headaches that involve the right frontotemporoparietal area. T he headaches typically last 60â€“90 minutes and occur once or twice daily. Over-the-counter medications have not provided relief. Chiropractic manipulation did not help. T he patient is desperate for relief because he cannot work during the headache episodes. A reasonable treatment strategy is to initiate: A. Bacl ofen B. Ami t ri pt yl i ne C. Indomet haci n D. Cort i cos t eroi ds E. Sumat ri pt an Vi ew Ans wer 17. T he answer is C [IV B 8]. The pat i ent 's hi s t ory i s s ugges t i ve of paroxys mal hemi crani a, an i ndomet haci n-res pons i ve di s order. In fact , a pos i t i ve res pons e t o t reat ment wi t h i ndomet haci n can confi rm a di agnos i s of paroxys mal hemi crani a. Bacl ofen, ami t ri pt yl ene, cort i cos t eroi ds , and s umat ri pt an are not cons i dered benefi ci al for paroxys mal hemi crani a. 18. A 53-year-old woman with the sudden onset of the worst headache of her life presents to the emergency department. She has a history of migraine but states that the current headache is not like her P.566 usual headaches. Results of her physical examination are unremarkable. T he initial preferred diagnostic test is a(an): A. Angi ogram

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B. CT s can C. TCD D. MRI E. MR angi ogram Vi ew Ans wer 18. T he answer is B [VII C 1 b (2); IV A 3 b]. The hi s t ory i s hi ghl y s ugges t i ve of s ubarachnoi d hemorrhage (SAH). A brai n comput ed t omography (CT) s can i s t he bes t t es t t o s creen for i nt racrani al hemorrhage and s houl d be emergent l y obt ai ned t o document s ubarachnoi d bl ood. If t he s can i s normal and t he hi s t ory i s s ugges t i ve of SAH, t he woman s houl d undergo a l umbar punct ure (LP) t o s creen for bl ood before t he phys i ci an concl udes t hat s he does not have a SAH. Convent i onal angi ography i s neces s ary t o eval uat e pat i ent s wi t h SAH t o defi ne t he pres ence of an aneurys m and det ai l s of i t s anat omi c confi gurat i on. As s oci at ed abnormal i t i es s uch as vas os pas m can al s o be as s es s ed. However, an angi ogram s houl d not be t he i ni t i al di agnos t i c t es t i n a pat i ent wi t h a s us pect ed SAH. Trans crani al Doppl er (TCD) s t udi es can det ect cerebral art ery vas os pas m but not t he pres ence of an aneurys m. Vas os pas m t ypi cal l y devel ops a few days aft er SAH; t herefore, i t woul d not be expect ed t o be apparent at t he t i me of pat i ent pres ent at i on. Brai n MRI i s not as s ens i t i ve as brai n CT for t he det ect i on of acut e i nt racrani al hemorrhage. Therefore, brain MRI i s not cons i dered t he procedure of choi ce for t he acut e det ect i on of SAH. Al t hough magnet i c res onance (or comput ed t omography) angi ography (MRA or CTA, res pect i vel y) can document t he pres ence of an aneurys m, t hey are not as s ens i t i ve as convent i onal angi ography. Nei t her MRA nor CTA i s adequat e t o det ermi ne t he charact eri s t i cs of t he aneurys m ful l y and t o di rect t herapy. Therefore, MRA and CTA are not t he fi rs t t es t s t o be obt ai ned i n pat i ent s wi t h a s us pect ed SAH. 19. A 78-year-old man with a history of type 1 (insulin-dependent) diabetes mellitus, hypertension, hypercholesterolemia, and remote smoking presents with the

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acute onset of aphasia. On examination, he has trouble expressing himself and has mild right facial and arm weakness. T here is a left carotid bruit. T he most definitive strategy for secondary stroke prevention will likely be: A. Acut e hepari n admi ni s t rat i on fol l owed by warfari n B. Ext racrani al i nt racrani al bypas s s urgery C. W arfari n and as pi ri n combi ned t herapy D. Carot i d endart erect omy E. As pi ri n monot herapy Vi ew Ans wer 19. T he answer is D [VIII B 4 c (1) (a), (3) (a)]. The pat i ent has a nondi s abl i ng s t roke. Hi s ri s k fact or profi l e and t he pres ence of an i ps i l at eral brui t s ugges t t hat t he mos t l i kel y caus e of hi s s t roke i s l eft i nt ernal carot i d art ery ori gi n s t enos i s . The defi ni t i ve i nt ervent i on t o prevent s ubs equent s t roke i s carot i d endart erect omy. Acut e hepari n admi ni s t rat i on and s ubs equent warfari n t herapy have not been demons t rat ed t o be effect i ve for s econdary s t roke prevent i on i n t hi s s et t i ng. Li kewi s e, t here i s no rol e for ext racrani al -i nt racrani al bypas s s urgery t o t reat ext racrani al i nt ernal carot i d art ery ori gi n s t enos i s . A combi nat i on of warfari n and as pi ri n has not been s hown t o be more effect i ve t han carot i d endart erect omy for s econdary s t roke prevent i on for a pat i ent s uch as t hi s . Al t hough as pi ri n i s appropri at e t herapy for s econdary s t roke prevent i on for s t roke due t o art eri al di s eas e, t reat ment wi t h as pi ri n s houl d not precl ude carot i d endart erect omy i n t he appropri at e s et t i ng. As pi ri n s houl d be admi ni s t ered aft er carot i d endart erect omy t o decreas e t he ri s k of pos t operat i ve s t roke. 20. A 32-year-old woman who is 1 week postpartum presents with progressive headache and confusion. On examination she is afebrile with a blood pressure of 110/65 mm Hg. Papilledema is noted. T he most likely diagnosis is: A. Ps eudot umor cerebri B. Pi t ui t ary apopl exy C. Bact eri al meni ngi t i s

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D. Sagi t t al s i nus t hrombos i s E. Ecl amps i a Vi ew Ans wer 20. T he answer is D [IV B 6]. The pat i ent 's pres ent at i on s ugges t s s agi t t al s i nus t hrombos i s . Al t hough t hi s condi t i on i s as s oci at ed wi t h t he hypercoagul abl e s t at e of pregnancy, furt her t es t i ng i s i ndi cat ed t o eval uat e t he pos s i bi l i t y of an underl yi ng chroni c hypercoagul abl e condi t i on. Ps eudot umor cerebri (i di opat hi c i nt racrani al hypert ens i on) can pres ent i n as s oci at i on wi t h pregnancy, and al t hough i t i s charact eri zed by headache and papi l l edema, confus i on i s not a part of ps eudot umor cerebri . Pi t ui t ary apopl exy can occur pos t part um. It i s charact eri zed by headache and vi s ual dys funct i on. Papi l l edema and confus i on are not common s equel ae of pi t ui t ary apopl exy. Al t hough bact eri al meni ngi t i s caus es headache, confus i on, and papi l l edema, pat i ent s are t ypi cal l y febri l e. Ecl amps i a can caus e headache and confus i on as wel l as papi l l edema. However, t he pat i ent 's l ow bl ood pres s ure i s evi dence agai ns t t hi s di agnos i s . Al s o, t here i s no ment i on of prot ei nuri a or s ei z ures . 21. A 67-year-old woman with a history of hypertension, diabetes mellitus, and smoking presents to the emergency department at 8:30 AM with a mild expressive aphasia, right facial weakness, and mild right arm weakness. She had awakened at 7:00 AM and was speaking to her husband when her speech suddenly became difficult and weakness was noted. Her husband called 911, and she was transported to the hospital, where her blood pressure was 165/85 mm Hg. T he preferred treatment is: A. As pi ri n B. Hepari n C. W arfai n D. rt -PA E. Cl opi dogrel

Pa g e 2 8 5 4


Vi ew Ans wer 21. T he answer is D [VIII B 1 c (1)]. The pat i ent has had t he acut e ons et of a neurol ogi c defi ci t cons i s t ent wi t h a s t roke. She i s pres ent i ng for medi cal care wi t hi n 3 hours of s ympt om ons et . No cont rai ndi cat i ons t o i nt ravenous t hrombol yt i c t herapy wi t h rt -PA i s ment i oned. The pat i ent s houl d have an emergent brai n CT s can and i f no al t ernat e di agnos es are s ugges t ed (t umor, s ubdural hemat oma, et c.), i nt ravenous rt -PA s houl d be admi ni s t ered. As pi ri n i s s t andard of care i f t he pat i ent had pres ent ed more t han 3 hours aft er s ympt om ons et . There i s l i t t l e evi dence t hat hepari n or warfari n t herapy i s benefi ci al i n t hi s s et t i ng, and t here i s an i ncreas ed i nci dence of bl eedi ng wi t h t hes e ant i coagul ant s . Cl opi dogrel i s a t herapeut i c al t ernat i ve for s econdary s t roke prevent i on, but i t s us e s houl d not t ake precedence over t he admi ni s t rat i on of rt -PA. If rt -PA i s admi ni s t ered, as pi ri n admi ni s t rat i on s houl d be del ayed 24 hours . Al s o, i f l ow-dos e hepari n i s admi ni s t ered for deep venous t hrombos i s prophyl axi s , i t s us e s houl d al s o be del ayed for 24 hours before rt -PA us e. 22. A 62-year-old woman has a 2-month history of mild confusion. She occasionally has difficulty following a conversation. On the morning of presentation to the hospital, she developed 30 seconds of right face and arm twitching, followed by increased confusion. Examination shows difficulties in speech comprehension and a subtle right homonymous hemianopia. A brain CT scan shows a 2 to 3-cm ill-defined region of low density in the left parietal lobe. T he most likely diagnosis is: A. Mul t i pl e s cl eros i s B. St roke C. As t rocyt oma D. Abs ces s E. Met as t as i s Vi ew Ans wer 22. T he answer is C [XVII A 1 a]. The pat i ent pres ent s wi t h a

Pa g e 2 8 5 5


2-mont h hi s t ory of progres s i ve neurol ogi c defi ci t s . The CT s can s hows an area of l ow dens i t y, and t here i s no ment i on of mas s effect . The mos t l i kel y di agnos i s i s an as t rocyt oma, whi ch may not have much i n t he way of mas s effect or enhancement on CT s can. The progres s i ve hi s t ory i s agai ns t a s t roke. Mul t i pl e s cl eros i s rarel y pres ent s i n t hi s age group and woul d not be expect ed t o caus e a l arge area of decreas ed dens i t y on CT s can. An abs ces s or met as t as i s woul d have s ubs t ant i al mas s effect and enhancement on CT s can.

Pa g e 2 8 5 6


Editors: Wolfsthal, Susan T itle: NMS Medicine, 6th Edition Copyri ght Â©2008 Li ppi ncot t W i l l i ams & W i l ki ns > T able of Cont ent s > Chapt er 12 - Dermat ologic Disorders

Chapter 12

Dermatologic Disorders Jeffrey Liu Jennifer Cooper

I. Structure and Function of Skin A. Structure The s ki n covers t he s ubcut aneous fat (adi pos e or panni cul us ) and cons i s t s of t wo l ayers : t he epi dermi s and t he dermi s . 



1. Epidermis. The epi dermi s i s a s t rat i fi ed, s quamous epi t hel i um t hat i s 0.1 mm t hi ck. It produces kerat i n i nt ermedi at e fi l ament s and cont i nual l y di fferent i at es i nt o t he corni fi ed (horny) l ayer t hat provi des t he barri er funct i on t o t he s ki n. It renews i t s el f every 28 days and gi ves ri s e t o t he fol l owi ng s ki n appendages : hai r fol l i cl es , s ebaceous gl ands , s weat gl ands , and nai l s . o

a. Compartments

(onl i ne Fi gure

12-1)

Page 2857


ONLINE FIGURE 12-1 Compart ment s of t he epi dermi s . 



(1) Basal layer or stratum germinativum i s t he l ayer of undi fferent i at ed cel l s t hat cont act s t he bas ement membrane zone (BMZ).





(2) Spinous layer or stratum spinosum i s t he l ayer i n whi ch kerat i n fi l ament format i on occurs .

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(3) Granular layer or stratum granulosum i s t he l ayer i n whi ch kerat i n fi l ament pai ri ng and as s embl y occurs .





(4) Cornified layer or stratum corneum, t he

Pa g e 2 8 5 8


fi nal di fferent i at i on product of t he epi dermi s , i s t he barri er l ayer. o

o

b. Cells 



(1) Keratinocytes are t he epi t hel i al cel l s of t he epi dermi s t hat undergo t ermi nal di fferent i at i on.





(2) Melanocytes are neural cres t â€“deri ved cel l s t hat produce pi gment (mel ani n). They are di s t ri but ed al ong t he bas al cel l l ayer and t rans fer pi gment t o bas al kerat i nocyt es t o prot ect agai ns t ul t ravi ol et (UV) i rradi at i on.





(3) Langerhans cells are bone marrowâ€“deri ved, dendri t i c, ant i gen-pres ent i ng cel l s di s t ri but ed wi t hi n t he epi dermi s t hat funct i on i n i mmune s urvei l l ance of t he s ki n.

o

o

c. Epidermal proteins 



(1) Products of differentiation 



(a) Keratins are i nt ermedi at e fi l ament prot ei ns and are cl as s i fi ed i nt o t wo t ypes , accordi ng t o mol ecul ar wei ght and charge. Type 1 kerat i ns pai r wi t h t ype 2 kerat i ns t o form a t i s s ue-s peci fi c kerat i n

Pa g e 2 8 5 9


fi l ament . 



(b) Filaggrin i s a kerat i n-as s oci at ed prot ei n t hat forms a mat ri x for kerat i n fi l ament s .



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(c) The terminal cell envelope encas es kerat i n fi l ament s . Toget her wi t h lipids, t he epi dermal prot ei ns provi de t he barri er funct i on of t he epi dermi s .



(2) Adhesion proteins

(onl i ne Fi gure 12-2)



online Figure 12-2 Adhes i on mol ecul es of t he epi dermi s . 



(a) Desmosomes are mul t i prot ei n compl exes t hat s erve as poi nt s of at t achment bet ween kerat i nocyt es . They cont ai n i nt racel l ul ar and i nt ercel l ul ar

Pa g e 2 8 6 0


prot ei ns (des mogl ei ns , des mocol l i ns , and pl aki ns ). 



(b) Hemidesmosomes are mul t i prot ei n compl exes t hat are l ocat ed on t he i nferi or s i de of bas al l ayer kerat i nocyt es and s erve as poi nt s of at t achment bet ween kerat i nocyt es and t he BMZ. They cont ai n i nt racel l ul ar and i nt ercel l ul ar prot ei ns (des mopl aki n, col l agen, and pl ect i n).





2. Dermis. The dermi s i s t he l ayer beneat h t he epi dermi s t hat provi des pl i abi l i t y and t ens i l e s t rengt h. It i s a mat ri x of fi brous and amorphous connect i ve t i s s ue t hat s upport s bl ood and l ymphat i c ves s el s , fi brobl as t s , s ki n appendages , and mas t cel l s . It prot ect s t he body from mechani cal i njury, bi nds wat er, ai ds i n t hermal regul at i on, and cont ai ns recept ors of s ens ory s t i mul i . o

o

a. Compartments 



(1) The BMZ i s t he dermalâ€“epidermal junction (DEJ) t hat forms t he i nt erface bet ween t he epi dermi s and t he dermi s . 



(a) It cons i s t s of t wo l ayers : t he lamina lucida, whi ch l i es di rect l y beneat h t he bas al l ayer, and t he lamina densa, whi ch l i es di rect l y beneat h t he l ami na l uci da.



Pa g e 2 8 6 1


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(b) It funct i ons t o anchor t he epi dermi s t o t he dermi s and provi de res i s t ance agai ns t ext ernal s heari ng forces .

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(c) It s erves as a s emi penet rabl e barri er and i nfl uences t he pol ari t y of bas al cel l growt h and cyt os kel et on organi zat i on.

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(2) The papillary dermis i s t he s uperfi ci al port i on of t he dermi s t hat l i es di rect l y bel ow t he BMZ.

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(3) The reticular dermis i s t he deeper port i on of t he dermi s

o

o

b. Cells 

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(1) Endothelial cells are t he cel l s t hat form cut aneous bl ood ves s el s and l ymphat i c channel s .

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(2) Fibroblasts s ecret e macromol ecul es and t he mat ri x component s of t he dermi s .

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(3) Mast cells are bone marrowâ€“deri ved cel l s t hat cont ai n preformed i nfl ammat ory medi at ors (e.g., hi s t ami ne and prot eas es ) and part i ci pat e i n a vari et y of bi ol ogi c res pons es , i ncl udi ng urt i cari a and defens e agai ns t paras i t es .

Pa g e 2 8 6 2


o

c. Matrix 

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(1) Collagen i s a macromol ecul e t hat gi ves t ens i l e s t rengt h t o t he s ki n.



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(2) Elastin i s a macromol ecul e t hat gi ves el as t i ci t y t o t he s ki n.



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(3) Ground substance forms t he dermal mat ri x and cons i s t s of compl ex s ugars ( mucopolysaccharides) and prot ei ns ( proteoglycans).

o

o

d. Nerves and nerve receptors. Thes e s t ruct ures provi de s ens ory i nput t hroughout t he ent i re s ki n s urface.

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3. Panniculus (adi pos e). The panni cul us i s t he s ubcut aneous fat l ayer t hat provi des t hermal i ns ul at i on. o

o

a. Hair follicles. Thes e epi dermal appendages ext end i nt o t he panni cul us .

o

o

b. Sebaceous glands. Thes e gl ands empt y i nt o hai r fol l i cl es , provi di ng l ubri cat i on t o t he horny l ayer.

o

Pa g e 2 8 6 3


c. Sweat glands. The gl andul ar port i on i nvol ved i n s weat product i on ext ends i nt o t he panni cul us , connect i ng t o t he s ki n s urface t hrough epi t hel i um-l i ned duct s . Thes e gl ands part i ci pat e i n t hermoregul at i on and fl ui d and el ect rol yt e bal ance.

B. Functions 



1. Barrier. The s t rat um corneum prot ect s agai ns t wat er l os s , ent rance of mi croorgani s ms , and envi ronment al t oxi ns . The deeper l ayers of t he s ki n prot ect from damage caus ed by UV i rradi at i on, mechani cal forces , and ext reme envi ronment al t emperat ures .

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2. Fluid and electrolyte balance. Aut onomi c nerves i nnervat e s weat gl ands t hat s t i mul at e s weat product i on and as s i s t i n wat er and el ect rol yt e regul at i on.

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3. T hermoregulation. The s ki n s erves as an out er s hel l t hat vari es bl ood fl ow and s weat s ecret i on t o regul at e heat exchange wi t h t he envi ronment t o mai nt ai n t he body's core t emperat ure.

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4. Vitamin D metabolism. The s ki n i s a major s ource of nondi et ary vi t ami n D. UV i rradi at i on from s un expos ure convert s 7-dehydrochol es t erol t o vi t ami n D 3 (chol ecal ci ferol ), whi ch i s t hen hydroxyl at ed i n t he l i ver and t he ki dney t o form act i ve vi t ami n D (1,25-di hydroxychol ecal ci ferol ).

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5. Sensory input. A neural net work provi des s ens ory i nput for t ouch, pai n, t emperat ure, i t ch, and mechani cal

Pa g e 2 8 6 4


s t i mul i . 



6. Immune surveillance. The s ki n i s an i mport ant component of t he i mmune s ys t em and part i ci pat es i n bot h i nnat e and acqui red i mmuni t y. It s res i dent i mmune cel l s (Langerhans cel l s ); endogenous cyt oki nes (i nt erl euki n-1 [IL-1], IL-3, and IL-6); and growt h fact ors [granul ocyt e col ony s t i mul at i ng fact or (G-CSF), granul ocyt e macrophage col ony-s t i mul at i ng fact or (GM-CSF), macrophage colony-s t i mul at i ng fact or (M-CSF), and t umor necros i s fact or-Î± [TNF-Î±]) i nt eract wi t h ci rcul at i ng l ymphocyt es and macrophages . Thes e i mmune fact ors part i ci pat e i n a wi de range of phys i ol ogi c and pat hol ogi c proces s es .

II. Dermatologic Diagnosis A. General considerations The foundat i on of dermat ol ogi c di agnos i s rel i es on phys i cal exami nat i on of t he s ki n t o fi rs t i dent i fy t he morphol ogy of t he pri mary s ki n l es i on(s ). Bas ed on morphol ogy, a di fferent i al di agnos i s i s generat ed, and a fi nal di agnos i s i s det ermi ned by us i ng t he dermat ol ogi c hi s t ory and appropri at e l aborat ory s t udi es .

B. Examination of the skin 



1. Inspection of t he s ki n defi nes morphol ogy, col or, di s t ri but i on, and confi gurat i on. o

o

a. Morphology. Pri mary l es i ons of t he s ki n are cl as s i fi ed bas ed on morphol ogy (Tabl e 12-1).

o

o

b. Distribution. The l ocat i on and ext ent of t he

Pa g e 2 8 6 5


pri mary erupt i on are i mport ant charact eri s t i cs i n defi ni ng t he di s eas e proces s . 

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(1) Local i zed: i nvol vement of l i mi t ed areas of t he s ki n

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(2) Di ffus e: wi des pread i nvol vement of t he s ki n

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(3) Bi l at eral : s ymmet ri cal i nvol vement

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(4) Dermat omal : i nvol vement l i mi t ed t o s ki n over a dermat ome (e.g., herpes zos t er)

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(5) Acral : i nvol vement of t he s ki n of t he di s t al ext remi t i es

o

c. Configuration

(Onl i ne Fi gures 12-3 t hrough 12-6). Several

feat ures of pri mary l es i ons are i mport ant i n defi ni ng t he di s eas e proces s . o

ONLINE FIGURE 12-3 Pri mary l es i on confi gurat i on: annul ar. (Court es y of St uart Les s i n, MD.)

Pa g e 2 8 6 6


ONLINE FIGURE 12-4 Pri mary l es i on confi gurat i on: l i near. (Court es y of St uart Les s i n, MD.) o

ONLINE FIGURE 12-5 Pri mary l es i on confi gurat i on: s erpi gi nous . (Court es y of St uart Les s i n, MD.)

Pa g e 2 8 6 7


ONLINE FIGURE 12-6 Pri mary l es i on confi gurat i on: pol ycycl i c. (Court es y of St uart Les s i n, MD.) 

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(1) Number (s i ngl e vers us mul t i pl e)

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(2) Spat i al rel at i ons hi p (i .e., grouped)

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(3) Shape (i .e., annul ar, l i near, s erpi gi nous , and pol ycycl i c)

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2. Palpation det ermi nes t he t ext ure, cons i s t ency, and dept h of l es i ons , as wel l as t he t emperat ure, t endernes s , and qual i t y of eryt hema (i .e., bl anchabl e).

C. Dermatologic history 



1. History of the eruption. The es s ent i al hi s t ori cal qual i fi ers for any cut aneous erupt i on i ncl ude t he fol l owi ng: o

o

a. Ons et and progres s i on

o

o

b. Durat i on and cours e

o

o

c. Sympt oms

o

o

d. Treat ment and res pons e



Pa g e 2 8 6 8


2. Medical history. A hi s t ory of medi cal probl ems focus ed on cut aneous fi ndi ngs , i ncl udi ng al l ergi es , s houl d be el i ci t ed.

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3. Medication history. A det ai l ed medi cat i on hi s t ory i s vi t al , es peci al l y when eval uat i ng erupt i ons t hat may be t ri ggered by medi cat i ons . The medi cat i on hi s t ory s houl d i ncl ude pres cri pt i on and over-t he-count er (OTC) medi cat i ons , vi t ami ns , eye drops , and herbal s uppl ement s . P.573

P.574

TABLE 12-1 Terms Used in the Morphologic Description of Skin Lesions D e sc ri pt T e io rm n Appearance Pa S pul m e

al l, s

Pa g e 2 8 6 9


ol id , el e v at e d le si o n. P a p ul e s ar e g e n er al ly s m al le r th a n

Pa g e 2 8 7 0


1 c m in di a m et er Pla Br qu o e

a db a s e d p a p ul e th at oc cu pi e s a re la ti v

Pa g e 2 8 7 1


el y la rg e s ur fa ce ar e a in co m p ar is o n wi th it s h ei g ht a b o v e sk in

Pa g e 2 8 7 2


le v el > 1 c m Ma Fl cul at e

le si o n of v ar ia bl e si z e a n d s h a p e th at di ff er

Pa g e 2 8 7 3


s fr o m s ur ro u n di n g sk in b ec a u s e of it s co lo r, < 1 c m Pa Des cri pt i on of tch very l arge macul es or a t hi n but l arge pl aque >1 cm

Pa g e 2 8 7 4


No P dul al e

p a bl e, fi r m , ro u n d to s p h er oi d le si o n wi th a d e pt h of in v ol

Pa g e 2 8 7 5


v e m e nt gr e at er th a n th at of a p a p ul e Cy Epi t hel i al -l i ned st s ac t hat cont ai ns l i qui d or s emi s ol i d mat eri al (fl ui d, cel l s , and cel l product s ) Ve Fl sicl ui e

dfi l le d, el

Pa g e 2 8 7 6


e v at e d le si o n < 1 c m in di a m et er Bul Large ves i cl e la (>1 cm) Pu R stu ai le

s e d le si o n th at co nt ai

Pa g e 2 8 7 7


n s p ur ul e nt e x u d at e (i .e ., p u s) Wh Fl eal at -t o p p e d p a p ul e or pl a

Pa g e 2 8 7 8


q u e th at is ch ar ac te ri st ic al ly e v a n e sc e nt , di s a p p e ar in g wi th

Pa g e 2 8 7 9


in h o ur s (i .e ., hi v e) Er Ci rcums cri bed, osi s uperfi ci al on depres s i on res ul t i ng from l os s of al l or port i on of vi abl e epi dermi s Ulc Deeper er depres s i on res ul t i ng from des t ruct i on of epi dermi s and at l eas t upper (papi l l ary) dermi s Fis Li sur n e

e ar cr ac k in sk

Pa g e 2 8 8 0


in Fur Deep un necrot i zi ng cle form of fol l i cul i t i s wi t h pus accumul at i on. Several furuncl es may coal es ce t o form carbuncl e Ab Local i zed sce accumul at i on ss of purul ent mat eri al s o deep i n dermi s or s ubcut aneous t i s s ue t hat pus i s us ual l y not vi s i bl e on s urface of s ki n Sin Tract l eadi ng us from s uppurat i ve cavi t y t o s ki n s urface or bet ween cys t i c or abs ces s cavi t i es Atr E op pi hy d er m al

Pa g e 2 8 8 1


at ro p h y: th in ni n g of e pi d er m is a ss oc ia te d wi th d ec re a s e in n u m

Pa g e 2 8 8 2


b er of e pi d er m al ce ll s D er m al at ro p h y: u s u al ly m a ni fe st e d a s

Pa g e 2 8 8 3


d e pr e ss io n of sk in ; re s ul ts fr o m d ec re a s e in d er m al co n n ec ti v

Pa g e 2 8 8 4


e ti ss u e Scl Ci rcums cri bed er or di ffus e osi hardeni ng or s

i ndurat i on i n

s ki n Sc A ali b ng n or m al s h e d di n g or ac cu m ul at io n of st ra tu

Pa g e 2 8 8 5


m co rn e u m in p er ce pt ib le fl a k e s Pa Erupt i ons pul cons i s t i ng of os s cal i ng papul es qu am ou s Cr H ust ar s

d e n e d d e p

Pa g e 2 8 8 6


o si ts of dr ie d s er u m , bl o o d, or p ur ul e nt e x u d at e Ex S cor u iati p on er s

fi ci al

Pa g e 2 8 8 7


e xc a v at io n s of e pi d er m is th at m a y b e li n e ar or p u nc ta te a n d

Pa g e 2 8 8 8


re s ul t fr o m sc ra tc hi n g Lic T he hi nifi ck cat e ion ni n g of th e e pi d er m is re s ul ti n g

Pa g e 2 8 8 9


fr o m ch ro ni c sc ra tc hi n g Poi Combi nat i on of kil at rophy, od t el angi ect as i a, er and pi gment ary ma changes (hyperpi gment a t i on and hypopi gment at i on) 



4. Social history. A det ai l ed s oci al hi s t ory oft en provi des di agnos t i c cl ues for cut aneous fi ndi ngs . The s oci al hi s t ory s houl d focus on s ki n care (habi t s and product s us ed), occupat i on, home envi ronment , s exual l y t rans mi t t ed di s eas es , and t ravel .





5. Family history. A fami l y hi s t ory i s i mport ant i n as s es s i ng s ki n di s eas e predi s pos i t i on and s us cept i bi l i t y, part i cul arl y for al l ergy, s ki n cancer, ps ori as i s , and rheumat i c di s eas e.

Pa g e 2 8 9 0


D. Dermatology laboratory tests 



1. Direct microscopic examination. Preparat i ons of s ki n s crapi ngs from s cal i ng and bl i s t eri ng erupt i ons can provi de i mport ant di agnos t i c i nformat i on. P.575

o

o

a. Potassium hydroxide (KOH) preparation. KOH di ges t s cel l ul ar mat eri al and faci l i t at es t he vi s ual i zat i on of fungal hyphae, yeas t forms , and s cabi es mi t es .

o

o

b. T zanck smear. Gi ems a- or W ri ght -s t ai ned s crapi ngs from herpet i c ves i cl es reveal mul t i nucl eat ed gi ant cel l s .

o

o

c. Gram stain. Gram-pos i t i ve and gram-negat i ve bact eri a may be i dent i fi ed.

o

o

d. Darkfield microscopy. Vi s ual i zat i on of s pi rochet es (T reponema pal l i dum) from preparat i ons of pri mary chancre and s econdary l es i ons i s di agnos t i c of s yphi l i s .





2. Skin cultures. Bact eri al , vi ral , and fungal cul t ures can be obt ai ned from s ki n s wabs or s ki n bi ops i es .



Pa g e 2 8 9 1




3. Patch testing. Thi s met hod i s us ed for i dent i fyi ng compounds res pons i bl e for cont act dermat i t i s . Common and s us pect ed compounds are pl aced on t he s ki n under occl us i on (i .e., pat ch) for 48â€“72 hours . Induct i on of cut aneous i nfl ammat i on at s peci fi c pat ch s i t es i dent i fi es s ens i t i zi ng agent s .





4. Phototesting and photopatch testing o

o

a. Phototesting us es s peci al i zed l i ght s ources t hat del i ver s peci fi c ranges and quant i t i es of UV l i ght t o document phot os ens i t i vi t y i n i ndi vi dual s wi t h s us pect ed phot os ens i t i vi t y.

o

o

b. Photopatch testing combi nes pat ch t es t i ng and phot ot es t i ng t o i dent i fy phot os ens i t i zi ng compounds , whi ch produce a phot os ens i t i vi t y react i on when expos ed t o UV l i ght . Sus pect ed phot os ens i t i zi ng compounds are pat ch t es t ed wi t h and wi t hout UV expos ure.





5. Skin biopsy provi des t i s s ue for hi s t opat hol ogi c eval uat i on. o

o

a. Biopsy techniques 



(1) Punch biopsy i s a commonl y us ed t echni que t o obt ai n 2â€“6-mm cyl i ndri cal s ki n s ampl es .



Pa g e 2 8 9 2




(2) T angential (shave) biopsy i s a rapi d t echni que us ed t o obt ai n s uperfi ci al s ki n s ampl es .





(3) Incisional biopsy i s us ed t o obt ai n l arge or deep (i ncl udi ng panni cul us ) s ki n s ampl es .





(4) Excisional biopsy i s us ed t o obt ai n an ent i re l es i on (e.g., s us pi ci ous pi gment ed l es i on) for hi s t ol ogi c revi ew.

o

o

b. Examination of biopsy tissue 



(1) Light microscopy i s us ed t o eval uat e rout i ne (hemat oxyl i n and eos i n) and s peci al (e.g., peri odi c aci dâ€“Schi ff) s t ai ns as wel l as i mmunohi s t ochemi cal (monocl onal ant i body) s t ai ns .





(2) Immunofluorescent microscopy i s us ed for i dent i fi cat i on of i mmunoreact ant s (e.g., aut oi mmune ant i bodi es ).





(3) Electron microscopy i s us ed for s peci al i zed s t udi es t hat requi re vi s ual i zat i on of s ubcel l ul ar s t ruct ures .

III. Dermatologic Therapy A. General considerations Topi cal t herapi es are frequent l y us ed i n t reat i ng dermat ol ogi c

Pa g e 2 8 9 3


di s eas es and oft en provi de al t ernat i ves t o s ys t emi c t herapi es . The chi ef advant ages of t opi cal t herapi es may i ncl ude hi gher effi cacy and l i mi t ed s ys t emi c t oxi ci t i es , whereas t he s el ect i on of t opi cal t herapi es and s ys t emi c t herapi es for dermat ol ogi c di s eas es i s gui ded by bas i c cl i ni cal management pri nci pl es . 



1. Therapeut i c goal s s houl d be defi ned. o

o

a. Is t herapy i nt ended t o cure or amel i orat e (cont rol ) t he di s eas e?

o

o

b. Is t herapy i nt ended t o be s hort -t erm or l ong-t erm?





2. Therapy s houl d maxi mi ze t he benefi t -t o-ri s k rat i o and mi ni mi ze t oxi ci t y.





3. Pat i ent compl i ance s houl d be cons i dered and promot ed.





4. Cos t -effect i venes s s houl d be eval uat ed as part of t herapeut i c deci s i on maki ng.

B. Topical therapy 



1. Two vari abl es are i nvol ved i n t he s el ect i on of t opi cal t herapy. Bot h t he medi cat i on and t he vehi cl e t o be us ed mus t be appropri at e for t he s peci fi c di s order bei ng t reat ed.



Pa g e 2 8 9 4




2. General l y, acut e i nfl ammat i on i s t reat ed wi t h aqueous dryi ng vehi cl es , and chroni c i nfl ammat i on i s t reat ed wi t h more l ubri cat i ng and moi s t uri zi ng preparat i ons (Fi gure 12-7).





3. Vehi cl e choi ce may be i nfl uenced by body s i t e. For exampl e, l ot i ons , s ol ut i ons , and s prays are more effect i ve i n hai ry areas (e.g., s cal p).





4. W at er, oi l , and part i cul at e compos i t i on of a vehi cl e det ermi ne i t s charact eri s t i cs . P.576

FIGURE 12-7 Vehi cl e s ui t abi l i t y for t opi cal s ki n t herapy i n t erms of cl i ni cal s et t i ng. o

o

a. Creams are emul s i ons of oi l , predomi nat el y i n wat er, t hus dryi ng t he s ki n out .

o

o

b. Oi nt ment s are emul s i ons of wat er,

Pa g e 2 8 9 5


predomi nat el y i n oi l , t hus more moi s t uri zi ng. o

c. Gel s are s emi s ol i d emul s i ons of al cohol or

o

acet one i n an organi c pol ymer (agar, gel at i n). o

d. Lot i ons are powders i n a wat er bas e.

o o

e. Sol ut i ons , s prays , and aeros ol s have a bas e of

o

wat er, al cohol , or propyl ene gl ycol . 



5. Topi cal cort i cos t eroi ds are pres cri bed for a vari et y of i nfl ammat ory and pruri t i c condi t i ons . o

a. Pot ency. Hal ogenat ed cort i cos t eroi ds have t he great es t pot ency. Pot ency of t opi cal cort i cos t eroi ds i s meas ured by vas ocons t ri ct i ve capaci t y and may be cat egori zed as l ow, medi um, or hi gh

(Onl i ne Tabl e 12-2).

o

ONLINE TABLE 12-2 Potency of Topical Steroids

Pa g e 2 8 9 6


Co Co nc mp ent ou rat nd ion Low poten cy Hy 0.5 dro %, cor * t i s 1% on ,*; e

2.5

ace % t at e Mid-p otency Bet 0.0 am 25 et h % as o ne be nz o at e Bet 0.1 am % et h as o ne val era te Cl o 0.1 cor %

Pa g e 2 8 9 7


t ol on e pi v al a te De 0.0 s on 5% i de Fl u 0.0 me 3% t ha s on e pi v al a te Fl u 0.0 oci 25 nol % on e ace t on i de Fl u 0.0 ran 5% dre nol i de Hy 0.1 dro % cor tis on e but

Pa g e 2 8 9 8


yra te Hy 0.2 dro % cor tis on e val era te Tri 0.1 am %, ci n 0.5 ol o % ne ace t on i de High poten cy Am 0.1 ci n % oni de Bet 0.0 am 5% et h as o ne di p rop i on at e Cl o 0.0 bet 5%

Pa g e 2 8 9 9


as o l pro pi o nat e De 0.0 s ox 25 im % et a s on e Di fl 0.0 ora 5% s on e di a cet at e Fl u 0.0 oci 5% no ni d e Hal 0.1 ci n % oni de Hal 0.0 ob 5% et a s ol pro pi o nat e Mo 0.1

Pa g e 2 9 0 0


me % t as on e fur oat e *Avai l abl e over-t he-cou nt er. o

o

b. Us e 



(1) Hi gh-pot ency t opi cal cort i cos t eroi ds are us ed for t he s hort -t erm t reat ment of acut e and s evere i nfl ammat ory erupt i ons (e.g., cl obet as ol ).





(2) Mi d-t o-l ow pot ency t opi cal s t eroi ds are us ed for t reat ment of mi l d t o moderat e i nfl ammat ory erupt i ons and for mai nt enance t herapy or prol onged t herapy (e.g., t ri amci nol one).





(3) Low-pot ency t opi cal s t eroi ds are t he onl y s t eroi ds t o be pres cri bed for t he face and i nt ert ri gi nous areas (s ki n fol ds of t he axi l l ae, i nframammary regi on, abdomi nal panus , and groi n) becaus e of t he i ncreas ed ri s k of l ocal s i de effect s i n t hes e areas (e.g., hydrocort i s one).

Pa g e 2 9 0 1




(4) In general , prol onged us e of t opi cal s t eroi ds s houl d be avoi ded. Tachyphyl axi s and s i de effect s are as s oci at ed wi t h prol onged t opi cal s t eroi d us e. If prol onged t opi cal s t eroi d t herapy i s requi red, t aperi ng t o s t eroi ds of a l ower pot ency i s advi s ed.





(5) Occl us i on i s an i mport ant adjuvant t o t opi cal t herapy and i ncreas es abs orpt i on by i ncreas i ng hydrat i on and t emperat ure. Mat eri al s s uch as pl as t i c (Saran) wrap and gl oves and s hower caps can be us ed as occl us i ve dres s i ngs .





(6) Twi ce-dai l y appl i cat i on i s general l y recommended becaus e of pat i ent compl i ance. Indi vi dual s are more l i kel y t o t reat t hei r s ki n i n t he morni ng and eveni ng when dres s i ng and undres s i ng. No compel l i ng cl i ni cal dat a demons t rat e an i ncreas e i n effi cacy wi t h a frequency of appl i cat i on of more t han t wi ce-dai l y appl i cat i on.



(7) See

onl i ne Tabl e 12-2 for compl et e s t eroi d pot ency l i s t i ng. o

o

c. Di s pens i ng 

(1) Pres cri bi ng t he appropri at e quant i t y of t opi cal s t eroi ds i s i mport ant for bot h compl i ance and s afet y.

Onl i ne Tabl e 12-3

pres ent s gui del i nes for pres cri bi ng t opi cal s t eroi ds .

Pa g e 2 9 0 2




ONLINE TABLE 12-3 Guidelines for Dispensing Topical Steroids Am ou nt for Tw ice -D Am ail ou y nt Ap for plic On ati e

on

Ap for Ar plic 7 ea ati Da T r on ys eat (g) (g) ed * * Fac 1 15 e Sca 1

15

lp Ha 2

30

nds Ar 2

30

m Fee 3

45

t Leg 4 Ant 4

60 60

eri or

Pa g e 2 9 0 3


t ru nk Pos 4

60

t eri or t ru nk Ent 30 42 i re

5

bo

(1

dy l b.) *Amou nt s repres ent averag es for creams us ed in adul t popul a t i on. 



(2) Mos t creams , oi nt ment s , and gel s are commerci al l y avai l abl e i n s mal l (15g or 30 g) or l arge (45 g or 60 g) t ubes .





(3) Mos t s ol ut i ons and l ot i ons are commerci al l y avai l abl e i n s mal l (30-mL) or l arge (60-mL) bot t l es .

o

o

d. Compl i cat i ons 

Pa g e 2 9 0 4


(1) Local s i de effect s occur wi t h prol onged us e, es peci al l y on i nt ert ri gi nous areas and on t he face




ONLINE TABLE 12-4 Local Side Effects of Topical Steroids At r Hy op po hy pi g me nt a tio n Ca Ro ndi s ac da eas up l i k eri e nfe eru ct i pt i on on St ri Im ae, pai s t e red l l at wo e

un

ps e d ud he os c al i ars ng Mi l i Acn ari ei f a

or m eru

Pa g e 2 9 0 5


pt i on Tel Exa an cer gi e bat ct a i on s i a of ,

cut

pur an pur eo a,

us

an i nf d

ect

ery i on t he s , ma bac t eri al an d der ma t op hyt e i nf es t at i ons , s ca bi e s, or pe

Pa g e 2 9 0 6


di c ul o sis Peri oro faci al dermat itis





(2) Sys t emi c s i de effect s may res ul t from s ys t emi c abs orpt i on. Sys t emi c abs orpt i on may res ul t i n hypot hal amus â€“pi t ui t aryâ€“adrenal (HPA) axi s s uppres s i on. Ri s k fact ors for HPA-axi s s uppres s i on i ncl ude i mpai red barri er funct i on, i ncreas ed s urface area of t reat ed s ki n, hi gh pot ency, and prol onged us e.

P.577





6. Topi cal ant i bi ot i cs are us eful agent s for t he t reat ment of s econdary bact eri al i nfect i on of s uperfi ci al wounds ; burns ; and s uperfi ci al , pri mary s ki n i nfect i ons (e.g., i mpet i go). Agent s i ncl ude mupi roci n cream or oi nt ment , s i l ver s ul fadi azi ne cream, pol ymyxi n B, baci t raci n oi nt ment (nonpres cri pt i on), and neomyci n oi nt ment (nonpres cri pt i on).



7. Topi cal ant i fungal s are pres cri bed for t he t reat ment of s uperfi ci al yeas t (e.g., candi di as i s ) and fungal (e.g., dermat ophyt e) i nfect i ons of t he s ki n. General l y, t he t opi cal

Pa g e 2 9 0 7


agent i s avai l abl e as a cream, but ot her formul at i ons i ncl ude powder, l acquer (for nai l s ), s pray, gel , s ol ut i on, vagi nal s uppos i t ory, and oral t roche. Topi cal ant i fungal agent s are l i s t ed in

Onl i ne Tabl e 12-5. 

ONLINE TABLE 12-5 Topical Antifungal Agents F or m ul R at x A io / g n O e (s T nt ) C Polyen e N C, R ys O, x ta O t i S, n P, * V T, T Imida zoles Cl C, O ot L, T ri S, C m T, az V ol T

Pa g e 2 9 0 8


e Ec C R o

x

n az ol e K C, C et S = oc h R o

x;

n

S

az

h

ol

=

e

O T

C Mi C, O co L, T n S, C az P ol e O C, R xi L x co n az ol e S C, R ul S x co n az ol e

Pa g e 2 9 0 9


Allyla mines and nonaz ole ergost erol synthe sis inhibit ors A N R m L x or ol fi n e B C R ut

x

e n af in e H Cl N C, R af O, x tif P in e T C, O er S T bi

C

n

Pa g e 2 9 1 0


af in e Other agent s Ci C, R cl L, x o N pi L, ro S x h ol a m in e H C R al

x

o pr o gi n T C, O ol S, T n P C af ta te U C, O n P, T d O, C ec S yl e n

Pa g e 2 9 1 1


at e *Act i v e agai ns t yeas t ( Candi d a) onl y. C, cream; L, l ot i on; NL, nai l l acque r; O, oi nt me nt ; OS, oral s us pen s i on; P, powder ; S, s ol ut i o n/s pra y; Sh, s hamp oo; T, t roche; VT, vagi na

Pa g e 2 9 1 2


l t abl et ; Rx, pres cri pt i on; OTC, over-t he-cou nt er (nonpr es cri pt i on). 



8. Topi cal ant i vi ral for human papi l l oma vi rus (HPV). Imi qui mod (5% cream) has been approved for t he t rea t ment of geni t al wart s . It i s an i mmune res pons e modi fi er t hat i nduces cyt oki nes , i ncl udi ng i nt erferon-Î± (IFN-Î±), at t he t reat ment s i t e.

C. Systemic therapy 



1. Systemic corticosteroids are an avai l abl e opt i on i n dermat ol ogi c t herapy for s evere i nfl ammat ory di s eas es of t he s ki n t hat are not amenabl e t o t opi cal s t eroi d t herapy. o

o

a. Prednisone i s t he oral s t eroi d of choi ce of t he oral agent s us ed for t reat ment of dermat ol ogi c di s eas es .

o

o

b. There are a vari et y of t reat ment regi mens . For s uppres s i on of mos t i nfl ammat ory dermat os es i n

Pa g e 2 9 1 3


adul t s , an i ni t i al s t art i ng oral dos e of 40â€“60 mg predni s one i s commonl y us ed. For acut e condi t i ons , t he predni s one i s t apered over 10â€“20 days . If t he cours e of t herapy for s uppres s i on i s t oo s hort , a fl are and exacerbat i on may occur when prednis one i s di s cont i nued. o

o

c. Long-t erm oral us e requi res t aperi ng t o an al t ernat e-day dos e, whi ch decreas es t he frequency of mos t s i de effect s except cat aract s and os t eoporos i s .





2. Oral ant i hi s t ami nes are oft en us ed t o t reat pruri t us as s oci at ed wi t h a wi de range of s ki n di s eas es , part i cul arl y t hos e t hat are medi at ed by t ype I hi s t ami ne-medi at ed i mmune res pons es (e.g., urt i cari a). o

o

a. Compet i t i ve ant agoni s t s for hi s t ami ne H 1 recept ors are commonl y pres cri bed. Thes e agent s are met abol i zed i n t he l i ver. The s hort er-act i ng agent s l as t 3â€“6 hours , and t he l onger act i ng agent s l as t 12â€“24 hours .

o

o

b. Compl i cat i ons of ant i hi s t ami nes i ncl ude chol i nergi c s i de effect s (e.g., gl aucoma, cons t i pat i on, and xeros t omi a) and s edat i on. The l onger-act i ng ant i hi s t ami nes produce l es s s edat i on.

o

c. In recal ci t rant cas es of pruri t us , H 2 ant agoni s t s are added i n combi nat i on wi t h H 1 ant i hi s t ami nes . H 1 and H 2 recept or bl ockade al s o may be achi eved wi t h t he us e of doxepi n, a t ri cycl i c ant i depres s ant wi t h s t rong H 1 and H 2 ant i hi s t ami ne bl ocki ng

Pa g e 2 9 1 4


effect s . Bot h H 1 and H 2 ant i hi s t ami nes are avai l abl e i n pres cri pt i on and nonpres cri pt i on form

(onl i ne Tabl e 12-6).

o

ONLINE TABLE 12-6 Antihistamines Used in Dermatologic Treatments C D o o m s R p e x o ( / u mO n g T d ) C Shortacting H1 antag onists C 4 O hl

T

or

C

p h e ni ra m in e Di 2 O p 5, T h 5 C e 0 n

Pa g e 2 9 1 5


hy dr a m in e H 1 R yd 0, x ro 2 xy 5, zi 5 n 0, e 1 0 0 Longacting H1 antag onists C 5, R et 1 x i ri 0 zi n e D 1 R es 0 x lo ra ta di n e Fe 6 R xo 0, x fe 1

Pa g e 2 9 1 6


n 8 a 0 di n e Lo 1 O ra 0 T ta

C

di n e H2 antag onists Ci 2 O m 0 T et 0, C id 3 in 0 e 0, 4 0 0, 8 0 0 Fa 2 O m 0, T ot 4 C id 0 in e R 7 O a 5, T ni 1 C ti 5 di 0,

Pa g e 2 9 1 7


n 3 e 0 0 H 1 /H 2 Antag onist D 1 O ox 0, T e 2 C pi 5 n Rx, pres cri pt i on; OTC, over-t he-cou nt er.

IV. Acne and Rosacea A. Acne vulgaris 



1. Definition. Acne vul gari s i s a common di s order of t he pilosebaceous unit (hai r fol l i cl e and s ebaceous gl ands ), l ocat ed pri mari l y on t he face and t runk. It i s mani fes t ed by fol l i cul ar comedones wi t h or wi t hout i nfl ammat ory papul es , pus t ul es , and nodul es .





2. Epidemiology. Acne vul gari s affect s 85%â€“100% of i ndi vi dual s t o s ome degree duri ng t hei r l i fet i me.





3. Etiology o

Pa g e 2 9 1 8


o

a. The obs t ruct i on of s ebaceous fol l i cl es i s due t o exces s i ve s ebum product i on by s ebaceous gl ands i n combi nat i on wi t h exces s i ve des quamat i on of t he fol l i cul ar epi t hel i um.

o

o

b. Infl ammat ory changes are l i nked t o t he pres ence of Propi oni bac t eri um ac nes , a res i dent , l i pophi l i c anaerobe. P. ac nes prol i ferat es i n t he mi croenvi ronment creat ed by exces s s ebum and des quamat ed fol l i cul ar cel l s . Thi s bact eri um produces chemot act i c fact ors and proi nfl ammat ory medi at ors t hat cont ri but e t o i nfl ammat i on.





4. Pathophysiology o

o

a. Acne may begi n i n t he prepubert al peri od, when i ncreas i ng amount s of adrenal androgens (dehydroepi andros t erone s ul fat e [DHEAS]) s t i mul at e s ebaceous gl and hyperpl as i a and i ncreas ed s ebum product i on. P.578

o

o

b. Abnormal fol l i cul ar di fferent i at i on i s coupl ed wi t h t hi s phenomenon, res ul t i ng i n t he devel opment of t he pri mary acne l es i ons , noni nfl ammat ory open and cl os ed comedones (â€œbl ackheads â€• and â€œwhi t eheads ,â€• res pect i vel y).

o

Pa g e 2 9 1 9


c. Dermal i nfl ammat i on and fol l i cul ar rupt ure can l ead t o acne s carri ng.



5. Clinical features




online Figure 12-8 Acne vul gari s . (Court es y of St uart Les s i n, MD.) o

o

a. Si t es of i nvol vement i ncl ude t he face and upper trunk.

o

o

b. Noninflammatory (comedonal) acne i s domi nat ed by open or cl os ed comedones wi t hout i nfl ammat ory l es i ons .

o

o

c. Mi l d inflammatory acne i s charact eri zed by i nfl ammat ory papul es and comedones .

o

o

d. Moderat e i nfl ammat ory acne i s charact eri zed by

Pa g e 2 9 2 0


comedones , i nfl ammat ory papul es , and pus t ul es . o

o

e. Nodulocystic acne i s charact eri zed by comedones , i nfl ammat ory papul es /pus t ul es , and i nfl ammat ory nodul es (>5 mm). Scarring i s oft en evi dent .





6. Diagnosis. The di agnos i s of acne vul gari s i s cl i ni cal .





7. T herapy. Treat ment i s di rect ed t oward t he pat hogeni c fact ors i nvol ved, i ncl udi ng fol l i cul ar dys kerat i ni zat i on, exces s s ebum product i on, and P. ac nes . The s everi t y of t he acne det ermi nes t he t ype and l evel of t herapy. o

o

a. T opical therapy 



(1) T opical retinoids are comedol yt i c and ant i -i nfl ammat ory. The mos t commonl y pres cri bed t opi cal ret i noi ds i ncl ude adapal ene, t azarot ene, and t ret i noi n. They are us ual l y us ed i n combi nat i on wi t h ot her t reat ment s .





(2) T opical antibiotics t arget P. ac nes . Commonl y pres cri bed t opi cal ant i bi ot i cs i ncl ude eryt hromyci n and cl i ndamyci n.





(3) Benzoyl peroxide has ant i mi crobi al propert i es agai ns t P. ac nes . Benzoyl peroxi de i s t he act i ve i ngredi ent i n many OTC t opi cal

Pa g e 2 9 2 1


s ki n care product s ; i t i s avai l abl e i n a vari et y of formul at i ons , i ncl udi ng s oaps , was hes , l ot i ons , creams , and gel s . In addi t i on, i t i s avai l abl e by pres cri pt i on. Benzoyl peroxi de i s oft en combi ned wi t h t opi cal ant i bi ot i cs t o i mprove effi cacy and reduce ant i bi ot i c res i s t ance. o

o

b. Systemic therapy 



(1) Oral antibiotics. Li pophi l i c ant i bi ot i cs are mos t effect i ve agai ns t P. ac nes . Tet racycl i ne, doxycycl i ne, and mi nocycl i ne are commonl y pres cri bed for i nfl ammat ory acne.





(2) Isotretinoin. Thi s s ys t emi c ret i noi d i s hi ghl y effect i ve i n t reat i ng s evere and nodul ocys t i c acne t hat i s recal ci t rant t o oral ant i bi ot i c and t opi cal t herapi es . It caus es normal i zat i on of epi dermal di fferent i at i on, depres s es s ebum product i on, i s ant i -i nfl ammat ory, and reduces l evel s of P. ac nes i n t he s ki n. Informed cons ent wi t h cont racept i on couns el i ng and bas el i ne l aborat ory t es t s (i ncl udi ng s erum pregnancy t es t ) are mandat ory before t he i ni t i at i on of t herapy. Mandatory participation in the iPLEDGEâ„¢ program is required for prescribers and patients receiving isotretinoin.





(3) Hormonal therapy. Thi s al t ernat i ve t o s ys t emi c ant i bi ot i cs and i s ot ret i noi n i n women

Pa g e 2 9 2 2


wi t h pers i s t ent acne i nvol ves t reat ment wi t h es t rogen or an ant i androgen. Oral cont racept i ves may be effect i ve. Combi nat i on oral cont racept i ve pi l l s (norges t i mat eâ€“et hi nyl es t radi ol ) cont ai ni ng l ow l evel s of proges t at i onal compounds are preferred. Spi ronol act one, whi ch reduces androgen product i on, may be us ed al one or i n combi nat i on wi t h an oral cont racept i ve.

B. Rosacea 



1. Definition. Ros acea i s a di s order of t he bl ood ves s el s and s ebaceous gl ands of t he face charact eri zed by eryt hema, t el angi ect as i a, fl us hi ng, and an i nfl ammat ory papul opus t ul ar erupt i on res embl i ng acne.





2. Epidemiology. Ros acea i s a common di s order t hat affect s approxi mat el y 14 mi l l i on adul t s i n t he Uni t ed St at es . It i s s een more frequent l y i n fai r-s ki nned i ndi vi dual s of European and Cel t i c des cent .





3. Etiology. The preci s e et i ol ogy of ros acea i s unknown. Cl i ni cal s i gns and s ympt oms res ul t from t he i nt eract i on of genet i c s us cept i bi l i t y wi t h envi ronment al t ri ggers (UV radi at i on, and t emperat ure changes ) and di et ary t ri ggers (hot dri nks , al cohol , and s pi cy foods ). P.579





4. Pathophysiology

Pa g e 2 9 2 3


o

a. Vas cul ar l abi l i t y res ul t s i n i nt ermi t t ent faci al fl us hi ng, l eadi ng t o pers i s t ent rednes s and t el angi ect as i as t hat affect t he cent ral face and occas i onal l y t he eyes .

o

o

b. The pat hogenes i s of t he s ebaceous hyperpl as i a and t he i nfl ammat ory papul es and pus t ul es i s uncl ear. Mi t es of t he genus Demodex (i ndi genous t o human hai r fol l i cl es ) appear i n great er numbers , but t hei r et i ol ogi c rol e has not been es t abl i s hed.



5. Clinical features




online Figure 12-9 Ros acea. (Court es y of St uart Les s i n, MD.) o

o

a. Fl us hi ng, eryt hema, and t el angi ect as i a can occur over t he cheeks , forehead, and chi n.

o

Pa g e 2 9 2 4


o

b. Infl ammat ory papul es and pus t ul es i nvol ve t he nos e, forehead, and t he cheeks , wi t h an abs ence of comedones and s carri ng.

o

o

c. Rhi nophyma i s a promi nence of s ebaceous gl ands of t he nos e t hat produces t hi ckened s ki n and di s fi gurement i n ext reme cas es .

o

o

d. Ocul ar ros acea produces ocul ar s i gns t hat may i ncl ude conjunct i val i nject i on, edema, chal azi on, and epi s cl eri t i s .





6. Diagnosis. The di agnos i s i s cl i ni cal . Overl appi ng feat ures of acne vul gari s may s omet i mes be pres ent , and i t may be di ffi cul t of di fferent i at e acne vul gari s and ros acea.





7. T herapy. Avoi dance of envi ronment al and di et ary t ri ggers i s an i mport ant s t rat egy t o reduce s i gns and s ympt oms . o

o

a. T opical antibiotics (e.g., t opi cal met roni dazol e) may be pres cri bed for mi l d di s eas e.

o

o

b. Systemic antibiotics (e.g., t et racycl i ne, doxycycl i ne, and mi nocycl i ne) are us ual l y effect i ve i n t reat i ng acnei form l es i ons but have l i mi t ed effect i venes s i n t reat i ng t he faci al eryt hema.

o

Pa g e 2 9 2 5


c. Retinoids (e.g., i s ot ret i noi n) are pres cri bed as a one-t i me cours e (s i mi l ar t o acne t herapy) and may be an effect i ve t reat ment for s evere cas es . Al t ernat i vel y, l ong-t erm, l ow-dos e i s ot ret i noi n can be us ed.

V. Autoimmune Blistering Diseases: Pemphigus and Bullous Pemphigoid A. General considerations 

1. Aut oi mmune bl i s t eri ng di s eas es are charact eri zed by



bl i s t eri ng of t he s ki n and mucous membranes as s oci at ed wi t h t he depos i t i on of aut oant i bodi es . 

2. Local i zat i on of aut oant i bodi es t o epi t opes i n t he epi dermi s , BMZ, or dermi s defi nes t he s peci fi c cl i ni cal feat ures , hi s t opat hol ogy, and di rect i mmunofl uores cent s t ai ni ng pat t ern (onl i ne Tabl e 12-7). 

ONLINE TABLE 12-7 Target Autoantibodies and Direct Immunofluorescence in Autoimmune Blistering Diseases

Pa g e 2 9 2 6


Di re ct I m m u A

n

ut

of

oi

lu

m

or

m

e

u

sc

n

e

e

n

Bl

c

is

e

te

(

ri

D

n

IF

g

)

Di Ig Fi s E n e pi di a to n s p g e e s P D In e es t e m m rc p o el hi gl l u g ei l a us n r vu 1, Ig

Pa g e 2 9 2 7


lg 3 G ar

st

is

ai ni n

g P D In e es t e m m rc p o el hi gl l u g ei l a us n r fo 1 Ig li

G

ac

st

e

ai

us

ni n

g P D In ar es t e a m rc n o el e gl l u o ei l a pl n r as 1, Ig ti 3 G c D st p es ai e m ni m o n p pl g hi ak a g in n

Pa g e 2 9 2 8


us 1, d 2 li E n nv e o ar pl B ak M in Z ,

C

p 3 er d ip e la p ki os n, i t pl s ec ti n B D Ig ul es G lo m a us o n p pl d e ak l i m in n p 1 e hi C ar g ol C oi l a 3 d g d e e n p X os VI i t

Pa g e 2 9 2 9


I s al o n g B M Z; o n e pi d er m al si d e of sa lt -s pl it sk in * Ci E Ig ca pi G t ri l i a ci gr n al i n d p C li e ol n

Pa g e 2 9 3 0


m la e p g ar hi e C g n 3 oi X d d VI e I p os it s al o n g B M Z; o n d er m al si d e of sa lt -s pl it sk in H C Ig

Pa g e 2 9 3 1


er ol G p la a es g n g e d es n l i ta X n t i VI e o I ar ni

C

s

3 d e p os it s al o n g B M Z; o n e pi d er m al si d e of

Pa g e 2 9 3 2


sa lt -s pl it sk in E C Ig pi ol G d la a er g n m e d ol n l i ys VI n is I e b

ar

ul

C

lo

3

sa

d

ac

e

q

p

ui

os

si

it

ta

s al o n g B M Z; o n d er

Pa g e 2 9 3 3


m al si d e of sa lt -s pl it sk in Li C Li n ol n e la e ar g ar Ig e Ig A n A d VI d er I e m C p at ol os os l a i t i s g al e o n n X g VI B I M Z a n d d

Pa g e 2 9 3 4


er m al si d e of sa lt -s pl it sk in B C Li ul ol n lo la e us g ar l u e Ig p n A us VI or er I gr yt

a

h

n

e

ul

m

ar

at

Ig

os

G

us

d e p os it s al

Pa g e 2 9 3 5


o n g B M Z a n d d er m al si d e of sa lt -s pl it sk in BMZ, bas em ent membr ane z one; Ig, i mmun ogl obu l i n. *Sal t -s

Pa g e 2 9 3 6


pl i t s ki n i s i ncuba t i on of s ki n bi ops y in 1 mol /L s al t before perfor mi ng t he DIF res ul t s in cl eava ge t hroug h t he l ami na l uci da of bas em ent membr ane. 



3. Mos t aut oi mmune bl i s t eri ng di s eas es are i di opat hi c but may be as s oci at ed wi t h medi cat i ons , s uch as pemphi gus (s ee V B) and l i near IgA dermat os i s (s ee XII E 14), pregnancy (herpes ges t at i oni s ; s ee Tabl e 12-7), aut oi mmune di s eas e (bul l ous l upus eryt hemat os us ; Tabl e 12-8), or mal i gnancy (paraneopl as t i c pemphi gus ).



Pa g e 2 9 3 7




4. Two of t he mos t commonl y encount ered forms of aut oi mmune bl i s t eri ng di s eas es are pemphi gus and bul l ous pemphi goi d. Paraneopl as t i c pemphi goi d i s al s o rarel y s een.

B. Pemphigus 



1. Epidemiology. The i nci dence of pemphi gus vari es from 1 per 1,000,000 t o 50 per 1,000,000 popul at i on dependi ng on t he t ype of pemphi gus and et hni ci t y. The ons et of pemphi gus i s t ypi cal l y young t o mi d adul t hood (1 cm) may be nodular wi t h ul cerat i on or s econdary crus t i ng.

o

o

d. A s ubs et of t hes e carci nomas are cons i dered hi gh ri s k for met as t as i s . Ri s k fact ors for met as t as i s i ncl ude l ocat i on on t he l ower l i p or ear, hi s t ol ogi c feat ures s uch as poor di fferent i at i on, i nvas i on more t han 4 mm i nt o t he dermi s , peri neural i nvas i on, occurrence i n i mmunos uppres s ed pat i ent s , and devel opment i n burn s i t es .





6. Diagnosis. The di agnos i s of s quamous cel l carci noma i s made by cl i ni cal i ns pect i on of s ki n and confi rmed by s ki n bi ops y.





7. T herapy o

o

a. Surgery. The cure rat e i s 90%â€“99% dependi ng on t he t umor s i t e and s urgi cal t echni que. Surgi cal t echni ques i ncl ude exci s i on, Mohs mi crographi c s urgery, curet t age wi t h el ect rodes i ccat i on, and cryos urgery.

o

Pa g e 2 9 9 1


o

b. Radiation therapy. The cure rat e i s 93%â€“97%. Prophyl act i c pos t operat i ve radi at i on t o t he s i t e may be i ndi cat ed i n hi gh-ri s k l es i ons .

C. Melanoma 



1. Definition. Mel anoma i s t he neopl as t i c growt h of mel anocyt es .





2. Epidemiology o

o

a. Incidence. Cl os e t o 60,000 new cas es of mel anoma occur each year i n t he Uni t ed St at es .

o

o

b. Risk factors 



(1) Genetic. Ten percent of cas es of mel anoma are fami l i al ; at l eas t one rel at i ve i s affect ed. From 1% t o 3% of cas es of mel anoma are heredi t ary; t wo or more fi rs t -degree rel at i ves are affect ed wi t h mel anoma and have a germ l i ne mut at i on i n t he CDKN2A gene.





(2) Previous melanoma. Pat i ent s who have had one mel anoma have a 5% probabi l i t y of a s econd pri mary mel anoma.





(3) Environmental. The ri s k of mel anoma

Pa g e 2 9 9 2


i ncreas es wi t h i ncreas ed UV expos ure, part i cul arl y wi t h an i ncreas ed number of s evere s unburns i n i ndi vi dual s younger t han 20 years of age. 



(4) Pigmentation. The fol l owi ng fact ors are as s oci at ed wi t h an i ncreas ed ri s k of mel anoma. 



(a) Fair complexion (readi l y s unburns and never t ans , bl ue eyes , red or bl onde hai r)





(b) Increased number of melanocytic nevi (moles) (>25)





(c) Pres ence of large melanocytic nevi (>6 mm)





(d) Pres ence of atypical (dysplastic) nevi (>5 mm wi t h varyi ng degrees of i rregul ar cl i ni cal feat ures [s ee X C 5]).





3. Etiology. The mul t i fact ori al et i ol ogy i ncl udes genet i c s us cept i bi l i t y and envi ronment al expos ure t o UV l i ght (s unl i ght ).





4. Pathophysiology. The i ni t i al s t ages of neopl as t i c t rans format i on res ul t i n upward (paget oi d) growt h of cyt ol ogi cal l y at ypi cal mel anocyt es wi t hi n epi dermi s (i n

Pa g e 2 9 9 3


s i t u). Tumor progres s i on res ul t s i n i nvas i on of underl yi ng dermi s and deeper t i s s ues . Regi onal l ymph node met as t as i s us ual l y precedes met as t as i s t o di s t ant s i t es , t ypi cal l y s ki n, l ung, brai n, and l i ver. In mos t cas es , BRAF gene mut at i ons are det ect ed i n earl y mel anoma t umor progres s i on. 

5. Clinical features. The vas t majori t y of cut aneous mel anomas have uns t abl e cl i ni cal feat ures t hat change over t i me. Charact eri s t i c feat ures may be remembered us i ng t he mnemoni c â€œABCDâ€•

(onl i ne Fi gure 12-24).



online Figure 12-24 Mel anoma. (Court es y of St uart Les s i n, MD.) o

o

a. Asymmetry: a devi at i on i n t he overal l round t o oval confi gurat i on

o

o

b. Border: an i rregul ar ci rcumference of t he l es i on. The i ndi s t i nct margi ns may bl end i n t o t he fl es h-col ored background. P.591

o

o

c. Color: nonuni formi t y of pi gment at i on wi t h

Pa g e 2 9 9 4


vari at i ons i n col or, i ncl udi ng bl ack, bl ue, and red hues o

o

d. Diameter: general l y great er t han 6 mm for det ect i on



6. Diagnosis. The di agnos i s of mel anoma i s made by



cl i ni cal i ns pect i on of s ki n and confi rmed by exci s i onal bi ops y. 

7. Staging

Refer t o Ameri can Joi nt Commi t t ee on Cancer

(AJCC) 2002 gui del i nes for ful l det ai l s




ONLINE TABLE 12-12 American Joint Committee on Cancer (AJCC) 2002 Tumor, Node, Metastasis (TNM) Classification and Stage Groupings for Melanoma Tu mo r (T ) Cla ssi fic ati on TX Pri ma

Pa g e 2 9 9 5


ry tu mo r can not be as s es s ed (e. g., s ha ve bi o ps y , reg res s ed pri ma ry) Ti s Mel an om a in sit u â ‰ ¤1. 0m

Pa g e 2 9 9 6


m T1 a: wi t ho ut ul c era tio n an d l ev el II/I II* b : wi t h ul c era tio n or l ev el IV or V* 1 .01 â€“ 2.0 mm

Pa g e 2 9 9 7


T2 a: wi t ho ut ul c era tio n b : wi t h ul c era tio n 2 .01 â€“ 4.0 mm T3 a: wi t ho ut ul c era tio n b : wi t h

Pa g e 2 9 9 8


ul c era tio n 5 cm i n di amet er) or wi t h unres ect abl e t umors may need neoadjuvant chemot herapy, whi ch means t hat t he chemot herapy i s gi ven fi rs t t o s hri nk t he t umor and t hen i s fol l owed by s urgery and radi at i on t herapy. Becaus e t he majori t y of breas t t umors res pond t o neoadjuvant chemot herapy t hi s approach can be very val uabl e as i t al l ows t he s urgeon t o compl et el y res ect t he t umor. Prognos i s vari es wi del y i n breas t cancer pat i ent s . Approxi mat el y 50% of pat i ent s wi t h operabl e breas t cancer devel op recurrent di s eas e unl es s t hey recei ve adjuvant chemot herapy or hormone t herapy. Prognos t i c fact ors i ncl ude t umor s i ze, axi l l ary node s t at us , t he hi s t opat hol ogy of t he t umor, hormone recept or s t at us (es t rogen and proges t erone), t he S-phas e fract i on and DNA i ndex, and oncogene expres s i on (Her2/neu). Mos t young premenopaus al women wi t h s t age II breas t cancer wi l l recei ve adjuvant chemot herapy and hormonal t herapy, i n addi t i on t o s urgery and radi at i on t herapy, i f t he t umor i s es t rogen or proges t erone pos i t i ve. W omen wi t h Her2/neu pos i t i ve breas t cancer wi l l al s o recei ve Tras t uz umab a monocl onal ant i body agai ns t Her2/neu.

Pa g e 3 1 5 6


Case 11 Acute Low Back Pain A 35-year-old man presents to the emergency department with a 2-day history of severe low back pain. T he pain is worse when he sits up and better when he lies flat on his back. He claims to be well, although he recently experienced polyarthralgias, chills, and sweating. He reports that he was hospitalized for some form of hepatitis 2 years ago; he says it resolved uneventfully and he does not know what caused it. He denies alcohol or drug abuse.

Questions 



What are your i mmedi at e c onc erns about t hi s pat i ent 's l ow bac k pai n?





What c ondi t i ons mi ght c aus e referred bac k pai n?





What addi t i onal i nformat i on do you w ant t o know about t he pai n?

Discussion The hi s t ory of chi l l s and s weat s makes one cons i der an i nfect i ous proces s more s eri ous l y t han ot her pos s i bl e caus es of t hi s l ow back pai n. The man des cri bes t he pai n as s evere, whi ch makes i t more worri s ome. The fact t hat t he pai n i s wors e when s i t t i ng upri ght and bet t er wi t h recumbency i s not part i cul arl y hel pful i n s ugges t i ng a s peci fi c, pot ent i al l y s eri ous caus e of t hi s back compl ai nt . Pai n t hat i s i ns i di ous i n ons et , as s oci at ed wi t h prol onged morni ng s t i ffnes s , rel i eved by exerci s e, and wors ened by res t s ugges t s underl yi ng i nfl ammat ory back pai n, t ypi cal l y t he s acroi l i i t i s of t he s pondyl oart hropat hi es . In cont ras t , mechani cal l ow back pai n oft en i s s udden i n ons et , wors ened by exerci s e, and i mproved by res t .

Pa g e 3 1 5 7


Pai n t hat i s ri ppi ng or t eari ng and perhaps as s oci at ed wi t h abdomi nal compl ai nt s i s t ypi cal of an expandi ng abdomi nal aort i c aneurys m. Pai n as s oci at ed wi t h bl adder or bowel i ncont i nence and s addl e anes t hes i a s ugges t s a mi d-l i ne l umbar di s k herni at i on wi t h cauda equi na compres s i on; pai n as s oci at ed wi t h l eg s ens ory or mot or compl ai nt s s ugges t s l at eral di s k herni at i on and s pi nal nerve compres s i on; and pai n as s oci at ed wi t h gas t roi nt es t i nal or geni t ouri nary compl ai nt s s ugges t s a need t o i nves t i gat e an i nt ra-abdomi nal s ource as t he caus e. Cons t i t ut i onal compl ai nt s s uch as fever and chi l l s make an i nfect i on more l i kel y. Pai n i ncreas i ng wi t h recumbency (t he oppos i t e of t hi s pat i ent 's compl ai nt ) s ugges t s a pos s i bl e t umor; mi d-l i ne pai n s ugges t s a t umor, an i nfect i on, or a compres s i on fract ure. Ni net y percent of l ow back pai n i s caus ed by s el f-l i mi t ed bi omechani cal or s t rai n probl ems , but i t i s i mport ant t o l ook for feat ures t hat make an acut e medi cal condi t i on more l i kel y. There i s i mport ant i nformat i on s t i l l t o be obt ai ned about t he nat ure of t hi s pat i ent 's back pai n. P.635

On initial examination, the patient is writhing in discomfort and asking for intramuscular narcotics. His temperature is 38.3Â°C, and prominent needle tracks are observed on his hands and legs. Diffuse tenderness and guarding are noted on abdominal examination. Marked tenderness is noted over the entire low back paraspinal region, and prominent percussion tenderness is noted over several lumbar and sacral vertebrae. T he patient cooperates poorly with strength testing, but deep tendon reflexes and sensation are intact and anal wink and perianal sensations are normal. T he patient complains of hamstring tenderness when either leg is raised in a straightened, extended position.

Questions 

Pa g e 3 1 5 8




How do t he fi ndi ngs on phys i c al exami nat i on hel p you i n t hi nki ng about your di fferent i al di agnos i s ?





What i nformat i on s houl d you s eek from l aborat ory t es t s and proc edures at t hi s t i me?

Discussion Several fi ndi ngs on phys i cal exami nat i on pl ace s el f-l i mi t ed mus cul os kel et al pai n far down t he di fferent i al di agnos i s l i s t . For one t hi ng, i t i s known t hat t he pat i ent i s l i kel y abus i ng i nt ravenous drugs , even t hough he deni ed t hi s i n t he hi s t ory. Narcot i c drug-s eeki ng behavi or makes t he phys i cal exami nat i on more di ffi cul t t o i nt erpret , becaus e exaggerat ed res pons es t o phys i cal exami nat i on maneuvers are common i n drug-abus i ng pat i ent s . In addi t i on, t he pat i ent has a fever and promi nent fi ndi ngs on abdomi nal and back pal pat i on as wel l as on s pi nal percus s i on. Int ravenous drug abus e and fever make an i nfect i ous proces s (e.g., epi dural abs ces s , paras pi nal or peri rect al col l ect i on, s ept i c s acroi l i i t i s ) much more l i kel y. No s peci fi c evi dence for an aort i c aneurys m exi s t s on abdomi nal exami nat i on, and t here i s no neurol ogi c evi dence for cauda equi na compres s i on or di s cogeni c nerve compres s i on. No evi dence has been pres ent ed for a pot ent i al referred s ource of pai n s uch as a penet rat i ng duodenal ul cer (gas t roi nt es t i nal s ource) or a renal i nfect i on or s t one (geni t ouri nary s ource). There i s no evi dence of a s pondyl oart hropat hy. A compl et e bl ood count (CBC) mi ght hel p wi t h eval uat i on of an i nfect i ous proces s , part i cul arl y i f l eukocyt os i s i s pres ent . Amyl as e woul d be i ncreas ed wi t h pancreat i t i s and bowel emergenci es (e.g., s mal l bowel obs t ruct i on). The eryt hrocyt e s edi ment at i on rat e i s nons peci fi c, but s i gni fi cant el evat i on al s o mi ght s ugges t an i nfect i on, part i cul arl y os t eomyel i t i s . Uri nal ys i s i s i mport ant for di s coveri ng a pot ent i al geni t ouri nary i nfect i on. Three s et s of pai red bl ood cul t ures s houl d be obt ai ned, becaus e bact eri al endocardi t i s can pres ent wi t h mus cul os kel et al compl ai nt s , and any bact eri al proces s i n t he l ow back mi ght be as s oci at ed wi t h bact eremi a. Pl ai n

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radi ographs of t he l ow back and s acroi l i ac joi nt s qui t e l i kel y mi ght be normal , al t hough pat i ent s wi t h di s ki t i s can have i nt ervert ebral narrowi ng and vert ebral end-pl at e des t ruct i on; t hos e wi t h s acroi l i i t i s can have s acroi l i ac joi nt eros i ons and s cl eros i s . A magnet i c res onance i magi ng (MRI) i s t he bes t i magi ng modal i t y for eval uat i ng s oft t i s s ue or i nt ras pi nal col l ect i ons , part i cul arl y t o rul e out an epi dural abs ces s . T he test results come back as follows: hemoglobin is 11.3 g/dL, the white blood cell (WBC) count is 15,000/ÂµL, and the platelet count is 500,000/ÂµL. T he Westergren erythrocyte sedimentation rate is 100 mm/hour. Chemistries indicate only an elevated alkaline phosphatase; amylase is normal. Urinalysis is negative. Chest radiograph, lumbar spine radiograph, and pelvic radiographs are unrevealing. Several hours later, the patient continues to require high doses of intramuscular narcotic for pain control and still complains of severe low back pain. He says that he is having difficulty walking to the bathroom because of leg weakness. His maximum temperature is 38.9Â°C. Physical examination indicates continuing poor cooperation with strength testing, but he appears to be severely weak (3/5 on muscle strength testing) in all lower extremity muscle groups. He also has decreased sensation to pinprick from the toes to the navel and prominent increased deep tendon reflexes in the lower extremities with four beats of clonus bilaterally.

Questions 



What i s t he mos t l i kel y di agnos i s at t hi s poi nt ?





What addi t i onal di agnos t i c t es t s are appropri at e t o c onfi rm a di agnos i s ?



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What t herapeut i c approac h i s mos t appropri at e now ?

P.636

Discussion The neurol ogi c fi ndi ngs (l eg weaknes s , abdomi nal s ens ory l evel , i ncreas ed refl exes , and cl onus ) s ugges t s pi nal cord compres s i on wi t h feat ures of an upper mot or neuron l es i on. W hen t he hi s t ory of i nt ravenous drug abus e, fever, l ow back pai n, and progres s i ve neurol ogi c defi ci t i s added, t he di fferent i al di agnos i s narrows markedl y. The pat i ent 's s ens ory l evel t o about T12 s ugges t s t hat t he cord compres s i on i s occurri ng at t hi s l evel , probabl y from an epi dural abs ces s . Condi t i ons s uch as t rans vers e myel i t i s or an i s chemi c myel opat hy at T12 cord l evel or a mi d-l i ne herni at ed t horaci c di s k are s t i l l pos s i bl e, but t hes e di agnos es are l es s l i kel y t o expl ai n t he fever or t o be as s oci at ed wi t h i nt ravenous drug abus e. Gi ven t he hi gh i ndex of s us pi ci on for i nfect i on, empi ri c ant i bi ot i c admi ni s t rat i on s houl d be s t rongl y cons i dered. The bes t procedure for confi rmi ng a di agnos i s i s an MRI s can. Thi s t es t wi l l bes t di s cri mi nat e bet ween an i nt ri ns i c cord l es i on (e.g., t rans vers e myel i t i s ) and an ext ri ns i c compres s i on (e.g., due t o an abs ces s or herni at ed di s k). The t es t s houl d be done emergent l y, becaus e earl y s urgi cal i nt ervent i on i s cri t i cal t o pres ervat i on of l ower ext remi t y funct i on. T he emergency MRI scan shows an epidural abscess at T 12, and surgical dÃ©bridement is carried out immediately. Staphylococcus aureus grows from one set of the blood cultures and the abscess.

Question 



What remai ni ng t reat ment modal i t i es s houl d be us ed now ?

Discussion

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The pat i ent s houl d be t reat ed for 4â€“6 weeks wi t h ant i bi ot i cs effect i ve agai ns t S. aureus , i ni t i al l y i nt ravenous l y. He s houl d be careful l y wat ched for feat ures of bact eri al endocardi t i s , des pi t e t he fact t hat onl y one bl ood cul t ure was pos i t i ve. Furt hermore, t he pat i ent s houl d recei ve i nt ens i ve phys i cal t herapy once t he acut e pai n s ubs i des s o t hat he can recover l ower ext remi t y s t rengt h and t he abi l i t y t o wal k.

Case 12 Gastrointestinal Bleeding A 54-year-old white man presents to his general practitioner' s office complaining of fatigue. He says that he tires easily and often feels light-headed and short of breath after climbing a single flight of steps or taking a short walk. He says that he is having difficulty at work because he is â€œ just not himself.â€•

Questions 



What are s ome pos s i bl e c aus es of general i zed fat i gue and w eaknes s ?





What ot her ques t i ons w oul d you l i ke t o as k t hi s pat i ent ?

Discussion Fat i gue and weaknes s are common compl ai nt s t hat can be ps ychogeni c or phys i cal i n ori gi n. It i s i mport ant t o di fferent i at e bet ween t hes e broad et i ol ogi c cat egori es . Ps ychogeni c caus es cons i s t of anxi et y s t at es and depres s i on. Phys i cal caus es i ncl ude i nfect i ous di s eas e, met abol i c di s orders , bl ood dys cras i as , renal di s eas e, l i ver di s eas e, chroni c pul monary di s eas e, chroni c cardi ovas cul ar di s eas e, neopl as t i c di s eas es , and neuromus cul ar di s eas e. To narrow t he di agnos t i c pos s i bi l i t i es for t hi s pat i ent 's fat i gue and weaknes s , addi t i onal hi s t ory s houl d be obt ai ned. The pat i ent

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s houl d be ques t i oned about whet her he has experi enced wei ght l os s , fever, chi l l s , ches t pai n, paroxys mal noct urnal dys pnea, ort hopnea, pedal edema, abdomi nal pai n, changes i n bowel habi t s , mel ena, hemat ochezi a, pol yuri a, pol ydi ps i a, pol yphagi a, i nt ol erance t o heat or col d, or i ns omni a. A pos i t i ve ans wer t o t hes e ques t i ons oft en, al t hough not al ways , i ndi cat es a phys i cal or organi c caus e of fat i gue and weaknes s . Further history indicates that the patient' s symptoms started about 2 months ago and have steadily worsened. He claims he was in excellent health until this time; in fact, he has not had a routine physical examination in approximately 2 years because he has felt healthy. T he patient takes no medications, except for the occasional use of acetaminophen or laxatives. He is an executive in a publishing company who smokes approximately half a pack of cigarettes per day and P.637 drinks a martini or two at lunch. He has no significant family history, except that an estranged older brother died after an abdominal operation for an unknown cause. T he patient denies chest pain or palpitations but has occasional shortness of breath and dyspnea on exertion, as described above. He has had no loss of appetite and even jokes that he can eat even on days when he is a bit â€œ irregular.â€• When asked about his constipation, he notes that he sometimes has difficulty passing his stool, but the stool is of normal consistency. He reports that his stools have seemed a bit darker lately, but he thought it might be due to laxatives he took for constipation; he has not noticed any bright red blood in the stool and denies hematemesis, nausea, vomiting, or diarrhea.

Question 



Whi c h of t hes e s i gns and s ympt oms c onc ern you?

Discussion

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Thi s pat i ent 's hi s t ory rai s es s everal poi nt s of concern. Hi s s ympt oms began 2 mont hs ago, meani ng t hey are chroni c compl ai nt s , and t hey have s t eadi l y wors enedâ€”an omi nous s i gn. Acut e compl ai nt s coul d be at t ri but ed t o an acut e vi ral or s el f-l i mi t ed i l l nes s . That t he pat i ent was i n excel l ent heal t h unt i l 2 mont hs ago al s o i ndi cat es a change from a preexi s t i ng pat t ern. Sympt oms t hat have been pres ent for a l ong t i me (2â€“3 years or more) s ugges t a chroni c nonprogres s i ve i l l nes s s uch as i rri t abl e bowel s yndrome. However, i n a pat i ent who was previ ous l y s ympt om-free and i n excel l ent heal t h, a 2-mont h hi s t ory of s ympt oms t hat have s t eadi l y wors ened woul d s ugges t a new and pot ent i al l y s eri ous change t hat coul d be compat i bl e wi t h i nfl ammat ory bowel di s eas e, i nfect i ous s t at es (e.g., gi ardi as i s ), or even mal i gnant di s eas e i nvol vi ng t he gas t roi nt es t i nal t ract , part i cul arl y t he col on. The abs ence of medi cat i ons woul d el i mi nat e t he pos s i bi l i t y t hat a s i de effect of a drug (e.g., an ant i hypert ens i ve agent ) i s res pons i bl e for t he fat i gue and s hort nes s of breat h. Smoki ng i s cl earl y as s oci at ed wi t h numerous mal i gnanci es , i ncl udi ng bronchogeni c and pancreat i c carci noma, i n addi t i on t o i t s known cardi ovas cul ar and pul monary effect s . The fami l y hi s t ory of an abdomi nal operat i on for an unknown caus e rai s es t he s pect er of pos s i bl e col oni c carci noma, whi ch has a t wo- t o t hreefol d i ncreas ed i nci dence i n fi rs t -degree rel at i ves . Dys pnea on exert i on coul d s i gni fy a cardi ovas cul ar caus e but al s o coul d be as s oci at ed wi t h an anemi c s t at e. The â€œabnormal l y dark s t ool s â€• mi ght be i ndi cat i ve of mel ena, whi ch woul d s ugges t t hat t he upper gas t roi nt es t i nal t ract (above t he l i gament of Trei t z) i s t he mos t l i kel y s ource of bl eedi ng; dark red or maroon-colored s t ool s t ypi cal l y i ndi cat e bl ood emanat i ng from t he ri ght col on. Physical examination shows a well-developed, overweight white man with a somewhat rapid respiratory rate (i.e., 20 respirations/min). Other vital signs show a pulse of 94 beats/minute, a blood pressure of 110/60 mm Hg, and a normal temperature. T he patient' s skin is pale, as are his mucous membranes. His lungs are clear on auscultation, and his heart

Pa g e 3 1 6 4


rhythm is regular, with normal first and second heart sounds (S 1 and S 2 ) and no third or fourth heart sound (S 3 or S 4 ). His abdomen is soft, without tenderness or obvious masses. His extremities show no cyanosis or edema; he has prolonged capillary refill. His rectal examination shows no palpable masses, but a dark, heme-positive stool is noted.

Questions 



Bas ed on t hi s phys i c al exami nat i on, w hat do you s us pec t i s t he c aus e of t hi s man's fat i gue?





What are s ome of t he c aus es of mel ena?





What s ort s of di s orders produc e hemat oc hezi a?





How w oul d you proc eed i n w orki ng up t he heme-pos i t i ve s t ool ?

Discussion Phys i cal exami nat i on s hows an i ndi vi dual whos e s ki n and mucous membranes are pal e and who has heme-pos i t i ve s t ool . Thes e s i gns s ugges t t hat t he pat i ent has gas t roi nt es t i nal bl eedi ng and i s mos t l i kel y anemi c, pos s i bl y t he reas on he i s feel i ng fat i gued. Mel ena i s t he pas s age of dark, t arry s t ool s due t o t he pres ence of bl ood al t ered by i nt es t i nal jui ces . It i s mos t commonl y caus ed by upper gas t roi nt es t i nal bl eedi ng (e.g., duodenal ul cer di s eas e, gas t ri c ul cer di s eas e, hemorrhagi c gas t ri t i s , eros i ve es ophagi t i s , es ophageal vari ces or Mal l ory-W ei s s t ears , or P.638 vas cul ar ect as i a of t he s t omach). In an i ndi vi dual who i s not acut el y i l l , pept i c ul cer di s eas e woul d be t he mos t common caus e;

Pa g e 3 1 6 5


es ophageal vari ces or a Mal l ory-W ei s s t ear of t he di s t al es ophagus woul d be unl i kel y. Hemat ochez i a i s t he pas s age of bl ood from t he rect um, whi ch vari es i n col or from dark red or maroon (from bl eedi ng i n t he ri ght col on) t o bri ght red (as a res ul t of bl eedi ng from a more di s t al col oni c s ource or t he anal ri ng i t s el f). Hemat ochezi a may be caus ed by col oni c di vert i cul os i s and angi odys pl as i a, hemorrhoi ds , fi s s ures , col on pol yps , col on carci noma, ul cerat i ve col i t i s , i nfect i ous dys ent ery (es peci al l y Shi gel l a, Campyl obac t er, and amebi c col i t i s ), and i s chemi c col i t i s . Unl i ke mel ena, hemat ochezi a i s oft en a s i gn of neopl as t i c l es i ons of t he gas t roi nt es t i nal t ract ; t herefore, t he pat i ent s houl d be eval uat ed for t hes e di s orders . Occas i onal l y, an upper gas t roi nt es t i nal s ource (e.g., bri s k bl eedi ng from a pept i c ul cer) coul d l ead t o t he pas s age of bri ght red bl ood from t he rect um. General l y, t hi s occurrence i s s een i n a pat i ent who i s ot herwi s e hemodynami cal l y uns t abl e and woul d be i dent i fi ed by t he fi ndi ng of bl ood on t he pas s age of a nas ogas t ri c t ube i nt o t he s t omach. The i ni t i al workup for heme-pos i t i ve s t ool depends on t he pat i ent 's hi s t ory and phys i cal exami nat i on. If t he hi s t ory and exami nat i on are s ugges t i ve of an upper gas t roi nt es t i nal s ource, i ni t i al eval uat i on s houl d i ncl ude upper endos copy. However, i n mos t cas es of occul t gas t roi nt es t i nal bl eedi ng when a l ower gas t roi nt es t i nal s ource i s expect ed, col onos copy i s i ndi cat ed. If t hi s s t udy i s unreveal i ng, an upper gas t roi nt es t i nal s ource s houl d be purs ued, i ncl udi ng eval uat i on of t he s mal l bowel . Upper gas t roi nt es t i nal endos copy i s t he bes t i ni t i al fi rs t s t udy. If no upper gas t roi nt es t i nal s ource i s i dent i fi ed, s mal l bowel ent eros copy, s mal l bowel fol l ow-t hrough, or wi rel es s caps ul e endos copy i s i ndi cat ed. A nasogastric tube is inserted but does not reveal any evidence of blood. T he physician has an anoscope in his office, but anoscopy does not show any obvious lesions. In-office hemoglobin and hematocrit tests give values of 9.4 g/dL and 36%, respectively. T he physician decides to refer the patient immediately to a gastroenterologist for further workup of the

Pa g e 3 1 6 6


gastrointestinal bleeding.

Questions 



Why does t he phys i c i an fi rs t l ook for evi denc e of upper gas t roi nt es t i nal bl eedi ng?





What are t he mos t c ommon c aus es of l ow er gas t roi nt es t i nal bl eedi ng i n t hi s age group?

Discussion The pat i ent 's hi s t ory s ugges t ed a dark s t ool but , on t he bas i s of t he hi s t ory, t he phys i ci an coul d not det ermi ne whet her t he s t ool was bl ack. Therefore, an upper gas t roi nt es t i nal s ource was s ought by t he pas s age of a nas ogas t ri c t ube. In approxi mat el y 75%â€“80% of cas es , an upper gas t roi nt es t i nal bl eedi ng s ource can be i dent i fi ed by bl ood i n t he nas ogas t ri c t ube. Occas i onal l y, bl eedi ng from a duodenal ul cer wi l l be s o s l i ght i t wi l l caus e a gas t ri c as pi rat e t o be negat i ve for bl ood. In t hi s pat i ent 's age group, t he t wo mos t common caus es of l ower gas t roi nt es t i nal bl eedi ng are di vert i cul os i s and angi odys pl as i a. The di fferent i al di agnos i s woul d al s o i ncl ude t hos e condi t i ons known t o caus e hemat ochezi a, as di s cus s ed earl i er. A bl eedi ng di at hes i s caus ed by a pri mary hemat ol ogi c s ource s uch as l eukemi a, t hrombocyt openi a, hemophi l i a, or di s s emi nat ed i nt ravas cul ar coagul at i on (DIC) s houl d al s o be cons i dered. T he gastroenterologist sees the patient immediately, and some laboratory tests are performed. A complete blood count (CBC) 3

shows a white blood cell (WBC) count of 7.2/mm , a platelet 3

count of 525,000/mm , and hemoglobin and hematocrit consistent with the previous values. Red blood cell (RBC) indices 3

show a mean corpuscular volume (MCV) of 70 Âµm and a mean corpuscular hemoglobin (MCH) of 25 pg. Serum iron and transferrin are decreased. Prothrombin time (PT ) and partial thromboplastin (PT T ) are normal, as are electrolyte, blood urea

Pa g e 3 1 6 7


nitrogen (BUN), and creatinine levels.

Questions 



What t ype of anemi a do t hes e val ues s ugges t ?





Whi c h of t he previ ous l y ment i oned di fferent i al di agnos es c an be rul ed out by t he l aborat ory val ues ?





What c ondi t i ons are t he hi ghes t on your di fferent i al ?





What are your i mmedi at e management pl ans ?

P.639

Discussion The l aborat ory fi ndi ngs s ugges t a mi crocyt i c, hypochromi c anemi a. 3

The MCV of 70 mm and t he MCH of 25 pg are compat i bl e wi t h t hi s di agnos i s . An el evat ed pl at el et count i s oft en s een i n pat i ent s wi t h chroni c bl ood l os s . The di fferent i al di agnos i s of t hi s t ype of anemi a i ncl udes i ron defi ci ency caus ed by poor i nt ake or l ack of abs orpt i on, or chroni c bl ood l os s . The us ual s ource of chroni c occul t bl ood l os s i s from t he gas t roi nt es t i nal t ract . Iron chel at i on t herapy for l ead i nt oxi cat i on al s o may caus e t hi s t ype of anemi a. Congeni t al anemi a s uch as t hal as s emi a i s al s o as s oci at ed wi t h hypochromi c, mi crocyt i c anemi a. Iron defi ci ency s t at es are charact eri zed by a l ow s erum i ron, a hi gh t ot al i ron-bi ndi ng capaci t y, and a l ow ferri t i n l evel . The normal PT and PTT make a bleedi ng di at hes i s unl i kel y. Anemi a of chroni c renal i ns uffi ci ency woul d be rul ed out by t he normal BUN and creat i ni ne l evel s . The mos t l i kel y caus es of t hi s pat i ent 's probl em are t hos e i nvol vi ng chroni c gas t roi nt es t i nal bl ood l os s (i .e., col oni c pol yp, col oni c

Pa g e 3 1 6 8


neopl as m, or angi odys pl as i a). Of part i cul ar concern i s col oni c neopl as m, i n l i ght of t he pat i ent 's recent hi s t ory of a change i n bowel habi t s (cons t i pat i on). Immedi at e management goal s i ncl ude fl ui d repl acement , correct i ng hypovol emi a i f pres ent , moni t ori ng s eri al hemogl obi n and hemat ocri t val ues t o be cert ai n t he pat i ent does not have ongoi ng bl eedi ng, arres t i ng any act i ve hemorrhage, and prevent i ng recurrent hemorrhage. T he gastroenterologist arranges for a colonoscopy. During the colonoscopy, several polyps are noted in the descending portion of the colon. T he polyps are 1â€“2 cm in size, and most are pedunculated. T hese lesions are removed by snare cautery and sent to pathology for evaluation.

Questions 



What ot her proc edures c oul d have been us ed t o i nves t i gat e t hi s probl em?





Why w as c ol onos c opy us eful i n t hi s c as e?





What w oul d have prevent ed c ol onos c opy from bei ng a us eful di agnos t i c t ool ?

Discussion If bl eedi ng were act i ve and profus e, a t echnet i um-l abel ed RBC s can, angi ography, or bot h coul d l ocat e a bl eedi ng s ource, es peci al l y i f t he bl ood l os s exceeded 0.2â€“1.0 mL/mi n. Col onos copy i s t he t es t of choi ce i n t hi s s i t uat i on, becaus e i t can be bot h di agnos t i c and t herapeut i c i f a col oni c pol yp i s di s covered. If unavai l abl e, fl exi bl e s i gmoi dos copy and hi gh-qual i t y ai r cont ras t bari um enema woul d have been an accept abl e means of eval uat i ng t he col on. In t hi s pat i ent , col onos copy was us eful becaus e t here was no

Pa g e 3 1 6 9


act i ve bl eedi ng t o l i mi t t ot al exami nat i on of t he col oni c mucos a. However, i f t he bowel l umen had been coat ed wi t h bl ood, a s mal l pol yp or art eri ovenous mal format i on coul d have been mi s s ed. Al s o, i f hemodynami c i ns t abi l i t y makes t he pat i ent a poor candi dat e for adequat e s edat i on, a t horough eval uat i on of t he col on may not be pos s i bl e. Pathology indicates villous adenomatous polyps with no foci of carcinoma. T he patient is reassured, treated with iron supplements, and told to return in 1 year for a follow-up colonoscopy. If unremarkable, a repeat colonoscopy at 3â€“5 years would be indicated.

Questions 



What fac t ors about pol yps i nc reas e t he ri s k of adenoc arc i noma?





What w oul d t he t reat ment have been i f foc i of mal i gnant c el l s had been found?

Discussion Adenomat ous and vi l l ous adenomat ous pol yps are cons i dered precurs ors for adenocarci noma. The ri s k of adenocarci noma i n pat i ent s wi t h col oni c pol yps i ncreas es i n proport i on t o t he amount of vi l l ous t i s s ue pres ent i n t he pol yp. Pol yps t hat are s es s i l e or great er t han 2 cm i n di amet er al s o carry an i ncreas ed ri s k for devel opi ng i nt o carci noma. Management of a mal i gnant focus i n a col oni c pol yp depends on t he t ype of pol yp. If a pol yp i s peduncul at ed on a l ong s t al k and t he mal i gnant cel l s have not i nvaded t he s t al k, t he pat i ent coul d be cured by s i mpl e col onos copi c pol ypect omy. However, i f t he mal i gnant cel l s have i nvaded t he s t al k, or i f t he pol yp i s s es s i l e and t he mal i gnant cel l s reach t he margi ns of res ect i on, t he pat i ent woul d requi re a s egment al col oni c res ect i on. In ei t her cas e, fol l ow-up col onos copy i s i ndi cat ed on a peri odi c bas i s i n pat i ent s who have adenomat ous

Pa g e 3 1 7 0


col oni c pol yps , or i f a mal i gnancy i s i dent i fi ed i n any s uch l es i ons . P.640

Case 13 HIV Infection A 37-year-old man, who was diagnosed with human immunodeficiency virus type 1 (HIV-1) infection 8 years ago presents to the emergency department with a one month history of headaches and mild confusion, with worsening symptoms, and increasing photophobia. He has experienced good overall health since diagnosis despite a steady decline in his CD4 count. He cannot recall his most recent CD4 count, but thinks it was about 3

200 cells/mm 1 year ago. He had been treated with various combinations of antiretroviral therapy (ART ), but had never achieved viral suppression due to poor adherence. He finally stopped ART completely due to intolerable side effects, and had not been back to clinic in the past 9 months. Imaging studies and spinal fluid analysis confirmed the diagnosis of cryptococcal meningitis, and the patient responded well to antifungal therapy. His CD4 count was found to be 36 cells/mm

3

and viral load is >100,000 copies/mL. He returns to clinic for follow-up, and after reviewing the risks and benefits of ART , with emphasis placed on the need to strict adherence to taking his medications regularly, he agrees to resume ART .

Questions 



What i s t he val ue of t he CD4 c ount i n moni t ori ng pat i ent s w ho are i nfec t ed w i t h HI V-1?





What are t he major neurol ogi c probl ems enc ount ered i n peopl e w i t h HI V-1 i nfec t i on?

Pa g e 3 1 7 1




Di s c us s t he i mport anc e of adherenc e t o ART and t he c ons equenc e of poor adherenc e?

Discussion Meas uri ng CD4 count and HIV-1 RNA l evel s (referred t o as â€œvi ral l oadâ€•) have become s t andard met hods of moni t ori ng HIV-1 i nfect ed pat i ent s over t i me. The t wo paramet ers , CD4 and vi ral l oad, refl ect di s t i nct as pect s of t he pat i ent 's cl i ni cal s t at us . CD4 i s an i ndex of t he current s t at e of t he i mmune s ys t em, and i n t he nat ural cours e of i nfect i on, wi t hout ant i ret rovi ral t reat ment , t he 3

CD4 count wi l l decl i ne, at an average rat e of 50 cel l s /mm per year (t he rat e of decl i ne oft en accel erat es wi t h advanced di s eas e). As t he CD4 count fal l s bel ow cert ai n t hres hol ds , t he pat i ent 's ri s k for cert ai n opport uni s t i c i nfect i ons (OIs ) i ncreas es â€”for i ns t ance, 3

bel ow 200 cel l s /mm t he ri s k of devel opi ng Pneumoc ys t i s c ari ni i pneumoni a (PCP) i ncreas es markedl y, and prophyl axi s s houl d be i ni t i at ed. In cont ras t , t he vi ral l oad meas ures ongoi ng repl i cat i on of t he vi rus , and predi ct s t he rat e of progres s i on of di s eas e (t he hi gher t he vi ral l oad, t he more rapi dl y t he CD4 count wi l l decl i ne over t i me), and i s mos t commonl y us ed t o moni t or t he s ucces s of ART. The goal of ART i s s uppres s i on of vi ral repl i cat i on t o bel ow t he l evel of det ect i on on s ens i t i ve vi ral RNA as s ays (us ual l y t o t he l evel of

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