Gastroparesis: Pathophysiology, Presentation and Treatment (Clinical Gastroenterology)

CLINICAL GASTROENTEROLOGY Series Editor George Y. Wu University of Connecticut Health Center, Farmington, CT, USA For...

Author: Henry P. Parkman | Richard W. McCallum

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CLINICAL GASTROENTEROLOGY

Series Editor George Y. Wu University of Connecticut Health Center, Farmington, CT, USA

For further volumes: http://www.springer.com/series/7672

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(ENRY00ARKMAN s 2ICHARD7-C#ALLUM Editors

Gastroparesis Pathophysiology, Presentation and Treatment

Editors (ENRY00ARKMAN -$ Gastroenterology Section 4EMPLE5NIVERSITY3CHOOLOF-EDICINE Philadelphia, Pennsylvania, USA [email protected]

2ICHARD7-C#ALLUM -$ )NTERNAL-EDICINE$EPARTMENT Texas Tech University Health Sciences Center 0AUL,&OSTER3CHOOLOF-EDICINE El Paso, Texas, USA 2ICHARDMCCALLUM TTUHSCEDU

ISBN 978-1-60761-551-4 e-ISBN 978-1-60761-552-1 $/) 3PRINGER.EW9ORK$ORDRECHT(EIDELBERG,ONDON ,IBRARYOF#ONGRESS#ONTROL.UMBER Ú3PRINGER3CIENCE"USINESS-EDIA ,,# !LL RIGHTS RESERVED 4HIS WORK MAY NOT BE TRANSLATED OR COPIED IN WHOLE OR IN PART WITHOUT THE WRITTEN PERMISSIONOFTHEPUBLISHER(UMANA0RESS CO3PRINGER3CIENCE"USINESS-EDIA ,,# 3PRING3TREET .EW9ORK .9 53! EXCEPTFORBRIEFEXCERPTSINCONNECTIONWITHREVIEWSORSCHOLARLYANALYSIS Use in connection with any form of information storage and retrieval, electronic adaptation, computer SOFTWARE ORBYSIMILARORDISSIMILARMETHODOLOGYNOWKNOWNORHEREAFTERDEVELOPEDISFORBIDDEN 4HEUSEINTHISPUBLICATIONOFTRADENAMES TRADEMARKS SERVICEMARKS ANDSIMILARTERMS EVENIFTHEYARE NOTIDENTIlEDASSUCH ISNOTTOBETAKENASANEXPRESSIONOFOPINIONASTOWHETHERORNOTTHEYARESUBJECT to proprietary rights. 7HILETHEADVICEANDINFORMATIONINTHISBOOKAREBELIEVEDTOBETRUEANDACCURATEATTHEDATEOFGOINGTO PRESS NEITHERTHEAUTHORSNORTHEEDITORSNORTHEPUBLISHERCANACCEPTANYLEGALRESPONSIBILITYFORANY ERRORSOROMISSIONSTHATMAYBEMADE4HEPUBLISHERMAKESNOWARRANTY EXPRESSORIMPLIED WITHRESPECT to the material contained herein. Printed on acid-free paper (UMANA0RESSISPARTOF3PRINGER3CIENCE"USINESS-EDIAWWWSPRINGERCOM

Preface

'ASTROPARESISHASBECOMEAWELL RECOGNIZEDGASTROINTESTINALDISORDER0ATIENTSWITH GASTROPARESIS CAN BE PARTICULARLY CHALLENGING THE DISORDER HAS LIMITED TREATMENTS THATAREEFFECTIVEINREDUCINGSYMPTOMSANDORARE&$!APPROVEDFORUSEINTHIS CONDITION4HEREALSOAPPEARSTOBEANINCREASINGNUMBEROFPATIENTSBEINGDIAGnosed with this condition, either due to increased recognition of this disorder, or POSSIBLY DUE TO AN INCREASED PREVALENCE OF THE DISORDER /NE CONTRIBUTION TO THIS OBSERVATIONISDUETOTHEINCREASEOFDIABETESINTHEGENERALPOPULATION4HEREARE OFTENMANYAREASOFTREATMENTTOADDRESSWITHTHESEPATIENTS-ANYTYPESOFHEALTH care providers may need to care for these patients, including gastroenterologists, nutritionists, endocrinologists, internists, pain management specialists, psychiatrists, ANDSURGEONS&ORTUNATELY GASTROPARESISISBEINGINCREASINGLYSTUDIEDOVERTHELAST decade from a variety of areas with a marked increase in information on gastric MOTILITY AND GASTROPARESIS 4HIS IS AN IDEAL TIME TO DEVELOP A BOOK ON THE MANY aspects of gastroparesis. 4HISBOOKREVIEWSTHEEPIDEMIOLOGY PATHOPHYSIOLOGY SYMPTOMATICPRESENTATION DIAGNOSIS AND TREATMENTS FOR GASTROPARESIS 4HIS BOOK DISCUSSES WHAT IS CURRENTLY KNOWNABOUTTHISDISORDER POINTINGOUTAREASOFCONTROVERSY DISCUSSINGUNMETNEEDS and areas for future research to help improve our understanding of gastroparesis. $ESPITETHEHIGHPREVALENCEOFGASTROPARESIS THEETIOLOGYANDPATHOPHYSIOLOGY of this heterogeneous disorder remain incompletely understood. Why does this disORDEROCCURMOREOFTENINWOMENnNOTONLYFORIDIOPATHICGASTROPARESIS BUTALSO FORDIABETICANDPOSTSURGICALGASTROPARESIS3YMPTOMSCANBEVARIEDINTHISCONDITION n SOME PRESENT WITH ABDOMINAL FULLNESS SOME WITH NAUSEA AND OTHERS WITH ABDOMINALDISCOMFORTORPAIN7HYDOSOMEPATIENTSHAVEABDOMINALDISCOMFORT OREVENPAIN(OWSHOULDABDOMINALPAINBETREATEDINTHESEPATIENTSINWHOMONE wants to avoid medications that can affect gastric emptying or cause new symptoms ASSIDEEFFECTS/URKNOWLEDGEANDUNDERSTANDINGOFWHATISKNOWN ASWELLASTHE CHALLENGESINTREATMENT ARETHOROUGHLYBROUGHTTOLIGHTBYTHEAUTHORSWHOADDRESS THESEASPECTSOFGASTROPARESISINTHISBOOK

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Preface

$IAGNOSIS OF GASTROPARESIS ENTAILS DEMONSTRATING DELAYED GASTRIC EMPTYING 3YMPTOMSOFGASTROPARESISCANBEMILDLYCORRELATEDWITHGASTRICRETENTION4HREE TESTS ARE CLINICALLY AVAILABLE FOR DEMONSTRATING DELAYED GASTRIC EMPTYING GASTRIC EMPTYINGSCINTIGRAPHY WIRELESSMOTILITYCAPSULE ANDGASTRICEMPTYINGBREATHTESTING'ASTRICEMPTYINGSCINTIGRAPHYHASBECOMESTANDARDIZEDINTOAHIMAGINGTEST However, many centers are reluctant to perform a 4 h scintigraphy study due to the investment in manpower and use of dedicated imaging facilities. How a shorter test impacts on diagnosis and treatment of patients is not clear. Gastric emptying occurs WITHPROXIMALGASTRICACCOMMODATIONFOLLOWEDBYANTRALCONTRACTILITYANDPYLORIC RELAXATION$OESASSESSMENTOFREGIONALGASTRICMOTILITYIMPROVETHEEVALUATIONAND MANAGEMENTOFTHEPATIENTS7IRELESSMOTILITYCAPSULEMEASURESGASTRICEMPTYING OFANINDIGESTIBLECAPSULE4HETESTPROVIDESINFORMATIONALSOONGASTRICCONTRACTILITY and information on whole gut transit. In some patients with gastroparesis, there are ABNORMALITIESINWHOLEGUTTRANSIT SUGGESTINGAMOREDIFFUSEPROCESS&INALLY GASTRICEMPTYINGBREATHTESTINGHASBEENUSEDINMANYCLINICALRESEARCHSTUDIES ANDIS UNDERGOINGTHE&$!APPROVALPROCESSFORUSEASANOFlCE BASEDCLINICALTEST!LL THESE DIAGNOSTIC OPTIONS THE PROS AND CONS ARE EXTENSIVELY AND OBJECTIVELY PRESENTEDANDDISCUSSEDINTHISBOOKBYEXPERTCONTRIBUTORS Treatment of gastroparesis is generally with dietary modification, prokinetic agents to gastric emptying, and antiemetic agents to reduce nausea and vomiting. Unfortunately, at the present time, there is a paucity of agents to treat gastroparesis. -ETOCLOPRAMIDEHASBEENUSEDFORSEVERALDECADES3IDEEFFECTS PRIMARILYINVOLVING the central nervous system, can occur in patients, necessitating to stop this treatment. 2ECENTLY THE&$!ISSUEDAWARNINGABOUTTHELONG TERMSIDEEFFECTSOFMETOCLOPRAMIDE PARTICULARLYTARDIVEDYSKINESIA4HEANTIBIOTICERYTHROMYCIN WHICHISALSOA MOTILINRECEPTORAGONIST HASBEENSHOWNTOINCREASEGASTRICEMPTYING(OWEVER THE prokinetic effects of erythromycin reduce over time due to receptor tolerance. The serotonin 5-HT4RECEPTORAGONISTS CISAPRIDEANDTEGASEROD WEREUSEDOFFLABELTO treat gastroparesis until they were pulled from the market. It is apparent that new PROKINETICAGENTSARENEEDEDTOTREATGASTROPARESIS(OWEVER ITHASBEENDIFlCULTTO ESTABLISH SYMPTOMATIC BENElT WITH PROKINETIC DRUGS IN GASTROPARESIS POSSIBLY BECAUSE OF THE PATHOPHYSIOLOGICAL HETEROGENEITY OF THE PATIENTS THE INCONSISTENT RELATIONSHIPSBETWEENCHANGESINMOTORFUNCTIONMEASUREDBYVARIABLEANDOFTEN NONSTANDARDIZEDMETHODSANDSYMPTOMATICOUTCOME ANDALACKOFWELL ACCEPTED SYMPTOMENDPOINTSFORCLINICALTRIALS-ANYEXPERIENCEDCLINICIANSAREUSINGDOMPERIDONEFORGASTROPARESIS ANAGENTAPPROVEDINMANYCOUNTRIESBUTNOTTHE53! THROUGHTHE&$!).$PROCESS4HERAPEUTICOPTIONS ASWELLASSURGICALSOLUTIONS AREEXTENSIVELYREVIEWEDBYEXPERTSWHOAREPRACTICINGGASTROENTEROLOGISTSFACING the challenges of managing gastroparesis every day in their practices as well as performing cutting edge clinical research. 4HEREHAVEBEENSEVERALORGANIZATIONSBEHINDADVANCINGTHElELDOFGASTROPAREsis, for which the authors appreciate their role in increasing our understanding of GASTROPARESISTHE!MERICAN.EUROGASTROENTEROLOGYAND-OTILITY3OCIETY!.-3 ANDTHE.)('ASTROPARESIS#LINICAL2ESEARCH#ONSORTIUM 4HE!.-3HASBEENPARTICULARLYACTIVEINTHElELDOFGASTROPARESISSINCEITISA RELATIVELYCOMMONDISORDEROFGASTROINTESTINALMOTILITY4HE!.-3HASHADASERIES

Preface

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of conferences and consensus manuscripts on gastroparesis. A clinical review was PUBLISHEDINONTHETREATMENTOFPATIENTSWITHGASTROPARESIS4HISWASAMULTIDISCIPLINARYEFFORTLEDBYTHE!.-3WITHINPUTFROMGASTROENTEROLOGISTSANDOTHER specialists who are involved in the care of patients with gastroparesis. A consensus DOCUMENT WAS DEVELOPED BY MEMBERS OF THE !.-3 AND THE 3OCIETY OF .UCLEAR -EDICINERECOMMENDINGASTANDARDIZEDMETHODFORMEASURINGGASTRICEMPTYINGBY scintigraphy using a low-fat, egg white meal with imaging at 0, 1, 2, 4 h after meal INGESTION WHICH PROVIDES STANDARDIZED INFORMATION ABOUT NORMAL RAPID AND DELAYEDGASTRICEMPTYING!DOPTIONOFTHISSTANDARDIZEDPROTOCOLWILLHELPRESOLVE THELACKOFUNIFORMITYOFTESTING ADDRELIABILITYANDCREDIBILITYTOTHERESULTS AND improve the clinical utility of the gastric emptying test. The proceedings from a CONFERENCESPONSOREDBYTHE!MERICAN'ASTROENTEROLOGICAL!SSOCIATIONAND THE!.-3REVIEWEDTHEADVANCESINTHEUNDERSTANDINGOFTHEEPIDEMIOLOGY PATHO physiology, diagnosis, and treatment of gastroparesis and functional dyspepsia. The !.-3ALSODEVELOPEDATASKFORCEFORGASTROPARESISENDPOINTSFORCLINICALTRIALS )NTHISINITIATIVE THE!.-3HELPEDCONVERTASYMPTOMQUESTIONNAIREFORGASTROPARESISINTOADAILYDIARYVERSION WHICHAPPEARSTOBEAUSEFULOUTCOMEENDPOINTFOR GASTROPARESISCLINICALTRIALS4HISVALIDATIONHASBECOMENECESSARYASAPRELUDEFOR NEWDRUGAPPLICATIONSTOTHE&OODAND$RUG!DMINISTRATION 4HE.)('ASTROPARESIS#LINICAL2ESEARCH#ONSORTIUM'P#2# ISACOOPERATIVE NETWORKOFSEVENCLINICALCENTERSANDA$ATA#OORDINATING#ENTERFUNDEDTHROUGH THE.ATIONAL)NSTITUTEOF$IABETESAND$IGESTIVEAND+IDNEY$ISEASESOFTHE.ATIONAL )NSTITUTESOF(EALTH4HEMISSIONOFTHE'P#2#ISTOIMPROVETHEUNDERSTANDINGOF GASTROPARESISBYCONDUCTINGMULTICENTER OBSERVATIONALSTUDIESONWELL CHARACTERIZED patients with gastroparesis. The studies emanating from the consortium involve a LARGENUMBEROFPATIENTS WHICHWILLBETTERDElNETHEDISORDERS3TUDIESHAVEBEEN DEVELOPEDFORIDIOPATHICGASTROPARESIS DIABETICGASTROPARESIS ANDTHECOMPARISON BETWEENTHETWOTYPESOFGASTROPARESIS0ATHOLOGICSTUDIESHAVERECENTLYBEENPUBLISHEDSHOWINGREDUCTIONSINTHEINTERSTITIALCELLSOF#AJALANDANINmAMMATORYINlLTRATE IN THE MYENTERIC PLEXUS ! WEALTH OF INFORMATION IS BEING EVALUATED ON THE clinical course of patients with gastroparesis. 4HISBOOK THElRSTTOFOCUSONTHEMANYASPECTSOFGASTROPARESISTHATHASBEEN PUBLISHEDOVERTHERECENTYEARS PROVIDESACOMPREHENSIVEREVIEWANDINDEPTHCRITIcal distilling of our knowledge, covering important areas for physicians, nutritionISTS NURSES ANDPARAMEDICALSTAFFASWELLASCLINICALINVESTIGATORSANDBASICSCIENTISTS INTERESTEDINTHISDISORDER%ACHCHAPTERHASBEENWRITTENBYANEXPERTINTHEAREA SPECIlCALLYSELECTEDBECAUSETHEYARERECOGNIZEDASNATIONALANDINTERNATIONALLEADers. This exhaustive test will place the reader at the cutting edge of the field and PREPARE THEM FOR FUTURE ADVANCES WHILE PERMITTING THIS KNOWLEDGE TO BE DIRECTLY applied to their patients suffering with gastroparesis. Philadelphia, PA %L0ASO 48

Henry P. Parkman 2ICHARD7-C#ALLUM

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Contents

1

Historical Perspectives on Gastric Motility ......................................... 2ICHARD7-C#ALLUM

1

2

Epidemiology of Gastroparesis ............................................................. "AHA-OSHIREE 3TEVEN"OLLIPO -ICHAEL(OROWITZ and Nicholas J. Talley

11

3

Clinical Presentations of Gastroparesis ............................................... 3HILPA#2EDDYAND*OHN-7O

25

4

Gastric Dysmotility at the Organ Level in Gastroparesis .................. -ICHAEL#AMILLERIAND-ARIA)6AZQUEZ 2OQUE

5

Cellular Pathogenesis of Gastroparesis................................................ 4AMAS/RDOG

47

6

Sensory Dysfunction in Gastroparesis ................................................. Jan Tack and Pieter Janssen

65

7

Pathology of Gastroparesis.................................................................... !MOL3HARMAAND2EBECCA4HOMAS

8

Natural History of Patients with Gastroparesis .................................. 2EZA!(EJAZI (ENRY00ARKMAN AND2ICHARD7-C#ALLUM

87

9

Gastric Emptying Scintigraphy ............................................................ !LAN(-AURER

97

10

Wireless Motility Capsule in Gastroparesis ........................................ 2ITA"RUNAND"RADEN+UO

11

Breath Tests for Assessment of Gastric Emptying .............................. (ENRY00ARKMANAND,AWRENCE!3ZARKA

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Contents

12

Ultrasonography for Evaluation of Patients with Suspected Gastroparesis ............................................................... +AREN,*ONES $IANA'ENTILCORE 4RYGVE(AUSKEN AND/DD(ELGE'ILJA

13

Magnetic Resonance Imaging for Gastric Motility............................. !DIL%"HARUCHAAND2OGER#'RIMM

14

Electrogastrography for Evaluation of Patients with Suspected Gastroparesis ............................................................... +ENNETH,+OCH

15

Antroduodenal Manometry for the Evaluation of Patients with Suspected Gastroparesis ............................................................... William J. Snape, Jr.

16

Diabetic Gastroparesis ........................................................................... #HRISTOPHER+2AYNER +AREN,*ONES AND-ICHAEL(OROWITZ

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17

Postsurgical Gastroparesis .................................................................... 2EZA!(EJAZI (ENRY00ARKMAN AND2ICHARD7-C#ALLUM

191

18

Idiopathic Gastroparesis ....................................................................... Linda Nguyen

205

19

Gastroparesis from Other Causes ........................................................ !LIA$ADABHAIAND2OBERT3&ISHER

20

Pediatric Gastroparesis ......................................................................... -IGUEL3APSAND#ARLO$I,ORENZO

21

Dietary Treatment for Gastroparesis ................................................... &RANK$UFFY

22

Prokinetic Agents for Gastroparesis .................................................... Henry P. Parkman

257

23

Antiemetic Treatment for Gastroparesis ............................................. William L. Hasler

279

24

Pain Management for Gastroparesis .................................................... Henry P. Parkman

289

25

Psychiatric Aspects of Gastroparesis ................................................... .ATALIA/RTIZ 4ORRENT

26

Sensory Neuromodulators in Disorders with Delayed Gastric Emptying ................................................................................... Gregory S. Sayuk and C. Prakash Gyawali

27

Alternative and Complementary Medicine for Gastroparesis ........... *EANNE!$RISKO

225

Contents

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28

Small Bowel Access for Jejunostomy Tube Feedings in Gastroparesis...................................................................................... -ARK($E,EGGE

29

Gastric Electrical Stimulation for Gastroparesis ................................ *IANDE$:#HEN *IEYUN9IN AND2ICHARD-C#ALLUM

30

The GI Surgeon and Gastroparesis ...................................................... 3EAN0(ARBISON

31

Endoscopic Full-Thickness Gastric Biopsy for Evaluation of Patients ............................................................................................... 2UKSHANA.#ADER -OUEN!+HASHAB AND!NTHONY.+ALLOO

32

A Brief History and Future Directions for Permanent, Temporary, and Endoscopic GES......................................................... 3UMANTH$ARAMAND4HOMAS,!BELL

33

Cell Transplantation for Gastroparesis................................................ ,AREN"ECKERAND0ANKAJ*0ASRICHA

405

Index ................................................................................................................

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Contributors

Thomas L. Abell, MD 0ROFESSORAND#HIEF $IVISIONOF$IGESTIVE$ISEASES 5NIVERSITYOF-ISSISSIPPI-EDICAL#ENTER *ACKSON -) 53! Laren Becker, MD, PhD Instructor in Gastroenterology, $EPARTMENTOF-EDICINE 3TANFORD-EDICAL#ENTER 3TANFORD #! 53! Adil E. Bharucha, MBBS, MD 0ROFESSOROF-EDICINE #LINICALAND%NTERIC.EUROSCIENCE4RANSLATIONALAND%PIDEMIOLOGICAL2ESEARCH 0ROGRAM#%.4%2 -AYO#LINIC 2OCHESTER -. 53! Steven Bollipo, MBBS, FRACP $IRECTOROF'ASTROENTEROLOGYAND%NDOSCOPY John Hunter Hospital, Newcastle, NSW, Australia Rita Brun, MD !DVANCED')-OTILITY&ELLOW -ASSACHUSETTS'ENERAL(OSPITAL (ARVARD-EDICAL3CHOOL 'ASTROINTESTINAL5NIT "OSTON -! 53! Rukshana N. Cader, MB, BCh, BAO Fellow in Gastroenterology, $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF-EDICINE 4HE*OHNS(OPKINS(OSPITAL "ALTIMORE -$ 53! Michael Camilleri, MD Atherton and Winifred W. Bean Professor, 0ROFESSOROF-EDICINEAND0HYSIOLOGY #OLLEGEOF-EDICINE -AYO#LINIC 2OCHESTER -. 53! #ONSULTANT $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY -AYO#LINIC 2OCHESTER -. 53! Jiande D.Z. Chen, PhD 0ROFESSOROF-EDICINE $IVISIONOF'ASTROENTEROLOGY 5NIVERSITYOF4EXAS-EDICAL"RANCH 'ALVESTON 48 53! Alia Dadabhai, MD 'ASTROENTEROLOGY&ELLOW $EPARTMENTOF-EDICINE Temple University Hospital, Philadelphia, PA, USA Sumanth Daram, MD &ELLOW $IVISIONOF$IGESTIVE$ISEASES 5NIVERSITYOF-ISSISSIPPI-EDICAL#ENTER *ACKSON -) 53!

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#ONTRIBUTORS

Mark H. DeLegge, MD 0ROFESSOROF-EDICINE $IGESTIVE$ISEASE#ENTER -EDICAL5NIVERSITYOF3OUTH#AROLINA #HARLESTON 3# 53! Carlo Di Lorenzo, MD 0ROFESSOROF0EDIATRICS 4HE/HIO3TATE5NIVERSITY #OLUMBUS /( 53! #HIEF $IVISIONOF0EDIATRIC'ASTROENTEROLOGY .ATIONWIDE#HILDRENS(OSPITAL #OLUMBUS /( 53! Jeanne A. Drisko, MD, CNS 0ROFESSORAND$IRECTOR $EPARTMENTOF)NTEGRATIVE -EDICINE 5NIVERSITYOF+ANSAS-EDICAL#ENTER +ANSAS#ITY +3 53! Frank Duffy, RD 2EGISTERED$IETICIAN $EPARTMENTOF.UTRITION Temple University Hospital, Philadelphia, PA, USA Robert S. Fisher, MD $EPARTMENTOF-EDICINE 4EMPLE5NIVERSITY(OSPITAL Philadelphia, PA, USA #HIEF 'ASTROENTEROLOGY3ECTIONAND$IGESTIVE$ISEASE#ENTER Temple University Hospital, Philadelphia, PA, USA Diana Gentilcore, Dip App Sci (Nuc Med), Grad Dip Med Rad, PhD $IVISIONOF(EALTH3CIENCES 3CHOOLOF(EALTH3CIENCES University of South Australia, Adelaide, SA, Australia Odd Helge Gilja, MD, PhD 0ROFESSOR $EPARTMENTOF-EDICINE National Centre for Ultrasound in Gastroenterology, Haukeland University (OSPITAL )NSTITUTEOF-EDICINE 5NIVERSITYOF"ERGEN "ERGEN .ORWAY Roger C. Grimm, MS -22ESEARCH,ABORATORY -AYO#LINIC 2OCHESTER -. 53! C. Prakash Gyawali, MD, MRCP !SSOCIATE0ROFESSOROF-EDICINE $IVISIONOF'ASTROENTEROLOGY 7ASHINGTON5NIVERSITY3CHOOLOF-EDICINE 3T,OUIS -/ 53! Sean P. Harbison, MD $EPARTMENTOF3URGERY 4EMPLE5NIVERSITY 3CHOOLOF-EDICINE 0ARKINSON0AVILION 0HILADELPHIA 0! 53! William L. Hasler, MD 0ROFESSOR $IVISIONOF'ASTROENTEROLOGY 5NIVERSITYOF-ICHIGAN(EALTH3YSTEM !NN!RBOR -) 53! Trygve Hausken, MD, PhD Professor, Gastroenterology Section, National Centre for Ultrasound in Gastroenterology, Haukeland University (OSPITAL )NSTITUTEOF-EDICINE 5NIVERSITYOF"ERGEN "ERGEN .ORWAY Reza A. Hejazi, MD 0OST$OCTORAL2ESEARCH!SSOCIATE $EPARTMENTOF)NTERNAL -EDICINE 5NIVERSITY-EDICAL#ENTER 0AUL,&OSTER3CHOOLOF-EDICINE Texas Tech University Health Sciences Center, El Paso, TX, USA Michael Horowitz, MBBS, PhD 0ROFESSOR $ISCIPLINEOF-EDICINE 5NIVERSITYOF!DELAIDE 2OYAL!DELAIDE(OSPITAL !DELAIDE 3! !USTRALIA

#ONTRIBUTORS

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Pieter Janssen, PhD $EPARTMENTOF'ASTROENTEROLOGY 5:,EUVEN Leuven, Belgium Karen L. Jones, PhD !SSOCIATE0ROFESSOR $ISCIPLINEOF-EDICINE 5NIVERSITYOF!DELAIDE 2OYAL!DELAIDE(OSPITAL !DELAIDE 3! !USTRALIA Anthony N. Kalloo, MD 4HE-OSESAND(ELEN'OLDEN0AULSON0ROFESSOR OF'ASTROENTEROLOGY 4HE*OHNS(OPKINS(OSPITAL "ALTIMORE -$ 53! #HIEF $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF-EDICINE 4HE*OHNS(OPKINS(OSPITAL "ALTIMORE -$ 53! $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY 4HE*OHNS(OPKINS(OSPITAL "ALTIMORE -$ 53! Mouen A. Khashab, MD !SSISTANT0ROFESSOROF-EDICINE $IRECTOROF4HERAPEUTIC%NDOSCOPY $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF-EDICINE 4HE*OHNS(OPKINS(OSPITAL "ALTIMORE -$ 53! Kenneth L. Koch, MD 0ROFESSOROF-EDICINE#HIEF 3ECTIONON'ASTROENTEROLOGY $IRECTOR $IGESTIVE(EALTH#ENTER7AKE&OREST5NIVERSITY"APTIST-EDICAL#ENTER 7AKE&OREST5NIVERSITY3CHOOLOF-EDICINE 7INSTON 3ALEM .# 53! Braden Kuo, MD, MSc !SSISTANTIN-EDICINE $IRECTOROF')-OTILITY,ABORATORY -ASSACHUSETTS'ENERAL(OSPITAL(ARVARD-EDICAL3CHOOL 'ASTROINTESTINAL5NIT "OSTON -! 53! Alan H. Maurer, MD 0ROFESSOROF2ADIOLOGYAND)NTERNAL-EDICINE $EPARTMENTOF2ADIOLOGY 4EMPLE5NIVERSITY(OSPITAL 0HILADELPHIA 0! 53! Richard W. McCallum, MD )NTERNAL-EDICINE$EPARTMENT 4EXAS4ECH5NIVERSITY (EALTH3CIENCES#ENTER 0AUL,&OSTER3CHOOLOF-EDICINE %L0ASO 4EXAS 53! Baha Moshiree, MD, MS $IVISIONOF'ASTROENTEROLOGY (EPATOLOGY and Nutrition, University of Florida, Gainesville, FL, USA Linda Nguyen, MD #LINICAL!SSISTANT0ROFESSOR $EPARTMENTOF'ASTROENTEROLOGY and Hepatology, Stanford University, Palo Alto, CA, USA Tamas Ordog, MD Associate Professor, Senior Associate Consultant, %NTERIC.EUROSCIENCE0ROGRAMAND'ASTROENTEROLOGY2ESEARCH5NIT $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF0HYSIOLOGY AND"IOMEDICAL%NGINEERING -AYO#LINIC 2OCHESTER -. 53! Natalia Ortiz-Torrent, MD, FAPA Assistant Professor of Psychiatry, -EDICAL$IRECTOR #ONSULTATIONAND,IAISON0SYCHIATRY $EPARTMENTOF0SYCHIATRY 4EMPLE5NIVERSITY3CHOOLOF-EDICINE 0HILADELPHIA 0! 53! Henry P. Parkman, MD 'ASTROENTEROLOGY3ECTION $EPARTMENTOF-EDICINE Temple University Hospital, Philadelphia, Pennsylvania, USA Pankaj J. Pasricha, MD 0ROFESSOROF-EDICINE#HIEF $IVISIONOF'ASTROENTEROLOGY AND(EPATOLOGY $EPARTMENTOF-EDICINE 3TANFORD-EDICAL#ENTER 3TANFORD CA, USA

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#ONTRIBUTORS

Christopher K. Rayner, MBBS, PhD Associate Professor, $ISCIPLINEOF-EDICINE 2OYAL!DELAIDE(OSPITAL 5NIVERSITYOF!DELAIDE North Terrace, Adelaide, SA, Australia $EPARTMENTOF'ASTROENTEROLOGYAND(EPATOLOGY 2OYAL!DELAIDE(OSPITAL North Terrace, Adelaide, SA, Australia #ENTREOF#LINICAL2ESEARCH%XCELLENCEIN.UTRITIONAL0HYSIOLOGY )NTERVENTIONS AND/UTCOMES 5NIVERSITYOF!DELAIDE !DELAIDE 3! !USTRALIA Shilpa C. Reddy, DO 'ASTROENTEROLOGY&ELLOWAND0ROFESSOROF-EDICINE $IVISIONOF'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION 5NIVERSITYOF,OUISVILLE 3CHOOLOF-EDICINE ,OUISVILLE +9 53! Miguel Saps, MD $IRECTOR 'ASTROINTESTINAL-OTILITYAND&UNCTIONAL"OWEL $ISORDERS0ROGRAM!SSISTANT0ROFESSOROF0EDIATRICS .ORTHWESTERN5NIVERSITYS &EINBERG3CHOOLOF-EDICINE #HICAGO ), 53! $EPARTMENTOF'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION #HILDRENS-EMORIAL Hospital, Chicago, IL, USA Gregory S. Sayuk, MD, MPH !SSISTANT0ROFESSOROF-EDICINE $IVISIONOF'ASTROENTEROLOGY 7ASHINGTON5NIVERSITY3CHOOLOF-EDICINE 3T,OUIS -/ 53! Amol Sharma, MD, MS 2ESIDENT0HYSICIAN $EPARTMENTOF)NTERNAL-EDICINE Temple University Hospital, Philadelphia, PA, USA William J. Snape, Jr, MD $IRECTOR #ALIFORNIA0ACIlC-EDICAL#ENTER San Francisco, CA, USA Lawrence A. Szarka, MD $EPARTMENTOF'ASTROENTEROLOGY -AYO#LINIC 2OCHESTER -. 53! Jan Tack, MD, PhD 0ROFESSOROF-EDICINE $EPARTMENTOF'ASTROENTEROLOGY University Hospitals Leuven, Leuven, Belgium Nicholas J. Talley, MD, PhD Professor, Faculty of Health, University of Newcastle, Callaghan, NSW, Australia Rebecca Thomas, MBBS 0ROFESSORAND$IRECTOROF3URGICAL0ATHOLOGY $EPARTMENTOF0ATHOLOGYAND,ABORATORY-EDICINE 4EMPLE5NIVERSITY(OSPITAL Philadelphia, PA, USA Maria I. Vazquez-Roque, MD &ELLOW $IVISIONOF'ASTROENTEROLOGY AND(EPATOLOGY -AYO#LINIC 2OCHESTER -. 53! John M. Wo, MD 0ROFESSOROF-EDICINE $IVISIONOF'ASTROENTEROLOGY (EPATOLOGY 5NIVERSITYOF)NDIANA 3CHOOLOF-EDICINE )NDIANAPOLIS ). 53! Jieyun Yin, MD !SSISTANT0ROFESSOR $IVISIONOF'ASTROENTEROLOGY 5NIVERSITYOF4EXAS-EDICAL"RANCH 'ALVESTON 48 53!

Chapter 1

Historical Perspectives on Gastric Motility Richard W. McCallum

Keywords 'ASTROINTESTINALMOTILITYs%NTERICNERVOUSSYSTEMs'ASTRICEMPTYING s2ADIOGRAPHICTECHNIQUESs3CINTIGRAPHY

Introduction 4HERECORDING QUANTITATION ANDUNDERSTANDINGOFGUTMOTILITYHAVEBEENACONSTANT GOALDURINGTHELASTCENTURY PARTICULARLYTHESTUDYOFPERISTALTICCONTRACTIONS2EMARKABLE PROGRESSHASBEENMADEINTHESTUDYOFGASTROINTESTINAL') MOTILITY PARTICULARLY GASTRICMOTILITY4HISPROGRESSRESULTSFROMCONTRIBUTIONSOFAWIDERANGEOFDISCIPLINES WITH ADVANCES IN SMOOTH MUSCLE PHYSIOLOGY ELECTROPHYSIOLOGY NEUROHORMONALREGULATIONOFTHE')TRACT ANATOMICMECHANICALFACTORS mOWDYNAMICS ASWELL ASBASICMOLECULARANDCELLULARBIOLOGY)NCREASINGLYSOPHISTICATEDINSTRUMENTATION BIOMEDICAL ENGINEERING AND PHARMACEUTICAL RESEARCH HAVE ALSO ADDED TO THIS RICH HARVESTOVERTHEPASTYEARS!CENTRALTHEMETOTHEPROGRESSISTHEGREATERUNDERSTANDINGOFTHEENTERICNERVOUSSYSTEM WHEREMORETHAN6 neurons intercommuNICATEANDINTEGRATEMESSAGESFROMTHEGUTANDBRAINTOORGANIZEANDCOORDINATETHE CONTROLOF')MOTILITY 4HISCHAPTERPROVIDESAHISTORICALPERSPECTIVETOHELPUNDERSTANDHOWTHEPATH HASBEENTAKENTOARRIVEATOURPRESENTUNDERSTANDINGOFGASTRICMOTILITY

R.W. McCallum (*) $EPARTMENTOF)NTERNAL-EDICINE 5NIVERSITY-EDICAL#ENTER 4EXAS4ECH5NIVERSITY (EALTH3CIENCES#ENTER 0AUL,&OSTER3CHOOLOF-EDICINE %L0ASO 48 53! E MAIL2ICHARDMCCALLUM TTUHSCEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_1, © Springer Science+Business Media, LLC 2012

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R.W. McCallum

Measurement of Flow Through the Gastrointestinal Tract !SIDEFROM"EAUMONTSFAMOUSOPPORTUNITYINTHESINHISPATIENTWITHAGASTRIC fistula [1= NOONEHADANYWAYTOEXAMINEDIRECTLYTHEmOWOFTHEGUTUNTILMORE THANYEARSLATER"EAUMONTCOULDONLYMAKEACRUDEEVALUATIONOFGASTRICmOW BECAUSEHISPATIENTSlSTULAEXTENDEDINTOTHEFUNDUS ANDSO"EAUMONTSEXPERIMENTS ONmOWDEPENDEDONTHEMEASUREMENTSOFRESIDUALVOLUMESCOLLECTEDBYASPIRATION !LSO HEWASMOREINTERESTEDINGASTRICJUICEANDDIGESTIONTHANGASTRICEMPTYING 4HEGREATIMPETUSTOTHESTUDYOFmOWCAMEWITHTHEDEVELOPMENTOFTHE8 RAY TUBEATTHEENDOFTHENINETEENTHCENTURY2OENTGENSDEVELOPMENTOFTHECONCEPTS ANDMETHODSFOR8 RAYSOONFOUNDAPPLICATIONINTHESTUDYOFGASTROINTESTINALmOW 4HEPIONEERS "OWDITCHAND#ANNON EXAMINEDTHESTOMACHANDINTESTINEBYCONTRAST RADIOGRAPHYBEFORETHETURNOFTHECENTURY;2–4=#ANNONANDOTHERSWEREMAINLY INTERESTEDINGASTRICMOTILITYANDADOPTEDCONTRASTRADIOGRAPHYASANEWMEANSTO VISUALIZE PERISTALSIS AND mOW FROM THE STOMACH 0HYSICIANS SOON RECOGNIZED THE ABILITYOFCONTRASTRADIOGRAPHYTODEMONSTRATEMORPHOLOGICLESIONSINTHESTOMACH (URSTLEDTHISADVANCEINTHECLINICALUSEOFRADIOGRAPHY;5, 6=4HEUSEOFCONTRAST lLMSTOOBSERVEmOWEXTENDEDTOTHEOTHERORGANS INCLUDINGTHECOLON4HEBIGGEST PROBLEMINTHESTUDYOFmOWINTHESTOMACHANDINTESTINEWASTHENEEDFORRAPID CHANGESOFlLM WHICHWASRESOLVEDWHENRAPIDlLM CHARGERSANDCINERADIOGRAPHY WEREDEVELOPED "Y RADIOGRAPHICTECHNIQUESHADREVEALEDSOMUCHTHATANAUTHORITATIVETEXTBOOKCOULDBEWRITTENONTHEDIGESTIVETRACTFROMTHEPOINTOFVIEWOFTHERADIOLOGIST;7]. )TCONTAINEDEXTENSIVEDESCRIPTIONSOFmOWSINALLTHEORGANSASWELLASDESCRIPTIONS OFPERISTALTICWALLMOVEMENTSANDMORPHOLOGICABNORMALITIES4HEDESCRIPTIONSSTILL APPEARQUITEMODERNTOTHECONTEMPORARYREADER /BSERVATIONS BY CONTRAST RADIOGRAPHY ARE HARD TO QUANTIFY CANNOT EASILY BE REPEATEDFORVERIlCATION AREUSUALLYPERFORMEDWITHTHESUBJECTFASTING ANDUSEA REMARKABLYUNPHYSIOLOGICMATERIAL4HESEPROBLEMSOFRADIOGRAPHYTODEMONSTRATE MOTILITYWEREOVERCOMEWITHTHEDEVELOPMENTOFSCINTIGRAPHYINTHES WHERE PHYSIOLOGIC MEALS ARE RADIOLABELED ;8= 3CINTIGRAPHY MADE IT FEASIBLE TO PERFORM mOWSTUDIESINROUTINECLINICALPRACTICEANDMADEmOWSTUDYMORESENSITIVE "EFORETHEADVENTOFSCINTIGRAPHY (UNTHADDEVELOPEDABEAUTIFULLYSIMPLEAND DIRECTMETHODTOADVANCEUNDERSTANDINGOFGASTRICEMPTYING ESPECIALLYOFITSREGUlation [9=(EUSEDTESTMEALSnLIQUIDVOLUMESOFVARIABLECOMPOSITIONnPASSED THROUGHANASOGASTRICTUBEINVARIOUSVOLUMESANDASPIRATEDATVARIABLETIMESAFTERWARDTODISCOVERTHERESIDUALVOLUME(EUSEDANESTHETIZEDHUMANSUBJECTS STUDYING THESAMESUBJECTSREPEATEDLYBECAUSEHABITUATIONELIMINATESTHEINHIBITIONPRODUCED BYANXIETY4HUS HEWASABLETODEVELOPDATAFORTHERATEOFGASTRICEMPTYINGASITIS REGULATEDBYMEALCOMPOSITION;10]. -OSTDISCUSSIONSOFmOWINTHEGUTHAVEDEALTWITHBULKmOWSnTHEMASSTRANSLOCATIONSOFmUID)NTERESTINMICROmOWSCAMEABOUTFROMTHEORETICCONSIDERATIONSOF INTESTINAL ABSORPTION IN WHICH THE PRESENCE OF AN UNSTIRRED LAYER AT THE LUMINAL SURFACEOFTHEINTESTINECAMETOBERECOGNIZEDASALIMITATIONTOTHERATEOFABSORPTION ,ITTLECANBEDONETOSTUDYMICROmOWSDIRECTLY BECAUSEITREQUIRESTHEUSEOFTHE

(ISTORICAL0ERSPECTIVESON'ASTRIC-OTILITY

PRINCIPLESOFmUIDMECHANICS ADISCIPLINETHATISLARGELYASFOREIGNTOGASTROINTESTINAL PHYSIOLOGISTSASGASTROINTESTINALPHYSIOLOGYISTOmUID MECHANISTS4HEmUIDMECHANICIST -ECAGNO WHOHADEXTENSIVEEXPERIENCEONmOWINRIVERSANDSEAS WASCURIOUS ABOUTmOWINASYSTEMTHATSEEMEDUNIQUETOHIM!mUID MECHANICALAPPROACHTO mOWINTHESMALLINTESTINEBY#HRISTENSENAND-ACAGNOYIELDEDAFOUNDATIONFORA RIGOROUSRHEOLOGICSTUDYOFGASTROINTESTINALMICROmOWANDAHOSTOFNEWMETHODS ANDIDEASINTHES;11= ANAREATHATREMAINSTOBEEXPLOITEDMOREFULLY

Measurement of Pressures in the Gastrointestinal Tract 4HEIDEATHATONECOULDSTUDYWALLMOTIONSBYTHEMEASUREMENTOFPRESSURESINTHE GUTLUMEN BYKYMOGRAPHYORMANOMETRY ASITCAMETOBECALLEDLATER AROSEQUITE EARLY EVENBEFORETHEDEVELOPMENTOFRADIOGRAPHICMETHODSTOSTUDYmOW)TBEGAN LARGELYWITHTHEUSEOFBALLOONSINmATEDINTHESTOMACHANDINTESTINE AMETHODUSED NOTABLYBY"AYLISSAND3TARLING;12], Carlson [1= AND4HOMAS;14= AMONGOTHERS )NVESTIGATORSCOULDRECORDPRESSURECHANGESINSUCHBALLOONSEASILYENOUGH BUTTHEY HADMUCHTROUBLEINTERPRETINGTHERECORDS4HEYSLOWLYCAMETOCONFRONTTHEPROBLEMSOFBALLOONRECORDING WHICHSEEMSOOBVIOUSTOUSTODAY4HESIZEOFTHEBALLOON DEGREETOWHICHITSTRETCHESTHEVISCOUSWALL THECOMPRESSIBILITYOFTHERECORDING mUID ANDTHECOMPLIANCEOFTHESYSTEMALLRESTRICTTHERELIABILITYOFCONCLUSIONSABOUT THEEXTERNALFORCESTHATALTERTHEPRESSUREINSUCHACLOSEDRECORDINGSYSTEM 4HEIDEAOFUSINGOPEN TIPCATHETERSRATHERTHANBALLOONSTORECORDPRESSURESWAS EXPLOREDINTHES BUTITWASMOSTAGGRESSIVELYDEVELOPEDINTHESMAINLY TOEXAMINETHEESOPHAGUS4HEPRINCIPALPLAYERSINTHISDEVELOPMENT WHICHINCLUDED Code [15=AND)NGELlNGER PROBABLYSOUGHT ATTHEOUTSET SIMPLYTOMEASUREPRESSURESRATHERTHANTOFULLYMAPPERISTALTICMOVEMENTS!TlRST THEYUSEDAIR lLLED CATHETERS LATERCHANGINGTOWATER lLLEDTUBES4HEYADOPTEDCATHETERSWITHDISTAL OPENINGSPLACEDLATERALLYRATHERTHANATTHETIPOFTHECATHETERSANDOBSERVEDTHAT IN THEESOPHAGUS THEYCOULDMEASURETHECHARACTERISTICSOFPERISTALSISnVELOCITYAND FORCEOFCONTRACTIONnWITHAPPARENTREPRODUCIBILITYANDACCURACY4HEMETHODWAS SOONIMPROVEDBY$ODDS;16=AND(OGANANDMANYOTHERSWITHTHEINTRODUCTIONOF THECONTINUOUSPERFUSIONOFTHECATHETERSWITHALOW COMPLIANCEPUMPTHE!RNDORFER PUMP DEVELOPEDBYACOLLEAGUEOF$ODDS ANDOTHERCHANGES ANDTHETECHNIQUE SOONPASSEDINTOSTANDARDCLINICALUSETODESCRIBEESOPHAGEALMOTORFUNCTIONS4HE TECHNIQUESUBSEQUENTLYHASFOUNDUSEINTHESMALLINTESTINE BUTUSEDMUCHLESSIN THESTOMACHANDCOLON3UBSEQUENTEXPERIMENTATIONWITHMETHODSLEDTODEVELOPMENTSOFMUCHMORECOMPLEXDEVICESINWHICHPRESSURESAREMEASUREDFROMMINIATUREPRESSURETRANSDUCERSMOUNTEDONmEXIBLECATHETERS4HESEDEVICES COMBINED WITHCOMPUTER AIDEDANALYSISOFPRESSUREPATTERNS NOWPROVIDEOBJECTIVELONG TERM HIGHRESOLUTIONMONITORINGOFMOTILITYINTHESTOMACHANDDISTALLY!PRESSURETRANSDUCERMOUNTEDONARADIOSIGNALGENERATOR THEhWIRELESSMOTILITYCAPSULE vHASALSO FOUNDUSE3UCHDEVICESHOLDTHEPROSPECTFORMORECAREFULLYCHARACTERIZINGGASTROINTESTINALMOTORDISORDERSTHROUGHOUTTHEWHOLE')TRACT

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0ERFUSION MANOMETRY AND OTHER METHODS FOR PRESSURE MEASUREMENT BROUGHT A NEW IMPORTANCE TO THE CONCEPT OF SPHINCTERS 0HYSIOLOGISTS HAD LONG DEBATED THE EXISTENCEOFSPHINCTERSBECAUSE ASIDEFROMEXTERNALANALSPHINCTER THESTRUCTURES COULD NOT BE DIRECTLY OBSERVED AND RADIOGRAPHY WAS SCARCELY ABLE TO SHOW THEM SATISFACTORILY -ANOMETRY HOWEVER MADE IT POSSIBLE TO DElNE THEM TO DESCRIBE THEIRDIMENSIONS THETIMINGOFTHEIROPENINGANDCLOSURE ANDTHEFORCEWITHWHICH THEYOCCLUDEDTHELUMEN4HUS BOTHTHEUPPERESOPHAGEALSPHINCTERANDTHEESOPHAGOGASTRICSPHINCTERWERENOTCLEARLYDESCRIBEDUNTILTHEMID S4HEAPPLICATION OF A SMALL BALLOON THE h$ENT SLEEVE v NAMED FOR ITS INVENTOR *OHN $ENT GREATLY FACILITATED THE STUDY OF SPHINCTERS IN VIVO AND IT REMAINS THE MAJOR CLINICAL AND INVESTIGATIVETECHNIQUETOSTUDYSPHINCTERS lNDINGUSEESPECIALLYINTHEESOPHAGUS PYLORUS ANDTHEANALCANAL

Gastrointestinal Wall Movements -AGENDIEKNEWWHATLITTLEHEDIDKNOWABOUTTHEMOVEMENTSOFTHEGUTWALLFROMTHE DIRECTOBSERVATIONOFTHEGUTINTHEOPENABDOMEN ANDTHISREMAINEDAMAJORMETHOD UNTILAFTERTHEENDOFTHECENTURY EVENRECEIVINGEXTENSIVEDISCUSSIONBY!LVAREZ;17] AS LATE AS !FTER THAT THE METHODS TO EXAMINE mOWS AND HENCE TO INFER WALL MOVEMENTSRADIOGRAPHYANDMANOMETRY CAPTUREDMOSTOFTHEATTENTION 4HEABILITYTOOBSERVEWALLMOVEMENTSMOREDIRECTLYWITHOUTTHEARTIFACTSASSOCIATEDWITHTHEOPENINGOFTHEABDOMENAROSEINTHESWITHTHEDEVELOPMENTOF MINIATUREFORCETRANSDUCERSTHATCOULDBESEWNTOTHEGUTWALL7IRESFROMTHESE TRANSDUCERSLEADINGTOCHRONICALLYIMPLANTEDCUTANEOUSPLUGSINEXPERIMENTALANIMALS PERMITTED INVESTIGATORS TO RECORD MOVEMENTS MAINLY FROM THE STOMACH AND THE INTESTINE OVERLONGPERIODSUNDERVARYINGCONDITIONS;18, 19=)NVESTIGATORSFURTHER DEVELOPEDTHEUSEOFELECTRODESIMPLANTEDINTHEGUTWALLTORECORDTHEELECTRICAL EVENTSINMUSCLEASSOCIATEDWITHCONTRACTIONS%LECTRODESHADBEENUSEDMUCHEARLIER BY!LVAREZAND-AHONEY;20= INTHESFOREXAMPLE BUTTHEYWERENEGLECTED FORFOURDECADES ONLYTOBESALVAGEDFORUSE ESPECIALLYBY"ASS;21= WHENITWAS REALIZEDTHATELECTROMYOGRAPHYTRACINGSGREATLYSUPPLEMENTEDTHETRACINGSOFWALL MOVEMENTS MADE WITH CHRONICALLY IMPLANTED TRANSDUCERS .OW BOTH IMPLANTED TRANSDUCERSANDIMPLANTEDELECTRODESlNDWIDESPREADUSEINCHRONICPREPARATIONSIN EXPERIMENTALANIMALS4HEOBVIOUSPROBLEMOFPROVIDINGHIGHRESOLUTIONISOVERCOME BYTHEUSEOFMULTIPLECLOSELYSPACEDSENSORS

The Electric Slow Waves of the Gut "ASICRESEARCHFOCUSEDINITIALLYONMYOGENICCOMPONENTSOF')MOTILITYFOLLOWED BYNEURALREGULATIONOF')MOTILITY)NTHES GUTMOTORACTIVITYWASBELIEVEDTO OCCUR AS A RESULT OF OPPOSITION BETWEEN EXCITATORY PARASYMPATHETIC CHOLINERGIC ANDINHIBITORYSYMPATHETICADRENERGIC NERVES%LECTRICALlELDSTIMULATIONOFGUT


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MUSCLEPREPARATIONSLEDTOTHEDISCOVERYOFNONADRENERGICNONCHOLINERGIC.!.# NERVESASTHEPREDOMINANTINTRINSICINHIBITORYNERVESOFTHE')TRACT4HEIDENTITYOF THE .!.# NEUROTRANSMITTERS VASOACTIVE INTESTINAL POLYPEPTIDE 6)0 AND NITRIC OXIDE ./ THEN EVOLVED %LECTRICAL SLOW WAVES WERE APPRECIATED TO GOVERN THE RHYTHMICITYOFCONTRACTIONS ANDSLOWWAVESOFTHESTOMACHANDSMALLBOWELBEGAN TOBESTUDIEDEXTENSIVELYBYMUSCLEELECTROPHYSIOLOGISTSINTHESANDS %LECTROPHYSIOLOGYWASAFULLYDEVELOPEDTECHNICALDISCIPLINEIN YET7IGGERS COULDSAYVIRTUALLYNOTHINGOFTHEELECTRICALACTIVITYOFTHEGUTINHISTEXTBOOK;22=OF THAT YEAR h.UMEROUS ATTEMPTS HAVE BEEN MADE TO RECORD ACTION POTENTIALS FROM ISOLATED AND INTACT VISCERA 5NFORTUNATELY THE ARRANGEMENT OF MUSCULAR TISSUE IN THESEORGANSISSOCOMPLEXANDTHEELECTRICALVARIATIONSDERIVEDARESOCOMPLICATED THATTHEYAREFORTHEPRESENTDIFlCULTTOINTERPRETINTERMSOFFUNCTIONALACTIVITYv"UT ELECTROPHYSIOLOGYWASTHEGREATBIOLOGICTECHNOLOGYOFTHETIMEJUSTASMOLECULAR BIOLOGYISTHEGREATTECHNOLOGYOFOURS ANDTHEREFOREITWASNOTLONGBEFOREIDEAS ANDMETHODSWEREMOREFULLYTRANSFERREDFROMTHEHEARTWHEREELECTROPHYSIOLOGY BEGAN TOTHEGUT !SEARLYAS INVESTIGATORSCOULDDETECTTHECHARACTERISTICELECTROMYOGRAMOF THESMALLINTESTINE;2 24= BUTITREMAINEDASEEMINGLYFRESHSUBJECTWHEN$ANIELS THOROUGHREVIEWAPPEAREDIN;25=4HESUBJECTADVANCEDRAPIDLYINTHES ESPECIALLY UNDER THE GUIDANCE OF #ODE AND 0ROSSER IN !MERICA AND OF $ANIEL IN #ANADA4HEIDEAOFELECTRICALSLOWWAVESDEVELOPEDRATHERSLOWLY GIVENTHEEASE WITH WHICH THEY ARE DETECTABLE AND THEIR OBVIOUS IMPORTANCE 4HUS IT WAS THREE DECADESAFTERTHEWORKOF!LVAREZ AND0UESTOWTHAT#ODE $ANIEL AND0ROSSERTOOK UPTHESUBJECTWITHTHEIRCHARACTERISTICENERGY)NVESTIGATORSFOCUSEDONTHESMALL INTESTINEFORALONGTIME ONLYLATEREXTENDINGTHEMETHODANDTHECONCEPTSTOTHE STOMACHANDCOLON &ROMTHEBEGINNING INVESTIGATORSRECOGNIZEDTHATELECTRICALSLOWWAVESGOVERN THE RHYTHMICITY OF CONTRACTION NOT MERELY THE FORCE OF CONTRACTION 4HAT IS LIKE CLOCKS THESLOWWAVESRESTRICTCONTRACTIONSINTIMEANDSPACE ACTINGASPACEMAKING SIGNALSTOWHICHTHEMUSCLEMAYORMAYNOTRESPOND)NDEED THEYWEREANEWSORT OFPHENOMENONINHAVINGTHISSTRICTLYPACEMAKERORCLOCKFUNCTION ANDSOINVESTIGATORSGAVETHEMAVARIETYOFNAMES SEEMINGLYTOFEELTHATEXISTINGTERMINOLOGY WASSOMEHOWINADEQUATE&ORSOMEYEARS hELECTRICALSLOWWAVES vhBASICELECTRICAL RHYTHM v hPACESETTER POTENTIALS v AND hELECTRICAL CONTROL ACTIVITYv COMPETED FOR USAGE TOTHEGREATCONFUSIONOFOUTSIDERS ANDTHEYSTILLDOTOSOMEEXTENT 4HEDISCOVERYOFTHEELECTRICALSLOWWAVESINTHEGUTSATISFACTORILYUNIlEDSOME OLDOBSERVATIONS&OREXAMPLE 2USSIANPHYSICIANSHADLONGTOYEDWITHTHETECHNOLOGY OFTHEELECTROGASTROGRAM ADEVICETORECORDTHEELECTRICALSIGNALSOFTHESTOMACHIN ANALOGYWITHTHEELECTROCARDIOGRAM4HISFASCINATIONOFTHE2USSIANSWITHELECTRICAL EVENTSINTHESTOMACHATATIMEWHENTHEYWERESCARCELYTHOUGHTOFINOTHERPARTSOF THEWORLDORINOTHERORGANSREmECTSTHELEGACYOF0AVOLVWHICHACCOUNTSFORTHEFACT THATSOMANYOFTHEEARLIESTAUTONOMICNEUROANATOMISTSWERE2USSIANS ORFROMTHE %ASTERNPARTOF%UROPE#ODE +ELLY 3ZURSZEWSKI;26= ANDTHEOTHERSWHOLATERDID SOMUCHTOADVANCEUNDERSTANDINGOFSLOWWAVESINTHESTOMACHVALIDATEDTHEELECTROGASTROGRAM HERETOFORELARGELYUNKNOWNINTHE7EST)THASGAINEDRENEWEDCURRENCY

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IF NOT ACTUAL VITALITY 3IMILARLY THE lNDING OF A DECLINING GRADIENT IN SLOW WAVE FREQUENCYALONGTHESMALLINTESTINETIEDINFREQUENCYALONGTHESMALLINTESTINETIED INWELLWITHTHETHEORYOFAMETABOLICGRADIENTALONGTHEINTESTINE WHICHHADBROUGHT !LVAREZTOTHEFOREFRONT;17=4HEFACTTHATTHETHEORYEXCITEDSOMECONTROVERSYWAS PARTLYATTRIBUTABLETOTHEPERSONALITYOF!LVAREZANDHISAPPEALSTOTHEPRESSANDTOTHE PUBLIC(ISINTESTINALGRADIENTTHEORYAROSEAGAINFROMTHEASHESONAlRMFOUNDATIONWITHTHEDISCOVERYOFTHEINTESTINALSLOW WAVEFREQUENCYGRADIENT 4HEELECTRICALSLOWWAVESGENERATEDBYTHESTOMACHANDINTESTINEWEREKNOWN LONG BEFORE THEY DID NOT ATTRACT DETAILED SCRUTINY BY MUSCLE ELECTROPHYSIOLOGISTS UNTILTHESANDS;26=4HISWASTRUEPARTLYBECAUSETHEEARLYINVESTIGATORS WERENOT FORTHEMOSTPART THEMSELVESHIGHLYTRAINEDINTHEELECTROPHYSIOLOGYOF SMOOTHMUSCLE ANDPARTLYBECAUSETHEELECTROPHYSIOLOGYOFSMOOTHMUSCLEASSTUDIED in vitroDIDNOTFULLYDEVELOPASASUBJECTUNTILTHES"OZLERINTHE53!AND "ULBRING IN %NGLAND ESPECIALLY DESERVE CREDIT FOR ADVANCING GUT SMOOTH MUSCLE FORWARDASASUBJECTWORTHYOFDETAILEDSTUDYINVITROBYDEDICATEDELECTROPHYSIOLOGISTS"OZLERSTUDIEDTHESTOMACHANDINTESTINE"ULBRINGCHOSETHETAENIACOLIOFTHE GUINEAPIGASHERMODEL)TWASSOMETIME UNTILTHEMIDSBEFORESTUDENTSOF GASTROINTESTINALMOTILITYFULLYREALIZEDTHESIGNIlCANCEOFTHEOBSERVATIONSOF"OZLER AND"ULBRINGINTHEIRBASICELECTROPHYSIOLOGICSTUDIES

The Interstitial Cells of Cajal: The Pacemaking System %XPERTSAGREENOWTHATTHESOURCEOFTHEELECTRICALSLOWWAVESARETHEINTERSTITIAL CELLSOF#AJALRATHERTHANTHESMOOTHMUSCLE ASPREVIOUSLYTHOUGHT#AJALDIDNOT hDISCOVERvTHEINTERSTITIALCELLSTHATBEARHISNAME BUTHERAISEDTHEMFROMOBSCURITY ATTHETURNOFTHECENTURY(EVIEWEDTHESETINYCELLSASSECONDARYNERVECELLSFORMING INTERMEDIATESINTHECOMMUNICATIONBETWEENTHEAXONSOFENTERICNERVESANDTHE CELLSOFEFFECTORSTISSUES LIKESMOOTHMUSCLESANDGLANDCELLS;27=(ETHOUGHTOF THEMASFORMINGATERMINALSYNCYTIUMORNETWORKOFNERVElBERSTHATALLOWEDINTEGRATINGCOMMUNICATIONWITHINTHESUBSTANCEOFTHESMOOTHMUSCLE &ORALONGTIME NEUROANATOMISTSARGUEDABOUTTHESECELLS THEIRFUNCTION DISTRIBUTION ANDINDEED THEIRVERYEXISTENCE#AJALSIDEASASTOTHEIRNATUREANDFUNCTIONWERE NEITHERDISPROVEDNORFULLYACCEPTED ANDTHEYREMAINEDCELLSWITHOUTACLEARFUNCTION FORALMOSTACENTURY!SEARLYAS SOMEINVESTIGATORSHADPROPOSEDTHATTHE CELLSMIGHTBERESPONSIBLEFORhMYOGENICvRHYTHMICCONTRACTIONSONLITTLEEVIDENCE 4HUNEBERGREVIVEDTHEIDEAIN;28= ONBETTEREVIDENCE ANDSTIMULATEDTHEIMMIGRATIONOFOTHERSWHO INFACT HAVEGATHEREDGOODEVIDENCEINITSSUPPORT;29]. )TISIRONICTHATTHEBESTEVIDENCEFORTHEIDEATHATINTERSTITIALCELLSOF#AJALGENERATE THEELECTRICALSLOWWAVESCOMESFROMTHECOLONOFTHECATANDDOG ONEOFTHELATEST PLACESWHERETHEYWEREDESCRIBEDANDTHEORGANWHEREMOTILITYISLESSWELLUNDERSTOOD THAN IN ANY OTHER STRUCTURE 4HE INTERSTITIAL CELLS OF THE MAMMALIAN COLON WEREONLYDISCOVEREDIN BY3TACH;0= WHOFOUNDTHEMASANEUROANATOMIST WORKING ON THE NEGLECTED TOPIC OF THE INNERVATIONS OF THE MAMMALIAN COLON 4HE ELECTRICAL SLOW WAVES OF THE MAMMALIAN COLON lRST DESCRIBED IN DETAIL ONLY


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ABOUTTHESAMETIME NOTBYDESIGNBUTBYACCIDENT THEDISCOVERERSIMPLYCHOOSING ANUNEXPLOREDTISSUEINWHICHTODEMONSTRATETHEUSEOFANEWKINDOFELECTRODE HEHADDEVISED;1=4HESMALLINTESTINEANDSTOMACHREMAINTHEORGANSINWHICH ELECTROPHYSIOLOGYHASBEENCONCENTRATED

Fasting and Postprandial Rhythmic Activity of the Gut 4HEIDEATHATTHEPATTERNORQUANTITIESOFRHYTHMICCONTRACTIONSINTHEGUTVARYASTHE ANIMALISFEDORFASTEDGOESBACKALONGTIME"EAUMONT WITHHISLIMITEDCAPACITY TOSEEGASTRICMOTIONSINHISPATIENTWITHAlSTULATOTHEGASTRICFUNDUS CONCLUDED THATGASTRICCONTRACTIONSOCCURONLYINTHEFEDSTATEANDTHESTOMACHBECOMESQUIET AFTERITHASEMPTIEDITSELFINTODUODENUM4HEIDEAPERSISTEDFORALONGTIME BUTNOT UNIVERSALLYHELD#ARLSON;1=CITESTHEWRITINGSOFANEIGHTEENTHCENTURYPHYSIOLOGIST (ALLER WHOBELIEVEDTHATHUNGERREPRESENTSCONTRACTIONSOFTHEEMPTYSTOMACH AND REFERREDTOOTHERSWHOAGREED ESPECIALLY"OLDYREFF WHOHADPUBLISHEDHISOBSERVAtions in 1905 [2=2ECORDINGFROMBALLOONSINmATEDINTHESTOMACHOFCONSCIOUS DOGS "OLDYREFFSAWALTERNATEPERIODSOFPOWERFULRHYTHMICCONTRACTIONSANDABSOLUTEORRELATIVEQUIESCENCEOVERAPERIODOFnDAYSOFSTARVATION4HEPERIODSOF CONTRACTIONSLASTEDFORnMIN THEPERIODSOFRELATIVEQUIESCENCE HORMORE "OLDYREFFNOTICEDTHATPERIODICCONTRACTIONSOFTHEINTESTINEACCOMPANIEDTHOSEOF THESTOMACH(URSTLATERPROPOSEDTHATTHESEPERIODICCONTRACTIONSGIVERISETOTHE SENSATIONOFHUNGER ANIDEATHAT"OLDYREFFHADREJECTEDBECAUSEHESAWTHECONTRACTIONSBECOMEWEAKERASSTARVATIONPROLONGED #ARLSONANDHISCOLLEAGUES AFTERFURTHEREXPERIMENTS CONCLUDEDTHATHUNGERIS INDEEDCAUSEDBYTHESEPERIODICPOWERFULCONTRACTIONSOFTHESTOMACH(EDESCRIBED HISSTUDIESWHICHINVOLVEDYETANOTHERPATIENTWITHAGASTRIClSTULA IN;1] ANDTHEIDEAOFhHUNGERCONTRACTIONS vOFAPARTICULARFORCEANDREGULARITY REMAINED PARTOFSTANDARDTEACHINGINGASTROINTESTINALPHYSIOLOGYUNTILABOUTTHES WHEN ITAPPEARSTOHAVEDIEDOUT"OLDYREFFSORIGINALWORKAND#ARLSONSOBSERVATIONS BOTHHAVEBEENFULLYREVIEWEDBY7INGATE;]. !LTHOUGH PERIODICITY IN GASTROINTESTINAL CONTRACTIONS IN THE FASTING ANIMAL WAS ESTABLISHEDBYTHESESTUDIES THEMATTERSOONFELLINTONEGLECTANDWASFORGOTTEN4HE PICTUREOFVASTLYDIFFERENTMOTILITYINFEEDINGANDFASTINGDIDNOTREEMERGEUNTILTHE WORKOF2UCKEBUSCH;4=IN&RANCEANDOF3ZURSZEWSKI;5=IN!MERICA3ZURSZEWSKI ANDHISCOLLEAGUESCONlNEDTHEMSELVESTOMANANDTHEDOG 2UCKEBUSCHRANGEDWIDELY ACROSSTHEANIMALKINGDOM2UCKEBUSCHWASABLETOSHOWTHATPERIODICITYISCONSTANT INMANYHERBIVORESTHATEATCONSTANTLY ANDTHATEATINGINTERRUPTSTHEPERIODICCYCLE MOSTLYINCARNIVORESTHATNORMALLYEATMEALSATWIDEINTERVALSOFTIME2UCKEBUSCHS BROADINTERESTSINCOMPARATIVEANIMALFUNCTIONSAREINDICATEDINHISTEXTBOOK;6]. 4HUS THE IDEA OF PERIODICITY OF GASTROINTESTINAL CONTRACTIONS IN FASTING AROSE APPARENTLYFROMCASUALOBSERVATION VERYLONGAGO BUTITFOUNDLITTLEUSETHENEXCEPT BY#ARLSONTOEXPLAINHUNGER)TWASlNALLYANDlRMLYREDISCOVEREDANDTHEPERIODIC ACTIVITYOFTHEGUTINFASTINGNEWLYCHRISTENEDTHEhMIGRATINGMOTORCOMPLEXv HAS BECOMEDEEPLYENTRENCHEDINTHEBODYOFKNOWLEDGE;5].

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R.W. McCallum

7" #ANNON AND &4 -URPHY IN n REPORTED THAT GASTRIC EMPTYING ANDINTESTINALMOTILITYMAYBEINHIBITEDBYBOTHCENTRALANDPERIPHERALMECHANISMS )N 7OLFAND7OLFFSUGGESTEDTHATCERTAINEMOTIONALSTATESCANALTERGASTRIC MOTILITY SECRETION ANDBLOODmOW/NGOINGRESEARCHDElNEDTHEINmUENCEOF') PEPTIDESANDHORMONESONTHEMIGRATINGMOTORCOMPLEX--# )NAREVIEW YEARSAFTERTHEDEMONSTRATIONOFTHEMIGRATINGCOMPLEX 7INGATENOTEDTHATNEURAL AND HORMONAL FACTORS ARE INVOLVED IN REGULATION BUT hSPECIlC DETAILS REMAIN BLURREDvnANOBSERVATIONWHICHISSLOWLYBEINGUNRAVELED

Gastric Sieving of Solids and Receptive Relaxation -AGENDIERECOGNIZEDTHATTHESTOMACHCONTRACTSTOSHIFTITSCONTENTS ANDBY (OFMEISTERAND3CHÓTZDESCRIBEDGASTRICPERISTALSIS/NLYAFTERTHEADVENTOFRADIOGRAPHYCOULD#ANNONREALLYVISUALIZEITINVIVO"EAUMONTHADPROPOSEDTHATFOOD ENTERING THE STOMACH FOLLOWS A PATHWAY ALONG THE GREATER CURVATURE TO REACH THE PYLORUS#ANNONWASABLETODISPROVETHATIDEA(ECOULDSEEDIFFERENTMOTORFUNCTIONSOFTHEANTRUMANDFUNDUSANDVISUALIZEDRETROPULSIONOFCONTENTSWITHANTRAL CONTRACTIONS#ANNONSVIEWSONGASTRICCONTRACTIONSPREVAILEDFORALONGTIME4HE FULL COMPLEXITY OF GASTRIC mOWS INCLUDING SIEVING THE SEPARATION OF SOLIDS FROM LIQUIDSBYTHEANTRUM BECAMECLEARONLYAFTERWITH-EYERSREVIEWANDFULL ACCOUNTOFTHISDEVELOPMENT;7, 8]. #ANNONRECOGNIZEDTHERESERVOIRFUNCTIONOFTHEPROXIMALSTOMACH ANDREALIZED THATITEXPANDEDACCOMMODATION WITHSWALLOWINGBYTHEPROCESSNOWCALLEDRECEPTIVERELAXATION"UTITWASNOTUNTILYEARSLATERTHATVAGALINHIBITIONOFTHESTOMACH RECEIVED CAREFUL STUDY WHEN (ARPER ;9= OBSERVED THAT THE ELECTRICAL STIMULATION OFTHECENTRALSTUMPOFTHESEVEREDVAGUS INDUCEDGASTRICRELAXATIONBYWAYOFTHE OTHERINTACTVAGUS)NTHES *ANSON;40=AND!BRAHAMSON;41=EXTENDEDTHECONCEPTOFVAGALLYMEDIATEDGASTRICRELAXATIONBYDEMONSTRATINGSEVERALREmEXES4HE EXCITATIONOFNONCHOLINERGIC NONADRENERGICINHIBITORYNERVESMEDIATESTHESEREmEXES FORTHEMOSTPART BUT-IOLANAND2OMAN;42=SHOWEDTHATRECEPTIVERELAXATIONALSO INVOLVESTHESUPPRESSIONOFACTIVITYINTONICEXCITATORYlBERSTOTHEGASTRICFUNDUS

Reverse Peristalsis in the Small Intestine 4HEIDEAOFREVERSEPERISTALSISASAPHENOMENONUNDERLYINGVOMITINGANDDYSPEPSIA GOESBACKALONGTIME6ARIOUSEARLYWRITERSCONSIDEREDITAWELL ESTABLISHEDPATTERN OFPERISTALSISINTHEESOPHAGUS STOMACH SMALLINTESTINE ANDCOLON EVENTHOUGHTHE EVIDENCE THEN EXISTED ONLY FROM THE STUDY OF THE STOMACH AND COLON -ANY WHO STUDIEDTHESMALLINTESTINEHADLOOKEDFORITINVAIN)N 3MITHAND"RIZZEE;4], INVESTIGATINGVOMITINGBYCINERADIOGRAPHYINTHECAT OBSERVEDTHATAPOMORPHINE INDUCEDVOMITINGPRODUCEDREVERSEPERISTALSISINTHESMALLINTESTINE7EISBRODTAND #HRISTENSENSAWITAGAININ;44=4HEYUSEDELECTRODESIMPLANTEDINTHESMALL


9

INTESTINEOFTHECAT4HEYNOTEDTHATVOMITINGWASPRECEDEDBYACOMPLEXCHANGE &IRST THEELECTRICALSLOWWAVESDIMINISHEDINAMPLITUDETOTHEPOINTOFEXTINCTION 4HENAPROLONGEDBURSTOFSPIKESAPPEAREDlRSTATTHEMOSTDISTALELECTRODEANDMOVED VERYSLOWLY CMS CEPHALADTHROUGHTHEWHOLESEGMENTUNDERSTUDY4HEANIMAL THENVOMITED4HEELECTRICALSLOWWAVESRETURNEDSOONTHEREAFTER RUNNINGCEPHALAD ATlRST SLOWLYORIENTINGTHEMSELVESTOTHENORMALCEPHALOCAUDALPROGRESSION

Conclusion 4HESEHISTORICPERSPECTIVESONGASTRICMOTILITYPROVIDEAFRAMEWORKFORAPPRECIATING THEFOLLOWINGCHAPTERSOFTHISBOOKTHATDESCRIBETHECURRENTKNOWLEDGEOFGASTRIC motility and gastric dysmotility, particularly gastroparesis.

References "EAUMONT7%XPERIMENTSANDOBSERVATIONSONTHEGASTRICJUICEANDTHEPHYSIOLOGYOFDIGESTION 0LATTSBURG .9&0!LLAN "OWDITCH(0-OVEMENTSOFTHEALIMENTARYCANAL3CIENCE #ANNON 7" 4HE MOVEMENTS OF THE STOMACH STUDIED BY MEANS OF THE ROENTGEN RAYS !M *0HYSIOL #ANNON 7" 4HE MOVEMENTS OF THE INTESTINES STUDIED BY MEANS OF THE ROENTGEN RAYS !M *0HYSIOL (URST!& "RIGGS0*4HEDIAGNOSISOFGASTRICANDDUODENALULCERWITHTHE8 RAYS'UYS(OSP 2EPORTS (URST!& .EWTON!4HENORMALMOVEMENTSOFTHECOLONINMAN*0HYSIOL,OND 47:57. "ARCLAY!%4HEDIGESTIVETRACT!RADIOLOGICALSTUDYOFITSANATOMY PHYSIOLOGY ANDPATHOLOGY #AMBRIDGE#AMBRIDGE5NIVERSITY0RESS !LAZRAKI .0 &AJMAN 7! #HRISTIAN 0% 'ASTROINTESTINAL RADIONUCLIDE IMAGING PROCEDURES )N9AMADA4ETAL EDITORS4EXTBOOKOFGASTROENTEROLOGY0HILADELPHIA*",IPPINCOTT#O #H (UNT*.4HEDUODENALREGULATIONOFGASTRICEMPTYING'ASTROENTEROLOGY +ELLY+!-OTILITYOFTHESTOMACHANDGASTRODUODENALJUNCTION)N*OHNSON,2ETAL EDITORS 0HYSIOLOGYOFTHEGASTROINTESTINALTRACTSTED.EW9ORK2AVEN0RESS#H -ACAGNO%/ #HRISTENSEN*&LUIDMECHANICSOFGASTROINTESTINALmOW)N*OHNSON,2ETAL EDITORS0HYSIOLOGYOFTHEGASTROINTESTINALTRACTSTED.EW9ORK2AVEN0RESS#H "AYLISS7- 3TARLING%(4HEMOVEMENTSANDINNERVATIONOFTHESMALLINTESTINE*0HYSIOL ,OND #ARLSON !* 4HE CONTROL OF HUNGER IN HEALTH AND DISEASE #HICAGO 5NIVERSITY OF #HICAGO 0RESS 7HEELON( 4HOMAS*%/BSERVATIONSONTHEMOTILITYOFTHEANTRUMANDTHERELATIONOFTHE RHYTHMICACTIVITYOFTHEPYLORICSPHINCTERTOTHATOFTHEANTRUM*,AB#LIN-ED #ODE#&ETAL EDITORS!N!TLASOFESOPHAGEALMOTILITYINHEALTHANDDISEASE3PRINGlELD #HARLES#4HOMAS $ODDS7* 3TEF** (OGAN7*&ACTORSDETERMININGPRESSUREMEASUREMENTACCURACYBYINTRALUMINALESOPHAGEALMANOMETRY'ASTROENTEROLOGY !LVAREZ7#4HEMECHANICSOFTHEDIGESTIVETRACTANINTRODUCTIONTOGASTROENTEROLOGYNDED .EW9ORK0AUL"(OEBER

10

R.W. McCallum

&ARRAR*4'ASTROINTESTINALSMOOTHMUSCLEFUNCTION!M*$IG$IS ,OUCKES(3 1UIGLEY*0 +ERSEY*)NDUCTOGRAPHMETHODOFRECORDINGMUSCLEACTIVITY ESPECIALLY PYLORICSPHINCTERPHYSIOLOGY!M*0HYSIOL !LVAREZ 7# -AHONEY ,* !CTION CURRENTS IN STOMACH AND INTESTINE !M * 0HYSIOL 58:476. "ASS4)NVIVOELECTRICALACTIVITYOFTHESMALLBOWEL)N#ODE#& EDITOR(ANDBOOKOFPHYSIOLOGY ACRITICAL COMPREHENSIVEPRESENTATIONOFPHYSIOLOGICALKNOWLEDGEANDCONCEPTS3ECTION ALIMENTARYTRACT VOLMOTILITY"ETHESDA!MERICAN0HYSIOLOGICAL3OCIETY 7IGGERS#*0HYSIOLOGYINHEALTHANDDISEASERDED0HILADELPHIA,EAAND&EBIGER "ERKSON* "ALDES%* !LVAREZ7#%LECTROMYOGRAPHICSTUDIESOFTHEGASTROINTESTINALTRACT) 4HE CORRELATION BETWEEN MECHANICAL MOVEMENT AND CHANGES IN ELECTRICAL POTENTIAL DURING RHYTHMICCONTRACTIONOFTHEINTESTINE!M*0HYSIOL 0UESTOW#"4HEACTIVITYOFISOLATEDINTESTINALSEGMENTS!RCH3URG $ANIEL%% #HAPMAN+-%LECTRICALACTIVITYOFTHEGASTROINTESTINALTRACTASANINDICATIONOF MECHANICALACTIVITY!M*$IG$IS 3ZURSZEWSKI*(%LECTRICALBASISFORGASTROINTESTINALMOTILITY)N*OHNSON,2ETAL EDITORS 0HYSIOLOGYOFTHEGASTROINTESTINALTRACTNDED.EW9ORK2AVEN0RESS#H #AJAL329(ISTOLOGIEDUSYTEMENERVEUXDELHOMMEETDESVERTEBRES0ARIS-ALOINE 4HUNEBERG , 4HE INTERSTITIAL CELLS OF #AJAL INTESTINAL PACEMAKER CELLS !DV %MBRYOL #ELL "IOL #HRISTENSEN*!COMMENTARYONTHEMORPHOLOGICALIDENTIlCATIONOFTHEINTERSTITIALCELLSOF#AJAL *!UTON.NERV3YST 3TACH7DER0LEXUSENTERICUSEXTREMUSDESDICKDARMESUNDSEINE"EZIEHUNGENZUDENINTERSTITIELLEN:ELLEN#AJAL :-IKROSK!NAT&ORSCH #HRISTENSEN* #APRILLI2 ,UNDD'&%LECTRICSLOWWAVESINCIRCULARMUSCLEOFCATCOLON!M *0HYSIOL "OLDYREFF7.,ETRAVAILPERIODIQUEDELAPPAREILDIGESTIFENDEHORSDEADIGESTION!RCH3CI"IOL 7INGATE$,"ACKWARDSANDFORWARDSWITHTHEMIGRATINGCOMPLEX$IG$IS3CI 2UCKEBUSCH9 ,APLACE*0,AMOTRICITEINTESTINALECHEZLEMOUTONPHENOMENESMECANIQUES ETELECTRIQUES#23OC"IOL 3ZURSZEWSKI*(!MIGRATINGELECTRICCOMPLEXOFTHECANINESMALLINTESTINE!M*0HYSIOL 2UCKEBUSCH90HYSIOLOGIEPHARMACOLGOIETHERAPEUTIQUEANIMALES0ARIS-ALOINE 3! -EYER*( 4HOMPSON*" #OHEN-0 3HADCHER!3IEVINGOFSOLIDFOODBYTHECANINESTOMACH ANDSIEVINGAFTERSURGERY'ASTROENTEROLOGY -EYER*(-OTILITYOFTHESTOMACHANDGASTRODUODENALJUNCTION)N*OHNSON,2ETAL EDITORS 0HYSIOLOGYOFTHEGASTROINTESTINALTRACT.EW9ORK2AVEN0RESS (ARPER!! +IDD# 3CRATHERD46AGO VAGALEFFECTSONGASTRICANDPANCREATICSECRETIONAND GASTROINTESTINALMOTILITY*0HYSIOL,OND *ANSSON'%XTRINSICNERVOUSCONTROLOFGASTRICMOTILITY!CTA0HYSIOL3CAND3UPPL !BRAHAMSON ( 3TUDIES ON THE INHIBITORY NERVOUS CONTROL OF GASTRIC MOTILITY !CTA 0HYSIOL 3CAND3UPPL -IOLAN *0 2OMAN # $ECHARGE UNITAIRE DES lBRES VAGALES EFFERENTES LORS DE LA RELAXATION RECEPTIVEDLESTOMACDUCHIEN*0HYSIOL0ARIS 3MITH## "RIZZEE+2#INERADIOGRAPHICANALYSISOFVOMITINGINTHECAT'ASTROENTEROLOGY 7EISBRODT.7 #HRISTENSEN*%LECTRICALACTIVITYOFTHECATDUODENUMINFASTINGANDVOMITING 'ASTROENTEROLOGY

Chapter 2

Epidemiology of Gastroparesis Baha Moshiree, Steven Bollipo, Michael Horowitz, and Nicholas J. Talley

Keywords 'ASTROPARESIS s 'ASTRIC EMPTYING s 0OSTINFECTIOUS GASTROPARESIS s$IABETICGASTROPARESISs)DIOPATHICGASTROPARESISs1UALITYOFLIFE

Introduction $ESPITE THE ENORMOUS PUBLIC HEALTH IMPACT OF GASTROPARESIS '0 SEVERAL GAPS IN OUR KNOWLEDGE STILL EXIST 4HIS CHAPTER FOCUSES ON THE EPIDEMIOLOGY OF '0 WITHPARTICULARATTENTIONTOTHOSESTUDIESWHICHHAVEATTEMPTEDTOSHEDLIGHTON THECONmICTINGDElNITIONSOFTHEDISORDER ITSMOSTCOMMONETIOLOGIES THEINCIDENCE PREVALENCE ANDTHECHANGINGSECULARTRENDS4HESOCIOECONOMICBURDENOF '0INTERMSOFCOSTS MORBIDITY ANDIMPACTONPATIENTSQUALITYOFLIFE1/, ARE also explored.

Definitions 0ATIENTSWITH'0CANEXHIBITABROADSPECTRUMOFCLINICALMANIFESTATIONS BUTSYMPTOM SEVERITY CORRELATES POORLY WITH THE DEGREE OF DELAY IN GASTRIC EMPTYING ;1= 4HE CLINICALMANIFESTATIONSOF'0INCLUDENAUSEA VOMITING POSTPRANDIALPAINANDEARLY SATIATIONINTHEABSENCEOFMECHANICALOBSTRUCTION4HE!MERICAN'ASTROENTEROLOGICAL !SSOCIATION !'! CONSENSUS HAS STATED THAT PAIN IS NOT A COMMON CONCERN IN

N.J. Talley (*) 5NIVERSITYOF.EWCASTLE #ALLAGHAN .37 !USTRALIA E MAIL.ICHOLAS4ALLEY NEWCASTLEEDUAU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_2, © Springer Science+Business Media, LLC 2012

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12

The extent of motility component known or susptected

The spectrum of Functional Dyspepsia and Gastroparesis 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Gastroparesis, 2

1 Functional 2 Dyspepsia (Adapted and modified with kind permission from Locke GR III. Gastroenterology clinics of North America. 1996; 25(1): Page 3, Figure 1)

Fig. 2.1 4HECONTINUUMOFDYSPEPSIAANDGASTROPARESIS

PATIENTSWITH'0 BUTTWOSTUDIESHAVEOBSERVEDTHATTHEPREVALENCEOFPAININ'0 CANBEASHIGHAS;2=(OWEVER THESEVERITYOFABDOMINALPAINDOESNOTSEEM TOCORRELATEWITHTHEDEGREEOFDELAYINGASTRICEMPTYING;2]. '0ISTHUSDElNEDASUPPER')SYMPTOMSINTHESETTINGOFDELAYEDGASTRICEMPTYING OBSTRUCTIONMUSTBEEXCLUDEDBEFOREMAKINGAlRMDIAGNOSIS(OWEVER THISBROAD SIMPLEDElNITIONISPROBLEMATICFORANUMBEROFREASONS -ILDLYDELAYEDEMPTYINGOVERLAPSWITHFUNCTIONALDYSPEPSIA&$ 3OMEEXPERTS INTHElELDHAVEPROPOSEDTHATDELAYEDGASTRICEMPTYINGAND'0ARETWODIFFERENT ENTITIES ANDTHATTHEDIAGNOSISOF'0SHOULDBERESTRICTEDONLYTOTHOSEWITHGROSSLY DELAYEDGASTRICEMPTYING;=/THERSHAVEPROPOSEDTHECONFUSINGTERMhGASTROPARESIS LIKEvSYNDROMETODESCRIBEPATIENTSWITHDYSPEPSIABUTNORMALEMPTYING WHICHFOR ALLINTENTSANDPURPOSESIS&$;4=!LTHOUGHTHEREISASIGNIlCANTOVERLAPOFSYMPTOMS STILLOTHERSHAVEARGUEDTHATITISTHEEXTENTOFDISORDEREDMOTILITYTHATDIFFERENTIATES &$FROMTRUE'0;5=&IG2.1). '0MAYBEACUTE ORCHRONICIFSYMPTOMSPERSISTFORMORETHANTHREEMONTHS;6]. 4HETWOMOSTCOMMONCAUSESOF'0AREIDIOPATHICANDDIABETESMELLITUS%VENIN THE ABSENCE OF SYMPTOMS OF '0 IN THOSE WITH INSULIN TREATED DIABETES DELAYED GASTRICEMPTYINGMAYPREDISPOSETOPOORCONTROLOFGLUCOSECONCENTRATIONS PARTICULARLYHYPOGLYCEMIAINTHEEARLYPOSTPRANDIALPERIOD;7=)NCONTRAST INPATIENTSWITH TYPEDIABETES4$- WHOARENOTMANAGEDWITHINSULIN DELAYEDGASTRICEMPTYING MAY REPRESENT AN ADVANTAGE PROVIDING BETTER GLUCOSE HOMEOSTASIS 7HETHER THE DElNITION OF '0 SHOULD BE BROADENED TO INCLUDE THESE PATIENTS WITH DISORDERED GLYCEMICCONTROLATTRIBUTABLETO'0ISUNRESOLVED

%PIDEMIOLOGYOF'ASTROPARESIS

6ARIATION IN DElNING WHAT CONSTITUTES '0 IS ALSO LIMITED BY THE ABSENCE OF STANDARDIZATIONININTERPRETINGSCINTIGRAPHY IE THECUTOFFAPPLIED VARIATIONSACROSS CENTERSINTHEVOLUMEANDCOMPOSITIONOFTESTMEALS THEPOSTUREOFPATIENTSDURING '%3 DURATIONOFTESTING ANDCALCULATIONSOFEMPTYINGAST ORRETENTION;8]. $ESPITERECENTEFFORTSTOSTANDARDIZE'%3 MANYINSTITUTIONSSTILLUSEHSCANNING WHICH MAY HAVE LOWER SENSITIVITY AND SPECIlCITY THAN H SCANNING THIS MAY POTENTIALLYUNDERESTIMATEPATIENTSWITH'0ANDTHUSTHETRUEPREVALENCEOFTHEDISORDER;8=! HGASTRICEMPTYINGSCANSHOWINGADELAYINGASTRICEMPTYINGTHREE STANDARDDEVIATIONSABOVENORMALUSINGASTANDARDTESTMEAL REGARDLESSOFSYMPTOMS SEEMSTOREPRESENTAPRACTICALDElNITIONOF'0THATISATLEASTSPECIlC

Causes of Gastroparesis '0ISIMPORTANTBUTISUNCOMMONWHILESOMEESTIMATESSUGGESTTHATUPTOOFTHE !MERICANPOPULATIONMAYBEAFFECTED THISISLIKELYANOVERESTIMATESEEBELOW ;9]. 4HEETIOLOGYOF'0ISMULTIFACTORIALWITHOVERCAUSESIDENTIlEDINTHELITERATURE ;10= 4ABLE 2.1 4HE MEAN AGE OF ONSET OF '0 IS YEARS RANGE n ;11]. 3OYKANETALSTUDIEDACOHORTOFPATIENTSlNDINGWEREIDIOPATHIC DIABETIC POSTGASTRICSURGERY 0ARKINSONSDISEASE COLLAGENVASCULAR DISORDERS DUETOINTESTINALPSEUDOOBSTRUCTION ANDFROMOTHERMISCELLANEOUSCAUSES;9=!LTHOUGHCHRONICCAUSESOF'0AREUSUALLYIRREVERSIBLE THEACUTE CASESOFTENRESOLVEAFTERCORRECTIONOFTHEUNDERLYINGETIOLOGY)DIOPATHICGASTROPARESIS )'0 COMPRISESTHELARGESTGROUPOFPATIENTSANDWHENFURTHERSUBDIVIDED MAY HAVEASUSPECTEDVIRALETIOLOGY;9]. Table 2.1 3ECONDARYCAUSESOFGASTROPARESISINTHEPOPULATION $ElNITEPLUSPROBABLE $ElNITE PLUSPOSSIBLE gastroparesis $ElNITEPLUSPROBABLE 0ROBABLECAUSE gastroparesis (n = 222) (n gastroparesis (n = 127) OFGASTROPARESIS n )DIOPATHIC 41 (49.1) $IABETESMELLITUS #ONNECTIVETISSUEDISEASE 9 (10.8) 12 (9.4) 15 (6.8) (YPOTHYROIDISM 1 (1.2) 2 (1.6) Malignancy 2 (2.4) 11 (5.0) Gastrectomy/ 6 (7.2) 10 (7.9) 12 (5.4) FUNDOPLICATION Drugs 19 (22.9) 29 (22.8) %ND STAGERENALDISEASE 4 (4.8) 7 (5.5) 19 (8.6) Note4HREEDIAGNOSTICDElNITIONSWEREUSEDDElNITEGASTROPARESISnDELAYEDGASTRICEMPTYINGAND TYPICALSYMPTOMSPROBABLEGASTROPARESISnTYPICALSYMPTOMSANDFOODRETENTIONONENDOSCOPYOR UPPER ') STUDY POSSIBLE GASTROPARESIS n TYPICAL SYMPTOMS ALONE OR DELAYED GASTRIC EMPTYING WITHOUT')SYMPTOMS#AUSESOFGASTROPARESISARENOTMUTUALLYEXCLUSIVE 2EPRODUCEDWITHPERMISSIONFROM*UNGETAL!PRIL 'ASTROENTEROLOGYPAGE

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Prevalence of Gastroparesis $ATAONTHEPREVALENCEOFADISEASEOFTENSHEDSLIGHTONTHEBURDENOFDISEASETO SOCIETY BUTFOR'0 THISISDIFlCULTTOASCERTAIN0OPULATION BASEDDATAASSESSINGTHE EXTENTOF'0ARESCARCE!SSYMPTOMSDONOTIDENTIFY'0 QUESTIONNAIRESALONEDO NOT PROVIDE ROBUST ESTIMATES ;1= &URTHERMORE POPULATION BASED STUDIES APPLYING '%3ARENOTAVAILABLE 4HEMOSTROBUSTDATARELATINGTOTHEPREVALENCEOF'0AREBASEDONALARGEHISTORICAL COHORT THE2OCHESTER%PIDEMIOLOGY0ROJECT2%0 AMEDICALRECORDLINKAGESYSTEM IN/LMSTED#OUNTY -INNESOTA4HE2%0WASUSEDTOIDENTIFYCOMMUNITYRESIDENTS WITH '0 BASED ON STRICT DElNITIONS OF DElNITE '0 DELAYED GASTRIC EMPTYING BY STANDARDSCINTIGRAPHYANDSYMPTOMSOF'0 PROBABLESYMPTOMSOF'0ANDFOOD RETENTIONONENDOSCOPYORUPPER')STUDY ANDPOSSIBLE'0TYPICALSYMPTOMSALONE ORDELAYEDGASTRICEMPTYINGBYSCINTIGRAPHY !MONGTHEELIGIBLECASESOF'0 STUDIEDBETWEENAND ONLYPATIENTSMETTHESTRICTCRITERIAFORDElNITE '0WITHBEINGFEMALEWITHPROBABLEANDPOSSIBLECASES ;10=4HEMOST COMMONCAUSEOFDElNITE'0WASIDIOPATHIC FOLLOWEDBYDIABETES ;10= 4HE OVERALL AGE ADJUSTED PREVALENCE OF DElNITE '0 PER PERSONS IN *ANUARY WAS#) n FORWOMENAND#) n FORMEN/VERALL THISSTUDYINDICATEDTHATALTHOUGH'0ISANUNCOMMONCONDITION INTHECOMMUNITY ITSTILLREPRESENTSAMAJORDISEASEBURDENGIVENTHEPOORPROGNOSIS LOWERSURVIVALANDREQUIREMENTFORCONTINUOUSCHRONICMEDICALCARESEEBELOW

Effect of Ethnicity on Prevalence .ODATAEXISTONTHEPREVALENCEOF'0IN(ISPANICSORBLACKSANDTHEREFOREWHETHER ETHNICDIFFERENCESMAYINmUENCETHEEPIDEMIOLOGYOF'0ISUNKNOWN4HEPREVALENCE OF DYSPEPSIA IN STUDIES FROM %UROPE AND .ORTH !MERICA IS REPORTED TO BE n BUTTHERATESOF'0CANNOTBEDETERMINED;12n14]. Generally, studies indiCATETHATTHEPREVALENCEOFCHRONIC')SYMPTOMS INCLUDINGDYSPEPSIA ISLOWERIN !SIAN COUNTRIES AS COMPARED TO THE 7EST ;15= (OWEVER #HANG ET AL REPORTED DELAYEDGASTRICEMPTYINGINOFMALE#HINESESUBJECTSWITH4$-PRESENTING WITHUPPER')SYMPTOMS;15].

Prevalence by Etiology of Gastroparesis 'IVENTHECAUSESOF'0AREMULTIFACTORIAL THEPREVALENCEOF'0INTHEGENERALPOPULATION IS BEST ASSESSED BY CONSIDERING THE POTENTIAL RISK FACTORS AND UNDERLYING PATHOPHYSIOLOGYOFTHEDISORDER


15

Prevalence of Diabetic GP 4HEPREVALENCEOF'0INTERTIARYREFERRALCENTERSISREPORTEDTOBEnOFTYPE) DIABETES4$- ANDnOF4$-BASEDONCROSS SECTIONALSTUDIES;16n18]. &OREXAMPLE INONEREFERRALCENTERDELAYED'%3WASPRESENTINnOFPATIENTS WITHDIABETES;16=(OWEVER THESELECTIONBIASINHERENTINTHISAPPROACHMAYSERIOUSLYOVERESTIMATETHETRUEPREVALENCEINTHECOMMUNITY!LARGEPOPULATION BASED STUDYDONEBY"YTZERETALEVALUATEDSUBJECTSRANDOMLYSELECTEDFROMTHECOMMUNITYWITHDIABETESTHEYOBSERVEDTHAThGASTROPARESIS LIKEvSYMPTOMSWEREMORE COMMONINDIABETICn THANNONDIABETICPEOPLE;19=-OREOVER THOSEDIABETIC SUBJECTSREPORTINGPOORGLYCEMICCONTROLHADHIGHERRATESOFUPPER')SYMPTOMS /2#) n (ENCE CONmICTINGEVIDENCEEXISTSASTOWHETHER ')SYMPTOMSAREMORECOMMONIN4$-WHICHCOMPRISESnOFCASESOF DIABETES;20]. 3TILLOTHERSTUDIESHAVEFAILEDTOESTABLISHANASSOCIATIONBETWEEN')SYMPTOMS AND$-;21=&OREXAMPLE ONESTUDYUSINGRECORDSTHROUGHTHE2%0INSUBJECTS WITH4$-AND4$-SUGGESTEDTHATTHEPREVALENCEOF')TRACTSYMPTOMSOTHER THAN CONSTIPATION IN PATIENTS WITH $- IN THE COMMUNITY WAS SIMILAR TO PERSONS WITHOUT$-AND INPARTICULAR SYMPTOMSOF'0ARENOTMORECOMMONINDIABETICS THANINTHEGENERALPOPULATION;21=(OWEVER THISDATABASE2%0 HASSOMESHORTCOMINGS INCLUDING ITS PREDOMINANTLY #AUCASIAN AND HOMOGENEOUS POPULATION !NOTHERPOPULATION BASEDSTUDYOF !USTRALIANADULTSFOUNDTHATTHOSEWITH 4$-TREATEDWITHORALHYPOGLYCEMICMEDICATIONSWITHORWITHOUTINSULINTHERAPY ANDTHOSEWITHPOORGLYCEMICCONTROLWEREMORELIKELYTOSUFFERFROMNAUSEAVOMITING ANDUPPER')ORDYSMOTILITYSYMPTOMS;22]. 4HENATURALHISTORYOF'0ISEXPLOREDINASUBSEQUENTCHAPTER HOWEVER INALONGITUDINALSTUDYDONEBY*ONESETALOFPATIENTSWITH$-FOLLOWEDOVERYEARS ONLYAMINIMALCHANGEINGASTRICEMPTYINGAND'0SYMPTOMSWASSEENOVERTIME DESPITEEVIDENCEFORPROGRESSIONOFAUTONOMICNEUROPATHY;2=!CUTEHYPERGLYCEMIA DELAYSEMPTYINGANDMAYWORSENSYMPTOMSSUCHASNAUSEAANDVOMITINGBYTHIS MECHANISM WHILE INSULIN INDUCED HYPOGLYCEMIA ACCELERATES GASTRIC EMPTYING SUBSTANTIALLY EVENWHENTHELATTERISABNORMALLYDELAYED;24=3TUDIESONTHEPREVALENCEOF'0DURINGEUGLYCEMIAARELACKING

Prevalence of Idiopathic Gastroparesis 4HEPROPORTIONOFPATIENTSWITHGASTROPARESISWITH)'0INASTUDYATAREFERRALCENTER BY 3OYKAN ET AL WAS COMPRISING THE LARGEST GROUP OF '0 PATIENTS IN THE COHORT REPORTING ACUTE VIRAL GASTROENTERITIS PRECEDING THEIR SYMPTOMS ;9]. 3TRIKINGLY AHISTORYOFPHYSICALANDSEXUALABUSEWASREPORTEDINOFFEMALES WITH)'0BUTTHERELEVANCEOFTHISASSOCIATIONREMAINSUNCLEAR

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Incidence of Gastroparesis 4HE TRUE incidence OF '0 IN POPULATION BASED SETTINGS IS UNCERTAIN (OWEVER A RECENT STUDY DONE IN /LMSTED #OUNTY -INNESOTA EVALUATED INCIDENT CASES OF '0 DIAGNOSED EITHER AT -AYO -EDICAL #ENTER OR /LMSTED -EDICAL #ENTER BETWEEN *ANUARY AND$ECEMBER ;10=4HROUGHTHE-AYO#LINICSCOMMON MEDICALRECORDSYSTEM DATAONOFTHEENTIREPOPULATIONINTHISCOUNTYAREMADE AVAILABLE WITH OF THE POPULATION SEEN AT LEAST ONCE DURING ANY GIVEN YEAR PERIODTHUSPROVIDINGTHECAPABILITYFORPOPULATION BASEDSTUDIES)NVESTIGATORSIN THESTUDYDElNEDINCIDENTCASEOF'0ASANYNEWCASEDIAGNOSEDOVERTHE YEAR PERIOD7HEN'0ISDElNEDBYSYMPTOMSANDDELAYEDGASTRICEMPTYINGDElNITE'0 THEAGEADJUSTEDTO53WHITES INCIDENCEOFDElNITE'0PER PERSON YEARSFORnIN/LMSTED#OUNTY -INNESOTA WAS#) n FOR WOMENAND#) n FORMEN;10=4HEINCIDENCEOFDElNITE'0WAS SIGNIlCANTLYGREATERINWOMENTHANINMENAND ASEXPECTED THEPREVALENCERATES WERE HIGHER AMONG WOMEN THAN MEN AGE ADJUSTED BEING ;10= 0ATIENTS WITH ADVANCEDAGEOVERYEARSOROLDERHADAPEAKINCIDENCEOFPER PERSON YEARS SUGGESTINGTHATTHEINCIDENCEOFGASTROPARESISMAYINCREASEWITHADVANCINGAGE;10=&IG2.2 4HESENUMBERSREMAINEDSIMILARIRRESPECTIVEOFTHEDIFFERENT DIAGNOSTICCRITERIAUSED;10].

Fig. 2.2 !GE SPECIlC INCIDENCE OF GASTROPARESIS IN /LMSTED #OUNTY -INNESOTA n &ROMREF WITHPERMISSION


17

Risk Factors and Predictors of Disease Progression in GP /NEAIMOFEPIDEMIOLOGYISTOIDENTIFYHOMOGENEOUSSUBGROUPSINTHEPOPULATION WHOAREEITHERATAPARTICULARLYHIGHORLOWRISKFORDEVELOPING'0!PROBLEMINHERENT INCROSS SECTIONALSTUDIESISTHATTHEETIOLOGICRISKFACTORSCANNOTBEDIFFERENTIATED FROMASSOCIATIONSWITHNOCAUSALRELEVANCE

Influence of Gender and GP "ASEDONSTUDIESDONEINREFERRALCENTERS AFEMALEPREDOMINANCEOF'0EXISTSWITH AFEMALETOMALERATIOOF;10=3OMESTUDIESHAVESHOWNTHATGASTRICEMPTYINGIS SLOWERINFEMALESCOMPAREDTOMALESANDMAYALSOBERELATEDTOTHEPHASEOFTHE MENSTRUAL CYCLE WITH SLOWER GASTRIC EMPTYING SEEN DURING THE LUTEAL PHASE OF THEMENSTRUALCYCLEWHENPROGESTERONELEVELSAREHIGH VERSUSTHEFOLLICULARPHASE OR MENOPAUSE WHEN PROGESTERONE LEVELS ARE LOW ;25= (OWEVER OTHER STUDIES HAVEFAILEDTOSHOWCORRELATIONSBETWEENPROLONGEDGASTRICEMPTYINGANDPHASESIN THEMENSTRUALCYCLE INSTEADDEMONSTRATINGONLYPOSTLAGGASTRICEMPTYINGRATESWERE SLOWERINWOMENTHANINMEN;26=&URTHERMORE -ONASETALARGUETHATTHEGREATER PREVALENCEOF'0INFEMALESMAYREmECTTHEDIFFERENCEINHEALTHCARESEEKINGBEHAVIOR WITHFEMALESSEEKINGHEALTHCAREMOREFREQUENTLYTHANMENINGENERAL;26].

Hyperglycemia in Diabetics and Gastric Emptying )NDIABETES DELAYINGASTRICEMPTYINGMAYBEDUETOELEVATIONSINTHEPLASMAGLUCOSE CONCENTRATIONS;7="LOODGLUCOSECONCENTRATIONOFMMOLLVERSUSMMOLLIN HEALTHY SUBJECTS AND DIABETICS ARE ASSOCIATED WITH DELAY OF BOTH SOLID AND LIQUID EMPTYING;7=!PROFOUNDEFFECTONMOTORFUNCTIONTHROUGHOUTTHE')TRACTCANBE SEENWITHANYACUTECHANGEINTHEBLOODGLUCOSECONCENTRATION WHICHISINDEPENDENT OFANYINTRINSICNEUROPATHY;24].

Hospitalizations 4HENUMBEROFHOSPITALIZATIONSFOR'0HASBEENINCREASINGINTHEPASTDECADE;27]. )NTHE53! HOSPITALIZATIONSFORAPRIMARYDIAGNOSISOF'0HAVEBEENINCREASED ESPECIALLYAMONGTHEELDERLYFROMTO;27=4ABLE2.2 4HEDATAAREBASED ON ALL PAYER INPATIENT CARE DATABASE THE (EALTHCARE #OST AND 5TILIZATION 0ROJECT (#50 .ATIONWIDE)NPATIENT3AMPLE.)3 INTHE53!COVERINGOFHOSPITALS 3TRIKINGLY HOSPITALIZATIONSFOR'0ASTHEPRIMARYDIAGNOSISINCREASEDFROM IN TO IN ANDUSING'0ASTHESECONDARYDIAGNOSISTHEREWAS ANINCREASEOF4HESESTATISTICSREPRESENTANOVERALLINCREASEOFINTHE

/THERUPPER')CONDITIONSASPRIMARYDIAGNOSISa '%2$ 569,048,424 122 258,741 1,266,554,967 Gastric ulcer 478,210 2,120 Gastritis 592,254 1,269 507,760 .AUSEAVOMITING 200,905,164 4ABLEREPRODUCEDWITHPERMISSIONFROM7ANGETAL'ASTROPARESIS 2ELATED(OSPITALIZATIONS!M*'ASTROENTEROL&EB 0AGE WITHPERMISSION GERDGASTROESOPHAGEALREmUXDISEASE a 3OMEHOSPITALIZATIONSHAD'%2$ GASTRICULCER ORNAUSEAVOMITINGASTHEPRIMARYDIAGNOSISANDGASTROPARESISASTHESECONDDIAGNOSIS4HESEHOSPITALIZATIONS WEREINCLUDEDINBOTHGROUPS

Table 2.2 .ATIONALESTIMATESOFLENGTHOFSTAY TOTALCHARGES ANDNUMBEROFIN HOSPITALDEATHSDUETOGASTROPARESISASTHEPRIMARYDIAGNOSIS GASTROPARESISAS THESECONDARYDIAGNOSISORACOMMONUPPER')CONDITIONASTHEPRIMARYDIAGNOSISINTHE53! AND Year 1995 2004 Outcome ,ENGTHOFSTAY 4OTALCHARGES )N HOSPITALDEATH ,ENGTHOFSTAY 4OTALCHARGES )N HOSPITALDEATH 'ASTROPARESISRELATEDHOSPITALIZATIONS Primary diagnosis 29,187 47,726,558 60 62,296 57 1,454 849,667 1,709 Secondary diagnosisa

18 "-OSHIREEETAL


19

53!DURINGn-OREOVER WHEN'0WASCOMPAREDTOOTHER')DISEASES SUCH AS GASTROESOPHAGEAL REmUX DISEASE '%2$ GASTRITIS AND PEPTIC ULCERS '0 PATIENTSHADTHELONGESTLENGTHOFHOSPITALSTAYANDTHESECONDHIGHESTTOTALCHARGES INAND;27='0PATIENTS ASCOMPAREDTOPATIENTSWITHPREDOMINANTLY NAUSEAANDVOMITING EXPERIENCEDMOREINPATIENTPROCEDURES ALONGERLENGTHOFSTAY ANDHIGHERTOTALCHARGES3IMILARLY THELIKELIHOODOFIN HOSPITALDEATHWASLOWERFOR PATIENTSWITH'%2$ASTHEPRIMARYDIAGNOSISTHANFORTHOSEWITH'04HEDRAMATIC INCREASEINHOSPITALIZATIONSFOR'0SEENAFTERISUNEXPLAINED BUTMAYBEREmECTIVEOFANINCREASINGINCIDENCEOF'0AND$- CHANGESINTHE'0DIAGNOSTICCRITERIA ANDMODESOFDIAGNOSIS THELACKOFTREATMENTOPTIONSSUBSEQUENTTOTHEREMOVALOF CISAPRIDEFROMTHE53MARKET ANDAPPROVALOFTHEGASTRICELECTRICALSTIMULATOR BYTHE&OODAND$RUG!DMINISTRATION

Economic Impact of GP 7HILE')DISEASESINTHE53!COSTOVERBILLIONDOLLARSINHEALTHCAREEXPENDITURES THE INPATIENT COST OF '0 AS PRIMARY DIAGNOSIS INCREASED DRAMATICALLY FROM MILLIONINTOMILLIONIN;28=-OREOVER THISUPWARDTRENDINCOSTS MAYCONTINUE AS'0INCREASESWITHTHEINCREASEDINCIDENCEOF$-;27]. "ASEDONTHE.ORTH#AROLINA(OSPITAL$ISCHARGE$ATABASEFROM "ELLETAL FOUND THAT PATIENTS WITH DIAGNOSES OF BOTH $- AND '0 WERE HOSPITALIZED FOR AN AVERAGEHOSPITALSTAYOFDAYSPERADMISSIONANDACCUMULATEDANAVERAGECOSTOF PERHOSPITALVISITWITHMEDICAREASTHEPRIMARYPAYER ;29=-OSTOF THESEPATIENTSWEREADMITTEDDIRECTLYFROMTHEEMERGENCYDEPARTMENT ;29]. !SARESULT PATIENTSWITHBOTH$-AND'0INCURREDABOUT53MILLIONINCHARGES INTHATYEARWITH HOSPITALDAYSFOR DISCHARGES

Impact on Health-Related Quality of Life (EALTH RELATEDQUALITYOFLIFE(21/, ISANIMPORTANTOUTCOMEFORPATIENTSWITH CHRONICILLNESSES INGENERAL ANDHASRECENTLYGAINEDMUCHINTERESTINTHEEPIDEMIOLOGICALLITERATURE!LTHOUGHSTUDIESIN'0PATIENTSARELIMITED (21/,ISREDUCEDIN PATIENTSWITHGASTROPARESIS;0, 1=3YSTEMATICREVIEWSINPATIENTSWITH&$SUGGEST THATIMPAIRMENTOF(21/,EXISTSINPATIENTSWITHMODERATETOSEVERE&$TREATED IN A REFERRAL SETTING AND %L 3ERAG ET AL SUGGEST THAT THE SAME WOULD BE TRUE FOR '0;2=4ALLEYETALSTUDIEDWHETHERDELAYEDGASTRICEMPTYINGINhMEAL RELATEDv DYSPEPSIAIMPAIRS1/, lNDINGTHATALTHOUGH1/,ISIMPAIREDINPATIENTSWITH&$ ASDEMONSTRATEDBYTHE3&GENERIC(21/,INSTRUMENT AND.EPEAN$YSPEPSIA )NDEX.$) ONLYFEMALESEX EPIGASTRICPAIN ANDNAUSEA BUTNOTDELAYEDGASTRIC EMPTYING WEREASSOCIATEDWITHANIMPAIREDTOTAL1/,SCORE;0=7ESPECULATETHAT ANEFFECTIVETHERAPEUTICRESPONSEINPATIENTSWITH'0WILLLEADTOACORRESPONDING IMPROVEMENT IN (21/, ALTHOUGH LARGE RANDOMIZED CONTROLLED TRIALS WOULD BE NECESSARYFORADElNITIVEDETERMINATION

20

"-OSHIREEETAL

Mortality ,ONG TERMSTUDIESINPATIENTSWITH'0INDICATETHAT'0ISPROBABLYNOTABENIGN DISEASE AND HAS CONSIDERABLE MORBIDITY WITH A POOR PROGNOSIS GIVEN THE LIMITED CURRENT THERAPEUTIC OPTIONS ;= -ORTALITY FROM '0 IS HIGHEST IN THE DECOMPENSATED'0PATIENTSMOREATRISKOFDEVELOPINGCOMPLICATIONS;9=&OREXAMPLE 3OYKAN ETALFOUNDOVERA YEARFOLLOW UPPERIODTHATOFTHOSEWITH'0HADDIEDWITH OF PATIENTS WITH '0 NEEDING EITHER LONG TERM ENTERAL OR PARENTERAL FEEDING 4WENTY SIX PERCENT OF THESE PATIENTS DID NOT RESPOND TO MEDICAL THERAPY AND UNDERWENTGASTRICELECTRICALSTIMULATION-ORTALITYINTHEPATIENTSTHATDIEDWAS ATTRIBUTABLE TO METABOLIC DERANGEMENTS CARDIAC COMPLICATIONS RENAL FAILURE SUICIDE ANDORBOWELISCHEMIADUETOADHESIONS /THERDATASUGGESTTHATINDIABETICS '0ISASSOCIATEDWITHHIGHERRISKOFMORBIDITY BUTNOTMORTALITY!USTRALIANPATIENTSWITHTYPEANDDIABETESWEREASSESSED BY SCINTIGRAPHY ') QUESTIONNAIRES AND AUTONOMIC NERVE FUNCTION TESTING AT THE 2OYAL!DELAIDE(OSPITAL;17=4HESUBJECTSWEREFOLLOWEDUPYEARSLATERANDOF PATIENTS HADDIED WITHCAUSESOFDEATHRELATEDTORENALANDCARDIOVASCULAR DISEASE4HOSEPATIENTSWHOHADDIEDHADLONGERDURATIONOFDIABETES HIGHERSCORES BASEDONAUTONOMICTESTING RETINOPATHY ANDSLOWERESOPHAGEALTRANSITTHANTHOSE WHOWEREALIVE BUTNODIFFERENCESINSOLIDORGASTRICEMPTYINGWEREEVIDENT!LARGE STUDYBY(YETTETALOFACOHORTOFPATIENTSINATERTIARYCAREREFERRALCENTER CONDUCTED FROMTO EVALUATEDWHETHERDELAYEDGASTRICEMPTYINGINDIABETICSPREDICTEDMORBIDITYANDMORTALITY;=&IG2. 4HESTUDYCOMPAREDDIABETICSWITH SYMPTOMSOF'0ANDDELAYEDEMPTYINGBASEDONGASTRICEMPTYINGSCINTIGRAPHY TOTHOSEWITHONLYSYMPTOMSOF'0 ANDFOUNDTHATDELAYED'%3WASAPREDICTOR

Fig. 2.3 /UTCOMESBETWEENGROUPSPERPATIENTDAYS2EPRODUCEDWITHPERMISSIONFROM;])


21

OFWORSEPROGNOSISWITHMOREHOSPITALDAYSPER PATIENTDAYSVS EMERGENCY ROOM VISITS MORE OFlCE VISIT PROCEDURES SUCH AS UPPER ENDOSCOPY PERFORMEDANDINCREASEDPREVALENCEOFOTHERCOMORBIDCONDITIONS SUCHASCORONARY ARTERYDISEASE ANDHYPERTENSION(OWEVER DELAYEDGASTRICEMPTYINGALONEINDIABETICS WAS NOT ASSOCIATED WITH HIGHER MORTALITY -ORE WORK IS NEEDED TO DElNE WHETHERDIABETICGASTROPARESISIMPACTSONMORTALITY 4HE YEAR ESTIMATED SURVIVAL OF /LMSTED #OUNTY RESIDENTS WITH DElNITE '0 SYMPTOMSANDDIAGNOSTICTESTINGCONSISTENTWITH'0 WAS#) n SIGNIlCANTLY LESS THAN THAT EXPECTED IN THAT POPULATION OF ;10= !MONG THE CAUSES OF DEATH IN THIS COHORT WERE CARDIOVASCULAR DISEASES RESPIRATORY FAILURE ANDCHRONICRENALFAILURE /LDERAGEATDIAGNOSISWASASSOCIATEDWITHDECREASEDSURVIVAL.ONDIABETIC'0INTHISCOHORTWASALSOASSOCIATED WITHABETTERSURVIVALTHANDIABETIC'0/THERDATASUGGESTTHATPOSTVIRAL'0HASA BETTERPROGNOSISANDASHORTERDURATIONOFDISEASETHAN)'0;4].

Future Studies 3EVERALGAPSEXISTINOURCURRENTKNOWLEDGEONTHEEPIDEMIOLOGYOF'03OMEOF THESEDElCIENCIESAREATTRIBUTABLETOTHESUBOPTIMALDElNITIONOF'0ANDALACKOF DIFFERENTIATION FROM &$ 7E LACK A CLEAR UNDERSTANDING OF ETHNIC DIFFERENCES IN PATIENTPOPULATIONSWITH'0&URTHERMORE ANUNDERSTANDINGOFTHENATURALHISTORYOF '0ASITRELATESTOTHEPEDIATRICPOPULATIONISUNKNOWN4HE.)$$+CREATEDA'0 REGISTRY IN TO UNDERTAKE AN OBSERVATIONAL STUDY TO CLARIFY THE EPIDEMIOLOGY NATURALHISTORY CLINICALCOURSE ANDOUTCOMESOF'0 ANDTHISSHOULDANSWERSOMEOF THESEQUESTIONS&UTURETECHNOLOGIES SUCHASSWALLOWEDWIRELESSMOTILITYCAPSULE USING TELEMETRY 3MART0ILL 3MART0ILL )NC "UFFALO .9 OFFER A NONRADIOACTIVE METHODFORASSESSINGGASTRICTRANSITTIMEINTHEAMBULATORYSETTING;5=/NCESUCH TESTSBECOMEAFFORDABLEANDWIDELYAVAILABLEFORUSEINTHEGENERALPOPULATION THE CURRENTESTIMATESOFINCIDENCEANDPREVALENCEOF'0INTHEGENERALPOPULATIONMAY CHANGESIGNIlCANTLY

Conclusions '0REPRESENTSAMAJORDISEASEBURDENASSOCIATEDWITHINCREASEDEMERGENCYROOM VISITS HOSPITALIZATIONS COMPLICATIONSANDPOORERSURVIVAL ESPECIALLYINTHEELDERLY "ECAUSETHENATURALHISTORYOF'0HASBEENINVESTIGATEDONLYOVERTHEPASTDECADE THELONG TERMOUTCOMEISNOTCLEARLYDElNED-OREAGGRESSIVESTRATEGIESTOSCREEN DIABETICSFOR'0 ANDBETTERDElNEDMANAGEMENTSTRATEGIESFORALLAFFECTEDARENECESSARYTOREDUCETHEMORBIDITYANDMORTALITYASSOCIATEDWITHTHISUSUALLYCHRONICAND DEBILITATINGCONDITION

22

"-OSHIREEETAL

References 4ALLEY.* 6ERLINDEN- *ONES-#ANSYMPTOMSDISCRIMINATEAMONGTHOSEWITHDELAYEDOR NORMALGASTRICEMPTYINGINDYSMOTILITY LIKEDYSPEPSIA!M*'ASTROENTEROLn #HERIAN$ 3ACHDEVA0 &ISHER23 0ARKMAN(0!BDOMINALPAINISAFREQUENTSYMPTOMOF GASTROPARESIS#LIN'ASTROENTEROL(EPATOLn 4ACK* 4ALLEY.* #AMILLERI- ETAL&UNCTIONALGASTRODUODENALDISORDERS'ASTROENTEROLOGY n !NAPARTHY2 0EHLIVANOV. 'RADY* 9IMEI( 0ASRICHA0*'ASTROPARESISANDGASTROPARESIS LIKE SYNDROMERESPONSETOTHERAPYANDITSPREDICTORS$IG$IS3CIn ,OCKE)))'24HEEPIDEMIOLOGYOFFUNCTIONALGASTROINTESTINALDISORDERSIN.ORTH!MERICA 'ASTROENTEROL#LIN.ORTH!M n (OROWITZ- 3U9 # 2AYNER#+ *ONES+,'ASTROPARESISPREVALENCE CLINICALSIGNIlCANCE ANDTREATMENT#AN*'ASTROENTEROL n 3CHVARCZ% 0ALMER- !MAN* (OROWITZ- 3TIDSBERG- "ERNE#0HYSIOLOGICALHYPERGLYCEMIASLOWSGASTRICEMPTYINGINNORMALSUBJECTSANDPATIENTSWITHINSULIN DEPENDENTDIABETES MELLITUS'ASTROENTEROLOGYn 4OUGAS' #HEN9 #OATES' ETAL3TANDARDIZATIONOFASIMPLIlEDSCINTIGRAPHICMETHODOLOGY FORTHEASSESSMENTOFGASTRICEMPTYINGINAMULTICENTERSETTING!M*'ASTROENTEROL n 3OYKAN) 3IVRI" 3AROSIEK) +IERNAN" -C#ALLUM27$EMOGRAPHY CLINICALCHARACTERISTICS PSYCHOLOGICALANDABUSEPROlLES TREATMENT ANDLONG TERMFOLLOW UPOFPATIENTSWITHGASTROPARESIS$IG$ISAND3CI n *UNG( #HOUNG23 ,OCKE)))'2 3CHLECK#$ :INSMEISTER!2 3ZARKA,! ETAL4HEINCIDENCE PREVALENCE ANDOUTCOMESOFPATIENTSWITHGASTROPARESISIN/LMSTED#OUNTY -INNESOTA FROM n'ASTROENTEROLOGYn 3TANGHELLINI6 4OSETTI# 0ATERNICO! "ARBARA' -ORSELLI ,ABATE!- -ONETTI. ETAL2ISK INDICATORS OF DELAYED GASTRIC EMPTYING OF SOLIDS IN PATIENTS WITH FUNCTIONAL DYSPEPSIA 'ASTROENTEROLOGYn 4ALLEY.* :INSMEISTER!2 3CHLECK#$ ETAL$YSPEPSIAANDDYSPEPSIASUBGROUPSAPOPULATION BASEDSTUDY'ASTROENTEROLOGYn !GREUS, 3VARDSUDD+ .YREN/ ETAL4HEEPIDEMIOLOGYOFABDOMINALSYMPTOMS0REVALENCE ANDDEMOGRAPHICCHARACTERISTICSINA3WEDISHADULTPOPULATION!REPORTFROMTHE!BDOMINAL 3YMPTOM3TUDY3CAND*'ASTROENTEROL n *ONES2( ,YDEARD3% (OBBS&$ ETAL$YSPEPSIAIN%NGLANDAND3COTLAND'UT n #HANG#3 +AO#( 7ANG93 ETAL$ISCREPANTPATTERNOFSOLIDANDLIQUIDGASTRICEMPTYINGIN #HINESEPATIENTSWITHTYPE))DIABETESMELLITUS.UCL-ED#OMMUNn *ONES+, 2USSO! 3TEVENS*% 7ISHART*- "ERRY-+ (OROWITZ-0REDICTORSOFDELAYED GASTRICEMPTYINGINDIABETES$IABETES#AREn +ONG-& (OROWITZ- *ONES+, 7ISHART*- (ARDING0%.ATURALHISTORYOFDIABETICGASTROPARESIS$IABETES#AREn (OROWITZ - (ARDING 0% -ADDOX !& 7ISHART *- !KKERMANS ,- #HATTERTON "% ET AL 'ASTRICANDESOPHAGEALEMPTYINGINPATIENTSWITHTYPENON INSULIN DEPENDENT DIABETESMELLITUS$IABETOLOGIA n "YTZER0 4ALLEY.* ,EEMON- ETAL0REVALENCEOFGASTROINTESTINALSYMPTOMSASSOCIATEDWITH DIABETES MELLITUS A POPULATION BASED SURVEY OF ADULTS !RCH )NTERN -ED n 7ORLD (EALTH /RGANIZATION 7(/ $IABETES &ACT 3HEET HTTPWWWWHOINTMEDACENTER FACTSHEETSFSENPRINTHTMLACCESSED.OVEMBER -ALEKI $ ,OCKE ))) 2' #AMILLERI - :INSMEISTER !2 9AWN "0 ,EIBSON # ET AL 'ASTROINTESTINALTRACTSYMPTOMSAMONGPERSONSWITHDIABETESMELLITUSINTHECOMMUNITY!RCH )NTERN-EDn


(AMMER* (OWELL3 "YTZER0 (OROWITZ- 4ALLEY.*3YMPTOMCLUSTERINGINSUBJECTSWITH AND WITHOUT DIABETES MELLITUS A POPULATION BASED STUDY OF !USTRALIAN ADULTS !M *'ASTROENTEROLn *ONES+, 2USSO! "ERRY-+ 3TEVENS*% 7ISHART*- (OROWITZ-!,ONGITUDINALSTUDYOF GASTRICEMPTYINGANDUPPERGASTROINTESTINALSYMPTOMSINPATIENTSWITHDIABETESMELLITUS!M *-EDn 2AYNER#+ 3AMSON- *ONES+, (OROWITZ-2ELATIONSHIPSOFUPPERGASTROINTESTINALMOTOR ANDSENSORYFUNCTIONWITHGLYCEMICCONTROL$IABETES#AREn 7ALD! 6AN4HIEL$( (OECHSTETTER, 'AVALER*3 %GLER+- 6ERM2 ETAL'ASTROINTESTINAL TRANSITTHEEFFECTOFTHEMENSTRUALCYCLE'ASTROENTEROLOGY n -ONES* #ARRIO) #ALABUIG2 ETAL)NmUENCEOFTHEMENSTRUALCYCLEANDOFMENOPAUSEONTHE GASTRICEMPTYINGRATEOFSOLIDSINFEMALEVOLUNTEERS%UR*.UC-EDn 7ANG92 &ISHER23 0ARKMAN(0'ASTROPARESIS RELATEDHOSPITALIZATIONSINTHE5NITED3TATES TRENDS CHARACTERISTICS ANDOUTCOMES n!M*'ASTROENTEROL&EB n %PUB.OV 3ANDLER23ETAL4HEBURDENOFSELECTEDDIGESTIVEDISEASESINTHE5NITED3TATES'ASTROENTEROLOGY "ELL2! *ONES 6ESSEY+ 3UMMERSON*((OSPITALIZATIONSANDOUTCOMESFORDIABETICGASTROPARESISIN.ORTH#AROLINA3OUTH-ED* n 4ALLEY.* ,OCKE)))'2 ,AHR"$ :INSMEISTER!2 4OUGAS' ,IGOZIO' ETAL&UNCTIONAL DYSPEPSIA DELAYEDGASTRICEMPTYING ANDIMPAIREDQUALITYOFLIFE'UTn 3AMUEL- "ADILO2 7ASEEM3 ,U8IAOMIN 4ALLEY.* -OSHIREE"3EVERITYOFSYMPTOMS IN GASTROPARESIS CORRELATES DIRECTLY WITH HIGHER DISABILITY SCORES !M * 'ASTROENTEROL /CT3UPPL ! %L 3ERAG(" 4ALLEY.*3YSTEMATICREVIEWHEALTH RELATEDQUALITYOFLIFEINFUNCTIONALDYSPEPSIA !LIMENT0HARMACOL4HERn (YETT" -ARTINEZ&* 'ILL"- -EHRA3 ,EMBO! +ELLEY#0 ETAL$ELAYEDRADIONUCLEOTIDE GASTRIC EMPTYING STUDIES PREDICT MORBIDITY IN DIABETICS WITH SYMPTOMS OF GASTROPARESIS 'ASTROENTEROLOGY n "ITYUTSKIY,0 3OYKAN) -C#ALLUM276IRALGASTROPARESISASUBGROUPOFIDIOPATHICGASTROPARESIS n CLINICAL CHARACTERISTICS AND LONG TERM OUTCOMES !M * 'ASTROENTEROL n +UO" -C#ALLUM27 +OCH+, 3ITRIN-$ 7O*- #HEY7$ ETAL#OMPARISIONOFGASTRIC EMPTYING OF A NONDIGESTIBLE CAPSULE TO A RADIO LABELLED MEAL IN HEALTHY AND GASTROPARETIC SUBJECTS!LIMENT0HARMACOL4HERn

sdfsdf

Chapter 3

Clinical Presentations of Gastroparesis Shilpa C. Reddy and John M. Wo

Keywords 'ASTROPARESISs#LINICALPRESENTATIONs.AUSEAs6OMITINGs!BDOMINAL PAINs2EGURGITATION

Introduction The clinical presentation of gastroparesis is very heterogeneous. Some patients present with predominant symptoms of nausea and vomiting resulting in weight loss, dehydration, and frequent hospitalizations. Some may present with early satiety, postpranDIAL FULLNESS EPIGASTRIC PAIN AND ABDOMINAL DISTENSION SUGGESTIVE OF POSTPRANDIAL distress syndrome of functional dyspepsia while others may report effortless regurGITATIONANDHEARTBURNRESEMBLINGGASTROESOPHAGEALREmUXDISEASE'%2$ )T IS IMPORTANT TO RECOGNIZE THAT THE PRESENCE OF DELAYED GASTRIC EMPTYING BY SCINTIGRAPHYORBREATHTESTINGDOESNOTALWAYSIMPLYADIAGNOSISOFGASTROPARESIS Gastroparesis is a clinical syndrome with chronic and recurrent symptoms. %STABLISHINGTHECAUSEANDEFFECTBETWEENGASTRICEMPTYINGIMPAIRMENTANDSYMPTOM GENERATIONCANBEDIFlCULTBECAUSETHEPATHOPHYSIOLOGYOFTHEDEVELOPMENTOFUPPER gastrointestinal symptoms is multifactorial. These symptoms involve gastric motor ANDSENSORYFUNCTION THEENTERICNERVOUSSYSTEM ANDTHEINTERACTIONBETWEENTHE CENTRALNERVOUSSYSTEMANDTHESTOMACH4HISMAYEXPLAINWHYTHESEVERITYOFGASTRIC emptying impairment, a measurement of motor dysfunction only, correlates poorly WITHSEVERITYOFSYMPTOMS4HEREISANURGENTNEEDTOIDENTIFYSPECIlCMARKERSOR characteristics which can predict prognosis and improve the management strategy of this heterogeneous syndrome. In this chapter, the many facets of the clinical presentation of gastroparesis are presented. J.M. Wo (*) Division of Gastroenterology/Hepatology, University of Indiana, 3CHOOLOF-EDICINE 7ISHARD"LVD 3UITE )NDIANAPOLIS ). 53! e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_3, © Springer Science+Business Media, LLC 2012

25

26

S.C. Reddy and J.M. Wo

Symptoms Associated with Gastroparesis 'ASTROPARESISHASBEENASSOCIATEDWITHNAUSEA VOMITING EARLYSATIETY BLOATING AND epigastric pain. These symptoms are very common in the general population. They MAYORMAYNOTBERELATEDTOGASTROPARESIS&ORTY lVEPERCENTOFTHEADULTSINTHE53 report at least one of these upper gastrointestinal symptoms over a 3-month period [1]. !DETAILEDCLINICALHISTORYISIMPORTANTTODETERMINEIFSYMPTOMSAREASSOCIATEDWITH DELAYEDGASTRICEMPTYING3YMPTOMSSHOULDBEEXACERBATEDWITHEATING ESPECIALLY AFTERFATTYFOODSANDINDIGESTIBLESOLIDS SUCHASSALADSANDLEAFYVEGETABLES(OWEVER persisting symptoms for many hours after meal ingestion are common. The symptoms and pathophysiology of gastroparesis and functional dyspepsia overlap. Patients with postprandial distress and/or epigastric pain with mild gastric EMPTYING IMPAIRMENT MAY BE CONSIDERED TO HAVE FUNCTIONAL DYSPEPSIA BY SOME PHYSICIANSANDGASTROPARESISBYOTHERS0ATIENTSWITHAMARKEDDELAYINGASTRICEMPTYINGSHOULDBECONSIDEREDTOHAVEGASTROPARESISINSTEADOFFUNCTIONALDYSPEPSIA;2].

Nausea, Retching, and Vomiting .AUSEAISASUBJECTIVESYMPTOMANDDIFlCULTTODElNE0ATIENTSOFTENFEELTHEYARE ABOUT TO VOMIT AND THEY USE TERMS SUCH AS hSICK TO THE STOMACHv OR hQUEASYv 3EVERITYOFNAUSEAISDIFlCULTTOMEASUREASITDEPENDSONSUBJECTIVEREPORTINGBYTHE patient. Different aspects of nausea, such as frequency, intensity, and duration, have BEENQUANTIlEDINPASTSTUDIESOFPATIENTSWITHCHEMOTHERAPY INDUCEDNAUSEA;3]. )NGASTROPARESIS NAUSEASHOULDBEPOSTPRANDIAL BUTMORNINGNAUSEAORPERSISTENT NAUSEAMAYBEPRESENT4HEINTENSITYOFNAUSEAMAYBECOMEDEBILITATINGENOUGHTO BECOMETHECHIEFCOMPLAINTINSOMEPATIENTSWITHGASTROPARESIS BUTITSHOULDNOTBE out of proportion to the other upper gastrointestinal symptoms. %MESISISANEVENTASSOCIATEDWITHRETCHINGANDFORCEFULEVACUATIONOFGASTRIC content in a retrograde fashion from the stomach up to and out of the mouth. Some PATIENTSMAYHAVERETCHINGWITHOUTEXPULSIONOFGASTRICCONTENTS%MESISANDRETCHING AREUSUALLYPOSTPRANDIALANDOCCURSOONAFTEREATING BUTTHEYCANOCCURHOURSAFTER MEAL INGESTION IN PATIENTS WITH VERY POOR GASTRIC EMPTYING %MESIS IMMEDIATELY after starting a meal should suggest other causes other than gastroparesis. The term hVOMITINGvISMORESUBJECTIVETHANEMESISBECAUSEhVOMITINGvISOFTENUSEDBYTHE PATIENT TO DESCRIBE BOTH EMESIS AND EFFORTLESS REGURGITATION OF UNDIGESTED FOODS 4HIS DISTINCTION BETWEEN EMESIS AND EFFORTLESS REGURGITATION MAY BE IMPORTANT %MESISISANEVENTRESULTINGFROMVISCERALAFFERENTINPUTFROMTHEABDOMINALVAGUS nerve to the central nervous system [4=%MESISMAYBEABSENTIFTHESEPATHWAYSARE not activated, such as in patients with postvagotomy gastroparesis, who may present with effortless regurgitation of undigested foods without retching. However, the PATHOPHYSIOLOGICDIFFERENCEBETWEENEMESISANDEFFORTLESSREGURGITATIONINGASTROPARESISHASYETTOBEDETERMINED

3 Clinical Presentations of Gastroparesis

27

Postprandial Fullness, Satiation, and Early Satiety Postprandial fullness is an unpleasant sensation of stomach fullness after meals. 0ATIENTSMAYDESCRIBEPOSTPRANDIALFULLNESSASAPROLONGEDSENSATIONOFFOODREMAINING in the stomach. Satiation is the disappearance of the hunger sensation after consumINGFOOD)TISTHEOPPOSITEOFHUNGERANDAPPETITE%ARLYSATIATIONISTHEEARLYDISAPPEARINGOFAPPETITEDURINGFOODINGESTIONANDBEFORENUTRIENTABSORPTION0ATIENTSOF GASTROPARESIS MAY DESCRIBE EARLY SATIATION AS LOSS OF APPETITE OR DISAPPEARING OF APPETITEWHILEEATING%ARLYSATIETYISAFEELINGOFSTOMACHFULLNESSSOONAFTERSTARTING to eat, out of proportion to the size of the meal. )T IS DIFlCULT TO DISTINGUISH BETWEEN THE COMPLAINTS OF POSTPRANDIAL FULLNESS satiation, and early satiety in patients with gastroparesis. These three complaints are GROUPEDTOGETHERINTHEPOSTPRANDIALFULLNESSEARLYSATIETYSUBSCALEOFTHEGASTROPARESISCARDINALSYMPTOMINDEX'#3) ;5]. Patients with gastroparesis often report a PROLONGEDPERIODOFSTOMACHFULLNESSAFTEREATING UNABLETOlNISHANORMALSIZED meal, and a loss of appetite. However, these are the same symptoms associated with FUNCTIONAL DYSPEPSIA WHERE ABOUT ONE THIRD OF THE PATIENTS HAVE DELAYED GASTRIC emptying of solids [6, 7=&EMALEGENDER POSTPRANDIALFULLNESS ANDVOMITINGSEEM to predict a greater prevalence of delayed gastric emptying in patients with functional DYSPEPSIA)THASBEENSUGGESTEDTHATSYMPTOMSBEGINNINGIMMEDIATELYORWITHIN 30 min after food ingestion are less likely due to gastroparesis. However, in a study of symptom measurement during 4-h gastric scintigraphy, the sensation of stomach fullness occurs and peaks immediately after ingestion of the standardized meal in patients with documented delayed gastric emptying [8].

Bloating and Abdominal Distension "LOATING IS ALSO A VERY SUBJECTIVE SENSATION OF INCREASED ABDOMINAL PRESSURE "LOATINGCANOCCURWITHOUTEATINGANDSHOULDBEDIFFERENTIATEDFROMPOSTPRANDIAL FULLNESS)TMAYORMAYNOTBERELATEDTOFOODINGESTION)NAPOPULATIONSURVEYOF UPPER GASTROINTESTINAL SYMPTOMS OF OVER ADULTS THE SENSATION OF BLOATING WASIDENTIlEDASASEPARATESYMPTOM SUBGROUPDISTINCTFROMNAUSEAVOMITINGAND POSTPRANDIALFULLNESSBYSTATISTICALCLUSTERANALYSIS;1]. In patients with functional DYSPEPSIA THEASSOCIATIONBETWEENBLOATINGANDDELAYEDGASTRICEMPTYINGHASBEEN MIXED;9, 10]. "LOATING SHOULD ALSO BE DISTINGUISHED FROM ABDOMINAL DISTENSION WHERE THE ABDOMEN IS VISIBLY LARGER WITH AN INCREASE OF ABDOMINAL GIRTH BY MEASUREMENT )NSOMEPATIENTS ABDOMINALDISTENSIONISMINIMALINTHEMORNINGBUTPROGRESSIVELY GETSWORSETHROUGHOUTTHEDAY3IGNIlCANTABDOMINALDISTENSIONMAYSUGGESTTHE PRESENCE OF SMALL INTESTINAL BACTERIAL OVERGROWTH OR CHRONIC INTESTINAL PSEUDOOBSTRUCTIONOFTHESMALLBOWEL;11].

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Abdominal Pain !BDOMINALDISCOMFORTORPAINISCOMMON OCCURRINGINnOFTHEPATIENTSWITH gastroparesis [12n15=0REVALENCEOFABDOMINALPAININGASTROPARESISISCOMPARABLE to functional dyspepsia [7, 14]. Patients with idiopathic gastroparesis may have more FREQUENT ABDOMINAL PAIN THAN THOSE WITH DIABETIC GASTROPARESIS ;14]. Postprandial EPIGASTRICPAINISPERCEIVEDBYPHYSICIANSASTHEMOSTCOMMONPRESENTATIONOFGASTROPARESIS MORETHANRETCHINGVOMITINGANDHEARTBURNREGURGITATION;16=!BDOMINAL pain is an important complaint for the patient, and it correlates with impairment of quality-of-life [14]. 4HECHARACTERISTICSOFABDOMINALPAINAREVARIABLE!BOUTOFPATIENTSHAVE LOCALIZEDEPIGASTRICPAIN BUTITCANBEDIFFUSEDINSOMEPATIENTS;14]. Pain is usually CHARACTERIZEDASPOSTPRANDIAL BUTITCANBECONSTANT OCCURATNIGHT ANDINTERFERE WITHSLEEP4HECAUSEANDEFFECTBETWEENDELAYEDGASTRICEMPTYINGANDABDOMINAL pain is poorly understood. The impairment of gastric emptying does not correlate WITHTHEINTENSITYOFABDOMINALPAIN;14, 17]. Persistent epigastric pain not related to meal ingestion should suggest epigastric pain syndrome of functional dyspepsia, rather than gastroparesis [18=)NPATIENTSWITHGASTROPARESIS THEPRESENCEOFABDOMINAL pain predicts poor response to gastric electrical stimulator placement [19].

Heartburn and Regurgitation 'ASTROPARESIS HAS BEEN CONSIDERED A POTENTIAL CAUSE FOR '%2$ (OWEVER THE precise mechanism on how delayed gastric emptying cause acid and nonacidic REmUX HAS BEEN DIFlCULT TO DETERMINE ;20= 3TUDIES HAVE SHOWN THAT n OF PATIENTSWITH'%2$ALSOHAVEDELAYEDGASTRICEMPTYING;21n23= BUTTHISMAYBEAN OVERESTIMATIONDUETOPATIENTSELECTIONINSTUDIESFROMTERTIARYCENTERS.EARLY OFPATIENTSWITHGASTROPARESISPRESENTWITHHEARTBURNANDORREGURGITATIONASTHEIR chief complaints [24=)TISESSENTIALTOOBTAINADETAILEDHISTORYINPATIENTSWHOARE REFRACTORY TO PROTON PUMP INHIBITORS 4HE PRESENCE OF EFFORTLESS REGURGITATION OF undigested foods, nausea, postprandial distress, or early satiety should suggest the POSSIBILITY OF GASTROPARESIS AND THE DIAGNOSTIC EVALUATION SHOULD BE REDIRECTED &UNDOPLICATIONSHOULDBEAVOIDEDTOPREVENTPOSTFUNDOPLICATIONGAS BLOATSYNDROME

Psychological Issues Associated with Gastroparesis It is important to consider the psychological state in patients with gastroparesis. .EARLY HALF OF PATIENTS REFERRED TO TERTIARY CENTERS HAVE EVIDENCE OF MODERATE TO SEVERE DEPRESSION AND MORE THAN HALF HAVE CLINICALLY SIGNIlCANT TEMPORARY AND PROLONGEDSYMPTOMSOFANXIETY;25]. These psychological illnesses are often unrecOGNIZEDANDUNTREATEDINMANYPATIENTS4HEPRESENCEOFDEPRESSIONANDANXIETYARE


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ASSOCIATEDWITHMOREFREQUENTHOSPITALIZATIONSANDSEVEREGASTROPARESISBYPHYSICIAN and patient assessments [15, 25]. However, psychological dysfunction is not associated with the etiology or severity of gastric retention [25]. )TISUNCLEARIFTHEPSYCHOLOGICALILLNESSISCONTRIBUTINGTOSYMPTOMGENERATION ORISARESULTOFTHECHRONICDISEASEBURDENOFGASTROPARESIS!SINIRRITABLEBOWEL SYNDROMEANDFUNCTIONALDYSPEPSIA PASTPHYSICALANDSEXUALABUSEMAYBEPRESENT in some patients with gastroparesis [12=0SYCHOLOGICISSUESSHOULDBEADDRESSED ANDAPPROPRIATEPHARMACOLOGICTHERAPYANDCONSULTATIONSHOULDBEINITIATED ESPECIALLY in patients with refractory gastroparesis.

Predominant Symptom Presentation 4HETERMhGASTROPARESIS vWHICHIMPLIESAPARALYZEDSTOMACH DOESNOTDESCRIBE the whole spectrum of this heterogeneous clinical syndrome. The severity of gastric emptying impairment does not correlate with the severity of symptoms. Physicians OFTENFEELOVERWHELMEDBECAUSEPATIENTSWITHGASTROPARESISPRESENTWITHMULTIPLE functional symptoms with varying intensity. It is essential to identify the most important chief complaints of each patient to focus the clinical history and to FORMULATEAMANAGEMENTSTRATEGY)TMAYBEUSEFULTOCONCEPTUALIZEPATIENTSWITH GASTROPARESISINTOTHREEDISTINCTSUBGROUPSBASEDONPREDOMINANTSYMPTOMPRESENTATIONS4ABLE3.1) [24]. However, there is no data at this time to support the CLINICALUSEFULNESSOFANYCLASSIlCATIONINPREDICTINGOUTCOMEORTOIMPROVECLINICAL management. 6OMITING PREDOMINANTGASTROPARESISCONSISTSOFPATIENTSWITHCHIEFCOMPLAINTS of nausea, retching, and vomiting, often resulting in dehydration, weight loss, and HOSPITALIZATION 4ABLE 3.1). Regurgitation-predominant gastroparesis consists of PATIENTSOFTENDESCRIBEDASHAVING'%2$ BUTTHEYALSOHAVESYMPTOMSOFNAUSEA postprandial fullness, and early satiety. These patients report regurgitation of undigested foods without retching, occurring many hours after meal ingestion or at night while they are asleep. Rumination, which is the immediate regurgitation of

Table 3.1 0ROPOSEDCLASSIlCATIONOFGASTROPARESISBASEDONPREDOMINANT SYMPTOMPRESENTATION $ElNITIONS 6OMITING PREDOMINANT 6OMITINGWITHRETCHINGANDNAUSEAARETHEMOSTBOTHERSOME gastroparesis symptoms Dyspepsia-predominant 5NPLEASANTORTROUBLESOMESENSATIONDISCOMFORTORPAIN gastroparesis CENTEREDINTHEUPPERABDOMENISTHEMOSTBOTHERSOME SYMPTOMTHISSENSATIONMAYBECHARACTERIZEDBYORASSOCIATED WITHUPPERABDOMINALFULLNESS FULLNESSAFTERSMALLMEALS BLOATING ORNAUSEA Regurgitation-predominant %FFORTLESSREGURGITATIONOFACIDORUNDIGESTEDFOODORHEARTBURN gastroparesis ISTHEMOSTBOTHERSOMESYMPTOM

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PARTIALLYDIGESTEDFOODTHATISSUBSEQUENTLYRESWALLOWED SHOULDNOTBEASSOCIATED with gastroparesis. Dyspepsia-predominant gastroparesis consists of patients INDISTINGUISHABLE FROM THOSE WITH POSTPRANDIAL DISTRESS SYNDROME OF FUNCTIONAL dyspepsia [18]. 3UBSCALE SCORES OF NAUSEAVOMITING AND HEARTBURNREGURGITATION USING THE PATIENTASSESSMENTOFGASTROINTESTINALSYMPTOM0!') 39- SEVERITYINDEX HAVE BEEN ASSOCIATED WITH THE VOMITING PREDOMINANT AND REGURGITATION PREDOMINANT GASTROPARESIS SUBGROUPS RESPECTIVELY ;24, 26]. However, the patients in the DYSPEPSIA PREDOMINANTGASTROPARESISSUBGROUPHAVEMULTIPLESYMPTOMSWITHVARIABLE INTENSITY4HISSUBGROUPWASUNABLETOBECHARACTERIZEDBYANYOFTHE0!')SYMPTOM SUBSCALES

Symptom Patterns 0ATTERNS OF PRESENTATION AND PROGRESSION IN GASTROPARESIS ARE VARIABLE 0ATIENTS SHOULDBEINQUIREDREGARDINGANYPRESENCEOFACUTERESPIRATORYORGASTROINTESTINAL INFECTIONBEFOREDEVELOPINGTHESYMPTOMSOFGASTROPARESIS!POST INFECTIOUSGASTROPARESISSYNDROMEHASBEENDESCRIBEDINRETROSPECTIVESERIESWITHISOLATIONOFBOTH THECYTOMEGALOVIRUSAND%PSTEIN "ARRVIRUSES;27, 28]. In these patients, symptoms MAYIMPROVEWITHTIME BUTLONGITUDINALCOHORTSTUDIESTOCONlRMTHISASSUMPTION is limited. However, most patients with gastroparesis report gradual onset of symptoms without any particular triggering event. 'ASTROPARESISISACHRONICANDRECURRENTSYNDROME BUTSYMPTOMPROGRESSIONIS VARIABLE3OMEPATIENTSHAVECHRONICSTABLEPOSTPRANDIALSYMPTOMSWITHMINIMAL mUCTUATIONS/THERSMAYREPORTPROGRESSIVEWORSENINGOFTHEIRSYMPTOMS0ERIODIC EXACERBATION MAY BE COMMON ESPECIALLY IN PATIENTS WITH VOMITING PREDOMINANT symptoms. In a retrospective review of patients with gastroparesis, poor glycemic CONTROLINDIABETICS INFECTION POORCOMPLIANCE ANDINTOLERANCEOFMEDICATIONSHAVE BEENIDENTIlEDASTHECULPRITFORANACUTEEXACERBATIONREQUIRINGHOSPITALIZATION;29]. !CYCLICPATTERNWITHRECURRENTNAUSEAANDVOMITINGWITHSYMPTOM FREEINTERVALS HASBEENDESCRIBEDINSOMEPATIENTSWITHDIABETICGASTROPARESIS;30]. These patients tend to have a higher incidence of migraine headache, greater impairment of gastric EMPTYING ANDMOREABNORMALITIESBYELECTROGASTROGRAPHY%''

Assessment of Disease Severity Measurement of Symptom Severity 3EVERALSYMPTOMSCALESHAVEBEENDEVELOPEDTOQUANTIFYAPATIENTSOWNASSESSMENT of gastroparesis symptoms [31n34=(OWEVER ONLYTHE'#3)HASBEENEXTENSIVELY VALIDATED AND FOUND TO BE RELIABLE AND RESPONSIVE TO CHANGES AND CORRELATE WITH


31

Table 3.2 'ASTROPARESISCARDINALSYMPTOMINDEXa 3UBSCALES Symptoms .AUSEAVOMITING s .AUSEAFEELINGSICKTOYOURSTOMACHASIFYOUWEREGOINGTOVOMIT or throw up) s 2ETCHINGHEAVINGASIFTOVOMIT BUTNOTHINGCOMESUP s 6OMITING Postprandial fullness/ early satiety

s s s s

3TOMACHFULLNESS .OTABLETOlNISHANORMAL SIZEDMEAL &EELINGEXCESSIVELYFULLAFTERMEALS ,OSSOFAPPETITE

s "LOATINGFEELINGLIKEYOUNEEDTOLOOSENYOURCLOTHES s 3TOMACHORBELLYVISIBLYLARGER a Graded from 0 to 5 (0 = none; 1 = very mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe) with a 2-week recall period Bloating

PHYSICIAN AND PATIENT ASSESSMENT 4ABLE 3.2) [34]. The GCSI is a multinational instrument with a 6-point Likert response scale ranging from 0 (none) to 5 (very severe). 4HE '#3) CONSISTS OF NINE SYMPTOMS WITH THREE SUBSCALES NAUSEAVOMITING POSTPRANDIALFULLNESSEARLYSATIETY ANDBLOATING THATAREGRADEDBYTHEPATIENTWITH ASYMPTOMRECALLOFWEEKS4ABLE3.2). Daily evaluation of the GCSI appears TO MAINTAIN ITS VALIDITY AND RELIABILITY ;35]. Bloating is differentiated from postprandial fullness/early satiety and nausea/vomiting in the GCSI, in a similar manner THATBLOATINGWASIDENTIlEDASADISTINCTSYMPTOMSUBGROUPBYSTATISTICALCLUSTER analysis [1]. 4HE'#3)WASDEVELOPEDASAPARTOFTHE0!') 39-SEVERITYINDEX WHICHWAS DESIGNEDASASINGLEINSTRUMENTFORPATIENTSWITH'%2$ FUNCTIONALDYSPEPSIA AND gastroparesis [26=4HE'#3)DOESNOTINCLUDETHEHEARTBURNREGURGITATIONITEMS UPPERABDOMINALPAINITEMS ANDLOWERABDOMINALPAINSUBSCALESITEMS OF THE0!') 39-SEVERITYINDEX3INCETHESYMPTOMSOFGASTROPARESISOVERLAPWITH '%2$ANDFUNCTIONALDYSPEPSIA ITISREASONABLETOUSETHEFULL0!') 39-INDEX in assessing the clinical spectrum of gastroparesis and its predominant-symptom presentation.

Measurement of Quality-of-Life !SSESSMENT OF QUALITY OF LIFE 1/, IS IMPORTANT IN UNDERSTANDING THE PATIENTS SYMPTOMSEVERITYANDIMPLICATIONSONTHEIRLIFE4HE3& (EALTH3URVEYISASELF administered 36-item questionnaire designed to measure generic health status of THEPATIENT)TCOMPRISESEIGHTMULTI ITEMSUBSCALESPHYSICALFUNCTION ROLELIMITATION DUE TO PHYSICAL HEALTH PROBLEM VITALITY GENERAL HEALTH PERCEPTIONS BODILY PAIN SOCIAL FUNCTIONING ROLE LIMITATION DUE TO EMOTIONAL PROBLEMS AND MENTAL health. The physical component summary (PCS) and the mental component sumMARY-#3 SCORESARECALCULATEDUSINGTHESESUBSCALES4HE3& ISASIMPLIlED

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SELF REPORTED ITEM QUESTIONNAIRE WHICH MEASURES PERCEIVED HEALTH 4HE 3& CORRELATESVERYWELLWITHTHE0#3AND-#3OFTHE3& "OTHTHE3& AND3& HAVEBEENUTILIZEDTOASSESSTHE1/,INPATIENTSWITHGASTROPARESIS;15, 24, 36, 37]. 4HEADVANTAGEOFUSINGTHE3& AND3& ISTHEABILITYTOCOMPARETHE1/,OF gastroparesis with the normal population and other disease states. 4HEPATIENTASSESSMENTOFGASTROINTESTINALQUALITY OF LIFE0!') 1/, ISDEVELOPED AS A SINGLE INSTRUMENT FOR PATIENTS WITH '%2$ FUNCTIONAL DYSPEPSIA AND gastroparesis [38=)TISAVALID RELIABLE ANDSENSITIVEINSTRUMENTFORASSESSINGTHE 1/,INTHESEPATIENTS4HE0!') 1/,ISA ITEMQUESTIONNAIREWITHlVEDOMAINS DAILYACTIVITIES CLOTHING DIETFOODHABITS RELATIONSHIP ANDPSYCHOLOGICALWELL BEING DISTRESS)TCORRELATESWELLWITHTHEGENERICHEALTH RELATED3&

Physician Assessment of Disease Severity 5NLIKE'%2$ WHEREEROSIVEESOPHAGITIS PEPTICSTRICTURE AND"ARRETTSESOPHAGUS ARE OBJECTIVE ENDOSCOPIC AND PATHOLOGIC IDENTIlERS FOR COMPLICATIONS OF '%2$ THERE ARE NO OBJECTIVE MARKERS SPECIlC FOR COMPLICATIONS OF GASTROPARESIS 3OME patients may have severe nausea and emesis resulting in dehydration, documented BYORTHOSTATICHYPOTENSIONANDACUTERENALINSUFlCIENCY&REQUENTEMERGENCYROOM VISITS AND HOSPITALIZATIONS MAY BE RELATED TO DEHYDRATION BUT SUBJECTIVE SEVERE ABDOMINALPAINISALSOCOMMONINHOSPITALIZEDPATIENTS3OMEPATIENTSWITHSEVERE GASTROPARESISHAVESIGNIlCANTWEIGHTLOSSANDNUTRITIONALDElCIENCYREQUIRINGSMALL BOWEL FEEDING ACCESS TO BYPASS THE STOMACH )NTOLERANCE OF NASOJEJUNAL FEEDING SHOULDALERTTHEPOSSIBILITYOFACHRONICINTESTINALPSEUDOOBSTRUCTIONOFTHESMALL BOWEL!GASTRICFOODBEZOARISACOMMONlNDINGDURINGUPPERENDOSCOPYDESPITE OVERNIGHTFASTING BUTAGASTRICBEZOARCAUSINGGASTRICOUTLETOBSTRUCTIONISRARE !PHYSICIAN ASSESSMENTSEVERITYSCALEFORGASTROPARESISHASBEENPROPOSEDBYA CONSENSUSPANELOFEXPERTS4ABLE3.3) [2=)TISBASEDONTHERESPONSETOTREATMENT ABILITYTOMAINTAINNUTRITIONORALLY ANDFREQUENCYOFHOSPITALIZATIONS(OWEVER THIS Table 3.3 0ROPOSEDCLASSIlCATIONOFGASTROPARESISBASEDONSEVERITY $ElNITIONS Grade 1: Mild gastroparesis s 3YMPTOMSRELATIVELYEASILYCONTROLLED s !BLETOMAINTAINWEIGHTANDNUTRITIONONREGULARDIETOR MINORDIETARYMODIlCATIONS Grade 2: Compensated gastroparesis

s -ODERATESYMPTOMSWITHPARTIALCONTROLWITHPHARMACOLOGIcal agents s !BLETOMAINTAINNUTRITIONWITHDIETARYANDLIFESTYLE adjustments s 2AREHOSPITALADMISSIONS

s 2EFRACTORYSYMPTOMSDESPITEMEDICALTHERAPY s )NABILITYTOMAINTAINNUTRITIONVIAORALROUTE s &REQUENTEMERGENCYROOMVISITSORHOSPITALIZATIONS &ROMTHE!MERICAN-OTILITY3OCIETY4ASK&ORCEONGASTROPARESIS;2]

Grade 3: Gastroparesis with gastric failure


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Table 3.4 'ASTROPARESISSEVERITYBASED on 4-h gastric scintigraphy [2] 2ETENTIONAT H Mild Moderate n Severe n 6ERYSEVERE

GRADINGSCALEHASNOTBEENVALIDATED ANDCRITERIAMAYBESUBJECTTOINTERPRETATIONBY THE PHYSICIAN !N OBJECTIVE GRADING OF GASTROPARESIS SEVERITY HAS BEEN PROPOSED BASEDONTHEAMOUNTOFGASTRICRESIDUALAT HBYGASTRICSCINTIGRAPHYUSINGTHESTANDARDIZEDINTERNATIONALMETHOD4ABLE3.4) [39, 40]. However, this scintigraphy gradINGSCALEDOESNOTCORRELATEWITHSYMPTOMSCORESBY'#3);25=&UTURESTUDIESARE needed to determine if these grading scales can predict prognosis and improve management strategy in patients with gastroparesis.

Conclusion The clinical presentation of gastroparesis is very heterogeneous. The presence of gastric emptying impairment does not always imply a diagnosis of gastroparesis. 4HECAUSEANDEFFECTBETWEENDELAYEDGASTRICEMPTYINGANDSYMPTOMSMAYBEDIFlCULT TOPROVE4HESYMPTOMSOFGASTROPARESISSHOULDBEASSOCIATEDWITHMEALINGESTION "OTHPREDOMINANTSYMPTOMPRESENTATIONANDSYMPTOMPATTERNSHOULDBEIDENTIlED In addition to the upper gastrointestinal symptoms, the psychological state of the PATIENTHASTOBECONSIDERED3YMPTOMSEVERITYANDQUALITY OF LIFEIMPAIRMENTCAN BE QUANTIlED USING CURRENTLY AVAILABLE VALIDATED INSTRUMENTS 3EVERITY GRADING SCALESFORGASTROPARESISHAVEBEENPROPOSED BUTFUTURESTUDIESARENEEDEDTODETERmine if they can predict prognosis and improve management strategy in patients with gastroparesis.

References #AMILLERI- $UBOIS$ #OULIE" ETAL0REVALENCEANDSOCIOECONOMICIMPACTOFUPPERGASTROintestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin 'ASTROENTEROL(EPATOL n !BELL4, BERNSTEINV #UTTS4 ETAL4REATMENTOFGASTROPARESISAMULTIDISCIPLINARYCLINICAL REVIEW 4HE !MERICAN -OTILITY 3OCIETY 4ASK &ORCE ON 'ASTROPARESIS .EUROGASTROENTEROL -OTIL n $EL&! 4ONATO- 2OILA&)SSUESINTHEMEASUREMENTOFNAUSEA"R*#ANCER3UPPL 3n (ORNBY0*#ENTRALNEUROCIRCUITRYASSOCIATEDWITHEMESIS!M*-ED3UPPL! 3n3

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2EVICKI$! 2ENTZ!- $UBOIS$ ETAL$EVELOPMENTANDVALIDATIONOFAPATIENT ASSESSED GASTROPARESISSYMPTOMSEVERITYMEASURETHE'ASTROPARESIS#ARDINAL3YMPTOM)NDEX!LIMENT 0HARMACOL4HER n 3TANGHELLINI 6 4OSETTI # 0ATERNIC INVERTED QUESTION M! ET AL 2ISK INDICATORS OF DELAYED gastric emptying of solids in patients with functional dyspepsia. Gastroenterol 1996;110(4): n +ARAMANOLIS' #AENEPEEL0 !RTS* 4ACK*!SSOCIATIONOFTHEPREDOMINANTSYMPTOMWITH clinical characteristics and pathophysiological mechanisms in functional dyspepsia. 'ASTROENTEROL n +HAYYAM5 3ACHDEVA0 'OMEZ* ETAL!SSESSMENTOFSYMPTOMSDURINGGASTRICEMPTYING SCINTIGRAPHY TO CORRELATE SYMPTOMS TO DELAYED GASTRIC EMPTYING .EUROGASTROENTEROL -OTIL n 4ALLEY.* ,OCKE)))'2 ,AHR"$ ETAL&UNCTIONALDYSPEPSIA DELAYEDGASTRICEMPTYING AND IMPAIREDQUALITYOFLIFE'UT n 3TANGHELLINI6 4OSETTI# (OROWITZ- ETAL0REDICTORSOFGASTROPARESISINOUT PATIENTSWITH SECONDARYANDIDIOPATHICUPPERGASTROINTESTINALSYMPTOMS$IG,IVER$IS n 2EDDYMASU 3# -C#ALLUM 27 3MALL INTESTINAL BACTERIAL OVERGROWTH IN GASTROPARESIS ARE THEREANYPREDICTORS*#LIN'ASTROENTEROL En 12. Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, PSYCHOLOGICALANDABUSEPROlLES TREATMENT ANDLONG TERMFOLLOW UPOFPATIENTSWITHGASTROPARESIS$IG$IS3CI n (OOGERWERF7! 0ASRICHA0* +ALLOO!. 3CHUSTER--0AINTHEOVERLOOKEDSYMPTOMIN GASTROPARESIS!M*'ASTROENTEROL n #HERIAN$ 3ACHDEVA0 &ISHER23 0ARKMAN(0!BDOMINALPAINISAFREQUENTSYMPTOMOF GASTROPARESIS#LIN'ASTROENTEROL(EPATn "IELEFELDT+ 2AZA. :ICKMUND3,$IFFERENTFACESOFGASTROPARESIS7ORLD*'ASTROENTEROL n "RILEY,# (ARRELL30 7O*-.ATIONALSURVEYOFPHYSICIANSPERCEPTIONONTHECAUSE COMPLICATION ANDMANAGEMENTOFGASTROPARESIS;ABSTRACT=!M*'ASTROENTEROLS +ARAMANOLIS' #AENEPEEL0 !RTS* 4ACK*$ETERMINANTSOFSYMPTOMPATTERNINIDIOPATHIC SEVERELYDELAYEDGASTRICEMPTYINGGASTRICEMPTYINGRATEORPROXIMALSTOMACHDYSFUNCTION 'UT n 4ACK * 4ALLEY .* #AMILLERI - ET AL &UNCTIONAL GASTRODUODENAL DISORDERS 'ASTROENTEROL n -ARANKI *, ,YTES 6 -EILAHN *% ET AL 0REDICTIVE FACTORS FOR CLINICAL IMPROVEMENT WITH %NTERRAGASTRICELECTRICSTIMULATIONTREATMENTFORREFRACTORYGASTROPARESIS$IG$IS3CI $ECEMBER %MERENZIANI 3 3IFRIM $ 'ASTROESOPHAGEAL REmUX AND GASTRIC EMPTYING REVISITED #URR 'ASTROENTEROL2EP n 21. Buckles DC, Sarosiek I, McMillin C, McCallum RW. Delayed gastric emptying in gastroeSOPHAGEALREmUXDISEASEREASSESSMENTWITHNEWMETHODSANDSYMPTOMATICCORRELATIONS!M *-ED3CI n 'ONLACHANVIT3 -AURER!( &ISHER23 0ARKMAN(02EGIONALGASTRICEMPTYINGABNORMALITIES IN FUNCTIONAL DYSPEPSIA AND GASTRO OESOPHAGEAL REmUX DISEASE .EUROGASTROENTEROL -OTIL n "ENINI, 3EMBENINI# #ASTELLANI' #ALIARI3 &IORETTA! 6ANTINI)'ASTRICEMPTYINGAND DYSPEPTIC SYMPTOMS IN PATIENTS WITH GASTROESOPHAGEAL REmUX !M * 'ASTROENTEROL n (ARRELL30 3TUDTS*, $RYDEN'7 %VERSMANN* #AI, 7O*-!NOVELCLASSIlCATIONSCHEME FOR GASTROPARESIS BASED ON PREDOMINANT SYMPTOM PRESENTATION * #LIN 'ASTROENTEROL n (ASLER7, 0ARKMAN(0 7ILSON,!ETAL0SYCHOLOGICALDYSFUNCTIONISASSOCIATEDWITHSYMPTOM SEVERITYBUTNOTDISEASEETIOLOGYORDEGREEOFGASTRICRETENTIONINPATIENTSWITHGASTROPARESIS !M*'ASTROENTEROL*UNE


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Chapter 4

Gastric Dysmotility at the Organ Level in Gastroparesis Michael Camilleri and Maria I. Vazquez-Roque

Keywords 'ASTROPARESISs'ASTRICEMPTYINGs'ASTRICACCOMMODATION

Introduction Gastric motor functions represent a complex series of events that are regulated by circulating blood glucose and hormones, such as the incretins, extrinsic neural control from the brain and spinal cord, the enteric nervous system, the interstitial cells of Cajal (ICC), smooth muscle cells, and locally released neurotransmitters. The normal function of the two major regions of the stomach, the fundus and antrum, depend on these neural and muscular mechanisms. The major motor function of the gastric fundus is to receive and store food, and the antrum triturates ingested food into chyme. To maximize nutrient absorption and digestion, the antrum and pylorus empty chyme into the duodenum through carefully regulated functions. Alterations in these functions lead to delayed gastric emptying and clinical symptoms, such as nausea, vomiting, early satiety, anorexia, bloating, or pain. To better understand the underlying mechanisms that characterize gastric dysmotility at the organ level, it is important to understand the normal gastric motor physiology.

Control of Gastric Motor Function Gastric motor functions depend on neuromuscular control mediated by enteric (intrinsic), parasympathetic, and sympathetic nervous system (extrinsic), ICC, and by smooth muscle cells [1] (Fig. 4.1).

M. Camilleri (*) College of Medicine, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_4, © Springer Science+Business Media, LLC 2012

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M. Camilleri and M.I. Vazquez-Roque

EXTRINSIC

INTRINSIC

Parasympathetic excitatory to nonsphincteric muscle

Sympathetic T5-10 excitatory to sphincters, inhibitory to nonsphincteric muscle

ICCs Enteric brain 108 neurons

Myogenic factors regulate electrical activity generated by GI smooth muscle cells.

smooth muscle cell with receptors for transmitters modulates peristaltic reflex

inter motor

ICC: interstitial cells of Cajal non-neural pacemaker systems in the wall of the gut

inter

IPAN: sensory

Ascending contraction

motor VIP/ NOS

ACh SubP/SubK

Descending relaxation

distention by bolus

Fig. 4.1 Schematic representation of the extrinsic and intrinsic control of gastric motor function. The extrinsic pathway is composed of vagal efferents and splanchnic efferents. The intrinsic pathway is composed of interstitial cells of Cajal and the motor function unit

The enteric nervous system (ENS), sometimes called the “gut brain,” is a collection of more than 100 million neurons organized in ganglia that function independently but they also integrate signals from the autonomic and central nervous system. The ENS is a network of ganglia arranged in the myenteric, deep mucosal, and submucosal plexi. The myenteric or Auerbach plexus is involved in control of gastrointestinal motility. The submucosal or Meissner plexus is involved the control of absorption, secretion, and mucosal blood flow. The ICC, located between the circular and longitudinal muscle layers in the stomach wall in the deep mucosal plexi, serve as a nonneuronal pacemaker system that creates the basic electrical rhythm for gastric propulsion, the migrating motor complex, and sensation [2, 3]. The ICC’s communicate signals between the ENS plexus and smooth muscle cells. Electrical control activity spreads through the contiguous segments of the gut through neurochemical activation by excitatory (e.g., acetylcholine [Ach], substance P) and inhibitory (e.g., nitric oxide [NO], somatostatin, vasoactive intestinal peptide [VIP]) transmitters. The autonomic regulation of gastric motor functions consists of extrinsic control by the parasympathetic and sympathetic nervous systems. Parasympathetic pathways reach the stomach through the vagus nerve. Vagal efferents arise in the dorsal motor nucleus of the vagus nerve and, to a lesser extent, from the nucleus ambiguus and tractus solitarius, the latter being predominantly involved in afferent (sensory) functions.

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Gastric Dysmotility at the Organ Level in Gastroparesis

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The sympathetic nervous system connects to the stomach from the intermediolateral columns of the spinal cord at the T5 to T10 levels, synapsing in the celiac ganglia. Splanchnic efferents, in the celiac ganglia, supply the myenteric ganglia mostly innervating the pyloric sphincter [4, 5]. Myogenic factors regulate the electrical activity generated by gastrointestinal smooth muscle cells [6]. The smooth muscle cells that control gastric motility have specific receptors for amines, peptides, and other transmitters that reach the smooth muscle membrane by neurocrine, endocrine, or paracrine routes. The ICCs are in close proximity to the smooth muscle cells and are responsible for integration and coordination of the electrical slow wave spreading through the smooth muscle syncytium to produce circumferential contractions. The motor function unit in the gastrointestinal tract responsible for the transfer of food from the stomach into small intestine is the peristaltic reflex (Fig. 4.1). This reflex is initiated either by luminal distention (mechanical stimulus) or by a chemical stimulus. Mucosal sensation is transmitted by intrinsic primary afferent neurons and leads to a contraction in the orad (more proximal) segment that is mediated by excitatory transmitters, chiefly Ach, substance P and serotonin. Relaxation in the aborad segment allows transport of the incoming bolus, and this is mediated by inhibitory neurotransmitters, such as NO and VIP. Interneurons, such as opiates or somatostatin, coordinate these functions.

Physiology of Gastric Motor Functions The fasting and postprandial periods have unique motility patterns in healthy individuals. The fasting period is characterized by a highly regulated cyclic motor pattern in the body and antrum called the migrating motor complex (MMC) [7, 8]. There are three phases in an MMC cycle, with approximate total duration of 60–90 min in healthy individuals. Phase I is a period of quiescence, with no contractile activity recorded, and phase II is characterized by intermittent irregular contractions. Phase III, the activity front, is contractile activity that occurs at frequency of up to 3 per minute in the stomach and up to 12 per minute in the upper small intestine. Phase III migrates for a variable distance through the small intestine. There is a gradient in the frequency of Phase III contractions from ~12 per minute in the duodenum to ~8 per minute in the ileum. During fasting, the stomach participates in the cyclical activity front that propagates through the antrum, thereby emptying nondigestible solid residue into the duodenum. Approximately 50% of phase III activity fronts originate in the stomach during fasting [7, 9]. Since nondigestible solid is not found in the stomach after 8 h fasting, antral contractions during phase III of the MMC are efficient in clearing nondigestible solids from the stomach despite the fact that only 50% of MMCs have an antral component. The two functional regions of the stomach, that is the fundus and antrum, are responsible for the reservoir and pump activity in the postprandial period (Fig. 4.2). The stomach muscle is organized in three layers with fibers organized

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Receptive relaxation Fundic emptying (3-1/min)

Pyloric resistance

Corpus antral filling/mixing

Duodenal resistance

Antroduodenal coordination

Antral peristalsis emptying (3/min)

Fig. 4.2 The different regions of the stomach and specific functions in the digestion of a meal. Modified from Koch KL. Electrogastrography: Physiological Basis and Clinical Application in Diabetic Gastropathy. Diabetes Technology and Therapeutics Vol. 3. Issue 1, July 5, 2004. Mary Ann Liebert, Inc., Publishers

on different axes: circular, oblique, and longitudinal. These are innervated by excitatory and inhibitory motor neurons of the ENS. The mid-portion of the greater curvature of the stomach is considered the functional site of the gastric electrical pacemaker, although ICCs which have spontaneous firing and reflect the cellular pacemaker activity that coordinates rings of contractions that sweep through the stomach. During fasting, the fundus is tonically contracted; after food is ingested, a neurally mediated reflex relaxes the proximal stomach to receive the meal. Food is then transferred from the esophagus into the fundus, which acts as a reservoir to accommodate the ingested meal, also called gastric accommodation. The decreased tone in the fundus allows large amounts of solid or liquid food with little or no increase in intragastric pressure, thus avoiding postprandial symptoms, such as fullness and pain [10]. The initial phase of fundic relaxation is a reflex called receptive relaxation which occurs during swallowing. During receptive relaxation and stimulation of mechanoreceptors by the arrival of food in the stomach, vagal afferents, and vagovagal reflexes are activated, stimulating the intrinsic inhibitory neurotransmitters NO and VIP. Adaptive relaxation is triggered by distention of the gastric reservoir [11]. This process facilitates the initial chemical digestion of food by acid and proteases before contents are transferred to the antrum. Fundic relaxation is impaired in patients with fundoplication due the mechanical effects of the operation, as well as a result of

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vagal injury [12]. Such patients are likely to have a lower threshold for postprandial fullness and pain. Another important function of the fundus is to contract and transfer the contents of the gastric reservoir into the antral pump [11]. Thus, the fundus produces contractile events that are most easily demonstrable as phasic volume changes by using a barostatically-controlled balloon [10, 13]. The antrum produces high amplitude contractions that grind solids by physical and liquid shearing forces. Chyme, which is composed of solid particles that have been reduced to 1–2 mm in size suspended in gastric juice, is then able to empty through the pylorus [14]. Particles that have not been reduced to this size are continually forced toward, and retropulsed from the distal stomach by an occluded pylorus until liquid shearing and chemical digestion achieve adequate trituration. In contrast, interdigestive antral motor function clears the stomach of nondigestible solid particles whose size has not been reduced by trituration. The pylorus is mostly composed of thickened circular muscle and presents a zone of high resting pressure controlled by Ach and NO. Through antropyloroduodenal coordination, 2–4 mL of chyme is emptied into the duodenum through phasic contractions that occur at a maximum rate of 3 per minute. Antropyloroduodenal coordination coordinates antral peristalsis with decreased duodenal pressure and pyloric resistance to ensure optimal emptying of gastric contents [6]. Physical characteristics, volume, and macronutrient content of ingested food determine the gastric emptying rate of a meal. Gastric emptying of liquids is faster than the emptying of solids, and it follows a simple exponential model for nonnutrient liquids [14]. The emptying of high-nutrient liquids or fully homogenized solids approximates a linear model. The gastric emptying half-time for noncaloric liquids is approximately 20 min for healthy individuals. Nonnutrient liquids empty from the stomach exponentially [15], but with increasing caloric content of liquids, the gastric emptying rate is approximately of 200 kcal/h [16, 17]. Gastric emptying of solids is characterized by two stages; an initial lag phase during which no food is emptied from the stomach, followed by a postlag emptying phase which tends to be linear [6, 18] (Fig. 4.3). The lag phase is associated with the time when there is accommodation of solids in the fundus and the transfer of food into the corpus and antrum for trituration and grinding. The duration of the lag phase depends on several meal factors, such as macronutrient content (e.g., it is longer with higher fat or calorie content of the meal) [19, 20], the chewing process or the degree to which the food is homogenized before ingestion, or is easily digestible or triturated. The lag phase duration typically may last up to 60 min. In healthy volunteers, a positive correlation between antral motility and overall emptying of solids has been demonstrated [15]; the lag time duration is inversely related to the antral motility index, consistent with the concept that more effective antral contractions facilitate trituration and the commencement of emptying. The emptying of liquids is significantly associated with antral contractility only after the lag time for trituration of solids has been completed and pyloric closure coincident with antral contractions is no longer required [15].

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Fig. 4.3 Gastric emptying of solids and liquids in health and in gastroparesis. Note the exponential emptying of liquids, in contrast to the initial retention of solids (lag phase) which is followed by a generally linear postlag emptying rate

Gastric Dysmotility Gastric motor dysfunction or dysmotility is typically characterized by an abnormality in one or more of the different gastric functional regions. Alterations in the ENS, pacemaker cells (ICCs), or smooth muscle cells [1] have been described in gastric dysmotility. Neuropathic or myopathic disorders can affect the mechanisms that control gastric motor functions leading to gastric dysmotility, such as diabetes mellitus, sarcoidosis, and amyloidosis, among others. Similarly, there are data suggesting the ICC pathology may cause the impaired motor function. Different pathophysiological processes may cause impaired intragastric distribution of food, and delayed emptying of the stomach, and they include impaired fundic relaxation (or accommodation), antral hypomotility, and pylorospasm.

Fundus Impaired postprandial fundic accommodation occurs in patients after vagotomy and partial gastric resection [21]. Patients with vagotomy have gastric emptying studies that show delayed emptying of solids (resulting from impaired vagal input to the antrum) and accelerated emptying of liquids (resulting from impaired vagal

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supply to the inhibitory innervation that normally relaxes the fundus). Patients with fundoplication may have impaired fundic accommodation, in part as a result of vagal injury [22]. Patients with diabetes mellitus and refractory gastroparesis may experience impaired gastric accommodation and visceral hypersensitivity [23], whereas others have increased compliance [24], thus leading to a longer lag phase in emptying of solids, with prolonged retention of a meal in the proximal stomach. Increased compliance in patients with diabetes mellitus and autonomic neuropathy compared to normal volunteers was reported to be associated with increased visceral sensation; these data suggest that hypersensitivity is related to increased symptoms, such as nausea, bloating and abdominal pain [25]. Conversely, patients with diabetes with no evidence of autonomic neuropathy may have increased fundic phasic contractions that explain the observed accelerated emptying of liquids observed in recently diagnosed diabetes mellitus [13]. The underlying pathophysiology in impaired accommodation is not well understood, but in theory abnormalities in the sensory apparatus, the vagovagal reflex pathway, the intrinsic inhibitory innervation or the smooth muscle in the proximal stomach may all be affected and result in reduced gastric accommodation [26].

Antrum Abnormalities of antral motor function lead to delayed gastric emptying. Antral hypomotility has been associated with a prolonged lag phase and half-time of gastric emptying of solids and delayed emptying of liquids in patients [27]. In most patients, this is due to a reduced frequency of antral contractions in the postprandial period. Although some patients demonstrate irregular, low-amplitude antral contractions [28, 29], the more common situation is a reduced frequency of distal antral contractions. In secondary or idiopathic hypomotility of neuropathic origin, less than 1 antral contraction per minute during the first hour after a solid meal correlates with significant antral hypomotility [30]. Antral hypomotility is associated with postsurgical gastroparesis, diabetic gastroparesis, and idiopathic gastroparesis [28]; it has also been described in functional dyspepsia [31, 32]. These findings contrast with observations in patients with systemic sclerosis, in which the average amplitude of antral contractions was ~35 mmHg, significantly less than controls [33].

Pylorus During the postprandial period, the pylorus typically opens during an antral peristaltic wave to ensure emptying of nutrients into the duodenal bulb in a coordinated fashion. However, dysfunction of the pylorus in the form of pylorospasm can cause delayed gastric emptying in diabetic gastroparesis likely secondary to a deficiency in inhibitory nitrergic neurons to relax the tonically contracted pylorus. In manometric studies,

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diabetic patients had prolonged and intense pyloric contractions compared to controls [34]. Pylorospasm was diagnosed with peak amplitude of tonic activity of 13 mmHg and duration of 7 min.

Small Bowel Dysmotility Small bowel dysfunction may also impair gastric emptying. A study of 14 patients with clinical and manometric confirmation of neuropathic chronic intestinal pseudoobstruction and normal antral motility demonstrated that gastric emptying of solids was significantly slower compared to healthy controls [35]. Similar findings have been described in paraneoplastic dysmotility, were histologic findings confirmed a disorganized ICC network in a patient with newly diagnosed small cell lung cancer [36]. The underlying mechanism of how small bowel dysmotility affects gastric motility is not well defined, but may be secondary to a diffuse process, such as a myopathy, neuropathy, or autoimmune-mediated disturbance of the ICCs rather than an isolated phenomenon.

Gastric Electrical Dysfunction Gastric electrical dysfunction is another mechanism of gastric (antral) dysmotility. The normal pacemaker rate is approximately 3 per minute. Gastric dysrhythmias range from reduced (bradygastria, 1–2 per minute), increased (tachygastria, 4–9 per minute) frequency, or a mixed bradytachygastria. Gastric dysrhythmias have been described in diabetic gastroparesis, functional dyspepsia, anorexia nervosa, and vomiting of pregnancy [28]. Although the precise mechanisms on how these dysrhythmias cause symptoms is unclear, normalization of the gastric electrical rhythm has been described in patients with diabetic gastroparesis after long-term treatment with domperidone [37].

Conclusion Stomach functions are regulated by a complex series of events that are controlled by extrinsic nerves, the enteric nervous system, excitatory and inhibitory neurotransmitters, and hormones. The stomach has distinct functional regions that result in the initial storage and subsequent trituration of food. Abnormalities of these regions are seen in specific disease states, such as diabetes mellitus, in which several factors lead to gastric dysfunction (including autonomic neuropathy and significant hyperglycemia), systemic sclerosis or amyloidosis. Thorough understanding of the pathophysiology in these disease states is important for selection of therapy.

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23. Kumar A, Attaluri A, Hashmi S, Schulze KS, Rao SS. Visceral hypersensitivity and impaired accommodation in refractory diabetic gastroparesis. Neurogastroenterol Motil. 2008;20(6): 635–42. 24. Rayner CK, Verhagen MA, Hebbard GS, DiMatteo AC, Doran SM, Horowitz M. Proximal gastric compliance and perception of distension in type 1 diabetes mellitus: effects of hyperglycemia. Am J Gastroenterol. 2000;95(5):1175–83. 25. Samsom M, Salet GA, Roelofs JM, Akkermans LM, Vanberge-Henegouwen GP, Smout AJ. Compliance of the proximal stomach and dyspeptic symptoms in patients with type I diabetes mellitus. Dig Dis Sci. 1995;40(9):2037–42. 26. Kindt S, Tack J. Impaired gastric accommodation and its role in dyspepsia. Gut. 2006; 55(12):1685–91. 27. Camilleri M, Brown ML, Malagelada JR. Relationship between impaired gastric emptying and abnormal gastrointestinal motility. Gastroenterology. 1986;91(1):94–9. 28. Koch KL. Stomach. In: Schuster MM, editor. Atlas of gastrointestinal motility. 1st ed. Baltimore, Maryland: Williams & Wilkins; 1993. p. 158–76. 29. Camilleri M, Malagelada JR. Abnormal intestinal motility in diabetics with the gastroparesis syndrome. Eur J Clin Invest. 1984;14(6):420–7. 30. Thumshirn M, Bruninga K, Camilleri M. Simplifying the evaluation of postprandial antral motor function in patients with suspected gastroparesis. Am J Gastroenterol. 1997;92(9): 1496–500. 31. Stanghellini V, Ghidini C, Maccarini MR, Paparo GF, Corinaldesi R, Barbara L. Fasting and postprandial gastrointestinal motility in ulcer and non-ulcer dyspepsia. Gut. 1992;33(2): 184–90. 32. Wilmer A, Van Cutsem E, Andrioli A, Tack J, Coremans G, Janssens J. Ambulatory gastrojejunal manometry in severe motility-like dyspepsia: lack of correlation between dysmotility, symptoms, and gastric emptying. Gut. 1998;42(2):235–42. 33. Weston S, Thumshirn M, Wiste J, Camilleri M. Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am J Gastroenterol. 1998;93(7):1085–9. 34. Mearin F, Camilleri M, Malagelada JR. Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology. 1986;90(6):1919–25. 35. Greydanus MP, Camilleri M, Colemont LJ, Phillips SF, Brown ML, Thomforde GM. Ileocolonic transfer of solid chyme in small intestinal neuropathies and myopathies. Gastroenterology. 1990;99(1):158–64. 36. Pardi DS, Miller SM, Miller DL, et al. Paraneoplastic dysmotility: loss of interstitial cells of Cajal. Am J Gastroenterol. 2002;97(7):1828–33. 37. Koch KL, Stern RM, Stewart WR, Vasey MW. Gastric emptying and gastric myoelectrical activity in patients with diabetic gastroparesis: effect of long-term domperidone treatment. Am J Gastroenterol. 1989;84(9):1069–75.

Chapter 5

Cellular Pathogenesis of Gastroparesis Tamas Ordog

Keywords )NTERSTITIAL CELLS OF #AJAL s %NTERIC NERVOUS SYSTEM s 3MOOTH MUSCLE s3LOWWAVEs.ITRICOXIDEs'ASTRICEMPTYINGs'ASTROPARESISs2ECEPTORTYROSINE KINASEs-ACROPHAGEs3TEMCELL

Introduction 4HEGASTRICNEUROMUSCULARAPPARATUSPLAYSIMPORTANTROLESINTHEDIGESTIVEPROCESS BY ACCOMMODATING AND RETAINING MEALS FOR INITIAL DIGESTION MIXING FOOD WITH GASTRICSECRETIONS REDUCINGPARTICLESIZE CONTROLLINGTHEDELIVERYOFCONTENTSINTO THEDUODENUM ANDPRODUCINGSIGNALSREGULATINGMEALTERMINATION'ASTRICNEUROMUSCULARDYSFUNCTIONISOFTENASSOCIATEDWITHSYMPTOMSWHICH WHENCHRONICOR frequently recurrent, cause considerable morbidity [1]. Gastroparesis, defined as SLOWEMPTYINGINTHEABSENCEOFMECHANICALOBSTRUCTION ISONEOFTHEMOSTSIGNIlcant manifestations of gastrointestinal dysmotility, particularly in females [2, 3]. It often accompanies diabetes and gastric surgery, but its cause remains obscure in ABOUTONE THIRDOFTHECASES;4=7HILEGASTROPARESISPERSEMAYNOTINCREASEMORTALITY ITCANADVERSELYAFFECTTHEQUALITYOFLIFEANDLEADTONUTRITIONALINSUFlCIENCY ELECTROLYTE IMBALANCE IMPAIRED GLYCEMIC CONTROL AND FREQUENT HOSPITALIZATIONS ;1]. #URRENTTREATMENTMODALITIES WHICHFOCUSONSYMPTOMCONTROLANDSTIMULATIONOF RESIDUALFUNCTION ARENOTCURATIVEANDFREQUENTLYINEFFECTIVE;2, 3, 5=4HEPURPOSE OFTHISCHAPTERISTOREVIEWRECENTADVANCESINDElNINGTHECELLULARPATHOGENESISAND POTENTIALNEWTHERAPEUTICTARGETSINTHISDISORDER)TISPROPOSEDTHATGASTROPARESIS

T. Ordog (*) %NTERIC.EUROSCIENCE0ROGRAMAND'ASTROENTEROLOGY2ESEARCH5NIT $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF0HYSIOLOGY AND"IOMEDICAL%NGINEERING -AYO#LINIC ST3TREET37 2OCHESTER -. 53! e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_5, © Springer Science+Business Media, LLC 2012

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ARISESFROMANINTERPLAYBETWEENFACTORSCAUSINGCELLULARSTRESSOROTHERFUNCTIONAL CHALLENGESANDTISSUEDYSTROPHYCAUSINGREDUCEDFUNCTIONALCAPACITYANDREmECTING ANIMBALANCEBETWEENDEGENERATIONANDREGENERATIONOFCELLSOFTHENEUROMUSCULAR apparatus [6=)NORDERTOBECURATIVE FUTURETHERAPEUTICAPPROACHESNEEDTOFOCUS ONRESTORINGTISSUEINTEGRITYBYTHEALLEVIATIONOFCELLULARSTRESS TROPHICSUPPORTOF SURVIVINGCELLS AND INCASESWHEREREGENERATIONFROMENDOGENOUSSOURCESISNOT POSSIBLE REPLACEMENTOFTHEMISSINGCELLSFROMEXOGENOUSSOURCES

Pathophysiology of Gastroparesis 'ASTRICEMPTYINGISAHIGHLYCOMPLEXFUNCTIONREmECTINGSEVERALASPECTSOFGASTRIC MOTORPHYSIOLOGY INCLUDINGFUNDICANDANTRALTONEANDMOTILITY SLOW WAVEACTIVITY pyloric function, and antropyloroduodenal coordination [7, 8]. Gastroparesis may MANIFESTINDELAYEDEMPTYINGOFBOTHDIGESTIBLEANDINDIGESTIBLESOLIDSANDNUTRIENT liquids and may be preceded by accelerated emptying [1, 9=%MPTYINGOFLIQUIDS DEPENDSMAINLYONTHEFUNDIChPRESSUREPUMPvMECHANISMCONTROLLEDBYPYLORIC OPENING,OSSOFNORMALPYLORICRELAXATIONHASBEENDEMONSTRATEDBOTHINPATIENTS and mouse models of gastroparesis [3, 10, 11]. In contrast, emptying of solids is more CLOSELYRELATEDTOPHASICANTRALMOTILITY;6]. Indeed, delayed solid emptying is caused PRIMARILYBYANTRALHYPOMOTILITYANDDILATION;2]. Reduced antral contractions may ARISE FROM ABNORMAL SMOOTH MUSCLE FUNCTION INADEQUATE OR ABNORMAL PACING BY SLOWWAVESORIMPAIREDELECTROMECHANICALCOUPLING;6, 12=4HELATTERMAYDEVELOP FROMREDUCEDNET NEURALEXCITATION;13= IMPAIREDSMOOTHMUSCLERESPONSIVENESS TONEURALANDHUMORALINPUT;14= ORWHENSLOW WAVEFREQUENCYISABNORMALLYRAPID ANDPLATEAUSARETOOSHORTTOPERMITSUFlCIENT#A2+INmUXINTOSMOOTHMUSCLECELLS [6, 12=3INCETHEORDERLYCORPUS TO ANTRUMPROPAGATIONOFPERISTALTICCONTRACTIONS DEPENDSONTHEORGANIZEDSPREADOFSLOWWAVES;13, 15= DYSRHYTHMIASDEVELOPING ALONGTHEPROPAGATIONPATHWAYDISRUPTTHENORMALPATTERNOFSLOW WAVEPROPAGATION ANDPERISTALSISAFTERMEALSCAUSINGDELAYEDGASTRICEMPTYINGANDALSODURINGPHASE )))OFTHEINTERDIGESTIVEMIGRATINGMOTORCOMPLEX WHICHMAYLEADTOBEZOARFORMAtion [7, 8=4HESEMOTORFUNCTIONSAREORCHESTRATEDBYACOMPLEXINTERPLAYBETWEEN SEVERALCELLTYPESWHOSESPECIlCCONTRIBUTIONSAREDISCUSSEDBELOW

Cellular Mechanisms Underlying Gastric Motility 'ASTRICMOTORFUNCTIONSARECONTROLLEDBYCELLSBOTHINTRINSICANDEXTRINSICTOTHE STOMACH 4HE GASTRIC NEUROMUSCULAR APPARATUS CONSISTS OF SMOOTH MUSCLE CELLS ENTERICNEURONSANDGLIA INTERSTITIALCELLSOF#AJAL)## ANDOTHERMESENCHYMAL CELLS%XTRINSICCELLSINCLUDEVAGALANDSYMPATHETICEFFERENTANDSENSORYNEURONS ASWELLASENDOCRINECELLSOFTHEGUTANDTHEPANCREAS WHICHARERESPONSIBLEFOR CALORICLOAD DEPENDENTFEEDBACKINHIBITIONOFGASTRICEMPTYING5NDERPATHOLOGICAL

#ELLULAR0ATHOGENESISOF'ASTROPARESIS

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CONDITIONS INmAMMATORYANDIMMUNECELLSALSOINmUENCEGASTRICMOTORFUNCTIONS BYREGULATINGOTHERCELLTYPES)NTHISCHAPTER WECONSIDERNEURALANDMESENCHYMAL CELLTYPESWITHPARTICULAREMPHASISONTHEGENERATIONOFPHASICMOTORACTIVITYCRITICAL for solid emptying. #ROSS BRIDGE CYCLING UNDERLYING SMOOTH MUSCLE CONTRACTION IS FACILITATED AND INHIBITED BY PHOSPHORYLATION AND DEPHOSPHORYLATION RESPECTIVELY OF THE K$A MYOSIN LIGHT CHAIN -,# ;16= 0HOSPHORYLATION STATUS OF -,# IS MAINLY DETERMINED BY THE RELATIVE ACTIVITIES OF -,# KINASE -,#+ AND PHOSPHATASE -,#0 5NDERPHYSIOLOGICALCONDITIONS SMOOTHMUSCLECONTRACTIONISINITIATEDBY CALMODULIN DEPENDENTACTIVATIONOF-,#+BYINCREASEDFREECYTOPLASMICCALCIUM ([Ca2+]i WHICH ALSO INHIBITS -,#0 INDIRECTLY 4HE INCREASE IN ;#A2+]i largely depends on Ca2+ENTRYVIAVOLTAGE SENSITIVE#A2+CHANNELSEG #AV ALTHOUGH Ca2+RELEASEFROMTHESARCOPLASMICRETICULUMVIAINOSITOL TRISPHOSPHATERECEPTOR operated Ca2+CHANNELS)032 ALSOCONTRIBUTES4HELATTERAREACTIVATEDBY' PROTEIN COUPLEDMEMBRANERECEPTORS WHICHALSOSTIMULATEMECHANISMSLEADINGTOINHIBITION of MLCP and consequent increased cross-bridge cycling in a Ca2+-independent MANNER3MOOTHMUSCLEMEMBRANEDEPOLARIZATIONABOVETHETHRESHOLDFORVOLTAGE dependent Ca2+ENTRYCANBEBROUGHTABOUTBYMYOGENIC )## MEDIATED ANDNEURONAL MECHANISMSANDTHEEFlCACYOFEXCITATION CONTRACTIONCOUPLINGCANBEFURTHERREGULATED BY ALTERING THE RESPONSIVENESS OF THE SMOOTH MUSCLE TO INPUT SIGNALS ;16]. 3TRETCHCANDEPOLARIZESMOOTHMUSCLECELLSVIAREGULATIONOFMECHANOSENSITIVEION CHANNELS INCLUDING#AV .AV ATETRODOTOXIN INSENSITIVE.A+CHANNEL+2P2.1, +2P AND+CaPOTASSIUMCHANNELSANDVARIOUSNONSELECTIVECATIONCHANNELS .3## ;17= 3INCE GASTROINTESTINAL SMOOTH MUSCLE CELLS ARE INTERCONNECTED INTO LARGERFUNCTIONALUNITSBYGAPJUNCTIONS DEPOLARIZATIONATONEPOINTWILLSPREADTO NEIGHBORINGCELLSANDACTIVATEENTIREBUNDLES !SECONDLAYEROFREGULATIONISPROVIDEDBY)## ANEVOLUTIONARILYPRESERVED HETEROGENEOUSGROUPOFMESENCHYMALCELLSIDENTIlABLEBYULTRASTRUCTURALFEATURES ANDTHEDEPENDENCEONSTEMCELLFACTORSIGNALINGVIA+IT ARECEPTORTYROSINEKINASE [18, 19=)##CANBECLASSIlEDBYTHEIRPRIMARYFUNCTIONASSOMEAREMAINLYINVOLVED IN ELECTRICAL RHYTHM GENERATION EG MULTIPOLAR )## IN THE MYENTERIC REGION OF PHASIC MUSCLES ;20= WHEREAS OTHERS EG SPINDLE SHAPED INTRAMUSCULAR )## MAINLYCONTRIBUTETOREGULATIONOFCONTRACTILEACTIVITYBYGENERATINGTONE;21] and by mediating neuroeffector inputs [22=ANDAFFERENTMECHANICALSIGNALS;17, 22, 23]. )## REGULATE SMOOTH MUSCLE MEMBRANE POTENTIAL VIA ELECTRICAL COUPLING AND THE HYPERPOLARIZINGGASEOUSMEDIATORCARBONMONOXIDE;24]. %LECTRICALSLOWWAVESTHATDRIVEPHASICCONTRACTILEACTIVITYMAINLYORIGINATEFROM PACEMAKER)##INTHEMYENTERICREGIONOFTHEGASTRICCORPUSANDANTRUM ALTHOUGH intramuscular and septal ICC also contribute [15, 20, 25]. In mutant rodents lacking PACEMAKER)##INPARTSOFTHEGASTROINTESTINALTRACT PERISTALSISANDSURVIVALDEPEND ON THE EMERGENCE OF A SECONDARY PACEMAKER ACTIVITY RESEMBLING #A2+ action potentials [13=(OWEVER THISACTIVITYCANNOTSUPPORTPROPULSIVEMOTILITYATTHESAME EFlCACYASSLOWWAVES;13, 26] and may not be able to fully compensate for ICC loss DEVELOPING POSTNATALLY ;27= 4HE MECHANISMS OF SLOW WAVE GENERATION BY )## ARENOTFULLYUNDERSTOOD!CCORDINGTOTHEMOSTCOMPREHENSIVEMODEL;15, 20, 28],

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Fig. 5.1 -ODEL FOR SLOW WAVE GENERATION BY )## a 4IME COURSE OF AN ELECTRICAL SLOW WAVE recorded from a pacemaker ICC. 5NITARY POTENTIALS UPSTROKE SLOW WAVE PLATEAU (b -ODELOFMAINEVENTSUNDERLYINGSLOW WAVEGENERATIONBASEDONREFS;19, 27–30]. SER sarcoENDOPLASMICRETICULUMMMITOCHONDRIONIP3RINOSITOL TRISPHOSPHATERECEPTOR OPERATED#A2+ CHANNEL MCU MITOCHONDRIAL #A2+ UNIPORTER NSCC NONSELECTIVE CATION CHANNEL VDCC VOLTAGE DEPENDENT DIHYDROPYRIDINE RESISTANT#A2+CHANNELAno1 anoctamin 1 Ca2+ ACTIVATED#L−CHANNEL blue dots: Ca2+ocher dots.A+purple dots: Cl−. ArrowsINDICATEDIRECTIONOFIONmUXESCircled numbersCORRESPONDTOSLOW WAVEPHASESINa circled + and − signs indicate membrane polarity. 5NITARYPOTENTIALSAREINITIATEDBYTHERELEASEOFASMALLQUANTUMOF#A2+FROMTHE3%2VIA)03R, WHICHACTIVATESCLOSELYAPPOSED-#53INCEMITOCHONDRIAL;#A2+=ISNOTINEQUILIBRIUMWITHCYTOplasmic [Ca2+= THISRESULTSIN#A2+INmUXINTOTHEMITOCHONDRIONANDANETDECREASEIN;#A2+=WITHIN APERIMITOCHONDRIALMICRODOMAINshaded area .3##WITHINTHISMICRODOMAINAREACTIVATEDBY reduced [Ca2+= WHICHLEADSTOMEMBRANEDEPOLARIZATION-EMBRANEDEPOLARIZATIONCAUSESTHE OPENINGOF6$## WHICHLEADSTOTHEUPSTROKEOFTHESLOWWAVE: Ca2+ENTERINGVIATHE6$## TOGETHER WITH #A2+-induced Ca2+ RELEASE FROM THE 3%2 ACTIVATES #L− EFmUX VIA !NO THE MAIN INWARDCURRENTUNDERLYINGTHESLOWWAVE-ITOCHONDRIAL CYTOPLASMICAND3%2;#A2+] are restored BYTHEMITOCHONDRIAL.A+/Ca2+EXCHANGERANDTHE3%2#A2+PUMPNOTSHOWN

THEYINVOLVESPONTANEOUSELEMENTARYEVENTSARISINGFROM#A2+CYCLINGBETWEENTHE SARCO ENDOPLASMICRETICULUMANDMITOCHONDRIA VOLTAGE SENSITIVE DIHYDROPYRIDINE INSENSITIVE#A2+ currents, and Ca2+ ACTIVATED ANDINWARD RECTIFYING#L− conductances (Fig. 5.1 4HE ELEMENTARY EVENT UNDERLYING SLOW WAVE ACTIVITY IS THE SO CALLED UNITARYPOTENTIALASMALL RANDOMDEPOLARIZATIONREmECTINGOPENINGSOF.3##REGUlated by periodic release of small quanta of Ca2+FROMTHESMOOTHSARCO ENDOPLASMIC


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RETICULUMVIA)03R. [Ca2+]iINDIRECTLYGOVERNSTHEOPENINGSOFTHE.3##BYSTIMULATING THEINmUXOF#A2+INTOENERGIZEDMITOCHONDRIA;29] causing a net decrease in [Ca2+]i INTHEIMMEDIATEVICINITYOF.3##3INCEINCREASED;#A2+]iINHIBITSTHESECHANNELS BYACALMODULIN DEPENDENTMECHANISM THEPERIODICDECREASESINLOCAL;#A2+]i lead TOCORRESPONDINGINCREASESIN.3##OPENPROBABILITY4HEGENERATIONOFSLOWWAVES REQUIRESTHESYNCHRONIZATIONOFMANYSUCHPACEMAKERUNITS4HISISACHIEVEDBYTHE SUMMATION OF UNITARY POTENTIALS AND SUBSEQUENT ACTIVATION OF VOLTAGE SENSITIVE DIHYDROPYRIDINE INSENSITIVE #A2+ currents [20= WHICH DIRECTLY OR INDIRECTLY BY facilitating Ca2+ release from intracellular stores, raise [Ca2+]iTOALEVELTHATACTIVATES ANINWARDCURRENTVIAA#A2+ ACTIVATED#L− conductance likely mediated by anoctamin !NOOR4MEMAOR$/' ;30= APROTEINUNIQUELYEXPRESSEDBY)##WITHIN THEGASTROINTESTINALMUSCULATURE;28, 31, 32=/THERCONDUCTANCESDESCRIBEDIN)## MAYALSOCONTRIBUTETOTHESEMECHANISMS;30]. 3INCEACTIVATIONOFTHEVOLTAGE SENSITIVE DIHYDROPYRIDINE RESISTANT#A2+ currents BYDEPOLARIZATIONOFELECTRICALLYCOUPLED NEIGHBORING)##CANPHASE ADVANCESLOW WAVES THESECHANNELSAREALSORESPONSIBLEFORSLOW WAVEPROPAGATIONBYSEQUENTIALLY TRIGGERINGTHEPACEMAKERMECHANISMSINNETWORKSOFELECTRICALLYCOUPLED)##;20]. )NTHESTOMACH SLOWWAVESORIGINATEINTHEORADCORPUSALONGTHEGREATERCURVATURE [33= AND SPREAD BOTH CIRCUMFERENTIALLY ACROSS THE THICKNESS OF THE MUSCULATURE ANDABORALLY0ROPAGATIONINALLTHREEDIRECTIONSCANBESUFlCIENTLYEXPLAINEDBYA DECREASING GRADIENT IN THE INTRINSIC FREQUENCIES OF PACEMAKER )## ;13, 34, 35], WHICHPERMITSSEQUENTIALENTRAINMENTOFSPONTANEOUSLYACTIVECELLS;34=%XPERIMENTS UTILIZINGHIGH RESOLUTIONMAPPINGOFELECTRICALACTIVITYHAVEINDICATEDTHATSLOW WAVE PROPAGATIONINTHECIRCUMFERENTIALDIRECTIONMAYONLYOCCURASPARTOFTHEINITIAL ISOTROPICPROPAGATIONAWAYFROMTHEPRIMARYPACEMAKERAREA ANDALLSUBSEQUENT PROPAGATIONREmECTSTHEANALSPREADOFTHERESULTANTCIRCUMFERENTIALBANDOFACTIVATION [13, 33=!NALTERNATIVEHYPOTHESISPROPOSEDFORTHECIRCUMFERENTIALPROPAGATIONOF GASTRICSLOWWAVESISTHATITMAYOCCURALONGALOW RESISTANCEPATHWAYPROVIDEDBY INTRAMUSCULAR)##THATAREEMBEDDEDWITHIN ANDRUNPARALLELTO THECIRCULARSMOOTH muscle cells [15=4HISMODELCANALSOEXPLAINWHYSLOWWAVESCANBERECORDEDCLOSE TOTHELESSERCURVATURE WHEREMYENTERIC)##NETWORKSARESPARSEORMISSING;34]. 3LOW WAVES REGULATE PHASIC CONTRACTILE ACTIVITY BY PERIODICALLY BRINGING THE SMOOTH MUSCLE MEMBRANE POTENTIAL CLOSE TO THE ACTIVATION THRESHOLD FOR VOLTAGE dependent Ca2+ENTRYWHICH IFSUFlCIENTLYLARGE RESULTSINAMECHANICALLYPRODUCTIVE contraction [16, 20=%LECTROMECHANICALCOUPLING IE THEFORCEOFSLOW WAVE DRIVEN CONTRACTIONS DEPENDSONTHEMAGNITUDEANDDURATIONOFSUPRATHRESHOLDDEPOLARIZATIONANDTHEPRESENCEORABSENCEOFSLOW WAVE ASSOCIATED REGENERATIVE#A2+ action POTENTIALS 4HUS DESPITE THE CONTINUOUS PRESENCE OF SLOW WAVES MECHANICALLY SIGNIlCANTCONTRACTIONSMAYNOTOCCURATTHEFREQUENCYDICTATEDBYTHEPACEMAKER INPUT0HASICCONTRACTIONSTHATHAVETHECHARACTERISTICFREQUENCYOFTHEPACEMAKER )## DO OCCUR POSTPRANDIALLY OR DURING AN INTERDIGESTIVE MIGRATING MYOELECTRIC COMPLEX;13, 19=INRESPONSETOINCREASEDELECTROMECHANICALCOUPLING WHICHCAN ARISEFROMDISTENSIONCAUSINGSMOOTHMUSCLEDEPOLARIZATIONVIATHEACTIVATIONOF MECHANOSENSITIVE ION CHANNELS ;17= NET NEURONAL EXCITATION OR SMOOTH MUSCLE SENSITIZATIONBYHUMORALFACTORS

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4HETHIRDLEVELOFREGULATIONISPROVIDEDBYTHEENTERICNERVOUSSYSTEM%.3 AND THESYSTEMICAUTONOMICNERVOUSSYSTEM;36=4HELATTEREXERTSEFFERENTCONTROLVIA THE%.3BYPARASYMPATHETICINPUTFROMTHEVAGALNUCLEIANDTHESACRALSPINALCORD ANDBYSYMPATHETICPOSTGANGLIONICNERVESFROMTHEPREVERTEBRALGANGLIA4HEREIS ALSODIRECTPOSTGANGLIONICSYMPATHETICINNERVATIONOFCERTAINSMOOTHMUSCLECELLSAND BLOODVESSELS"OTHTHEVAGUSANDSYMPATHETICNERVESCARRYAFFERENTAXONSASWELL 4HE %.3 IN HUMANS CONTAINS ^8 NEURONS THAT INCLUDE PRIMARY AFFERENT NEURONS EXCITATORYANDINHIBITORYMOTORNEURONS ASCENDINGANDDESCENDINGINTERNEURONS SECRETOMOTOR VASOMOTOR ANDINTESTINOFUGALNEURONS;36=%.3NEURONSAREORGANIZEDINTOFUNCTIONALCIRCUITSTHATEXECUTEREmEXRESPONSES SOMEOFWHICHINVOLVE EVENINTESTINOFUGALNEURONSANDTHEPREVERTEBRALGANGLIA;37=4HE%.3MAYALSO HAVEhHARD WIREDvCIRCUITSSIMILARTOCENTRALPATTERNGENERATORSTHATMAYBERESPONSIBLEFORREPETITIVEBEHAVIORS;38=.EURALCONTROLISEXERTEDBYACTIONPOTENTIAL DRIVEN NEUROTRANSMITTERRELEASEAND DEPENDINGONTHENEUROTRANSMITTERS CANBEEXCITATORY ;EG ACETYLCHOLINE SEROTONIN SUBSTANCE030 =ORINHIBITORY;NITRICOXIDE./ VASOACTIVEINTESTINALPOLYPEPTIDE6)0 !40=;36]. .EURALCONTROLOFSMOOTHMUSCLEFUNCTIONISEITHERDIRECTORINDIRECTVIASPINDLE SHAPEDINTRAMUSCULAR)##;22=AND+IT− PLATELET DERIVEDGROWTHFACTORRECEPTOR D ALPHA EXPRESSING MESENCHYMAL CELLS ;lBROBLAST LIKE CELLS &,# = ;39, 40]. )NFACT ./ DEPENDENTCONTROLOFGASTROINTESTINALSMOOTHMUSCLERELAXATIONINTHE MOUSEISENTIRELYINDIRECTANDLIKELYMEDIATEDBYBOTH)##AND&,#;40]. ICC may TRANSMITTHEEFFECTSOFBOTHEXCITATORYANDINHIBITORYNEURALINPUTSTOTHESMOOTH muscle cells and also to pacemaker ICC by electrical coupling or paracrine mediators. &OREXAMPLE PROSTAGLANDINS WHICHHAVEBEENSHOWNTOMEDIATETHEARRHYTHMOGENIC EFFECTS OF HYPERGLYCEMIA ;41= MAY ELICIT ANTRAL TACHYARRHYTHMIAS BY ACTIVATING DOMINANTPACEMAKERACTIVITYININTRAMUSCULAR)##VIA%03 receptors [42=!ROLEFOR intramuscular ICC in efferent neural control is supported by reduced postjuncTIONALRESPONSESINTISSUESOFRODENTSLACKINGTHESECELLSDUETOPHARMACOLOGICAL+IT blockade or mutations in KitORITSLIGAND THEPRESENCEOFSYNAPSE LIKESPECIALIZATIONSINCLOSELYAPPOSEDNERVESAND)## EXPRESSIONININTRAMUSCULAR)##OFGENES proteins related to neurotransmitter-mediated signal transduction, and receptormediated internalization of neurotransmitters [19, 22, 31, 39, 40]. Intramuscular )##MAYALSOHELPMAINTAINTHEPROXIMAL TO DISTALSLOW WAVEFREQUENCYGRADIENT BY CONTRIBUTING TO THE METABOLISM OF ACETYLCHOLINE ;43= AND THEREBY PREVENTING EXCESSIVECHRONOTROPICSTIMULATIONINTHEANTRUMDURINGVAGALSTIMULATION7HEREAS )##CONTRIBUTETOCHOLINERGICANDNITRERGICRESPONSES PURINERGICINHIBITIONANDNONCHOLINERGICPEPTIDERGIC EXCITATIONARERATHERPRESERVEDINTHEIRABSENCE;22, 43]. )N MICE DElCIENT IN INTRAMUSCULAR )## PARTIAL PRESERVATION OF NITRERGIC NEUROmuscular neurotransmission [19, 21=ISLIKELYDUETOTHEOVERLAPPINGFUNCTIONSOF FLC [39, 40=4HECONSEQUENCESOFSELECTIVE&,#LOSSREMAINTOBEINVESTIGATED )NTRAMUSCULAR)##ALSOCONTRIBUTETOAFFERENTNEURALSIGNALING3IMILARLYTOSMOOTH MUSCLECELLS )##CANSENSEMECHANICALSTIMULI EG BYEXPRESSINGMECHANOSENSITIVE IONCHANNELSEG #AVAND.AV1.5) [17=ANDMEDIATETHEEFFECTSOFDISTENTIONTO neuronal circuits [23=)NTERESTINGLY MAINTENANCEOFTHELATTERFUNCTIONDEPENDSON AMUTUALTROPHICSUPPORTBETWEEN)##ANDCERTAINVAGALNERVETERMINALS;19, 23].


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)NTRAMUSCULAR)##CANALSOTRANSDUCEPASSIVESTRETCHINTOEXCITATORYINPUTTOPACEMAKER )##INTHESTOMACHWITHOUTTHEINVOLVEMENTOFENTERICNEURONALACTIVITY POSSIBLYBY releasing prostaglandins [22]. )NSUMMARY HIGHERORDERMOTORFUNCTIONSSUCHASGASTRICEMPTYINGARESUPPORTED BY AN INTRICATE AND HIGHLY REDUNDANT CONTROL SYSTEM WITH SIGNIlCANT FUNCTIONAL RESERVE;13=)NTHENEXTSECTION WEREVIEWCHANGESTOTHEKEYREGULATORYCELLTYPES WHICHCOULDREDUCETHEFUNCTIONALCAPACITYOFTHEMOTORAPPARATUSANDCONTRIBUTETO THEDEVELOPMENTOFGASTROPARESIS

Cellular Degeneration in Gastroparesis $EGENERATIVECHANGESAFFECTINGEXTRINSICNERVES THE%.3 SMOOTHMUSCLECELLS AND )## HAVE BEEN DESCRIBED BOTH IN PATIENTS AND ANIMAL MODELS OF GASTROPARESIS particularly in diabetes (Fig. 5.2 (EREIN WEPROVIDEABRIEFSUMMARYOFTHEKEY CELLULARCHANGESANDTHEIRFUNCTIONALCONSEQUENCESFORMOREDETAILEDDESCRIPTIONS THEREADERISREFERREDTORECENTREVIEWS;3, 6, 8, 12, 44].

Extrinsic Nerves Vagotomy itself can result in delayed solid emptying [2= BY ELICITING SLOW WAVE ARRHYTHMIAS AND UNCOUPLING ;45= AND BY BLOCKING THE GASTRIC ACCOMMODATION REmEX;46=(OWEVER THELATTERSPONTANEOUSLYRECOVERSWITHTIMEDUETOTHEEMERGENCE OF AN %.3 REmEX UTILIZING A PHARMACOLOGICALLY INDISTINGUISHABLE NITRERGIC EFFERENT MECHANISM ;46= 6AGAL NEUROPATHY HAS BEEN PROPOSED AS A MAJOR FACTOR INOTHERFORMSOFGASTROPARESISASWELL%ARLYSTUDIESFOCUSEDONMYELINATEDAXONS OFTHETHORACICVAGUSBUTMOSTOFTHOSElBERSDONOTINNERVATEABDOMINALVISCERA )NAPATIENTWITHINTRACTABLEGASTROPARESIS 'UYETALDESCRIBEDSEVEREREDUCTIONIN THE DENSITY AND DIAMETER OF UNMYELINATED AXONS ;47= AND SIMILAR lNDINGS WERE reported in spontaneously diabetic BioBreeding (BB) rats [48= (OWEVER OTHERS FAILEDTODETECTVAGALINVOLVEMENTINLARGERSERIES;6=4HEDEGENERATIONDESCRIBEDIN THEDORSALMOTORNUCLEUSOFTHEVAGUSOFRATSnDAYSAFTERSTREPTOZOTOCIN34: treatment [49=ISDIFlCULTTOASCRIBETODIABETESBECAUSEOFTHERAPIDDEVELOPMENTOF THECHANGESANDTHEWELL KNOWNNEUROTOXICEFFECTSOF34:;50=4HUS WHILEDEGENERATIVECHANGESINTHEVAGUSNERVEMAYOCCURINNONSURGICALGASTROPARESIS THEIRTRUE SIGNIlCANCEREMAINSUNCLEAR$IABETICAUTONOMICNEUROPATHYALSOAFFECTSSYMPATHETIC NERVES)NPATIENTSANDANIMALMODELS ENLARGEDDISTALAXONSANDNERVETERMINALS WERE DESCRIBED IN PREVERTEBRAL GANGLIA ;51= AND DECREASED TYROSINE HYDROXYLASE IMMUNOLABELINGWASREPORTEDINARELATIVELYSMALLSUBSETOFPATIENTSWITHGASTROparesis [52, 53=7HILETHESEARECOMPELLINGRESULTS THEIRRELEVANCETOGASTROPARESIS is uncertain [3].

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Fig. 5.2 #ELLULARDYSTROPHYINTHESTOMACHOFPATIENTSWITHDIABETICGASTROPARESISANDREFRACTORY SYMPTOMS&ULLTHICKNESSSPECIMENSFROMTHEANTERIORWALLOFTHEMID CORPUSABOVETHEINCISURA Reprinted from [51=UNDERTERMSOFTHE#REATIVE#OMMONS!TTRIBUTION,ICENSEHTTPCREATIVEcommons.org/licenses/by/2.0). Left panels, control tissues obtained from nondiabetic obese patients undergoing gastric bypass surgery. Middle panels YEAR OLD FEMALE PATIENT WITH A HISTORY OF WELL CONTROLLEDTYPEDIABETESFORABOUTYEARSCASE Right panels YEAR OLDWHITEFEMALE PATIENTWITHAHISTORYOFPOORLYCONTROLLEDTYPEDIABETESFORABOUTADECADECASE CM circular MUSCLELM longitudinal muscle. (a–c )MMUNOREACTIVITYFORNEURONALNITRICOXIDESYNTHASEN./3 .ORMALIMMUNOREACTIVITYFORN./3INCONTROLa) and case 1 (b N./3IMMUNOREACTIVITYWAS markedly decreased in case 2 (c). (d–f +ITEXPRESSIONASAMARKERFORINTERSTITIALCELLSOF#AJAL Control (d) and case 1 (e SHOWEDNORMAL+ITIMMUNOREACTIVITYWHILEINCASEf THEREWASALOSS OF+ITIMMUNOREACTIVITYSUGGESTINGADECREASEDNUMBEROF)##2OUNDCELLSLACKINGPROCESSESAND PRESENTINALLTISSUESARE+IT+ mast cells. Scale bar in (f), is 100 Pm and applies to (a–f). (g–i) -ASSONSTRICHROMESTAININGCONNECTIVETISSUEblueNUCLEIdark red/purpleCYTOPLASMred/pink). 4HECONTROLg) and sections from case 1 (h SHOWEDNOINCREASEINlBROSIS WHEREASSECTIONSFROM case 2 (i SHOWEDANINCREASEINlBROSISINBOTHMUSCLELAYERSANDALONGTHEMYENTERICPLEXUS Scale bar, 200 Pm


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Enteric Nervous System $EGENERATIVE CHANGES IN MYENTERIC NEURONS AND AXONS AS WELL AS REDUCED NERVE lBERS OR PERIKARYA HAVE BEEN DESCRIBED IN THE STOMACHS OF PATIENTS WITH SEVERE diabetic [52, 54, 55=ANDIDIOPATHICGASTROPARESIS;55, 56=(OWEVER OTHERSFAILEDTO DETECT SIMILAR CHANGES IN PATIENTS WITH LONG STANDING DIABETES ;57, 58] and no GENERAL NEURON DEGENERATION WAS OBSERVED IN SEVERAL ANIMAL MODELS INCLUDING ""7RATS 34: DIABETIC AND./$MICE;10, 59, 60]. In a recent study conducted INPATIENTSPATIENTSEACHWITHDIABETICANDIDIOPATHICGASTROPARESISANDAGE ANDSEX MATCHEDCONTROLS BYTHE.ATIONAL)NSTITUTEOF$IABETESAND$IGESTIVEAND +IDNEY$ISEASES.)$$+ 'ASTROPARESIS#LINICAL2ESEARCH#ONSORTIUM'P#2# ASMALLBUTSIGNIlCANTDECLINEININTRAMURALNERVElBERS ABNORMALULTRASTRUCTUREOF NERVEENDINGS ANDDEGENERATIONOFENTERICGLIALCELLSWEREFOUND;53=!MORECONSIStent finding in gastroparesis, particularly in females [61], is a specific reduction in NITRERGICSIGNALING$ECREASED./PRODUCTIONLIKELYCONTRIBUTESTOIMPAIREDACCOMMODATIONANDPYLORICRELAXATION;10, 11, 59=2EDUCEDEXPRESSIONOFNEURONAL./ SYNTHASEN./3 M2.!ORPROTEIN ASWELLASLOWERNUMBERSOFN./3 EXPRESSING NEURONSWEREOBSERVEDIN""7RATS;59= 34: DIABETICRATSANDMICE;10, 62, 63] AND./$MICE;9, 10=(OWEVER IN34: DIABETICRATSOTHERSFOUNDNOCHANGEINTHE NUMBER OF N./3+ neurons [64= AND N./3 EXPRESSION WAS ACTUALLY INCREASED IN male rats [61, 64=,OSSOFN./3 EXPRESSINGNERVElBERSORNEURONSWEREREPORTED INTHESTOMACHOFTYPE;52, 55] and type 2 diabetic patients [65] and also in patients WITH IDIOPATHIC GASTROPARESIS ;55= )N THE .)$$+ 'P#2# STUDY REDUCED N./3 EXPRESSIONWASFOUNDINANDOFPATIENTSWITHIDIOPATHICANDDIABETICGASTROPARESIS RESPECTIVELY ;53= (OWEVER SIMILARLY TO 6)0 AND 30 EXPRESSION N./3 IMMUNOLABELINGDIDNOTCHANGESIGNIlCANTLY;53=7HILEDROPOUTOFN./3+ neurons MAYDOMINATELATEINGASTROPARESIS REDUCEDNITRERGICSIGNALINGSEENINEARLYPHASES MAY REmECT IMPAIRED AXONAL TRANSPORT ;11= N./3 DIMERIZATION ;61], or function FROMREDUCEDCOFACTORLEVELS;66=RATHERTHANREDUCEDEXPRESSION

Smooth Muscle $EGENERATIONOFSMOOTHMUSCLECELLSHASBEENDESCRIBEDINPATIENTSWITHTHERAPY RESISTANTGASTROPARESISANDSEVEREWEIGHTLOSSARISINGFROMLONG STANDING COMPLICATED diabetes [52, 54, 58=(ISTOLOGICALlNDINGSINCLUDEDSCATTERED HOMOGENEOUS EOSINOPHILICBODIESh-vBODIES ANDATROPHYWITHINTERCELLULARCOLLAGENACCUMULATION 3IMILARCHANGESWEREALSONOTEDINAPATIENTWITHSEVEREIDIOPATHICGASTROPARESIS [56] but not in larger series of diabetic and/or gastroparetic patients [53, 55, 57]. )NTHEABSENCEOFOVERTSMOOTHMUSCLEDEGENERATION IMPAIREDSMOOTHMUSCLEFUNCTION ASSOCIATEDWITHGASTROPARESISMAYBEDUETOMORESUBTLEABNORMALITIESSEENBOTHIN PATIENTSANDANIMALMODELS SUCHASIMPAIREDCELLULARRESPONSESTOMUSCARINICOR

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TACHYKININERGICSTIMULATION;14, 67= REDUCEDEXPRESSIONOFSTEMCELLFACTOR;60, 68], MYOSIN HEAVY CHAIN ;60= AND SMOOTHELIN ;53= AS WELL AS MARKEDLY INCREASED CONNECTIVETISSUESTROMASURROUNDINGSMOOTHMUSCLECELLSANDSEPARATINGTHEM FROM)##ANDENTERICNERVES;53, 69=4HUS DETERIORATIONOFINTRACELLULARPATHWAYSMEDIATINGNEUROTRANSMITTERRESPONSESANDADECREASEINCONTRACTILEPROTEIN EXPRESSIONMAYPRECEDETHEMOREPROFOUNDCHANGESDETECTEDINADVANCED THERAPY resistant cases.

Interstitial Cells of Cajal 3INCETHElRSTREPORTSONTHEROLEOF)##INDIABETICGASTROENTEROPATHIES;69, 70], )##LOSSHASBEENFOUNDNOTONLYINTYPEANDTYPEMODELS;9, 60, 68, 71–74], but ALSOINPATIENTSWITHIDIOPATHIC;56, 75], diabetic [52, 55, 65, 76, 77], and postsurgical gastroparesis [76, 77=2ECENTLY THE.)$$+'P#2#;53] identified ICC loss, found INOFPATIENTSWITHEITHERDIABETICORIDIOPATHICGASTROPARESIS ASTHEMOSTCONSISTENTLYOCCURRINGHISTOLOGICALABNORMALITY)NRODENTS )##DEPLETIONUSUALLYBECOMES NOTICEABLESEVERALWEEKSAFTERTHEONSETOFDIABETESCOINCIDINGWITHTHEDEVELOPMENTOFDELAYEDEMPTYINGOFSOLIDS ELECTRICALDYSRHYTHMIAS ANDREDUCEDPOSTJUNCtional electrical responses [9, 60, 68, 69, 71, 73=4HE)##INJURYHASBEENREPORTED to be focal [69] or diffuse [68=ANDMORESEVEREINDISTALSTOMACH;69, 73=)N./$ and db/dbMICE ALL)##CLASSESWEREAFFECTED;60, 68, 69= WHEREASIN34: DIABETIC RATS DAMAGEWASRESTRICTEDTOINTRAMUSCULAR)##ANDSUBMUCOUSBORDER)##OFTHE antrum [73]. Besides reducing neuromuscular neurotransmission [69], loss of intraMUSCULAR)##MAYALSOPREDISPOSETHEANTRALPACEMAKER)##TOTACHYGASTRIAUNDER TONICCHOLINERGICEXCITATION;43=-AJORULTRASTRUCTURALABNORMALITIESINTHEREMAINING CELLSWEREONLYREPORTEDIN34: DIABETICRATS;71, 73] and, more recently, in gastroparetic patients [53=!LOSSOFCLOSEASSOCIATIONBETWEEN)##ANDENTERICNERVES WASNOTEDBOTHINDRUG INDUCEDANDSPONTANEOUSDIABETES;53, 69, 73=)NVASIONOF MYENTERIC )## INTO THE FUNDUS AND APPEARANCE OF ECTOPIC ELECTRICAL RHYTHMICITY WEREALSODESCRIBEDIN./$MICE;69=ANDMAYHAVECONTRIBUTEDTOREDUCEDACCOMMODATION)NFOURLARGERSTUDIESINVOLVINGnGASTROPARETICPATIENTS MAJORLOSS OF)##WASDETECTEDINnOFTHESUBJECTS;53, 55, 76, 77=0ATIENTSWITHSEVERE )## LOSS HAD LESS NORMAL SLOW WAVES MORE TACHYGASTRIA BOTH IN FASTING AND FED STATE AND SHOWED LESS IMPROVEMENT TO ELECTRICAL STIMULATION THAN PATIENTS WITH normal ICC [76, 77=(OWEVER THELOSSOF)##DIDNOTCORRELATEWITHTHEDEGREEOF gastric emptying or symptoms [77=)NANOTHERSTUDYINVOLVINGDIABETICPATIENTS )WASAKIETAL;65] detected a significant reduction in intramuscular ICC in 8 patients WITHSEVEREDIABETES.O)##LOSSWASFOUNDINTHEMYENTERICREGIONORINPATIENTS WITH MILDER FORMS OF THE DISEASE 4HUS )## LOSS IS COMMONLY ASSOCIATED WITH GASTROPARESISOFANYETIOLOGYINBOTHPATIENTSANDANIMALMODELS4HEDEGREEOF CELLULARDYSTROPHYSEEMSTOBERELATEDTOTHESEVERITYOFDIABETES;9, 52, 60, 65, 69]. )MPORTANTLY )##LOSSALSOPREDICTSRESISTANCETOCONVENTIONALTHERAPYORELECTRICAL stimulation [76, 77].


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Cellular Mechanisms of Gastroparesis and the Road to Curative Therapy 4HEFOREGOINGINDICATESTHATTHECOMPLEXPATHOPHYSIOLOGYUNDERLYINGGASTROPARESIS REmECTSNOTONLYIMPAIREDORGANFUNCTION BUTALSOPROFOUNDCHANGESINTHECELLULAR COMPOSITIONOFTHEtunica muscularis4HISISINCONTRASTWITHCURRENTLYAVAILABLE THERAPIES WHICH FOCUS ON SYMPTOM CONTROL AND STIMULATION OF RESIDUAL FUNCTION #LEARLY FORBETTERRESULTS THERAPEUTICEFFORTSSHOULDFOCUSONRESTORINGTISSUEINTEGRITY(OWEVER SEVERALQUESTIONSNEEDTOBEANSWEREDBEFORECURATIVETHERAPIESCOULD be designed.

How Exactly Does Cell Loss Lead to Gastroparesis? 3TUDIES IN ANIMAL MODELS AND REDUCED SYSTEMS HAVE IDENTIlED SPECIlC FUNCTIONS OFKEYCELLTYPESOFTHEGASTRICMUSCULATURE(OWEVER ASDISCUSSEDABOVE THESEINDIVIDUALFUNCTIONSADDUPTOAHIGHLYCOMPLEXANDREDUNDANTCONTROLSYSTEM WHERETHE RELATIONSHIPBETWEENCELLDElCITANDLOSS OF FUNCTIONISNOTLINEARDUETOTHEEXISTENCE OFSIGNIlCANTFUNCTIONALRESERVES4HUS WITHINTHERANGEOFCOMPENSATION DAMAGETO ANYPARTICULARCOMPONENTISLIKELYTORESULTINDYSFUNCTIONTHATISLESSTHANPREDICTED WHEREASBEYONDACERTAINLIMIT INJURIESMAYBECOMECATASTROPHIC)TCANBEASSUMED THAT IN A COMPENSATED BUT FUNCTIONALLY LIMITED STOMACH NEW CHALLENGES SUCH AS HYPERGLYCEMIA ELECTROLYTE IMBALANCES INFECTIONS STRESS AND OTHER PSYCHOLOGICAL factors [1, 8, 78, 79], can more easily precipitate dysfunction and symptoms [2, 58] (Fig. 5.3 4HISCONCEPTISSUPPORTEDBYRECENTlNDINGSINPROGERICMICEDElCIENT IN THE ANTI AGING PEPTIDE +LOTHO ;80= AND IN AGING HUMANS ;81= WHICH REVEALED PROGRESSIVE DIFFUSE AGE RELATED LOSS OF )## THROUGHOUT THE GASTROINTESTINAL TRACT ^PERDECADEOFLIFE OCCURRINGINTHEABSENCEOFGASTROPARESIS(OWEVER DETAILED STUDIES IN THE PROGERIC MICE DEMONSTRATED REDUCED FUNCTIONAL RESERVES INCLUDING REDUCED INHIBITORY NEUROTRANSMISSION AND SLOW WAVES )T IS THEREFORE LIKELY THAT FORGASTROPARESISTOMANIFEST DIFFUSECELLULARDYSTROPHYMUSTBEACCOMPANIEDBY FACTORS TRIGGERINGDECOMPENSATION&OREXAMPLE GASTROPARESISMAYBEPRECIPITATED by dominant ectopic pacemakers [82= DEVELOPING IN THE DEPLETED )## NETWORKS in response to a focal damage [25= ABNORMALRESPONSETOEXCITATORYNEUROTRANSmitters [43= HYPERGLYCEMIA;41], and increased prostaglandin secretion [42]. Models, SUCHAS+LOTHO DElCIENTMICE WILLALLOWDIRECTTESTINGOFTHISHYPOTHESIS

Is There a Common Mechanism of Cell Deficit in Gastroparesis? ! VARIETY OF MECHANISMS INCLUDING HYPERGLYCEMIA OXIDATIVENITROSATIVE STRESS REDUCEDTROPHICFACTORS IMPAIREDDIFFERENTIATIONFROMPRECURSORS VIRALINFECTIONS AUTOIMMUNITY ANDINmAMMATION HAVEBEENPROPOSEDTOUNDERLIECELLLOSSINGASTROparesis [2, 6=3OMEOFTHEBESTUNDERSTOODMECHANISMS SUCHASTHELOSSOFNITRERGIC

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Fig. 5.3 0ROPOSEDINTERACTIONBETWEENCELLULARDYSTROPHYANDACUTEFUNCTIONALCHALLENGESINTHE GENERATIONOFORGANDYSFUNCTIONANDASSOCIATEDSYMPTOMSUSING)##ASANEXAMPLE4HEsloping line on topDEPICTSGRADUALLYDECLININGCELLNUMBERSDURINGTHECOURSEOFADISEASEDownward deflectionsFROMTHISlineINDICATETHEEFFECTSOFACUTEFUNCTIONALCHALLENGESHYPERGLYCEMICEPISODES infections, stress, etc.). Closed areasINDICATESYMPTOMATICEPISODES7HILEDIFFUSECELLLOSSITSELF MAY NOT LEAD TO DETECTABLE DYSFUNCTION OR SYMPTOMS IT ENABLES ACUTE CHALLENGES TO PRECIPITATE clinical disorder

NEURONSFROMOXIDATIVENITROSATIVESTRESSANDCONSEQUENTAPOPTOSIS;11=ARE HOWEVER SPECIlCFORDIABETESANDCANNOTEXPLAINGASTROPARESISDEVELOPINGINTHEABSENCEOF ELEVATED BLOOD GLUCOSE EG IN ANOREXIA NERVOSA ;83= )N VARIOUS ETIOLOGIES CELL depletion may be precipitated by entirely different factors or mediated by common DOWNSTREAMMECHANISMS2ECENTREPORTSSUGGESTTHATINmAMMATORYIMMUNEMECHANISMSANDORREDUCEDSIGNALINGFROMTROPHICFACTORSMAYSERVEAShCOMMONDENOMINATORSv OF GASTROPARESIS !UTOIMMUNE PROCESSES ARE KNOWN TO CONTRIBUTE TO THE PATHOGENESIS OF GASTROINTESTINAL NEUROMUSCULAR DISORDERS ;84= AND INmAMMATORY MEDIATORS SUCH AS INTERFERON J MAY ALSO CAUSE DEPLETION OF VARIOUS CELLS EG ICC [85=!CCUMULATIONOF#$+LEUKOCYTESMAINLYMACROPHAGES WASNOTEDIN AND OF BIOPSIES FROM PATIENTS WITH IDIOPATHIC AND DIABETIC GASTROPARESIS RESPECTIVELY ;53= AND A MILD LYMPHOCYTIC INlLTRATE OF THE MYENTERIC REGION WAS DETECTEDINOFDIABETICTISSUESINANOTHERCOHORT;55=(OWEVER OTHERCLINICAL AND EXPERIMENTAL STUDIES FAILED TO DETECT SIMILAR CHANGES AND IN SOME MODELS INmAMMATORYINlLTRATESAPPEARTOBEACONFOUNDINGVARIABLERATHERTHANATRUEPATHOgenetic factor [6=2ECENTLY #HOIETAL;72=FOUNDTHATANINCREASEIN-MACROPHAGES EXPRESSING HEME OXYGENASE MAY PROTECT )## FROM OXIDATIVE STRESS IN DIABETES ANDLOSSOFTHESECELLSCOULDPRECIPITATEGASTROPARESIS4HUS GASTROPARESISMAYINDEED INVOLVEIMMUNE RELATEDMECHANISMSALTHOUGHRECRUITMENTOFIMMUNECELLSPERSE MAYNOTNECESSARILYSIGNALAPATHOGENETICEVENT 3INCE MANY CELLS DEPEND ON SIGNALING FROM VARIOUS RECEPTOR TYROSINE KINASES 24+S FORSURVIVAL LOSSOF24+LIGANDSMAYALSOMEDIATETHEEFFECTSOFDISPARATE


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ETIOLOGICAL FACTORS &OR EXAMPLE SMOOTH MUSCLE CELLS )## PRECURSORS AND EVEN PERIPHERALNEURONSUTILIZEINSULINANDINSULIN LIKEGROWTHFACTOR))'& ) ASDIFFERENTIATION SURVIVAL ANDGROWTHFACTORS;6= ANDTHEYAREREDUCEDORINEFFECTIVEIN DIABETES CALORIC RESTRICTION AND OTHER FORMS OF STRESS ;86= 3TEM CELL FACTOR+IT signaling critical for maintenance of ICC is also dependent on insulin/IGF-I [60] AND THE TROPHIC EFFECT OF VAGAL INNERVATION ON )## ;23] may also be mediated BY 24+ LIGANDS 24+ ACTIONS MAY BE NEGATIVELY INmUENCED BY HYPERGLYCEMIA ANDOXIDATIVESTRESSVIATHEUPREGULATIONOFFORKHEADBOX/&/8/ TRANSCRIPTION factors [63= WHICHCANCOMPETEWITHOTHERTRANSCRIPTIONFACTORSFORSIGNALINGINTERmediates [87=)NCREASEDNUCLEARACCUMULATIONOF&/8/AHASBEENSHOWNTOPLAY AROLEINHYPERGLYCEMIA INDUCEDAPOPTOSISOFENTERICNEURONS;63=4HUS STUDYING 24+ SIGNALING IN DIFFERENT FORMS OF GASTROPARESIS MAY LEAD TO THE DISCOVERY OF NOVELTHERAPEUTICTARGETS

Strategies to Restore Tissue Integrity and Function 'ASTRICFUNCTIONSINVOLVEBOTHSTORAGE PROMOTINGANDPROPULSIVEFUNCTIONSAND)## NITRERGICNERVES ANDSMOOTHMUSCLECELLSCONTRIBUTETOBOTH&OREXAMPLE LOSSOF NITRERGICINHIBITIONORLOSSOF)##THATMEDIATETHISEFFECT INTHEFUNDUSMAYCAUSE ACCELERATED GASTRIC EMPTYING WHEREAS SIMILAR CHANGES IN THE PYLORUS MAY CAUSE DELAYEDEMPTYING)TALSOFOLLOWSTHATPHARMACOLOGICALTREATMENTSTOINCREASE./ LEVELSOREFFECTSWILLINmUENCEBOTHASPECTSOFGASTRICMOTILITYANDMAYNOTRESULTIN THEDESIREDOUTCOME)NDEED TRIALSWITHNITROGLYCERINANDSILDENAlLINPATIENTSWITH GASTROPARESISHAVEBEENDISAPPOINTING LIKELYDUETOTHEOPPOSINGEFFECTSOF./ON GASTRIC EMPTYING VIA STIMULATING PROXIMAL GASTRIC RELAXATION WHICH ENCOURAGES STORAGE ANDPYLORICRELAXATIONWHICHINCREASESEMPTYING ;88=!BETTERTHERAPEUTICAPPROACHMAYBETOIMPROVEORRESTORETHEINTEGRITYOFTHE%.3ANDOR)## $EPENDINGONTHESTAGEOFDISEASE THISMAYBEACCOMPLISHEDBYDIFFERENTMEANS !TANEARLYSTAGE CELLULARINJURYLIKELYMANIFESTSEXCLUSIVELYATTHELEVELOFIMPAIRED GENEEXPRESSIONANDINTRACELLULARSIGNALINGANDELIMINATINGFACTORSCAUSINGCELLULAR STRESSSHOULDPERMITCELLULARREPAIRANDPREVENTFURTHERPROGRESSION;9, 89]. Sustained INSULT EVENTUALLY PRECIPITATES CELL DYSTROPHY AND DEPLETION BUT OPPORTUNITIES FOR RESTORINGTISSUEINTEGRITYFROMLOCALSTEMPROGENITORCELLS SUCHASTHOSEDESCRIBEDIN postnatal mice for enteric neurons [90] and ICC [85= ORBYAXONREGENERATION;91] PROBABLY PERSIST FOR EXTENDED PERIODS OF TIME 3UPPORTING ENDOGENOUS DEFENSE MECHANISMSANDREPLACINGMISSINGTROPHICFACTORSWOULDSTILLBEEXPECTEDTOLEADTO RECOVERYFROMTHISSTAGE-AJORCELLLOSSANDREMODELINGWITHANACCUMULATIONOF EXTRACELLULAR MATRIX ONLY OCCUR AFTER REPEATED INSULTS !T THIS POINT ENDOGENOUS progenitor cells may also be affected and if so, tissue regeneration may require stem cell replacement [92–94=COUPLEDWITHTREATMENTSSUPPORTINGTHEIRSURVIVALINTHE DISEASEDHOSTTISSUES

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Summary !JOINTEFFORTOFBASICANDCLINICALRESEARCHGROUPSOVERTHELASTDECADEHASRESULTED INASIGNIlCANTINCREASEINOURUNDERSTANDINGOFTHECELLULARBASISOFGASTROPARESIS 7HILEMANYUNSOLVEDISSUESREMAIN PARTICULARLYINTHECONTEXTOFTRANSLATINGTHE NEW lNDINGS INTO NOVEL THERAPIES THE AVAILABILITY OF RELEVANT ANIMAL MODELS AND CLINICALRESEARCHINFRASTRUCTURE INCLUDINGOPPORTUNITIESFORCOLLABORATIONSRAISETHE HOPEFORlNDINGACUREFORGASTROPARESIS Acknowledgment 4HISREVIEWANDWORKINTHEAUTHORSLABORATORYHAVEBEENSUPPORTEDBY.)( GRANTS$+AND$+ Disclosure: 4HEAUTHORHASNOCOMPETINGlNANCIALINTERESTS

References 0ARKMAN(0 #AMILLERI- &ARRUGIA' ETAL'ASTROPARESISANDFUNCTIONALDYSPEPSIAEXCERPTS FROMTHE!'!!.-3MEETING.EUROGASTROENTEROL-OTIL n 0ARKMAN (0 (ASLER 7, &ISHER 23 !MERICAN 'ASTROENTEROLOGICAL !SSOCIATION TECHNICAL REVIEW ON THE DIAGNOSIS AND TREATMENT OF GASTROPARESIS 'ASTROENTEROLOGY 1592–622. 6ITTAL( &ARRUGIA' 'OMEZ' 0ASRICHA0*-ECHANISMSOFDISEASETHEPATHOLOGICALBASISOF GASTROPARESIS n A REVIEW OF EXPERIMENTAL AND CLINICAL STUDIES .AT #LIN 0RACT 'ASTROENTEROL (EPATOL n 0ARKMAN(0 9ATES+ (ASLER7, ETAL#LINICALFEATURESOFIDIOPATHICGASTROPARESISVARYWITHSEX BODYMASS SYMPTOMONSET DELAYINGASTRICEMPTYING ANDGASTROPARESISSEVERITY'ASTROENTEROLOGY n .ATIONAL )NSTITUTES OF (EALTH &UNCTIONAL GASTROINTESTINAL DISORDERS AND MOTILITY DISORDERS )N/PPORTUNITIESANDCHALLENGESINDIGESTIVEDISEASESRESEARCHRECOMMENDATIONSOFTHENATIONAL COMMISSION ON DIGESTIVE DISEASES .)( 0UBLICATION .O n . "ETHESDA -$ 53 $EPARTMENTOF(EALTHAND(UMAN3ERVICES .ATIONAL)NSTITUTESOF(EALTHPn /RDOG4 (AYASHI9 'IBBONS3*#ELLULARPATHOGENESISOFDIABETICGASTROENTEROPATHY-INERVA 'ASTROENTEROL$IETOL n 7. Hasler WL. Type 1 diabetes and gastroparesis: diagnosis and treatment. Curr Gastroenterol 2EP n 0HILLIPS,+ 2AYNER#+ *ONES+, (OROWITZ-!NUPDATEONAUTONOMICNEUROPATHYAFFECTING THEGASTROINTESTINALTRACT#URR$IAB2EP n #HOI+- 'IBBONS3* .GUYEN46 ETAL(EMEOXYGENASE PROTECTSINTERSTITIALCELLSOF#AJAL FROM OXIDATIVE STRESS AND REVERSES DIABETIC GASTROPARESIS 'ASTROENTEROLOGY 2055–64. 7ATKINS## 3AWA! *AFFREY3 ETAL)NSULINRESTORESNEURONALNITRICOXIDESYNTHASEEXPRESSION ANDFUNCTIONTHATISLOSTINDIABETICGASTROPATHY*#LIN)NVEST n #ELLEK 3 &OXWELL .! -ONCADA 3 4WO PHASES OF NITRERGIC NEUROPATHY IN STREPTOZOTOCIN INDUCEDDIABETICRATS$IABETES n /RDOG 4 )NTERSTITIAL CELLS OF #AJAL IN DIABETIC GASTROENTEROPATHY .EUROGASTROENTEROL -OTIL n (UIZINGA*$ ,AMMERS7*'UTPERISTALSISISGOVERNEDBYAMULTITUDEOFCOOPERATINGMECHANISMS!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n


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4AKAHASHI4 +OJIMA9 4SUNODA9 ETAL)MPAIREDINTRACELLULARSIGNALTRANSDUCTIONINGASTRIC SMOOTHMUSCLEOFDIABETIC""7RATS!M*0HYSIOL0T 'n (IRST'$ %DWARDS&2%LECTRICALEVENTSUNDERLYINGORGANIZEDMYOGENICCONTRACTIONSOFTHE GUINEAPIGSTOMACH*0HYSIOL0T n 3ANDERS +- 2EGULATION OF SMOOTH MUSCLE EXCITATION AND CONTRACTION .EUROGASTROENTEROL -OTIL3UPPLn +RAICHELY 2% &ARRUGIA ' -ECHANOSENSITIVE ION CHANNELS IN INTERSTITIAL CELLS OF #AJAL AND SMOOTHMUSCLEOFTHEGASTROINTESTINALTRACT.EUROGASTROENTEROL-OTIL n 3ANDERS+- /RDOG4 +OH3$ 4ORIHASHI3 7ARD3-$EVELOPMENTANDPLASTICITYOFINTERSTITIAL CELLSOF#AJAL.EUROGASTROENTEROL-OTIL n (UIZINGA *$ :ARATE . &ARRUGIA ' 0HYSIOLOGY INJURY AND RECOVERY OF INTERSTITIAL CELLS OF #AJALBASICANDCLINICALSCIENCE'ASTROENTEROLOGY n 3ANDERS+- +OH3$ 7ARD3-)NTERSTITIALCELLSOF#AJALASPACEMAKERSINTHEGASTROINTESTINAL TRACT!NNU2EV0HYSIOLn 3IVARAO $6 -ASHIMO ( 'OYAL 2+ 0YLORIC SPHINCTER DYSFUNCTION IN N./3−/− AND 77V MUTANT MICE ANIMAL MODELS OF GASTROPARESIS AND DUODENOGASTRIC REmUX 'ASTROENTEROLOGY n 7ARD3- 3ANDERS+-)NVOLVEMENTOFINTRAMUSCULARINTERSTITIALCELLSOF#AJALINNEUROEFFECTOR TRANSMISSIONINTHEGASTROINTESTINALTRACT*0HYSIOL0T n &OX%! 0HILLIPS2* "YERLY-3 "ARONOWSKY%! #HI-- 0OWLEY4,3ELECTIVELOSSOFVAGAL INTRAMUSCULAR MECHANORECEPTORS IN MICE MUTANT FOR STEEL FACTOR THE C +IT RECEPTOR LIGAND !NAT%MBRYOL"ERL n &ARRUGIA')NTERSTITIALCELLSOF#AJALINHEALTHANDDISEASE.EUROGASTROENTEROL-OTIL 20 Suppl 1:54–63. /RDOG4 7ARD3- 3ANDERS+-)NTERSTITIALCELLSOF#AJALGENERATEELECTRICALSLOWWAVESIN THEMURINESTOMACH*0HYSIOL0T n (ENNIG'7 3PENCER.* *OKELA 7ILLIS3 ETAL)## -9COORDINATESMOOTHMUSCLEELECTRICAL ANDMECHANICALACTIVITYINTHEMURINESMALLINTESTINE.EUROGASTROENTEROL-OTIL e138–51. -AEDA( 9AMAGATA! .ISHIKAWA3 ETAL2EQUIREMENTOFC KITFORDEVELOPMENTOFINTESTINAL PACEMAKERSYSTEM$EVELOPMENT n (WANG3* "LAIR0* "RITTON&# ETAL%XPRESSIONOFANOCTAMIN4-%-!BYINTERSTITIAL CELLS OF #AJAL IS FUNDAMENTAL FOR SLOW WAVE ACTIVITY IN GASTROINTESTINAL MUSCLES * 0HYSIOL 0T n 7ARD3- /RDOG4 +OH3$ ETAL0ACEMAKINGININTERSTITIALCELLSOF#AJALDEPENDSUPONCALCIUM HANDLINGBYENDOPLASMICRETICULUMANDMITOCHONDRIA*0HYSIOL0T n :HU-( +IM47 2O3 ETAL!#A ACTIVATED#L CONDUCTANCEININTERSTITIALCELLSOF#AJAL LINKEDTOSLOWWAVECURRENTSANDPACEMAKERACTIVITY*0HYSIOL0T n #HEN( /RDOG4 #HEN* ETAL$IFFERENTIALGENEEXPRESSIONINFUNCTIONALCLASSESOFINTERSTITIAL CELLSOF#AJALINMURINESMALLINTESTINE0HYSIOL'ENOMICS n 'OMEZ 0INILLA0* 'IBBONS3* "ARDSLEY-2 ETAL!NOISASELECTIVEMARKEROFINTERSTITIAL CELLSOF#AJALINTHEHUMANANDMOUSEGASTROINTESTINALTRACT!M*0HYSIOL'ASTROINTEST,IVER 0HYSIOL 'n /'RADY' $U0 #HENG,+ ETAL/RIGINANDPROPAGATIONOFHUMANGASTRICSLOW WAVEACTIVITY DElNEDBYHIGH RESOLUTIONMAPPING!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL G585–92. /RDOG4 "ALDO- $ANKO2 3ANDERS+-0LASTICITYOFELECTRICALPACEMAKINGBYINTERSTITIAL CELLSOF#AJALANDGASTRICDYSRHYTHMIASIN77VMUTANTMICE'ASTROENTEROLOGY 2028–40. ,EE(4 (ENNIG'7 &LEMING.7 ETAL3EPTALINTERSTITIALCELLSOF#AJALCONDUCTPACEMAKER ACTIVITYTOEXCITEMUSCLEBUNDLESINHUMANJEJUNUM'ASTROENTEROLOGY n ,INDEN$2 &ARRUGIA'!UTONOMICCONTROLOFGASTROINTESTINALFUNCTION)N,OW0! "ENARROCH%% EDITORS#LINICALAUTONOMICDISORDERSRDED"ALTIMORE -$,IPPINCOTT7ILLIAMS7ILKINS 2008. p. 88–105.

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Chapter 6

Sensory Dysfunction in Gastroparesis Jan Tack and Pieter Janssen

Keywords 'ASTROPARESIS s 6ISCERAL HYPERSENSITIVITY s 'ASTRIC BAROSTAT s#HEMOSENSITIVITY

Introduction 'ASTROPARESISISACHRONIC SYMPTOMATIC GASTROINTESTINALDISORDERCHARACTERIZEDBY DELAYEDGASTRICEMPTYINGOFFOODSOLIDS INTHEABSENCEOFMECHANICALOBSTRUCTIONOF THESTOMACH3YMPTOMSOFGASTROPARESISAREVARIABLEANDINCLUDENAUSEA VOMITING ABDOMINAL PAIN POSTPRANDIAL FULLNESS BLOATING EARLY SATIETY AND WEIGHT LOSS $IABETESMELLITUSANDPRIORSURGERYARECONSIDEREDTHETWOMAJORORGANICCAUSESOF GASTROPARESIS BUTINALARGESUBSETOFPATIENTSNOOBVIOUSUNDERLYINGCAUSEISFOUND 4HISCONDITIONISREFERREDTOASIDIOPATHICGASTROPARESIS;1–3]. Traditionally, motor DYSFUNCTION ANDESPECIALLYDELAYEDEMPTYINGOFSOLIDS WASCONSIDEREDTHEPRINCIPAL UNDERLYINGPATHOPHYSIOLOGICALMECHANISM2ECENTSTUDIESHAVEINDICATEDAROLEFOR VISCERALHYPERSENSIVITYINSYMPTOMGENERATIONINGASTROPARESIS

Role of Delayed Gastric Emptying 4RADITIONALLY DELAYEDGASTRICEMPTYINGISCONSIDEREDTHEMAJORPATHOPHYSIOLOGICAL MECHANISMUNDERLYINGTHESYMPTOMSINPATIENTSWITHGASTROPARESIS(OWEVER THE CORRELATIONBETWEENSYMPTOMPATTERNANDSEVERITY ANDTHERATEOFGASTRICEMPTYING ORSEVERITYOFGASTROPARESIS HASTRADITIONALLYBEENPOOR

J. Tack (*) 4RANSLATIONAL2ESEARCH#ENTERFOR'ASTROINTESTINAL$ISORDERS4!2')$ 5NIVERSITYOF,EUVEN ,EUVEN" "ELGIUM E MAIL*AN4ACK MEDKULEUVENACBE H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_6, © Springer Science+Business Media, LLC 2012

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Table 6.1 !SSOCIATION BETWEEN DELAYED GASTRIC EMPTYING AND THE SYMPTOM PATTERN IN PATIENTS PRESENTINGWITHDYSPEPTICSYMPTOMS 0REVALENCEOFDELAYED Study (ref.) N EMPTYING Correlation 43 No correlation 7EGENERETAL;5] *IANETAL;6] 28 No correlation 4ALLEYETAL;7] 32 No correlation 7ALDRONETAL;8] 50 No correlation 69 No correlation +LAUSERETAL;9] 3COTTETAL;10] 75 No correlation 343 !SSOCIATEDWITHFEMALESEX 3TANGHELLINIETAL;11] POSTPRANDIALFULLNESS VOMITING -AESETAL;12] 344 Not studied 0ERRIETAL;13] 304 !SSOCIATEDWITHPOSTPRANDIAL FULLNESS NAUSEA ANDVOMITING 4ALLEYETAL;16] 551 No correlation 3ARNELLIETAL;17] 392 !SSOCIATEDWITHPOSTPRANDIAL FULLNESS NAUSEA ANDVOMITING 4ALLEYETAL;18] 864 !SSOCIATEDWITHPOSTPRANDIAL fullness Table 6.2 !SSOCIATION BETWEEN DELAYED GASTRIC EMPTYING AND THE SYMPTOM PATTERN IN DIABETIC patients 0REVALENCEOFDELAYED Study (ref.) N EMPTYING Correlation 34 No correlation :IEGLERETAL;20] *ONESETAL;21] 101 !SSOCIATEDWITHFEMALESEXAND ABDOMINALBLOATINGFULLNESS 0UNKKINENETAL;22] 27 No correlation 31 !SSOCIATEDWITHABDOMINALFULLNESS &ARAJETAL;23]

3EVERAL STUDIES ASSESSED THE PRESENCE OF DELAYED GASTRIC EMPTYING AND THE SYMPTOMPATTERNINPATIENTSPRESENTINGWITHFUNCTIONALDYSPEPSIASYMPTOMS;4–18]. $EPENDINGONTHESTUDY THEPREVALENCEOFDELAYEDGASTRICEMPTYINGINFUNCTIONAL DYSPEPSIA RANGES BETWEEN AND )N THE LARGEST STUDIES THE PREVALENCE OF DELAYEDEMPTYINGOFSOLIDSRANGESAROUND;4–18]. Most studies failed to find a CONVINCING RELATIONSHIP BETWEEN DELAYED GASTRIC EMPTYING AND SYMPTOM PATTERN 4ABLE6.1 -ORERECENTLY THREELARGESCALESINGLE CENTERSTUDIESFROM%UROPEFOUND ASSOCIATIONSBETWEENDELAYEDGASTRICEMPTYINGFORSOLIDSAREMOREPREVALENTSYMPTOMSOFPOSTPRANDIALFULLNESS NAUSEA ORVOMITING;11, 13, 17=/NTHEOTHERHAND TWOLARGEMULTICENTERSTUDIESFROMTHE53!FOUNDNOORONLYAVERYWEAKASSOCIATION ;16, 18=4ABLE6.1 !LMOSTALLSTUDIESFOCUSEDONSOLIDEMPTYINGRATEONLY/NLY FEWSTUDIESLOOKEDATDELAYEDEMPTYINGFORLIQUIDS REPORTINGAFAIRLYHIGHPREVALENCE ANDASSOCIATIONWITHSYMPTOMSOFPOSTPRANDIALFULLNESS;17, 19]. 3IMILARLY INDIABETES THERELATIONSHIPBETWEENTHEPRESENCEOFDELAYEDEMPTYING AND EPIGASTRIC SYMPTOM PATTERN OR SEVERITY IS INCONSISTENT ;20–23= 4ABLE 6.2). 4WO STUDIES REPORTED AN ASSOCIATION OF DELAYED EMPTYING WITH THE SEVERITY OF ABDOMINALBLOATINGFULLNESS

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Sensory Dysfunction in Gastroparesis

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Role of Visceral Hypersensitivity )N A LARGE SUBSET OF PATIENTS WITH FUNCTIONAL GASTROINTESTINAL DISORDERS INCLUDING FUNCTIONALDYSPEPSIA INCREASEDVISCERALSENSITIVITYISPRESENT ALLOWINGPHYSIOLOGICAL STIMULITOINDUCESYMPTOMS3EVERALSTUDIESHAVECLEARLYESTABLISHEDTHAT ASAGROUP PATIENTSWITHFUNCTIONALDYSPEPSIAHAVEENHANCEDSENSITIVITYTOGASTRICDISTENSION ANDTHISISCONSIDEREDANIMPORTANTMECHANISMUNDERLYINGSYMPTOMGENERATION ;4, 24–29]. )T HAS ONLY BEEN RECENTLY APPRECIATED THAT EPIGASTRIC PAIN IS ALSO AN IMPORTANT SYMPTOMINPATIENTSWITHGASTROPARESIS;30=!SNONEOFTHESTUDIESMENTIONEDABOVE HAVE SHOWN AN ASSOCIATION BETWEEN DELAYED GASTRIC EMPTYING AND SYMPTOMS OF ABDOMINAL OR EPIGASTRIC PAIN THE UNDERLYING PATHOPHYSIOLOGY REMAINS TO BE FULLY ELUCIDATED)NFUNCTIONALDYSPEPSIA HYPERSENSITIVITYTOGASTRICDISTENTIONWASASSOCIATEDWITHSYMPTOMSOFEPIGASTRICPAIN BELCHING ANDWEIGHTLOSS;29=4HEPOSSIBILITY THATVISCERALHYPERSENSITIVITYISPRESENTINGASTROPARESIS ANDITSPOTENTIALCONTRIBUTIONTOSYMPTOMPATTERNANDSEVERITY ISONLYBEINGBEGINNINGTOBEINVESTIGATED )NASTUDYOFPATIENTSWITHIDIOPATHICGASTROPARESIS THERELATIONSHIPBETWEEN THESYMPTOMPATTERN GASTRICEMPTYINGRATEANDSENSITIVITYTOGASTRICDISTENTIONWAS STUDIED (YPERSENSITIVITY TO GASTRIC DISTENTION WAS FOUND IN OF THE PATIENTS (Fig. 6.1 ANDTHEYREPORTEDAHIGHERPREVALENCEOFEPIGASTRICPAIN EARLYSATIETY AND WEIGHT LOSS ;31= 3YMPTOM SCORES FOR EPIGASTRIC PAIN AND BELCHING WERE SIGNIlCANTLYHIGHERINTHEHYPERSENSITIVESUBGROUP&IG6.2 )NTHESAMESTUDY VISCERAL SENSITIVITYWASALSOASIGNIlCANTDETERMINANTOFSYMPTOMSEVERITY;31]. 4WOSTUDIESINDIABETESCONlRMEDTHATDIABETICPATIENTS ASAGROUP AREMORE SENSITIVETOGASTRICBALLOONDISTENTIONCOMPAREDHEALTHYVOLUNTEERS;32, 33]. More RECENTLY +UMARETALREPORTEDTHATOFPATIENTSWITHDIABETICGASTROPARESIS WEREHYPERSENSITIVETOGASTRICBALLOONDISTENTION BUTNOASSOCIATIONWITHTHESYMPTOM PATTERNWASREPORTED;34=4HECONTRIBUTIONOFIMPAIREDGLYCEMICCONTROLINGASTRIC HYPERSENSITIVITY TO BALLOON DISTENTION IS UNCLEAR AS CONmICTING RESULTS HAVE BEEN REPORTED ON THE IMPORTANCE OF HYPERGLYCEMIA IN SENSITIZATION OF THE STOMACH TO BALLOONDISTENTION;33, 35].

Fig. 6.1 0REVALENCEOF VISCERALHYPERSENSITIVITYIN CONSECUTIVEPATIENTS DIAGNOSEDWITHIDIOPATHIC GASTROPARESISIN,EUVEN

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J. Tack and P. Janssen 3.0

* Hypersensitivity Normal sensitivity

Symptom severity score

2.5

*

2.0

1.5

1.0

0.5

0.0

Pain

Fullness

Bloating

Early satiely

Nausea Vomiting Belching Epigastric burning

Fig. 6.2 3YMPTOMSEVERITYSCORESFORDYSPEPTICSYMPTOMSINPATIENTSWITHIDIOPATHICGASTROPARESIS AND VISCERAL HYPERSENSITIVITY COMPARED TO PATIENTS WITH IDIOPATHIC GASTROPARESIS AND NORMALVISCERALSENSITIVITYIN,EUVEN pCOMPAREDTONORMOSENSITIVEPATIENTS

)NFUNCTIONALDYSPEPSIA VISCERALHYPERSENSITIVITYISNOTLIMITEDTOMECHANOSENSITIVITYOFTHEPROXIMALSTOMACH BUTTHEREISALSOEVIDENCEOFHYPERSENSITIVITYTO ANTRAL AND DUODENAL DISTENTION AND INCREASED DUODENAL CHEMOSENSITIVITY TO ACID LIPIDS ANDCAPSAICIN;11, 36–40=7HETHERTHESEAREALSOPRESENTINASUBSETOF GASTROPARESISPATIENTSREMAINSTOBESTUDIED

Associated Features of Visceral Hypersensitivity )N FUNCTIONAL DYSPEPSIA VISCERAL HYPERSENSITIVITY IS ASSOCIATED WITH A NUMBER OF PSYCHOSOCIALFEATURES SUCHASANXIETY AHISTORYOFABUSEANDSOMATIZATION;41–43]. %MERGING EVIDENCE FROM BRAIN IMAGING STUDIES SUGGESTS THAT THESE PSYCHOPATHOLOGICALEVENTSMAYALTERVISCERALPAINPROCESSINGATTHELEVELOFTHEBRAIN;44, 45]. "ASEDONTHESEASSOCIATIONSIN&$ PSYCHOSOCIALCOMORBIDITYCOULDALSOCONTRIBUTE TOINCREASEDSYMPTOMSEVERITYINGASTROPARESIS THROUGHCHANGESINVISCERALSENSITIVITY )NDEED A NUMBER OF STUDIES HAVE REPORTED ON COMORBIDITIES AND THEIR IMPACT IN gastroparesis patients.

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)N A SINGLE CENTER COHORT OF PATIENTS WITH GASTROPARESIS HIGH PREVALENCES WEREREPORTEDOFAHISTORYOFPHYSICALORSEXUALABUSEOFWOMENWITHIDIOPATHIC GASTROPARESIS ANDPHYSICALABUSEWASSIGNIlCANTLYASSOCIATEDWITHABDOMINALPAIN SOMATIZATION DEPRESSION ANDLIFETIMESURGERIES;46]. In 299 gastroparesis patients ENROLLEDINTHE.ATIONAL)NSTITUTEOF$IABETESAND$IGESTIVEAND+IDNEY$ISEASES 'ASTROPARESIS#LINICAL2ESEARCH#ONSORTIUMDATABASE HIGHERDEPRESSIONANDANXIETY SCORESWEREASSOCIATEDWITHMORESEVERESYMPTOMGASTROPARESISSYMPTOMSEVERITY WHILETHEDEGREEOFDELAYEDEMPTYINGWASNOTAMAJORDETERMINANTOFSEVERITY;47]. 7HILE IT STILL NEEDS TO BE ESTABLISHED THAT THESE ARE POTENTIAL MARKERS OF VISCERAL HYPERSENSITIVITYINGASTROPARESIS THEASSOCIATEDPSYCHOPATHOLOGYANDITSIMPACTON SYMPTOM SEVERITY CLEARLY INDICATES THAT THE PATHOPHYSIOLOGY OF GASTROPARESIS INVOLVESMORETHANADELAYEDGASTRICEMPTYINGRATE

Therapeutic Implications: Summary )TISLIKELY BUTUNPROVEN THATVISCERALHYPERSENSITIVITYISONEOFTHEREASONSOFTHE POORCORRELATIONBETWEENGASTRICEMPTYINGRATEANDSYMPTOMPROlLE ANDTHELACKOF GOODCORRELATIONBETWEENENHANCEMENTOFGASTRICEMPTYINGANDSYMPTOMIMPROVEMENT IN GASTROPARESIS ;48–51= 4HIS WOULD IMPLICATE THAT TREATMENTS DIRECTED AT VISCERALSENSITIVITYMIGHTBEEFFECTIVEINGASTROPARESIS REGARDLESSOFTHEIREFFECTON gastric emptying rate or gastric motility. .OOPTIMALTREATMENTAPPROACHFORVISCERALHYPERSENSITIVITYHASCURRENTLYBEEN ESTABLISHED)THASBEENSUGGESTEDTHATANTIDEPRESSANTS SUCHASTRICYCLICAGENTSOR SELECTIVESEROTONINREUPTAKEINHIBITORS MAYACTTHROUGHADECREASEINVISCERALSENSITIVITY;52=(OWEVER THEAVAILABLEEVIDENCESUGGESTSTHATTHEYMAYACTCENTRALLY NOTONVISCERALSENSITIVITYITSELF BUTONTHEAFFECTIVECOMPONENTOFPAINSENSATION PROCESSING;53, 54=.OCONTROLLEDTRIALSAREAVAILABLEOFANTIDEPRESSANTSINGASTROPARESIS BUT MOST TREATMENT ALGORITHMS RECOMMEND THEIR USE IN GASTROPARESIS PATIENTSTHATFAILTORESPONDTOPROKINETICTHERAPY BASEDONCLINICALIMPRESSIONSOF EFFECTIVENESS;55]. ,EVOSULPIRIDE IS AN ANTIPSYCHOTIC DRUG WITH DOPAMINE RECEPTOR ANTAGONISTIC PROPERTIES)NFUNCTIONALDYSPEPSIA LEVOSULPIRIDEWASSHOWNTODECREASESENSITIVITY TOGASTRICDISTENTION;56=0LACEBO CONTROLLEDTRIALSWITHLEVOSULPIRIDEARELACKING (OWEVER INADOUBLE BLINDCROSS OVERTRIALINASMALLGROUPOFPATIENTSWITHIDIOPATHIC GASTROPARESISANDDYSPEPTICSYMPTOMS LEVOSULPIRIDEWASSUPERIORTOCISAPRIDEIN PROVIDINGRELIEFOFSYMPTOMSANDDECREASINGTHEIRIMPACTONDAILYACTIVITIES;57]. 4HEEFFECTSOFOTHERDRUGSPOTENTIALLYAFFECTINGVISCERALSENSITIVITY SUCHASGABAPENTIN ORPREGABALIN HAVENOTBEENADDRESSEDINGASTROPARESIS !LTEREDVISCERALSENSITIVITYHASALSOBEENIMPLICATEDINTHETHERAPEUTICEFFECTOF GASTRICELECTRICALSTIMULATIONINGASTROPARESIS!CTIVEGASTRICELECTRICALSTIMULATION THERAPY INCREASED THRESHOLD FOR PAIN DURING GASTRIC BALLOON DISTENTION AND WAS ASSOCIATEDWITHCHANGESINCENTRALNERVOUSSYSTEMBLOODmOWONPOSITRONEMISSION TOMOGRAPHIC IMAGING SUGGEST THAT INCREASED VAGAL EFFERENT FUNCTION MIGHT BE INVOLVED;58].

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VALIDATION AND RELATIONSHIP TO GASTRIC SYMPTOMS AND CARDIOVASCULAR AUTONOMIC FUNCTION $IABETOLOGIA n *ONES+, 2USSO! 3TEVENS*% 7ISHART*- "ERRY-+ (OROWITZ-0REDICTORSOFDELAYED GASTRICEMPTYINGINDIABETES$IABETES#ARE n &ARAJ * -ELANDER / 3UNDKVIST ' /LSSON 2 4HORSSON / %KBERG / ET AL /ESOPHAGEAL DYSMOTILITY DELAYEDGASTRICEMPTYINGANDGASTROINTESTINALSYMPTOMSINPATIENTSWITHDIABETES MELLITUS$IABET-ED n 0UNKKINEN* &ÛRKKILÛ- -ÛTZKE3 +ORPPI 4OMMOLA4 3ANE4 0IIRILÛ0 ETAL5PPERABDOMINAL SYMPTOMSINPATIENTSWITH4YPEDIABETESUNRELATEDTOIMPAIRMENTINGASTRICEMPTYINGCAUSED BYAUTONOMICNEUROPATHY$IABET-ED n ,EMANN- $EDERDING*0 &LOURIE" &RANCHISSEUR# 2AMBAUD*# *IAN2!BNORMALPERCEPTION OFVISCERALPAININRESPONSETOGASTRICDISTENSIONINCHRONICIDIOPATHICDYSPEPSIA4HEIRRITABLE STOMACHSYNDROME$IG$IS3CIn "RADETTE- 0ARE0 $OUVILLE0 -ORIN!6ISCERALPERCEPTIONINHEALTHANDFUNCTIONALDYSPEPSIA #ROSSOVERSTUDYOFGASTRICDISTENSIONSWITHPLACEBOANDDOMPERIDONE$IG$IS3CIn -EARIN& #UCALA- !ZPIROZ& -ALAGELADA*24HEORIGINOFSYMPTOMSONTHEBRAIN GUTAXIS INFUNCTIONALDYSPEPSIA'ASTROENTEROLOGYnABSTRACT -ERTZ ( &ULLERTON 3 .ALIBOFF " -AYER %! 3YMPTOMS AND VISCERAL PERCEPTION IN SEVERE functional and organic dyspepsia. Gut. 1998;42:814–22. 2HEE0, +IM9( 3ON(* +IM** +OH+# 0AIK37 ETAL%VALUATIONOFINDIVIDUALSYMPTOMS ACANNOT PREDICT PRESENCE OF GASTRIC HYPERSENSITIVITY IN FUNCTIONAL DYSPEPSIA $IG $IS 3CI 2000;45:1680–4. 4ACK* #AENEPEEL0 &ISCHLER" 0IESSEVAUX( *ANSSENS*3YMPTOMSASSOCIATEDWITHHYPERSENSITIVITYTOGASTRICDISTENTIONINFUNCTIONALDYSPEPSIA'ASTROENTEROLOGYn #HERIAN$ 3ACHDEVA0 &ISHER23 0ARKMAN(0!BDOMINALPAINISAFREQUENTSYMPTOMOF GASTROPARESIS#LIN'ASTROENTEROL(EPATOL-AY;%PUBAHEADOFPRINT= +ARAMANOLIS' #AENEPEEL0 !RTS* 4ACK*$ETERMINANTSOFSYMPTOMPATTERNINIDIOPATHIC SEVERELYDELAYEDGASTRICEMPTYINGGASTRICEMPTYINGRATEORPROXIMALSTOMACHDYSFUNCTION Gut. 2007;56(1):29–36. 3AMSOM- 3ALET'! 2OELOFS*- !KKERMANS,- 6ANBERGE (ENEGOUWEN'0 3MOUT!* #OMPLIANCEOFTHEPROXIMALSTOMACHANDDYSPEPTICSYMPTOMSINPATIENTSWITHTYPE)DIABETES mellitus. Dig Dis Sci. 1995;40(9):2037–42. 2AYNER#+ 6ERHAGEN-! (EBBARD'3 $I-ATTEO!# $ORAN3- (OROWITZ-0ROXIMAL GASTRICCOMPLIANCEANDPERCEPTIONOFDISTENSIONINTYPEDIABETESMELLITUSEFFECTSOFHYPERGLYCEMIA!M*'ASTROENTEROLn +UMAR! !TTALURI! (ASHMI3 3CHULZE+3 2AO336ISCERALHYPERSENSITIVITYANDIMPAIRED ACCOMMODATION IN REFRACTORY DIABETIC GASTROPARESIS .EUROGASTROENTEROL -OTIL 635–42. (EBBARD '3 3AMSOM - 3UN 7- $ENT * (OROWITZ - (YPERGLYCEMIA AFFECTS PROXIMAL GASTRICMOTORANDSENSORYFUNCTIONDURINGSMALLINTESTINALTRIGLYCERIDEINFUSION!M*0HYSIOL 1996;271(5 Pt 1):G814–9. #ALDARELLA-0 !ZPIROZ& -ALAGELADA*2!NTRO FUNDICDYSFUNCTIONSINFUNCTIONALDYSPEPSIA Gastroenterology. 2003;124(5):1220–9. (OLTMANN' 'OEBELL( *OCKENHOEVEL& 4ALLEY.*!LTEREDVAGALANDINTESTINALMECHANOSENSORY FUNCTIONINCHRONICUNEXPLAINEDDYSPEPSIA'UT n 3AMSOM- 6ERHAGEN-! VAN"ERGE(ENEGOUWEN'0 3MOUT!*!BNORMALCLEARANCEOF EXOGENOUSACIDANDINCREASEDACIDSENSITIVITYOFTHEPROXIMALDUODENUMINDYSPEPTICPATIENTS Gastroenterology. 1999;116(3):515–20. "ARBERA2 &EINLE# 2EAD.7!BNORMALSENSITIVITYTODUODENALLIPIDINFUSIONINPATIENTS WITHFUNCTIONALDYSPEPSIA%UR*'ASTROENTEROL(EPATOL n (AMMER * &ÓHRER - 0IPAL , -ATIASEK * (YPERSENSITIVITY FOR CAPSAICIN IN PATIENTS WITH functional dyspepsia. Neurogastroenterol Motil. 2008;20(2):125–33. &ISCHLER" 4ACK* $E'UCHT6 3HKEDY:) 0ERSOONS0 "ROEKAERT$ ETAL(ETEROGENEITYOF SYMPTOMPATTERN PSYCHOSOCIALFACTORS ANDPATHOPHYSIOLOGICALMECHANISMSINSEVEREFUNCTIONAL dyspepsia. Gastroenterology. 2003;124(4):903–10.

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6AN/UDENHOVE, 6ANDENBERGHE* 'EERAERTS" 6OS2 0ERSOONS0 $EMYTTENAERE+ ETAL 2ELATIONSHIP BETWEEN ANXIETY AND GASTRIC SENSORIMOTOR FUNCTION IN FUNCTIONAL DYSPEPSIA 0SYCHOSOM-ED n 'EERAERTS" 6AN/UDENHOVE, &ISCHLER" 6ANDENBERGHE* #AENEPEEL0 *ANSSENS* ETAL )NmUENCE OF ABUSE HISTORY ON GASTRIC SENSORIMOTOR FUNCTION IN FUNCTIONAL DYSPEPSIA Neurogastroenterol Motil. 2009;21(1):33–41. 6AN/UDENHOVE, 6ANDENBERGHE* $UPONT0 'EERAERTS" 6OS2 $IRIX3 ETAL!BNORMAL REGIONALBRAINACTIVITYDURINGRESTANDANTICIPATED GASTRICDISTENSIONINFUNCTIONALDYSPEPSIA ANDTHEROLEOFANXIETYA( / 0%4STUDY!M*'ASTROENTEROL n 6AN /UDENHOVE , 6ANDENBERGHE * $UPONT 0 'EERAERTS " 6OS 2 $IRIX 3 6AN ,AERE + "ORMANS' 6ANDERGHINSTE$ $EMYTTENAERE+ &ISCHLER" 4ACK*2EGIONALBRAINACTIVITYIN FUNCTIONALDYSPEPSIA! ( / 0%4STUDY ON THE ROLE OF GASTRIC SENSITIVITYAND ABUSE HISTORY'ASTROENTEROLOGY!PR;%PUBAHEADOFPRINT= 3OYKAN) 3IVRI" 3AROSIEK) +IERNAN" -C#ALLUM27$EMOGRAPHY CLINICALCHARACTERISTICS PSYCHOLOGICALANDABUSEPROlLES TREATMENT ANDLONG TERMFOLLOW UPOFPATIENTSWITHGASTROparesis. Dig Dis Sci. 1998;43(11):2398–404. (ASLER7, 0ARKMAN(0 7ILSON,! 0ASRICHA0* +OCH+, !BELL4, 3NAPE7* &ARRUGIA' ,EE, 4ONASCIA* 5NALP !RIDA! (AMILTON&0SYCHOLOGICALDYSFUNCTIONISASSOCIATEDWITH SYMPTOM SEVERITY BUT NOT DISEASE ETIOLOGY OR DEGREE OF GASTRIC RETENTION IN PATIENTS WITH GASTROPARESIS!M*'ASTROENTEROL*UN;%PUBAHEADOFPRINT= #ORINALDESI 2 3TANGHELLINI 6 2AITI # 2EA % 3ALGEMINI 2 "ARBARA , %FFECT OF CHRONIC administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in PATIENTSWITHIDIOPATHICGASTROPARESIS'UT n !RTS* #AENEPEEL0 6ERBEKE+ 4ACK*)NmUENCEOFERYTHROMYCINONGASTRICEMPTYINGAND MEAL RELATED SYMPTOMS IN FUNCTIONAL DYSPEPSIA WITH DELAYED GASTRIC EMPTYING 'UT 54(4):455–60. !RTS * (OLVOET , #AENEPEEL 0 "ISSCHOPS 2 3IFRIM $ 6ERBEKE + ET AL #LINICAL TRIAL A RANDOMIZED CONTROLLEDCROSSOVERSTUDYOFINTRAPYLORICINJECTIONOFBOTULINUMTOXININGASTROPARESIS!LIMENT0HARMACOL4HER n "RADEN" #ASPARY7 "RNER. 6INSON" 3CHNEIDER!2#LINICALEFFECTSOF347)BEROGAST ARENOTBASEDONACCELERATIONOFGASTRICEMPTYINGINPATIENTSWITHFUNCTIONALDYSPEPSIAAND gastroparesis. Neurogastroenterol Motil. 2009;21(6):632–8. "UENO, DE0ONTI& &RIED- +ULLAK 5BLICK'! +WIATEK-! 0OHL$ ETAL3EROTONERGICAND NON SEROTONERGICTARGETSINTHEPHARMACOTHERAPYOFVISCERALHYPERSENSITIVITY.EUROGASTROENTEROL Motil. 2007;19(1 Suppl):89–119. -ERTZ ( &ASS 2 +ODNER ! 9AN 'O & &ULLERTON 3 -AYER %! %FFECT OF AMITRIPTYLINE ON SYMPTOMS SLEEP AND VISCERAL PERCEPTION IN PATIENTS WITH FUNCTIONAL DYSPEPSIA !M J Gastroenterol. 1998;93(2):160–5. -ORGAN6 0ICKENS$ 'AUTAM3 +ESSLER2 -ERTZ(!MITRIPTYLINEREDUCESRECTALPAINRELATED ACTIVATIONOFTHEANTERIORCINGULATECORTEXINPATIENTSWITHIRRITABLEBOWELSYNDROME'UT 54(5):601–7. 4ACK * 4HE DIFlCULT PATIENT WITH GASTROPARESIS "EST 0RACT 2ES #LIN 'ASTROENTEROL 21(3):379–91. $ISTRUTTI% &IORUCCI3 (AUER3+ 0ENSI-/ 6ANASIA- -ORELLI!%FFECTOFACUTEANDCHRONIC LEVOSULPIRIDEADMINISTRATIONONGASTRICTONEANDPERCEPTIONINFUNCTIONALDYSPEPSIA!LIMENT 0HARMACOL4HER n -ANSI# "ORRO0 'IACOMINI- "IAGINI2 -ELE-2 0ANDOLFO. ETAL#OMPARATIVEEFFECTS OFLEVOSULPIRIDEANDCISAPRIDEONGASTRICEMPTYINGANDSYMPTOMSINPATIENTSWITHFUNCTIONAL DYSPEPSIAANDGASTROPARESIS!LIMENT0HARMACOL4HER n -C#ALLUM27 $USING27 3AROSIEK) #OCJIN* &ORSTER* ,IN:-ECHANISMSOFSYMPTOMATIC IMPROVEMENTAFTERGASTRICELECTRICALSTIMULATIONINGASTROPARETICPATIENTS.EUROGASTROENTEROL Motil. 2010;22(2):161–7. e50-1.

Chapter 7

Pathology of Gastroparesis Amol Sharma and Rebecca Thomas

Keywords 'ASTRICEMPTYINGPATTERNSs'ASTRICEMPTYINGSCINTIGRAPHYs'ASTRICWALL s$UODENUMs%NTERICGLIALCELLS

Introduction 7HILESYMPTOMSOFGASTROPARESISAREDElNED;1= THEPATHOGENESISOFTHISCONDITION ISPOORLYUNDERSTOOD&URTHERMORE GASTRICEMPTYINGSCINTIGRAPHY THEGOLDSTANDARD FORDIAGNOSTICTESTING DOESNOTCORRELATEWITHSYMPTOMSEVERITY3OMEPATIENTSWITH THECLASSICCONSTELLATIONOFSYMPTOMSFORGASTROPARESISHAVENORMALORNEAR NORMAL GASTRIC EMPTYING PATTERNS ;2= 5NCERTAINTY OF UNDERLYING PATHOPHYSIOLOGY UNDERSCORESTHESTRUGGLETODEVELOPEFFECTIVETHERAPIES4HEINABILITYOFTHESTOMACHTO EFFECTIVELYEMPTYITSSOLIDANDLIQUIDCONTENTSINTOTHEDUODENUMINTHEABSENCEOF AMECHANICALOBSTRUCTIONDElNESGASTROPARESIS;1]. Gastric emptying is dependent ONWELL COORDINATEDEFFORTSBYMULTIPLECOMPONENTSINTHEGASTRICWALL$IFFERENT CELLS STRUCTURES ANDMECHANISMSAREHYPOTHESIZEDTOBERESPONSIBLEFORGASTROPARESIS #URRENTLY HOWEVERTHEREISALACKOFHISTOPATHOLOGICEVIDENCETOSUBSTANTIATEMOST OFTHESEHYPOTHESES

Anatomy 4HEGASTRICWALLCONSISTSOFTHEMUCOSA SUBMUCOSA MUSCULARISPROPRIA ANDSEROSA 4HEMUCOSAINCLUDESTHESURFACEEPITHELIUM GASTRICGLANDS LAMINAPROPRIA ANDTHE MUSCULARIS MUCOSAE 4HE SURFACE EPITHELIUM CONSISTS OF TALL COLUMNAR CELLS WITH 24HOMAS*) $EPARTMENTOF0ATHOLOGYAND,ABORATORY-EDICINE 4EMPLE5NIVERSITY(OSPITAL 0HILADELPHIA 0! 53! E MAILREBECCATHOMAS TUHSTEMPLEEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_7, © Springer Science+Business Media, LLC 2012

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!3HARMAAND24HOMAS

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75

Fig. 7.1 (EMATOXYLINAND%OSINSTAINMAGNIlCATION8)NTERMYENTERICPLEXUSWITHGANGLION CONTAININGGANGLIONCELLSANDNERVEPROCESSES

Fig. 7.2 )MMUNOHISTOCHEMICALSTAINFOR.3%MAGNIlCATION80OSITIVELYSTAININGGANGLION cells

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Fig. 7.3 )MMUNOHISTOCHEMICALSTAINFOR3MAGNIlCATION80OSITIVELYSTAINING3CHWANN cells

Fig. 7.4 )MMUNOHISTOCHEMICALSTAININGFOR'&!0MAGNIlCATION80OSITIVELYSTAININGGLIAL CELLSENWRAPPINGGANGLIONCELLS


77

ACTIVATED ONLY AT LEVELS OF DISTENSION OR CONTRACTION THAT WOULD BE CONSIDERED NOXIOUS3ENSORYMODULATIONMAYOCCURDURINGINmAMMATION ISCHEMIA INJURY OR INFECTIONSUCHTHATPREVIOUSLYINSENSITIVEAFFERENTSCANDEVELOPMECHANOSENSITIVITY DURINGINmAMMATION APHENOMENONKNOWNASPLASTICITY$IFFERENTIMMUNOMODULATORS RELEASEDBYVARIOUSCELLS SUCHASPLATELETS LEUKOCYTES LYMPHOCYTES MACROPHAGES GLIALORMASTCELLSARETHOUGHTTOINmUENCETHISPROCESS 3INCEAFFERENTNEURONSDONOTEXTENDINTOTHELUMENOFTHE')TRACT THEIRACTIVATION MAY RESULT FROM SUBSTANCES ABSORBED FROM THE LUMEN OR NEUROTRANSMITTERS RELEASEDINTOTHELAMINAPROPRIABYENDOCRINECELLS(4ACTSASAPARACRINEAGENTBY ACTIVATINGITSOWNRECEPTORONTHEAFFERENTNERVETERMINAL-ECHANICALORCHEMICAL STIMULIMAYTRIGGERTHERELEASEOF(4 )NADDITIONTOSMOOTHMUSCLECELLS THEMUSCULARISPROPRIAALSOCONTAINSINTERSTITIAL CELLSOF#AJAL)## 4HESECELLSAREMODIlEDMYOlBROBLASTSOFMESENCHYMALORIGIN WITHFUSIFORMCELLBODIES ALARGEROUNDNUCLEUSANDONEORMOREDENDRITICPROCESSES 4HEREARETWODISTINCTLAYERSOF)##ANETWORKOFCELLSLYINGINTHEINTERMYENTERIC PLEXUSBETWEENTHEINNERCIRCULARANDOUTERLONGITUDINALLAYERS)##MY ANDASECOND GROUP INTERSPERSED BETWEEN THE SMOOTH MUSCLE lBERS OF THE MUSCULARIS PROPRIA )##IM 4HEMAJORITYOFTHE)##LIESWITHINTHEMUSCULARCOAT WHERETHEYCOMPOSE APPROXIMATELY OF THE CELL BURDEN ;4= 4HESE CELLS ARE PRESENT THROUGHOUT THE GASTROINTESTINAL TRACT WHERE THEY SHOW DISTRIBUTIONAL VARIATIONS IN THE DIFFERENT REGIONS)NTHEGASTRICANTRUMFOREXAMPLE )##IMAREGENEROUSLYDISTRIBUTEDINTHE INNERCIRCULARLAYER BUTARERAREINTHEOUTERLONGITUDINALLAYER)NTHEFUNDUS )## AREABSENTINTHEINTERMYENTERICPLEXUS BUTAREPRESENTINBOTHTHEINNERCIRCULARAND OUTERLONGITUDINALLAYERSOFTHEMUSCULARISPROPRIA )##MYAREMOSTLIKELYTHEPACEMAKERCELLSWHILE)##IMMEDIATECHANGESIN PACEMAKINGACTIVITYVIAENTERICNEUROTRANSMISSION)##IMALSOPLAYAROLEINAFFERENT NEURALSIGNALINGINTHE')TRACT-ORPHOLOGICANDMOLECULARSTUDIESHAVEIDENTIlED )## IN CLOSE PROXIMITY TO ENTERIC NEURONS )## ALSO EXPRESS RECEPTORS THAT ARE REQUIREDFORMOTORNEUROTRANSMISSION&URTHERMORE )##ARECRUCIALTOTHENORMAL DEVELOPMENT AND MAINTENANCE OF VAGAL )-! IN THE STOMACH 4HE SYNAPTIC LIKE CONTACTSBETWEENNERVETERMINALSAND)##IMFACILITATERAPIDDIFFUSIONOFTRANSMITTERS TOTHE)##IM)NTURN )##IMTRANSMITELECTRICALIMPULSESTOSMOOTHMUSCLECELLS VIAGAPJUNCTIONS;5=)##MYSPONTANEOUSLYGENERATEELECTRICALACTIVITYHOWEVER ONLYANTRAL)##IMINITIATEELECTRICALACTIVITY ANDFUNDIC)##IMDONOT4HEABSENCE OF)##MYINTHEFUNDUSMAYBETHEREASONWHYTHEFUNDUSISNOTMYOGENICALLY ACTIVE )##EXPRESSC KIT APROTO ONCOGENEANDTYROSINEKINASERECEPTOR3TAININGOFTHIS PROTEINHASPERMITTEDIMMUNOHISTOCHEMICALIDENTIlCATIONOFTHEMORPHOLOGYAND DISTRIBUTIONOFTHESECELLS ASC KITISACOMMERCIALLYAVAILABLEANTIBODY&IG7.5). -ONOCLONALANTIBODIESAGAINSTTHISRECEPTORRESULTINLOSSOF)##ANDPARALYTICILEUS INMICE IMPLICATINGTHEFUNCTIONALIMPORTANCEOFC KITTOTHESECELLS;6]. Mast cells ALSOSTAINPOSITIVELYFORC KIT4HEREFORE ITISIMPORTANTTORECOGNIZETHEROUNDED MORPHOLOGYOFMASTCELLS ASOPPOSEDTOTHEDENDRITIC)## SINCEMASTCELLSMAY ALSOBEPRESENTINTHEMUSCULARISPROPRIA&IG7.6).

78

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Fig. 7.5 )MMUNOHISTOCHEMICALSTAININGFORC KITMAGNIlCATION80OSITIVELYSTAININGINTERSTITIAL CELLSOF#AJALWITHDENDRITICPROCESSES WITHINMUSCULARISPROPRIA

Fig. 7.6 )MMUNOHISTOCHEMICALSTAININGFORC KITMAGNIlCATION80OSITIVELYSTAININGMAST CELLSWITHROUNDEDMORPHOLOGY WITHINMUSCULARISPROPRIA


79

Pathophysiology .ITRIC OXIDE ./ IS A FREE RADICAL SIGNALING MOLECULE GENERATED BY NITRIC OXIDE SYNTHASE./3 4HEREARETHREEINDEPENDENTGENESENCODINGNEURONAL ENDOTHELIAL ANDINDUCIBLE./3N./3 E./3 ANDI./3 RESPECTIVELY 4HESE./SIGNALING PATHWAYSCONTRIBUTETOMOTILITYANDVASCULARREGULATIONINTHE')TRACT ASWELLASTHE ASSOCIATED DISEASES 7HILE THE INmUENCE OF ./ ON ') MOTILITY IS GENERALLY CONTROLLEDBYN./3 ./EFFECTSONVASCULARFUNCTIONUSUALLYOCCURTHROUGHE./34HE MOSTIMPORTANTROLEOFN./3 DERIVED./IN')MOTILITYISASANINHIBITORYNONADRENERGICNONCHOLINERGIC.!.# SMOOTHMUSCLERELAXANTVIAACTIVATIONOFSMOOTH MUSCLE CELL GUANYLATE CYCLASE ;7= .ERVES THROUGHOUT THE ') TRACT EXPRESS N./3 WITHHIGHESTLEVELSINTHEPYLORICSPHINCTER/THERTRANSMITTERS SUCHASVASOACTIVE PEPTIDE6)0 ADENOSINETRIPHOSPHATE ANDCARBONMONOXIDE ALSOFUNCTIONINCONJUNCTIONWITH./AS.!.#INHIBITORYSIGNALS./PROMOTESGASTRICACCOMMODATION 0HARMACOLOGICAL INHIBITORS OF ./3 INCREASE FREQUENCY OF GASTRIC CONTRACTIONS HASTENGASTRICEMPTYING ANDDECREASEGASTRICFUNDICVOLUME)NCONTRAST ./DONORS ;7=SLOWGASTRICEMPTYINGANDIMPROVEACCOMMODATIONOFTHEPROXIMALSTOMACH (YPERTROPHICPYLORICSTENOSISISALSOASSOCIATEDWITHADECREASEINN./3EXPRESSION WITHINTHEHYPERTROPHIEDCIRCULARMUSCLEOFTHESPHINCTERWHILENORMALDISTRIBUTION OF./3PROTEINISPRESENTINTHELONGITUDINALMUSCLE .ORMAL GASTRIC EMPTYING REQUIRES THE COORDINATION OF FUNCTION OF SEVERAL CELL TYPES INCLUDINGEXTRINSICNEURONS ENTERICMOTORNEURONS )## ANDSMOOTHMUSCLE CELLS4HEPACEMAKERREGIONOFTHESTOMACHISLOCATEDONTHEGREATERCURVATUREOFTHE BODY )N THIS REGION )## INITIATE A PACEMAKER SIGNAL POTENTIATING A SLOW WAVE RHYTHM OF APPROXIMATELY THREE CYCLES PER MINUTE AND DICTATING THE FREQUENCY OF SMOOTHMUSCLECONTRACTION-OTORNEURONSAREMODULATEDBYSIGNALSFROMTHE#.3 PRIMARILYTHROUGHTHEVAGALNERVE#ONTRACTIONSARECOORDINATEDBETWEENDIFFERENT PARTSOFTHESTOMACH ANDBETWEENTHESTOMACHANDSMALLBOWEL3ENSORYINFORMATION ISRELAYEDTOTHE#.3VIATHEVAGALANDSPINALAFFERENTNERVES #OORDINATED GASTRIC FUNCTION REQUIRES A COMBINATION OF STIMULI THAT PROMOTE CONTRACTION SUCHASACETYLCHOLINEANDSUBSTANCE0 ANDSTIMULITHATINHIBITCONTRACTION SUCHAS6)0ANDNITRICOXIDE4HEREFORE NEURONAL./ANDTHEENZYMERESPONSIBLE FORITSSYNTHESIS N./3AREOFGREATINTERESTINTHESTUDYOFGASTROPARESIS

Pathology 4WOSEPARATEANIMALSTUDIESDEMONSTRATEANASSOCIATIONBETWEENIMPAIREDGASTRIC RELAXATIONANDADECREASEINN./3EXPRESSIONONESTUDYINRATSWITHSTREPTOZOTOCIN INDUCEDDIABETESANDTHEOTHERSTUDYOFTHEANTRUMOFOBESEDIABETICMICE ARECOGNIZEDMODELFORTYPE))DIABETES;8, 9=&ACTORSRESPONSIBLEFORTHECHANGESINGASTRIC N./3EXPRESSIONINDIABETICSAREUNCLEARBUTTHREEMECHANISMSAREHYPOTHESIZED NEURONAL LOSS OR DEGENERATION INHIBITION OF N./3 TRANSCRIPTION AND IMPAIRED N./3FUNCTION;10=3UBSEQUENTLY DECREASEDN./3EXPRESSIONRESULTSINLOSSOF

80

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PROXIMAL RELAXATION AND DELAYED GASTRIC EMPTYING AS A COMBINATION OF INTENSE PYLOROSPASM AND DISORDERED NONPROPULSIVE ANTRAL MOTILITY )N NONOBESE DIABETIC ./$ MICE INSULINACTINGASATROPHICFACTORREVERSESTHEDECREASEDEXPRESSION OF ./3 ;11= (OWEVER IF THESE MICE WERE DEPRIVED OF INSULIN FOR GREATER THAN WEEKSDECREASEDEXPRESSIONOF./3BECOMESIRREVERSIBLE;12=!NIMALSTUDIES HAVE ALSO DEMONSTRATED DECREASED NUMBERS OF )## IN DIABETIC MODELS )N ./$ MICE A MODEL FOR TYPE ) DIABETES REDUCED NUMBERS OF )##MY AND )##IM WERE OBSERVEDINTHEGASTRICANTRUMANDCORPUSCOMPAREDTOCONTROLS;13, 14]. In strepTOZOTOCIN INDUCEDDIABETICRATS DEPLETIONANDDEGENERATIVECHANGESWEREOBSERVED INTHE)##IMWHILETHE)##MYWERESPARED;15=4HISREDUCTIONOF)##ISASSOCIATED WITH SIGNIlCANT DISRUPTION OF SLOW WAVE ACTIVITY AND ATTENUATED NEURONAL RESPONSES )N CELL CULTURES PROLONGED HYPERGLYCEMIA RESULTS IN LOSS OF )## NETWORKS;16= ANEFFECTTHATWASPREVENTEDBYINSULIN.ITRICOXIDEMAYBERESPONSIBLE FORTHEMAINTENANCEOF)##ANDTHELOSSOFN./3COULDRESULTINDEPLETIONOF)## )NANIMALMODELSWITHSTREPTOZOCIN INDUCEDDIABETES AVAGALNEUROPATHYAPPEARS TOBEPRESENT"OTHDEGENERATIVECHANGESOFTHESENSORY;17=ANDMOTOR;18] nuclei OFTHEVAGALNERVEANDSYMPATHETICAXONALDYSTROPHY;19=HAVEBEENNOTEDINTHIS MODEL )N ADDITION ANOTHER STUDY SHOWS THAT TRUNCAL VAGOTOMY SIGNIlCANTLY DECREASESTHEEXPRESSIONOFN./3INRATS WHICHISREVERSEDBYNICOTINICRECEPTOR STIMULATION;10]. 0ATHOLOGICASSESSMENTOFGASTRICTISSUEINPATIENTSWITHGASTROPARESISISLIMITED &URTHERMORE HUMAN BIOPSY STUDIES ARE SUSCEPTIBLE TO SAMPLING ERRORS DUE TO AN INHOMOGENEOUSDISTRIBUTIONOF)##THROUGHTHEGASTROINTESTINALTRACT;20=!RECENT STUDYTHATREVEALEDSEVERALPATHOLOGICABNORMALITIESINTHEGASTRICTISSUEHASBEEN SHOWNINSOMEPATIENTSWITHREFRACTORYGASTROPARESIS;21=4HEREWASAREDUCTIONIN NERVECELLBODIESINBOTHIDIOPATHICANDDIABETICGASTROPARESIS!REDUCEDNUMBEROF )##SWEREFOUNDINTHEMYENTERICPLEXUS!NINmAMMATORYINlLTRATEWASPRESENTIN NEARLYHALFOFTHEPATIENTSWITHDIABETICGASTROPARESIS4HUS HISTOLOGICABNORMALITIES INGASTROPARESISAREHETEROGENEOUSANDINCLUDEMYENTERICINmAMMATION DECREASED INNERVATION AND REDUCTION OF )##S /NE STUDY REPORTED THAT NO )## WERE FOUND INTHEGASTRICANTRUMOFNINEOFTHETWENTY THREEPATIENTSWITHREFRACTORYDIABETIC GASTROPARESIS;22=%XAMININGTHEGASTRICANTRUMOFDIABETICPATIENTSAFTERGASTRECTOMY FORGASTRICCANCER RESEARCHERSOBSERVEDALOSSOF)##IM BUTNOT)##MY INTHOSE WITHSEVEREUNCONTROLLEDDIABETES;23].

Etiology 4HEPATHOGENESISOFGASTROPARESISISPOORLYUNDERSTOODANDPROBABLYMULTIFACTORIAL !LTHOUGHDIABETICGASTROPARESISISTHEMOSTSTUDIEDANDCHARACTERIZEDETIOLOGYOF GASTROPARESIS IDIOPATHICGASTROPARESISISTHEMOSTCOMMON,ESSCOMMONETIOLOGIES INCLUDEPOSTSURGICAL MEDICATION RELATED POSTVIRAL COLLAGENVASCULARDISEASE AND autoimmune.


81

Diabetes Mellitus /URUNDERSTANDINGOFTHEPATHOPHYSIOLOGYOFGASTROPARESISISBESTINDIABETICS&ROM APROSPECTIVESTUDYOVERMONTHSOFDIABETICSWHOATTENDEDA')CLINICANDHAD GASTRIC EMPTYING STUDIES PERFORMED MORE THAN OF THE PATIENTS HAD DELAYED GASTRICEMPTYING7OMENHADSLOWERGASTRICEMPTYING BUTTHEREWASNOCORRELATION BETWEENGASTRICEMPTYINGANDAGE TYPEOFDIABETES DURATIONOFDIABETES FASTING GLUCOSE CONCENTRATION GLYCOSYLATED HEMOGLOBIN LEVEL OR THE PRESENCE OF OTHER DIABETIC COMPLICATIONS 4HE PATHOPHYSIOLOGIC FACTORS THOUGHT TO CONTRIBUTE TO GASTROPARESIS INCLUDE ELECTRICAL DYSRHYTHMIA IDENTIlED BY ELECTROGASTROGRAPHY ANTRALHYPOMOTILITYANDDISTENSION PYLOROSPASM LOSSOFNITRERGICINPUTTOSMOOTH MUSCLE ANDPOSSIBLEVAGALANDSPINALNEUROPATHIES $IABETICPATIENTSAREATHIGHRISKOFDEVELOPINGGASTROPARESIS4HEPREVALENCEOF GASTROPARESISRANGESFROMTOINTYPEDIABETES;24, 25] and occurs in 30% OFTYPEDIABETES)TWOULDBEHARDTOOVERESTIMATETHECONTRIBUTIONOFDIABETESTO THE PATHOLOGY OF GASTROPARESIS )NCREASED lBROSIS AND COLLAGEN DEPOSITION IN THE muscularis propria (Fig. 7.7 ANDADECREASEINTHENUMBEROF)##&IG7.8) seem TOBEARECURRINGTHEMEINTHELITERATURE(ISTOPATHOLOGICANALYSISOFTHESTOMACHOF FOUR PATIENTS WITH PARTIAL GASTRECTOMIES FOR INTRACTABLE DIABETIC GASTROPARESIS WAS PERFORMEDANDREVEALEDSEVERElBROSISOFTHEMUSCULARLAYER;26=4HECHANGESIN THESMOOTHMUSCLEOFDIABETICSRESULTINASTIFFERSTOMACHWITHLOWERCOMPLIANCE THANINHEALTHYSUBJECTS)NACASESTUDY FULLTHICKNESSBIOPSYFROMAPATIENTWITH BRITTLE AND POORLY CONTROLLED DIABETES DEMONSTRATED MUSCULAR lBROSIS AND FEWER NERVES MYENTERICNEURONS INHIBITORYNEURALINPUT AND)##COMPAREDTOCONTROL;27]. 3TUDIESSHOWCONmICTINGRESULTSINWHETHERTHEREARESTRUCTURALCHANGESINHUMANS INTHEVAGALNERVES ENTERICNEURONS )## ANDSMOOTHMUSCLECELLS4HEREISPROBABLYASPECTRUMOFPATHOLOGICALlNDINGSINTHESEPATIENTS

Idiopathic Gastroparesis )DIOPATHICGASTROPARESISISTHEMOSTCOMMONSUBTYPEANDAFFECTSMAINLYYOUNGTO MIDDLE AGEDWOMEN)NHERENTINITSDESIGNATION NOPRIMARYETIOLOGYFORTHISSUBTYPE HASBEENIDENTIlED-ANYSTUDIESSUSPECTAVIRALETIOLOGY!PPROXIMATELYn OFTHEPATIENTSSUFFERINGFROMIDIOPATHICGASTROPARESISIDENTIFYADISTINCTVIRALPRODROMEPRECEDINGONSETOFSYMPTOMSOFDELAYEDGASTRICEMPTYING;28=0ATHOLOGIC MECHANISMS INCLUDE 4 CELL MEDIATED OR ANTIBODY MEDIATED DAMAGE TO NEURONAL ELEMENTS)NONECASE AYOUNGMANHADANACUTEONSETOFCHRONICINTRACTABLEVOMITING ANDWEIGHTLOSS REQUIRINGTHEPLACEMENTOFAFEEDINGTUBE5PONHISTOLOGICALEVALUATIONOFTHEGASTRICWALL ASIGNIlCANTINlLTRATEOF#$AND#$4LYMPHOCYTESWAS IDENTIlED;29=ASSOCIATEDWITHGANGLIONCELLS4REATMENTOFTHISPATIENTWITHSTEROIDS RESULTED IN A DRAMATIC RECOVERY #ASE REPORTS HAVE ALSO DEMONSTRATED A MARKED REDUCTIONIN)##MYAND)##IMALONGWITHDECREASEDNUMBERSOFMYENTERICGANGLIA INMYENTERICGANGLIAINSEVEREIDIOPATHICGASTROPARESIS;30, 31].

82

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Fig. 7.7 (a -ASSON4RICHROMESTAINMAGNIlCATION8.ORMALMUSCULARISPROPRIAWITHNO lBROSIS b -ASSON 4RICHROME STAIN MAGNIlCATION 8 -USCULARIS PROPRIA WITH EXTENSIVE lBROSISSURROUNDINGAFEWRESIDUALMUSCLEBUNDLES

Autoimmune 4HE LINK BETWEEN AUTOIMMUNITY AND GASTROPARESIS HAS BEEN BEST ESTABLISHED FOR PARANEOPLASTIC GASTROPARESIS MOST OFTEN ASSOCIATED WITH SMALL CELL CARCINOMA LYMPHOMA OROVARIANCANCER;10=4HESEPATIENTSHAVEANINmAMMATORYINlLTRATEIN THE MYENTERIC PLEXUS AND A CIRCULATING ANTIBODY KNOWN AS ANTI (U !..! !NTI (UAND. TYPECALCIUMCHANNELANTIBODIESARETHEBESTRECOGNIZEDOFNUMEROUS AUTOANTIBODIESINTHEPATHOGENESISOFGASTRICDYSMOTILITY/THERANTIBODIESINCLUDE


83

Fig. 7.8 )MMUNOHISTOCHEMICAL STAINING FOR C KIT MAGNIlCATION 8 !BSENCE OF INTERSTITIAL CELLSOF#AJALMASTCELLSPRESENT

GANGLIONICACETYLCHOLINERECEPTORAUTOANTIBODY 01 TYPECALCIUMCHANNELANTIBODY GANGLIONIC AND MUSCLE TYPE NICOTINIC ACETYLCHOLINE RECEPTOR ANTIBODY STRIATIONAL ANTIBODY AND RARELY IN ASSOCIATION WITH OVARIAN OR BREAST CANCER 0URKINJE CELL AUTOANTIBODY TYPE ) OR ANTI 9O ;32= (ISTOLOGICAL EXAMINATION OF TISSUE SECTIONS OFTENSHOWSAMARKEDINmAMMATORYCELLINlLTRATEOFPREDOMINANTLY4LYMPHOCYTES (Fig. 7.9 OFTHEMYENTERICPLEXUSWITHMUCHLESSSUBMUCOSALPLEXUSINVOLVEMENT -YENTERIC PLEXUS NEURONS ARE DECREASED IN NUMBER BUT NERVE lBERS WITHIN THE MUSCULARISPROPRIAAPPEARNORMAL!CASEREPORTDEMONSTRATESADECREASEDNUMBER ANDDISORDEREDNETWORKOF)##INAPATIENTWITHSMALLCELLCARCINOMAOFTHELUNG;32]; THE HYPOTHESIS BEING THAT THE AUTOANTIBODY RECOGNIZED A CELL SURFACE ANTIGEN COMMONTOTHESMALLCELLCARCINOMA ASWELLASTOTHE)##C KITISTHEMOSTLIKELY candidate.

Infectious Causes 6ARIOUS INFECTIOUS CAUSES HAVE BEEN IMPLICATED IN THE ETIOLOGY OF GASTROPARESIS ESPECIALLY IN CHILDREN THEY INCLUDE ROTAVIRUS .ORWALK CYTOMEGALOVIRUS (ERPES SIMPLEXVIRUSANDVACCINATIONSTOHEPATITIS"ANDTETANUS ASWELLAS,YMEDISEASE !PRIORVIRALINFECTIONMAYWELLBEUNRECOGNIZEDASMOSTCASESOFVIRALGASTROPARESIS ARESELF LIMITING4HEREFORE FEWSTUDIESHAVEISOLATEDVIRALCULPRITSDURINGPERIODS

84

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Fig. 7.9 )MMUNOHISTOCHEMICALSTAININGFOR#$MAGNIlCATION84LYMPHOCYTESAROUNDAND WITHINAGANGLION

OFACTIVESHEDDING)NONESERIESOFCHILDRENWHODEVELOPEDGASTROPARESISAFTERAN ACUTEVIRALINFECTION TESTEDPOSITIVEFORROTAVIRUS;33=)NANOTHERSERIESOFCASES OFPOSTINFECTIOUSINmAMMATORYCAUSESOFGASTROPARESIS ALLlVECASESWEREYOUNG WOMENTHREEWERETHOUGHTTOHAVEANASSOCIATIONWITHVACCINATIONSAGAINSTANTHRAX TETANUSANDHEPATITIS"WHILETWODEVELOPED,YMEDISEASE;34=4HEAUTHORSHYPOTHESIZETHATGASTROPARESISOCCURREDASARESULTOFINmAMMATIONTOTHEENTERICNERVOUS SYSTEMORTHEAUTONOMICNERVOUSSYSTEMVIAIMMUNEACTIVATION

Future Directions %NTERICGLIALCELLSAREANEMERGINGAREAOFINTERESTINGASTROINTESTINALMOTILITYDISORDERS #URRENTLY LITTLE IS KNOWN OF THESE CELLS 4HEY WERE ORIGINALLY THOUGHT TO SIMPLY PROVIDE A PROTECTIVE MICROENVIRONMENT FOR THE ENTERIC NERVOUS SYSTEM SIMILAR TO ASTROCYTESINTHECENTRALNERVOUSSYSTEMHOWEVER NUMEROUSOBSERVATIONSIMPLICATE AROLEOFENTERICGLIAINNEUROTRANSMISSION!DDITIONALLY TWOANIMALMODELSHAVE SHOWN THAT ABLATION OF ENTERIC GLIA BY DIFFERENT METHODS RESULT IN INmAMMATORY INSULTSTOTHEMUCOSA;35, 36=4HESESTUDIESSUGGESTTHATENTERICGLIAAREINTEGRALTO GASTROINTESTINAL MUCOSA WHICH MIGHT ALSO IMPLY THEIR SIGNIlCANCE IN MUCOSAL INmAMMATORYDISEASES SUCHASINmAMMATORYBOWELDISEASE4HESTUDYOFGLIALCELLS WILLBEGREATLYENHANCEDBYTHEIDENTIlCATIONOFASENSITIVEANDSPECIlCIMMUNOHISTOCHEMICALMARKER


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-C#ALLUM27 ,IN: $AMJANOV) 3AROSIEK) &ORSTER*)NTERSTITIALCELLSOF#AJALINTHESTOMACH OFPATIENTSWITHGASTROPARESIS.EUROGASTROENTEROL-OTIL )WASAKI( +AJIMURA- /SAWA3 ETAL!DElCIENCYOFGASTRICINTERSTITIALCELLSOF#AJALACCOMPANIEDBYDECREASEDEXPRESSIONOFNEURONALNITRICOXIDESYNTHASEANDSUBSTANCE0INPATIENTS WITHTYPEDIABETESMELLITUS*'ASTROENTEROLn 0ARKMAN (0 ET AL !MERICAN 'ASTROENTEROLOGICAL !SSOCIATION MEDICAL POSITION STATEMENT DIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGYn -ALEKI$ETAL'ASTROINTESTINALTRACTSYMPTOMSAMONGPERSONSWITHDIABETESMELLITUSINTHE COMMUNITY!RCH)NTERN-EDn 0ASRICHA0* 0EHLIVANOV.$ 'OMEZ' 6ITTAL(#HANGESINTHEGASTRICENTERICNERVOUSSYSTEM AND MUSCLE A CASE REPORT ON TWO PATIENTS WITH DIABETIC GASTROPARESIS "-# 'ASTROENTEROL n !NVARI-ETAL2OLEOFNITRICOXIDEMECHANISMSINCONTROLOFPYLORICMOTILITYANDTRANSPYLORIC mOWOFLIQUIDSINCONSCIOUSDOGS$IG$IS3CIn 3PILLER 2# )NFECTION IMMUNE FUNCTION AND FUNCTIONAL GUT DISORDERS #LIN 'ASTROENTEROL (EPATOLn $E'IORGIO2 "ARBARA' 3TANGHALLINI6 ETAL)DIOPATHICMYENTERICGANGLIONITISUNDERLYING INTRACTABLEVOMITINGINAYOUNGMAN%UR*'ASTROENT(EPATOLn "ATTAGLIA% "ASSOTTI' "ELLONE' $UGHERA, 3ERRA!- #HIUSA, ETAL,OSSOFINTERSTITIAL CELLSOF#AJALINSEVEREIDIOPATHICGASTROPARESIS7*'ASTROENTEROLn :ARATE . -EARIN & 7ANG 89 (EWLETT " (UIZINGA *$ -ALAGELADA *2 3EVERE IDIOPATHIC GASTROPARESISDUETONEURONALANDINTERSTITIALCELLSOF#AJALDEGENERATIONPATHOLOGICALlNDINGS ANDMANAGEMENT'UTn 0ARDI$3 -ILLER3- -ILLER$, ETAL0ARANEOPLASTICDYSMOTILITYLOSSOFINTERSTITIALCELLSOF #AJAL!M*'ASTROENTEROLn 3IGURDSSON , &LORES ! 0UTNAM 0% (YMAN 0% $I ,ORENZO # 0OST VIRAL GASTROPARESIS PRESENTATION TREATMENTANDOUTCOME*0EDIATRn 0ANDE( ,ACY"% #ROWELL-$)NmAMMATORYCAUSESOFGASTROPARESIS2EPORTOFCASES$IG $IS3CIn "USH4' 3AVIDGE4# &REEMAN4# ETAL&ULMINANTJEJUNO ILEITISFOLLOWINGABLATIONOFENTERIC GLIAINADULTTRANSGENICMICE#ELLn #ORNET! 3AVIDGE4# #ABARROCAS* ETAL%NTEROCOLITISINDUCEDBYAUTOIMMUNETARGETINGOF ENTERICGLIALCELLSAPOSSIBLEMECHANISMIN#ROHNSDISEASE0ROC.ATL!CAD3CI n

Chapter 8

Natural History of Patients with Gastroparesis Reza A. Hejazi, Henry P. Parkman, and Richard W. McCallum

Keywords $ELAYED GASTRIC EMPTYING s $IABETIC GASTROPARESIS s 'ASTRIC MOTILITY disorder

Introduction 'ASTROPARESIS IS A SYNDROME CHARACTERIZED BY DELAYED GASTRIC EMPTYING IN THE ABSENCE OF MECHANICAL OBSTRUCTION OF THE STOMACH ;1]. The three most common ETIOLOGIESOFGASTROPARESISAREDIABETES POSTSURGICAL ANDIDIOPATHICIE OFUNKNOWN CAUSE 3YMPTOMS ASSOCIATED WITH GASTROPARESIS INCLUDE NAUSEA VOMITING POSTPRANDIAL FULLNESS EARLY SATIETY BLOATING ANDOR ABDOMINAL PAIN !SYMPTOMATIC CASES OF DELAYED GASTRIC EMPTYING CAN BE SEEN PARTICULARLY IN DIABETIC PATIENTS WHERE DIFlCULT TO CONTROL GLUCOSES CAN BE ASSOCIATED WITH THE ONSET OF DELAYED gastric emptying. 4HETRUEPREVALENCEOFGASTROPARESISISDIFlCULTTOESTIMATEDUETOTHERELATIVELY POORCORRELATIONOFSYMPTOMSWITHGASTRICEMPTYINGANDTHENEEDTOAPPLYADIAGNOSTICTESTTODIAGNOSETHISCONDITIONINACOMMUNITYSETTING;2=)TISUNCLEARIFTHE MAJORITYOFPATIENTSWITHGASTROPARESISSEEKHEALTHCAREORHOWOFTENTHEYAREREFERRED TO GASTROENTEROLOGISTS AND THEREFORE THE TRUE PREVALENCE OF GASTROPARESIS IS NOT KNOWN #OMMUNITY STUDIES OF THE OUTCOME OF GASTROPARESIS ARE FEW AND STUDIES CONDUCTED IN TERTIARY REFERRAL CENTERS MAY NOT REmECT lNDINGS ENCOUNTERED IN THE GENERALPOPULATION%STIMATESFORTHEPREVALENCEOFGASTROPARESISHAVEBEENAPPROXIMATELY;3= BASEDONTHEPREVALENCEOFFUNCTIONALDYSPEPSIAINTHECOMMUNITY ANDTHEPREVALENCEOFDELAYEDGASTRICEMPTYINGINPATIENTSWITHFUNCTIONAL

R.W. McCallum (*) $EPARTMENTOF)NTERNAL-EDICINE 5NIVERSITY-EDICAL#ENTER 0AUL,&OSTER3CHOOL OF-EDICINE 4EXAS4ECH5NIVERSITY(EALTH3CIENCES#ENTER %L0ASO 48 53! e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_8, © Springer Science+Business Media, LLC 2012

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DYSPEPSIA (OWEVER IN A RECENT EPIDEMIOLOGIC STUDY OF /LMSTED #OUNTY -INNESOTA THEPREVALENCEOFGASTROPARESISWASLOWERWITHTHEPREVALENCEOFDElNITE GASTROPARESISSYMPTOMATICINDIVIDUALWITHDELAYEDGASTRICEMPTYING REPORTEDTO BEPER FORMENANDPER FORWOMEN;4]. !LTHOUGHGASTROPARESISWASINITIALLYDESCRIBEDYEARSAGO;5= LITTLEISKNOWN ABOUTTHENATURALHISTORY CLINICALCOURSEANDOUTCOMEOFPATIENTSWITHGASTROPARESIS .ATURAL HISTORY OF PATIENTS WITH GASTROPARESIS IS MOSTLY REPORTED IN SYMPTOMATIC PATIENTSSEEKINGHEALTHCAREANDTREATMENT4HEMAJORITYOFTHEPUBLISHEDLITERATURE INNATURALHISTORYANDOUTCOMEAREINTHEDIABETICGASTROPARESISPOPULATION;6, 7]. 4HERE ARE FEW DATA IN PATIENTS WITH IDIOPATHIC AND POSTSURGICAL GASTROPARESIS -ILDGASTROPARESISISBELIEVEDTOHAVEALOWMORTALITYRATE WHEREASPATIENTSWITH SEVEREGASTROPARESISMAYDEVELOPCOMPLICATIONSFROMTHEIRGASTRICMOTILITYDISORDER ANDORTHEIRUNDERLYINGDISORDER;4, 8=-OSTPATIENTSARETREATEDFORSYMPTOMATIC GASTROPARESIS WHICHMIGHTIMPROVESYMPTOMSANDALTERNATURALHISTORY)NPATIENTS WITH GASTROPARESIS REFERRED TO TERTIARY CENTERS WITH OVER YEARS FOLLOW UP THE majority (74%) required long-term prokinetic therapy, 22% needed long-term PARENTERALORENTERALFEEDING ANDHADDIED SUGGESTINGGASTROPARESISISNOTA BENIGNCONDITION;8]. Postsurgical gastroparesis and idiopathic gastroparesis assoCIATEDWITHPROMINENTABDOMINALPAINAREOFTENMOREREFRACTORYTOPHARMACOLOGIC therapy.

Clinical Course of Gastroparesis )NFORMATIONONTHECLINICALCOURSEOFGASTROPARESISISBEINGOBTAINEDINTHE.)$$+ 'ASTROPARESIS#LINICAL2ESEARCH#ONSORTIUMWHICHHASAREGISTRYOFPATIENTSWITH GASTROPARESISTHATHAVEBEENFOLLOWEDFORSEVERALYEARSWHILERECEIVINGCLINICALCARE ;9=2ECENTLY PATIENTSWITHGASTROPARESISWITHFOLLOW UPDATAAFTERWEEKS WERE REPORTED ;9= 4HE MOST COMMONLY USED MEDICATIONS WERE ANTIEMETICS AND PROKINETICSFOLLOWEDBYOPIATES ANTIDEPRESSANTS ANDNEUROPATHICPAINMODULATORS 4HE CLINICAL SEVERITY OF GASTROPARESIS SYMPTOMS IMPROVED AT FOLLOW UP WITH A MEDIANREDUCTIONINTHEGASTROPARESISCARDINALSYMPTOMINDEX'#3) SCORESFROM TO)MPROVEMENTSWERESEENINSYMPTOMSOFNAUSEAANDVOMITINGWITHLESS IMPROVEMENTSFOREARLYSATIETY POSTPRANDIALFULLNESS BLOATING ANDABDOMINALPAIN !FTERWEEKS QUALITYOFLIFE0!') 1/, SHOWEDIMPROVEMENTINTOTALSCORES VS WITHIMPROVEMENTSINDAILYACTIVITYSUBSCOREVS DIETSUBSCORE VS ANDPSYCHOLOGICALSUBSCOREVS (OSPITALIZATIONSFORGASTROPARESISDIDNOTCHANGEVSOFPATIENTS $URINGTHEFOLLOW UPPERIOD 40. WASINSTITUTEDINOFPATIENTS * TUBEFEEDINGIN ANDGASTRICELECTRICALSTIMULATION'%3 IN4HISSTUDYSHOWSTHATOVERYEAR THEBURDENOFGASTROPARESIS IN PATIENTS REMAINS HIGH DESPITE MILD IMPROVEMENTS IN SEVERAL PARAMETERS 4HE PATTERNOFIMPROVEMENTISHETEROGENEOUSWITHIMPROVEMENTSINNAUSEAANDVOMITING BUTNOTINBLOATINGANDABDOMINALPAIN4HESERESULTSEMPHASIZETHECHRONICNATURE OFGASTROPARESISANDTHENEEDFORNOVELTHERAPEUTICAPPROACHES

.ATURAL(ISTORYOF0ATIENTSWITH'ASTROPARESIS

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-OSTTREATMENTSTUDIESFORGASTROPARESISHAVEBEENOFONLYnMONTHSDURATION ! MONTHTRIALOFTHEPROKINETICAGENT CISAPRIDEMGTHREETIMESDAILY WAS ASSESSED IN PATIENTS WITH GASTROPARESIS AND PATIENTS WITH CHRONIC INTESTINAL PSEUDOOBSTRUCTION ;10= &OR THE WHOLE GROUP OF PATIENTS GASTRIC EMPTYING OF BOTH SOLIDS AND LIQUIDS IMPROVED SIGNIlCANTLY AFTER YEAR OF CISAPRIDE !MONG CHRONICINTESTINALPSEUDOOBSTRUCTIONPATIENTS THEREWASPREDOMINANTLYANIMPROVEMENT IN GASTRIC EMPTYING OF SOLIDS IN CONTRAST PATIENTS WITH GASTROPARESIS HAD A GREATER IMPROVEMENT IN LIQUID EMPTYING 4OTAL SYMPTOM SCORE IMPROVED SIGNIlCANTLYINTHEGASTROPARESISGROUPMEDIANSCOREATBASELINEVSATYEAR BUTNOT INTHECHRONICINTESTINALPSEUDOOBSTRUCTIONPATIENTSMEDIANSCOREATBASELINEVS ATYEAR )NTHIS MONTHOPENTRIAL THEPROKINETICAGENT CISAPRIDE WASEFFECTIVE INIMPROVINGGASTRICEMPTYINGINPATIENTSWITHGASTRICSTASISANDCONSISTENTLYIMPROVED SYMPTOMSINTHOSEWITHGASTROPARESIS,ONG TERMTREATMENTSTUDIESWITHOTHERPROKINETICAGENTS WHENAVAILABLE ARENEEDED ,ONG TERMTREATMENTSTUDIESWITHGASTRICELECTRICSTIMULATIONAREBEINGREPORTED !BELL ET AL REPORTED LONG TERM DATA USING '%3 FOR DRUG REFRACTORY GASTROPARESIS ;11, 12=4WOHUNDREDANDFOURTEENCONSECUTIVEDRUG REFRACTORYPATIENTSWITHTHE SYMPTOMSOFGASTROPARESISWEREASSESSEDPATIENTSIMPLANTEDWITHA'%3DEVICE ANDANOTHERPATIENTSNOTIMPLANTEDPRIMARILYFORINSURANCEPURPOSESSERVINGAS CONTROLS!TLATESTFOLLOW UP MEDIANYEARS MOSTPATIENTSIMPLANTEDOF WEREALIVEWITHINTACTDEVICES SIGNIlCANTLYREDUCEDGASTROINTESTINALSYMPTOMS AND IMPROVEDHEALTH RELATEDQUALITYOFLIFE WITHEVIDENCEOFIMPROVEDGASTRICEMPTYING -OSTPATIENTSEXPLANTED USUALLYFORPOCKETINFECTIONS WERELATERREIMPLANTEDSUCCESSFULLY4HEREWERENODEATHSDIRECTLYRELATEDTOTHEDEVICE-C#ALLUMETALALSO REPORTED LONG TERM OUTCOMES IN GASTROPARETIC PATIENTS RECEIVING '%3 THERAPY BEYONDYEARS;13=/FTHEPATIENTS TENDIEDOFNONPACEMAKER RELATEDCOMPLICATIONS SIXHADTHEDEVICESREMOVEDANDTWOCOULDNOTBEREACHED4HEREMAINING PATIENTSHADTHEDEVICEACTIVATEDFORAMEANOFMONTHS4OTALSYMPTOMSCORE HOSPITALIZATIONDAYSANDTHEUSEOFMEDICATIONSWEREALLSIGNIlCANTLYREDUCEDATYEAR ANDWERESUSTAINEDBEYONDYEARS4HETOTALSYMPTOMSCOREDECREASEDBYFOR THEPATIENTSCOMPLETINGYEARSOF'%3!TIMPLANTATION OFPATIENTSREQUIRED NUTRITIONAL SUPPORT BUT ONLY lVE CONTINUED BEYOND YEARS -EAN (B!C LEVEL IN DIABETICS WAS SIGNIlCANTLY REDUCED FROM TO AT YEARS 4HESE OPEN LABEL STUDIESSHOWIMPROVEMENTINSYMPTOMSANDOTHERMEASURESOFCLINICALOUTCOMECAN BEMAINTAINEDFORLONGTERMWITH'%3INPATIENTSWITHREFRACTORYGASTROPARESIS

Hospitalizations for Gastroparesis 4HECOURSEOFPATIENTSWITHGASTROPARESISISVARIABLE/NEGRADINGSCHEMEFORTHE CLINICALSEVERITYOFGASTROPARESISUSESASCALEORIGINALLYPROPOSEDBY4ACKETAL AND REPORTED IN THE !MERICAN .EUROGASTROENTEROLOGY AND -OTILITY 3OCIETY !.-3 REVIEWONTHETREATMENTOFGASTROPARESIS;3]: grade 1 or mild gastroparesis SYMPTOMSRELATIVELYEASILYCONTROLLEDANDABLETOMAINTAINWEIGHTANDNUTRITIONON

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AREGULARDIET GRADEORCOMPENSATEDGASTROPARESISMODERATESYMPTOMSWITHONLY PARTIAL CONTROL WITH THE USE OF DAILY MEDICATIONS ABLE TO MAINTAIN NUTRITION WITH DIETARY ADJUSTMENTS AND GRADE OR GASTROPARESIS WITH GASTRIC FAILURE REFRACTORY SYMPTOMSTHATARENOTCONTROLLEDASSHOWNBYTHEPATIENTHAVING%2VISITS FREQUENT DOCTOR VISITS OR HOSPITALIZATIONS ANDOR INABILITY TO MAINTAIN NUTRITION VIA AN ORAL ROUTE 4HUS SOME PATIENTS WITH RELATIVELY MILD SYMPTOMS CAN BE MAINTAINED ON DIETARYTREATMENTSMALLMEALS LOWFAT LOWlBERDIET ANDORALPROKINETICANDANTIEMETICMEDICATIONS WHEREASOTHERPATIENTSMAYNEEDMOREINVASIVETREATMENTSWITH JEJUNOSTOMYFEEDINGTUBESANDORTHEUSEOFGASTRICELECTRICSTIMULATION 0ATIENTSMAYHAVEPERIODICHOSPITALIZATIONSFOREXACERBATIONSOFSYMPTOMS4HE NUMBEROFGASTROPARESIS RELATEDHOSPITALIZATIONSHASBEENINCREASINGINTHE53! ANDTHEECONOMICIMPACTOFGASTROPARESIS RELATEDHOSPITALIZATIONSISSIGNIlCANTAND MAYBEINCREASING;4=4HETRENDS CHARACTERISTICS ANDOUTCOMESOFGASTROPARESIS RELATEDHOSPITALIZATIONSDURINGnWERESTUDIEDUSINGTHEPUBLICLYAVAILABLE (EALTHCARE #OST AND 5TILIZATION 0ROJECT .ATIONWIDE )NPATIENT 3AMPLE WHICH COMPRISESANATIONALLYREPRESENTATIVESAMPLEOFnMILLIONHOSPITALIZATIONSPERYEAR ;14='ASTROPARESIS RELATEDHOSPITALIZATIONSWEREIDENTIlEDUSINGTHE)NTERNATIONAL #LASSIlCATIONOF$ISEASES)#$ CODE(OSPITALIZATIONSWITHGASTROPARESIS ASTHEPRIMARYDIAGNOSISINCREASEDFROM INTO IN ANDHOSPITALIZATIONSWITHGASTROPARESISASTHESECONDARYDIAGNOSISINCREASEDFROM TO 4HESE COMPARED TO SMALLER INCREASES IN DIABETES related hospitalizations (+53%), and all hospitalizations (+130%). The increased NUMBEROFGASTROPARESIS RELATEDHOSPITALIZATIONSINTHE53!MAYBERELATEDTOSEVERAL FACTORS INCLUDINGTHEINCREASINGPREVALENCEOFDIABETES THEWITHDRAWALOFPHARMACOLOGICAGENTSCISAPRIDEANDTEGASEROD THELACKOFCURRENTLYEFFECTIVEPHARMACOLOGIC TREATMENT THENEEDFORHOSPITALIZATIONFORIMPLANTATIONOFGASTRICSTIMULATORS AND POSSIBLYANINCREASEINTHEPREVALENCEANDSEVERITYOFGASTROPARESIS 4OINVESTIGATEPRECIPITATINGFACTORSLEADINGTOHOSPITALIZATIONFOREXACERBATIONOF SYMPTOMSINPATIENTSWITHGASTROPARESIS ARETROSPECTIVEREVIEWOFADMISSIONS PATIENTS FORGASTROPARESISEXACERBATIONATONECENTERWASREPORTED;15]. Poor GLYCEMICCONTROLWASPRESENTIN INFECTIONINURINARYTRACTINFECTIONS ANDTWOBACTEREMIA ANDNONCOMPLIANCEWITHANDINTOLERANCEOF MEDICATIONSIN ANDOFPATIENTS RESPECTIVELY)NTHEEPIDEMIOLOGICSTUDYREPORTEDFROM/LMSTEAD #OUNTY -INNESOTA OFPATIENTSWITHGASTROPARESISREQUIREDTHERAPEUTICINTERVENTIONS WITH OF PATIENTS NEEDING HOSPITALIZATIONS FOR TUBE FEEDING OR TOTAL PARENTERAL NUTRITION ;4= 4HUS POOR GLYCEMIC CONTROL INFECTION NONCOMPLIANCE WITHINTOLERANCEOFMEDICATIONS ANDNEEDFORINVASIVETREATMENTOPTIONSWERECONTRIBUTORYFACTORSLEADINGTOHOSPITALIZATIONSOFGASTROPARETICPATIENTS

Mortality of Gastroparesis 4HECAUSESOFDEATHINPATIENTSWITHGASTROPARESISARENOTWELLDESCRIBED-ORTALITY IN PATIENTS WITH GASTROPARESIS CAN BE FROM GASTROPARESIS RELATED COMPLICATIONS COMPLICATIONSFROMTHETREATMENTFORGASTROPARESIS THEUNDERLYINGDISEASECAUSING


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GASTROPARESIS OR DEATH FROM DISORDERS THAT ALSO AFFECT THE GENERAL POPULATION #ONTRARYTOCURRENTTHINKING SOMESTUDIESSUGGESTTHATDIABETICGASTROPARESISISNOT ASSOCIATEDWITHAPOORPROGNOSISWITHSIMILARMORTALITYCOMPAREDTODIABETICPATIENTS WITHOUT GASTROPARESIS ;7= (OWEVER OTHERS SUGGEST THAT THERE IS A HIGH MORTALITY INPATIENTSWITHGASTROPARESIS PARTICULARLYDIABETICGASTROPARESISWITHSEVERESYMPTOMS;11=!BELLETALHAVESHOWNAHIGHERMORTALITYRATEINSEVERELYSYMPTOMATIC GASTROPARETICPATIENTSREFERREDFORCONSIDERATIONOFGASTRICELECTRICSTIMULATIONWHO DONOTUNDERGOGASTRICELECTRICSTIMULATIONCOMPAREDTOTHOSETHATDID;11=4HREEOF NINEPATIENTSINTHEMEDICALTREATMENTGROUPDIEDPRIMARILYFROMINTRAVENOUSACCESS RELATEDPROBLEMSNONEOFTHESTIMULATORPATIENTSDIED 4HEPOPULATIONDATAFROM/LMSTED#OUNTYIN-INNESOTAREVEALSTHATTHEOVERALL SURVIVALOFPATIENTSWITHGASTROPARESISOVERYEARSISSIGNIlCANTLYLOWERTHANTHE AGEANDSEX SPECIlCEXPECTEDSURVIVAL;4=4HEESTIMATED YEARSURVIVALINPATIENTS WITHGASTROPARESISWASCOMPAREDTOANEXPECTEDSURVIVALOF/LDERAGEAT DIAGNOSIS AND MALE GENDER WERE ASSOCIATED WITH DECREASED SURVIVAL )DIOPATHIC GASTROPARESISWASASSOCIATEDWITHBETTERSURVIVALTHANNONIDIOPATHICGASTROPARESIS #AUSES OF DEATH WERE CARDIOVASCULAR DISEASE IN RESPIRATORY FAILURE IN MALIGNANCYIN CHRONICRENALFAILUREIN CEREBRALVASCULARACCIDENTIN ANDOTHERCAUSESIN4HISSTUDYTHATSUGGESTSGASTROPARESISISASSOCIATEDWITHA poor outcome.

Aspects on the Natural History of Different Etiologies of Gastroparesis Diabetic Gastroparesis 4YPICALLY GASTROPARESISDEVELOPSAFTERDIABETESHASBEENPRESENTFORYEARSAND PATIENTS HAVE EVIDENCE FOR OTHER COMPLICATIONS OF DIABETES SUCH AS RETINOPATHY NEPHROPATHY PERIPHERALNEUROPATHY ANDOFTEN AUTONOMICDYSFUNCTION4HEPROGNOSISINDIABETICGASTROPARESISHASBEENASSUMEDTOBEPOOR BUTFOLLOW UPOVERAT LEASTADECADEINDICATESTHATTHISISNOTNECESSARILYTHECASE;7, 16]. In a longitudinal STUDYOFGASTRICEMPTYINGANDUPPERGASTROINTESTINALSYMPTOMSINPATIENTSWITHDIABETES MELLITUS *ONESETALDIDNOTOBSERVEANYMARKEDCHANGESINEITHERGASTRICEMPTYING OR UPPER GASTROINTESTINAL SYMPTOMS DURING A YEAR PERIOD ;6= )N THIS STUDY OF DIABETIC PATIENTS DELAYED GASTRIC EMPTYING WAS NOT RELATED TO THE MORTALITY AFTER ADJUSTMENTOFCOMORBIDITIES;6=4HEASSOCIATIONBETWEENDIABETICGASTROPARESISAND MORTALITYHASALSOBEENASSESSEDINOTHERSTUDIES)NACOHORTOFOUTPATIENTSWITH DIABETESFOLLOWEDBY+ONGETAL ITWASDETERMINEDTHATGASTROPARESISWASNOTASSOCIATEDWITHAPOORPROGNOSIS;7=$IABETESPREDISPOSESTOMANYMEDICALCOMPLICATIONS THAT INmUENCE MORBIDITY AS WELL AS MORTALITY 4HE INCREASED MORTALITY IN PATIENTS WITH DIABETIC GASTROPARESIS IS USUALLY RELATED TO OTHER ORGAN DYSFUNCTION 4HE MEDIAN TIME OF DEATH AFTER THE DIAGNOSIS OF GASTROPARESIS IN A PATIENT WITH

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DIABETESWASYEARSRANGEn WITHMAJORCAUSESOFDEATHWERECARDIOVASCULAR ORRENALDISEASE)NTHOSEPATIENTSWHOHADDIED THEDURATIONOFDIABETESANDSCORES FORAUTONOMICNEUROPATHY RETINOPATHY ANDESOPHAGEALTRANSITWEREGREATERTHANIN THEPATIENTSWHOWEREALIVE4HESTUDYSHOWEDTHATGASTROPARESISWASNOTDIRECTLYA DETERMINANTOFMORTALITYOVERAFOLLOW UPPERIODOFABOUTYEARS BUTBROUGHTUP THEPOSSIBILITYTHATGASTROPARESISWASASSOCIATEDWITHAGREATERRISKOFCOMPLICATIONS ANDTHEREFOREINDIRECTLYWITHMORTALITY (YPERGLYCEMIAANDAUTONOMICNEUROPATHYARETWOFACTORSTHATHAVEBEENIMPLICATEDINTHEPATHOGENESISOFDIABETICGASTROPARESIS;17, 18=4HEASSOCIATIONBETWEEN OVERALLGLYCEMICCONTROLANDDIABETICMICROVASCULARANDMACROVASCULARCOMPLICATIONS IS WELL DOCUMENTED IN BOTH TYPE ;19, 20= AND TYPE DIABETES ;21]. Poor GLYCEMIC CONTROL IS ASSOCIATED WITH INCREASED PREVALENCE OF UPPER ') SYMPTOMS )NACROSS SECTIONALQUESTIONNAIRESTUDYOF SUBJECTS "YTZERETALFOUNDTHAT GASTROINTESTINALSYMPTOMSAREINDEPENDENTLYASSOCIATEDWITHBOTHDIABETICCOMPLIcations (particularly peripheral neuropathy) and glycemic control in the general DIABETICPOPULATION;22]. Interestingly, psychological distress is also linked to GI SYMPTOMSINDIABETESMELLITUS PARTICULARLYNAUSEAANDEARLYSATIETY;23]. (YETTETALREPORTONTHEINCREASEDMORBIDITYOFPATIENTSWITHDIABETICGASTROPARESIS;24=$IABETICPATIENTSTYPEANDTYPE WITHCLASSICSYMPTOMSOFGASTROparesis and delayed gastric emptying had more hospitalizations, emergency room VISITS ANDOFlCECOMPAREDTOSYMPTOMATICDIABETICPATIENTSWITHNORMALGASTRIC EMPTYING AND DIABETIC PATIENTS WITHOUT SYMPTOMS OF GASTROPARESIS )N ADDITION DIABETICPATIENTSWITHSYMPTOMATICGASTROPARESISHADMORECARDIOVASCULARDISEASE hypertension, and retinopathy. This study suggests that delayed gastric emptying CORRELATESWITHNEGATIVEOUTCOMESINDIABETICPATIENTSWHOHAVESYMPTOMSOFGASTROPARESISWITHDELAYEDGASTRICEMPTYINGBEINGANINDEPENDENTMAKERFORMORBIDITY ! NONSIGNIlCANT INCREASE IN MORTALITY WAS SEEN IN THE SYMPTOMATIC DIABETIC gastroparesis group.

Idiopathic Gastroparesis -UCH LESS IS KNOWN ABOUT THE EPIDEMIOLOGY AND NATURAL HISTORY OF IDIOPATHIC GASTROPARESIS COMPARED TO DIABETIC GASTROPARESIS )N A TERTIARY REFERRAL SERIES OF PATIENTSWITHIDIOPATHICGASTROPARESIS;8= SEVERALSUBGROUPSWEREIDENTIlED HADAPRESENTATIONCONSISTENTWITHAVIRALETIOLOGYANDASMALLSUBSET HADTHE ONSETOFSYMPTOMSAFTERCHOLECYSTECTOMY &ROMASYMPTOMSTANDPOINT HADPROMINENTABDOMINALPAINOTHERSUBGROUPSINCLUDEDPATIENTSWITHPREDOMINANT SYMPTOMSOFGASTROESOPHAGEALREmUXDISEASEORFUNCTIONALDYSPEPSIA -C#ALLUMETALREPORTONVIRALINDUCEDGASTROPARESISASASUBGROUPOFIDIOPATHIC GASTROPARESIS;25=4WELVEOF PATIENTSWITHIDIOPATHICGASTROPARESISWERE IDENTIlED AS CONSISTENT WITH A POSTVIRAL ETIOLOGY 4HE hPOSTVIRAL GASTROPARESISv PATIENTS REPORTED GRADUAL IMPROVEMENT OF THEIR SYMPTOMS NO HOSPITALIZATIONS DURING THE PREVIOUS MONTHS STABLE WEIGHT WERE NOT DISABLED AND REMAINED PROFESSIONALLYACTIVE)NCOMPARISON NONPOSTVIRALhIDIOPATHICvPATIENTSHADAN


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INDOLENT SLOWLY PROGRESSIVE CLINICAL PRESENTATION 4HESE AUTHORS SUGGEST THAT A VIRALETIOLOGYSHOULDBECONSIDEREDINGASTROPARESISPATIENTSWHENTHEIRILLNESSIS CHARACTERIZEDBYANACUTEONSET INITIALSEVEREILLNESSANDSLOWRESOLUTIONTOWARDA SATISFACTORYQUALITYOFLIFE)DIOPATHICGASTROPARESISISAMORESLOWLYPROGRESSIVE ILLNESS ANDPATIENTSREMAINSIGNIlCANTLYMORESYMPTOMATICFORALONGERPERIODOF TIME)NFECTIOUSPRODROMESATTHEONSETOFGASTROPARETICSYMPTOMSWEREALSOREPORTED BYOFGASTROPARESISPATIENTSFOLLOWEDINTHE.)(GASTROPARESISREGISTRY;26]. 4HEMOSTCOMMONTYPEOFINFECTIOUSPRODROMEWASGASTROENTERITISORFOODPOISONING 0OSTINFECTIOUSGASTROPARESISPATIENTSWEREYOUNGERANDSHOWEDLESSERGASTRICRETENTION4HEREWEREGREATERDECREASESINPOSTPRANDIALFULLNESSOVERWEEKSINTHE POSTINFECTIOUS GASTROPARESIS GROUP COMPARED TO THE NONPOSTINFECTIOUS GROUP %VOLUTIONOFOTHERSYMPTOMSANDMEASURESOFSEVERITYWERENOTDIFFERENTINRELATION TOINFECTIOUSPRODROMES,ONGERFOLLOW UPMAYUNCOVEROTHERATTRIBUTESSPECIlCFOR POSTINFECTIOUSGASTROPARESIS !RECENTSTUDYOFPATIENTSWITHGASTROPARESISSOUGHTTODETERMINEIFMILD MODERATE AND SEVERE DEGREES OF GASTROPARESIS BASED ON THE SCINTIGRAPHIC GASTRIC EMPTYINGTESTCANPREDICTTREATMENTRESPONSESFORGASTROPARESIS;27]. In this study, GASTRICEMPTYINGINPATIENTSWHOSEGASTROPARETICSYMPTOMSWEREREFRACTORYTOSTANDARD MEDICAL THERAPY AND REQUIRED GASTRIC ELECTRIC STIMULATION WAS SIGNIlCANTLY SLOWERTHANINGASTROPARETICPATIENTSWHOSESYMPTOMSRESPONDEDTOMEDICALTHERAPY 3TRATIFYING GASTRIC EMPTYING INTO MILD MODERATE AND SEVERE DEGREES OF GASTRIC RETENTION HELPED CORRELATE THE NEED FOR GASTRIC ELECTRIC STIMULATION TO CONTROL THE SYMPTOMSINPATIENTSWITHIDIOPATHICGASTROPARESIS BUTNOTINPATIENTSWITHDIABETIC GASTROPARESIS;27].

Postsurgical Gastroparesis 0OSTSURGICAL GASTROPARESIS IS IDENTIlED AS A CHRONIC FORM OF GASTRIC ATONY IN THE ABSENCEOFMECHANICALOBSTRUCTION(ISTORICALLY OPERATIONSFORULCERDISEASE SUCH ASVAGOTOMYWITHORWITHOUTHEMIGASTRECTOMYMAYBEFOLLOWEDBYDELAYEDGASTRIC EMPTYING0OSTSURGICALGASTROPARESISDEVELOPSINUPTOOFPATIENTSWHOUNDERGO VAGOTOMY EITHER DELIBERATE OR INADVERTENT AS PART OF THEIR UPPER GASTROINTESTINAL SURGERY 4HE INCIDENCE INCREASES TO AS HIGH AS IN THOSE WITH CHRONIC GASTRIC OUTLETOBSTRUCTIONBEFOREVAGOTOMYSURGERIES/VERTHELASTDECADE SURGERYFORULCER disease has decreased. Currently, the most common surgical procedure resulting in GASTROPARESISAPPEARSTOBE.ISSENFUNDOPLICATION $ATAONNATURALHISTORYOFPOSTSURGICALGASTROPARESISISLIMITED-ANYSYMPTOMS FOLLOWINGABDOMINALSURGERYMAYDECREASEWITHTIME4HERESOLUTIONOFSYMPTOMS MAYALSOBEACCOMPANIEDBYTHEIMPROVEMENTINGASTRICEMPTYING SUGGESTINGTHAT EITHERTHEENTERICNERVOUSSYSTEMMAYBEABLETOADAPTTOLOSSOFVAGALINPUTORTHAT VAGALREINNERVATIONORREGENERATIONOFNERVElBERMAYOCCUR ASSHOWNFORAFFERENT BUTNOTEFFERENT lBERSINEXPERIMENTALMODELS 3YMPTOMATIC MANAGEMENT OF POSTSURGICAL GASTROPARESIS INCLUDES DIETARY MANIPULATIONANDTHECOMBINATIONOFPROKINETICANDANTIEMETICAGENTS7ITHOUTAN

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ANTRUM MEDICALTHERAPIESARELESSSUCCESSFUL ANDMEDICATIONSMIGHTNOTBERELIABLY ABSORBEDBECAUSEOFBEZOARFORMATION)NSEVERECASES PATIENTSMIGHTBEPLACEDON A LIQUID CALORIC DIET -EDICAL THERAPY IS TRIED WITH AVOIDANCE OF REPEAT SURGERY (OWEVER AFTERAYEARORMOREHASPASSEDSINCETHEPUTATIVEINJURY THELIKELIHOODOF SPONTANEOUSIMPROVEMENTBEGINSTODECLINE-ANAGEMENTOFPATIENTSWITHPOSTSURGICAL GASTROPARESIS CAN BE PARTICULARLY CHALLENGING AT THIS POINT 4HEIR ILLNESS HAS GENERALLYBEENLONGSTANDING ANDTHEIRSYMPTOMSHAVEREMAINEDDESPITEAVARIETYOF MEDICAL AND SURGICAL INTERVENTIONS WITH EACH NEW PROCEDURE OFTEN DIRECTED AT hREVISINGvTHEONEPRECEDINGIT #HRONICABDOMINALPAINANDASSOCIATEDPSYCHOSOCIAL BEHAVIORALPATTERNSARECOMMONINSUCHPATIENTS ASISNARCOTICDEPENDENCY!MULTIDISCIPLINARY APPROACH IS IMPORTANT FOR PATIENT CARE WITH CAREFUL COUNSELING AND INPUTFROMPSYCHOLOGISTS NUTRITIONISTS PAINSPECIALISTS ANDSURGEONSSPECIALIZINGIN THECAREOFSUCHPATIENTS&ORPATIENTSWHOFAILTHESETHERAPIES SURGICALINTERVENTIONS AREOFTENCONTEMPLATED4HESEINCLUDETUBEGASTROSTOMYFORGASTRICDECOMPRESSION ANDJEJUNOSTOMYFORENTERALFEEDINGSANDGASTRICELECTRICSTIMULATIONTHERAPY4OTAL GASTRECTOMYISPREFERREDTO%NTERRATHERAPYWHENTHEREISLESSTHANOFSTOMACH REMAININGAFTERA"ILLROTH)OR))WITHORWITHOUTA2OUX EN 9RECONSTRUCTION;28].

Conclusions 4HE COURSE OF GASTROPARESIS FOR AN INDIVIDUAL PATIENT IS DIFlCULT TO DETERMINE 'ASTROPARESISISOFTENACHRONICDISORDER3OMEPATIENTSSLOWLYIMPROVE PARTICULARLY IDIOPATHICGASTROPARESISWITHANABRUPTONSETOFSYMPTOMSSUGGESTINGANINFECTIOUS PRODROME)NCONTRAST DIABETICGASTROPARETICPATIENTSOFTENHAVEPROLONGEDDURATION OFSYMPTOMS)NDIABETICPATIENTS SYMPTOMSMAYIMPROVE INPART WITHIMPROVEMENT INGLUCOSECONTROL)NDIABETICPATIENTS GASTROPARESISAPPEARSTOBEANOTHERDIABETIC COMPLICATIONALONGWITHNEPHROPATHY NEUROPATHY ANDRETINOPATHYTHUS GASTROPARESISMAYBEANOTHERMARKEROFTHESEVERITYOFTHEDIABETICDISORDER-ANYPATIENTS HAVE EXACERBATIONS OF THEIR SYMPTOMS LEADING TO INTERMITTENT HOSPITALIZATIONS PRIMARILYDUETOPOORGLYCEMICCONTROL INFECTION NONCOMPLIANCEWITHINTOLERANCE OFMEDICATIONS ANDNEEDFORINVASIVETREATMENTOPTIONS3TUDIESONTHETREATMENTFOR GASTROPARESISAREGENERALLYSHORTTERMOVERSEVERALMONTHS&EWLONG TERMTREATMENT STUDIESOVERAYEARORMOREHAVEBEENREPORTED4HOSELONG TERMnYEARS STUDIES REPORTEDAPPEARTOBEFAVORABLEFORTREATMENTIMPROVINGSYMPTOMSANDHELPINGTO IMPROVETHENATURALHISTORYFORAGIVENPATIENT

References 0ARKMAN(0 (ASLER7, &ISHER23!MERICAN'ASTROENTEROLOGICAL!SSOCIATIONMEDICALPOSITION STATEMENTDIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGYn 4ALLEY.* ,OCKE)))'2 ,AHR"$ ETAL&UNCTIONALDYSPEPSIA DELAYEDGASTRICEMPTYING AND IMPAIREDQUALITYOFLIFE'UTn


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0ARKMAN(0 #AMILLERI- &ARRUGIA' ETAL'ASTROPARESISANDFUNCTIONALDYSPEPSIAEXCERPTS FROMTHE!'!!.-3MEETING.EUROGASTROENTEROL-OTIL n *UNG(+ #HOUNG23 ,OCKE)))'2 ETAL4HEINCIDENCE PREVALENCE ANDOUTCOMESOFPATIENTS WITH GASTROPARESIS IN /LMSTED #OUNTY -INNESOTA FROM TO 'ASTROENTEROLOGY n +ASSANDER 0 !SYMPTOMATIC GASTRIC RETENTION IN DIABETICS GASTROPARESIS DIABETICORUM !NN)NTERN-EDn *ONES +, 2USSO ! "ERRY -+ ET AL ! LONGITUDINAL STUDY OF GASTRIC EMPTYING AND UPPER GASTROINTESTINALSYMPTOMSINPATIENTSWITHDIABETESMELLITUS!M*-EDn +ONG-& (OROWITZ- *ONES+, ETAL.ATURALHISTORYOFDIABETICGASTROPARESIS$IABETES #AREn 3OYKAN) 3IVRI" 3AROSIEK) ETAL$EMOGRAPHY CLINICALCHARACTERISTICS PSYCHOLOGICALAND ABUSEPROlLES TREATMENT ANDLONGTERMFOLLOW UPOFPATIENTSWITHGASTROPARESIS$IG$IS3CI n 0ASRICHA 0* .GUYEN , 3NAPE 7* #OLVIN 2 ,EE ,! !BELL 4, +OCH +, 0ARKMAN (0 4ONASCIA* !NALP !RIDA! (ASLER7, &ARRUGIA' (AMILTON&!#HANGESINQUALITYOFLIFE ANDSYMPTOMSINALARGECOHORTOFPATIENTSWITHGASTROPARESISFOLLOWEDPROSPECTIVELYFOR WEEKS'ASTROENTEROLABSTRACT !BELL4, #AMILLERI- $I-AGNO%0 (ENCH63 :INSMEISTER!2 -ALAGELADA*2,ONG TERM EFlCACY OF ORAL CISAPRIDE IN SYMPTOMATIC UPPER GUT DYSMOTILITY $IG $IS 3CI n #UTTS4& ,UO* 3TARKEBAUM7 2ASHED( !BELL4,)SGASTRICELECTRICALSTIMULATIONSUPERIOR TO STANDARD PHARMACOLOGIC THERAPY IN IMPROVING ') SYMPTOMS HEALTHCARE RESOURCES AND LONG TERMHEALTHCAREBENElTS.EUROGASTROENTEROL-OTIL n !NAND# !L *UBURI! &AMILONI" 2ASHED( #UTTS4 !BIDI. ETAL'ASTRICELECTRICALSTIMULATIONISSAFEANDEFFECTIVEALONG TERMSTUDYINPATIENTSWITHDRUG REFRACTORYGASTROPARESISIN THREEREGIONALCENTERS$IGESTIONn n ,IN : 3AROSIEK ) &ORSTER * -C#ALLUM 27 3YMPTOM RESPONSES LONG TERM OUTCOMES AND ADVERSEEVENTSBEYONDYEARSOFHIGH FREQUENCYGASTRICELECTRICALSTIMULATIONFORGASTROPARESIS .EUROGASTROENTEROL-OTIL n 7ANG92 &ISHER23 0ARKMAN(0'ASTROPARESIS RELATEDHOSPITALIZATIONSINTHE5NITED3TATES TRENDS CHARACTERISTICS ANDOUTCOMES n!M*'ASTROENTEROL n 5PPALAPATI33 2AMZAN: &ISHER23 0ARKMAN(0&ACTORSCONTRIBUTINGTOHOSPITALIZATIONFOR GASTROPARESISEXACERBATIONS$IG$IS3CI n 2AYNER #+ (OROWITZ - .EW MANAGEMENT APPROACHES FOR GASTROPARESIS .AT #LIN 0RACT 'ASTROENTEROL(EPATOL n 3CHVARCZ% 0ALMER- !MAN* ETAL0HYSIOLOGICALHYPERGLYCEMIASLOWSGASTRICEMPTYINGIN NORMAL SUBJECTS AND PATIENTS WITH INSULIN DEPENDENT DIABETES MELLITUS 'ASTROENTEROLOGY n *ONES+, (OROWITZ- "ERRY- ETAL"LOODGLUCOSECONCENTRATIONINmUENCESPOSTPRANDIAL FULLNESSIN)$$-$IABETES#AREn .ATHAN$- #LEAJY0! "ACKLUND*9 ETAL)NTENSIVEDIABETESTREATMENTANDCARDIOVASCULAR DISEASEINPATIENTSWITHTYPEDIABETES.%NGL*-EDn 4HE$IABETES#ONTROLAND#OMPLICATIONS4RIAL;$##4=2ESEARCH'ROUP4HEEFFECTOFINTENSIVE TREATMENTOFDIABETESONTHEDEVELOPMENTANDPROGRESSIONOFLONG TERMCOMPLICATIONSININSULIN DEPENDENTDIABETESMELLITUS.%NGL*-EDn 5+0ROSPECTIVE$IABETES3TUDY;5+0$3=GROUP)NTENSIVEBLOODGLUCOSECONTROLWITHSULPHONYLUREASORINSULINCOMPAREDWITHCONVENTIONALTREATMENTANDRISKOFCOMPLICATIONSINPATIENTS WITHTYPEDIABETES5+0$3 ,ANCETn "YTZER0 4ALLEY.* (AMMER* ETAL')SYMPTOMSINDIABETESMELLITUSAREASSOCIATEDWITHBOTH POORGLYCEMICCONTROLANDDIABETICCOMPLICATIONS!M*'ASTROENTEROLn 4ALLEY .* "YTZER 0 (AMMER * 9OUNG , *ONES - (OROWITZ - 0SYCHOLOGICAL DISTRESS IS LINKED TO GASTROINTESTINAL SYMPTOMS IN DIABETES MELLITUS !M * 'ASTROENTEROL n

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(YETT" -ARTINEZ&* 'ILL"- -EHRA3 ETAL$ELAYEDRADIONUCLEOTIDEGASTRICEMPTYINGSTUDIES PREDICTMORBIDITYINDIABETICSWITHSYMPTOMSOFGASTROPARESIS'ASTROENTEROLOGY n "ITYUTSKIY ,0 3OYKAN ) -C#ALLUM 27 6IRAL GASTROPARESIS A SUBGROUP OF IDIOPATHIC GASTROPARESIS CLINICAL CHARACTERISTICS AND LONG TERM OUTCOMES !M * 'ASTROENTEROL n (ASLER7 7ILSON, -AY+ 0ARKMAN( !BELL4 +OCH+ 3NAPE7 .GUYEN, -C#ALLUM2 0ASRICHA 0 &ARRUGIA ' 4ONASCIA * ,EE , 5NALP !RIDA ! (AMILTON & AND THE .)$$+ 'P#2#0OST INFECTIOUSGASTROPARESISDIFFERENCESINBASELINEANDCLINICALCHARACTERISTICSAND EVOLUTIONOFSYMPTOMSANDDISEASESEVERITYAFTERWEEKSVERSUSPATIENTSWITHOUTINFECTIOUS PRODROMES'ASTROENTEROLABSTRACT (EJAZI2! 3AROSIEK) 2OESER+ ETAL$OESGRADINGTHESEVERITYOFGASTROPARESISBASEDON SCINTIGRAPHICGASTRICEMPTYINGPREDICTTHETREATMENTOUTCOMEOFPATIENTSWITHGASTROPARESIS $IG$IS3CIn -C#ALLUM 2 ,IN : 7ETZEL 0 3AROSIEK ) &ORSTER * #LINICAL RESPONSE TO GASTRIC ELECTRICAL STIMULATION IN PATIENTS WITH POSTSURGICAL GASTROPARESIS #LIN 'ASTROENTEROL (EPATOL n

Chapter 9

Gastric Emptying Scintigraphy Alan H. Maurer

Keywords 'ASTRICEMPTYINGs3CINTIGRAPHYs2ADIOLABELEDSOLIDMEALs2ADIOLABELED liquid meal

Introduction $YSPEPTIC SYMPTOMS ARE CHARACTERIZED BY EARLY SATIETY POSTPRANDIAL FULLNESS NAUSEA VOMITING ABDOMINALDISTENTION ANDBLOATING4HETERMFUNCTIONALDYSPEPSIA USEDINTHEABSENCEOFOBSTRUCTIONORULCERS ISESTIMATEDTOAFFECTOFTHEPOPULATIONOFTHE53!;1=)NSPITEOFTHEDEVELOPMENTOFMANYNEWSCINTIGRAPHICAND NONSCINTIGRAPHICMETHODSFOREVALUATINGGASTROINTESTINAL') MOTILITY THEGASTRIC EMPTYINGSCINTIGRAPHY'%3 STUDYHASREMAINEDTHEMOSTRECOMMENDEDSTUDYFOR EVALUATINGPATIENTSWITHDYSPEPSIAFORSUSPECTED')DYSMOTILITY;2=4HISISINSPITE OFTHEFACTTHATDELAYED'%ISDOCUMENTEDINONLYnOFPATIENTSWITHDYSPEPSIA ANDTHESEVERITYOFDELAYED'%DOESNOTCORRELATEWELLWITHSYMPTOMS/THER') MOTORABNORMALITIES ALTEREDVISCERALSENSATIONANDPSYCHOSOCIALFACTORSHAVEBEEN SHOWNTOBEIMPORTANTFACTORSWHICHSHOULDALSOBECONSIDEREDINEVALUATINGPATIENTS WITHFUNCTIONALDYSPEPSIA;]. !'%3STUDYISINDICATEDFORPATIENTSWITHDYSPEPSIAAFTERANANATOMICCAUSEHAS BEENEXCLUDED!'%3STUDYMAYALSOBEINDICATEDFORPATIENTSWITHSEVEREGASTROESOPHAGEALREmUXDISEASENOTRESPONDINGTOACIDSUPPRESSANTS EVALUATINGADIABETIC WITHPOORGLYCEMICCONTROLORASAPARTOFWHOLE GUTTRANSITSCINTIGRAPHYFORIDENTIlCATION OF A hPAN MOTILITYv ') DISORDER ;4= -OST OFTEN THE GOAL OF IDENTIFYING DELAYED'%ISTOIDENTIFYWHICHPATIENTSWILLBENElTFROMAPROKINETICDRUGTOALLEVIATE SYMPTOMS;5]. !(-AURER*) $EPARTMENTOF2ADIOLOGY 4EMPLE5NIVERSITY(OSPITAL 0HILADELPHIA 0! 53! e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_9, © Springer Science+Business Media, LLC 2012

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4HE USE OF A RADIOLABELED MEAL REMAINS THE GOLD STANDARD FOR MEASURING '% /NCETHESOLIDORLIQUIDPHASEOFAMEALISCOMBINEDWITHARADIOISOTOPERADIOLABELED THERADIOACTIVECOUNTSDETECTEDBYTHENUCLEARMEDICINECAMERAAREDIRECTLY PROPORTIONAL TO THE VOLUME OF THE MEAL REMAINING INDEPENDENT OF ANY GEOMETRIC ASSUMPTIONSTYPICALLYNEEDEDFORESTIMATINGVOLUMEWITHOTHERIMAGINGMODALITIES 7HILEACONVENTIONALSINGLE HEADNUCLEARMEDICINEGAMMACAMERACANBEUSED FORIMAGING ONEWITHALARGElELDOFVIEWISPREFERRED$UAL HEADTWODETECTOR 30%#4CAMERASARENOWINCOMMONUSEANDPERMITSIMULTANEOUSANTERIORnPOSTERIOR IMAGING REQUIRED FOR DEPTH AND ATTENUATION CORRECTION 4HE TWO MOST COMMONLY USEDRADIOISOTOPESFORLABELINGSOLIDANDLIQUIDMEALSARE99m4CAND111)N4OIMAGE SOLIDS AND LIQUIDS SIMULTANEOUSLY THE CAMERA AND COLLIMATOR MUST BE CAPABLE OF SEPARATING THE LOWER KE6 SIGNAL OF 99m4C FROM THE HIGHER SIGNAL ENERGY KE6 OF111In. 7HICHRADIOPHARMACEUTICALISUSEDTOLABELTHEMEALDEPENDSONTHESTUDYTOBE PERFORMED&ORSOLID PHASE'%STUDIES 99m4CSULFURCOLLOID99m4C 3# LABELEDEGG is used. 99m4C 3#HASASHORTRADIOACTIVEDECAYHALFLIFEH WHICHLIMITSRADIATIONEXPOSUREANDWHENCOOKEDISTIGHTLYBOUNDTOEGGPROTEINSOTHATNORADIOACTIVEMATERIALISABSORBEDFROMTHE')TRACT4HISFURTHERREDUCESRADIATIONEXPOSURE &ORAM#IDOSEOF 99m4C 3# THEESTIMATEDTOTALEFFECTIVEDOSERECEIVEDBYTHE PATIENTISM3V;6]. 111)N DIETHYLENETRIAMINEPENTAACETICACID$40! ISUSUALLY GIVEN WITH WATER AS THE LIQUID COMPONENT OF THE MEAL )T IS ALSO NONABSORBABLE Because oral 111)N IS NOT APPROVED FOR ROUTINE CLINICAL USE IN THE 53! A SPECIAL BROAD SCOPE RADIOPHARMACEUTICAL LICENSE MAY BE REQUIRED FOR ITS USE &OR A M#I DOSE OF 111)N $40! THE ESTIMATED TOTAL EFFECTIVE DOSE RECEIVED BY THE PATIENTISM3V;6].

Patient Preparation 4HE STUDY SHOULD BE PERFORMED THE MORNING AFTER AN OVERNIGHT FAST 0ATIENTS ARE INSTRUCTEDTOTAKEREGULARMEDICATIONSWITHASMALLQUANTITYOFWATERBEFORECOMING FORTHETEST)NGENERAL THEREFERRINGPHYSICIANSHOULDDETERMINEIFTHEPATIENTISTO BESTUDIEDONOROFFANYMEDICATIONSTHATMAYAFFECTGASTRICEMPTYING!NYMEDICATIONDIRECTIONSSHOULDBEDIRECTLYCOMMUNICATEDTOTHEPATIENT4YPICALPROKINETIC AGENTS SUCHASMETOCLOPRAMIDE2EGLAN TEGASEROD:ELNORM ERYTHROMYCIN AND DOMPERIDONE-OTILIUM ARESTOPPEDTWODAYSPRIORTOTHETEST/PIATEANALGESICS SUCH AS DEMEROL CODEINE MORPHINE OXYCONTIN PERCODAN AND PERCOCET WHICH DELAYGASTRICEMPTYING SHOULDBESTOPPEDTWODAYSBEFORETHETEST!NTICHOLINERGIC AGENTS SUCHASBENTYL DONNATAL LEVSIN ANDROBINUL AREALSOSTOPPEDFORTWODAYS PRIORTOTHETEST4HEPHYSICIANINTERPRETINGTHEGASTRICEMPTYINGSTUDYSHOULDBE INFORMEDIFTHEPATIENTISTAKINGSUCHMEDICATIONS -ENSTRUATING FEMALES ARE PREFERABLY STUDIED DURING THE lRST DAYS OF THEIR MENSTRUALCYCLE$IABETICPATIENTSSHOULDSELFTESTANDMEASURETHEIRBLOODGLUCOSE

'ASTRIC%MPTYING3CINTIGRAPHY

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PRIORTOBEGINNINGTHESTUDY&ORINSULIN DEPENDENTPATIENTSORTHOSEWITHAHISTORY OF POOR GLYCEMIC CONTROL THE IMAGING CENTER SHOULD MEASURE THE BLOOD GLUCOSE -ARKEDHYPERGLYCEMIAGLUCOSEMGDL ISARELATIVECONTRAINDICATIONASITMAY SLOW GASTRIC EMPTYING )NSULIN DEPENDENT DIABETICS ARE USUALLY INSTRUCTED TO TAKE ONE HALFTHEIRNORMALINSULINDOSEJUSTPRIORTOTHETESTMEALANDTOSUPPLEMENTANY NEEDEDINSULINIMMEDIATELYAFTERCOMPLETIONOFIMAGING 3UBJECTSSHOULDBEINFORMEDTHATTHEYWILLBEINTHEIMAGINGFACILITYFORATLEAST HANDADVISEDTOBRINGABOOK AMUSICPLAYER OROTHERMATERIALTOOCCUPYTHEMFOR THEHOFTHESTUDY0ATIENTSSHOULDREFRAINFROMSMOKINGTHEMORNINGOFTHETEST ANDTHROUGHOUTTHETIMEOFIMAGING

The Test Meal .ORMALVALUESMUSTBEESTABLISHEDNOTONLYFORTHEMEAL BUTALSOFORTHEMETHOD USED FOR IMAGE ACQUISITION AND PROCESSING '% IS DEPENDENT ON BODY POSITION SMOKING GENDER PHASEOFTHEMENSTRUALCYCLE ANDONTHETIMEOFDAYTHETESTIS PERFORMED;7n9=.ORMALVALUESFORAVARIETYOFMEALS INCLUDINGMEAT PORRIDGE PANCAKES ANDEGGS HAVEBEENREPORTED&ORANYTESTMEAL THESTABILITYOFTHERADIOISOTOPEBOUNDTOTHESOLIDPHASEMUSTBEESTABLISHEDTOENSURETHATTHERADIOISOTOPE DOES NOT DISSOCIATE IN ACIDIC GASTRIC JUICE 7HEN 99m4C 3# IS INJECTED INTO A LIVE CHICKEN ITISPHAGOCYTOSEDBYTHE+UPFFERCELLSOFTHELIVERRESULTINGINANINTRACELLULARLYBOUNDRADIOLABELEDFOOD4HISMEALHASBEENTHEGOLDSTANDARDTOWHICHALL OTHERRADIOLABELEDSOLIDFOODSHAVEBEENCOMPARED "ECAUSEOFTHEEASEOFPREPARATION HIGHSTABILITYANDLARGENORMATIVEDATABASE SOLID PHASE '%STUDIESARENOWPERFORMEDWITH99m4C 3#LABELEDEGGWHITE!RECENT CONSENSUSREPORTHASRECOMMENDEDTHEUSEOFASTANDARDIZED SOLIDMEALCONSISTING OFM#IOF99m4C 3# GOFLIQUIDEGGWHITE%GG"EATERSÍOROTHERGENERICEGG WHITE SLICESOFWHITEWHEATBREAD GOFSTRAWBERRYJAM ANDMLOFWATER KCAL PROTEIN FAT CARBOHYDRATE lBER ;10=4HENORMALVALUES FORTHISMEALAREBASEDONTHELARGESTNUMBEROFNORMALSINCLUDEDINAMULTICENTER STUDY4HE AND HVALUESFORTHEPERCENTAGEOFTHEMEALRETAINEDAREVERYSIMILAR TOANOTHERPOPULARMEALCONSISTINGOFTWOLARGENATURALEGGS TWOPIECESOFWHITE TOAST ANDMLOFWATERKCAL FAT PROTEIN CARBOHYDRATE ;11]. 7ITH THE CURRENTLY CONSENSUS RECOMMENDED EGG WHITE MEAL '% IS ABNORMAL IF GREATERTHATOFTHEMEALISRETAINEDATHORGREATERTHANATH 4OPREPARETHEMEAL THELIQUIDEGGISPOUREDINTOACONTAINERANDMIXEDWITHTHE 99m 4C 3# 4HE EGG CAN BE COOKED EITHER SCRAMBLED ON A NONSTICK FRYING PAN OR MICROWAVED IN AN APPROPRIATELY SHIELDED CONTAINER 4HE EGG MIXTURE SHOULD BE STIRREDONCEORTWICEDURINGCOOKINGANDISCOOKEDUNTILITHASTHECONSISTENCYOFAN OMELETnMIN 4HEBREADISTOASTED*ELLYISSPREADONTHEBREAD5SUALLY ASANDWICHISMADEOFTHEJELLIEDBREADANDCOOKEDEGGHOWEVER THEEGGANDBREADCAN BESERVEDSEPARATELYWITHTHEWATER

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!PROLONGEDTIMEMIN FORMEALINGESTIONCANAFFECTTHEQUANTIlCATIONOF GASTRICEMPTYING4HEPATIENTISENCOURAGEDTOCONSUMETHEENTIRETESTMEALWITHIN nMIN&ORQUALITYCONTROL THENUCLEARMEDICINETECHNOLOGISTSHOULDRECORDHOW LONGITTAKESTHESUBJECTTOCONSUMETHEMEALANDHOWMUCHWASCONSUMED)FLESS THAN THE ENTIRE STANDARD MEAL IS INGESTED THE STUDY IS TECHNICALLY NONDIAGNOSTIC SINCEASMALLERMEALWILLEMPTYFASTERTHANTHEENTIRESTANDARDMEAL

Imaging Protocol and Image Analysis )MMEDIATELYAFTEREATINGTHEMEAL THEPATIENTISPOSITIONEDSTANDINGINFRONTOFTHE NUCLEARMEDICINECAMERA5PRIGHTIMAGINGISPREFERREDSINCESUPINEPOSITIONINGCAN SLOWGASTRICEMPTYINGOFSOLIDSEMPTYINGATHINASUPINEPOSITIONVERSUS INANUPRIGHTPOSITION ;12=&REQUENTIMAGEACQUISITIONISNEEDEDTOQUANTIFY ALAGPHASEANDTOACCURATELYQUANTIFYARATEOFEMPTYING4HESEAREPROBABLYUNNECESSARY FOR CLINICAL PURPOSES AND A SIMPLIlED STANDARD METHOD FOR SCREENING FOR ABNORMAL'%ISDESIREDBYTHEGASTROENTEROLOGISTS !SSOLIDSMOVEFROMTHEPOSTERIORLOCATEDFUNDUSTOTHEANTERIORANTRUM THEREIS ANINCREASEINMEASUREDCOUNTSASTHEDEPTHOFTHEMEALMOVESCLOSERTOACAMERA POSITIONEDINFRONTOFTHEPATIENT$EPTHATTENUATIONCORRECTIONISTHEREFORENEEDED #ORRECTIONUSINGTHEGEOMETRICMEANANTERIORCOUNTS¾POSTERIORCOUNTS 1/2 is most COMMONLYUSED4HISCORRECTIONRESULTSINONLYAnVARIATIONINCOUNTSFORTHE DEPTHSTYPICALLYENCOUNTERED&ORPATIENTSWHOCANNOTSTAND ASINGLELEFTANTERIOR OBLIQUE VIEW MAY BE USED ;1= "ETWEEN IMAGES PATIENTS ARE PERMITTED NORMAL DAILYACTIVITIESSITTING STANDING ORWALKING INTHENUCLEARMEDICINEWAITINGAREA USUALLYINCLOSEPROXIMITYTOTHEIMAGINGROOM 4HEIMAGESAREACQUIREDUSINGAKE699m4CPHOTOPEAKWITHAWINDOW %ITHERALOWENERGYALLPURPOSE,%!0 COLLIMATORORALOWENERGYHIGHRESOLUTION COLLIMATORCANALSOBEUSED#OMPUTERIZEDDIGITALIMAGESAREREQUIREDFORQUANTIlCATION4HESEAREACQUIREDINA¾WORD MODEMATRIX #OMPUTERREGIONSOFINTERESTCORRESPONDINGTOTHESTOMACHAREDElNEDTOOBTAIN THETOTALGASTRICCOUNTS-ANUALREGIONSOFINTERESTAREDRAWNONTHEANTERIORAND POSTERIORIMAGESFORALLACQUISITIONTIMESUSINGANIRREGULAR2/)TOOLTOOUTLINETHE STOMACH&IG9.1 4HETOTALGASTRIC2/)SHOULDINCLUDETHEFUNDUSANDANTRUMWITH PARTICULAR ATTENTION TO AVOID ANY LOOPS OF SMALL BOWEL IN CLOSE PROXIMITY TO THE STOMACH!NEXCEPTIONWOULDBEIFTHEPATIENTHASSMALLBOWELACTIVITYONTHElRST IMAGEORTHEREISRETAINEDESOPHAGEALACTIVITY4HEN THEENTIRElELDOFVIEWSHOULD BEUSEDSOTHATTIMEtMINIMMEDIATELYPOSTMEALINGESTION INCLUDESALLACTIVITY INGESTED4HEGEOMETRICMEANCORRECTEDCOUNTSFOREACHTIMEPOINTISCALCULATEDAND CORRECTEDFOR99m4CDECAY4HEGASTRICCOUNTSREMAININGATEACHTIMEARETHENGRAPHED ANDTHEPERCENTAGESOFACTIVITYREMAININGINTHESTOMACHARENORMALIZEDBASEDON TAKENASTHEINITIALMAXIMALGASTRICCOUNTS&IG9.1).


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Fig. 9.1 .ORMALSOLID PHASEIMAGESANDANALYSIS'ASTRICEMPTYINGSOFTWARESHOULDPERMITANALYSIS OF ALL ANTERIOR AND POSTERIOR 99m4C GASTRIC IMAGES left upper and lower panels TO CALCULATE THE GEOMETRICMEANANDDECAYCORRECTEDCOUNTSATlXEDTIMEINTERVALSAFTERMEALINGESTION4HERAW counts are plotted (open circles ASAFUNCTIONOFTIME4HELOWERTABLESINDICATEBOTHTHETOTAL corrected gastric counts (right lower table ANDTHEDERIVEDPERCENTAGEEMPTIEDleft lower table) FOREACHTIMEINTERVAL4HEPERCENTRETAINEDISMINUSTHEPERCENTEMPTIED4HESOLIDGASTRIC EMPTYINGCURVEISSIGMOIDALINSHAPEDUETOTHEEARLYLAGPHASEFORSOLIDS-ANYSOFTWAREPROGRAMS WILLALSOPERFORMACOMPUTERIZEDCURVElTsolid dots TOTHEDATATOCALCULATEAT1/2 emptying value. )N ADDITION TO THE QUANTITATIVE ANALYSIS THE IMAGES SHOULD BE REVIEWED TO LOOK FOR THE NORMAL PROGRESSIONOFSOLIDSFROMTHEFUNDUSdouble arrows TOTHEANTRUMsingle arrow 3OLIDSSHOULD INITIALLYLOCALIZEPRIMARILYINTHEFUNDUSREmECTINGNORMALFUNDALACCOMMODATION7ITHTIME THE SOLIDSMOVEDISTALLYINTOTHEANTRUM WHERETHEYARETRITURATEDANDTHENEMPTIED

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Test Interpretation and Reporting Results 5NDERSTANDINGTHEDIFFERENTROLESOFTHEFUNDUSANDANTRUMHASBECOMEINCREASINGLY IMPORTANTFORANALYZING'%STUDIES.ORMALLY SOLIDSARETEMPORARILYSTOREDINTHE FUNDUSUNTILSLOW SUSTAINEDCONTRACTIONSTRANSFERSOLIDSTOTHEANTRUM4HENORMAL EARLYSEGREGATIONOFSOLIDSINTHEFUNDUSISUSUALLYAPPARENTININITIALIMAGESOFA'% STUDY&IG9.1 !PERSISTENTTRANSVERSEBANDSEPARATINGTHEFUNDUSANDANTRUMIS COMMONLYOBSERVED3OLIDSTHENMOVEFROMTHEPOSTERIORLYLOCATEDFUNDUSTOTHE MOREANTERIORLYLOCATEDANTRUM!FTERTHESOLIDSAREINTHEANTRUM PERISTALTICCONTRACTIONSWORKBYAPROCESSCALLEDTRITURATION,INWHICHTHESOLIDSAREMIXEDWITH GASTRICDIGESTIVEJUICESANDAREGROUNDINTOPARTICLESOFnMM WHICHARETHENABLE TOPASSTHROUGHTHEPYLORUS4HECONTRACTILEACTIVITYOFTHEANTRUMISCONTROLLEDBYA PACEMAKERLOCATEDHIGHONTHEGREATERCURVATURE ATTHEBOUNDARYBETWEENTHEFUNDUS ANDTHEANTRUM4HETIMEREQUIREDTOCOMPLETETRITURATIONSOTHATSOLIDPARTICLESCAN THENBEGINTOEMPTYFROMTHESTOMACHISREFERREDTOASTHELAGPHASE. %MPTYINGOFLIQUIDSISCONTROLLEDBYASUSTAINEDPRESSUREGRADIENTGENERATEDBY THEFUNDUS,IQUIDSREQUIRENOTRITURATIONANDAREDISTRIBUTEDRAPIDLYAFTERINGESTION THROUGHOUTTHESTOMACHANDEMPTYINGMONOEXPONENTIALLY&IG9.2 ,IQUID'%CAN BEADEQUATELYDESCRIBEDBYASIMPLEHALF TIMET1/2 ORTHETIMETOEMPTYING 5NTILRECENTLY LIQUID'%STUDIESHAVEBEENCONSIDEREDOFLITTLECLINICALVALUEASLIQUID EMPTYINGWASBELIEVEDNOTTOBEABNORMALUNTILGASTROPARESISWASADVANCED;14]. 2ECENTSTUDIES HOWEVER HAVECREATEDRENEWEDINTERESTINLIQUIDGASTRICEMPTYING SHOWINGTHATLIQUIDEMPTYINGMAYBEABNORMALWHENSOLIDSARENORMALINUPTO PATIENTS;15]. 2ADIOLABELEDWATERMAYBEADMINISTEREDSIMULTANEOUSLYWITHRADIOLABELEDSOLIDS DURING'%SCINTIGRAPHYFOREVALUATION NOTONLYOFLIQUIDGASTRICEMPTYING BUTALSO ASPARTOFTHEMEASUREMENTOFSMALLBOWELTRANSITANDORWHOLEGUTTRANSIT7HOLEGUT TRANSITSTUDIESHAVEBEENSHOWNTOBEBENElCIALINTHECLINICALEVALUATIONOFPATIENTS WHOPRESENTWITHBOTHUPPERORLOWERGASTROINTESTINALSYMPTOMS;4]. Occasionally, a LIQUIDONLYSTUDYISUSEFULIFAPATIENTISUNABLETOTOLERATEASOLIDMEAL 4HESIMPLESTAPPROACHTOANALYZE'%DATAHASBEENTOREPORTEITHERTHETIMETO EMPTYINGOFTHEMEALT1/2 ORTOUSETHEPERCENTOFEMPTYINGMEASUREDATlXED TIMES AFTER MEAL INGESTION &IGS 9.1 and 9.2 5NTIL RECENTLY '%3 STUDIES WERE COMMONLYPERFORMEDUPTOHAFTERMEALINGESTION2ECENTSTUDIES HOWEVER HAVE SHOWNTHATTHEPERCENTRETAINEDATHISMOREREPRODUCIBLE;16] and detects more PATIENTSWITHABNORMAL'%;11=)TREMAINSIMPORTANT HOWEVER TOMEASUREBOTH EARLYPHASEnH GASTRICRETENTIONASWELLASLATEPHASEnH RETENTIONASITIS NOTUNCOMMONTOlNDABNORMALRETENTIONATHBUTNORMALRETENTIONATH&IG9.) ORNORMALATHBUTABNORMALATH&IG9.4). 4HESTUDYREPORTSHOULDALSOINCLUDEMENTIONOFTHEPRESENCEOFDELAYEDESOPHAGEALEMPTYINGWHICHMAYBEOBSERVEDWHENFOODISSEENINTHEDISTALESOPHAGUS ESPECIALLYINTHEINITIALIMAGESIMMEDIATELYPOSTMEALINGESTIONORTHEPRESENCEOF ANYGASTROESOPHAGEALREmUXTHATMAYBEOBSERVEDDURINGTHECOURSEOFTHESTUDY &IG9.5).


Fig. 9.2 .ORMALLIQUIDPHASEIMAGESANDANALYSIS!SFORSOLIDS THEANTERIORANDPOSTERIOR 111 )N LIQUID GASTRIC IMAGES ARE ANALYZED TO OBTAIN GEOMETRIC MEAN DECAY CORRECTED COUNTS 4HELIQUIDEMPTYINGCURVEISMONOEXPONENTIALSINCETHEREISNOLAGPHASEFORTHEONSETOFLIQUID EMPTYING,IQUIDSSHOULDDEMONSTRATEEARLYDIFFUSEDISTRIBUTIONOFLIQUIDSTHROUGHOUTTHESTOMACH WITHNOFUNDALACCOMMODATION

.UMEROUS STUDIES HAVE CONlRMED THE OCCURRENCE OF A LAG PHASE FOLLOWED BY EMPTYING DURINGWHICHTHESTOMACHEXPELSSOLIDSATACHARACTERISTICRATE;17n19]. 4OMORECOMPLETELYCHARACTERIZEALLPHASESOF'% ONECANlTTHEDATATOAMATHEMATIC FUNCTION SUCHASAMODIlEDPOWEREXPONENTIAL;20=WHICHISGIVENBY y(t ) 1 [1 exp( kt )]B WHEREy(t ISTHEPERCENTAGEOFGASTRICACTIVITYREMAININGATTIMEtkISTHESLOPE OFTHEEXPONENTIALPORTIONOFTHECURVEANDb (beta ISTHEyINTERCEPT&IG9.1).

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Fig. 9.3 !BNORMALEARLYSOLIDEMPTYINGANDFUNDALDYSMOTILITY4HEIMAGESnMIN SHOW NORMALFUNDALACCOMMODATIONWITHADELAYINEMPTYINGFROMTHEFUNDUS4HEREISAPPROXIMATELY RETAINEDEMPTIED ATMIN6ISUALLY THEREIS RETENTION OF THE LABELED MEAL IN THE FUNDUS double arrows /NCE THE MEAL HAS PROGRESSED TO THE ANTRUM single arrow) it empties NORMALLYWITHLESSTHANRETAINEDATMIN4HISISCONSISTENTWITHAPRIMARYMOTILITYDISORDER OFTHEFUNDUS)TISHELPFULIFTHISCANBECORRELATEDWITHEARLYPOSTPRANDIALSYMPTOMSOFBLOATING FULLNESS NAUSEA ANDABDOMINALPAIN

4HELAGPHASELNb (b e t a)/k CORRESPONDSTOTHETIMEOFPEAKACTIVITYINTHEANTRUM WHICHPHYSICALLYCORRESPONDSTOMAXIMALlLLINGOFTHEANTRUMJUSTBEFORETHETRITURATEDANDSUSPENDEDSOLIDSANDLIQUIDSBEGINTOEMPTYATAUNIFORMRATEk). Definition OFTHELAGPHASEHASBEENCONTROVERSIAL2ECENTDATASUGGESTMEASUREMENTOFTHELAG PHASEHASNOADDITIONALCLINICALVALUEOVERSIMPLEREPORTINGOFTHEPERCENTAGEOF GASTRICRETENTIONATANDH;21].


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Fig. 9.4 !BNORMALLATESOLIDEMPTYINGANDPRIMARYANTRALDYSMOTILITY4HEIMMEDIATEPOSTMEAL image (tMIN SHOWSNORMALFUNDALACCOMMODATIONdouble arrows 4HEREISAPPROXIMATELY RETAINEDATMINANDATMIN6ISUALLY THEMEALMOVESNORMALLYFROMTHEFUNDUS TOTHEANTRUM WHEREITISRETAINEDsingle arrow CONSISTENTWITHAPRIMARYMOTILITYDISORDEROFTHE antrum

Other Specialized Tests of Gastric Function $ELAYED '% IS FOUND IN A SIGNIlCANT NUMBER n BUT NOT ALL PATIENTS WITH DIABETESORFUNCTIONALDYSPEPSIA;=)TISINCREASINGLYRECOGNIZEDTHATOTHERSPECIAL STUDIES ARE NEEDED TO MORE COMPLETELY EVALUATE THE STOMACH INCLUDING SEPARATE FUNDALANDANTRALMOTORFUNCTION FUNDICRELAXATION VISCERALHYPERSENSITIVITY ASYNCHRONOUSANTRODUODENALCOORDINATION ANDGASTRICDYSRHYTHMIAS;22n24].

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Fig. 9.5 'ASTROESOPHAGEALREmUXANDDELAYEDGASTRICEMPTYING'ASTROESOPHAGEALREmUXMAYBE VISUALIZEDDURINGA'%STUDYsingle arrows 6ISUALIZEDACTIVITYINTHEESOPHAGUSMAYBEDUE EITHERTOESOPHAGEALRETENTIONFROMESOPHAGEALDYSMOTILITYORREmUX)NSUCHCASES ABARIUMSWALLOW MAYHELPDIFFERENTIATETHESETWOPOSSIBILITIES4HISPATIENT HOWEVER SHOWSINTERMITTENTEPISODES OFREmUXASSOCIATEDWITHAMARKEDDELAYIN'%RETAINEDATMIN

Bicompartmental (Fundal and Antral) Gastric Emptying 3INCESCINTIGRAPHYEASILYPERMITSANALYSISOFTHEINTRAGASTRICDISTRIBUTIONOFTHETEST MEAL BETWEEN THE FUNDUS AND ANTRUM IT IS IDEAL FOR MEASURING BOTH REGIONAL AND GLOBAL'%3TUDIESHAVESHOWNANASSOCIATIONBETWEENSYMPTOMSOFNAUSEA EARLY SATIETY ABDOMINALDISTENTION ANDACIDREmUXWITHPROXIMALGASTRICRETENTIONAND VOMITINGISASSOCIATEDMOREWITHDELAYEDDISTAL'%)NSPECTIONOFFUNDALANDANTRAL GASTRICEMPTYINGINTHEIMAGESANDQUANTIlCATIONOFREGIONALEMPTYINGCANBEHELPFUL


107

Fig. 9.6 !NTRAL CONTRACTION STUDY )N ORDER TO MEASURE THE AMPLITUDE AND FREQUENCY OF ANTRAL CONTRACTIONS IMAGES OF THE STOMACH a CAN BE ACQUIRED RAPIDLY MIN ONE SECOND PER FRAME "YPLACINGAREGIONOFINTERESTOVERTHEANTRUMleft arrows) (b THERESULTINGACTIVITYCURVECHARACTERIZESANTRALCONTRACTIONS4HESEDATAARETHENANALYZEDBY&OURIERANALYSISc TOMEASUREBOTH THEAMPLITUDEANDDOMINANTFREQUENCYOFANTRALCONTRACTIONS(Z

FOREXPLAININGDYSPEPTICSYMPTOMSESPECIALLYWHENGLOBAL'%VALUESARENORMAL ;25, 26= 2EGIONAL ANALYSIS OF '% CAN BE QUALITATIVELY ASSESSED AND SHOULD BE INCLUDEDASAPARTOFTHEINTERPRETATIONOF'%STUDIES&IGS9. and 9.4).

Antral Contraction Scintigraphy -ETHODSFORANALYZING'%DATAHAVEBEENDEVELOPEDWHICHPERMITANALYSISOFTHE FREQUENCYANDAMPLITUDEOFANTRALCONTRACTIONS.ORMALANTRALCONTRACTIONSOCCURAT ARATEOFTHREEPERMINUTE&IG9.6 )NDIABETICGASTROPARESIS '%ISDELAYEDDUENOT ONLYTORETENTIONOFFOODINTHEFUNDUS BUTALSOTODECREASEDSTRENGTHOFANTRALCONTRACTIONS;27=!MAJORITYOFPATIENTSWITHGASTROPARESISAREWOMENWITHUPTOAN PREDOMINANCEINONELARGESTUDY;28=$IFFERENCESINNORMALMALEANDFEMALE '%3HAVEBEENSHOWNTOBEDUETOTHEAMPLITUDEOFANTRALCONTRACTIONSANDNOTTHE FREQUENCY 5SING SCINTIGRAPHY TO MEASURE THE AMPLITUDE OF ANTRAL CONTRACTIONS WOMENHAVEBEENSHOWNTOHAVELOWERAMPLITUDECONTRACTIONSNOTASSOCIATEDWITH HIGHERPROGESTERONEDURINGTHELUTEALLATE PHASEOFTHEMENSTRUALCYCLE;29].

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Fig. 9.7 30%#4$GASTRICACCOMMODATIONSTUDY4HESE$IMAGESDEMONSTRATETHECONTRACTED STATEOFTHESTOMACHPRIORTOAGASTRICEMPTYINGMEAL!TMIN THEREISAMARKEDINCREASEINTHE VOLUMEOFTHEGASTRICFUNDUSACCOMMODATION 'ASTRICDILATATIONMAYPERSISTTOHINSPITEOFTHE CONTINUALGASTRICEMPTYINGOFTHESOLIDS

Fundal Accommodation Studies &UNDAL RELAXATION ACCOMMODATION IS A WELL ESTABLISHED PHYSIOLOGIC RESPONSE WHICHALLOWSTHESTOMACHTOINCREASEDINTRAGASTRICVOLUMEWITHOUTINCREASEDINTRAGASTRICPRESSURE4HEBAROSTATISTHECURRENTREFERENCEMETHODTOASSESSACCOMMODATIONBUTHASBEENCRITICIZEDASINVASIVEANDNONPHYSIOLOGIC;0]. In addition to IMAGINGTECHNIQUES NUTRIENTORWATERLOADINGTESTSHAVEALSOBEENUSEDTOASSESS GASTRIClLLINGCAPACITYANDSENSATIONVISCERALHYPERSENSITIVITY 3INCE THE GASTRIC MUCOSA ACCUMULATES 99m4C PERTECHNETATE AFTER INTRAVENOUS ADMINISTRATION THISPERMITS$30%#4VOLUMETRICIMAGINGOFTHEWALLOFTHESTOMACH 4HISHASBEENVALIDATEDASANONINVASIVEMETHODTOMEASUREGASTRICVOLUMESPRIOR TOAMEALANDATANYTIMEAFTERMEALINGESTION;1, 2=&IG9.7 )TISALSOPOSSIBLE TO SIMULTANEOUSLY ASSESS THE RELATIONSHIP OF LIQUID OR SOLID MEAL EMPTYING AND GASTRICACCOMMODATION3UCHSTUDIESHAVESHOWNMAXIMALGASTRICVOLUMECHANGE MEAN OCCURS IMMEDIATELY AFTER MEAN INGESTION AND PERSISTS IN SPITE OF RELATIVELYRAPIDEMPTYINGOFTHEMEAL;]. )TISEXPECTEDTHATMETHODSTOMEASUREGASTRICACCOMMODATIONWILLBEOFCLINICAL VALUE TO STUDY PATIENTS WITH DYSPEPSIA AND NORMAL '% PARAMETERS AND MAY HELP DIRECTMEDICALTHERAPY

Pediatric Gastric Emptying $ELAYED'%MAYBESUSPECTEDININFANTSUNDERYEARSOFAGEWHOHAVEVOMITING ABDOMINALPAIN OREARLYSATIETY)NINFANTS '%SCINTIGRAPHYISUSUALLYPERFORMED COMBINEDWITHEVALUATIONFOR'%2WITHTHEPATIENTSMILKORFORMULAFEEDINGTO WHICH 99m4C 3#ISADDED5NFORTUNATELY THEREISLESSCONSENSUSONHOWPEDIATRIC '%STUDIESSHOULDBEPERFORMEDANDNORMALVALUESFOR'%FORINFANTSFORVARIOUS


109

MEALS HAVE NOT BEEN ESTABLISHED (OWEVER A RANGE OF GASTRIC RETENTION BETWEEN ANDATHHASBEENREPORTEDANDISINGENERALUSE;4]. )NCHILDREN THEhMILKSCANvISUSEDTOEVALUATENOTONLY'% BUTALSOPOTENTIAL GASTROESOPHAGEAL REmUX AND PULMONARY ASPIRATION 0RIOR STUDIES WHICH COMPARED SCINTIGRAPHY WITH SIMULTANEOUS P( PROBE MONITORING REPORTED A SENSITIVITY AND SPECIlCITY OF AND RESPECTIVELY )N RECENT STUDIES SCINTIGRAPHY FOUND AN INCIDENCE OF REmUX RANGING FROM TO IN CHILDREN FROM LESS THAN YEAR TO YEARSOFAGE;5]. 99m 4C 3#ISMIXEDWITHTHECHILDSUSUALVOLUMEOFMILK FORMULA APPLEJUICE OR GLUCOSEWATERANDISGIVENATTHETIMEOFROUTINEFEEDING)MAGESARERECORDEDAFTER THEFEEDINGISCOMPLETED!HIGH SENSITIVITYCOLLIMATORISRECOMMENDEDTOINCREASE COUNTINGEFlCIENCY)NITIALSWALLOWINGCURVESARERECORDEDTOEVALUATEESOPHAGEAL TRANSIT7ITHTHEPATIENTPLACEDSUPINEANDDIRECTLYONTHECAMERA POSTERIORIMAGES OFTHECHESTANDABDOMENAREOBTAINEDFORATLEASTMIN;6=6ISUALCINEREVIEW OFCOMPUTER ENHANCEDIMAGESINCREASESSENSITIVITYFORDETECTINGSMALLVOLUMESOF REmUX4IME ACTIVITYCURVESAREHELPFULTODOCUMENTTHEFREQUENCYOFREmUX DELAYED ESOPHAGEAL CLEARANCE AND TO IMPROVE REPRODUCIBILITY IN THE READINGS ;7]. Rapid IMAGINGnSIMAGE ISIMPORTANTBECAUSETRANSIENTREmUXCANRAPIDLYDISSIPATE $ELAYEDIMAGESAT ANDHCANBEACQUIREDTODETECTPULMONARYASPIRATION 0ULMONARYASPIRATIONISDOCUMENTEDWITHTHISMETHODINnOFCHILDRENWITH SEVEREPULMONARYDISEASE;8].

Conclusion .EWSTANDARDSFORPERFORMINGRADIOISOTOPE SOLIDPHASEGASTRICEMPTYINGSTUDIESIN ADULTSHAVEBEENESTABLISHEDWHICHNOWPERMITMOREREPRODUCIBLEANDCOMPARABLE RESULTSBETWEENIMAGINGCENTERS4HEREISINCREASINGRECOGNITION HOWEVER THATTHE MEASUREMENTOFGASTRICRETENTIONFROMASOLID MEALGASTRICEMPTYINGSTUDYMAYNOT BESUFlCIENTTOEXPLAINALLPATIENTSSYMPTOMS4HEREISINCREASINGEVIDENCETHAT SEPARATEANALYSISOFFUNDALANDANTRALFUNCTIONASWELLASTHEMEASUREMENTOFLIQUID GASTRIC EMPTYING MAY IMPROVE OUR ABILITY TO DETECT GASTRIC MOTOR DYSFUNCTION IN SYMPTOMATICPATIENTS0EDIATRICGASTRICEMPTYINGSTUDIESREMAINLESSWELLSTANDARDIZED 4HEREARENOWELL DElNEDSTANDARDS ANDTHEIRINTERPRETATIONISSTILLUSUALLYBASEDON LOCALLYESTABLISHEDCRITERIA

References 0ARKMAN(0 (ASLER7 &ISHER2!MERICAN'ASTROENTEROLOGICAL!SSOCIATIONMEDICALPOSITION STATEMENTDIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGYn ,IN( 0RATHER# &ISHER2 ETAL-EASUREMENTOFGASTROINTESTINALTRANSIT!-34ASK&ORCE #OMMITTEEON'ASTROINTESTINAL4RANSIT $IG$IS3CI n

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4HUMSHIRN-0ATHOPHYSIOLOGYOFFUNCTIONALDYSPEPSIA'UT3UPPLIn "ONAPACE%3 -AURER!( $AVIDOFF3 +REVSKY" &ISHER23 0ARKMAN(07HOLEGUTTRANSIT SCINTIGRAPHY IN THE CLINICAL EVALUATION OF PATIENTS WITH UPPER AND LOWER GASTROINTESTINAL SYMPTOMS!M*'ASTROENTEROL n &ELDMAN- 3MITH(*%FFECTOFCISAPRIDEONGASTRICEMPTYINGOFINDIGESTIBLESOLIDSINPATIENTS WITHGASTROPARESISDIABETICORUM'ASTROENTEROLOGYn $ONOHOE+ -AURER! :IESSMAN( 5RBAIN* 2OYAL( -ARIN #OMIN*0ROCEDUREGUIDELINE FORADULTSOLID MEALGASTRICEMPTYINGSTUDY*.UCL-ED4ECHNOLn $ATZ & #HRISTIAN 0 -OORE * 'ENDER RELATED DIFFERENCES IN GASTRIC EMPTYING * .UCL -ED n 'ILL2 -URPHY0 (OOPER( "OWES+ +INGMA9%FFECTOFTHEMENSTRUALCYCLEONGASTRIC EMPTYING$IGESTIONn +NIGHT ,# 0ARKMAN (0 "ROWN +, ET AL $ELAYED GASTRIC EMPTYING AND DECREASED ANTRAL CONTRACTILITYINNORMALPREMENOPAUSALWOMENCOMPAREDWITHMEN!M*'ASTROENTEROL n 4OUGAS' %AKER%9 !BELL4, ETAL!SSESSMENTOFGASTRICEMPTYINGUSINGALOWFATMEAL ESTABLISHMENTOFINTERNATIONALCONTROLVALUES!M*'ASTROENTEROL n 'UO*0 -AURER!( &ISHER23 0ARKMAN(0%XTENDINGGASTRICEMPTYINGSCINTIGRAPHYFROM TWOTOFOURHOURSDETECTSMOREPATIENTSWITHGASTROPARESIS$IG$IS3CI n -OORE *' $ATZ &, 'REENBERG #% !LAZRAKI . %FFECT OF BODY POSTURE ON RADIONUCLIDE MEASUREMENTSOFGASTRICEMPTYING$IG$IS3CI n -AURER!( +NIGHT,# 6ITTI2! 3IEGEL*! +REVSKY" #HARKES.$'EOMETRICMEANVSLEFT ANTERIOROBLIQUEATTENUATIONCORRECTIONAFFECTONHALFEMPTYINGTIME LAGPHASE ANDRATEOF GASTRICEMPTYING*.UCL-ED #OUTURIER/ "ODET -ILIN# 1UERELLOU3 #ARLIER4 4URZO! "IZAIS9'ASTRICSCINTIGRAPHY WITHALIQUID SOLIDRADIOLABELLEDMEALPERFORMANCESOFSOLIDANDLIQUIDPARAMETERS.UCL-ED #OMMUN n :IESSMAN( !NKIT# #LARKE* 2AMOS! 7AHL24HEADDEDVALUEOFLIQUIDGASTRICEMPTYING COMPAREDWITHSOLIDEMPTYINGALONE*.UCL-EDn #REMONINI & $ELGADO !ROS 3 4ALLEY .* &UNCTIONAL DYSPEPSIA DRUGS FOR NEW AND OLD THERAPEUTICTARGETS"AILLIERES"EST0RACT2ES#LIN'ASTROENTEROL n #AMILLERI- -ALAGELADA*2 "ROWN-, "ECKER' :INSMEISTER!22ELATIONBETWEENANTRAL MOTILITY AND GASTRIC EMPTYING OF SOLIDS AND LIQUIDS IN HUMANS !M * 0HYSIOL 'n #OLLINS 0* (OROWITZ - #HATTERTON "% 0ROXIMAL DISTAL AND TOTAL STOMACH EMPTYING OF A DIGESTIBLESOLIDMEALINNORMALSUBJECTS"R*2ADIOLn 5RBAIN*, 3IEGEL*! #HARKES.$ -AURER!( -ALMUD,3 &ISHER234HETWO COMPONENT STOMACHEFFECTSOFMEALPARTICLESIZEONFUNDALANDANTRALEMPTYING%UR*.UCL-ED n 3IEGEL *! 5RBAIN *, !DLER ,0 ET AL "IPHASIC NATURE OF GASTRIC EMPTYING 'UT n :IESSMAN( "ONTA$ 'OETZE3 2AVICH7%XPERIENCEWITHASIMPLIElED STANDARDIZED HOUR GASTRIC EMPTYINGPROTOCOL*.UCL-EDn $ELGADO !ROS3 #AMILLERI- #REMONINI& &ERBER) 3TEPHENS$ "URTON$#ONTRIBUTIONSOF GASTRIC VOLUMES AND GASTRIC EMPTYING TO MEAL SIZE AND POSTMEAL SYMPTOMS IN FUNCTIONAL DYSPEPSIA'ASTROENTEROLOGY n 3ARNELLI' #AENEPEEL0 'EYPENS" *ANSSENS*3YMPTOMSASSOCIATEDWITHIMPARIEDGASTRIC EMPTYING OF SOLIDS AND LIQUIDS IN FUNCTIONAL DYSPEPSIA !M * 'ASTROENTEROL n 3COTT! +ELLOW* 3HUTER" ETAL)NTRAGASTRICDISTRIBUTIONANDGASTRICEMPTYINGOFSOLIDSAND LIQUIDSINFUNCTIONALDYSPEPSIA$IG$IS3CIn 'ONLACHANVIT3 !RONCHICK2 +ANTOR3 -AURER! &ISHER2 0ARKMAN(2EGIONALGASTRIC EMPTYING ABNORMALITIES IN NONULCER DYSPEPSIA AND GASTROESOPHAGEAL REmUX DISEASE !M *'ASTROENTEROLn


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Chapter 10

Wireless Motility Capsule in Gastroparesis Rita Brun and Braden Kuo

Keywords #APSULE TECHNOLOGY s 'ASTROINTESTINAL TRACT s 'ASTROINTESTINAL TRANSIT s%LECTRONICRADIOTELEMETRYCAPSULE

Introduction Capsule technology has opened up a new era in the evaluation of the gastrointestinal tract, being an alternative to more invasive conventional methods. The intricate activity of gastrointestinal transit is coordinated by the motor function of the stomach, small intestine, and colon. The concept of a swallowable electronic radiotelemetry capsule dates back to the 1950s [1, 2]. The Heidelberg capsule had been used to measure pH inside the gastrointestinal tract and the GI transit times in the late 1980s [3, 4]. However, the Heidelberg capsule was not widely clinically available. Recently, there has been a reemergence of capsule technology, devices able to provide internal physiologic parameters as video, pressure, pH, and temperature. Assessment of GI transit times by wireless motility capsule (WMC) is one of the first important clinical applications of this new technology.

B. Kuo (*) Massachusetts General Hospital/Harvard Medical School, Gastrointestinal Unit, Boston, MA 02114, USA e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_10, © Springer Science+Business Media, LLC 2012

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Wireless Motility Capsule Procedure Description Wireless Motility Capsule The WMC (SmartPill, The SmartPill Corporation, Buffalo, NY, USA) is a wireless device able to evaluate whole gut and regional gut transit and motility. The capsule houses sensors for pH, temperature, and pressure and transmits the data to a receiver worn by the subject during ambulatory monitoring. The WMC is 13 mm across and ·26 mm long. The capsule and receiver have battery lives rated for 5 days. pH is accurate to within 0.5 pH units and pressure is accurate to ±5 mmHg. After completion of the test, data is downloaded to a computer from the data receiver through a docking station and analyzed using pressure analysis software (GIMS 1.8; The Smart Pill Corporation) Fig. 10.1.

Wireless Motility Capsule Test After overnight fasting, the patient ingests a standard eggbeaters sandwich meal with a total caloric value of (255 kcal, 72% carbohydrate, 24% protein, 2% fat, and 2% fiber) or granola bar [SmartBar] (260 kcal, 62% carbohydrate, 18% protein, 2.2% fat, 3 g fiber), followed by the patient swallowing the WMC with 50 cc of water. Patients do not eat or drink for the next 6 h. Six hours after capsule ingestion, PATIENTS CONSUME ML %NSURE AND WATER AD LIBITUM !FTER THE SECOND MEAL patients may resume their diet routine. At 120 h postingestion, patient returns with the data receiver and diary.

Fig. 10.1 SmartPill System (a) and SmartPill Capsule (b)

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Indications for Use The SmartPill system is FDA approved for the following indications: %VALUATIONOFGASTRICEMPTYINGTIME'%4 INPATIENTSWITHSUSPECTEDGASTROPAresis or delayed gastric emptying and those with idiopathic and diabetic gastroparesis and functional nonulcer dyspepsia. %VALUATION OF COLONIC AND 7'44 OR COMBINED SMALL AND LARGE BOWEL TRANSIT time in chronic constipation and differentiate slow versus normal transit.

Interpretation of the Results Gastric Emptying Time.4HE'%4ISTHETIMEDIFFERENCEBETWEENCAPSULEINGESTION and an abrupt rise of pH to >4 or at least a rise in 3 pH units above baseline. Patients are advised to stop proton pump inhibitors (PPIs) for 7 days prior to the test and histamine type 2 antagonists for 3 days prior to the test. For patients treated WITH00)SANDHAVEDIFlCULTYSTOPPINGTHESEMEDICATIONS MODIlED'%4CRITERIA may be considered based on the study of subjects treated with 40 mg of esomeprazole twice daily. Using the sudden sustained pH increase of >0.6 pH-units, the PATTERN FOR '%4 WITH 7-# WAS IDENTIlABLE IN ALL PATIENTS TAKING 00)S ;16]. However, if possible, it is better to be off acid suppression medications during the test to prevent confusion because the pH transition is much less pronounced between the stomach and small bowel. Small Bowel Transit Time (SBTT). SBTT is defined as the time interval between the pH rise in the proximal duodenum to a more than 1 unit pH drop in the cecum that LASTEDFORATLEASTMIN.ORMALSUBJECTSHADAMEAN'%4OFÕH MEANSMALL bowel and large bowel transit time of 25 ± 14 h and mean WGTT of 29.4 ± 14.3 h [5]. Colonic Transit Time (CTT) and Whole Gut Transit Time (WGTT). The CTT is defined as the time interval between capsule entry into the cecum and the temperature drop from 98°C as well as signal loss representing exit of capsule from the body, and the WGTT as the time interval between capsule ingestion and capsule exit from the body.

Physiologic Basis of Definition of GET by WMC After overnight fast and ingestion of the standard meal, the patients swallow the capsule. This order of actions resets the gastric motility pattern by starting the postprandial pattern and thus ensuring the functional recalibration of the GI tract.

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Ingesting the WMC after the meal allows standardization of the emptying times measured by device. The gastric emptying occurs in the following order: first the fluid empties, then the solid meal empties, and finally emptying of indigestible objects, such as WMC mediated by high amplitude contractions or MMC [6, 7]. As a result of this phenomena, 5 h cut off for normal gastric emptying measured by WMC as an indigestible particle is used, compared with 4 h cut off for radioactive meals [8]. Meal ingestion before capsule ingestion ensures that capsule stays in the stomach during the initial part of the study to measure the gastric emptying of a meal and helps to prevent its premature emptying from an MMC during the fasting state. Attempts to measure the GI transit times using the capsule video endoscopy are reported [9]. The test is performed in fasting state; otherwise, the food will obscure the landmarks. During fasting, MMC cycle is activated in GI tract every approximately 90 min [10]. If the capsule is ingested during the fasting state which is the typical protocol for wireless video capsules, capsule emptying from the stomach into the small intestine occurs randomly depending on the timing of the ingestion relative to the MMC cycle. This unpredictability disrupts any standardization of gastric emptying time. Severe cases of gastroparesis probably will be captured by capsule endoscopy. However, this method does not allow having quantitative information.

Diagnosis of Gastroparesis with WMC The use of WMC for diagnosis of gastroparesis was evaluated in the study on 87 healthy and 61 gastroparetic subjects (based on clinical symptoms and previous '%3DOCUMENTINGDELAYEDGASTRICEMPTYING 4HESUBJECTSUNDERWENTSIMULTANEOUS WMC monitoring and gastric emptying scintigraphy. In fasted state, they ingested capsule and [99mTc]-SC radio-labeled meal. Scintigraphic images were obtained EVERYMINFORH'%4ANDPERCENTAGEOFMEALREMAININGATANDHWERE determined for each subject. As can be seen by Fig. 10.2a, b, the scintigraphic meal empties almost completely before the emptying of the capsule. Correlation between '%4AND'%3 HWASAND'%3 HWAS4HE MINH CUT OFFTIME FOR'%4HADSENSITIVITYOFANDSPECIlCITYOFFORTHEDIAGNOSISOFGASTROPARESIS4HECORRESPONDINGSENSITIVITYbSPECIlCITYFORANDHSTANDARD'%3MEASURES were 0.34⁄0.93 and 0.44⁄0.93, respectively. This study demonstrated that WMC is able to discriminate between normal gastric transit time and gastroparesis, and it is a reliable test with good specificity/sensitivity ratio with the 5 h cut off time, increasing specificity of diagnosis [8] Table 10.1, Fig. 10.2a, b.

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Fig. 10.2 (a, b) Relationship between scintigraphic emptying of a meal (gastric emptying scintigraphy) and gastric emptying time of the capsule. The magenta tracing and axis on the left show the percent meal remaining over time. The green tracing and axis on the right show pH as measured by the capsule. The pH tracing shows the pH changes induced by the meal in the first hour followed by reacidification of gastric pH. (a) Healthy subject. The emptying of the meal OCCURSALMOSTCOMPLETELYBYH%MPTYINGOFTHECAPSULEOCCURSATABOUTHNORMALLIMITH when the pH rapidly changes more than 3 pH units from the acidic gastric pH to the alkaline duodenum pH. (b) Gastroparetic subject shows more than 10% of the meal remaining at 4 h with the emptying of the capsule at 5.5 h. [8]. (c 7-#TRACINGINAHEALTHYSUBJECT'%4H d) WMC TRACINGINAGASTROPARETICPATIENT'%4H .OTICETHELOWAMPLITUDEANTRALCONTRACTIONS

Table 10.1 Correlation OF'%3HAND'%3HWITH GASTRICEMPTYINGTIME'%4 by WMC along with sensitivity and specificity values [8]

Gastric emptying 7-# '%4 parameter correlation Sensitivity Specificity '%3H 0.63 0.34 0.93 '%3H 0.73 0.44 0.93 '%4 n/aa 0.65 0.87 GES gastric emptying scintigraphy, GET gastric emptying time, WMC wireless motility capsule a Not applicable

WMC Data About Other Physiologic Parameters in Gastroparesis In addition to the assessment of gastric emptying time, WMC data provides other interesting insights into gastroparesis pathophysiology, by measuring various physiologic parameters as whole GI transit times, contractile activity during fasting and

118 Table 10.2 Median values of motility parameters for healthy vs. gastroparetic subjects [11]

R. Brun and B. Kuo Stomach Small bowel Ct/h MI Ct/h MI Normal 72 11.83 145 12.78 Gastroparesis 47 11.12 93 12.12 p = 0.01 p = 0.02 p = 0.02 p = 0.04 Ct frequency of contractions, MI motility index

fed state, and pH profiles. Further characterization of dysmotility in gastroparetic patients could help in understanding of underlining pathophysiology and developing appropriate treatments.

Contractions Patterns and Intraluminal Pressure in Health and Gastroparesis The phasic pressure profiles of the stomach and small intestine were compared in 71 healthy and 42 gastroparetic subjects. Significant differences were observed between healthy and gastroparetic subjects for frequency of contractions (Ct) and motility index (MI) (P -EDIANVALUESOFTHEMOTILITYPARAMETERSINGASTRICWINDOW were Ct = 72, MI = 11.83 for healthy and Ct = 47, MI = 11.12 for gastroparetics. In the small bowel, median values were Ct = 144.5, MI = 12.78 for healthy and Ct = 93, MI = 12.12 for gastroparetics. The 5th percentile of normals was 29/h for Ct and 9.82 for MI. 4HECORRELATIONBETWEEN'%4ANDFREQUENCYWASONLYPARTIALFROMGASTROPARETIC PATIENTSWHOHADA'%4H HADABNORMALLOWGASTRICCONTRACTILITY SUGGESTING that contractile and transit abnormalities can occur independently. On the other HAND OF THE SEVERE GASTROPARETICS WITH PROLONGED H '%4 HAD GASTRIC frequencies below the 5% of normal. Diabetic subjects with gastroparesis showed significantly lower Ct and MI compared with healthy subjects in both gastric and small bowel windows while idiopathic gastroparetic subjects did not show significant differences. The WMC was able to differentiate between healthy and gastroparetic subjects based on gastric and small bowel motility profiles [11]. Interestingly, studies of antral motility using imaging modalities as the US and MRI have also showed decreased antral motility in gastroparesis [12, 13]. These findings suggest that the emptying time is important in the understanding of pathophysiology of gastroparesis, however other factors, as altered pressure characteristics contribute further to the diverse clinical picture of gastroparesis. Table 10.2, Fig. 10.2c, d.

Regional GI Tract Transit Times The regional gut transit times in healthy controls and patients with gastroparesis were investigated using wireless motility technology. A total of 66 healthy controls

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and 34 patients with GP (15 diabetic and 19 idiopathic) swallowed WMC together with standardized meal [13= '%4 COLON TRANSIT TIME #44 AND 7'44 BUT NOT SBTT were significantly longer in GP than in controls. Median WGTT in healthy was 27.7 (25th percentile = 22.9 h, 75th percentile = 34.3 h). Median WGTT in gastroparetics was 45.9 h (25th percentile = 30.0 h, 75th percentile = 59.0 h), p = 0.0001. Median SBTT in healthy was 4.6 h (25th percentile = 4.0 h, 75th percentile = 5.9 h). Median SBTT in gastroparetics was 4.5 h (25th percentile = 3.6 h, 75th percentile = 5.5 h), p%IGHTEENPERCENTOFGASTROPARETICPATIENTSHADDELAYED7'44 Both diabetic and idiopathic etiologies of gastroparetics had significantly slower WGTT (P INADDITIONTOSIGNIlCANTLYSLOWER'%4THANHEALTHYCONTROLS Diabetic gastroparetics additionally had significantly slower CTT than healthy controls (P = 0.0054). The prolongation of CTT and WGTT indicates that dysmotility beyond the stomach in is present in gastroparesis, and it could contribute to symptoms presentation [14].

pH Profiles Gastric pH profiles were found to be different in gastroparesis of different etiologies and varying degrees of gastric stasis compare to healthy stomach in the study by Hasler et al. Sixty-four healthy control subjects and 44 gastroparesis patients (20 diabetic, 24 idiopathic) underwent simultaneous WMC and gastric scintigraphy off any acid suppression treatment. Basal pH was higher in diabetic (3.64 ± 0.41) vs. control subjects (1.90 ± 0.18) and idiopathic subjects (2.41 ± 0.42; P = 0.05). Meals evoked initial pH increases that were greater in diabetic (4.98 ± 0.32) than idiopathic patients (3.89 ± 0.39; P = 0.03) but not control subjects (4.48 ± 0.14). pH nadirs prior to gastric capsule evacuation were higher in diabetic patients (1.50 ± 0.23) than control subjects (0.58 ± 0.11; P = 0.003). Compared with control subjects, those with moderate–severe stasis (>20% retention at 4 h) had higher basal (3.91 ± 0.55) and nadir pH (2.2 ± 0.42) values (P = 0.05). Both diabetic and idiopathic patients with moderate–severe gastroparesis exhibited increased pH parameters vs. those with mild gastroparesis. Diabetic patients with gastroparesis exhibit reduced gastric acid, an effect more pronounced in those with severely delayed gastric emptying. Idiopathic gastroparetic subjects exhibit nearly normal acid profiles, although those with severely delayed emptying show reduced acid vs. those with mild delays. Thus, both etiology and degree of gastric stasis determine gastric acidity in gastroparesis [15]. Another study compared small bowel pH in gastroparetic and healthy subjects. '0HADSIGNIlCANTLYHIGHERMEANGASTRICP(BEFORE'%4p ANDALSOSIGNIlcantly more alkaline pH (p THROUGHOUT THE ENTIRE SMALL BOWEL ;16]. The increased small bowel pH of gastroparetic patients may imply that the rate at which acid is delivered from the stomach into the duodenum is slower than in healthy population. Although the SBTT is not affected, the change in SB pH may impact the absorption of nutrients, drug metabolism and might be predisposing to bacterial overgrowth; those factors may further impair GI motility in gastroparetic patients.

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Clinical Use and Implications of WMC Testing The information obtained by WMC contributes to our understanding of gastroparesis and can pave the way for more rational therapeutic choices to optimize clinical management. Documentation of extremely prolonged capsule retention in the stomach (e.g., more than 24 h) helps to recognize the most severe cases which fall far beyond traditional 4 h assessment available by scintigraphy. At the same manner, lack or very low contractile activity of the stomach may help to evaluate the degree of gastric motor function impairment. Measurement of gastric and small bowel pressures are not easily available with conventional techniques, such as gastroduodenal manometry, and this new modality can noninvasively collect such measurements in the stomach and small bowel. The new data obtained by WMC as very prolonged stomach capsule retention and very low contractility may help to identify the most severe cases which imply early aggressive management of those selected patients with J tube feeding or gastric pacing. 4HEDISCORDANCEBETWEENGASTRICEMPTYINGSCINTIGRAPHY'%3 AND7-#ASSESSment of gastric motility is another interesting issue. Some patients might have normal GASTRICEMPTYINGBY'%3ANDABNORMALGASTRICEMPTYINGBY7-# ANDVICEVERSA %ACHMODALITYASSESSESDIFFERENTPHYSIOLOGICFUNCTIONSOFTHESTOMACH '%3MEASURES the emptying of the meal, and WMC measures the emptying of indigestible particles. The WMC test also indirectly measures the meal emptying because capsule empties only after the meal was emptied. Scintigraphy alone cannot assess the emptying of indigestible particles and recognize this phenomenon. Various upper GI physiologic parameters can be measured noninvasively in gastroparetic patients and not all the patients may have the same defects contributing to their symptoms. Different pathophysiologies may explain why correlation of symptoms with a single parameter may be poor [17]. Another advantage is that the information about whole GI and regional transit times can be defined with the single test, which could be especially relevant in gastroparetic patients. Coexistent constipation is not uncommon in this patients’ group and quantitative data about small bowel and colonic motility is helpful while choosing appropriate treatment and nutritional access [14].

Summary WMC has good sensitivity and specificity diagnosing gastroparesis and could serve AN ALTERNATIVE TO '%3 IN APPROPRIATE CASES PROVIDING STANDARDIZED AMBULATORY noninvasive, nonradiation, and convenient way to assess gastric and small bowel motility. Additional data that provided by this multisensor device gives us important new insights into the pathophysiology of gastroparesis and potentially can make clinical management of these patients more efficient.

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References 1. Hopkins HH. A flexible fibrescope, using static scanning. Nature. 1954;173(4392):39–41. -ACKAY23 *ACOBSON"%NDORADIOSONDE.ATURE n 9ARBROUGHRD$2 ETAL%VALUATIONOFTHE(EIDELBERGP(CAPSULE-ETHODOFTUBELESSGASTRIC analysis. Am J Surg. 1969;117(2):185–92. 4. Mojaverian P, et al. Gastrointestinal transit of a solid indigestible capsule as measured by radiotelemetry and dual gamma scintigraphy. Pharm Res. 1989;6(8):719–24. 5. Sarosiek I, et al. SmartPill as a novel nonscintigraphic, ambulatory method for assessing GI transit. Gastroenterology. 2006;130(4 Suppl 1):A741. 6. Mojaverian P, et al. Mechanism of gastric emptying of a nondisintegrating radiotelemetry capsule in man. Pharm Res. 1991;8(1):97–100. 7. Cassilly D, et al. Gastric emptying of a non-digestible solid: assessment with simultaneous SmartPill pH and pressure capsule, antroduodenal manometry, gastric emptying scintigraphy. Neurogastroenterol Motil. 2008;20(4):311–9. 8. Kuo B, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. 2008;27(2):186–96. 9. Nakamura M, et al. Advance of video capsule endoscopy and the detection of anatomic landmarks. Hepatogastroenterology. 2009;56(96):1600–5. 10. Sarna SK. Cyclic motor activity; migrating motor complex: 1985. Gastroenterology. 1985; 89(4):894–913. 11. Kloetzer L, et al. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol Motil. 22(5):527–33, e117. 12. Sogabe M, et al. Ultrasonographic assessment of gastric motility in diabetic gastroparesis before and after attaining glycemic control. J Gastroenterol. 2005;40(6):583–90. 13. Ajaj W, et al. Real time high resolution magnetic resonance imaging for the assessment of gastric motility disorders. Gut. 2004;53(9):1256–61. 14. Sarosiek I, et al. The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology. Aliment Pharmacol Ther. 31(2):313–22. 15. Hasler WL, et al. Differences in intragastric pH in diabetic vs. idiopathic gastroparesis: relation to degree of gastric retention. Am J Physiol Gastrointest Liver Physiol. 2008;294(6): G1384–91. 16. Michalek W, Bucur MC, McCallum R, Koch KL, Sitrin MD, Chey WD, Hasler WL, Parkman HP, Rao SS, Semler JR, Kuo B. A comparison of small bowel pH profiles in healthy subjects and patients with gastroparesis as measured by a non-invasive wireless capsule. DDW 2009 Program Page 842, W1234. 17. Lee A, Michalek W, Kuo B, and The SmartPill Trial Group. Variable upper GI tract pathophysiological motility in gastroparesis. American Neurogastroenterology and Motility Society 2009 Program, page 73, Abstract #241

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Chapter 11

Breath Tests for Assessment of Gastric Emptying Henry P. Parkman and Lawrence A. Szarka

Keywords 'ASTROPARESISs'ASTRICEMPTYINGs3CINTIGRAPHYs2ADIATIONEXPOSURE s.ONRADIOACTIVEISOTOPEBREATHTESTING

Introduction 0ATIENTSAREOFTENEVALUATEDFORGASTRICMOTILITYDISORDERS SUCHASGASTROPARESISBY MEASURINGGASTRICEMPTYING&ORNEARLYYEARS SCINTIGRAPHYHASBEENCONSIDERED THE MAIN TEST FOR MEASURING GASTRIC EMPTYING AND DOCUMENTING DELAYED GASTRIC EMPTYING4HEREAREAVARIETYOFWAYSTOMEASUREGASTRICEMPTYINGWITHSCINTIGRAPHY WITHMARKEDVARIATIONSINTHETYPEOFMEALANDDURATIONOFIMAGING#LINICALLY ITIS BESTTOMEASURETHEEMPTYINGOFSOLIDSBECAUSELIQUIDEMPTYINGCANOFTENBENORMAL WHENSOLIDEMPTYINGISMARKEDLYDELAYED;1=2ECENTLY ITHASBECOMEAPPARENTTHAT PROLONGINGTHE'%3FORHMAYIMPROVETHEDIAGNOSTICUTILITYOFTHETEST;2, 3]. (OWEVER INSTITUTIONSPERFORMTHETESTINDIFFERENTWAYSWITHREGARDSTOMEALCONTENT IMAGINGINTERVALS ANDLENGTHOFTEST4HESEDIFFERENCESINPERFORMANCEOFGASTRIC EMPTYING SCINTIGRAPHY AT DIFFERENT INSTITUTIONS HAVE MADE THIS TEST LESS HELPFUL IN CLINICALSETTINGS3CINTIGRAPHYISALSOLIMITEDBYSEVERALDRAWBACKS INCLUDINGRADIATION EXPOSURE EXPENSIVEEQUIPMENT ANDTHELIMITEDAVAILABILITYOFFACILITIES4HUS THERE HASBEENGREATINTERESTINDEVELOPINGALTERNATIVESFOREFFECTIVEMEASUREMENTOFGASTRIC EMPTYINGINASTANDARDIZEDFASHION/NESUCHALTERNATIVEISNONRADIOACTIVEISOTOPE BREATHTESTING

H.P. Parkman (*) 'ASTROENTEROLOGY3ECTION 4EMPLE5NIVERSITY3CHOOLOF-EDICINE 0HILADELPHIA 0! 53! E MAILHENRYPARKMAN TEMPLEEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_11, © Springer Science+Business Media, LLC 2012

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(00ARKMANAND,!3ZARKA

Breath Tests for Gastric Emptying 3TABLENONRADIOACTIVEISOTOPEBREATHTESTSFORGASTRICEMPTYINGREPRESENTAPROMISING WAYTOEVALUATEGASTRICEMPTYINGNONINVASIVELY4HESEBREATHTESTS ALTHOUGHINITIALLY DEVELOPED WITH RADIOACTIVE # NOW USE NONRADIOACTIVE 13# LABELED SUBSTANCES ; 5="REATHTESTINGISANINDIRECTMEASUREOFGASTRICEMPTYINGTHEPROlLEOF13CO2 EXCRETIONISUSEDTOESTIMATETHEHALF LIFEOFGASTRICEMPTYING;6] since gastric empTYINGISTHERATELIMITINGSTEPINTHEPULMONARYEXCRETIONOFINGESTED13# SUBSTANCES ! PATIENTS GASTRIC EMPTYING CAN BE CALCULATED BY MEASURING THE EXPIRATION OF LABELEDCARBONDIOXIDEINBREATHSAMPLESWHICHRESULTSFROMTHEBREAKDOWNOFTHE 13 # LABELEDSUBSTRATE4HEPRESENCEOF13CO2INTHEBREATHARISESFROMTHEDIGESTION ANDABSORPTIONOFTHE13# LABELEDSUBSTRATEINTHEGUTLUMENANDlNALLYITSMETABOLISM INTHEBODY4HE13CO2ISTHEENDPRODUCTOFMETABOLISMANDISEXHALED4HEOPTIMAL METHODSUSEDBYLABORATORIESTOMATHEMATICALLYMODELTHEGASTRICEMPTYINGPROCESS CONTINUETOBERElNEDSINCETHEORIGINAL PIONEERINGWORKOF'HOOSETAL;]. -ANYSTUDIESHAVESHOWNTHATTHISTESTISCOMPARABLETOGASTRICEMPTYINGSCINTIGRAPHY13# BREATHTESTSCANBEUSEDTOTESTPATIENTSINAGASTROENTEROLOGYPRACTICE THE COMMUNITY OR EVEN AT A PATIENTS BEDSIDE AREAS WHERE GAMMA CAMERA FACILITIES ARENOTREADILYAVAILABLE"REATHSAMPLESCANBEPRESERVEDANDSHIPPEDTOACENTRAL LABORATORYFORANALYSIS -OSTGASTRICEMPTYINGBREATHTESTING'%"4 ISPERFORMEDFORCLINICALRESEARCH ANDPHARMACEUTICALSTUDIES SINCEITISNOTYET&$!APPROVEDFORCLINICALUSE4HE INDICATIONFORTHE'%"4ISTHEEVALUATIONOFGASTRICEMPTYINGINAPATIENTSUSPECTED OFHAVINGAGASTRICMOTILITYDISORDERAFTERUPPERENDOSCOPYANDORARADIOGRAPHIC UPPERGASTROINTESTINALSERIESHAVEEXCLUDEDGASTRICOUTLETOBSTRUCTION

Types of Breath Tests for Gastric Emptying 4HEREARESEVERAL13# LABELEDSUBSTRATESUSEDTOMEASUREGASTRICEMPTYING INCLUDING octanoic acid, glycine, acetic acid, and most recently Spirulina platensis4HECHOICE OFSUBSTRATEDEPENDSONWHETHERTHEPHYSICIANISMEASURINGTHEGASTRICEMPTYINGOF SOLIDS OR LIQUIDS 13C-glycine and 13# ACETIC ACID ARE BEST USED FOR MEASURING THE LIQUIDPHASEOFGASTRICEMPTYING;7, 8= WHEREAS13C-octanoic acid and 13C-S. platensis AREPREFERREDTOASSESSGASTRICEMPTYINGOFSOLIDS;9, 10=&ORTHEDETERMINATIONOF GASTROPARESIS MEASURINGTHEGASTRICEMPTYINGOFSOLIDSISMORESENSITIVEBECAUSE LIQUIDEMPTYINGMAYREMAINNORMALEVENINPATIENTSWITHADVANCEDDISEASE 4HEREARESEVERALTYPESOFBREATHTESTSAVAILABLEFORCLINICALRESEARCH0RESENTLY THESETESTSARENOT&$!APPROVEDFORCLINICALEVALUATIONOFPATIENTS)NGENERAL THERE ARETWOTYPESOFBREATHTESTSAVAILABLEINTHE53! THESTANDARD CLASSIC13# LABELED OCTANOATE AMEDIUM CHAINTRIGLYCERIDE ISBOUNDINTOASOLIDMEAL SUCHASAMUFlN ; 10, 11=AND 13#BOUNDTOEDIBLEALGAES. platensis) administered as part of ANEGGMEAL;12=&OREACHTEST PATIENTSSHOULDDISCONTINUEMEDICATIONSTHATMAY AFFECTGASTRICEMPTYINGFORHBEFORETHETEST ANDFASTOVERNIGHTFORH ANDREFRAIN FROMSMOKINGDURINGTHETEST

"REATH4ESTSFOR!SSESSMENTOF'ASTRIC%MPTYING

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Octanoate Breath Test # LABELEDOCTANOATE AMEDIUM CHAINTRIGLYCERIDE ISBOUNDINTOASOLIDMEAL SUCH ASANEGGMEALORAMUFlN!FTERINGESTIONANDSTOMACHEMPTYING 13C-octanoate is ABSORBEDINTHESMALLINTESTINEANDMETABOLIZEDTO 13CO2 WHICHISTHENEXPELLED FROMTHELUNGSDURINGRESPIRATION4HERATE LIMITINGSTEPFOREXCRETIONOF13C is usually GASTRICEMPTYINGANDNOTPOSTGASTRICEMPTYINGPROCESSING;=4HUS BYMEASURING THEAMOUNTOF13#INBREATHSAMPLES GASTRICEMPTYINGISINDIRECTLYDETERMINED4HE OCTANOATEBREATHTEST/"4 HASBEENSHOWNTOBEREPRODUCIBLEANDCORRELATEWITH '%3INNORMALSUBJECTS ASWELLASPATIENTS;6–8]. It also appears useful for intrainDIVIDUAL TREATMENT COMPARISONS ;13= 4HE HALF EMPTYING TIME OF SOLIDS USING THE /"4SIGNIlCANTLYACCELERATESINBOTHPATIENTSANDCONTROLSWITHTHEADMINISTRATION OFPROKINETICAGENTS;1]. 4HEGASTRICMOTILITYBREATHTEST'-"4 AVAILABLETHROUGH-ETABOLIC3OLUTIONS )NC USESANEASYTOPREPARE LOWFATMUFlNMEALCALORIES WHICHISLABELED WITH13# OCTANOATE;11, 15=4HEBREATHSAMPLESARECOLLECTEDEVERYMINOVERH 4HESEBREATHSAMPLESAREANALYZEDUSINGAGASISOTOPERATIOMASSSPECTROMETERTO ANALYZETHERATIOOF 13CO2/12CO24HE 13#ENRICHMENTISEXPRESSEDASTHEDELTAPER MILLILITERDIFFERENCEBETWEENTHE 13CO2/12CO2RATIOOFTHESAMPLEANDTHESTANDARD 4OCALCULATETHEQUANTITYOF13#APPEARINGINBREATHPERUNITTIME DELTAOVERBASELINE $/" ISUSED;16=4HEPERCENTDOSERECOVEREDPERHOURANDTHECUMULATIVEPERCENT DOSECURVESAREMODELEDACCORDINGTOTHEORIGINAL NONLINEARREGRESSIONMETHODOF 'HOOSETAL;=.ORMALVALUESFOR4 AREnMIN 13

Spirulina Gastric Emptying Breath Test # CAN BE INCORPORATED INTO THE EDIBLE BLUE GREEN ALGAE S. platensis BY SPECIAL CULTIVATIONTECHNIQUESS. platensisISNONTOXIC ANDITISUSEDASAFOODSOURCEAND NUTRITIONALSUPPLEMENTINMANYPARTSOFTHEWORLD;17=4HE13#LABELEDS. platensis ISUSUALLYADMINISTEREDASPARTOFANEGGMEALGIVINGREPRODUCIBLE13CO2-kinetics in BREATHREmECTINGGASTRICEMPTYING ! STANDARDIZED 13C-S. platensis '%"4 THAT IS EASY TO PREPARE IN A MICROWAVE OVENISAVAILABLETHROUGH!DVANCED"REATH$IAGNOSTICS ,LCANDCONSISTSOFMG 13 C-S. platensis GFREEZE DRIEDEGGMIX SALTINECRACKERS ANDM,OFWATER !FTER INGESTION BREATH SAMPLES ARE BE COLLECTED AT JUST A FEW lXED TIME POINTS ( MIN 4HESAMPLESCANBEMAILEDTOAREFERENCELABORATORYFORMASS SPECTROMETRYTODETERMINETHE13CO2/12CO2RATIOINTHESAMPLES4HECURRENTLYPREFERRED'%"4METRICISTHEPERCENTDOSEABBREVIATED0#$ EXCRETEDATTIMEt after CONSUMPTIONOFTHETESTMEAL 4HERE ARE DIFFERENT MATHEMATICAL ANALYSES USED TO DERIVE GASTRIC BREATH TEST EMPTYINGPARAMETERS;18=4HEANALYSISPROPOSEDBY'HOOSETALREQUIRESASTEADY STATEINTHE13CO2EXCRETIONTOHAVEBEENACHIEVEDBYTHEENDOFTHEBREATHCOLLECTION OTHERWISE THIS NEEDS TO BE ESTIMATED )N MANY INSTANCES PARTICULARLY IN PATIENTS 13

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WITHSEVERELYDELAYEDGASTRICEMPTYING THISCANBEOVERESTIMATEDLEADINGTOERRATIC PERFORMANCEOFTHEMATHEMATICMODELINGFOR'%"4;18=-ULTIPLEMATHEMATICAL ANALYSISMETHODSHAVEBEENPROPOSEDFORTHEINTERPRETATIONOFTHEBREATHTESTMETRICS ; 19–21= BUTTHELINEARREGRESSIONMETHODHADTHEHIGHESTCONCORDANCECORRELATION COEFlCIENTWITHSCINTIGRAPHICT1/2;18].

Performance Characteristics of Breath Tests )NTRA ANDINTERINDIVIDUALVARIATIONSOFMEASUREMENTSOF'%WITHTHE 13C-octanoic ACID '%"4 WERE NOT SIGNIlCANTLY DIFFERENT FROM THE VARIATIONS OBSERVED WITH SCINTIGRAPHY;9]. 4HEINTRAINDIVIDUALVARIATIONSFORSCINTIGRAPHYANDTHE13C-Spirulina'%"4WERE HIGHLYCOMPARABLEWITHINnDIFFERENT ATALLTIMEPOINTSFROMTOMININ HEALTHYSUBJECTS)NTERINDIVIDUALVARIATIONSATEACHTIMEFORTHE'%"4ANDSCINTIGRAPHY WERETYPICALLYABOUTnHIGHERTHANINTRASUBJECT#/6S;12=!SCOMPAREDWITH DETAILEDSCINTIGRAPHYOVERAPERIODOFH THE13C-Spirulina'%"4UTILIZINGTIME POINTSAT ANDMINHASASENSITIVITYOFANDSPECIlCITYOFFOR DETECTINGDELAYEDGASTRICEMPTYING ANDASENSITIVITYOFANDSPECIlCITYOF FORDETECTINGACCELERATEDGASTRICEMPTYING;12]. 3EVERAL STUDIES UTILIZING THE 13# OCTANOIC ACID AND THE 13C –S. platensis BASED BREATHTESTSHAVEDOCUMENTEDTHEEFFECTOFPHARMACOLOGICALAGENTSONTHEGASTRIC EMPTYINGPARAMETERSINHEALTHANDDISEASES SUCHASDIABETESMELLITUS;20, 22].

Pitfalls and Common Artifacts in Breath Testing 4HE 13C-containing S. platensis UNDERGOES INTRALUMINAL DIGESTION BEFORE MUCOSAL ABSORPTION HEPATIC METABOLISM AND PULMONARY EXCRETION "REATH TESTS ASSUME GASTRIC EMPTYING IS THE RATE LIMITING STEP IN A BODYS HANDLING OF THE INGESTED 13 # SUBSTRATEHOWEVER INSOMEDISEASESTATESITISPOSSIBLE THATOTHERSTEPSMAY BECOMERATELIMITING)NTHEVALIDATIONSTUDIESOFTHESTANDARDIZED 13C-S. platensis '%"4 SUBJECTSWHOHADAHISTORYOFMALABSORPTIONDUETOMUCOSALDISEASE PANCREATIC DISEASE ORLIVERDYSFUNCTIONWEREEXCLUDED/CTANOICACIDHASTHEADVANTAGETHATIT IS ABSORBED DIRECTLY FROM THE INTESTINAL LUMEN WITHOUT UNDERGOING DIGESTION AND postgastric emptying processing of 13# OCTANOICACIDDOESNOTSEEMTOBEAFFECTEDBY LIVER KIDNEY ORLUNGDISEASE;23, 2=!RTIFACTSTHATMAYAFFECTBOTHTHE13C-octanoic ANDTHE 13C-SpirulinaBREATHTESTSINCLUDEFACTORSTHATALTERTHEENDOGENOUSCARBON DIOXIDEPRODUCTIONANDEXCRETION SUCHASEXERCISE THYROIDDISEASE ANDFEVER 7HENINTERPRETINGANYGASTRICEMPTYINGSTUDY ITISIMPORTANTTOBEAWARETHAT MANYMEDICATIONS ASWELLASHYPERGLYCEMIAWHICHCANDELAYGASTRICEMPTYINGAND lead to improper diagnosis. 4HEBESTTIMEINTERVALSFORBREATHSAMPLINGANDTHEIDEALLENGTHOFTHETESTARENOT CLEAR-OREFREQUENTBREATHSAMPLINGOVERAPROLONGEDDURATIONH MAYINCREASE


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THE SENSITIVITY AND SPECIlCITY OF THE TEST IN DETECTING GASTROPARESIS HOWEVER THIS OFTENINCONVENIENCESTHEPATIENT PHYSICIAN ANDANCILLARYSTAFFTHATHASTOPERFORM THETEST3TUDIESBY#AMILLERIETAL;10=HAVEREDUCEDTHENUMBEROFBREATHSAMPLES NEEDEDTOASSESSGASTRICEMPTYING BUTTHESERESULTSARESPECIlCTOTHESTANDARDIZED 13 C-S. platensis'%"4

Use of Results in Patient Management "OTHTHE13C-S. platensis and 13# OCTANOICACIDBREATHTESTSAREPROMISINGASNONINVASIVE ACCESSIBLETESTSTHATCOULDEMERGEASWIDELYAVAILABLEANDACCEPTABLESCREENING tests for gastric motility disorders. 'ASTRICEMPTYINGRATEDOESNOTCORRELATEWELLWITHSYMPTOMSANDISPOORLYPREDICTIVE OF THERAPEUTIC RESPONSES TO PROKINETIC AGENTS ;25, 26= !N ABNORMAL GASTRIC EMPTYINGTESTSUGGESTS BUTDOESNOTPROVE THATTHESYMPTOMSARECAUSEDBYGASTROparesis or accelerated gastric emptying. 3TABLEISOTOPEBREATHTESTINGHASSEVERALADVANTAGESOVERGAMMASCINTIGRAPHY THEGOLDSTANDARDMETHODFORMEASURINGGASTRICEMPTYING INCLUDINGTHEABSENCEOF RADIATIONEXPOSURE!DDITIONALLY ONLYLIMITEDTRAININGISREQUIREDTOADMINISTERTHE BREATHTESTRESULTSARENOTOPERATORINDEPENDENT4HEBREATHTESTCANALSOBEADMINISTEREDINVIRTUALLYANYLOCATION FACILITATINGASSESSMENTATTHEBEDSIDE INTHECLINIC INUNDERSERVEDAREAS ORATDIFFERENTSITESINMULTICENTERRESEARCHSTUDIES4HEMAJOR DISADVANTAGEOFTHE'%"4WITH13C-S. platensisISTHENEEDFORNORMALSMALLINTESTINALDIGESTION(OWEVER THEMULTIPLEADVANTAGESOFSTABLEISOTOPEBREATHTESTING MAKEITVERYAPPEALINGFORTHEINCORPORATIONINTOCLINICALPRACTICE

Conclusions # '%"4ARESIMPLE SAFE RADIATIONFREE ANDVALIDATEDTESTFORASSESSING'%4HEY AREPRESENTLYUSEDPRIMARILYFORCLINICALRESEARCHIN%UROPEANDTHE53!4HEYARE USEDCLINICALLYINSOMECENTERSIN%UROPE BUTARENOTPRESENTLYAVAILABLEFORCLINICAL USEINTHE53! 13

References !BELL4 #AMILLERI- $ONOHOE+ ETAL#ONSENSUSRECOMMENDATIONSFORGASTRICEMPTYING SCINTIGRAPHYAJOINTREPORTOFTHE!MERICAN.EUROGASTROENTEROLOGYAND-OTILITY3OCIETYAND THE3OCIETYOF.UCLEAR-EDICINE!M*'ASTROENTEROLn #AMILLERI- :INSMEISTER!2 'REYDANUS-0 ETAL4OWARDSALESSCOSTLYBUTACCURATETESTOF GASTRICEMPTYINGANDSMALLBOWELTRANSIT$IG$IS3CIn 'UO*0 -AURER!( &ISHER23 0ARKMAN(0%XTENDINGGASTRICEMPTYINGSCINTIGRAPHYFROM TWOTOFOURHOURSDETECTSMOREPATIENTSWITHGASTROPARESIS$IG$IS3CIn

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'HOOS 9& -AES "$ 'EYPENS "* -YS ' (IELE -) 2UTGEERTS 0* ET AL -EASUREMENT OF GASTRIC EMPTYING RATE OF SOLIDS BY MEANS OF A CARBON LABELED OCTANOIC ACID BREATH TEST 'ASTROENTEROLOGYn -AES"$ 'HOOS9& 2UTGEERTS0* (IELE-) 'EYPENS" 6ANTRAPPEN'; #=OCTANOICACID BREATH TEST TO MEASURE GASTRIC EMPTYING RATE OF SOLIDS $IG $IS 3CI 3UPPL 3n3 ,EE *3 #AMILLERI - :INSMEISTER !2 ET AL 4OWARD OFlCE BASED MEASUREMENT OF GASTRIC EMPTYINGINSYMPTOMATICDIABETICSUSING#/CTANOICACIDBREATHTEST!M*'ASTROENTEROL n "RADEN" !DAMS3 $UAN,0 /RTH+( -AUL&$ ,EMBCKE" ETAL4HE;#=ACETATEBREATH TEST ACCURATELY REmECTS GASTRIC EMPTYING OF LIQUIDS IN BOTH LIQUID AND SEMISOLID TEST MEALS 'ASTROENTEROLOGYn -AES"$ 'HOOS9& 'EYPENS"* -YS' (IELE-) 2UTGEERTS0* ETAL#OMBINEDCARBON GLYCINECARBON OCTANOICACIDBREATHTESTTOMONITORGASTRICEMPTYINGRATESOFLIQUIDSAND SOLIDS*.UCL-EDn -AES"$ 'EYPENS"* 'HOOS9& (IELE-) 2UTGEERTS0*# /CTANOICACIDBREATHTESTFOR GASTRICEMPTYINGRATEOFSOLIDS'ASTROENTEROLOGYn #HOI-' #AMILLERI- "URTON$$ :INSMEISTER!2 &ORSTROM,! .AIR+32EPRODUCIBILITY AND SIMPLIlCATION OF # OCTANOIC ACID BREATH TEST FOR GASTRIC EMPTYING OF SOLIDS !M *'ASTROENTEROLn "ROMER-1 +ANTOR3. 7AGNER$! +NIGHT,# -AURER!( 0ARKMAN(03IMULTANEOUS MEASUREMENTOFGASTRICEMPTYINGWITHASIMPLEMUFlNMEALUSING# OCTANOATEBREATHTEST ANDSCINTIGRAPHYINNORMALSUBJECTSANDPATIENTSWITHINDYSPEPTICSYMPTOMS$IG$IS3CI n 3ZARKA,! #AMILLERI- 6ELLA! "URTON$ "AXTER+ 3IMONSON* ETAL!STABLEISOTOPE BREATHTESTWITHASTANDARDMEALFORABNORMALGASTRICEMPTYINGOFSOLIDSINTHECLINICANDIN RESEARCH#LIN'ASTROENTEROL(EPATOLn #HOI-' #AMILLERI- "URTON$$ ETAL13# /CTANOICACIDBREATHTESTFORGASTRICEMPTYING OF SOLIDS ACCURACY REPRODUCIBILITY AND COMPARISON WITH SCINTIGRAPHY 'ASTROENTEROLOGY n $UAN,0 "RADEN" #ASPARY7& ETAL)NmUENCEOFCISAPRIDEONGASTRICEMPTYINGOFSOLIDSAND LIQUIDSMONITOREDBY13#BREATHTESTS$IG$IS3CIn #HEY 7$ 3HAPIRO " :AWADSKI ! ET AL 'ASTRIC EMPTYING CHARACTERISTICS OF A NOVEL # OCTANOATE LABELEDMUFlNMEAL*#LIN'ASTROENTEROLn +LEIN0$ -ALATY(- #ZINN3* %MMONS3# -ARTIN& 'RAHAM$9.ORMALIZINGRESULTSOF # UREA BREATH TESTING FOR #/2 PRODUCTION RATES IN CHILDREN * 0EDIATR 'ASTROENTEROL .UTR n $ILLON*# 0HUC!0 $UBACQ*0.UTRITIONALVALUEOFTHEALGA3PLATENSIS7ORLD2EV.UTR$IET n /DUNSI34 #AMILLERI- 3ZARKA,! :INSMEISTER!2/PTIMIZINGANALYSISOFSTABLEISOTOPE BREATH TESTS TO ESTIMATE GASTRIC EMPTYING OF SOLIDS .EUROGASTROENTEROL -OTIL 706–38. 3ZARKA,! #AMILLERI- 6ELLA! ETAL!STABLEISOTOPEBREATHTESTWITHASTANDARDMEALFOR ABNORMALGASTRICEMPTYINGOFSOLIDSINTHECLINICANDINRESEARCH#LIN'ASTROENTEROL(EPATOL n 6IRAMONTES"% +IM$ 9 #AMILLERI- ETAL6ALIDATIONOFASTABLEISOTOPEGASTRICEMPTYING TESTFORNORMAL ACCELERATEDORDELAYEDGASTRICEMPTYING.EUROGASTROENTEROL-OTIL n 3ANAKA- 5RITA9 3UGIMOTO- 9AMAMOTO4 +UYAMA9#OMPARISONBETWEENGASTRICSCINTIGRAPHYANDTHE;#= ACETATEBREATHTESTWITH7AGNERn.ELSONANALYSISINHUMANS#LIN%XP 0HARMACOL0HYSIOLn 6ELLA ! ,EE *3 #AMILLERI - ET AL %FFECTS OF PRAMLINTIDE AN AMYLIN ANALOGUE ON GASTRIC EMPTYINGINTYPEANDDIABETESMELLITUS.EUROGASTROENTEROL-OTILn


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+ELLER* !NDRESEN6 7OLTER* ,AYER0 #AMILLERI-)NmUENCEOFCLINICALPARAMETERSONTHE RESULTSOF# OCTANOICACIDBREATHTESTSEXAMINATIONOFDIFFERENTMATHEMATICALMODELSINA LARGEPATIENTCOHORT.EUROGASTROENTEROL-OTIL nE VANDE#ASTEELE- ,UYPAERTS! 'EYPENS" &EVERY* 'HOOS9 .EVENS&/XIDATIVEBREAKDOWN OF OCTANOIC ACID IS MAINTAINED IN PATIENTS WITH CIRRHOSIS DESPITE ADVANCED DISEASE .EUROGASTROENTEROL-OTIL n *IIAN2 $UCROT& 2USKONE! ETAL3YMPTOMATIC RADIONUCLIDEANDTHERAPEUTICASSESSMENT OF CHRONIC IDIOPATHIC DYSPEPSIA ! DOUBLE BLIND PLACEBO CONTROLLED EVALUATION OF CISAPRIDE $IG$IS3CIn *ANSSENS * 0EETERS 4, 6ANTRAPPEN ' ET AL )MPROVEMENT OF GASTRIC EMPTYING IN DIABETIC GASTROPARESISBYERYTHROMYCIN0RELIMINARYSTUDIES.%NGL*-EDn

Chapter 12

Ultrasonography for Evaluation of Patients with Suspected Gastroparesis Karen L. Jones, Diana Gentilcore, Trygve Hausken, and Odd Helge Gilja

Keywords 'ASTROPARESIS s 5LTRASONOGRAPHY s 'ASTRIC EMPTYING s 'ASTRIC MOTOR function

Introduction 5LTRASONOGRAPHYREPRESENTSARELATIVELYSIMPLE NON INVASIVE INEXPENSIVEANDREADILY AVAILABLETECHNIQUEFORTHEASSESSMENTOFGASTROINTESTINALMOTORFUNCTIONWHICHHAS THECAPACITYTOASSESSSTRUCTURALANDFUNCTIONALABNORMALITIES7HILESCINTIGRAPHY REMAINSTHEhGOLDSTANDARDvFORTHEMEASUREMENTOFGASTRICEMPTYING ITISASSOCIATEDWITHARADIATIONBURDENANDREQUIRESEXPENSIVEEQUIPMENT4WODIMENSIONAL $ ULTRASONOGRAPHYISNOWUSEDCLINICALLYTOQUANTIFYGASTRICEMPTYING!RGUABLY OFGREATERSIGNIlCANCEISTHATTHEUSEOFULTRASONOGRAPHYHASALSOPROVIDEDFUNDAMENTALINSIGHTSINTOTHEPATHOPHYSIOLOGYOFDISORDEREDGASTRICMOTORFUNCTIONnIT HASBEENUSEDTOEVALUATEGASTRICDISTENSIONACCOMMODATION;1n4], antral contractility ;5n7= MECHANICALDEFORMATIONSTRAIN ;8n13= TRANSPYLORICmOW;6, 7, 14], intraGASTRICDISTRIBUTIONASWELLASGASTRICEMPTYING;14n21=)NTHISSECTION THEROLEOF ULTRASONOGRAPHYINTHEMEASUREMENTOFGASTRICEMPTYING DISTALANDPROXIMALSTOMACH AREAACCOMMODATION TRANSPYLORICmOWANDGASTRICMOTILITY ISDISCUSSED

K.L. Jones (*) $ISCIPLINEOF-EDICINE 5NIVERSITYOF!DELAIDE 2OYAL!DELAIDE(OSPITAL !DELAIDE 3! !USTRALIA e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_12, © Springer Science+Business Media, LLC 2012

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Gastric Emptying 4HE $ MEASUREMENT OF GASTRIC EMPTYING IS WIDELY USED CLINICALLY PARTICULARLY IN %UROPE ANDHASSEVERALADVANTAGESOVEROTHERMETHODS4HETECHNIQUEWASESTABLISHED INTHEEARLYS;22=ANDISRELATIVELYEASILYACQUIREDBYINSTRUCTIONFROMANINDIVIDUAL EXPERIENCEDINTHETECHNIQUE)TISANINDIRECTMEASUREMENTOFGASTRICEMPTYINGWHICH ISDETERMINEDBYQUANTIFYINGCHANGESINANTRALAREADISCUSSEDBELOW OVERTIME;15, 16, 22=FOLLOWINGINGESTIONOFAMEAL;19=3EVERALTESTMEALSHAVEBEENUSED EGLOWNUTRIENTBEEFSOUP BEANS PASTA ORANGEJUICEANDDEXTROSE ALTHOUGHINTHEMAJORITYOFSTUDIES TEST MEALS HAVE BEEN LIQUID OR SEMI SOLID ;15n19, 22= 4HE $ ULTRASONOGRAPHY TECHNIQUEHASBEENVALIDATEDAGAINSTSCINTIGRAPHY;16, 19=)TISINTRIGUINGTHATCHANGES INANTRALAREACANBEUSEDTOEVALUATEGASTRICEMPTYINGFROMTHETOTALSTOMACH PARTICULARLY AS SCINTIGRAPHIC STUDIES HAVE SHOWN A RELATIONSHIP BETWEEN TOTAL STOMACH WITH PROXIMALSTOMACH BUTNOTDISTALSTOMACHCONTENT;23=)N (OLTETAL;16] reported ACORRELATIONINMEASUREMENTSOFTHETIMEFOROFALOWNUTRIENTBEEFSOUPTOEMPTY FROMTHESTOMACH4 BETWEENULTRASONOGRAPHYANDSCINTIGRAPHY3TUDIESBY(VEEM ETAL;19=FURTHERVALIDATEDTHETECHNIQUEAGAINSTSCINTIGRAPHYINHEALTHYSUBJECTSBY QUANTIFYINGEMPTYINGOFALOWNUTRIENTBEEFSOUPANDHIGHNUTRIENTGDEXTROSE DRINK ANDDETERMININGSTRONGCORRELATIONSBETWEENTHEGASTRICEMPTYING4SFORULTRASONOGRAPHY AND SCINTIGRAPHY AND MODEST LIMITS OF AGREEMENT )N PATIENTS WITH FUNCTIONAL DYSPEPSIA $ULTRASONOGRAPHYHASPRIMARILYBEENUSEDFORRESEARCHPURPOSESTODEMONSTRATEOVERALLDELAYEDGASTRICEMPTYINGANDOCCASIONALLY MORERAPIDhEARLYvEMPTYING ;24= WHILE IN LONGSTANDING DIABETES GASTRIC EMPTYING HAS BEEN REPORTED TO BE DELAYEDINÔFPATIENTS!LIMITATIONOF$MEASUREMENTSOFGASTRICEMPTYINGIS THATTHETECHNIQUERELIESONASSUMPTIONSABOUTTHEGEOMETRYOFTHESTOMACHBASEDONA SINGLE SAGITTAL ANTRALIMAGE;19=ANDIMAGINGMAYBECHALLENGINGINTHEOBESE 4HREE DIMENSIONAL $ ULTRASONOGRAPHY DESCRIBED IN THE MID S AND PIONEEREDBYTHEGROUPIN"ERGEN .ORWAY OFFERSSIGNIlCANTADVANTAGESOVER$ PARTICULARLYTHEABILITYTOASSESSINTRAGASTRICMEALDISTRIBUTIONWHICHISOFTENDISORDEREDIN FUNCTIONALDYSPEPSIAANDDIABETICGASTROPARESIS;25]. Measurements of gastric emptyINGBY$ULTRASONOGRAPHYALSOSHOWGREATERACCURACY ANDLESSVARIABILITY THAN$ ;26=4HEUSEOF$ULTRASONOGRAPHYNECESSITATESSCANNINGINACONTINUOUSSWEEPING MOVEMENT COMMENCINGPROXIMALLYATTHELEFTSUBCOSTALMARGINWITHTHETRANSDUCER TILTEDCRANIALLY ANDMOVINGDISTALLYTOWARDSTHEPYLORUS;20, 26=4HETRANSDUCERIS lTTEDWITHASNAP ONSENSORTODETECTINFORMATIONEMITTEDFROMAPOSITIONINGANDORIENTATIONMEASUREMENT0/- TRANSMITTERTHATPRODUCESAMAGNETIClELD PLACEDNEXT TOTHESUBJECTPATIENT$EDICATEDRECONSTRUCTIONSOFTWARE%CHO0!# $ ;27] is used TOCONVERTIMAGESOFTRANSVERSESECTIONSOFTHEENTIRESTOMACHTOVOLUMES&IG12.1), WHICHCANTHENBEDIVIDEDINTODISTALANDORPROXIMALSTOMACHVOLUMES;26]. 4HEUSEOFTHE$ULTRASONOGRAPHYTECHNIQUEFORTHEMEASUREMENTOFGASTRICEMPTYING WASVALIDATEDINITIALLYINVITROINAPORCINEMODEL WHICHSHOWEDANEXCELLENT CORRELATIONBETWEENTRUEANDESTIMATEDVOLUMES;26= ANDSUBSEQUENTLY INHUMANS USINGAGASTRICBAROSTAT;28=-ORERECENTLY THETECHNIQUEHASBEENVALIDATEDAGAINST SCINTIGRAPHYINBOTHHEALTHYSUBJECTS;20=ANDPATIENTSWITHDIABETICGASTROPARESIS;21]. 7HILE$ULTRASONOGRAPHYOFFERSANUMBEROFADVANTAGESOVER$ULTRASONOGRAPHY CURRENTLYITISNOTUSEDEXTENSIVELYFOREITHERCLINICALORRESEARCHPURPOSES

5LTRASONOGRAPHYFOR%VALUATIONOF0ATIENTSWITH3USPECTED'ASTROPARESIS

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Fig. 12.1 5LTRASONOGRAPHIC IMAGE OF THE STOMACH FOLLOWING $ RECONSTRUCTION DEMONSTRATING (a) region-of-interest and (b $RECONSTRUCTEDVOLUMETRICIMAGEOFTHESTOMACH

Fig. 12.2 $SAGITTALULTRASOUNDIMAGEOFTHEANTRUM

Antral Area $ULTRASONOGRAPHYHASBEENUSEDTOIMAGETHEDISTALSTOMACH THEREBYPROVIDING INFORMATIONRELATINGTOANTRALDISTENSION!PROBEn-(Z ISPLACEDOVERTHE ABDOMENANDASAGITTALIMAGEOFTHEANTRUM INTHEREGIONOFTHEAORTAANDSUPERIOR MESENTERICVEIN ISOBTAINED&IG12.2 ;15, 19=3TUDIESUSING$ULTRASONOGRAPHY HAVE DEMONSTRATED THAT FUNCTIONAL DYSPEPSIA IS FREQUENTLY ASSOCIATED WITH AN INCREASEINANTRALAREABOTHFASTINGANDPOSTPRANDIALLY ;29= WHICHCANBEREDUCED WITHCISAPRIDE;29=)NPATIENTSWITHDIABETES BOTHFASTINGANDPOSTPRANDIALANTRAL AREA ARE ALSO FREQUENTLY INCREASED ;30= 0ERCEPTIONS OF FULLNESS AND SUBSEQUENT ENERGYINTAKEHAVEBEENSHOWNTOCORRELATEDIRECTLYWITHPOSTPRANDIALANTRALAREAIN BOTHHEALTHYSUBJECTS;31=ANDTHEELDERLY;32= SUGGESTINGTHATANTRALhDISTENSIONv ISASIGNIlCANTDETERMINANTOFAPPETITE;31, 32=4HERELATIVESIMPLICITYANDNONINVASIVENESSOFULTRASOUNDISPARTICULARLYAPPEALINGINSUCHSTUDIES

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Proximal Stomach (Accommodation) "OTH $ AND $ ULTRASONOGRAPHY HAVE BEEN USED TO EVALUATE PROXIMAL STOMACH FUNCTIONACCOMMODATION;1, 26, 33, 34=7ITHTHE$TECHNIQUE PROXIMALSTOMACHAREA CANBECALCULATEDFROMASAGITTALIMAGEBYDRAWINGAREGION OF INTERESTFROMTHETOP MARGINDOWNCMALONGTHELONGAXIS&IG12.3a OFTHESTOMACH;33=!NADDITIONAL MEASUREMENT REPRESENTINGTHEDIAMETEROFTHEFUNDUS ISDERIVEDUSINGANOBLIQUE FRONTALSECTIONMAINTAINEDWITHINCMOFTHELONGAXIS&IG12.3B OFTHEPROXIMAL STOMACH;33=$VOLUMERECONSTRUCTIONSOFTHESTOMACHCANBEDIVIDEDINTOPROXIMAL ANDDISTALSTOMACHPORTIONS THEREBYPROVIDINGINFORMATIONRELATINGTOINTRAGASTRIC MEALDISTRIBUTION;26=3TUDIESUSINGULTRASONOGRAPHYHAVEDEMONSTRATEDTHEFREQUENT OCCURRENCEOFIMPAIREDPROXIMALSTOMACHRELAXATIONINBOTHPATIENTSWITHFUNCTIONAL DYSPEPSIA;1=ANDDIABETES;35=)NPATIENTSWITHFUNCTIONALDYSPEPSIABOTHSYMPTOMS ANDPROXIMALSTOMACHACCOMMODATION INDUCEDBYAMEAL IMPROVEDBYADMINISTRATION OF SUBLINGUAL GLYCERYL TRINITRATE ;36= BUT NOT IN PATIENTS WITH DIABETES ;37]. 'ASTRICACCOMMODATIONUSINGULTRASONOGRAPHY ASASSESSEDBYCHANGESINTHERATIO OFTHETOTALPROXIMALGASTRICVOLUME ISDECREASEDINFUNCTIONALDYSPEPSIA;3, 38] AND INCREASED IN '%2$ PATIENTS ;38= 4HE hGOLD STANDARDv FOR THE ASSESSMENT OF PROXIMALSTOMACHACCOMMODATIONISTHEGASTRICBAROSTATBUTTHISHASSIGNIlCANTDISADVANTAGES SUCHASTHEINVASIVENATUREOFTHEPROCEDUREANDTHEINABILITYTOCALCULATE GASTRICVOLUME)TSHOULD HOWEVER BEACKNOWLEDGEDTHATIMAGINGMETHODS SUCHAS ULTRASONOGRAPHY PROVIDEONLYANINDIRECTMEASUREOFGASTRICRELAXATION THEREFORE PROVIDING SLIGHTLY DIFFERENT INFORMATION ABOUT THE ACCOMMODATION PROCESS WHEN COMPAREDTOTHEBAROSTATTHEBAROSTATADJUSTSVOLUMEINRESPONSETOGASTRICMUSCLE TONE WHEREASULTRASONOGRAPHYDIRECTLYVISUALISESGASTRICSIZEANDVOLUME!SSESSMENT OFPROXIMALGASTRICVOLUMESBY$ULTRASONOGRAPHYHASBEENSHOWNTOCORRELATE CLOSELY WITH MEASUREMENTS MADE WITH THEGASTRICBAROSTAT;3=)NACOHORTOF PATIENTSWITHFUNCTIONALDYSPEPSIA ASASSESSEDBYTHEBAROSTAT HADABNORMAL ACCOMMODATION COMPAREDTO WITH$ULTRASONOGRAPHYnPATIENTSHAD

Fig. 12.3 $ULTRASOUNDIMAGESOFTHEPROXIMALSTOMACHINa) sagittal section and (b OBLIQUE frontal section


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EVIDENCEOFDISORDEREDACCOMMODATIONUSINGBOTHTECHNIQUES;2, 3=)NBOTHPATIENTS WITHFUNCTIONALDYSPEPSIAANDHEALTHYSUBJECTS SENSATIONSOFFULLNESSARERELATEDTO DISTAL BUTNOTTOTAL ORPROXIMAL GASTRICVOLUME;3= CONSISTENTWITHOBSERVATIONS USING$ULTRASONOGRAPHY;31, 35].

Antropyloroduodenal Motility 'ASTRICCONTRACTIONSCANBEDIVIDEDBROADLYINTOTWOCATEGORIESnLUMEN ANDNON LUMEN OCCLUSIVE-ANOMETRYISFREQUENTLYUSEDTOASSESSGASTRICMOTILITYBYMEASURING LUMINAL PRESSURE BUT REQUIRES INVASIVE INTUBATION OF AN ANTROPYLORODUODENAL CATHETER AND IS LIMITED TO THE ASSESSMENT OF ONLY OCCLUSIVE EVENTS )N CONTRAST ULTRASONOGRAPHYHASTHECAPACITYTOASSESSTHEFREQUENCYANDMAGNITUDEOFBOTH LUMEN ANDNON LUMENOCCLUSIVEEVENTS)NHEALTHYSUBJECTSWHOHADCONCURRENT ANTROPYLORODUODENALMANOMETRYANDULTRASONOGRAPHYMEASUREMENTSFOLLOWINGA LOWNUTRIENTSOUP ONLY^;5, 39=OFULTRASONOGRAPHICCONTRACTIONSWERESHOWN TOBEASSOCIATEDWITHCORRESPONDINGGASTRICMANOMETRICPRESSURES INDICATINGTHAT ULTRASONOGRAPHY HAS THE CAPACITY TO PROVIDE MORE COMPREHENSIVE INFORMATION RELATINGTOPATTERNSOFANTRALMOTILITYTHANMANOMETRY

Transpyloric Flow )TWASTRADITIONALLYBELIEVEDTHATTHESTOMACHEMPTIEDATACONTINUOUSRATEHOWEVER METHODSTOASSESSGASTRICEMPTYINGWERELIMITEDINTEMPORALRESOLUTION3TUDIESIN DOGS;40=ANDHUMANS;6=HAVESUBSEQUENTLYDEMONSTRATEDTHAThGASTRICvEMPTYING ISINFACTPREDOMINANTLYPULSATILESOTHATEMPTYINGOCCURSINASERIESOFGUSHESTHAT MAY VARY ON A SECOND BY SECOND BASIS $UPLEX ULTRASOUND INCORPORATING BOTH $OPPLERAND" MODEIMAGING CANBEUSEDTOMEASURETHEDIRECTIONANDVELOCITYOF TRANSPYLORICmOW;6, 41, 42=(AUSKENETAL;14=HAVEDEVELOPEDA$$OPPLERTECHNIQUETODETERMINEhSTROKEVOLUMESvOFTRANSPYLORICmOWEPISODES7HILESEVERAL TECHNIQUESHAVEBEENUSEDTOASSESSTRANSPYLORICmOWINHUMANS ULTRASONOGRAPHY HASTHEADVANTAGEOFBEINGABLETOALSOPROVIDEINFORMATIONRELATINGTOGASTRICEMPTYING ANDMOTILITYWITHINTHEONEEXAMINATION7HILEITSUSEISLARGELYRESTRICTEDTOTHE RESEARCHSETTING CONSIDERABLYMOREINFORMATIONRELATINGTOGASTRICPHYSIOLOGYCAN BEPROVIDEDBYTHESEMEASUREMENTSATLOWCOST

Gastric Strain Rate Imaging 'ASTRICSTRAINRATEIMAGING32) ISARELATIVELYRECENTULTRASONOGRAPHYTECHNIQUE BASED ON TISSUE VELOCITY IMAGING PROVIDING QUANTITATIVE INFORMATION RELATING TO GASTRICWALLDEFORMATION;8n13=4HEACCURACYOF32)HASBEENVALIDATEDINVITROIN

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APORCINEMODEL;9=32)HASTHECAPACITYTOEVALUATETHECONTRACTILEACTIVITYOFBOTH LONGITUDINALANDCIRCULARMUSCLELAYERSANDINHEALTHYSUBJECTSSTUDIESUSINGBOTH 32)ANDGASTRICBALLOONDISTENSIONDEMONSTRATEANINVERSECORRELATIONBETWEENPRESSURE AND RADIAL STRAIN ;10= )N PATIENTS WITH FUNCTIONAL DYSPEPSIA DIVIDED INTO SUBGROUPSOFhEPIGASTRICPAINSYNDROMEv%03 ANDhPOSTPRANDIALDISTRESSSYNDROMEv 0$3 ANTRALSTRAINWASSHOWNTOBEHIGHERIN%03PATIENTSWHENCOMPAREDTOBOTH NORMALSUBJECTSAND0$3PATIENTSDURINGBOTHTHEFASTINGSTATEANDPOSTPRANDIALLY;43]. 4HISNON INVASIVETECHNIQUEISCURRENTLYLIMITEDTOTHERESEARCHSETTING

Conclusions 4RANSABDOMINALULTRASONOGRAPHYOFFERSANUMBEROFADVANTAGESOVEROTHERTECHNIQUES TOEVALUATEGASTRICMOTORFUNCTIONINHUMANS)TISNON INVASIVE READILYAVAILABLE INEXPENSIVE DOESNOTINVOLVEARADIATIONBURDEN CANBEPERFORMEDATTHEBEDSIDE ANDHASTHECAPACITYTOASSESSGASTRICEMPTYING TRANSPYLORICmOWANDANTROPYLORODUODENALMOTILITYCONCURRENTLY7HILE$ULTRASONOGRAPHYPROVIDESMOREINFORMATION ABOUTGASTRICPATHOPHYSIOLOGYTHAN$ULTRASONOGRAPHY ITISAMORETIMECONSUMING TECHNIQUETHATREQUIRESTHESKILLOFANEXPERIENCEDOPERATORANDRELATIVELYEXPENSIVE EQUIPMENT&ORTHESEREASONS$ULTRASONOGRAPHYSHOULD ATTHEMOMENT BEREGARDED ASANEXCELLENTRESEARCHTOOL$ULTRASONOGRAPHYPROVIDESASIMPLEANDSTRAIGHTFORWARDASSESSMENTOFGASTRICEMPTYINGANDISCURRENTLYMORESUITEDTOTHECLINICAL SETTINGFORTHEDIAGNOSISOFGASTROPARESIS

References 'ILJA/( (AUSKEN4 7ILHELMSEN) "ERSTAD!)MPAIREDACCOMMODATIONOFPROXIMALSTOMACH TOAMEALINFUNCTIONALDYSPEPSIA$IG$IS3CI n -UNDT-7 (AUSKEN4 3MOUT!* 3AMSOM-2ELATIONSHIPSBETWEENGASTRICACCOMMODATION ANDGASTROINTESTINALSENSATIONSINHEALTHYVOLUNTEERS!STUDYUSINGTHEBAROSTATTECHNIQUEAND TWO ANDTHREE DIMENSIONALULTRASONOGRAPHY$IG$IS3CI n -UNDT -7 3AMSOM - &UNDAL DYSACCOMMODATION IN FUNCTIONAL DYSPEPSIA HEAD TO HEAD COMPARISONBETWEENTHEBAROSTATANDTHREE DIMENSIONALULTRASONOGRAPHICTECHNIQUE'UT n 'ILJA/( ,UNDING* (AUSKEN4 'REGERSEN('ASTRICACCOMMODATIONASSESSEDBYULTRASONOGRAPHY7ORLD*'ASTROENTEROL n (VEEM+ 3UN7- (EBBARD' (OROWITZ- $ORAN3 $ENT*2ELATIONSHIPBETWEENULTRASONICALLYDETECTEDPHASICANTRALCONTRACTIONSANDANTRALPRESSURE!M*0HYSIOL'ASTROINTEST ,IVER0HYSIOL 'n +ING0- !DAM2$ 0RYDE! -C$ICKEN7. (EADING2#2ELATIONSHIPSOFHUMANANTRODUODENAL MOTILITY AND TRANSPYLORIC mUID MOVEMENT NON INVASIVE OBSERVATIONS WITH REAL TIME ULTRASOUND'UT n (AUSKEN4 /DEGAARD3 -ATRE+ "ERSTAD!!NTRODUODENALMOTILITYANDMOVEMENTSOFLUMINAL CONTENTSSTUDIEDBYDUPLEXSONOGRAPHY'ASTROENTEROLOGY n !HMED!" 'ILJA/( (AUSKEN4 'REGERSEN( -ATRE+3TRAINMEASUREMENTDURINGANTRAL CONTRACTIONSBYULTRASOUNDSTRAINRATEIMAGINGINmUENCEOFERYTHROMYCIN.EUROGASTROENTEROL -OTIL n


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!HMED!" 'ILJA/( 'REGERSEN( /DEGAARD3 -ATRE+)NVITROSTRAINMEASUREMENTINTHE PORCINE ANTRUM USING ULTRASOUND DOPPLER STRAIN RATE IMAGING 5LTRASOUND -ED "IOL n 'ILJA/( (EIMDAL! (AUSKEN4 ETAL3TRAINDURINGGASTRICCONTRACTIONSCANBEMEASURED USING$OPPLERULTRASONOGRAPHY5LTRASOUND-ED"IOLn n 'REGERSEN( 'ILJA/( (AUSKEN4 ETAL-ECHANICALPROPERTIESINTHEHUMANGASTRICANTRUM USING" MODEULTRASONOGRAPHYANDANTRALDISTENSION!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n 'REGERSEN( (AUSKEN4 9ANG* /DEGAARD3 'ILJA/(-ECHANOSENSORYPROPERTIESINTHE HUMAN GASTRIC ANTRUM EVALUATED USING " MODE ULTRASONOGRAPHY DURING VOLUME CONTROLLED ANTRALDISTENSION!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n (EIMDAL! 'ILJA/(3TRAINRATEIMAGINGnANEWTOOLFORSTUDYINGTHE')TRACT)N/DEGAARD 3 'ILJA/( 'REGERSEN( EDITORS"ASICANDNEWASPECTSOFGASTROINTESTINALULTRASONOGRAPHY 3INGAPORE7ORLD3CIENTIlCPn (AUSKEN4 ,I8. 'OLDMAN" ,EOTTA$ /DEGAARD3 -ARTIN271UANTIlCATIONOFGASTRIC EMPTYING AND DUODENOGASTRIC REmUX STROKE VOLUMES USING THREE DIMENSIONAL GUIDED DIGITAL COLOR$OPPLERIMAGING%UR*5LTRASOUND n "OLONDI, "ORTOLOTTI- 3ANTI6 #ALLETTI4 'AIANI3 ,ABO'-EASUREMENTOFGASTRICEMPTYING TIMEBYREAL TIMEULTRASONOGRAPHY'ASTROENTEROLOGY n (OLT 3 #ERVANTES * 7ILKINSON !! 7ALLACE *( -EASUREMENT OF GASTRIC EMPTYING RATE IN HUMANSBYREAL TIMEULTRASOUND'ASTROENTEROLOGY n "ROWN"0 3CHULZE $ELRIEU+ 3CHRIER*% !BU 9OUSEF--4HECONlGURATIONOFTHEHUMAN GASTRODUODENAL JUNCTION IN THE SEPARATE EMPTYING OF LIQUIDS AND SOLIDS 'ASTROENTEROLOGY n "ENINI, "RIGHENTI& #ASTELLANI' ETAL'ASTRICEMPTYINGOFSOLIDSISMARKEDLYDELAYEDWHEN MEALSAREFRIED$IG$IS3CI n (VEEM + *ONES +, #HATTERTON "% (OROWITZ - 3CINTIGRAPHIC MEASUREMENT OF GASTRIC EMPTYING AND ULTRASONOGRAPHIC ASSESSMENT OF ANTRAL AREA RELATION TO APPETITE 'UT n 'ENTILCORE$ (AUSKEN4 (OROWITZ- *ONES+,-EASUREMENTSOFGASTRICEMPTYINGOFLOW AND HIGH NUTRIENT LIQUIDS USING $ ULTRASONOGRAPHY AND SCINTIGRAPHY IN HEALTHY SUBJECTS .EUROGASTROENTEROL-OTIL n 3TEVENS *% 'ILJA /( 'ENTILCORE $ (AUSKEN 4 (OROWITZ - *ONES +, -EASUREMENT OF GASTRIC EMPTYING OF A HIGH NUTRIENT LIQUID BY $ ULTRASONOGRAPHY IN DIABETIC GASTROPARESIS .EUROGASTROENTEROL-OTIL n (OLT3 -C$ICKEN7. !NDERSON4 3TEWART)# (EADING2#$YNAMICIMAGINGOFTHESTOMACH BY REAL TIME ULTRASOUND n A METHOD FOR THE STUDY OF GASTRIC MOTILITY 'UT n 3HEINER (* 1UINLAN -& 4HOMPSON )* 'ASTRIC MOTILITY AND EMPTYING IN NORMAL AND POST VAGOTOMYSUBJECTS'UT n ,UNDING*! 4EFERA3 'ILJA/( ETAL2APIDINITIALGASTRICEMPTYINGANDHYPERSENSITIVITYTO gastric filling in functional dyspepsia: effects of duodenal lipids. Scand J Gastroenterol. n *ONES+, (OROWITZ- 7ISHART-* -ADDOX!& (ARDING0% #HATTERTON"%2ELATIONSHIPS BETWEENGASTRICEMPTYING INTRAGASTRICMEALDISTRIBUTIONANDBLOODGLUCOSECONCENTRATIONSIN DIABETESMELLITUS*.UCL-ED n 'ILJA/( $ETMER02 *ONG*- ETAL)NTRAGASTRICDISTRIBUTIONANDGASTRICEMPTYINGASSESSED BYTHREE DIMENSIONALULTRASONOGRAPHY'ASTROENTEROLOGYn -ARTENS$ 'ILJA/(4HE%CHO0!# $SOFTWAREFOR$IMAGEANALYSIS)N/DEGAARD3 'ILJA/( 'REGERSEN( EDITORS"ASICANDNEWASPECTSOFGASTROINTESTINALULTRASONOGRAPHY3INGAPORE 7ORLD3CIENTIlCPn 4EFERA3 'ILJA/( /LAFSDOTTIR% (AUSKEN4 (ATLEBAKK*' "ERSTAD!)NTRAGASTRICMALDISTRIBUTION OF A LIQUID MEAL IN PATIENTS WITH REmUX OESOPHAGITIS ASSESSED BY THREE DIMENSIONAL ULTRASONOGRAPHY'UT n

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(AUSKEN4 "ERSTAD!7IDEGASTRIC ANTRUM INPATIENTSWITH NON ULCER DYSPEPSIA %FFECT OF CISAPRIDE3CAND*'ASTROENTEROL n 5NDELAND+! (AUSKEN4 3VEBAK3 !ANDERUD3 "ERSTAD!7IDEGASTRICANTRUMANDLOW VAGAL TONE IN PATIENTS WITH DIABETES MELLITUS TYPE COMPARED TO PATIENTS WITH FUNCTIONAL DYSPEPSIAANDHEALTHYINDIVIDUALS$IG$IS3CI n *ONES+, $ORAN3- (VEEM+ ETAL2ELATIONBETWEENPOSTPRANDIALSATIATIONANDANTRALAREA INNORMALSUBJECTS!M*#LIN.UTR n 3TURM+ 0ARKER" 7ISHART* ETAL%NERGYINTAKEANDAPPETITEARERELATEDTOANTRALAREAIN HEALTHYYOUNGANDOLDERSUBJECTS!M*#LIN.UTR n 'ILJA/( (AUSKEN4 /DEGAARD3 "ERSTAD!-ONITORINGPOSTPRANDIALSIZEOFTHEPROXIMAL STOMACHBYULTRASONOGRAPHY*5LTRASOUND-ED n 'ILJA/( (AUSKEN4 /DEGAARD3 ,UNDING* "ERSTAD!'ASTRICACCOMMODATIONANDULTRASONOGRAPHY.EUROGASTROENTEROL-OTIL n 5NDELAND+! (AUSKEN4 'ILJA/( !ANDERUD3 "ERSTAD!'ASTRICMEALACCOMMODATION STUDIEDBYULTRASOUNDINDIABETES2ELATIONTOVAGALTONE3CAND*'ASTROENTEROL n 'ILJA/( (AUSKEN4 "ANG#* "ERSTAD!%FFECTOFGLYCERYLTRINITRATEONGASTRICACCOMMODATION ANDSYMPTOMSINFUNCTIONALDYSPEPSIA$IG$IS3CI n 5NDELAND+! (AUSKEN4 'ILJA/( !ANDERUD3 "ERSTAD!'ASTRICMEALACCOMMODATION ANDSYMPTOMSINDIABETES!PLACEBO CONTROLLEDSTUDYOFGLYCERYLTRINITRATE%UR*'ASTROENTEROL (EPATOL n VAN,ELYVELD. 3CHEFFER2 -UNDT- 3AMSOM-0ARTIALGASTRICVOLUMESANDUPPERABDOMINAL SENSATIONS IN FUNCTIONAL DYSPEPTIC AND '%2$ PATIENTS A $ ULTRASONOGRAPHIC STUDY !M *'ASTROENTEROL n (AUSKEN4 -UNDT- 3AMSOM-,OWANTRODUODENALPRESSUREGRADIENTSARERESPONSIBLEFOR GASTRICEMPTYINGOFALOW CALORICLIQUIDMEALINHUMANS.EUROGASTROENTEROL-OTIL n -ALBERT#( 2UCKEBUSCH92ELATIONSHIPSBETWEENPRESSUREANDmOWACROSSTHEGASTRODUODENAL JUNCTIONINDOGS!M*0HYSIOL0T 'n +ING0- 0RYDE! (EADING2#4RANSPYLORICmUIDMOVEMENTANDANTRODUODENALMOTILITYIN PATIENTSWITHGASTRO OESOPHAGEALREmUX'UT n (AUSKEN4 'ILJA/( /DEGAARD3 "ERSTAD!&LOWACROSSTHEHUMANPYLORUSSOONAFTERINGESTION OFFOOD STUDIEDWITHDUPLEXSONOGRAPHY%FFECTOFGLYCERYLTRINITRATE3CAND*'ASTROENTEROL n !HMED!" -ATRE+ (AUSKEN4 'REGERSEN( 'ILJA/(42OME)))SUBGROUPSOFFUNCTIONALDYSPEPSIAEXHIBITDIFFERENTCHARACTERISTICSOFANTRALSTRAINMEASUREDBYSTRAINRATEIMAGING 'ASTROENTEROLOGY 3UPPL !

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Chapter 13

Magnetic Resonance Imaging for Gastric Motility Adil E. Bharucha and Roger C. Grimm

Keywords 'ASTROPARESISs-2)s)MAGINGMODALITIESs'ASTRICMOTORFUNCTIONS

Introduction $RIVENBYTECHNOLOGICALADVANCES THEABILITYOFMAGNETICRESONANCEIMAGING-2) TOASSESSGASTRICMOTORFUNCTIONSHASSUBSTANTIALLYADVANCEDSINCETHEEARLIESTSTUDIES OFGASTRICEMPTYINGANDANTRALANDSMALL BOWELMOTILITYNEARLYTWODECADESAGO;1, 2]. Those studies used the echo-planar imaging (EPI) sequence on a home-built scanner TOACQUIREANIMAGEPLANEWITHINTENSOFMILLISECONDSUSINGASINGLESHOTSEQUENCE SCHEMETHATALLOWSEASYWEIGHTINGOFTHESEQUENCETOTHERELAXATIONTIMEST1 and T2 OR DIFFUSION AND TO MEASURE THESE -2) PARAMETERS QUANTITATIVELY ;3= (OWEVER %0) IS PRONE TO ARTIFACTS AND HAS LIMITED SPATIAL RESOLUTION 3INCE THEN IMAGING modalities have improved substantially, initially through spin echo sequences and MORERECENTLYWITHDEVELOPMENTOFFASTSPINECHOANDSPOILEDGRADIENTECHOSEQUENCES WHICHPROVIDEHIGH RESOLUTIONABDOMINALIMAGINGINAMATTEROFHUNDREDSOFMILLISECONDS PERMITTING')FUNCTION INCLUDINGGASTRICVOLUMESANDCONTRACTILITY TOBE evaluated in real time by MRI.

A.E. Bharucha (*) Clinical and Enteric Neuroscience Translational and Epidemiological Research Program (C.E.N.T.E.R.), Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905, USA e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_13, © Springer Science+Business Media, LLC 2012

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Advantages and Limitations of MRI for Assessing Gastric Motor Functions -ULTIPLANARIMAGINGCAPABILITY RAPIDIMAGING EXCELLENTSPATIALRESOLUTIONANDSOFT TISSUECONTRAST ANDLACKOFEXPOSURETOIONIZINGRADIATIONAREAMONGTHEADVANTAGES OF-2)3INCETHESIGNALORIGINATESFROMENDOGENOUSHYDROGENPROTONS THECONTRAST depends on their physicochemical environment, mobility, and concentration. )MAGINGPARAMETERSCANBEADJUSTEDTOHIGHLIGHTDESIREDCHARACTERISTICSOFTHEORGAN OR TEST MEAL BEING EXAMINED AND THE SIGNAL FROM BODY FAT CAN BE SUPPRESSED IF desired. With some rapid imaging sequences, high-resolution scans can be obtained WITHINONEBREATHHOLDTOREDUCEMOTIONARTIFACTINREAL TIME PERMITTINGhcine” MRI ORh-2)mUOROSCOPYv 3INCENONIONIZINGRADIATIONISUSED REPEATEDSCANS EG TO OBSERVEPOSTPRANDIALPHENOMENAATMULTIPLETIMESONONEDAYORFORLONGITUDINAL assessments over time, are possible. Moreover, providing appropriate imaging sequences are used, MRI can simultaneously measure gastric volumes, emptying, ANDMOTILITYANDALSODOCUMENTEXTRALUMINALDISEASE5LTRASOUNDCANALSOMEASURE ALLPARAMETERS(OWEVER INCONTRASTTOULTRASOUND GASTRICVISUALIZATIONBY-2)IS NOTLIMITEDBYTHEPRESENCEOFAIRINTHESTOMACH $ESPITETHESEADVANTAGES THEUSEOF-2)TOEVALUATEGASTRICMOTILITYISALMOST EXCLUSIVELYLIMITEDTORESEARCH PARTLYCONSTRAINEDBYTHEAVAILABILITYOFSCANNERS SCANNERTIME ANDEXPENSE-OSTSCANNERSPERMITSCANNINGINTHESUPINEPOSITION only. Studies evaluating gastric motility by MRI have included a relatively small NUMBEROFHEALTHYSUBJECTSANDIMAGINGPROTOCOLSARENOTSTANDARDIZED0ERFORMANCE CHARACTERISTICSREQUIREFURTHERSTUDY

Overview of MR Imaging Sequences Used to Evaluate Gastric Motor Functions )MAGINGOFGASTRICMOTILITYREQUIRESHIGHTEMPORALRESOLUTIONANDLENDSITSELFTO$ imaging techniques. Typically, 2D imaging provides higher in-plane than throughPLANERESOLUTION/BTAINABLEIN PLANERESOLUTIONSFORGASTRICMOTILITYSTUDIESRANGE FROMTOMMWITHTHROUGH PLANERESOLUTIONSINTHEnMMRANGE!VARIETY OFSEQUENCESIE GRADIENTRECALLECHO'2% STEADY STATEFREEPRECESSION33&0 %0) ANDHALF&OURIERACQUISITIONSINGLE SHOTTURBOSPINECHO(!34% SEQUENCES have been used to evaluate gastric motility (Table 13.1). These sequences have been DETAILED ELSEWHERE ;4, 5]. GRE sequences employ RF and gradient spoiling to REMOVECOHERENTSIGNALBETWEENREPETITIONSOFTHEPLAYOUT4HISPRODUCESAROBUST ANDSTABLESIGNALATTHECOSTOFSPOILINGTHEREMAININGSIGNALAFTERECHOREADOUT"Y CONTRAST 33&0 SEQUENCES ATTEMPT TO REFOCUS THE ENTIRE SIGNAL AT THE END OF EACH playout to increase signal. While this approach accentuates signal in homogeneous AREAS IMPERFECTIONSINlELDHOMOGENEITY ASTHOSEOCCURINGATAIRBOUNDARIES WHICH CAUSEMAGNETICSUSCEPTIBILITYINTERFACES CANCAUSEBANDSINTHERESULTINGIMAGETHAT

Temporal resolution (s) 1

1 3 1 1

1

In plane resolution (mm) 3.1 × 3.1

3.1 × 3.1 3.5 × 2.5 1.8 × 3.5 2.0 × 1.6

2.0 × 1.6

-OTILITYWASREDUCEDINGASTROPARESISAND increased in pylorospasm

#OMPAREDANTRALMOTILITYAFTERLIQUID MIXED LIQUIDSOLID ORMIXEDVISCOUSSOLIDMEALS 'ASTRICVOLUMESANDMOTILITYWERESIMULTANEously assessed by MRI and a barostat Metoclopramide increased and scopolamine decreased motility

%VALUATEDEMPTYINGOFLIQUIDANDSOLIDMEALS

Comments Cisapride improved gastric emptying and PROXIMALBUTNOTDISTALGASTRICCONTRACTILITY

1.56 × 1.95

1.4

!SSESSMENTOFGASTRICVOLUMESANDMOTILITY AFTERGLUCOSE Not available 1.3 3EQUENCECHARACTERISTICSREFERTOASSESSMENTS PERFORMEDINRIGHTPOSITION$IFFERENT sequences used to assess gastric motility in seated position $FAST'2% SLICE MM 1.8 × 3.5 1 #OMPAREDVOLUMESANDMOTILITYWITH-2) DE:WART HEALTHY;22] thick, 300 s WITHORWITHOUTABAROSTAT Bharucha, 20 healthy, 2D SSFP, 3 slices, 10 mm thick, 60 s 1.6 × 1.6 0.8 'ASTRICCONTRACTILITY WHICHWASANALYZEDBYA DYSPEPSIA;34] FOREACHSLICE SEMIAUTOMATEDTECHNIQUE WASINCREASEDIN idiopathic rapid gastric emptying DM diabetes mellitus, GRE gradient recalled echo, SSFPSTEADY STATEFREEPRECESSION EPI echo planar imaging

Author, n, subject group Imaging parameters "OROVICKA $-WITHDELAYED 2D GRE sequence, 2 coronal slices, IMAGESOVERMIN SHALLOW (8) or normal (7) gastric breathing EMPTYING;32] 2D GRE sequence; Coronal slice, +UNZ HEALTHY;40] 10 mm thick, 120 images over 2 min -ARCIANI HEALTHY;41] 2D EPI sequence, 8 slices, 10 mm thick, 72 time samples over 3.6 min DE:WART HEALTHY;42] $FAST'2%SEQUENCE SLICE MM THICK nS !JAJ HEALTHY ;43] 2D SSFP sequence, 1 slice, 5 mm thick, 20 s during breathhold. Scanned WITHANDWITHOUTMMTAGLINES 2D SSFP sequence, 1 slice, 5 mm thick, Ajaj, 10 each healthy, 20 s during breathhold. Scanned gastroparesis, and WITHANDWITHOUTTAGLINES PYLOROSPASM ;33] +WIATEK HEALTHY ;44] 33&0WITH3%.3% SLICESMMTHICK 120 images over 167 s 4RIER HEALTHY;15] 33&0WITH3%.3% SLICES MM thick, interleaved acquisition, 155 s

Table 13.1 #OMPARISONOFSTUDIESEVALUATINGGASTRICMOTILITYBY-2)

-AGNETIC2ESONANCE)MAGINGFOR'ASTRIC-OTILITY 141

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INCREASEWITHDISTANCEFROMTHEISOCENTEROFTHEMAGNET4HE%0)SEQUENCESAMPLES MULTIPLELINESOFDATAWITHEACH2&EXCITATIONPULSE7HILETHISISEFlCIENTINTIME T2DECAYALONGTHESAMPLINGWINDOWPRODUCESBLURRINGINTHEPHASEENCODINGDIRECTIONOFTHEIMAGE!DDITIONALLY AREASOFMAGNETICSUSCEPTIBILITY PARTICULARLYATTISSUEn AIRINTERFACES CANCAUSESIGNALVOIDSANDSIGNALPILEUP'EOMETRICDISTORTIONSIN%0) SCANSCAUSEDBYGRADIENTIMPERFECTIONCANALSOBEANISSUEIFCAREISNOTTAKENIN pulse sequence design and calibration. The HASTE sequence acquires all image DATALINESDURINGASINGLEACQUISITION)TDIFFERSFROMTHE%0)SEQUENCEINTHATTHE ACQUISITIONOFINDIVIDUALLINESISSEPARATEDWITH2&REFOCUSINGPULSES4HEADDED REFOCUSINGPULSESELIMINATEGEOMETRICDISTORTIONSANDSUSCEPTIBILITYARTIFACTSFOUND IN%0)SCANSWHILEADDING2&ENERGYDEPOSITIONCANCAUSETISSUEHEATINGORDECREASED SLICETHROUGHPUTATHIGHERMAGNETlELDSTRENGTHS,IKE%0) (!34%SCANSWILLSUFFER FROMBLURRINGINTHEPHASEENCODINGDIRECTION0ARALLELIMAGINGCANBEUSEDWITH ANY OF THESE IMAGING SEQUENCES IN A TRADEOFF OF SIGNAL FOR INCREASED TEMPORAL OR SPATIALRESOLUTION;6=4HESENSITIVITYENCODING3%.3% TECHNIQUEEXPLOITSSPATIAL INFORMATIONWHICHCANBEOBTAINEDWITHACALIBRATIONSCANOFTHEMULTIPLERECEIVER COILSUSEDINA-2)EXAM)NDYNAMICEXAMS SUCHASGASTRICMOTILITY COILSENSITIVITIES WOULDALSOBEDYNAMIC ANDAPARALLELIMAGINGMETHOD SUCHASGENERALIZEDAUTOCALIBRATINGPARTIALLYPARALLELACQUISITIONS'2!00! WHICHEMPLOYSANEMBEDDED DYNAMICCALIBRATIONSCAN ISPREFERRED 6OLUMETRICSCANSCANBEPERFORMEDWITHMULTIPLANARVERSIONSOFANYOFTHEPREVIously mentioned 2D sequences or higher through-plane resolution can be obtained WITHA$'2%SEQUENCE/NETECHNIQUEISTHELIVERACQUISITIONWITHVOLUMEACCELERATION,!6! SEQUENCE WHICHUSESFATSUPPRESSIONALONGWITH3%.3%PARALLEL imaging.

Assessment of Gastric Volumes 4HESTOMACHRELAXESORACCOMMODATESAFTERAMEAL PROVIDINGROOMFORFOODTOBE BROKENDOWNINTOSMALLERPARTICLES4HISPROCESS REFERREDTOASACCOMMODATION CAN BEMEASUREDBYABAROSTATORBYLESSINVASIVETECHNIQUES;IE SINGLEPHOTONEMISSION COMPUTEDTOMOGRAPHY30%#4 ULTRASOUND OR-2)=3TUDIESWITHABAROSTATAND SEPARATELYWITHULTRASOUNDSUGGESTTHATIMPAIREDACCOMMODATIONMAYEXPLAINEARLY SATIETYINFUNCTIONALDYSPEPSIA;7n9]. Most studies evaluating gastric volumes and emptying by MRI labeled the nutrient MEALWITHGADOLINIUM WHICHAPPEARSBRIGHTONT2 WEIGHTEDSEQUENCESALLOWINGTHE MEALTOBEDISCRIMINATEDFROMAIRWITHINTHELUMEN;10n20]. These imaging sequences PROBABLYALSOSUFlCEFORMEASURINGTOTALGASTRICVOLUMEUNDERFASTINGCONDITIONS (OWEVER INTRAGASTRICmUIDANDAIRAPPEARDARK ANDITISCHALLENGINGTODEMARCATE THEBOUNDARYBETWEENTHEINNERSTOMACHWALLANDGASTRICCONTENTSORTODISTINGUISH BETWEEN GASTRIC mUID AND AIR WITH THESE SEQUENCES 4HEREFORE IF IT IS NECESSARY TO DISCRIMINATE BETWEEN INTRAGASTRIC AIR AND mUID UNDER FASTING AND POSTPRANDIAL

-AGNETIC2ESONANCE)MAGINGFOR'ASTRIC-OTILITY

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Fig. 13.1 Fasting (upper panel) and postprandial (lower panel) images acquired by MRI. In the FASTING HALF &OURIER ACQUISITION SINGLE SHOT TURBO SPIN ECHO (!34% IMAGES THE DISTINCTION BETWEENHIGHSIGNALINTENSITYmUID WHICHISLAYEREDPOSTERIORLYIE INTHEDEPENDENTPOSITION ANDLOWSIGNALINTENSITYAIR WHICHISANTERIOR ISOBVIOUS)NTHE,!6!IMAGES THEAIRnmUIDINTERFACE is subtle (arrow 0OSTPRANDIALLY AIRANDmUIDHAVELOWSIGNALINTENSITYIN(!34%IMAGESBUT EASILYDISTINGUISHABLEON,!6!SEQUENCEIE NUTRIENTLABELEDWITHGADOLINIUMAPPEARSBRIGHT WHILEAIRISDARK 2EPRODUCEDWITHPERMISSIONFROM&IDLER*, "HARUCHA!% #AMILLERI- #AMP* "URTON$ 'RIMM2 2IEDERER3* 2OBB2 AND:INSMEISTER!2!PPLICATIONOF-AGNETIC2ESONANCE Imaging to Measure Fasting and Postprandial Volumes in Humans. Neurogastroenterol Motil n

CONDITIONS IMAGES SHOULD BE ACQUIRED BY TWO SEQUENCES EG TWO DIMENSIONAL T2 WEIGHTED(!34% ANDATHREE DIMENSIONAL,!6!SEQUENCES &IG13.1 ;21]. 4HEREISEXCELLENTAGREEMENTBETWEENVOLUMESMEASUREDBYBOTHSEQUENCES4HE $,!6!SEQUENCE WHICHACQUIRES MMSLICESWITH MMOVERLAP IMAGESTHEENTIRE STOMACHINASINGLEBREATHHOLD WHILETHE(!34%SEQUENCEIMAGESTHEENTIRESTOMACH INS)NTHELARGESTSTUDYTOMEASUREGASTRICVOLUMES;21], comprising 20 subjects, THE POSTPRANDIAL CHANGE IN EXCESS OF THE INGESTED MEAL M, %NSURE WAS ÕM,-EANÕ3%- WHICHISCOMPARABLETOTHEAVERAGEINCREASEM, AFTERDEXTROSEM, KCAL INANOTHERSTUDY;17]. Together, these observations SUGGESTTHATPOSTPRANDIALGASTRICEXPANSIONMEASUREDBY-2)EXCEEDSTHEVOLUME OF THE INGESTED NUTRIENT (OWEVER ANOTHER STUDY OBSERVED THAT THE POSTPRANDIAL GASTRICVOLUMEDIDNOTEXCEEDTHEFASTINGVOLUMEPLUSVOLUMEOFINGESTEDNUTRIENT ARGUINGAGAINSTTHECONCEPTOFACCOMMODATION;22].

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4HEINTRAINDIVIDUAL DAY TO DAYREPRODUCIBILITYFORGASTRICVOLUMESMEASUREDBY -2) WAS BETTER FOR POSTPRANDIAL THAN FASTING VOLUMES AND BETTER FOR (!34% THAN ,!6!SEQUENCES;21=4HUS FORPOSTPRANDIALVOLUMESANDVOLUMECHANGESMEASURED BYTHE(!34%SEQUENCE THEWITHINSUBJECTCOEFlCIENTOFVARIATIONWASGENERALLYLESS THANANDOFTENORLOWER WHICHISCOMPARABLETOTHEINTRASUBJECTCOEFlCIENT OFVARIATIONOFGASTRICEMPTYINGHALF TIMEMEASUREDBYSCINTIGRAPHY;23]. 4HEPOSTPRANDIALCHANGEINGASTRICVOLUMEISLARGERWHENASSESSEDBYABAROSTAT than by noninvasive techniques (e.g., ultrasound or MRI), perhaps because an intraGASTRICBALLOONDISTENDSTHESTOMACHANDDISPLACESFOODTOWARDTHEANTRUM;22, 24]. )NTHEONLYHEAD TO HEADCOMPARISONOFGASTRICVOLUMESMEASUREDBYNONINVASIVE TECHNIQUES VOLUMES MEASURED BY -2) AND 30%#4 WERE NOT CORRELATED PERHAPS BECAUSETHETECHNIQUESUSEDIFFERENTAPPROACHESTOVISUALIZETHESTOMACH;21]. )N ADDITION TO GASTRIC RELAXATION SWALLOWED AIR GASTRIC EMPTYING AND GASTRIC SECRETION CONTRIBUTE TO THE POSTPRANDIAL INCREASE IN GASTRIC VOLUME ;17, 22, 25], WHICHISALSOINmUENCEDBYTHEINGESTEDMEALVOLUMEANDCALORICINTAKE4HEPOSTPRANDIALhEXCESSvVOLUMEMEASUREDBY-2)MAINLYCOMPRISESAIR WHICHINCREASED BYAPPROXIMATELYM,INSTUDIES;17, 21=0RESUMABLY SOMEOFTHEPOSTPRANDIAL INCREASEINGASTRICAIRCONTENTREPRESENTSAIRDISPLACEDFROMTHEHYPOPHARYNXINDEED HEALTHYSUBJECTSSWALLOWANAVERAGEOFM,OFAIRWITHASINGLEBOLUSOFM,;26]. (OWEVER THE POSTPRANDIAL INCREASE IN GASTRIC AIR WAS NOT SIGNIlCANTLY DIFFERENT WHENVOLUNTEERSWEREASKEDTODRINKTHESAMENUTRIENTLIQUIDVOLUMEINORSIPS SUGGESTINGTHATTHEMODEOFDRINKINGDIDNOTSIGNIlCANTLYAFFECTTHEPOSTPRANDIAL INCREASEINGASTRICAIRMEASUREDBY-2);21=(OWEVER THENUMBEROFSWALLOWS NECESSARYTOSWALLOWAM,ALIQUOTWASNOTCOUNTED7HENNUTRIENTSAREINFUSED INTOTHESTOMACHBYANASOGASTRICTUBE THEVOLUMEOFGASTRICAIR AVERAGINGM, IS STABLE DURING GASTRIC lLLING ;27]. Together, these observations suggest that THE POSTPRANDIAL INCREASE IN GASTRIC AIR VOLUME PROBABLY REmECTS SWALLOWED AIR #ONCEIVABLY THE RECUMBENT POSITION MIGHT LIMIT BELCHING OF AIR TRAPPED IN THE FUNDUS ABOVE THE GASTROESOPHAGEAL JUNCTION IN THE RECUMBENT POSITION (OWEVER ACOMPARISONOFGASTRIC-2)INTHESEATEDANDRECUMBENTPOSITIONSREVEALEDSIGNIlCANT DIFFERENCES IN INTRAGASTRIC AIR ONLY DURING THE LATE IE n MIN AND NOT DURINGTHEEARLYPOSTPRANDIALPERIODnMIN ;15]. 5SING A VARIETY OF TECHNIQUES IE SCANNING FREQUENTLY ;EG EVERY MIN FOR MIN POSTPRANDIALLY= ADMINISTERING PENTAGASTRIN COMPARING EFFECTS OF SMALLER and larger meals, measuring gastric pressures during MRI and T1 mapping), the :URICHGROUPHAVEPARTIALLYDECONVOLUTEDTHECONTRIBUTIONOFGASTRICSECRETIONAND EMPTYINGTOPOSTPRANDIALGASTRICVOLUMECHANGESANDALSOEVALUATEDTHEEFFECTSOF CALORICCOMPOSITIONONPOSTPRANDIALGASTRICVOLUMES;17, 20, 27]. T1MAPPINGUTILIZES THEINVITRORELATIONSHIPBETWEENTHECONCENTRATIONOFTHECONTRASTAGENTANDTHET1 RELAXATIONTIMETOESTIMATETHEDILUTIONOFGASTRICCONTENTSINVIVO4HEKEYINFERENCES FROM THESE STUDIES ARE AS FOLLOWS &IRST GASTRIC VOLUME RESPONSES AFTER NUTRIENT DELIVERYCANBECHARACTERIZEDBYAlLLINGPHASE DURINGWHICHGASTRICVOLUMEGENERALLY INCREASES FOLLOWEDBYANEMPTYINGPHASE DURINGWHICHGASTRICVOLUMEDECLINES 7HENNUTRIENTSAREDELIVEREDBYANASOGASTRICTUBE WHICHAVOIDSSWALLOWINGOFAIR


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THEVOLUMEOFGASTRICCONTENTSINCREASESIFTHERATEOFSECRETIONEXCEEDSTHERATEOF GASTRICEMPTYING;18=3ECOND AFTERNASOGASTRICDELIVERYOFNUTRIENTS POSTPRANDIAL CHANGESINGASTRICPRESSUREAREREMARKABLYSMALL AVERAGINGMM(GEVENFORA KCALM, MEAL3UBSEQUENTLY EMPTYINGOFNUTRIENTSINTOTHEDUODENUM TRIGGERS GASTROINTESTINAL NEUROHORMONAL RESPONSES WHICH INmUENCE POSTPRANDIAL GASTRICVOLUMES4HIRD WITHRESPECTTOMACRONUTRIENTCOMPOSITION THEPOSTPRANDIAL INCREASEINGASTRICVOLUMEWASHIGHERAFTERISOVOLUMICANDNEARLYISOCALORICGLUCOSE MEALSTHANAFTERLIPIDORPROTEINMEALSDELIVEREDVIAANASOGASTRICTUBE;17=(OWEVER THESElNDINGSAREDIFlCULTTOINTERPRETSINCETHEOSMOLALITYOFGLUCOSEMEALSUSEDIN THISSTUDY MOSMOLL WASHIGHERTHANTHATOFTHEFATORPROTEINMSMOLL MEALS -OREOVER WHILE EMPTYING OF ALL NUTRIENTS WAS COMPARABLE FOR THE lRST MIN FATS EMPTIED AT A FASTER RATE THEREAFTER 4HESE OBSERVATIONS CONTRAST WITH other studies suggesting that among isocaloric meals, lipids delay gastric emptying. 0ERHAPS THESE DIFFERENCES ARE ALSO PARTLY EXPLAINED BY THE TENDENCY FOR LIPIDS TO mOCCULATEANDLAYERABOVEGASTRICNONLIPIDCONTENT WHICHINTURNMAYAFFECTGASTRIC EMPTYING;28].

Assessment of Gastric Emptying 'ASTRICEMPTYINGCANBEMEASUREDFROMATIMESERIESOFGASTRICVOLUMES(OWEVER SINCEALIQUIDMEALISGENERALLYUSED ANDBECAUSEVOLUMESAREALSOINmUENCEDBY GASTRICSECRETION FREQUENTSCANSARENECESSARY PARTICULARLYEARLYAFTERTHEMEALIS GIVEN)NTHElRSTSTUDYTOEVALUATEGASTRICEMPTYINGBY-2)FROM 3CHWIZER ETALOBSERVEDCOMPARABLEGASTRICEMPTYINGPROlLESOFALIQUIDMEALM,GLUCOSE ;= MIXEDWITH'D $/4!GADOLINIUMTETRAAZACYCLODODECANETETRAACETICACID WHENMEASUREDBY-2)ANDSCINTIGRAPHYINHEALTHYSUBJECTSANDPATIENTSWITH UPPERGASTROINTESTINALSYMPTOMS OFWHOMHADDELAYED HADNORMAL ANDHAD RAPIDGASTRICEMPTYING;10=0ERHAPSBECAUSETHESETWO DIMENSIONALIMAGESWERE ACQUIREDWITHAWEAKEROR4 MAGNETANDLONGACQUISITIONTIMES IMAGEQUALITY WASPOORANDCORRELATIONBETWEEN-2)ANDSCINTIGRAPHYWASIMPERFECT4HEREAFTER &EINLECOMPAREDGASTRICEMPTYINGOFISOCALORICKCAL LIQUID)NTRALIPID G ALBUMIN AND WATER AND MIXED SOLIDnLIQUID MEALS PANCAKE WITH WATER BY -2)ANDSCINTIGRAPHYONSEPARATEDAYSINHEALTHYSUBJECTS;13]. This is the only STUDYTHATEVALUATEDGASTRICEMPTYINGOFSOLIDSANDALSOCOMPAREDGASTRICEMPTYING OFSOLIDSBY-2)ANDSCINTIGRAPHY7HILETHELIQUIDMEALWASLABELEDWITH'D $/4! THESOLIDMEALWASNOTBOTHMEALSWEREVISIBLEONPOSTPRANDIAL-2IMAGES4HEENTIRE STOMACHWASIMAGEDDURINGFOURSBREATHHOLDS SEPARATEDBYANINTERVALDURING WHICH BREATHING WAS PERMITTED AT SEVERAL TIME POINTS AFTER A MEAL 'ASTRIC MEAL VOLUMEWASCORRECTEDFORPROGRESSIVEDILUTIONDUETOGASTRICSECRETIONUSINGINVITRO DATAEXAMININGTHESIGNALCHARACTERISTICSOFMEALSMIXEDWITHDIFFERENTCONCENTRATIONS OF - HYDROCHLORIC ACID #ONSISTENT WITH THE RELATIVELY HIGH CALORIC CONTENT THE AVERAGE GASTRIC EMPTYING HALF TIMES WERE RELATIVELY LONG HIGHER FOR

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solids (MRI 129 ± 9 min, Mean ± SEM; scintigraphy 123 ± 11 min) than liquids -2)ÕMIN SCINTIGRAPHYÕMIN ANDCOMPARABLEFOR-2)ANDSCINTIGRAPHY(OWEVER INDIVIDUALVALUESFORSUBJECTSWERENOTPROVIDED-OREOVER FOR THIS STUDY AND FOR ANOTHER STUDY WHICH USED ECHO PLANAR IMAGING MORE SCANNER TIMEWASREQUIREDBECAUSETHEGASTRICEMPTYINGHALF TIMEWASLONG LIMITINGCLINICAL UTILITY;29]. Lauenstein measured gastric volumes and emptying by a time-resolved $GRADIENTECHO'2% SEQUENCEWHEREBYCONTIGUOUS MMTHICKSLICESWERE ACQUIREDDURINGANENDINSPIRATORYBREATHHOLDLASTINGFORS;30]. 7HILEMOSTSTUDIESHAVEBEENLIMITEDTOHEALTHYSUBJECTS DELAYEDEMPTYINGOF caloric liquids has been demonstrated in diabetic autonomic neuropathy (15 patients), ;31=DIABETICGASTROPARESIS;32= ANDFUNCTIONALDYSPEPSIA;30].

Assessment of Gastric Motility !SSESSMENT OF GASTRIC CONTRACTIONS REQUIRES FASTER IMAGING SEQUENCES THAN THOSE used to measure gastric volumes or emptying. These studies have employed a variety OF$-2SEQUENCES MOSTLYIMAGINGTHESTOMACHATONEORMORESLICESPARALLEL to the antrum every second over a variable duration (Table 13.1). Images can be ANALYZED MANUALLY ;33] or by an semiautomated process by measuring gastric dimensions along equidistant points along the gastric contour, typically along planes PERPENDICULARTOANAXISDRAWNTHROUGHTHELONGAXISOFTHESTOMACH;34]. The contracTIONFREQUENCY AMPLITUDE ANDVELOCITYCANBECALCULATEDBYMANUALORSEMIAUTOMATED analysis (Figs. 13.2 and 13.3 4HELATTERENTAILSASPECTRALANALYSISOFATIME SERIES OFGASTRICCROSS SECTIONALDIAMETERSTOIDENTIFYTHEDOMINANTCONTRACTILEFREQUENCY 4HEN THE PHASE AT THIS FREQUENCY IS PLOTTED AGAINST LOCATION ALONG THE LONG AXIS )NTHESEPHASESHIFTPLOTS ALINEARCHANGEIE R2 t 0.93) in phase versus location WAS USED TO DOCUMENT PROPAGATED CONTRACTIONS 4HE VELOCITY OF PROPAGATION WAS ESTIMATEDFROMTHEINVERSE SLOPEOFTHISLINE4HERELATIVEAMPLITUDEOFCONTRACTIONSWASESTIMATEDBYCALCULATINGTHEMAGNITUDEOFTHE&OURIERCOEFlCIENTATTHE DOMINANTPEAK WHICHWASNORMALIZEDTOTHELARGESTDIAMETERATTHATPERPENDICULAR PLANEOVERTHEENTIRE SEPOCH!LTERNATIVELY MOTILITYCANBEQUANTIlEDBYhTAGGING v WHEREINAREFERENCEGRIDISMAGNETICALLYSUPERIMPOSEDONTOTHEIMAGEOFTHESTOMACH BYSPATIALLYMODULATINGTHEMAGNETIZATIONPRIORTOIMAGING!FTERIMAGING MOTILITY ISCALCULATEDWITHREFERENCETOTHESPATIALGRID;33]. 7HILE INTRALUMINAL MANOMETRY MAY AFFECT GASTRODUODENAL MOTILITY -2) DOES NOT;35=-2)ISALSOMORELIKELYTHANMANOMETRYTOIDENTIFYNON LUMEN OCCLUDING CONTRACTIONS ;36, 37=WHICHISANIMPORTANTADVANTAGESINCEASIGNIlCANTPROPORTION OFANTRALCONTRACTIONSAPPROACHINGTHEPYLORUSASSHOWNPREVIOUSLYANDCONlRMED HEREARENONOCCLUSIVE;38=)NONESTUDY -2)WASMORESENSITIVETHANMANOMETRY FORDETECTINGCONTRACTIONS;39]. MRI has been used to document altered gastric motility due to pharmacological modulation and disease (Table 13.1 )N ONE STUDY PROXIMAL AND DISTAL GASTRIC CONTRACTION PARAMETERS WERE NOT SIGNIlCANTLY DIFFERENT AMONG DIABETIC PATIENTS


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Fig. 13.2 4IMESEQUENCEOF$OBLIQUECORONALPLANE-2IMAGESMULTIPHASE$&)30SEQUENCE OFTHESTOMACHINAPATIENTWITHRAPIDGASTRICEMPTYING&ORCLARITY ONLYEVERYlFTHIMAGEIE AT SINTERVALS ISSHOWN4HELONGITUDINALAXISANDPERPENDICULARPLANESUSEDTOMEASUREGASTRIC DIMENSIONSARESHOWNIN0ANELa). Panels (b) and (c) depict a propagating contraction (arrowhead), WHICHDISTENDSTHEANTRALBULBPROXIMALTOTHEPYLORUSarrow). Panel (d SHOWSATERMINALANTRAL contraction (arrowhead WITH lLLING OF THE DUODENAL BULB DISTAL TO THE PYLORUS arrow WHICH CONTRASTSTOTHETYPICALPATTERNWHEREINTHEPYLORUSISCLOSEDAHEADOFATERMINALANTRALCONTRACTION 2EPRODUCED WITH PERMISSION FROM "HARUCHA !% -ANDUCA ! ,AKE $3 &IDLER * %DWARDS 0 'RIMM2# :INSMEISTER!2 2IEDERER3*'ASTRIC-OTOR$ISTURBANCES)N0ATIENTS7ITH)DIOPATHIC 2APID'ASTRIC%MPTYING.EUROGASTROENTEROL-OTIL nE

WITH AND WITHOUT GASTROPARESIS AND HEALTHY SUBJECTS ;32= (OWEVER CISAPRIDE INCREASEDTHEAMPLITUDEOFPROXIMALGASTRICCONTRACTIONSINDIABETICGASTROPARESIS;32]. By contrast, another study observed increased antral motility in pylorospasm and REDUCEDANTRALMOTILITYINGASTROPARESIS;33=#OMPAREDTOHEALTH THEAMPLITUDEOF GASTRICCONTRACTIONSWASALSOINCREASEDINPATIENTSWITHFUNCTIONALDYSPEPSIAAND RAPIDBUTNOTNORMALGASTRICEMPTYING DEMONSTRATINGFORTHElRSTTIMETHATPATIENTS

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WITH IDIOPATHIC RAPID GASTRIC EMPTYING HAVE INCREASED GASTRIC MOTILITY ;34]. (OWEVER FASTING AND POSTPRANDIAL GASTRIC VOLUMES AND THE POSTPRANDIAL GASTRIC VOLUMECHANGEWERENOTSIGNIlCANTLYDIFFERENTBETWEENHEALTHYPEOPLEANDPATIENTS WITHDYSPEPSIA

Other Applications of Gastric MRI -2)CANDOCUMENTTO AND FROmOWOFCONTENTSACROSSTHEPYLORUS ;35] Integrated ASSESSMENTSOFWALLMOTIONBY-2)ANDGASTRICPRESSURESBYAlBER OPTICRECORDING SYSTEM WHICHISCOMPATIBLEWITHTHE-2)ENVIRONMENT CANASSESSTHERELATIONSHIP BETWEENGASTRICVOLUMES WALLMOTION PRESSURECHANGES ANDEMPTYINGINDETAIL;27]. 4HESElNDINGSCONlRMTHATGASTRICWALLSTRESSPASSIVESTRAINANDACTIVETONE PROVIDE THEDRIVINGFORCEFORGASTRICEMPTYING BUTDISTALRESISTANCETOGASTRICOUTmOWREGULATES FURTHERPASSAGEOFNUTRIENTS

Summary and a Look at the Future Among non invasive techniques, MRI has the unique ability to measure gastric VOLUMES EMPTYINGOFLIQUIDS ANDMOTILITYWITHOUTRADIATIONEXPOSURE/FFSETTING these advantages, most scanners permit imaging in the supine position only. Other LIMITATIONSOFEXISTINGSTUDIESIE SMALLSAMPLESIZE PREDOMINANTLYHEALTHYPEOPLE CANBEOVERCOME PARTICULARLYASTHEAVAILABILITYOFSCANNERSANDIMAGINGSEQUENCES INCREASES7HILETHEPERFORMANCECHARACTERISTICSOF-2)FOREVALUATINGGASTRICVOLUMES AREEXCELLENT FURTHERVALIDATIONFORASSESSMENTSOFGASTRICEMPTYINGANDMOTILITYIS NECESSARY !LTHOUGH IT IS UNLIKELY THAT GASTRIC -2) WILL REPLACE SCINTIGRAPHY FOR evaluating gastric emptying, its ability to simultaneously assess gastric contractility, VOLUMES AND PYLORIC mOW SHOULD FACILITATE OUR UNDERSTANDING OF GASTRIC MOTOR DYSFUNCTIONS

Fig. 13.3 CONTINUED TOTHEMAXIMUMDIAMETERATTHATLOCATIONMAXIMUMDIAMETERISSHOWNIN DARKREDANDMINIMUMINDARKBLUE4HREENARROWCONTRACTIONS WHICHARESHADEDINBLUE PROPAGATEDFROMTHEBODYTOTHEPYLORUSIE FROMTOMMALONGTHECENTERLINE 4HEHORIZONTAL LINEATMMSEPARATESAPROXIMALPROPAGATINGCONTRACTIONFROMAMORESLOWLYPROPAGATINGDISTAL contraction (see panel c). The spectral analysis (Panel b REVEALSADOMINANTFREQUENCYOFCPM 4HEPHASESHIFTPLOT0ANELc SHOWSLINEARCONTRACTIONS IE FROMTOANDFROMTOMM WITHDIFFERINGPROPAGATIONVELOCITIES0ANELd SHOWSTHERELATIVEDIAMETERCHANGEATMMALONG THELINETHECONTRACTIONS WHICHAREIDENTIlEDBYBLACKARROWS ARENOTONLYEXTREMELYPOWERFUL and completely occlude the lumen, but also relatively prolonged, lasting 10 s or longer. Panels (e-h SHOWGASTRICCONTRACTIONShCONTRACTOGRAMSv DERIVEDFROMGASTRIC-2)IMAGESMULTIPHASE 2D FISP sequence) in a healthy subject. In contrast to Panels (a-d THECONTRACTIONSAREWEAKER 2EPRODUCED WITH PERMISSION FROM "HARUCHA !% -ANDUCA ! ,AKE $3 &IDLER * %DWARDS 0 'RIMM2# :INSMEISTER!2 2IEDERER3*'ASTRIC-OTOR$ISTURBANCES)N0ATIENTS7ITH)DIOPATHIC 2APID'ASTRIC%MPTYING.EUROGASTROENTEROL-OTIL nE

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Acknowledgments 4HIS STUDY WAS SUPPORTED IN PART BY 0/ $+ FROM THE .ATIONAL )NSTITUTESOF(EALTH

References 3TEHLING -+ ET AL 'ASTROINTESTINAL TRACT DYNAMIC -2 STUDIES WITH ECHO PLANAR IMAGING 2ADIOLOGY n %VANS $& ET AL 0ROLONGED MONITORING OF THE UPPER GASTROINTESTINAL TRACT USING ECHO PLANAR MAGNETICRESONANCEIMAGING'UT n (OWSEMAN !- ET AL )MPROVEMENTS IN SNAP SHOT NUCLEAR MAGNETIC RESONANCE IMAGING "R*2ADIOL n -UGLERRD*0/VERVIEWOF-2IMAGINGPULSESEQUENCES-AGN2ESON)MAGING#LIN.!M n "ERNSTEIN-! +ING+& :HOU8* EDITORS(ANDBOOKOF-2)PULSESEQUENCES"URLINGTON -! Elsevier Academic Press; 2004. "LAIMER-ETAL3-!3( 3%.3% 0),3 '2!00!HOWTOCHOOSETHEOPTIMALMETHOD 4OP-AGN2ESON)MAGING n "REDENOORD !* ET AL 'ASTRIC ACCOMMODATION AND EMPTYING IN EVALUATION OF PATIENTS WITH UPPERGASTROINTESTINALSYMPTOMS#LIN'ASTROENTEROL(EPATOLn +ARAMANOLIS'ETAL!SSOCIATIONOFTHEPREDOMINANTSYMPTOMWITHCLINICALCHARACTERISTICSAND PATHOPHYSIOLOGICALMECHANISMSINFUNCTIONALDYSPEPSIA;COMMENT='ASTROENTEROLOGY n -UNDT -7 3AMSOM - &UNDAL DYSACCOMMODATION IN FUNCTIONAL DYSPEPSIA HEAD TO HEAD COMPARISONBETWEENTHEBAROSTATANDTHREE DIMENSIONALULTRASONOGRAPHICTECHNIQUE'UT n 3CHWIZER7 -AECKE( &RIED--EASUREMENTOFGASTRICEMPTYINGBYMAGNETICRESONANCE IMAGINGINHUMANS'ASTROENTEROLOGY n 3CHWIZER7ETAL-EASUREMENTOFGASTRICEMPTYINGANDGASTRICMOTILITYBYMAGNETICRESONANCE IMAGING-2) $IG$IS3CI3UPPL 3n3 +UNZ0ETAL'ASTRICEMPTYINGANDMOTILITYASSESSMENTWITH-2IMAGING PRELIMINARYOBSERVATIONS;COMMENT=2ADIOLOGY n &EINLE#ETAL3CINTIGRAPHICVALIDATIONOFAMAGNETICRESONANCEIMAGINGMETHODTOSTUDYGASTRIC EMPTYINGOFASOLIDMEALINHUMANS'UT n 3CHWIZER7ETAL.ON INVASIVEMEASUREMENTOFGASTRICACCOMMODATIONINHUMANS'UT 3UPPLIn 4REIER2ETAL'ASTRICMOTORFUNCTIONANDEMPTYINGINTHERIGHTDECUBITUSANDSEATEDBODYPOSITIONASASSESSEDBYMAGNETICRESONANCEIMAGING*-AGN2ESON)MAGING n &RUEHAUF ( ET AL )NTERSUBJECT AND INTRASUBJECTVARIABILITY OF GASTRIC VOLUMES IN RESPONSE TO ISOCALORICLIQUIDMEALSINFUNCTIONALDYSPEPSIAANDHEALTH.EUROGASTROENTEROL-OTIL n 'OETZE/ETAL4HEEFFECTOFMACRONUTRIENTSONGASTRICVOLUMERESPONSESANDGASTRICEMPTYING INHUMANSAMAGNETICRESONANCEIMAGINGSTUDY!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n 'OETZE/ETAL%FFECTOFGASTRICSECRETIONONGASTRICVOLUMERESPONSES EMPTYINGANDINTRAGASTRIC dilution in humans: a magnetic resonance imaging (MRI) study. Gastroenterology. 2007;132 (4; Suppl 2):T1903. &RUEHAUF(ETAL#HARACTERIZATIONOFGASTRICVOLUMERESPONSESANDLIQUIDEMPTYINGINFUNCtional dyspepsia and health by MRI or barostat and simultaneous C-acetate breath test. .EUROGASTROENTEROL-OTIL nE 'OETZE/ETAL4HEEFFECTOFGASTRICSECRETIONONGASTRICPHYSIOLOGYANDEMPTYINGINTHEFASTED ANDFEDSTATEASSESSEDBYMAGNETICRESONANCEIMAGING.EUROGASTROENTEROL-OTIL nE


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&IDLER*ETAL!PPLICATIONOFMAGNETICRESONANCEIMAGINGTOMEASUREFASTINGANDPOSTPRANDIAL VOLUMESINHUMANS.EUROGASTROENTEROL-OTILn DE:WART)-ETAL'ASTRICACCOMMODATIONANDMOTILITYAREINmUENCEDBYTHEBAROSTATDEVICE ASSESSMENT WITH MAGNETIC RESONANCE IMAGING !M * 0HYSIOL 'ASTRO ,IVER 0HYSIOL 'n #REMONINI&ETAL0ERFORMANCECHARACTERISTICSOFSCINTIGRAPHICTRANSITMEASUREMENTSFORSTUDIES OFEXPERIMENTALTHERAPIES!LIMENT0HARMACOL4HER n -UNDT-7 (AUSKEN4 3AMSOM-%FFECTOFINTRAGASTRICBAROSTATBAGONPROXIMALANDDISTAL GASTRICACCOMMODATIONINRESPONSETOLIQUIDMEAL!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n "URTON$$ETAL2ELATIONSHIPOFGASTRICEMPTYINGANDVOLUMECHANGESAFTERASOLIDMEALIN HUMANS!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n 0OUDEROUX 0 ET AL %SOPHAGEAL BOLUS TRANSIT IMAGED BY ULTRAFAST COMPUTERIZED TOMOGRAPHY 'ASTROENTEROLOGY n +WIATEK-!ETAL%FFECTOFMEALVOLUMEANDCALORIELOADONPOSTPRANDIALGASTRICFUNCTIONAND EMPTYINGSTUDIESUNDERPHYSIOLOGICALCONDITIONSBYCOMBINEDlBER OPTICPRESSUREMEASUREMENT AND-2)!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n +UNZ0ETAL%FFECTOFINGESTIONORDEROFTHEFATCOMPONENTOFASOLIDMEALONINTRAGASTRIC FATDISTRIBUTIONANDGASTRICEMPTYINGASSESSEDBY-2)*-AGN2ESON)MAGING n -ARCIANI,ETAL%CHOPLANARIMAGINGIN')CLINICALPRACTICEASSESSMENTOFGASTRICEMPTYING ANDANTRALMOTILITYINFOURPATIENTS*-AGN2ESON)MAGING n ,AUENSTEIN4#ETAL4IME RESOLVEDTHREE DIMENSIONAL-2IMAGINGOFGASTRICEMPTYINGMODIlED BY)6ADMINISTRATIONOFERYTHROMYCIN!*2!M*2OENTGENOLn ,EHMANN2ETAL%VALUATIONOFDELAYEDGASTRICEMPTYINGINDIABETICPATIENTSWITHAUTONOMIC NEUROPATHY BY A NEW MAGNETIC RESONANCE IMAGING TECHNIQUE AND RADIO OPAQUE MARKERS $IABETES#ARE n "OROVICKA*ETAL%VALUATIONOFGASTRICEMPTYINGANDMOTILITYINDIABETICGASTROPARESISWITH MAGNETICRESONANCEIMAGINGEFFECTSOFCISAPRIDE!M*'ASTROENTEROL n !JAJ 7 ET AL 2EAL TIME HIGH RESOLUTION MAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF GASTRICMOTILITYDISORDERS'UT n "HARUCHA!% ETAL'ASTRICMOTORDISTURBANCESINPATIENTSWITHIDIOPATHICRAPIDGASTRICEMPTYING. .EUROGASTROENTEROL-OTIL nE "OULBY0ETAL&ATDELAYSEMPTYINGBUTINCREASESFORWARDANDBACKWARDANTRALmOWASASSESSED BYmOW SENSITIVEMAGNETICRESONANCEIMAGING.EUROGASTROENTEROL-OTIL n )NDIRESHKUMAR + ET AL 2ELATIVE CONTRIBUTIONS OF hPRESSURE PUMPv AND hPERISTALTIC PUMPv TOGASTRICEMPTYING!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n &AAS(ETAL0RESSURE GEOMETRYRELATIONSHIPINTHEANTRODUODENALREGIONINHUMANS!M*0HYSIOL 'ASTROINTEST,IVER0HYSIOL 'n +ING0-ETAL2ELATIONSHIPSOFHUMANANTRODUODENALMOTILITYANDTRANSPYLORICmUIDMOVEMENT NON INVASIVEOBSERVATIONSWITHREAL TIMEULTRASOUND'UT n 7RIGHT*ETAL6ALIDATIONOFANTRODUODENALMOTILITYMEASUREMENTSMADEBYECHO PLANARMAGNETIC RESONANCEIMAGING.EUROGASTROENTEROL-OTIL n +UNZ0ETAL!SSESSMENTOFGASTRICMOTORFUNCTIONDURINGTHEEMPTYINGOFSOLIDANDLIQUID MEALSINHUMANSBY-2)*-AGN2ESON)MAGING n 41. Marciani L et al. Antral motility measurements by magnetic resonance imaging. Neurogastroenterol -OTIL n DE:WART)-ETAL'ASTRICMOTILITYCOMPARISONOFASSESSMENTWITHREAL TIME-2IMAGINGOR BAROSTATMEASUREMENTINITIALEXPERIENCE2ADIOLOGY n !JAJ7ETAL2EAL TIMEHIGH RESOLUTION-2)FORTHEASSESSMENTOFGASTRICMOTILITYPRE AND POSTPHARMACOLOGICALSTIMULI*-AGN2ESON)MAGING n +WIATEK-!ETAL1UANTIlCATIONOFDISTALANTRALCONTRACTILEMOTILITYINHEALTHYHUMANSTOMACH WITHMAGNETICRESONANCEIMAGING*-AGN2ESON)MAGING n

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Chapter 14

Electrogastrography for Evaluation of Patients with Suspected Gastroparesis Kenneth L. Koch

Keywords %LECTROGASTROGRAPHYs%LECTROGASTROGRAMs4ACHYGASTRIAs"RADYGASTRIA s'ASTROPARESISs3LOWWAVESs-YOELECTRICALACTIVITY

Introduction %LECTROGASTROGRAPHYREFERSTOMETHODSFORRECORDINGGASTRICMYOELECTRICALACTIVITY FROMELECTRODESPLACEDONTHEABDOMINALSURFACE4HEGASTRICMYOELECTRICALSIGNAL ISTERMEDANELECTROGASTROGRAMOR%''4HE%''REmECTSTHEGASTRICSLOWWAVE DURING FASTING AND IN THE POSTPRANDIAL CONDITION THE %'' REmECTS THE MIGRATING SLOWWAVELINKEDTOPLATEAUORACTIONPOTENTIALACTIVITYOCCURRINGINTHESTOMACH;1]. )NNORMALCIRCUMSTANCES THECPM%''FREQUENCYREmECTSTHECYCLEPERMINUTE CPM SLOW WAVEFREQUENCY#HANGESINTHEAMPLITUDEOFTHECPM%''SIGNAL AFTERANONCALORICWATERLOADORACALORICMEALREmECTTHEhELECTRICALSUMMATIONv OFSLOWWAVEANDPLATEAUORACTIONPOTENTIALACTIVITY;2=/NTHECONTRARY AVARIETY OFGASTRICDYSRHYTHMIASHAVEBEENFOUNDINCLINICALCONDITIONSTHATINCLUDENAUSEA VOMITING AND GASTROPARESIS ;3–7= 4HESE DYSRHYTHMIAS INCLUDE TACHYGASTRIAS (3.5–10.0 cpm), bradygastrias (0–2.5 cpm), and nonspecific or mixed dysrhythmias, ALL OF WHICH ARE DESCRIBED BELOW IN THE EVALUATION OF THE PATIENT WITH SUSPECTED gastroparesis.

K.L. Koch (*) 3ECTIONON'ASTROENTEROLOGY 7AKE&OREST5NIVERSITY3CHOOLOF-EDICINE -EDICAL#ENTER"OULEVARD 7INSTON 3ALEM .# 53! E MAILKKOCH WFUBMCEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_14, © Springer Science+Business Media, LLC 2012

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Physiological Basis of the Electrogastrogram 4HESTOMACHHASAhPACEMAKERREGIONvLOCATEDONTHEGREATERCURVATUREBETWEEN THEFUNDUSANDTHEPROXIMALCORPUS;8]. From this pacemaker region, spontaneous ELECTRICALEVENTSTERMEDSLOWWAVESORIGINATEANDMIGRATEINARING LIKEhELECTRICAL HALOvACROSSTHECORPUSANDANTRUMTOTHEPYLORUSATAPPROXIMATELYSINTERVALS !SONEWAVEFRONTOFSLOWWAVETERMINATESINTHEANTRUM ANOTHERELECTRICALWAVE sequence has begun to form and migrate distally from the pacemaker region. 4HUS THENORMALSLOWWAVEFREQUENCYRECORDEDBY%''ISAPPROXIMATELYCPM nCPM INHEALTHYHUMANS;8, 9]. 4HEINTERSTITIALCELLSOF#AJAL)##S LOCATEDBETWEENTHECIRCULARANDLONGITUDINAL MUSCLELAYERS)## -9 ARETHEhPACEMAKERCELLSvRESPONSIBLEFORTHESLOWWAVE FREQUENCY OF CPM ;10= )N THE POSTPRANDIAL PERIOD RECURRENT PERISTALTIC WAVES produced by circular muscle contractions triturate the ingested food and then empty THENUTRIENTCHYMEINTOTHEDUODENUM4HEELECTROPHYSIOLOGICALBASISOFCIRCULAR MUSCLECONTRACTIONSINVOLVEPLATEAUPOTENTIALSORACTIONPOTENTIALSLINKEDTOSLOW WAVES4HISLINKAGEOFPLATEAUPOTENTIALSANDSLOWWAVESRESULTSINTHEPERISTALTIC CONTRACTIONSREQUIREDFORTRITURATIONANDEMPTYINGOFFOODSATANORMALRATE;9=4HE normal rate of emptying also requires normal fundic motility, antral-duodenal coorDINATION AND APPROPRIATE VAGAL SYMPATHETIC NEURAL INPUTS TO THE STOMACH FOR THE TYPEOFINGESTEDMEAL;11=4HEINGESTEDFOODITSELF RANGINGFROMCARBOHYDRATEAND PROTEINTOFAT ALSOAFFECTSTHEGASTRICNEUROMUSCULARACTIVITYREQUIREDFORMIXINGAND emptying. When one or more of these elements of gastric electrophysiology and/or NEURAL HORMONALACTIVITYISABNORMAL THENTHERATEOFGASTRICEMPTYINGMAYBECOME DELAYEDANDTHERESULTISGASTROPARESIS;11, 12]. 3LOWWAVESPRODUCEDBYTHE)##SARECRUCIALELEMENTSINTHEORGANIZATIONOF normal gastric peristalsis in the postprandial period. ICCs are decreased in murine DIABETESANDGASTROPARESISSECONDARYTODIABETESINHUMANS;13, 14]. Furthermore, INPATIENTSWITHGASTRICDYSRHYTHMIASANDNAUSEAWHOWERETREATEDWITHDOMPERIDONE ORCISAPRIDE SYMPTOMSWEREREDUCEDANDNORMALCPM%''ACTIVITYWASRESTORED ;15, 16=4HESEOBSERVATIONSSUGGESTGASTRICDYSRHYTHMIASAREAhBIOMARKERvFORTHE symptom of nausea and also represent a key pathophysiological mechanism for the DELAYINGASTRICEMPTYING4HEPRESENCEOFGASTRICDYSRHYTHMIASEG TACHYGASTRIA disrupts the normal 3 cpm EGG rhythm and the associated peristaltic contractions TOVARYINGDEGREES

Recording EGGs in Patients with Symptoms Suspicious for Gastroparesis 2ECORDINGTHE%''ISRELATIVELYSIMPLEWITHTHEDEDICATEDHARDWAREANDSOFTWARE NOWAVAILABLE(OWEVER THEELECTRODESMUSTBEAPPLIEDPROPERLYANDTHERAW%'' signal must be carefully inspected to identify quality EGG signals for analysis ANDMOVEMENTARTIFACTSTHATDISTORT%''SIGNALSElectrodes. High-quality, fresh, disposable electrodes such as those used for EKG recording are recommended.

%LECTROGASTROGRAPHYFOR%VALUATIONOF0ATIENTSWITH3USPECTED'ASTROPARESIS

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4HEELECTRODESSHOULDSHOWLITTLEBIASOROFFSETPOTENTIALSINCETHE%''SIGNALIS RELATIVELYLOWAMPLITUDEANDLOWFREQUENCYRecording Equipment!HIGH QUALITY recording system is needed to amplify and process the 100–500 PV EGG signals. 3EVERALMEDICALDEVICECOMPANIESPRODUCECOMPLETE %'' RECORDING AND ANALYSIS SYSTEMSTHATINCLUDEAPPROPRIATEAMPLIlERSANDlLTERSWITHANALOG TO DIGITALBOARDS THAT DIGITIZE THE %'' SIGNAL FOR ANALYSIS WITH SOFTWARE EG #0- #OMPANY 4OWSON -$!LPINE"IO-ED &OUNTAIN6ALLEY #! 6ISUALDISPLAYOFTHERAW%'' SIGNALISVERYIMPORTANTTOSELECTARTIFACT FREE%''SIGNALFORVISUALORCOMPUTER analysis. Electrode Placement. Electrodes are placed on the skin surface of the epiGASTRIUMOVERTHEGENERALAREAOFTHECORPUSANDANTRUMOFTHESTOMACH4HElRST ACTIVEELECTRODEISPLACEDAPPROXIMATELYlNGERBREADTHSBELOWTHELEFTANTERIORRIB MARGIN IN THE MIDCLAVICULAR LINE 4HE SECOND ACTIVE ELECTRODE IS PLACED MIDWAY BETWEENTHEUMBILICUSANDXIPHOIDONTHEMIDLINEOFTHEABDOMEN4HEREFERENCE ELECTRODEISPLACEDTWOlNGERBREADTHSBELOWTHELOWESTANTERIORRIBONTHERIGHTSIDE ALONGTHEMIDCLAVICULARLINE;1].

EGG Recording Procedure 0ATIENTSFASTAFTERMIDNIGHTANDTHENINGESTA KCALBREAKFASTOFTWOPIECESOF TOASTANDOZOFAPPLEJUICEHPRIORTOTHE%''TESTTOSTANDARDIZETHEBASELINE EGG recording. By controlling the pretest meal, a consistent baseline EGG is OBTAINEDPRIORTOPROVOCATIVEWATERLOADORCALORICTESTMEAL;3]. Before placement OFTHE%''ELECTRODES THEPATIENTSSKINMUSTBEPREPAREDBYSHAVINGEXCESSHAIR AND CLEANING THE AREA WITH ALCOHOL TO LOWER ELECTRICAL RESISTANCE AND ACHIEVE AN OPTIMALELECTRODEnSKININTERFACE4HISISAVERYIMPORTANTPARTOFTHE%''RECORDING PROCEDURE)FTHEELECTRICALRESISTANCEBETWEENTHEELECTRODEANDSKINISHIGH THEN THE%''SIGNALAMPLITUDEWILLBEDECREASEDANDARTIFACTSMAYINCREASEINTHESIGNAL 4HEBEST%''RECORDINGSAREOBTAINEDIFTHEPATIENTRECLINESnINACOMFORTABLE CHAIR4HEPATIENTSHOULDBEINSTRUCTEDTOMINIMIZETALKINGANDMOVEMENTDURING %''RECORDINGTOPREVENTMOVEMENTARTIFACTS)FPOSSIBLE THEPATIENTSHOULDBEINA quiet room separated by some distance from the person doing the testing. Loud noises, crying children, and other stimuli that might startle the patient should be AVOIDED -OVEMENT OF LIMBS OR BODY MAY PHYSICALLY DISTURB THE ELECTRODEnSKIN INTERFACEANDCREATEMOVEMENTARTIFACTSINTHE%''SIGNAL

Analysis of EGG Recordings 4HE %'' SIGNAL IS CHANNELED FROM THE AMPLIlER TO AN ANALOG TO DIGITAL !$ CONVERTER 4HE SIGNAL IS DIGITIZED INTO A SERIES OF NUMERICAL VALUES REPRESENTING DISCRETEVOLTAGELEVELSOFTHERAW%''SIGNAL!$CONVERSIONUNITSTYPICALLYALLOW AWIDERANGEOFSAMPLINGRATES SUCHAS(ZTOPREVENTALIAS!LIASREFERSTOTHE PROCESSWHEREBYUNWANTEDHIGH FREQUENCYCOMPONENTS SUCHASTHE%+' APPEAR UNDER THE ALIAS OF THE DESIRED LOW FREQUENCY SIGNAL IN THIS CASE THE %'' ;17].

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/NCETHEENTIRE%''RECORDINGHASBEENDIGITIZED THEDATAMUSTBEPREPROCESSEDTO MEETTHEASSUMPTIONSOF&&4ANALYSISTHEREFORE ANALYSISOFATLEASTMINOF%'' DATAISRECOMMENDED;17].

Evaluation of Patients with Suspected Gastroparesis 4HE POSSIBILITY OF A GASTRIC NEUROMUSCULAR DISORDER SUCH AS A GASTRIC DYSRHYTHMIA OR GASTROPARESIS SHOULD BE CONSIDERED IN PATIENTS WHO HAVE UNEXPLAINED NAUSEA VOMITINGOFUNDIGESTEDFOOD EARLYSATIETY PROLONGEDFULLNESS ANDVAGUEEPIGASTRIC DISCOMFORT ANDINWHOMUPPERENDOSCOPYISNORMAL4HE%''RECORDINGISAPARTOF THE NEUROMUSCULAR EVALUATION OF THE STOMACH WHICH INCLUDES ASSESSMENT OF SOLID PHASEGASTRICEMPTYING;3, 12=3EVERALTECHNIQUESFORMEASURINGSOLIDORLIQUIDFOOD EMPTYINGAREDESCRIBEDINOTHERSECTIONS(OWEVER THESTANDARDGASTRICEMPTYINGTESTS DONOTREVEALTHEmechanismOFTHEGASTROPARESIS4HE%''TESTISADIAGNOSTICTESTTO DETERMINETHESTATUSOFGASTRICMYOELECTRICALACTIVITYATBASELINEANDAFTERAPROVOCATIVETESTSUCHASTHENONCALORICWATERLOADTEST;3=ORANUTRIENT BASEDSATIETYTEST;18]. 4HECOMBINATIONOFAGASTRICEMPTYINGSTUDYANDAN%''WITHPROVOCATIVETESTIS ANALOGOUSTOTHESTUDYOFCARDIACNEUROMUSCULARFUNCTIONDURINGWHICHCARDIACOUTPUT (by echocardiography) and the electrical rhythm (by EKG) during the exercise stress TEST ARE MEASURED IN PATIENTS BEING EVALUATED FOR PALPITATIONS OR CHEST DISCOMFORT 3IMILARLY hGASTRICOUTPUTvISMEASUREDWITHTHESOLID PHASEGASTRICEMPTYINGSTUDY ANDTHEELECTRICALACTIVITYOFTHESTOMACHISMEASUREDWITHTHE%''4HUS THE%'' recording results are important in interpreting the cause of the gastric emptying results ANDTHEUPPERGASTROINTESTINALSYMPTOMS4ABLE14.1 outlines the four pathophysiologICALCATEGORIESTHATAREDElNEDWHEN%''ANDGASTRICEMPTYINGTESTSARECOMBINED !SSHOWNIN4ABLE14.1, the EGG results indicate the presence of gastric dysRHYTHMIASORNORMALCPM%''ACTIVITY)NPATIENTSWITHGASTROPARESISANDGASTRIC Table 14.1 #OMBINEDELECTROGASTROGRAMANDGASTRICEMPTYINGTESTRESULTSINPATIENTSWITHSUSPECTED gastroparesis Patients with symptoms suggesting gastroparesis Electrogastrogram (EGG) ȣ Abnormal (gastric dysrhythmia) ȣ Gastric Emptying Test Ȼ ȣ Abnormal (gastroparesis)

ȣ Normal

ȣ

ȣ

Severe gastric myoelectrocontractile disorder

Gastric myoelectrical disorder

ȣ Normal (3 cpm) ȣ Gastric Emptying Test Ȼ ȣ ȣ Normal Abnormal (gastroparesis) ȣ ɵ Visceral hypersensitivity ɵ Nongastric causes

#ATEGOTY

#ATEGOTY

#ATEGOTY

ȣ ɵ Mechanical obstruction ɵ Electro-contractile dissociation #ATEGORY


157

Fig. 14.1 .ORMALCPM TACHYGASTRIA ANDBRADYGASTRIASIGNALSRECORDEDWITH%''METHODS

dysrhythmias, electrical and contractile abnormalities are both present (Category 1). /NTHECONTRARY ANORMALCPM%''INAPATIENTWITHGASTROPARESIS#ATEGORY SUGGESTSMECHANICALORFUNCTIONALOBSTRUCTION;7]. Electromechanical dissociation is another physiological explanation for this finding. Some symptomatic patients HAVE A DYSRHYTHMIA ONLY #ATEGORY AND OTHER PATIENTS HAVE NORMAL %'' AND EMPTYINGTESTS#ATEGORY )NRECORDINGTHE%''BEFOREANDAFTERAPROVOCATIVE test meal, the EGG rhythms of greatest interest occur in the time after the test meal ISCOMPLETED THETIMEWHENTHENEUROMUSCULARAPPARATUSOFTHESTOMACHHASBEEN CHALLENGEDWITHAWATERVOLUMEORFOOD)TISDURINGTHEPOSTINGESTIONPERIODTHAT the diagnosis of normal 3 cpm rhythm, tachygastria, bradygastria, or mixed gastric dysrhythmia is made (Fig. 14.1).

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EGG Test Results in Patients with Suspected Gastroparesis !N%''DIAGNOSISOFNORMALCPMACTIVITYISASSOCIATEDWITHANORMALORH GASTRICEMPTYINGSTUDYOFTHETIME;3=(OWEVER HIGH AMPLITUDECPM%'' SIGNAL IS UNUSUAL AND DISCORDANT IN THE PATIENT WITH DOCUMENTED GASTROPARESIS (Fig. 14.2 4HISDISCORDANTlNDINGOFCPM%''ACTIVITYANDGASTROPARESISSUGGESTS THAT THE INTERSTITIAL CELLS OF #AJAL ARE NORMAL BUT THE GASTRIC SMOOTH MUSCLE CELL CONTRACTIONSAREUNABLETOEMPTYTHETESTMEAL4HEREASONSFORTHISDISCORDANTlNDING MAYBEDIVIDEDINTOTWOCATEGORIESA OBSTRUCTION EG ASTENOSISORhSPASMvATTHE PYLORUSORPOSTDUODENALBULBREGION ORB ELECTROMECHANICALDISSOCIATION;7=4HIS finding of normal 3 cpm EGG and gastroparesis is clinically important because a MECHANICAL OBSTRUCTION AT THE PYLORUS OBSTRUCTIVE GASTROPARESIS CAN BE RELIEVED WITHPYLORICDILATION STENTSORSURGERY/THERFORMSOFOBSTRUCTIONSUCHASPYLOROSPASM WITHhFUNCTIONALvOBSTRUCTIONAREMOREDIFlCULTTOPROVE BUTMAYBETHEMECHANISM OFhOBSTRUCTIVEGASTROPARESISvINSOMEPATIENTS2IGHTUPPERQUADRANTPOSTPRANDIAL DISCOMFORTINPATIENTSWITHGASTROPARESISANDANORMALCPM%''RHYTHMSUGGESTS THISPOSSIBILITY4HESEPATIENTSMAYUNDERGOINJECTIONOF"OTOXnMCGINTO

Fig. 14.2 2UNNING SPECTRAL ANALYSIS OF %'' SIGNALS RECORDED FROM A PATIENT WITH OBSTRUCTIVE GASTROPARESIS DUE TO PYLORIC CHANNEL NARROWING FROM CHRONIC ULCER DISEASE .OTE THE EXTREMELY REGULARANDHIGHAMPLITUDE%''SIGNALSINTHERHYTHMSTRIP4HERUNNINGSPECTRALANALYSISOFTHE %''RECORDINGSSHOWSANEXTREMELYUNIFORMSERIESOFPEAKSATCPM


159

Fig. 14.3 2UNNING SPECTRAL ANALYSIS OF THE %'' SIGNAL RECORDED BEFORE AND AFTER A WATER LOAD OF ML IN A PATIENT WITH IDIOPATHIC GASTROPARESIS 4HE %'' RHYTHM STRIPS SHOW A n CPM TACHYGASTRIA4HERUNNINGSPECTRALANALYSISSHOWSMOSTPEAKSBEFOREANDAFTERTHEWATERTHATRANGE FROM TO CPM 4HERE ARE SEVERAL PEAKS AT CPM IMMEDIATELY AFTER WATER LOAD VOLUME WAS INGESTED BUTFEWPEAKSATCPMTHEREAFTER

THEPYLORUSTOHELPTHESYMPTOMSANDIMPROVETHERATEOFTHEGASTRICEMPTYING;19]. )NTHERARECASEWHERETHE%''SHOWSNORMALCPMSIGNALWITHNORMALAMPLITUDE and there is no mechanical obstruction and no pylorospasm to explain the gastroparesis, electromechanical dissociation may explain the gastroparesis. Gastric dysrhythmias, on the other hand, are seen more frequently than the 3 cpm PATTERN IN PATIENTS WITH GASTROPARESIS ;7= 4HESE PATIENTS MAY HAVE TACHYGASTRIAS WHICH RANGE IN FREQUENCY FROM TO CPM &IG 14.3 4HESE RAPID ELECTRICAL WAVESGENERALLYORIGINATEINTHEANTRUMANDMAYBEUNIFOCALORMULTIFOCALINNATURE 4HEPRESENCEOFTACHYGASTRIASANDBRADYGASTRIASnCPM INTERFEREWITHNORMAL CPMSLOWWAVEACTIVITYANDDISRUPTNORMALGASTRICPERISTALSIS4HECORRECTIONOF THESE GASTRIC DYSRHYTHMIAS AND RESTORATION OF CPM RHYTHM WITH CISAPRIDE AND DOMPERIDONE IS ASSOCIATED WITH IMPROVEMENT IN NAUSEA ;15, 16= 4HUS GASTRIC dysrhythmias also represent a peripheral pathophysiological mechanism for nausea symptoms. Correction of the dysrhythmias may not affect the rate of gastric emptying, DEPENDINGONTHEFUNCTIONOFTHE%.3ANDSMOOTHMUSCLE

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2ECENTSTUDIESSUGGESTTHEENTERICNERVESANDTHE)##SAREDAMAGEDMOREOFTEN THAN SMOOTH MUSCLE IN PATIENTS WITH TYPE AND TYPE DIABETIC AND IDIOPATHIC GASTROPARESIS ;20= 4HE PRESENCE OF CPM %'' ACTIVITY CORRELATED WITH NORMAL NUMBERSOF)##SINGASTRICBIOPSIESONTHECONTRARY THEPATIENTSWITHPOORCPM ACTIVITYANDGASTRICDYSRHYTHMIASHADGREATERLOSSOF)##SANDAPOORERRESPONSETO GASTRICELECTRICALSTIMULATION;21, 22=4HUS WHENTHE%''TESTSHOWSNORMALCPM ACTIVITY THENTHERESPONSETOGASTRICELECTRICALSTIMULATIONISIMPROVEDINPATIENTS WITH REFRACTORY NAUSEA AND VOMITING FROM GASTROPARESIS COMPARED WITH PATIENTS WHOHAVEDIMINISHEDCPM%''ACTIVITY;21, 22=4HESESTUDIESINDICATETHATTHE PRESERVATIONOFSOMELEVELOF)##SANDOFCPM%''ACTIVITYISAMARKERFORMORE FAVORABLERESPONSETOELECTRICALSTIMULATIONTHERAPY Other electrocontractile abnormalities may result in abnormal EGG tests and CONTRIBUTETOTHEDELAYINGASTRICEMPTYINGABNORMALCOUPLINGOFTHE)##ACTIVITYTO the smooth muscle, abnormal enteric neuron function, and/or abnormal gastric smooth muscle. Recent histological studies of full thickness gastric tissues from PATIENTSWITHGASTROPARESISSHOWEDTHATOFTHEPATIENTSHADABNORMALITIESINTHE )##SORNEURALELEMENTSOFTHEGASTRICWALL;20]. Furthermore, almost 40% of the PATIENTSHADINCREASEDINmAMMATORYCELLINlLTRATESMACROPHAGES INTHEMYENTERIC PLEXUS WHILETHESMOOTHMUSCLEWASNORMALINTHESESUBJECTSWITHDIABETICORIDIOPATHICGASTROPARESIS;20=4HUS ABNORMALITIESOF)##SANDINTRINSICNEURONSOFTHE STOMACHARECOMMONINPATIENTSWITHGASTROPARESISANDREmECTTHEHISTOLOGICALUNDERpinnings of gastric dysrhythmias and poor smooth muscle function, abnormalities THAT ALTER THE RATES OF GASTRIC EMPTYING AND ULTIMATELY RESULT IN GASTROPARESIS 4HE %'' RECORDINGS PROVIDE IMPORTANT CLINICAL INSIGHTS INTO THE PATHOPHYSIOLOGY OF gastroparesis and associated nausea, much like EKG, and cardiac output recordings PROVIDEINSIGHTSINTOTHEPATHOPHYSIOLOGYOFHEARTFAILUREANDASSOCIATEDVAGUESYMPTOMS)NMOSTCASEShIDIOPATHICvGASTROPARESISISNOTTRULYIDIOPATHICBUTISSECONDARY to gastric dysrhythmia (e.g., tachygastria) and related smooth muscle dysfunction.

Conclusion )NSUMMARY PATIENTSWITHGASTROPARESISMAYHAVEGASTRICDYSRHYTHMIASORNORMAL CPMACTIVITY4HUS THE%''TESTRESULTSPROVIDEIMPORTANTINFORMATIONWITHTHERApeutic implications about the pathophysiology of the gastroparesis in each patient. 4HEDISCORDANTlNDINGOFAHIGH AMPLITUDECPM%''RHYTHMANDGASTROPARESIS REQUIRES AN EVALUATION TO EXCLUDE TREATABLE MECHANICAL OR SPASM RELATED PYLORIC DYSFUNCTION4HE%''PATTERNMAYALSOHELPINTHESELECTIONOFPATIENTSWITHGASTROPARESISWHOWILLRESPONDTOGASTRICELECTRICSTIMULATION4ACHYGASTRIASANDBRADYgastrias represent the electrical abnormalities underlying delayed gastric emptying ANDUPPER')SYMPTOMS4HUS %''TESTRESULTSCOMPLEMENTANDPROVIDEINSIGHTS about gastric emptying test results. Future studies to determine the mechanisms of GASTRICDYSRHYTHMIASWILLAIDDEVELOPMENTOFANTIARRHYTHMICDRUGSTOCORRECTTHE DYSRHYTHMIASANDIMPROVEGASTRICEMPTYINGFUNCTIONANDSYMPTOMS


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References +OCH+, 3TERN2- EDITORS(ANDBOOKOFELECTROGASTROGRAPHY.EW9ORK/XFORD0RESS 3MOUT !*0- VAN DER 3CHEE %* 'RASHUIS *, 7HAT IS MEASURED IN ELECTROGASTROGRAPHY $IG$IS3CIn +OCH+, (ONG3 0 8U,2EPRODUCIBILITYOFGASTRICMYOELECTRICALACTIVITYANDTHEWATERLOAD TEST IN PATIENTS WITH DYSMOTILITY LIKE DYSPEPSIA SYMPTOMS AND IN CONTROL SUBJECTS * #LIN 'ASTROENTEROL n +OCH +, 3TERN 2- 6ASEY - "OTTI ** #REASY '7 $WYER ! 'ASTRIC DYSRHYTHMIAS AND NAUSEAOFPREGNANCY$IG$IS3CIn 3TERN2- +OCH+, 3TEWART72 ,INDBLAD)-3PECTRALANALYSISOFTACHYGASTRIARECORDED DURINGMOTIONSICKNESS'ASTROENTEROLn +OCH+, 3TERN2- 6ASEY-* 3EATON*& $EMERS,- (ARRISON43'ASTRICMYOELECTRICAL ANDENDOGENOUSNEUROENDOCRINERESPONSESTOILLUSORYSELF MOTIONINMAN!M*0HYSIOL 258:E304–10. "RZANA2* "INGAMAN3 +OCH+,'ASTRICMYOELECTRICALACTIVITYINPATIENTSWITHGASTRICOUTLET OBSTRUCTIONANDIDIOPATHICGASTROPARESIS!M*'ASTROENTEROLn (INDER2! +ELLEY+!(UMANGASTRICPACESETTERPOTENTIALSIGHTOFORIGIN SPREAD ANDRESPONSE TOGASTRICTRANSECTIONANDPROXIMALVAGOTOMY!M*3URGn 9. Koch KL. Gastric neuromuscular function and neuromuscular disorders. In: Feldman M, &RIEDMAN,3 "RANDT,* EDITORS'ASTROINTESTINALANDLIVERDISEASES0HILADELPHIA3AUNDERS 2010. p. 789–815. 3ANDERS+- +OH3$ 7ARD3-)NTERSTITIALCELLSOF#AJALASPACEMAKERSINTHEGASTROINTESTINAL TRACT!NNU2EV0HYSIOLn #AMILLERI-)NTEGRATEDUPPERGASTROINTESTINALRESPONSETOFOODINTAKE'ASTROENTEROLOGY 131:640–58. 0ARKMAN( -ILLER- 4RATE$ ETAL%LECTROGASTROGRAPHYANDGASTRICEMPTYINGSCINTIGRAPHY ARECOMPLEMENTARYFORASSESSMENTOFDYSPEPSIA*#LIN'ASTROENTEROLn /RDOG 4 )NTERSTITIAL CELLS OF #AJAL IN DIABETIC GASTROENTEROPATHY .EUROGASTROENTEROL -OTIL n (E#, 3OFFER%% &ERRIS#$ 7ALSH2- 3ZURSZEWSKI*( &ARRUGIA',OSSOFINTERSTITIALCELLS OF#AJALANDINHIBITORYINNERVATIONININSULIN DEPENDENTDIABETES'ASTROENTEROLOGY 427–34. +OCH +, 3TERN 2- 3TEWART 72 6ASEY -7 'ASTRIC EMPTYING AND GASTRIC MYOELECTRICAL ACTIVITYINPATIENTSWITHSYMPTOMATICDIABETICGASTROPARESISEFFECTSOFLONG TERMDOMPERIDONE TREATMENT!M*'ASTROENTEROLn #UCCHIARA3 -INELLA2 2IEZZO' 6ALLONE' 6ALLONE0 #ASTELLONE& ETAL2EVERSALOFGASTRIC ELECTRICAL DYSRHYTHMIAS BY CISAPRIDE IN CHILDREN WITH FUNCTIONAL DYSPEPSIA REPORT OF THREE CASES$IG$IS3CIn 3TERN 2- +OCH +, !NALYSIS OF THE ELECTROGASTROGRAM )N +OCH +, 3TERN 2- EDITORS (ANDBOOKOFELECTROGASTROGRAPHY.EW9ORK/XFORD0RESSPn 4ALLEY .* #AMILERI - "URTON $ 4HOMFORDE ' +OCH + 2UCKER -* ET AL $OUBLE BLIND PLACEBO CONTROLLED STUDY TO EVALUATE THE EFFECTS OF TEGASEROD ON GASTRIC MOTOR SENSORY AND MYOELECTRICALFUNCTIONINHEALTHYVOLUNTEERS!LIMENT0HARMACOL4HERn "ROMER-1 &RIEDENBERG& -ILLER,3 ETAL%NDOSCOPICPYLORICINJECTIONSOFBOTULINUMTOXIN !FORTHETREATMENTOFREFRACTORYGASTROPARESIS'ASTROINTEST%NDOSCn ,URKEN -3 +ASHYAP 0 0ARKMAN (0 ET AL 4HE PATHOLOGICAL BASIS OF GASTROPARESIS 'ASTROENTEROLOGY! &ORSTER* $AMJANOV) ,IN: 3AROSIEK) 7ETZEL0 -C#ALLUM27!BSENCEOFTHEINTERSTITIAL CELLSOF#AJALINPATIENTSWITHGASTROPARESISANDCORRELATIONWITHCLINICALlNDINGS*'ASTROINTEST 3URGn ,IN: 3AROSIEK) &ORSTER* $AMJANOV) (OU1 -C#ALLUM27!SSOCIATIONOFTHESTATUSOF INTERSTITIALCELLSOF#AJALANDELECTROGASTROGRAMPARAMETERS GASTRICEMPTYINGANDSYMPTOMSIN PATIENTSWITHGASTROPARESIS.EUROGASTROENTEROL-OTIL n

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Chapter 15

Antroduodenal Manometry for the Evaluation of Patients with Suspected Gastroparesis William J. Snape, Jr.

Keywords !NTRODUODENALMANOMETRYs'ASTROPARESISs-IGRATINGMOTORCOMPLEX s0SEUDOOBSTRUCTIONs0ARTIALSMALL BOWELOBSTRUCTIONs$YSPEPSIA

Introduction 4HESYMPTOMPATTERNOFPATIENTSWITHADOCUMENTEDDELAYINGASTRICEMPTYINGHAS BEENEVALUATEDRECENTLYINALARGECOHORTOFPATIENTSENTEREDINTHE'ASTROPARESIS 2EGISTRY SUPPORTED BY THE .)( 4HE PREDOMINANT SYMPTOMS OF GASTROPARESIS ARE NAUSEA VOMITINGANDINALARGEPERCENTAGEOFPATIENTS ABDOMINALPAIN.AUSEAIS the predominant symptom in 34.5% of 319 patients and occurs in 84.3% of patients. 3IMILAR NUMBERS OF THESE PATIENTS HAVE VOMITING AND ABDOMINAL PAIN PERSONALCOMMUNICATION )NTERESTINGLY PATIENTSWITHCHRONIC NAUSEA VOMITING OR ABDOMINAL PAIN MAY HAVE A NORMAL GASTRIC EMPTYING 4HIS CHAPTERADDRESSESHOWANTRODUODENALMANOMETRYCANASSISTINMANAGINGPATIENTS WITHCHRONICNAUSEA VOMITINGANDABDOMINALPAINBYMEASURINGBASELINEGASTRIC pyloric, and small intestinal contractions and the response to a meal or drugs.

Physiology of Gastric Emptying 4HESTOMACHANDTHESMALLINTESTINEWORKASACOORDINATEDUNITTOPROCESSANDUTILIZE ingested food, propelling the digested and triturated food distally out of the stomach AND DOWN THE SMALL INTESTINE )N ADDITION COORDINATED ABORAL CONTRACTIONS OF THE

W.J. Snape, Jr. (*) California Pacific Medical Center, 2340 Clay Street, Room 210, San Francisco, CA 94115, USA E MAIL3NAPEW SUTTERHEALTHORG H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_15, © Springer Science+Business Media, LLC 2012

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STOMACHANDSMALLINTESTINEPREVENTTHEREmUXOFINTESTINALCONTENTSBACKINTOTHE STOMACH$ISTURBANCEOFTHISCOORDINATEDPATTERNALTERSTHEORDERLYABORALPROPULSION of luminal contents through the stomach and intestines leading to different clinical CONDITIONS SUCH AS GASTROPARESIS FUNCTIONAL DYSPEPSIA OR INTESTINAL PSEUDOOBSTRUCTION ALLOFWHICHCANBEASSOCIATEDWITHDELAYEDGASTRICEMPTYING!TTHISTIME it is unclear if these different clinical syndromes are associated as part of a spectrum of disease. The stomach has multiple functions including accommodation to ingested food, trituration or grinding of the food, and controlled emptying into the small intestine. !CCOMMODATIONISANEURALREmEXTHATINITIATESANACTIVERELAXATIONOFTHEFUNDUS ANDTHEPROXIMALBODYOFTHESTOMACH ALLOWINGTHESTOMACHTOSERVEASARESERVOIR FORFOODASITISEATEN4HISFUNCTIONISEVALUATEDBESTWITHTHEBAROSTAT WHICHMEASURES CHANGESINTONEINTHESTOMACH0OWERFULANTRALCONTRACTIONSTHENGRINDTHEFOODAND propel the food into the small intestine. The coordinated propulsion of the food into THEDUODENUMISDEPENDENTONPERISTALTICCONTRACTIONSINTHEANTRUM RELAXATIONOF THEPYLORUS ANDCONTRACTIONSINTHEDUODENUMCOORDINATEDWITHTHESTOMACHAND pylorus. High-pressure or uncoordinated contractions in the duodenum can decrease the rate of gastric emptying [1]. These motor functions of the distal stomach and SMALLINTESTINEAREBESTMEASUREDWITHANTRODUODENALMANOMETRY0YLORICSPHINCTER PRESSURECANBEMEASUREDBYDISCRETEMANOMETRICPORTS ALTHOUGHAPERFUSEDSLEEVE MANOMETERMAYPROVIDEMOREACCURATEMEASUREMENTS 0HASICCONTRACTIONSINTHESTOMACHAREARESULTOFTHERAPIDDEPOLARIZATIONOFTHE SMOOTH MUSCLE MEMBRANE INITIATING THE RELEASE OF CALCIUM FROM THE INTRACELLULAR STORES4HEFREQUENCYANDRHYTHMOFTHECONTRACTIONSISDETERMINEDBYTHEGASTRIC PACEMAKERONTHEGREATERCURVATUREOFTHEPROXIMALBODYOFTHESTOMACH)NTERSTITIAL cells of Cajal (ICC) are present throughout the human stomach and small intestine WITHINMUSCULARISPROPRIAANDMYENTERICPLEXUS FORMINGBOTHTHEGASTRICINTESTINAL pacemaker and conduction system relaying the rhythm throughout the gastrointestinal WALL;2=4HE)##INTHEMYENTERICPLEXUSARESPONTANEOUSLYACTIVEANDSETTHEPACE OF THE STOMACH OR INTESTINE 4HE INTRAMUSCULAR )## FORM NEXUSES BETWEEN BOTH MYENTERICNERVESANDSMOOTHMUSCLECELLSANDINTEGRATETHECONTROLOFSMOOTHMUSCLE contractions [3= ! DISTINCT SMALL INTESTINAL PACEMAKER IS PRESENT APPROXIMATELY 10 cm distal to the pylorus in the feline small intestine [4]. The decreasing frequency GRADIENTINTHEDISTALSMALLINTESTINEAPPEARSDUETOSLOW WAVEDROPOUTFROMTHE electrical refractory period of the smooth muscle. The ICC also paces intestinal MOTILITYINHUMANS GENERATINGAPLATEAUOFSLOW WAVEFREQUENCYATAPPROXIMATELY CYCLESMINTHATEXTENDSINTOTHEPROXIMALJEJUNUMWITHADECREASINGSLOW WAVE frequency gradient distally in the small intestine [5]. 4HEFREQUENCYOFCONTRACTIONSDIFFERSBETWEENTHESTOMACHWHICHISCYCLESMIN and the duodenum at 11 cycles/min. It is surprising that muscles that are spatially CLOSEHAVESUCHDIFFERINGSLOW WAVEFREQUENCIES%VIDENCEINMICEANDRATSSUGGESTS THATTHE)##ANDSLOW WAVEACTIVITYAREABSENTINTHEPYLORUS;6=(OWEVER )## MAYBEPRESENTINTHEPYLORUSINHUMANS;7]. In healthy controls, pyloric contractions AREAMIXTUREOFANTRAL TYPEANDDUODENAL TYPECONTRACTIONSWITHORWITHOUTTONIC ELEVATIONS IN THE BASAL PRESSURE 4ONIC AND PHASIC PYLORIC CONTRACTIONS INCREASE

!NTRODUODENAL-ANOMETRYFORTHE%VALUATIONOF0ATIENTSx

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Fig. 15.1 Fasting antroduodenal manometric tracing from the stomach (top 2 ports) and duodenum (bottomPORTS 4HENORMALPHASEOFTHEMIGRATINGMOTORCOMPLEXPROPAGATESFROMTHEANTRUM INTOTHEPROXIMALJEJUNUM

RESISTANCEACROSSTHEANTRODUODENALJUNCTION GIVINGRISETOGASTRICRETENTIONOFSOLID particles [8]. Different patterns of gastric and intestinal contractions occur depending on WHETHERTHEPATIENTISFASTINGORHASRECENTLYEATENFOOD;9=.ORMALLYDURINGFASTING THEREISAWELL DElNEDPATTERNOFCONTRACTIONS&IG15.1) ranging from quiescence (phase 1) through intermittent contractions (phase 2) and continuous contractions at the inherent frequency of the stomach or small intestine (phase 3). This pattern CYCLESAPPROXIMATELYEVERYMININHUMANSANDISRESPONSIBLEFORTHEABORALmOW OFGASTROINTESTINALCONTENTSDURINGFASTING4HE0HASEOFTHEMIGRATINGCOMPLEXIS IMPORTANTFORTRANSPORTINGNONDIGESTIBLEOBJECTSFROMTHESTOMACHANDREDUCINGTHE BACTERIALmORAINTHESMALLINTESTINEBYPERIODICALLYTRANSPORTINGTHELUMINALCONTENTS distally. %ATINGSWITCHESTHEPATTERNTOAFEDPATTERNWHICHINITIATESINCREASEDCONTRACTIONS in the stomach and small intestine. The length of time that the patient’s gastrointestinal TRACTREMAINSINTHEFEDSTATEISDETERMINEDBYTHEVOLUMEANDTHEFATCONTENTOFTHE MEAL)NTHESTOMACH THECONTRACTIONSGRINDSOLIDFOODINTOPARTICLESnMMINSIZE

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THATCANBEEMPTIEDTHROUGHTHEPYLORUSATARATEOFKCALMIN,IQUIDSEMPTYTHROUGH ADIFFERENTMECHANISMCONTROLLEDBYPRESSUREINTHEPROXIMALSTOMACH4HEPOSTPRANDIAL SMALL INTESTINAL CONTRACTIONS MIX THE INTESTINAL CONTENTS WITH THE DIGESTIVE ENZYMESANDMOVEITALONGTHESMALLINTESTINEATARATEOPTIMALFORABSORPTION Locally released neurotransmitters or circulating gut hormones are also important INTHECONTROLOFTHEMIGRATINGCOMPLEX;10]. The gut hormone, motilin, stimulates THEGASTRICCOMPONENTOFTHEMIGRATINGCOMPLEXTHROUGHRECEPTORSONTHESMOOTH MUSCLECELLSORONTHEPRESYNAPTICNEURONSINTHEENTERICPLEXUS;11, 12]. In humans, MOTILINSTIMULATIONINITIATESAMIGRATINGCOMPLEXONLYINTHEANTRUMANDGENERALLY does not stimulate phasic increases in pyloric or small intestinal contractions [11]. 'HRELIN A NEWLY DESCRIBED HORMONAL AGENT HAS BEEN IMPLICATED IN THE POSSIBLY physiologic control of gastric motility [13=4HISCOMPOUNDMAYWORKTHROUGHA RECEPTORONTHESMOOTHMUSCLE WHICHISSIMILARTOTHEMOTILINRECEPTOR ORTHROUGH CHOLINERGICNERVES;14, 15=)NTHESMALLINTESTINE THEMIGRATINGCOMPLEXISINITIATED BYOPIATES;16] and somatostatin agonists.

Pathophysiology of Gastroparesis $IFFERENT PATTERNS OF ALTERED ANTRODUODENAL MOTILITY ARE ASSOCIATED WITH UPPER ABDOMINALSYMPTOMS%LECTROGASTROGRAPHYANDANTRODUODENALMOTILITYWEREABNORMAL INMANYPATIENTSWITHFUNCTIONALDYSPEPSIA;17=(OWEVER THEABNORMALITIESDONOT NECESSARILYCORRELATEWITHEACHOTHER!NTRALHYPOMOTILITYMAYDELAYGASTRICEMPTYING ANDCAUSEABDOMINALPAIN NAUSEAANDVOMITING;18, 19]. Antral hypomotility may BEASSOCIATEDWITHALONGLAGPHASE WHICHWILLPROLONGTHETIMENECESSARYFORTHE stomach to empty a solid meal [20=4HELAGPHASEISAVARIABLETIMEPERIODUSEDTO grind the meal into small particles that empty in a linear emptying pattern. In addition TOANTRALHYPOMOTILITY DIABETICPATIENTSWITHRECURRENTNAUSEAANDVOMITINGHAVEA PROLONGEDDURATIONOFPYLORICACTIVITYDURINGFASTINGANDAFTERFEEDING0YLOROSPASM DElNEDASTHEPROLONGEDMIN ELEVATIONOFTHEBASALPYLORICPRESSUREMM(G OCCURS IN APPROXIMATELY OF PATIENTS WITH GASTROPARESIS PARTICULARLY DIABETIC gastroparesis [8]. Pathophysiologic alterations of the smooth muscle (myopathic) or neurons NEUROPATHIC WILLCAUSEANABNORMALMANOMETRICAPPEARANCE WHICHDISRUPTSTHE ORDERLY MOVEMENT OF CONTENT OUT OF THE STOMACH AND THROUGH THE SMALL INTESTINE [21–23=-YOPATHYISREmECTEDBYLOW AMPLITUDECONTRACTIONSTHATAREUNDERNORMAL NEURAL CONTROL ,ACK OF SMOOTHELIN ! WHICH BINDS TO ACTIN DECREASES SMOOTH muscle contraction in mice [24= )N NEUROPATHY THE CONTRACTIONS HAVE NORMAL OR INCREASEDAMPLITUDE BUTTHECONTRACTIONSAREUNCOORDINATEDBECAUSEALTEREDNEURAL CONTROL4HEPRESENCEOFABNORMALNEURALCONTROLOFTHEANTRODUODENALMANOMETRY ISGENERALLYIDENTIlEDBYTHEABSENCEOFAPHASEOFTHE--# ORRETROGRADEUNCOORDINATEDMIGRATIONOFTHEPHASEOFTHE--#4HEMIGRATINGMOTORCOMPLEXIS ASSOCIATEDWITHTHEEMPTYINGOFINDIGESTIBLEMATERIALSFROMTHESTOMACHANDCLEANSING


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of the small intestine [25=)FTHECOMPLEXISDISRUPTEDINTHESTOMACH THEPATIENTHAS ANINCREASEDLIKELIHOODOFDEVELOPINGBEZOARSORIFDISRUPTEDINTHESMALLINTESTINE THEYMAYHAVESMALL BOWELBACTERIALOVERGROWTH;26, 27].

Techniques for Recording Antroduodenal Manometry Water-perfused or solid-state catheters are typically used to record antroduodenal MANOMETRYTRACINGS2ECENTLY ANINGESTIBLECAPSULEHASBEENDEVELOPEDTORECORD pressure from the stomach and small intestine [28, 29]. Magnetic resonance and ultrasonography are used in some centers to measure antroduodenal motility. 7ATER PERFUSEDCATHETERSHAVESIDEHOLES WHICHMEASUREINTRALUMINALPRESSURE BYACONSTANTmOWOFWATER#ONTRACTIONSOFBOWELSEGMENTSOCCLUDETHESIDEHOLES ANDALTERTHERESISTANCETOTHEmOWOFWATER7ATER PERFUSEDMANOMETRYREQUIRESA LOWCOMPLIANCE PNEUMOHYDRAULICPERFUSIONSYSTEMLINKEDTOAMULTILUMENCATHETER ANDEXTERNALSTAINGAUGETRANSDUCERS;30]. 3OLID STATE MANOMETERS RESPOND MORE QUICKLY TO THE PRESSURE EVENT GIVING A higher fidelity response. The solid-state catheter may record a higher percentage of PRESSUREEVENTS4HECOSTOFTHESECATHETERSHASDECREASEDANDTHEYCANBEEASILY REPAIRED!RECENTREPORTDESCRIBESTHEUSEOFHIGH RESOLUTIONMANOMETRICTECHNIQUE for recording gastric and small intestinal motility [31]. 4HENUMBERANDSPACINGOFMANOMETRYSENSORSCANBEVARIABLEDEPENDINGONTHE DESIREDINFORMATIONFROMTHESTUDY3ENSORSCANBEPLACEDnCMAPARTIFLOCALIZED SEGMENTSORSPHINCTERSAREBEINGSTUDIED3PHINCTERPRESSUREALSOCANBEACCURATELY MEASURED USING A WATER PERFUSED OR ELECTRONIC SLEEVE WHICH RECORDS THE HIGHEST PRESSUREOVERASHORTSEGMENT)FTHESTUDYOFLONGERSEGMENTSISDESIRED SENSORS CANBEPLACEDnCMAPART4OEVALUATEADEQUATEPROPAGATIONOFAMIGRATINGMOTOR COMPLEX THELENGTHOFSMALLBOWELMEASUREDSHOULDBECM 4HEANTRODUODENALMANOMETRICTESTISOFVARIABLELENGTH-OSTOFTHELITERATURE REPORTS MOTILITY OVER A RELATIVELY SHORT PERIOD OF TIME H 4HE USE OF PERFUSED catheters for antroduodenal manometry restricts the recording of antroduodenal manometry to short periods of time [27=(OWEVER STUDIESUSINGSOLID STATECATHETERS CANRUNFORH4HELONGERSTUDIESALLOWEVALUATIONOFTHEEFFECTOFSLEEPAND DIFFERENTMEALSONANTRODUODENALMOTILITY4HESHORTERSTUDIESSHOULDBELONGERTHAN HTOHAVEAREASONABLECHANCEOFOBSERVINGTHEPHASEOFTHEMIGRATINGCOMPLEX 4HEMOTILITYTRACINGISANALYZEDFORTHEPRESENCEOFAMIGRATINGCOMPLEXDURINGTHE FASTINGPERIODANDTHECONVERSIONTOAFEDPATTERNAFTERAMEAL!LTHOUGHTHEREIS GENERALLYAMIGRATINGCOMPLEXEVERYMIN AnHFASTINGPERIODISNECESSARYTO DElNETHEMIGRATINGCOMPLEX SINCESOMENORMALSUBJECTSMAYHAVEALONGERTIME INTERVALBETWEENTHEMIGRATINGCOMPLEXES4HEFEDRESPONSESHOULDBERECORDED for at least 1 h after eating. The response is irregular and frequent contractions THROUGHOUTTHESTOMACHANDSMALLINTESTINE4HECONTRACTIONSMAYNOTBEGINFORUP TOMINAFTERTHEMEAL4HEREMAYBEAPROLONGEDDELAYIFGASTRICEMPTYINGIS

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SLOWED4HEMAJORITYOFTHESTUDIESEXAMINETHEEFFECTOFFASTINGANDEATINGAMEAL ONTHEGASTRICANDTHESMALLINTESTINALCONTRACTIONSINNORMALSUBJECTSANDPATIENTS WITHDIFFERENTCLINICALCONDITIONS;19, 21, 27, 32, 33]. Using this technique, clinicians AREABLETODETERMINEIFTHEPATIENTHASABNORMALITIESOFTHEFASTINGORMEAL RELATED ACTIVITY Since opiates and prokinetic drugs can alter the antroduodenal motility pattern, THESESHOULDBESTOPPEDATLEASTHBEFORETHESTUDY(YPERGLYCEMIADELAYSGASTRIC emptying and also decreases the antral contractions. Therefore, the patient should BEEUGLYCEMICFORTHESTUDY Parenteral administration of pharmaceutical agents also can demonstrate normal ORABNORMALRESPONSESOFTHESTOMACHORSMALLINTESTINE;34, 35]. Drugs that stimulate SPECIlCALLYTHESTOMACHORTHESMALLINTESTINEAREUSEDTODElNEANABNORMALITYIN THEANTRODUODENALREGION%RYTHROMYCINBINDSTOTHEMOTILINRECEPTORANDINITIATESA PROLONGEDPERIODOFPHASICGASTRICCONTRACTIONSTHATMIMICSTHEMIGRATINGCOMPLEX in the stomach [36=%RYTHROMYCINUSUALLYDOESNOTSTIMULATEINCREASEINCONTRACTIONS of the pylorus or the small intestine [37]. Octreotide stimulates a similar prolonged INCREASEOFSMALLINTESTINALPHASICCONTRACTIONS WITHINHIBITIONOFSTOMACHCONTRACtility [26, 34, 38=/CTREOTIDEBLOCKSTHEFEDRESPONSEINTHESTOMACHANDINITIATESA PHASEINTHESMALLINTESTINEPOSSIBLEBYNEURALINHIBITIONMEDIATEDINTHEENTERIC PLEXUS;39, 40]. 4HEUSEOFSOLID STATECATHETERSPLACEDTHROUGHTHENOSEALLOWSANTRODUODENAL MANOMETRYTOBEPERFORMEDFORLONGERPERIODSOFTIME SAYUPTOH3OLID STATE CATHETERSALSOALLOWHIGH RESOLUTIONMANOMETRYOFTHESTOMACHANDSMALLBOWEL High-resolution manometric recordings from the upper gastrointestinal tract SHOWMULTIPLEPACEMAKERSANDRETROGRADECONTRACTIONSINTHEANTRUMANDSMALL intestine [31]. !WIRELESSMOTILITYCAPSULE3MART0ILL CONTAININGAPRESSURE P( ANDTEMPERATURESENSORCANBEUSEDTOMEASURESIMULTANEOUSLYGASTRICEMPTYINGANDPRESSUREIN the stomach and small intestine [28=4HEMOVEMENTTHROUGHDIFFERENTREGIONSOFTHE GASTROINTESTINALTRACTCANBEMEASUREDBYCHANGESINP(STOMACHnACIDIC SMALL INTESTINEnALKALINE ANDTHECECUMnACIDIC ANDTEMPERATURE ASTHECAPSULEEXITS THE BODY 4HE EMPTYING OF THE CAPSULE FROM THE STOMACH CORRELATED CLOSELY WITH RADIONUCLIDEGASTRICEMPTYINGANDWASASSOCIATEDWITHABURSTOFHIGH AMPLITUDE GASTRIC CONTRACTIONS 3MALL BOWEL CONTRACTIONS AND TRANSIT CHANGES CAN ALSO BE MEASUREDUSINGTHEWIRELESSMOTILITYCAPSULE;41].

Interpretation of Antroduodenal Manometry Antroduodenal manometric recordings are recorded during fasting and after stimuLATIONWITHEITHERAMEALORPHARMACEUTICALS4HETRACINGISEVALUATEDFORTHEPRESENCE and pattern of the phase III MMC during fasting, and the types of contractions after meals or stimulating drugs such as erythromycin, octreotide, or neostigmine. Additionally, the amplitude of contractions is measured in the stomach, pylorus, and


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SMALLINTESTINEDURINGTHESTUDIES4HUS THESESTUDIESPROVIDEINFORMATIONONALTERED neural control of small intestinal contractions and the integrity of the smooth muscle response. $URINGFASTING THEPHASEOFTHEMIGRATINGCOMPLEXINTHEANTRUMANDDUODENUM ISDElNEDASCONTRACTILEACTIVITYATTHEMAXIMUMFREQUENCYFORMININTHEANTRUM (2–3 cycles/min) and 2 min in the duodenum (10–12 cycles/min). A phase 3 is ABNORMALWHENITISRETROGRADE SIMULTANEOUS ORISINTERRUPTEDFORMORETHANMIN ONONEOFTHEINTESTINALSEGMENTS%ATINGABOLISHESTHEFASTINGPATTERNOFTHEMIGRATING COMPLEXANDREPLACESITWITHANINCREASEDANDMOREIRREGULARPATTERNOFCONTRACTIONS This is a neural response that is dependent on the caloric and fat content of the meal. 0HASE LIKECONTRACTIONSCANBEALSOMONITOREDINTHESTOMACHAFTERADMINISTRATION OFINTRAVENOUSERYTHROMYCINANDINTHESMALLINTESTINEAFTERSUBCUTANEOUSOCTREOTIDE A normal response to erythromycin is 3 cycle/min gastric contractions that last for greater than 1 min and to octreotide 11 cycle/min small intestinal contractions that last for greater than 1 min. !NTRALHYPOMOTILITYISDElNEDASABSENCEOFTHEGASTRICPHASE LOW AMPLITUDE GASTRICCONTRACTIONSMM(G ANDNORESPONSETOERYTHROMYCIN)TCANBESECONDARY to either altered neural control or smooth muscle function. Findings in functional DYSPEPSIA INCLUDE RETROGRADE OR CLUSTER CONTRACTIONS WITH A NORMAL AMPLITUDE (>15 mmHg) in the small intestine [42, 43= .EUROPATHIC PSEUDOOBSTRUCTION IS DElNED BY DISORGANIZED HIGH AMPLITUDE SMALL INTESTINAL CONTRACTIONS -YOPATHIC PSEUDOOBSTRUCTIONHASNORMALLYCOORDINATEDCONTRACTIONSWITHLOW AMPLITUDEANTRAL (10 mmol/L) !NDATLEASToneOFTHEFOLLOWING s 0ERSISTENTUPPERGASTROINTESTINALSYMPTOMSEARLYSATIATION NAUSEA BLOATINGFULLNESS VOMITING PAIN SUFlCIENTTOIMPACTONQUALITYOFLIFE s )NINSULIN TREATEDPATIENTS OCCASIONALUNSTABLEGLYCEMICCONTROLHYPERGLYCEMIAANDOR hypoglycemia) attributable to inability to co-ordinate insulin delivery with nutrient absorption Severe s -ARKEDLYABNORMALSLOWRATEOFGASTRICEMPTYINGOFSOLIDSANDORNUTRIENTLIQUIDS AS QUANTIlEDBYSCINTIGRAPHYORBREATHTEST INTHEABSENCEOFMECHANICALOBSTRUCTIONOR significant hyperglycemia (blood glucose >10 mmol/L) !NDATLEASToneOFTHEFOLLOWING s 0ERSISTENT SEVEREUPPERGASTROINTESTINALSYMPTOMSEARLYSATIATION NAUSEA BLOATINGFULLNESS VOMITING PAIN WITHSIGNIlCANTLYIMPAIREDQUALITYOFLIFE s )NABILITYTOMAINTAINADEQUATEORALINTAKE RESULTINGINNUTRITIONALDElCIENCIESANDLOSS OFBODYWEIGHTWITHINMONTHS s )NINSULIN TREATEDPATIENTS MARKEDLYUNSTABLEGLYCEMICCONTROLHYPERGLYCEMIAANDOR hypoglycemia) attributable to inability to co-ordinate insulin delivery with nutrient absorption !DAPTED FROM %XPERT 2EV 'ASTROENTEROL (EPATOL n ;69] with permission OF%XPERT2EVIEWS,TD

are only weakly related [17= ANDTHEOUTCOMEPOTENTIALLYAFFECTSTHEDIETARYADVICE GIVENFOREXAMPLE IFLIQUIDEMPTYINGISRELATIVELYPRESERVED ITMAYBELOGICALTO GIVEAGREATERPROPORTIONOFNUTRITIONALREQUIREMENTSINLIQUIDFORM 7HILELIMITEDVALIDATIONOFTHESTABLEISOTOPEBREATHTESTHASBEENPERFORMEDIN diabetes [70= AND IT REPRESENTS A POTENTIALLY USEFUL SCREENING TEST VALIDATION IN PATIENTSWITHEXTREMELYDELAYEDGASTRICEMPTYINGISLACKING

Therapy for Diabetic Gastroparesis 4HEGOALSOFTHERAPYVARYINDIFFERENTPATIENTSWITHDIABETICGASTROPARESIS!SDISCUSSED ABOVE ACCELERATIONOFGASTRICEMPTYINGWITHPROKINETICDRUGSMAYNOTALWAYSBETHE MOSTIMPORTANTENDPOINT ANDINSOMECASESCOULDAFFECTGLYCEMICCONTROLADVERSELY )N PATIENTS PRESENTING WITH SYMPTOMS ANTIEMETIC ANDOR PAIN MODIFYING DRUGS (e.g., low-dose tricyclic antidepressants) may have an important place in management, EVENDESPITETHEANTICHOLINERGICPROPERTIESOFTHELATTER 'LYCEMIC CONTROL IS AN IMPORTANT ASPECT OF THE MANAGEMENT FOR THE REASONS discussed above, and may need to be monitored with capillary blood glucose measureMENTSTHATAREMOREFREQUENTTHANUSUALEG HAFTERMEALS 4YPEPATIENTSMAY NEED TO COMMENCE INSULIN IF NOT ALREADY USING THIS THERAPY 4HE USE OF INSULIN ANALOGSTHATHAVEASHORTDURATIONOFACTIONEG LISPROORASPART CANALLOWFORMORE

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PRECISEDOSINGTHATCANBEGIVENWITH ORAFTER MEALINGESTION;71], while insulin PUMPSCANALSOALLOWFORmEXIBILITYOFBASALANDBOLUSINSULINDOSING.ONEOFTHESE ASPECTSHAVEBEENFORMALLYEVALUATEDINDIABETICGASTROPARESIS HOWEVER $IETARYTHERAPYISOFFUNDAMENTALIMPORTANCEINTHEMANAGEMENTOFDIABETESIN GENERAL WHERE AS DISCUSSED MODULATION OF GASTRIC EMPTYING TO LIMIT THE RATE OF small intestinal carbohydrate delivery to about 1 kcal/min is advantageous. This can be achieved by low-carbohydrate diets, dietary fiber, or guar gum ingestion, or with THE USE OF FAT ;72] or protein [7= hPRELOADSv TO INDUCE SMALL INTESTINAL FEEDBACK MECHANISMS THAT SLOW THE RATE OF GASTRIC EMPTYING IN ADVANCE OF THE MAIN MEAL Protein also stimulates endogenous insulin secretion, both via incretin release and DIRECTSTIMULATIONOFTHEBETACELLSBYABSORBEDAMINOACIDS4HESESTRATEGIESMAY BEINAPPROPRIATEINPATIENTSWITHMARKEDLYDELAYEDGASTRICEMPTYINGTHEMAJORITY OF WHOM WILL BE INSULIN TREATED ANDOR THOSE WITH SEVERE UPPER GASTROINTESTINAL SYMPTOMS INWHOMALOWlBER LOW FATDIETISTYPICALLYRECOMMENDED(OWEVER IT should be noted that these recommendations have not been evaluated in randomized CONTROLLEDTRIALS ALTHOUGHTHEYAPPEARTOBEPHYSIOLOGICALLYAPPROPRIATE!NOTHER POTENTIALLY USEFUL STRATEGY IS TO CONSUME SMALLER MORE FREQUENT MEALS EG n MEALSDAILY !SMALLSTUDYINDICATEDTHATMEALSINCORPORATINGASMALLPARTICLESIZE ASOPPOSEDTOLESSlNELYDIVIDEDSOLIDS IMPROVEDTHERATEOFEMPTYINGANDREDUCED the postprandial glycemic “dip” in patients with type 1 diabetes [74]. Patients with EXOCRINEPANCREATICINSUFlCIENCYSHOULDHAVETHEIRPANCREATICENZYMEREPLACEMENT therapy optimized [9]. $ETAILEDDISCUSSIONOFDRUGTHERAPYISBEYONDTHESCOPEOFTHISCHAPTER)NSOME CASESITMAYBEAPPROPRIATETOGIVEANINITIALEMPIRICTRIALOFPROKINETICTHERAPY EG FORnWEEKS ANDRESERVEFORMALEVALUATIONOFGASTRICEMPTYINGFORTHOSEWHO DONOTIMPROVEADEQUATELYORRELAPSE;75=(OWEVER THISSTRATEGYISMOREDIFlCULT IN COUNTRIES SUCH AS THE 53! WHERE AVAILABILITY OF PROKINETIC AGENTS OTHER THAN metoclopramide is severely restricted. It should be noted that subcutaneous metoCLOPRAMIDEMAYBEIDEALLYSUITEDTOINSULIN TREATEDDIABETICPATIENTS/FRELEVANCE to diabetic gastroparesis, however, is that hyperglycemia has the capacity to impair THEACTIONOFTHEPROKINETICDRUGSERYTHROMYCIN;76, 77] and cisapride [78]; whether THISPHENOMENONEXTENDSTOOTHERPROKINETICMEDICATIONSREMAINSTOBEESTABLISHED 'ASTRIC ELECTRICAL STIMULATION WITH THE %NTERRAÍ DEVICE REMAINS INADEQUATELY evaluated in sham controlled trials, but open label evidence suggests that patients WITHDIABETESAREMORELIKELYTOEXPERIENCESYMPTOMIMPROVEMENTTHATTHOSEWITH idiopathic gastroparesis [79]. Limited evidence suggests that combined kidney/pancreas transplantation can improve gastroparesis in patients with long-standing diabetes complicated by renal FAILURE ;80]. Pancreatic islet cell transplantation can normalize glycemic control ANDPOSSIBLYREVERSEAUTONOMICDYSFUNCTION BUTTHEREISNOTYETCONCLUSIVEEVIDENCE that gastrointestinal symptoms or gastric emptying are improved [81]. However, THISISSUEISWORTHYOFFURTHERSTUDY SINCEMANYPATIENTSWITHRECURRENTHYPOGLYCEMIA n THE MAIN INDICATION FOR ISLET CELL TRANSPLANT n ALSO HAVE DELAYED GASTRIC emptying [60].

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Summary and Conclusions 2ECENTINSIGHTSRELATINGTOTHEROLEOFUPPERGASTROINTESTINALFUNCTIONINGLYCEMIC CONTROL ARE FUNDAMENTALLY IMPORTANT IN THE RECOGNITION OF THE SPECTRUM OF DISORdered gastric emptying in diabetes and in determining appropriate management. 0ARADOXICALLY DIETARYANDPHARMACOLOGICALINTERVENTIONSTHATSLOWDELIVERYOFNUTRIENT to the small intestine are generally beneficial in diabetes, unless they result in a MISMATCHBETWEENNUTRIENTDELIVERYANDTHEACTIONOFEXOGENOUSINSULIN ORINDUCE SYMPTOMSSUCHASNAUSEAANDVOMITING#ONVERSELY OPTIMIZATIONOFGLYCEMIAISA priority in patients presenting with diabetic gastroparesis. Future studies are needed TORElNEOURUNDERSTANDINGOFTHEUNDERLYINGPATHOGENESISOFTHISDISORDERSOTHAT more specific therapies can be developed.

References +ASSANDER 0 !SYMPTOMATIC GASTRIC RETENTION IN DIABETICS GASTROPARESIS DIABETICORUM 'ASTROENTEROLOGYn 2. Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological and ABUSEPROlLES TREATMENT ANDLONG TERMFOLLOW UPOFPATIENTSWITHGASTROPARESIS$IG$IS3CI n (OROWITZ- -ADDOX!& 7ISHART*- ETAL2ELATIONSHIPSBETWEENOESOPHAGEALTRANSITAND SOLIDANDLIQUIDGASTRICEMPTYINGINDIABETESMELLITUS%UR*.UCL-EDn *ONES +, 2USSO ! 3TEVENS *% ET AL 0REDICTORS OF DELAYED GASTRIC EMPTYING IN DIABETES $IABETES#AREn &RANK*7 3ASLOW3" #AMILLERI- ETAL-ECHANISMOFACCELERATEDGASTRICEMPTYINGOFLIQUIDS and hyperglycemia in patients with type II diabetes mellitus. Gastroenterology. 1995;109: n *ONES+, (OROWITZ- #ARNEY") ETAL'ASTRICEMPTYINGINEARLYNONINSULIN DEPENDENTDIABETES MELLITUS*.UCL-EDn ,IPP27 3CHNEDL7* (AMMER(& ETAL%VIDENCEOFACCELERATEDGASTRICEMPTYINGINLONGSTANDINGDIABETICPATIENTSAFTERINGESTIONOFASEMISOLIDMEAL*.UCL-EDn (EJAZI2! 0ATIL( -C#ALLUM27$UMPINGSYNDROMEESTABLISHINGCRITERIAFORDIAGNOSIS ANDIDENTIFYINGNEWETIOLOGIES$IG$IS3CIn +UO0 3TEVENS*% "ELLON- ETAL!CUTEEFFECTSOFPANCREATICENZYMEREPLACEMENTONGASTRIC emptying and postprandial glycaemia in patients with cystic fibrosis (abstract). Gastroenterology. 3UPPL 0 "YTZER0 4ALLEY.* ,EEMON- ETAL0REVALENCEOFGASTROINTESTINALSYMPTOMSASSOCIATEDWITH DIABETES MELLITUS A POPULATION BASED SURVEY OF ADULTS !RCH )NTERN -ED n 3AMSOM- 6ERMEIJDEN*2 3MOUT!* ETAL0REVALENCEOFDELAYEDGASTRICEMPTYINGINDIABETIC patients and relationship to dyspeptic symptoms: a prospective study in unselected diabetic PATIENTS$IABETES#AREn "HARUCHA !% #AMILLERI - &ORSTROM ,! ET AL 2ELATIONSHIP BETWEEN CLINICAL FEATURES AND GASTRICEMPTYINGDISTURBANCESINDIABETESMELLITUS#LIN%NDOCRINOL/XF n #ASSILLY$7 7ANG92 &RIEDENBERG&+ ETAL3YMPTOMSOFGASTROPARESISUSEOFTHEGASTROPARESISCARDINALSYMPTOMINDEXINSYMPTOMATICPATIENTSREFERREDFORGASTRICEMPTYINGSCINTIGRAPHY$IGESTIONn

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+ONG-& (OROWITZ- *ONES+, ETAL.ATURALHISTORYOFDIABETICGASTROPARESIS$IABETES#ARE n *ONES+, 2USSO! "ERRY-+ ETAL!LONGITUDINALSTUDYOFGASTRICEMPTYINGANDUPPERGASTROINTESTINALSYMPTOMSINPATIENTSWITHDIABETESMELLITUS!M*-EDn (OROWITZ- $ENT* &RASER2 ETAL2OLEANDINTEGRATIONOFMECHANISMSCONTROLLINGGASTRIC EMPTYING$IG$IS3CISnS *ONES+, (OROWITZ- 7ISHART*- ETAL2ELATIONSHIPSBETWEENGASTRICEMPTYING INTRAGASTRIC MEALDISTRIBUTIONANDBLOODGLUCOSECONCENTRATIONSINDIABETESMELLITUS*.UCL-ED n -ERIO2 &ESTA! "ERGMANN( ETAL3LOWGASTRICEMPTYINGINTYPE)DIABETESRELATIONTO autonomic and peripheral neuropathy, blood glucose, and glycemic control. Diabetes Care. n !NNESE 6 "ASSOTTI ' #ARUSO . ET AL 'ASTROINTESTINAL MOTOR DYSFUNCTION SYMPTOMS AND NEUROPATHY IN NONINSULIN DEPENDENT TYPE DIABETES MELLITUS * #LIN 'ASTROENTEROL n (OROWITZ- (ARDING0% -ADDOX! ETAL'ASTRICANDOESOPHAGEALEMPTYINGININSULIN DEPENDENTDIABETESMELLITUS*'ASTROENTEROL(EPATOLn 21. Rayner CK, Horowitz M. Gastrointestinal motility and glycemic control in diabetes: the chicken ANDTHEEGGREVISITED*#LIN)NVESTn ,URKEN -3 0ARKMAN (0 !BELL 4, ET AL (ISTOLOGICAL CHANGES IN IDIOPATHIC AND DIABETIC GASTROPARESISABSTRACT .EUROGASTROENTEROL-OTS n #HOI+- 'IBBONS3* .GUYEN46 ETAL(EMEOXYGENASE PROTECTSINTERSTITIALCELLSOF#AJAL FROMOXIDATIVESTRESSANDREVERSESDIABETICGASTROPARESIS'ASTROENTEROLOGYn 2064 e1-2. +ASHYAP0# #HOI+- $UTTA. ETAL#ARBONMONOXIDEREVERSESDIABETICGASTROPARESISIN ./$MICE!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL'n 7ATKINS## 3AWA! *AFFREY3 ETAL)NSULINRESTORESNEURONALNITRICOXIDESYNTHASEEXPRESSION ANDFUNCTIONTHATISLOSTINDIABETICGASTROPATHY*#LIN)NVESTn 'ANGULA02 -ANER7, -ICCI-! ETAL$IABETESINDUCESSEX DEPENDENTCHANGESINNEURONAL NITRIC OXIDE SYNTHASE DIMERIZATION AND FUNCTION IN THE RAT GASTRIC ANTRUM !M * 0HYSIOL 'ASTROINTEST,IVER0HYSIOL'n $ISHY 6 #OHEN 0OUR - &ELDMAN , ET AL 4HE EFFECT OF SILDENAlL ON GASTRIC EMPTYING IN PATIENTS WITH END STAGE RENAL FAILURE AND SYMPTOMS OF GASTROPARESIS #LIN 0HARMACOL 4HER n &RASER2 (OROWITZ- -ADDOX! ETAL(YPERGLYCAEMIASLOWSGASTRICEMPTYINGINTYPE DIABETESMELLITUS$IABETOLOGIAn 2USSO! 3TEVENS*% #HEN2 ETAL)NSULIN INDUCEDHYPOGLYCEMIAACCELERATESGASTRICEMPTYING OF SOLIDS AND LIQUIDS IN LONG STANDING TYPE DIABETES * #LIN %NDOCRINOL -ETAB n 3CHVARCZ% 0ALMER- !MAN* ETAL0HYSIOLOGICALHYPERGLYCEMIASLOWSGASTRICEMPTYING IN NORMAL SUBJECTS AND PATIENTS WITH INSULIN DEPENDENT DIABETES MELLITUS 'ASTROENTEROLOGY n 2AYNER#+ 6ERHAGEN-! (EBBARD'3 ETAL0ROXIMALGASTRICCOMPLIANCEANDPERCEPTIONOF DISTENSIONINTYPEDIABETESMELLITUSEFFECTSOFHYPERGLYCEMIA!M*'ASTROENTEROL n 3AMSOM- !KKERMANS,- *EBBINK2* ETAL'ASTROINTESTINALMOTORMECHANISMSINHYPERGLYCAEMIAINDUCEDDELAYEDGASTRICEMPTYINGINTYPE)DIABETESMELLITUS'UTn &RASER2 (OROWITZ- $ENT*(YPERGLYCAEMIASTIMULATESPYLORICMOTILITYINNORMALSUBJECTS 'UTn (ASLER7, 3OUDAH(# $ULAI' ETAL-EDIATIONOFHYPERGLYCEMIA EVOKEDGASTRICSLOW WAVE DYSRHYTHMIASBYENDOGENOUSPROSTAGLANDINS'ASTROENTEROLOGYn (EBBARD'3 3UN7- $ENT* ETAL(YPERGLYCAEMIAAFFECTSPROXIMALGASTRICMOTORANDSENSORY FUNCTIONINNORMALSUBJECTS%UR*'ASTROENTEROL(EPATOLn *ONES+, (OROWITZ- "ERRY- ETAL4HEBLOODGLUCOSECONCENTRATIONINmUENCESPOSTPRANDIALFULLNESSININSULINDEPENDENTDIABETESMELLITUS$IABETES#AREn

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+UO0 'ENTILCORE$ .AIR. ETAL4HENITRICOXIDESYNTHASEINHIBITOR .G NITRO l-argininemethyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy HUMANS.EUROGASTROENTEROL-OTILnE ,IU- 3EINO3 +IRCHGESSNER!,)DENTIlCATIONANDCHARACTERIZATIONOFGLUCORESPONSIVENEURONS INTHEENTERICNERVOUSSYSTEM*.EUROSCIn 9OUNG2, 3UTHERLAND+ 0EZOS. ETAL%XPRESSIONOFTASTEMOLECULESINTHEUPPERGASTROINTESTINALTRACTINHUMANSWITHANDWITHOUTTYPEDIABETES'UTn -ONNIER,)SPOSTPRANDIALGLUCOSEANEGLECTEDCARDIOVASCULARRISKFACTORINTYPEDIABETES %UR*#LIN)NVEST3UPPLn -ONNIER, ,APINSKI( #OLETTE##ONTRIBUTIONSOFFASTINGANDPOSTPRANDIALPLASMAGLUCOSE INCREMENTS TO THE OVERALL DIURNAL HYPERGLYCEMIA OF TYPE DIABETIC PATIENTS VARIATIONS WITH INCREASINGLEVELSOF(B!C $IABETES#AREn #ERIELLO! (ANEFELD- ,EITER, ETAL0OSTPRANDIALGLUCOSEREGULATIONANDDIABETICCOMPLICATIONS!RCH)NTERN-EDn (OROWITZ- %DELBROEK-! 7ISHART*- ETAL2ELATIONSHIPBETWEENORALGLUCOSETOLERANCE ANDGASTRICEMPTYINGINNORMALHEALTHYSUBJECTS$IABETOLOGIAn 0ILICHIEWICZ!. #HAIKOMIN2 "RENNAN)- ETAL,OAD DEPENDENTEFFECTSOFDUODENALGLUCOSE on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in HEALTHYMEN!M*0HYSIOL%NDOCRINOL-ETAB%n 2AYNER #+ -A * 0ILICHIEWICZ ! ET AL %FFECTS OF VARIATIONS IN DUODENAL GLUCOSE LOAD ON glycaemia, insulin and GLP-1 in type 2 diabetes (abstract). Diabetologia. 2009;52 Suppl 1: 3n /$ONOVAN$' $ORAN3 &EINLE "ISSET# ETAL%FFECTOFVARIATIONSINSMALLINTESTINALGLUCOSE DELIVERY ON PLASMA GLUCOSE INSULIN AND INCRETIN HORMONES IN HEALTHY SUBJECTS AND TYPE DIABETES*#LIN%NDOCRINOL-ETABn 3CHWARTZ *' -C-AHAN #! 'REEN '- ET AL 'ASTRIC EMPTYING IN -EXICAN !MERICANS COMPAREDTONON (ISPANICWHITES$IG$IS3CIn 'ONLACHANVIT3 (SU#7 "ODEN'( ETAL%FFECTOFALTERINGGASTRICEMPTYINGONPOSTPRANDIAL PLASMA GLUCOSE CONCENTRATIONS FOLLOWING A PHYSIOLOGIC MEAL IN TYPE )) DIABETIC PATIENTS $IG$IS3CIn %NCK0 $UBOIS$ -ARQUIS01UALITYOFLIFEINPATIENTSWITHUPPERGASTROINTESTINALSYMPTOMS RESULTSFROMTHE$OMESTIC)NTERNATIONAL'ASTROENTEROLOGY3URVEILLANCE3TUDY$)'%34 3CAND *'ASTROENTEROL3UPPLn (OOGERWERF7! 0ASRICHA0* +ALLOO!. ETAL0AINTHEOVERLOOKEDSYMPTOMINGASTROPARESIS !M*'ASTROENTEROLn #HERIAN$ 3ACHDEVA0 &ISHER23 ETAL!BDOMINALPAINISAFREQUENTSYMPTOMOFGASTROPARESIS #LIN'ASTROENTEROL(EPATOLn #HRISTENSEN #* *OHNSON 7$ !BELL 4, 0ATIENTS WITH CYCLIC VOMITING PATTERN AND DIABETIC gastropathy have more migraines, abnormal electrogastrograms, and gastric emptying. Scand *'ASTROENTEROLn 3CHVARCZ % 0ALMER - )NGBERG #- ET AL )NCREASED PREVALENCE OF UPPER GASTROINTESTINAL SYMPTOMSINLONG TERMTYPEDIABETESMELLITUS$IABETIC-EDn 1UAN# 4ALLEY.* #ROSS3 ETAL$EVELOPMENTANDVALIDATIONOFTHE$IABETES"OWEL3YMPTOM 1UESTIONNAIRE!LIMENT0HARMACOL4HERn +UMAR! !TTALURI! (ASHMI3 ETAL6ISCERALHYPERSENSITIVITYANDIMPAIREDACCOMMODATION INREFRACTORYDIABETICGASTROPARESIS.EUROGASTROENTEROL-OTILn )SHII- .AKAMURA4 +ASAI& ETAL%RYTHROMYCINDERIVATIVEIMPROVESGASTRICEMPTYINGAND INSULINREQUIREMENTINDIABETICPATIENTSWITHGASTROPARESIS$IABETES#AREn .AUCK-! .IEDEREICHHOLZ5 %TTLER2 ETAL'LUCAGON LIKEPEPTIDEINHIBITIONOFGASTRICEMPTYINGOUTWEIGHSITSINSULINOTROPICEFFECTSINHEALTHYHUMANS!M*0HYSIOL%n 3AMSOM- 3ZARKA,! #AMILLERI- ETAL0RAMLINTIDE ANAMYLINANALOG SELECTIVELYDELAYS GASTRICEMPTYINGPOTENTIALROLEOFVAGALINHIBITION!M*0HYSIOL'ASTROINTEST,IVER0HYSIOL 'n ,INNEBJERG( 0ARK3 +OTHARE0! ETAL%FFECTOFEXENATIDEONGASTRICEMPTYINGANDRELATIONSHIP TOPOSTPRANDIALGLYCEMIAINTYPEDIABETES2EGUL0EPTn

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Chapter 17

Postsurgical Gastroparesis Reza A. Hejazi, Henry P. Parkman, and Richard W. McCallum

Keywords 0OSTSURGICAL GASTROPARESIS s 'ASTROENTEROLOGISTS s .UTRITIONISTS s*EJUNOSTOMYTUBEFEEDINGSs'ASTRICELECTRICALSTIMULATION

Introduction 0OSTSURGICALGASTROPARESIS03' ISACHRONICFORMOFGASTRICATONYINTHEABSENCEOF MECHANICALOBSTRUCTIONRESULTINGFROMSURGICALDISRUPTIONOFTHENORMALMECHANISMS THATGOVERNGASTRICMOTILITYANDEMPTYING4HESURGERIESCANINVOLVERESECTIONOF PARTOFTHESTOMACHANDORDISRUPTINGVAGALPATHWAYSCONTROLLINGGASTRICMOTILITY 03'DEVELOPSINUPTOOFPATIENTSWHOUNDERGOVAGOTOMYEITHERDELIBERATEOR INADVERTENT ASPARTOFUPPERGASTROINTESTINALSURGERY SUCHASPEPTICULCERDISEASEOR gastroesophageal reflux disease (GERD). The incidence increases to as high as 50% INPATIENTSWITHREFRACTORYULCERDISEASEWHOHADCHRONICGASTRICOUTLETOBSTRUCTION BEFORESURGERY4YPICALSYMPTOMSOF03'INCLUDENAUSEA VOMITING EARLYSATIETY AND ABDOMINALPAIN OFTENWITHSIGNIlCANTWEIGHTLOSS;1, 2=!NEXCELLENTREVIEWOFPOSTSURGICALANDOBSTRUCTIVEGASTROPARESISHASBEENPUBLISHEDBY3HAlAND0ASRICHA;2].

R.W. McCallum (*) $EPARTMENTOF)NTERNAL-EDICINE 5NIVERSITY-EDICAL#ENTER 0AUL,&OSTER3CHOOLOF-EDICINE 4EXAS4ECH5NIVERSITY (EALTH3CIENCES#ENTER !LBERTA!VENUE %L0ASO 48 53! e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_17, © Springer Science+Business Media, LLC 2012

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Gastric Motility and Vagal Function Normal Gastric Motility #ONTROLLEDGASTRICEMPTYINGOFANINGESTEDMEALISIMPORTANTFORPROPERDELIVERY OF PREPARED DIGESTED FOOD CHYME INTO THE SMALL INTESTINE WHERE NUTRIENTS ARE ABSORBED;1='ASTRICCONTRACTIONSANDSUBSEQUENTGASTRICEMPTYINGARECONTROLLED BYSEVERALMECHANISMS4HEINTERSTITIALCELLSOF#AJAL ENTERICMOTORNEURONSINTHE GASTRIC MYENTERIC PLEXUS AND GASTRIC SMOOTH MUSCLE ARE RESPONSIBLE FOR GASTRIC CONTRACTIONSALLOWINGTRITURATIONOFFOODINTOSMALLPARTICLESWITHPERISTALSISTOWARD THE PYLORUS ;2= 'ASTRIC MOTILITY IS MODULATED BY THE CENTRAL NERVOUS SYSTEM AND TRANSMITTEDTOTHESTOMACHPREDOMINANTLYBYTHEVAGUSNERVE6AGALNERVESTIMULATION CAUSESBOTHFUNDICRELAXATIONANDANTRALCONTRACTIONS4HEVAGUSNERVEINNERVATES THESTOMACHVIAPRESYNAPTICCHOLINERGICNERVESTHATSYNAPSEONTWOTYPESOFPOSTGANGLIONICENTERICNEURONS/NEPATHWAYACTIVATESINHIBITORY PREDOMINATELYNITRICOXIDE CONTAINING NERVES IN THE FUNDUS MEDIATING RECEPTIVE ACCOMMODATION 4HE OTHER PATHWAY ACTIVATES EXCITATORY PREDOMINANTLY ACETYLCHOLINE CONTAINING MYENTERIC NEURONSINTHEANTRUMREGULATINGCONTRACTIONS3EQUENTIALACTIVATIONOFTHESENEURONS ISNECESSARYFOREFFECTIVEGASTRICEMPTYINGAFTERMEALINGESTION;2]. !DISTINCTCYCLEOFELECTROMECHANICALACTIVITYDURINGTHEFASTINGSTATEBEGINSIN THEPROXIMALSTOMACHANDMIGRATESDISTALLYTHROUGHTHESMALLBOWEL;1]. This cycle, the migratory motor complex (MMC), occurs approximately every 90 min. The --#ISCOMPOSEDOFTHREEPHASES0HASEISAPERIODOFMOTORINACTIVITYWITHONLY rare contractions, lasting 45–60 min. Phase 2 has intermittent peristaltic contracTIONSTHATINCREASEINFREQUENCYANDAMPLITUDEOVERANAPPROXIMATELYMINPERIOD 0HASEHASANINTENSEINCREASEINPERISTALTICCONTRACTIONS LASTINGnMIN OCCURRING ATTHEPACESETTERPOTENTIALFREQUENCYIE CONTRACTIONSPERMINUTEINTHESTOMACH 0HASEOFTHE--#ISPERISTALTICTHROUGHTHESTOMACHANDSMALLINTESTINE FACILITATING EMPTYING OF INDIGESTIBLE SOLIDS OUT OF THE STOMACH -EAL INGESTION OF ADEQUATE CALORICINTAKECAL CONVERTSTHEFASTING--#PATTERNTOTHEDIGESTIVEhFEDv PATTERNRESPONSIBLEFORGASTRICEMPTYINGOFTHEINGESTEDMEAL3IMULTANEOUSINCREASE INGASTRIC BILIARY ANDPANCREATICSECRETIONWITHTHE--#PROMOTESTHISSWEEPING hHOUSEKEEPERvEFFECT PROVIDINGADETERRENTFORBEZOARFORMATIONINTHESTOMACHAND BACTERIALCOLONIZATIONOFSMALLINTESTINEASWELLASAIDINGTHEDIGESTIONOFREMAINING chyme.

Effects of Vagotomy 4RUNCALVAGOTOMYRESULTSINSEVERALEFFECTSLOSSOFFUNDICRELAXATION REDUCEDANTRAL CONTRACTIONS AND LOSS OF PYLORIC RELAXATION ;2, = ,OSS OF FUNDIC RELAXATION AND ACCOMMODATIONMAYLEADTOSYMPTOMSOFEARLYSATIETY FULLNESS ANDBLOATING WITH RAPIDTRANSITOFTHEINGESTEDFOODFROMTHEPROXIMALSTOMACHTOTHEDISTALSTOMACH

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Postsurgical Gastroparesis

2EDUCEDANTRALCONTRACTIONSAREASSOCIATEDWITHLOSSOFTRITURATIONANDRETENTIONOF SOLIDSINTHESTOMACH,OSSOFPYLORICRELAXATIONALSOCAUSESGASTRICRETENTION4HE EFFECTOFATOTALVAGOTOMYISTODELAYEMPTYINGOFSOLIDSWHILEACCELERATINGGASTRIC EMPTYINGOFLIQUIDS4RUNCALVAGOTOMYALSOAFFECTSTHEFASTING--#WITHRESULTANT GASTRICRETENTIONOFLARGERINDIGESTIBLEFOODINTHESTOMACHANDOCCASIONALLYBEZOAR FORMATION!GASTRICDRAINAGEPROCEDURESUCHASAPYLOROPLASTYORGASTROENTEROSTOMY ISUSUALLYPERFORMEDINANATTEMPTTOOFFSETTHEGASTROPARETICEFFECTSOFVAGOTOMY )NMOSTPATIENTS THENETRESULTISTHATVAGOTOMYCOMBINEDWITHADRAINAGEPROCEDURE produces little alteration in gastric emptying. Selective vagotomy procedures (parietal cell vagotomy, proximal gastric vagoTOMY ORHIGHLYSELECTIVEVAGOTOMY AREUSEDTOREDUCEGASTRICACIDSECRETIONWHILE PRESERVINGANTRALINNERVATIONTOPRESERVEGASTRICMOTILITYANDEMPTYING;2=!TRIALOF PATIENTSCOMPAREDPROXIMALGASTRICVAGOTOMY TRUNCALVAGOTOMYWITHDRAINAGE ANDTRUNCALVAGOTOMYWITHANTRECTOMYFORTHETREATMENTOFCHRONICDUODENALULCER;4]. 4HE PROXIMAL GASTRIC VAGOTOMY OPERATION WAS ASSOCIATED WITH LESS SYMPTOMS OF DUMPING EPIGASTRICFULLNESS ANDDIARRHEAAFTERSURGERY 3OMEPATIENTSAFTERAVAGALNERVEINJURYHAVERAPIDGASTRICEMPTYINGDUMPING SYNDROME WHILEOTHERSMAYHAVEDELAYEDGASTRICEMPTYINGGASTROPARESIS 4HERE SEEMSTOBETWOMAINEXPLANATIONSFORTHIS -INORORMINIMALTRAUMAORDAMAGE TOTHEVAGUSMAYAFFECTTHEFUNDUSANDPROXIMALSTOMACHANDNOTTHEANTRUMWITH LOSSOFFUNDALRELAXATIONORSTORAGE4HISPRESENTSASRAPIDEMPTYING-ORESEVERE VAGAL NERVE DAMAGE INVOLVES THE NERVES OF ,ATARJET AFFECTING ANTRAL INNERVATION RESULTING IN GASTRIC STASIS 0ATIENTS WITH PROLONGED GASTRIC OUTLET OBSTRUCTION CAUSEDBYPEPTICULCERDISEASEHAVEADILATED DISTENDEDSTOMACHWHICHIMPAIRSTHE CONTRACTILITYOFGASTRICSMOOTHMUSCLEEVENAFTERSURGICALRELIEFOFTHEOBSTRUCTION )NHIBITIONOFMOTILITYBYAVAGOTOMYRELATEDTOPEPTICULCERSURGERYFURTHERCOMPROmises this situation and leads severe delay in gastric emptying. 4HEVAGUSNERVE ALTHOUGHPRIMARILYTHOUGHTOFASANEFFERENTMOTORNERVEREGULATING')MOTILITY ISALSOANAFFERENTSENSORYNERVE CONVEYINGSENSORYINFORMATION FROMTHESTOMACHTOTHEBRAIN AND UNDERPATHOLOGICCONDITIONS NAUSEA;2=)NJURYOF THEVAGUSNERVEMAYGENERATESYMPTOMSDUETODYSFUNCTIONOFMOTORANDSENSORY components.

Incidence, Etiology, and Mechanisms of Postsurgical Gastroparesis 4HEINCIDENCEOFPOSTSURGICALGASTROPARESISISDIFlCULTTODETERMINE-OSTPATIENTS REPORTEDARETHOSEREFERREDTOSPECIALIZEDCENTERSFROMANUMBEROFSMALLERHOSPITALS WITHTHERESPONSIBLESURGERYFORTHE03'PERFORMEDATVARYINGTIMEPERIODSBEFORE REFERRALTHESEREFERREDPATIENTSTOSPECIALIZEDCENTERSPROBABLYREPRESENTTHEMOST SEVERECASESOF03';2]. 0OSTSURGICALGASTROPARESISREPRESENTSAMINORITYOFPATIENTSWITHGASTROPARESIS )NAREPORTFROM5NIVERSITYOF6IRGINIA 03'WASPRESENTINOFALLPATIENTSWITH

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GASTROPARESIS COMPAREDWITHOFDIABETICCASESANDOFIDIOPATHICONES;5]. )NANOTHERREPORTFROM4EMPLE5NIVERSITY OUTOFPATIENTSWITHDELAYEDGASTRIC EMPTYING HAD03'WITHAPRIORSURGICALPROCEDURETHATCOULDACCOUNTFOR THEIRGASTROPARESIS;6]. 03'ISOFTENACONSEQUENCEOFVAGOTOMYORVAGALNERVEINJURYDURINGGASTROINTESTINALSURGERY#LASSICALLY OPERATIONSFORPEPTICULCERDISEASESUCHASVAGOTOMY WITHORWITHOUTHEMIGASTRECTOMYHAVEBEENTHOSERESULTINGINGASTROPARESIS;7, 8]. (OWEVER SURGERYFORULCERDISEASEHASDECREASEDOVERTHELASTDECADEBECAUSEOF TREATMENTSWITHPROTONPUMPINHIBITORSANDTHERAPYAGAINST(ELICOBACTERPYLORIFOR ULCERDISEASE/THERSURGERIESSUCHAS.ISSENFUNDOPLICATIONFOR'%2$ANDBARIATRIC SURGERYFOROBESITYHAVEINCREASED4HUS THESURGERIESCAUSING03'MAYALSOBE CHANGINGASTHETYPESOFGASTRICSURGERIESEVOLVE;2=)NTHECLASSICSERIESOFPOSTSURGICAL GASTROPARESIS REPORTED IN FROM THE -AYO #LINIC ;7= TWO THIRDS OF THE patients had prior peptic ulcer operations: 12 patients had undergone truncal vagotomy ANDAhDRAINAGEOPERATIONvANDHADRECEIVEDAPARTIALGASTRECTOMYWITHAGASTROenterostomy: Billroth I (n = 8), Billroth II (n = 11), Roux-en-Y (n = 29). Interestingly, THEPATIENTSHADDELAYEDGASTRICEMPTYINGOFSOLIDSBUTRAPIDGASTRICEMPTYINGOF LIQUIDS"YCONTRAST THEPATIENTSCURRENTLYBEINGSEENATANACADEMICTERTIARYCARE CENTERWERERECENTLYREPORTED;6]. Fundoplication/hiatal hernia repair accounted FOROFTHE03'PATIENTS LUNGTRANSPLANTATIONOFPATIENTS WHEREASPARTIAL GASTRECTOMYVAGOTOMYCOMPRISEDOFTHEPATIENTS

Common Operations Lead to Postsurgical Gastroparesis 3URGERIESTHATAREASSOCIATEDWITHPOSTOPERATIVEDELAYEDGASTRICEMPTYINGINCLUDE "ILLROTH ) AND )) ANTRAL RESECTIONS 2OUX EN 9 GASTROJEJUNOSTOMY FUNDOPLICATION BARIATRIC SURGERY INVOLVING POUCHES AND GASTROJEJUNOSTOMY ESOPHAGECTOMY WITH colonic interpositions or gastric pull-up, pylorus-preserving Whipple procedure, ANDLUNGTRANSPLANTATION;8=)NANANALYSISOFCONSECUTIVEPATIENTSWHOUNDERWENT GASTROJENJUNOSTOMY PATIENTSDEVELOPEDDELAYEDGASTRICEMPTYING;9=2ISKFACTORS FORDELAYEDGASTRICEMPTYINGAFTERGASTROJEJUNOSTOMYINCLUDEDPATIENTSYEARSOLD UNDERGONENONRESECTIVEGASTRICBYPASS UNDERGONE2OUX EN 9 ANDPRIORREOPERATION FORPOSTSURGICALGASTROPARESIS

Postvagotomy Gastroparesis 03'HASBEENCLASSICALLYDESCRIBEDASACONSEQUENCEOFPEPTICULCERSURGERY USUALLY WITHCONCURRENTPERFORMANCEOFTRUNCALVAGOTOMYINADDITIONTOA"ILLROTH)ANTRAL resection and gastrodoudenal anastomosis) or Billroth II (a 50% or greater gastric RESECTIONWITHAGASTROJEJUNOSTOMYANASTOMOSIS ;2, 8]. Although these procedures

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ARELESSCOMMONLYPRACTICED VAGALDYSFUNCTIONREMAINSTHEUNIFYINGCAUSEFORTHIS ANDOTHERFORMSOF03' 2OUX EN 9ANASTOMOSISISPARTICULARLYASSOCIATEDWITHGASTRICSTASISSYNDROMES )NADDITIONTOTHEVAGOTOMYANDDISTALGASTRICRESECTION THE2OUXLIMBMAYCONTRIBUTE TO GASTRIC STASIS BY GENERATING ECTOPIC PACEMAKER ACTIVITY WITH ORAD RETROGRADE PROPAGATION!DDITIONALLY STASISWITHINTHE2OUXLIMBITSELFMAYBEANINDEPENDENT CAUSEOFSYMPTOMSINTHISSYNDROME;2, 10–12].

Abdominal and Thoracic Surgery )NADVERTENTVAGOTOMYHASBEENESTIMATEDTOOCCURINnOFOPENSURGERIESONTHE ABDOMEN;2=4HISCOMPLICATIONSHOULDBESUSPECTEDINPATIENTSWHOPRESENTWITH GASTROPARETICSYMPTOMSFOLLOWINGABDOMINALSURGERY4HESURGERIESTHATAREMORE LIKELYTOACCIDENTALLYINJURETHEVAGUSNERVEINCLUDEANTIREmUXSURGERY GALLBLADDER RESECTION LIGATINGGASTRICANDDUODENALBLEEDINGVESSELS ANDRESECTINGGASTROINTESTINAL STROMALTUMOR')34 OFTHESTOMACH

Antireflux Surgery 4HEMOSTCOMMONCAUSEOFPOSTSURGICALGASTROPARESISCURRENTLYAPPEARSTOBE.ISSEN FUNDOPLICATION 4HE DEVELOPMENT OF POSTOPERATIVE GASTROPARESIS AFTER AN OPEN OR LAPAROSCOPIC.ISSENFUNDOPLICATIONMAYRESULTINSIGNIlCANTMORBIDITY;1=6AGAL NERVE INJURY HAS BEEN REPORTED IN TO AS MANY AS OF PATIENTS UNDERGOING LAPAROSCOPICFUNDOPLICATION;1 14]. 'ASTROINTESTINAL SYMPTOMS ARE COMMON IN THE lRST FEW WEEKS AFTER ANTIREmUX PROCEDURES ;2= )N A SERIES OF PATIENTS WHO UNDERWENT LAPAROSCOPIC .ISSEN FUNDOPLICATION ALLHADSYMPTOMSDURINGTHElRSTPOSTOPERATIVEMONTHS WITHEARLY SATIETY BLOATINGmATULENCE AND DYSPHAGIA BEING THE MOST COMMON;15=(OWEVER BYYEARTHESESYMPTOMSHADRESOLVEDINMORETHAN OFPATIENTS)NAMINORITYOFPATIENTS SYMPTOMSSUGGESTIVEOFGASTRICDYSFUNCTION CANPERSIST;2=4HEYCANTAKETHEFORMOFMILDEARLYSATIETY THECLASSICGAS BLOAT SYNDROME IMPAIRED ABILITY TO BELCH PAIN AND BLOATING AFTER A MEAL AND RARELY GASTROPARESIS 4WO EXPLANATIONS HAVE BEEN OFFERED FOR THESE SYMPTOMS 4HE lRST INVOKESVAGALDAMAGE;2, 15, 16= WHICHCANBEASSESSEDWITHASHAMMEALSTUDY WITHMEASUREMENTOFPLASMAPANCREATICPOLYPEPTIDE;17, 18]. In a regional survey OF GASTROENTEROLOGISTS AND SURGEONS IN THE NORTHWESTERN 53! THE INCIDENCE OF INTRACTABLEGAS BLOATSYNDROMEANDVAGALINJURYWITHEITHERGASTROPARESISORDIARRHEA WAS FOR EACH ;14]. The second explanation suggests that, in some patients, FUNDOPLICATIONUNMASKSAPREEXISTINGBUTSUBCLINICALGASTRICDYSMOTILITY;14]. In a SERIESOFPATIENTSWITHLONG STANDINGSEVEREGASTROESOPHAGEALREmUX APREEXISTING DELAYINGASTRICEMPTYINGOFSOLIDSBEFORETHEPROCEDUREWASASSOCIATEDWITHPOSTOPERATIVEBLOATING PAIN ANDEARLYSATIETY;19].

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4HEEFFECTSOFFUNDOPLICATIONONGASTRICEMPTYINGARECOMPLEX;2=)NTHEABSENCE OFVAGALINJURY MILDACCELERATIONOFINITIALGASTRICEMPTYINGMAYRESULTANDHASBEEN ATTRIBUTEDTOLIMITEDFUNDICRECEPTIVERELAXATIONFROMTHEMECHANICALEFFECTSOFTHE WRAP;20=)NSOMEPATIENTSWITHREmUXWHOHAVEPREEXISTINGDELAYEDGASTRICEMPTYING FUNDOPLICATIONBYITSELFMAYNORMALIZEEMPTYINGTHROUGHTHESEMECHANISMS;21]. !DELAYINGASTRICEMPTYINGISNOTREGARDEDASACONTRAINDICATIONTOFUNDOPLICATION )FGASTRICEMPTYINGISSLOWBEFOREANTIREmUXSURGERY SOMESUGGESTTHATALOOSEWRAP SHOULD BE PERFORMED OVER A & BOUGIE TO IMPROVE BELCHING AND DECREASE GAS BLOATING !PYLOROPLASTYISANOTHERCONSIDERATION)NCHILDREN COMBININGPYLORIC DRAINAGEPROCEDUREEITHERPYLOROMYOTOMYORPYLOROPLASTY WITHFUNDOPLICATIONIN PATIENTSWITHGASTROESOPHAGEALREmUXANDDELAYEDGASTRICEMPTYING ISANACCEPTABLE APPROACH ;22= 4HE VALUE OF THIS PROCEDURE REMAINS UNCLEAR WITH SOME STUDIES SHOWINGADECREASEINRECURRENTREmUXANDOTHERSSHOWINGNOBENElT;22, 2].

Heart/Lung Transplantation !TYPEOFRECENTLYDESCRIBED03'SEENPREDOMINATELYINACADEMICMEDICALCENTERS IS GASTROPARESISAFTERLUNGTRANSPLANTATIONORHEARTnLUNGTRANSPLANTATION;6=!FTER lung transplantation, delayed gastric emptying may predispose to gastroesophageal REmUXWITHMICROASPIRATIONANDSUBSEQUENTPULMONARYINFECTION WHICHCANHAVE DELETERIOUS EFFECTS ON THE TRANSPLANTED LUNGS $ELAYED GASTRIC EMPTYING MAY ALSO DECREASE BIOAVAILABILITY OF ORALLY ADMINISTERED IMMUNOSUPPRESSIVE AGENTS WHICH COULDLEADTOREJECTIONOFTHETRANSPLANTEDLUNGS;24]. Symptomatic delayed gastric EMPTYING WAS PRESENT IN OF PATIENTS AFTER SINGLE LUNG TRANSPLANTATION AND IN OFPATIENTSAFTERCOMBINEDHEARTANDLUNGTRANSPLANTATION;25]. Another study REPORTEDDELAYEDGASTRICEMPTYINGINEIGHTOFTENPATIENTSAFTERCOMBINEDHEARTAND LUNGTRANSPLANTATION;26=3EVERALCAUSESMAYEXPLAINGASTROPARESISAFTERHEARTAND LUNGTRANSPLANTATIONVAGALNERVEDYSFUNCTION VIRALINFECTION ANDIMMUNOSUPPRESSIVE MEDICATIONS6AGALNERVEDYSFUNCTIONFROMTHERMALORISCHEMICINJURYORDISSECTION OFTHEPOSTERIORMEDIASTINUMDURINGSURGERYHASBEENSUGGESTEDASTHEMOSTLIKELY CAUSE;24–26].

Bariatric Surgery 3URGICAL THERAPY FOR MORBID OBESITY HAS INCREASED SINCE THE LATE S 3EVERAL PROCEDURESAREDESIGNEDTORESTRICTSTOMACHSIZE;27=4HEMOSTCOMMONLYPERFORMED SURGICALPROCEDUREISTHE2OUX EN 9GASTRICBYPASS4HESTOMACHISPARTITIONEDINTO A SMALL PROXIMAL FUNDIC POUCH AND A BYPASSED DISTAL STOMACH A LOOP GASTROJEJUNOSTOMY THROUGH A SMALL GASTROENTEROSTOMY DRAINS THE PROXIMAL POUCH ;27]. )NGESTIONOFLARGEMEALSISPREVENTEDBYEARLYSATIETYRESULTINGFROMTHESMALLGASTRIC POUCH3OLIDEMPTYINGISSLOWER ANDLIQUIDEMPTYINGISFASTERAFTERGASTRICBYPASS SURGERY;28=,ESSCOMMONLYPERFORMEDAREGASTRICRESTRICTIVEPROCEDURESINCLUDING

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VERTICAL BANDING GASTROPLASTY AND ADJUSTABLE GASTRIC BANDING ;27= 6OMITING CAN OCCUR IN OF PATIENTS AFTER VERTICAL BANDING GASTROPLASTY ;29]. Another study FOUNDTHATEMPTYINGFROMTHEPROXIMALPOUCHWASNORMALANDCOULDNOTEXPLAINTHE EARLYSATIETY;0=3LEEVEGASTRECTOMYISGAININGPOPULARITYASANADDITIONALBARIATRIC PROCEDURE;1=4HEPROCEDUREUSESARESTRICTIVECOMPONENTANDINDUCESFAVORABLE HORMONALCHANGESWITHANANOREXIGENICEFFECT'ASTROENTEROLOGISTSAREINCREASINGLY SEEINGCOMPLICATIONSAFTERBARIATRICSURGERYRELATEDTOPARTITIONINGTHESTOMACHTO FORMING A GASTRIC POUCH WITH AN ACCOMPANYING GASTROJEJUNOSTOMY 4HIS CAN BE ASSOCIATEDTOVAGUSNERVEDAMAGE;2, 2].

Evaluation of PSG 03' SHOULD BE SUSPECTED IN PATIENTS WITH PERSISTENT DYSPEPTIC SYMPTOMS AFTER GASTRICSURGERY;2=)NTHE-AYO#LINICSTUDY NAUSEAWASPRESENTIN VOMITING IN ABDOMINALPAININ ANDWEIGHTLOSSWERETHEMOSTCOMMONSYMPTOMS EXPERIENCEDBYTHEPATIENTS;7=)NTHE4EMPLE5NIVERSITYSTUDY PATIENTSWITH03' RATEDFEELINGEXCESSIVELYFULLAFTERMEALS NOTBEINGABLETOlNISHAMEAL ANDBLOATING SIGNIlCANTLYHIGHERTHANOTHERSYMPTOMS;6=#OMPAREDTOPATIENTSWITHDIABETICOR IDIOPATHICGASTROPARESIS PATIENTSWITH03'HADGREATERSYMPTOMSOFEARLYSATIETY POSTPRANDIALFULLNESS ANDBLOATINGBUTLESSNAUSEAANDUPPERABDOMINALPAIN )NTHEEVALUATIONOFTHEPATIENTS ANUPPERENDOSCOPYISPERFORMEDTOEVALUATEFOR STRICTURESANDULCERSATTHEANASTOMOSES;1=4HEUPPERENDOSCOPYMAYSHOWRETAINED FOOD IN THE REMAINING STOMACH OR EVEN BEZOAR FORMATION 5PPER ') RADIOLOGY CANALSOBEOBTAINEDTOEVALUATEFOROBSTRUCTIONATTHEANASTOMOSIS!SPECTRUMOF RADIOLOGIClNDINGSHAVEBEENREPORTEDFORGASTRICBEZOAR APPEARINGASAMOTTLEDOR HOMOGENEOUS MOBILEORIMMOBILE MASSSOMETIMESlLLINGTHEGASTRICPOUCH;]. Gastric emptying is used to document delayed gastric emptying. Generally, gastric EMPTYINGSCINTIGRAPHYISUSED'ASTRICEMPTYINGIN03'CANBEPARTICULARLYSEVERE 5SING THE 4OUGAS %GG"EATERS MEAL GASTRIC EMPTYING FOR SOLIDS IS CONSIDERED DELAYEDIFGASTRICRETENTIONWASATHANDORATH;4, 5]. In the 4EMPLE5NIVERSITYSTUDY GASTRICRETENTIONIN03'WASSEVEREWITHANAVERAGE GASTRICRETENTIONHPOSTPRANDIALLY;6=4HESEVERITYOFTHEDELAYWASMOREMARKED INPATIENTSWITHPARTIALGASTRECTOMYVAGOTOMYRETENTIONATH COMPARED TOFUNDOPLICATIONRETENTIONATH ANDPYLOROPLASTYVAGOTOMYRETENTION ATH /FNOTE THENORMALVALUESFORGASTRICEMPTYINGSCINTIGRAPHYAREDERIVED FROMNORMAL NONOPERATED SUBJECTS4HEREAREFEWAPPROPRIATEhNORMALvDATABASES TO USE FOR PATIENTS AFTER GASTRIC SURGICAL PROCEDURES )N POSTSURGICAL PATIENTS THE ALTERED ANATOMY IS LIKELY TO ALTER GASTRIC EMPTYING COMPARED TO NORMAL SUBJECTS WITHOUTGASTRICSURGERY;7=)NGENERAL THEREISDELAYINTHEEMPTYINGOFSOLIDSAND ACCELERATEDEMPTYINGOFLIQUIDS;7=!FTER2OUXGASTRECTOMY THEREMAYBERETENTION OFSOLIDSINBOTHGASTRICREMNANTANDTHE2OUXLIMB;12]. The normal gastric emptying IN PATIENTS WITH DIFFERENT DEGREES OF PARTIAL GASTRIC RESECTIONS EG ANTRECTOMY ANDDIFFERENTDRAINAGEPROCEDURESISNOTKNOWN4HISISALSORELEVANTWITHSURGICAL RECONSTRUCTIONOFTHESTOMACH ESPECIALLYPOSTBARIATRICSURGERYOFTHESTOMACH

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'ASTRICSURGERYWITHEITHERPARTIALGASTRICRESECTIONANDORVAGOTOMYCANAFFECT DIFFERENTREGIONSOFTHESTOMACHANDHAVEDELAYEDEMPTYINGOFSOLIDSBUTRAPIDGASTRIC EMPTYINGOFLIQUIDS;7=)NSOMEPOSTSURGICALPATIENTS DETERMINATIONOFBOTHGASTRIC EMPTYINGOFSOLIDSANDLIQUIDSISNEEDED$UALLABELINGOFSOLIDSWITH99mtechnetium ANDLIQUIDSWITH 111INDIUMALLOWSFORASSESSMENTOFGASTRICEMPTYINGOFSOLIDSAND LIQUIDSWHICHMAYBEUSEFULFORPATIENTSAFTERGASTRICSURGERYTOASSESSTHEIRDIFFERENTIAL HANDLINGBYTHEPOSTSURGICALSTOMACH;5]. 3YMPTOMS SUGGESTING GASTROPARESIS IN PATIENTS AFTER GASTRIC AND ESOPHAGEAL surgeries may not give a clear picture on the pathophysiologic process. In patients UNDERGOINGGASTRICSURGERY BOTHDELAYEDGASTRICEMPTYINGANDRAPIDGASTRICEMPTYING CAN BE SEEN 4HE .)$$+ 'ASTROPARESIS #ONSORTIUM HAS REPORTED ITS EXPERIENCE WITH03';6=4HEPATIENTSWITHSYMPTOMSOF03'HADTHEFOLLOWINGSURGERIES .ISSENFUNDOPLICATION PARTIALGASTRICRESECTION MYOTOMYORESOPHAGOgastrectomy (9% each), and stomach stapling and vagotomy (4% each). Overall, the HIGHESTMEANSYMPTOMSCOREWASFORNAUSEAANDEARLYSATIETYOFPATIENTSHAD BEENHOSPITALIZEDINTHEPASTYEARWITHNAUSEAANDABDOMINALPAINBEINGTHEINDICATIONSFOROFTHESEADMISSIONS'ASTRICEMPTYINGRESULTSSEPARATEDPATIENTSWITH 03'SYMPTOMSINTO 0ATIENTSWITHDELAYEDGASTRICEMPTYING WITHMEAN VALUE OF RETENTION AT H AND 0ATIENTS WITHOUT DELAYED GASTRIC EMPTYING WITHAMEANOFFOODRETENTIONATH4WOPATIENTS OFTHESEPATIENTS METTHECRITERIONFORDUMPINGSYNDROMEWITHRETENTIONATH4HUS INTHE SETTING OF POSTGASTRIC AND POSTESOPHAGEAL SURGERIES SYMPTOMS ASSOCIATED WITH DELAYED NORMALORRAPIDEMPTYINGOFTHESTOMACHMAYBESIMILAR.ISSENFUNDOPLICATIONWASTHEMAJORSURGERYASSOCIATEDWITH03'SYMPTOMSANDCOULDBEATTRIBUTED TOhACCIDENTALvVAGALNERVEINJURYDURINGSURGERY

Management of PSG 4HEGENERALPRINCIPLESFORTREATMENTOFSYMPTOMATICGASTROPARESISAREMAINTENANCE OF HYDRATION mUID AND ELECTROLYTE BALANCE CORRECTION OF NUTRITIONAL DElCIENCIES REVERSALOFTHECAUSE IFPOSSIBLEANDALLEVIATIONOFSYMPTOMS;1=-ANAGEMENTOF 03'FOLLOWSTHESEGENERALPRINCIPLES -ANYSYMPTOMSFOLLOWINGABDOMINALSURGERYMAYDECREASEWITHTIME;2]. Thus, INITIALMANAGEMENTSHOULDBECONSERVATIVE2ESOLUTIONOFSYMPTOMSMAYALSOBE ACCOMPANIEDBYIMPROVEMENTINGASTRICEMPTYING SUGGESTINGTHATEITHERTHEENTERIC NERVOUSSYSTEMMAYBEABLETOADAPTTOLOSSOFVAGALINPUTORTHATVAGALREINNERVATION ORREGENERATIONOFNERVElBERMAYOCCUR ASSHOWNFORAFFERENTBUTNOTEFFERENT lBERSINEXPERIMENTALMODELS;7]. 3YMPTOMATICMANAGEMENTOF03'INCLUDESDIETARYMANIPULATIONANDTHECOMBINATIONOFPROKINETICANDANTIEMETICAGENTS$IETARYMANAGEMENTCONSISTSOFSMALL LOW FAT LOW lBER MEALS )N SEVERE CASES PATIENTS NEED TO BE PLACED ON A LIQUID caloric diet.

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0RIMARYMEDICALTHERAPYISWITHPROKINETICANDANTIEMETICAGENTSTOHELPREDUCE SYMPTOMS/LDERLITERATURESUGGESTSSOMEEFlCACYWITHMETOCLOPRAMIDE CISAPRIDE ANDTEGASEROD;8, 9=-ETOCLOPRAMIDEISAVAILABLEASANORALTABLET LIQUIDFORMULATION ORALDISINTEGRATINGTABLET ANDININTRAVENOUSFORMULATIONS$OMPERIDONEIS ALSOADOPAMINETYPERECEPTORANTAGONISTBUTWITHLESSSIDEEFFECTSTHANMETOCLOPRAMIDEDUETOLESSPENETRATIONINTOTHE#.3)NTRAVENOUSERYTHROMYCINHASBEEN SHOWNTOIMPROVEGASTRICEMPTYINGINPATIENTSWITH2OUX EN 9STASISSYNDROME;40]. )N03' WITHOUTANANTRUM PROKINETICAGENTSARELESSSUCCESSFUL;41]. In addition, MEDICATIONSMIGHTNOTBERELIABLYABSORBEDBECAUSEOFBEZOARFORMATION3OMEOF THEANTIEMETICS SUCHASONDANSETRON AREAVAILABLEASLIQUIDMEDICATIONSANDASORAL DISSOLVINGTABLETSWHICHMIGHTBEBETTERABSORPED /THER NONSURGICAL OPTIONS FOLLOW TREATMENTS FOR OTHER FORMS OF GASTROPARESIS ! TRIAL OF LOW DOSE TRICYCLIC ANTIDEPRESSANTS EG NORTRIPTYLINE UP TO MGKG AS TOLERATED ASASYMPTOMMODULATOR MAYBECONSIDERED;1, 2=0YLORICINJECTIONOF BOTULINUMTOXINHASBEENPOSTULATEDINSOMESTUDIESASATHERAPEUTICOPTIONTOOVERCOMEPROLONGEDPERIODSOFINCREASEDPHASICANDTONICMOTORACTIVITYOFTHEPYLORUS TERMEDhPYLOROSPASMvWHICHCANOCCURAFTERVAGOTOMY!LTHOUGHITHASBEENSTUDIED ISSEVERALSERIESWITHVARIABLEDEGREEOFSUCCESS ARECENTSYSTEMATICREVIEWOF STUDIESINCLUDINGRANDOMIZEDCONTROLLEDTRIALSSHOWEDTHATINTRAPYLORICBOTULINUM TOXIN INJECTION COULD NOT SIGNIlCANTLY RELIEVE SUBJECTIVE SYMPTOMS AND IMPROVE OBJECTIVEMEASUREMENTINPATIENTSWITHGASTROPARESIS;42=!NOPEN LABELSTUDYOF ENDOSCOPICPYLORICINJECTIONOFBOTULINUMTOXIN!WASREPORTEDSPECIlCALLYFORTREATMENT OF PATIENTS WITH POSTVAGOTOMY GASTROPARESIS POSTFUNDOPLICATION ;4]. 4HEREWEREREDUCTIONSSEENINSYMPTOMSATANDMONTHSAFTERTREATMENTWITHRETURN OFSYMPTOMSAFTERMONTHSSUGGESTINGBOTULINUMTOXINMAYPRODUCESHORT TERM BUTNOTSUSTAINED REDUCTIONOFSYMPTOMS 4HE LIKELIHOOD OF SPONTANEOUS IMPROVEMENT BEGINS TO DECLINE AFTER A YEAR OR MOREHASPASSEDSINCETHEPUTATIVESURGICALINJURY;2=-ANAGEMENTOFPATIENTSWITH PERSISTENTREFRACTORY03'CANBEPARTICULARLYCHALLENGING4HEIRILLNESSHASGENERALLY BEENLONG STANDING ANDTHEIRSYMPTOMSHAVEREMAINEDDESPITEAVARIETYOFMEDICAL ANDPOSSIBLESUBSEQUENTSURGICALINTERVENTIONS#HRONICABDOMINALPAINANDASSOCIATEDPSYCHOSOCIALBEHAVIORALPATTERNSARECOMMONINSUCHPATIENTS ASISNARCOTIC DEPENDENCY!MULTIDISCIPLINARYAPPROACHIS THEREFORE IMPORTANT WITHINPUTFROM gastroenterologists, nutritionists, surgeons, pain specialists, and psychologists specialIZINGINTHECAREOFTHESEPATIENTS &ORPATIENTSWHOFAILMEDICALTHERAPIES SURGICALINTERVENTIONSAREOFTENCONTEMPLATED;44=4HESEINCLUDETUBEGASTROSTOMYFORGASTRICDECOMPRESSIONANDJEJUNOSTOMYFORENTERALFEEDINGS4OTALGASTRECTOMYISRESERVEDFORINTRACTABLEVOMITINGAND WEIGHTLOSSAFTERALLOTHEROPTIONSHAVEFAILED4HISISUSUALLYINTHEPATIENTAFTER PARTIALGASTRICRESECTIONWITHEITHERA"ILLROTH)OR))WITHORWITHOUTA2OUX EN 9 RECONSTRUCTION;45=-OSTOFTHELITERATURESUGGESTSPERFORMANCEOFAhCOMPLETIONv GASTRECTOMY;2, 44]. The largest series have yielded conflicting conclusions. In one SERIES OF PATIENTS WITH 03' WHO UNDERWENT hNEAR COMPLETION GASTRECTOMYv THEGASTRICREMNANTISRESECTED LEAVINGA TO CMPORTIONTOANASTOMOSEWITHTHE JEJUNUM FOLLOW UPDATAWEREAVAILABLEONPATIENTSOVERANAVERAGEOFNEARLYYEARS

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5SING A RELATIVELY SIMPLE SUBJECTIVE SCORE THE INVESTIGATORS REPORTED THAT ALMOST OFPATIENTSREPORTEDLONG TERMRELIEFOFSYMPTOMS;46]. By contrast, another STUDY LED TO A CONSIDERABLY LESS OPTIMISTIC CONCLUSION 4HIS STUDY INVOLVED PATIENTS OFWHOMWEREFOLLOWEDFORAMEANOFYEARSAFTERNEAR COMPLETION GASTRECTOMY 4HE RESULTS OF THIS STUDY WHICH APPLIED MORE ROBUST OBJECTIVE AND SUBJECTIVE CRITERIA SUGGEST THAT ONLY OF PATIENTS HAD FAVORABLE RESULTS ;47]. 3URGERYWASMOSTBENElCIALFORTHERELIEFOFNAUSEA ANDVOMITING BUTNOTFORRELIEF OF CHRONIC PAIN )N THE MOST RECENT THIRD STUDY PATIENTS WERE REPORTED WHO UNDERWENTNEAR TOTALORTOTALCOMPLETIONGASTRECTOMIESFORREFRACTORYPOSTSURGICAL GASTROPARESIS;48=0OSTOPERATIVECOMPLICATIONSOCCURREDIN MOSTCOMMONLY BOWELOBSTRUCTION ANASTOMOTICSTRICTURE ANDANASTOMOTICLEAK0ATIENTSRATEDTHEIR IMPROVEMENTFELTBETTER NEUTRAL ANDWORSE4HEREWERESYMPTOM IMPROVEMENTS IN ABDOMINAL PAIN VOMITING AND NAUSEA (OWEVER MOST PATIENTS HADSIGNIlCANTONGOINGGASTROINTESTINALCOMPLAINTSANDTHEINCIDENCEOFOSTEOPOROSIS WASHIGH 'ASTRICELECTRICALSTIMULATION'%3 ISANEMERGINGOPTIONFORREFRACTORYSYMPTOMS FROM03'!LTHOUGHELECTRICALPACINGOFTHE2OUXLIMBHASBEENAPPLIEDEXPERIMENTALLYANDWASSHOWNTORESULTINABOLITIONOFECTOPICPACEMAKERSRESPONSIBLEFOR JEJUNOGASTRICREmUX ITHASNOTBEENESTABLISHEDASAPRACTICALCLINICALAPPROACH;8]. 4HEINTRODUCTIONOFHIGH FREQUENCY'%3FORPATIENTSWITHDIABETICANDIDIOPATHIC GASTROPARESISHASRAISEDHOPEFORPATIENTSWITH03';49]. Some technical surgical ISSUESAREPRESENTWITHGASTRICELECTRICSTIMULATIONFOR03'&IRST THEPLACEMENTOF ELECTRODESANDBEDIFlCULTDUETOTHESMALLSTOMACHREMAINING3ECOND THEPLACEMENT OFTHEELECTRODESMAYNOTBEATTHELOCATIONOFTHEGASTRICPACEMAKERASISDONEIN IDIOPATHICANDDIABETICGASTROPARETICPATIENTSWITHINTACTSTOMACHSINWHOMTHESTIMULATORWIRESAREPLACEDANDCMPROXIMALTOTHEPYLORUS!RECENTREPORTPROVIDES SOMEOPTIMISMINTHISREGARDTHEAUTHORSREPORTEDSIXPATIENTSWITH03'TREATEDWITH '%3ANDFOLLOWEDFORUPTOMONTHS)MPRESSIVEIMPROVEMENTSINSYMPTOMATIC SCORES QUALITYOFLIFE ANDSOLIDANDLIQUIDGASTRICEMPTYINGWERESEEN;50]. In another STUDY '%3WASIMPLANTEDINPATIENTSWITHPOSTSURGICALGASTROPARESISWHOFAILED STANDARDMEDICALTHERAPY;45=4HESEVERITYANDFREQUENCYOFALLUPPER')SYMPTOMS TOTALSYMPTOMSCORE QUALITYOFLIFESCORESWERESIGNIlCANTLYIMPROVEDAFTER 6 months and sustained at 12 months. All patients had delayed gastric emptying ATBASELINE'ASTRICEMPTYINGWASNOTSIGNIlCANTLYFASTERATMONTHS ALTHOUGH NORMALIZED!TIMPLANTATION OFPATIENTSREQUIREDNUTRITIONALSUPPORTWITHA FEEDINGJEJUNOSTOMYTUBEAFTER'%3 WEREABLETODISCONTINUEJEJUNALFEEDING 4HE MEAN NUMBER OF HOSPITALIZATION DAYS WAS SIGNIlCANTLY REDUCED BY A MEAN DAYS COMPARED WITH THE PRIOR YEAR /NE PATIENT HAD THE DEVICE REMOVED AFTER MONTHSBECAUSEOFINFECTIONAROUNDTHEPULSEGENERATOR4HESEOBSERVATIONSSUGGEST THAT '%3 CAN IMPROVE UPPER ') SYMPTOMS QUALITY OF LIFE THE NUTRITIONAL STATUS AND HOSPITALIZATION REQUIREMENTS OF PATIENTS WITH POSTSURGICAL GASTROPARESIS ;45]. !LTHOUGHVAGALNERVEDAMAGEORDISRUPTIONWASPARTOFTHEUNDERLYINGPATHOPHYSIOLOGY '%3 THERAPY WAS STILL EFFECTIVE AND IS A POTENTIAL TREATMENT OPTION FOR THE LONG TERM MANAGEMENT OF POSTSURGICAL GASTROPARESIS ;45= 4HE PATIENTS THAT WERE LEASTLIKELYTOBENElTFROM'%3WERETHESEWITHTHEIRSTOMACHSTILLREMAINING

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Summary 0OSTSURGICALGASTROPARESISREMAINSANIMPORTANTCAUSEOFGASTROPARESIS ALTHOUGHIT ISLESSCOMMONTHANDIABETICANDIDIOPATHICETIOLOGIES4HESURGICALSETTINGFOR03' HASCHANGEDNOWTHATSURGERYFORPEPTICULCERDISEASEISLESSCOMMONLYPERFORMED #URRENTLY 03'ISMORELIKELYTOBEASSOCIATEDWITHVAGALNERVEINJURYFOLLOWING ANTIREmUXANDBARIATRICSURGERY-ANAGEMENTOFPATIENTSWITHPERSISTENTREFRACTORY POSTSURGICALGASTROPARESISCANBECHALLENGING!MULTIDISCIPLINARYAPPROACHISHELPFUL WITHINPUTFROMGASTROENTEROLOGISTS SURGEONS ANDNUTRITIONISTS

References 1. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical REVIEWONTHEDIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGYn 3HAl-! 0ASRICHA0*0OST SURGICALANDOBSTRUCTIVEGASTROPARESIS#URR'ASTROENTEROL2EP n 7OODWARD%24HEHISTORYOFVAGOTOMY!M*3URG n +OO* ,AM3+ #HAN0 ETAL0ROXIMALGASTRICVAGOTOMY TRUNCALVGOTOMYWITHDRAINAGE AND TRUNCAL VAGOTOMY WITH ANTRECTOMY FOR CHRONIC DUODENAL ULCER ! PROSPECTIVE RANDOMIZED CONTROLLEDTRIAL!NN3URGn 3OYKAN) 3IVRI" 3AROSIEK) ETAL$EMOGRAPHY CLINICALCHARACTERISTICS PSYCHOLOGICALPROlLES TREATMENT AND LONGTERM FOLLOW UP OF PATIENTS WITH GASTROPARESIS $IG $IS 3CI n -ALHOTRA. 0ATHIKONDA- 3ACHDEVA0 -AURER!( &ISHER23 0ARKMAN(00OST SURGICAL GASTROPARESIS!MODERNDESCRIPTION.EUROGASTROENTEROL-OTILITYABSTRACT &ICH! .ERI- #AMILLERI- ETAL3TASISSYNDROMESFOLLOWINGGASTRICSURGERYCLINICALAND MOTILITYFEATURESOFSYMPTOMATICPATIENTS*#LIN'ASTROENTEROLn %AGON *# -IEDEMA "7 +ELLY +! 0OSTGASTRECTOMY SYNDROMES 3URG #LIN .ORTH !M n +UNG30 ,UI79 0ENG&+!NANALYSISOFTHEPOSSIBLEFACTORSCONTRIBUTINGTODELAYEDRETURN OFGASTRICEMPTYINGAFTERGASTROJEJUNOSTOMY3URG4ODAYn -ATHIAS *2 &ERNANDEZ ! 3NINSKY #! ET AL .AUSEA VOMITING AND ABDOMINAL PAIN AFTER 2OUX EN 9ANASTOMOSISMOTILITYOFTHEJEJUNALLIMB'ASTROENTEROLOGYn VANDER-IJLE(# "EEKHUIS( "LEICHRODT20 +LEIBEUKER*(4RANSITDISORDERSOFTHEGASTRIC REMNANTAND2OUXLIMBAFTER2OUX EN 9GASTROJEJUNOSTOMYRELATIONTOSYMPTOMATOLOGYAND VAGOTOMY"R*3URGn -IEDEMA"7 +ELLY+! #AMILLERI- (ANSON2" :INSMEISTER!2 /#ONNOR-+ ETAL (UMANGASTRICANDJEJUNALTRANSITANDMOTILITYAFTER2OUXGASTROJEJUNOSTOMY'ASTROENTEROLOGY n (UNTER2* -ETZ$# -ORRIS*" ETAL'ASTROPARESISAPOTENTIALPITFALLOFLAPAROSCOPIC.ISSEN FUNDOPLICATION!M*'ASTROENTEROL +OZAREK2! ,OW$% 2ALTZ3,,APAROSCOPICANTI REmUXSURGERY%ARLYCOMMUNITYEXPERIENCE WITHDISCORDANTRESULTSWHENQUERYINGGASTROENTEROLOGISTSORSURGEONS;ABSTRACT='ASTROINTEST %NDOSC

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&RANTZIDES #4 #ARLSON -! :OGRAFAKIS *' ET AL 0OSTOPERATIVE GASTROINTESTINAL COMPLAINTS AFTERLAPAROSCOPIC.ISSENFUNDOPLICATION*3,3n +OZAREK 2! ,OW $% 2ALTZ 3, #OMPLICATIONS ASSOCIATED WITH LAPAROSCOPIC ANTI REmUX SURGERY/NEMULTISPECIALTYCLINICSEXPERIENCE'ASTROINTEST%NDOSCn $E6AULT +2 &LOCH .2 !CHEM 32 (INDER 2! 6AGAL NERVE DYSFUNCTION BEFORE AND AFTER ANTIREmUXSURGERY!M*'ASTROENTEROL3 (EJAZI2! -C#ALLUM27'ASTROINTESTINALHORMONETESTING)N0ARKMAN(0 -C#ALLUM27 2AO33 EDITORS'ASTROINTESTINALMOTILITYTESTINGLABORATORYANDOFlCEHANDBOOK3LACK ,UNDELL,2 -YERS*# *AMIESON''$ELAYEDGASTRICEMPTYINGANDITSRELATIONSHIPTOSYMPTOMS OFhGAS BLOATvAFTERANTIREmUXSURGERY%UR*3URGn "AIS*% 3AMSON- "OUDESTEIJN%! ETAL)MPACTOFDELAYEDGASTRICEMPTYINGONTHEOUTCOME OFANTIREmUXSURGERY!NN3URGn &ARRELL4- 2ICHARDSON73 (ALKAR2 ETAL.ISSENFUNDOPLICATIONIMPROVESGASTRICMOTILITY INPATIENTSWITHDELAYEDGASTRICEMPTYING3URG%NDOSCn -AXSON24 (ARP3 *ACKSON2* ETAL$ELAYEDGASTRICEMPTYINGINNEUROLOGICALLYIMPAIRED CHILDRENWITHGASTROESOPHAGEALREFUXTHEROLEOFPYLOROPLASTY*0EDIATR3URGn "USTORFF 3ILVA* 0EREZ#! &ONKALSRUD%7 ETAL'ASTRICEMPTYINGPROCEDURESDECREASETHE RISKOFPOSTOPERATIVERECURRENTREmUXINCHILDRENWITHDELAYEDGASTRICEMPTYING*0EDIATRY3URG n 3ODHI33 'UO* 0 -AURER!( /"RIEN' 3RINIVASAN2 0ARKMAN(0'ASTROPARESISAFTER COMBINEDHEARTANDLUNGTRANSPLANTATION*#LIN'ASTROENTEROLn "ERKOWITZ. 3CHULMAN,, -C'REGOR# ETAL'ASTROPARESISAFTERLUNGTRANSPLANTPOTENTIAL ROLEINPOSTOPERATIVERESPIRATORYCOMPLICATIONS#HEST !U* (AWKINS4 6ENABLES# ETAL5PPERGASTROINTESTINALDYSMOTILITYINHEART LUNGTRANSPLANT RECIPIENTS*4HORAC3URG -UN %# "LACKBURN ', -ATTHEWS *" #URRENT STATUS OF MEDICAL AND SURGICAL THERAPY FOR OBESITY'ASTROENTEROLOGY (OROWITZ- #OOK$* #OLLINS0* ETAL-EASUREMENTOFGASTRICEMPTYINGAFTERGASTRICBYPASS SURGERYUSINGRADIONUCLIDES"R*3URG "ALSIGER"- 0OGGIO*, -AI* ETAL4ENANDMOREYEARSAFTERVERTICALBANDEDGASTROPLASTYAS PRIMARYOPERATIONFORMORBIDOBESITY*'ASTROINTEST3URG -ISTIAEN7 6ANEERDEWEG7 "LOCKX0 ETAL'ASTRICEMPTYINGRATEMEASUREMENTAFTERVERTICAL BANDEDGASTROPLASTY/BES3URG 'OITEIN$ 'OITEIN/ &EIGIN! :IPPEL$ 0APA-3LEEVEGASTRECTOMYRADIOLOGICPATTERNS AFTERSURGERY3URG%NDOSCn !BELL4, -INOCHA!'ASTROINTESTINALCOMPLICATIONSOFBARIATRICSURGERYDIAGNOSISANDTHERAPY !M*-ED3CIn (EWITT!. ,EVINE-3 2UBESION3% ,AUFER)'ASTRICBEZOARSREASSESSMENTOFCLINICALAND RADIOGRPHIClNDINGSINPATIENTS"R*2ADIOLn 4OUGAS' %AKER%9 !BELL4, !BRAHAMSSON( "OIVIN- #HEN* ETAL!SSESSMENTOFGASTRIC EMPTYINGUSINGALOW FATMEALESTABLISHMENTOFINTERNATIONALCONTROLVALUES!M*'ASTROENTEROL n !BELL4, #AMILLERI- $ONOHOE+ (ASLER7, ,IN(# -AURER!( ETAL#ONSENSUSRECOMMENDATIONSFORGASTRICEMPTYINGSCINTIGRAPHY!JOINTREPORTOFTHE3OCIETYOF.UCLEAR-EDICINE AND4HE!MERICAN.EUROGASTROENTEROLOGYAND-OTILITY3OCIETY!M*'ASTROENTEROL n 3AROSIEK) -C#ALLUM27 ETAL)NTERPRETINGSYMPTOMSSUGGESTINGGASTROPARESISINPATIENTS AFTERGASTRICANDESOPHAGEALSURGERIES'ASTROENTEROLOGYABSTRACT 0HILLIPS2* "ARONOWSKY%! 0OWLEY4,,ONG TERMREGENERATIONOFABDOMINALVAGUSEFFERENTS FAILWHILEAFFERENTSSUCCEED*#OMP.EUROLn -ALAGELADA*2 2EES7$ MAZZOTTA,* 'O6,'ASTRICMOTORABNORMALITIESINDIABETICAND POSTVAGOTOMY GASTROPARESIS EFFECT OF METOCLOPRAMIDE AND BETHANECHOL 'ASTROENTEROLOGY n

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Chapter 18

Idiopathic Gastroparesis Linda Nguyen

Keywords )DIOPATHIC GASTROPARESIS s 0OSTINFECTIOUS GASTROPARESIS s &UNCTIONAL DYSPEPSIAs0SYCHOLOGICALDYSFUNCTION

Introduction )DIOPATHIC GASTROPARESIS IS A DISORDER OF DELAYED GASTRIC EMPTYING WITHOUT AN IDENTIlABLE CAUSE 3EVERAL SERIES OF PATIENTS WITH GASTROPARESIS FOUND IDIOPATHIC GASTROPARESISTOBETHEMOSTCOMMONCAUSEOFGASTROPARESIS COMPRISINGn OFPATIENTS;1n=5PTOOFPATIENTSWITHIDIOPATHICGASTROPARESISMAYHAVEA POSTINFECTIOUS FORM OF GASTROPARESIS PRESENTING AFTER A VIRAL PRODROME AND ACUTE ONSETOFSYMPTOMS;1=0ATIENTSWITHPOSTINFECTIOUSGASTROPARESISTYPICALLYHAVEA BETTER PROGNOSIS COMPARED TO THOSE WITH IDIOPATHIC GASTROPARESIS ;n6]. Some PATIENTSWITHPOSTINFECTIOUSGASTROPARESISHAVEBEENREPORTEDTOEXPERIENCESYMPTOM IMPROVEMENTANDEVENRESOLUTIONOFSYMPTOMSANYWHEREFROMTOMONTHSAFTER THEONSETOFSYMPTOMS;5, 6].

Epidemiology 4HETRUEPREVALENCEOFIDIOPATHICGASTROPARESISISNOTKNOWNDUETOLACKOFPOPULATION based studies. A recent study using the National Inpatient Sample Database on INPATIENTHOSPITALIZATIONS SHOWEDTHATTHENUMBEROFGASTROPARESIS RELATEDHOSPITALIZATIONSHASBEENINCREASINGINTHE53! ANDASSOCIATEDWITHSIGNIlCANTECONOMIC

L. Nguyen (*) $EPARTMENTOF'ASTROENTEROLOGYAND(EPATOLOGY 3TANFORD5NIVERSITY 0ALO!LTO #! 53! E MAILNGUYENLB STANFORDEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_18, © Springer Science+Business Media, LLC 2012

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COSTS AND INPATIENT MORTALITY ;7= )NTERESTINGLY THE RISE IN GASTROPARESIS WAS PREDOMINANTLYRELATEDTOARISEIN#AUCASIANWOMENWITHNONDIABETICGASTROPARESIS ;8=$ELAYEDGASTRICEMPTYINGISREPORTEDINnOFPATIENTSWITHFUNCtional dyspepsia, a condition that, at least by questionnaire data, is present in about OF THE POPULATION "Y THESE ESTIMATES DYSPEPTIC SYMPTOMS WITH DELAYED GASTRIC EMPTYING IE IDIOPATHIC GASTROPARESIS MIGHT BE PRESENT IN OF THE general population. The Mayo Clinic group, using the Rochester Epidemiology 0ROJECT FOUNDTHATTHEAGE ADJUSTEDPREVALENCEOFDElNITEGASTROPARESISWASMUCH LOWERFORMENANDFORWOMENPER PERSONS;2]. 7OMENACCOUNTFORAPPROXIMATELYOFPATIENTSWITHGASTROPARESIS WITHAN AVERAGEAGEOFAPPROXIMATELYYEARS;1, 2, 9=4HEFEMALEPREDOMINANCEISPRESENT in idiopathic, diabetic, and postsurgical gastroparesis. Despite chronic gastrointestiNALSYMPTOMS THE.)(GASTROPARESISCLINICALRESEARCHCONSORTIUMFOUNDTHAT OFPATIENTSWITHIDIOPATHICGASTROPARESISWEREOBESE"-)KGM2 ;9]. 0SYCHOLOGICALDYSFUNCTION EITHERDEPRESSIONORANXIETY CANBEPRESENTINMANY OFTHESEPATIENTSWITHIDIOPATHICGASTROPARESIS;1, 10]. The associated or causal relaTIONSHIPBETWEENSYMPTOMSOFGASTROPARESISANDPSYCHOLOGICALDYSFUNCTIONISNOT CLEAR 0SYCHOLOGICAL DYSFUNCTION IN THE FORM OF DEPRESSION AND ANXIETY DOES NOT CORRELATE WITH THE DEGREE OF GASTRIC EMPTYING DELAY OR ETIOLOGY OF GASTROPARESIS HOWEVER DEPRESSIONANDANXIETYCORRELATEDWITHPHYSICIANANDPATIENT RATEDGASTROPARESISSEVERITY;10=!HISTORYOFABUSEHASBEENREPORTEDTOBEPRESENTINSOME PATIENTSWITHIDIOPATHICGASTROPARESIS;1].

Evaluation of Patients with Suspected Idiopathic Gastroparesis #HAPTERCONTAINSADETAILEDDISCUSSIONOFSPECIlCTESTSFORDIAGNOSINGGASTROPARESIS &OR PATIENTS WITH DOCUMENTED GASTROPARESIS WITHOUT A KNOWN UNDERLYING CAUSE ADDITIONALTESTINGSHOULDBEPERFORMEDTOEXCLUDEOTHERCAUSESOFDELAYED GASTRICEMPTYING!CAREFULHISTORYANDPHYSICALEXAMINATIONSHOULDBEPERFORMED TOEVALUATEFORTHEPRESENCEOFANUNDERLYINGMALIGNANCYORCONCOMITANTNEUROlogic, autoimmune, or connective tissue disorder. A thorough drug history should BEOBTAINEDTOEVALUATEFORMEDICATIONSTHATMAYDELAYGASTRICEMPTYINGNARCOTICS ;11= ANTICHOLINERGIC AGENTS ;12= TRICYCLIC ANTIDEPRESSANTS ;1], calcium channel BLOCKERS;1= DOPAMINEAGONISTS;15= ANDNICOTINE;16]. Opiate narcotic analgeSICSCANDELAYGASTRICEMPTYINGANDALSOCAUSESYMPTOMSOFNAUSEAANDVOMITING Laboratory testing has limited value in diagnosing gastroparesis. Testing is recomMENDED TO EXCLUDE THYROID DYSFUNCTION AND TO EVALUATE FOR METABOLIC DERANGEMENTS SUCH AS HYPOKALEMIA OR RENAL INSUFlCIENCY "ASIC TESTING SHOULD INCLUDE COMPLETE BLOOD COUNT COMPLETE METABOLIC PANEL MAGNESIUM THYROID FUNCTION TESTS AND!.!4HEPATIENTSNUTRITIONALSTATUSCANBESCREENEDWITHASSESSINGA prealbumin level.

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Symptoms 3IMILARTOOTHERCAUSESOFGASTROPARESIS SYMPTOMSARENONSPECIlC INCLUDINGNAUSEA VOMITING ABDOMINALPAIN EARLYSATIETY ANDORABDOMINALDISTENSION3YMPTOMSOF IDIOPATHIC GASTROPARESIS OFTEN OVERLAP WITH FUNCTIONAL DYSPEPSIA 5P TO OF PATIENTSMEETING2OME)OR))CRITERIAFORFUNCTIONALDYSPEPSIAWEREFOUNDTOHAVE DELAYEDGASTRICEMPTYING;17, 18=(OWEVER THERATEOFGASTRICEMPTYINGCORRELATES POORLY WITH SYMPTOM SEVERITY ;19n21= 6OMITING AND POSTPRANDIAL FULLNESS IS REPORTEDTOBEASSOCIATEDWITHDELAYEDGASTRICEMPTYINGINPATIENTSWITHFUNCTIONAL DYSPEPSIA!LTHOUGHGASTROPARESISISCLASSICALLYTHOUGHTOFASBEINGADISORDEROF PREDOMINANT NAUSEA VOMITING AND FULLNESS ABDOMINAL PAIN IS PRESENT IN MANY PATIENTSIRRESPECTIVEOFTHECAUSEOFGASTROPARESIS;22=!BDOMINALPAINWASPRESENT IN UP TO OF PATIENTS WITH GASTROPARESIS ;1, 22n2= 4HE PREVALENCE OF UPPER ABDOMINALPAINWASSIMILARBETWEENDIABETICANDIDIOPATHICGASTROPARESISHOWEVER THE SEVERITY OF PAIN WAS GREATER IN PATIENTS WITH IDIOPATHIC GASTROPARESIS ;22]. !BDOMINALPAINALSOCORRELATEDWITHIMPAIRMENTINQUALITYOFLIFE;22]. )THASALSOBEENPROPOSEDTHATPATIENTSWITHGASTROPARESISBECLASSIlEDBASEDON PREDOMINANTSYMPTOMSIMILARLYTOPATIENTSWITHIRRITABLEBOWELSYNDROME VOMITING PREDOMINANT DYSPEPSIAPREDOMINANTAND REGURGITATIONPREDOMINANT;25]. )NASTUDYOFPATIENTSWITHGASTROPARESIS HADVOMITINGPREDOMINANT HAD DYSPEPSIA PREDOMINANT AND REGURGITATION PREDOMINANT 0ATIENTS WITH VOMITINGPREDOMINANTGASTROPARESISWEREMORELIKELYTOBEYOUNGERANDMORELIKELY TOEXPERIENCEWEIGHTLOSSANDDEHYDRATION0ATIENTSWITHREGURGITATIONPREDOMINANT SYMPTOMSWEREMORELIKELYTOBEOLDERANDHEAVIER4HISISANINTRIGUINGCONCEPT ASITMAYHELPGUIDETHERAPY(OWEVER FURTHERSTUDIESAREREQUIREDTODETERMINEIF THIS SYMPTOM BASED CLASSIlCATION CORRELATES WITH PATHOPHYSIOLOGY AND TREATMENT response.

Pathophysiology 4HEPATHOPHYSIOLOGYOFGASTROPARESISISDISCUSSEDINDETAILIN#HAPTERSn$ELAYED GASTRICEMPTYINGCANOCCURASARESULTOFALTERATIONSINAVARIETYOFGASTROINTESTINAL MOTORFUNCTIONIMPAIREDGASTRICACCOMMODATION;2= ANTRALHYPOMOTILITY;26, 27], PYLOROSPASM;28, 29= ALTEREDANTRODUODENALCOORDINATION ORSMALLBOWELDYSMOTILITY;28=)NASTUDYOFPATIENTSWITHIDIOPATHICGASTROPARESIS WEREFOUNDTO HAVEIMPAIREDGASTRICACCOMMODATIONANDWEREFOUNDTOHAVEVISCERALHYPERSENSITIVITY ;2= )N THIS STUDY EARLY SATIETY AND WEIGHT LOSS WERE ASSOCIATED WITH IMPAIREDGASTRICACCOMMODATIONWHILEPAIN EARLYSATIETY ANDWEIGHTLOSSWEREASSOCIATEDWITHHYPERSENSITIVITYTOGASTRICDISTENTION)NASTUDYOFCONSECUTIVEPATIENTS WITHIDIOPATHICNAUSEAANDVOMITING WEREFOUNDTOHAVEPOSTPRANDIALANTRAL HYPOMOTILITY;27=0RELIMINARYDATAREVEALEDTHATAPPROXIMATELYOFPATIENTSWITH IDIOPATHICGASTROPARESISHADPYLOROSPASM;0=)NASERIESOFPATIENTSWITHGASTROPARESIS OFPATIENTSHADTHEPRESENCEOFINTESTINALDYSMOTILITY;28].

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Treatment of Idiopathic Gastroparesis 4REATMENT OF IDIOPATHIC GASTROPARESIS IS SIMILAR TO OTHER CAUSES OF GASTROPARESIS This involves supportive measures through dietary modifications, promotility agents, AND ANTIEMETIC THERAPY $ETAILED DISCUSSIONS OF SPECIlC TREATMENTS OF EACH ARE DISCUSSEDINSEPARATECHAPTERS(OWEVER IDIOPATHICGASTROPARESISAPPEARSTORESPOND DIFFERENTLY TO CERTAIN THERAPIES COMPARED TO DIABETIC GASTROPARESIS 4HESE INCLUDE INTRAPYLORICBOTULINUMTOXININJECTIONANDGASTRICELECTRICALSTIMULATION

Intrapyloric Botulinum Toxin Injection /PENLABELSTUDIESOFGASTROPARESISFOUNDINTRAPYLORICINJECTIONOFBOTULINUMTOXIN EFFECTIVE IN TREATING GASTROPARESIS ;1n= (OWEVER PLACEBO CONTROLLED STUDIES FAILEDTODEMONSTRATEABENElTOFBOTULINUMTOXINOVERPLACEBO;5, 6]. A retroSPECTIVEANALYSISOFALARGESERIESOFPATIENTSFOUNDTHATFEMALEGENDER YOUNGERAGE ANDADIAGNOSISOFIDIOPATHICGASTROPARESISWASASSOCIATEDWITHAPOSITIVERESPONSE TOINTRAPYLORICBOTULINUMTOXININJECTION;7=4HISSTUDYALSOFOUNDTHATAHIGHER DOSEOFBOTULINUMTOXINWASASSOCIATEDWITHAGREATERRESPONSEVS FORTHE)5VS)5OFBOTULINUMTOXINp = 0.02).

Gastric Electrical Stimulation 'ASTRICELECTRICALSTIMULATIONUSESANIMPLANTABLENEUROSTIMULATORFORTHETREATMENT OFREFRACTORYGASTROPARESIS3INCETHE($%APPROVALOFHIGHFREQUENCY LOWENERGY gastric stimulation, several open label studies have demonstrated variable response RATES RANGING FROM TO IMPROVEMENT IN GASTROPARESIS SYMPTOMS ;8n0]. )NTHESTUDIESTHATLEDTOTHECOMPASSIONATEUSEAPPROVALOFGASTRICELECTRICSTIMULATIONFORPATIENTSWITHGASTROPARESIS PATIENTSWITHDIABETICGASTROPARESISRESPONDED BETTERWITHADECREASEINVOMITINGFREQUENCYCOMPAREDTOPATIENTSWITHIDIOPATHIC GASTROPARESIS;1=4WOSINGLECENTERSTUDIESHAVEFOUNDTHATPATIENTSWITHNAUSEA vomiting predominant gastroparesis and diabetic gastroparesis responded better THANPATIENTSWITHIDIOPATHICGASTROPARESISORTHOSEREQUIRINGCHRONICDAILYNARCOTICSFORPAIN;8, 2].

Impact $ESPITETHEhFUNCTIONALvCLASSIlCATIONOFIDIOPATHICGASTROPARESISANDOVERLAPWITH FUNCTIONAL DYSPEPSIA IDIOPATHIC GASTROPARESIS IS ASSOCIATED WITH SIGNIlCANT MORBIDITYANDEVENINCREASEDMORTALITY;1]. Several studies report decrease in the

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QUALITY OF LIFE AND IMPAIRMENT IN FUNCTIONAL ABILITY (OWEVER THERE ARE LIMITED POPULATION BASEDSTUDIESTHATDESCRIBETHEIMPACTOFIDIOPATHICGASTROPARESIS)N A POPULATION BASEDSTUDYOF/LMSTED#OUNTY -INNESOTA THEOVERALLSURVIVALFOR GASTROPARESISWASSIGNIlCANTLYLESSTHANEXPECTEDINTHATPOPULATIONVS 5 year survival, p ATTESTING TO THE SERIOUSNESS OF THIS CONDITION ;2]. )MPORTANTLY IDIOPATHICGASTROPARESISWASASSOCIATEDWITHSIGNIlCANTLYBETTERSURVIVALTHANOTHERCAUSESOFGASTROPARESIS SUCHASDIABETICGASTROPARESIS

Summary )DIOPATHIC GASTROPARESIS IS THE MOST COMMON CAUSE OF GASTROPARESIS 4HE RATE OF gastroparesis hospitalizations has been increasing over the past decade. This is assoCIATEDWITHINCREASEDHEALTHCAREBURDENANDDECREASEDSURVIVAL.AUSEA VOMITING POSTPRANDIALFULLNESS ANDABDOMINALPAINARECOMMONSYMPTOMSSIMILARTOTHOSE OFDIABETICGASTROPARESIS#URRENTTREATMENTSFORIDIOPATHICGASTROPARESISAPPEARTO IMPROVEUPONSYMPTOMSOFNAUSEAORVOMITINGRATHERTHANPAIN4HEPRESENCEOF PAINPREDOMINANTGASTROPARESISCORRELATESPOORLYWITHTREATMENTRESPONSE PARTICULARLY GASTRICELECTRICALSTIMULATION'ASTRICEMPTYINGHASBEENFOUNDTOCORRELATEPOORLY WITH SYMPTOMS OF GASTROPARESIS ,IKEWISE ACCELERATING GASTRIC EMPTYING HAS CORRELATEDPOORLYWITHSYMPTOMRESPONSE WHICHSUGGESTSTHATTHEPATHOPHYSIOLOGY OF GASTROPARESIS IS MORE COMPLEX THAN PURELY MECHANICAL EMPTYING #LINICIANS CARING FOR PATIENTS WITH GASTROPARESIS IN ORDER TO MAKE THE GREATEST IMPACT IN patient’s symptoms, must take these into account. Much more needs to be learned ABOUTTHISDISORDEROFIDIOPATHICGASTROPARESIS BOTHINTERMSOFPATHOPHYSIOLOGYAND TREATMENT SINCE PATIENTS WITH THIS DISORDER HAVE SIGNIlCANT SYMPTOMS IMPACTING THEIRFUNCTIONANDLIFE

References 1. Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, PSYCHOLOGICALANDABUSEPROlLES TREATMENT ANDLONG TERMFOLLOW UPOFPATIENTSWITHGASTROPARESIS$IG$IS3CI n *UNG (+ #HOUNG 23 ,OCKE RD '2 ET AL 4HE INCIDENCE PREVALENCE AND OUTCOMES OF PATIENTSWITHGASTROPARESISIN/LMSTED#OUNTY -INNESOTA FROMTO'ASTROENTEROLOGY n "IELEFELDT+ 2AZA. :ICKMUND3,$IFFERENTFACESOFGASTROPARESIS7ORLD*'ASTROENTEROL n "ITYUTSKIY,0 3OYKAN) -C#ALLUM276IRALGASTROPARESISASUBGROUPOFIDIOPATHICGASTROPARESIS CLINICAL CHARACTERISTICS AND LONG TERM OUTCOMES !M * 'ASTROENTEROL n /H** +IM#('ASTROPARESISAFTERAPRESUMEDVIRALILLNESSCLINICALANDLABORATORYFEATURES ANDNATURALHISTORY-AYO#LIN0ROC n .AFTALI4 9ISHAI2 :ANGEN4 ,EVINE!0OST INFECTIOUSGASTROPARESISCLINICALANDELECTEROGASTROGRAPHICASPECTS*'ASTROENTEROL(EPATOL n

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7ANG92 &ISHER23 0ARKMAN(0'ASTROPARESIS RELATEDHOSPITALIZATIONSINTHE5NITED3TATES TRENDS CHARACTERISTICS ANDOUTCOMES n!M*'ASTROENTEROL n 8. Pasricha PJ, Mannalithara A, Mithal A, Sehgal A, Morton JM, Singh G. Gastroparesis hospitalizations in the US: non-diabetic gastroparesis is a distinct and more serious health problem THANDIABETICGASTROPARESIS'ASTROENTEROLOGY 3UPPLEMENT ! !BSTRACT 0ARKMAN (0 9ATES + (ASLER 7, ET AL #LINICAL FEATURES OF IDIOPATHIC GASTROPARESIS VARY WITH SEX BODY MASS SYMPTOM ONSET DELAY IN GASTRIC EMPTYING AND GATROPARESIS SEVERITY 'ASTROENTEROLOGY n (ASLER 7, 0ARKMAN (0 7ILSON ,! ET AL 0SYCHOLOGICAL DYSFUNCTION IS ASSOCIATED WITH SYMPTOM SEVERITY BUT NOT DISEASE ETIOLOGY OR DEGREE OF GASTRIC RETENTION IN PATIENTS WITH GASTROPARESIS!M*'ASTROENTEROL n 9UAN#3 &OSS*& /#ONNOR- 2OIZEN-& -OSS*%FFECTSOFLOW DOSEMORPHINEONGASTRIC EMPTYINGINHEALTHYVOLUNTEERS*#LIN0HARMACOL n 0ARKMAN(0 4RATE$- +NIGHT,# "ROWN+, -AURER!( &ISHER23#HOLINERGICEFFECTSON HUMANGASTRICMOTILITY'UT n "OURAS%0 4ALLEY.* #AMILLERI- ETAL%FFECTSOFAMITRIPTYLINEONGASTRICSENSORIMOTORFUNCTION and postprandial symptoms in healthy individuals: a randomized, double-blind, placeboCONTROLLEDTRIAL!M*'ASTROENTEROL n 9AVORSKI24 (ALLGREN3% "LUE07%FFECTSOFVERAPAMILANDDILTIAZEMONGASTRICEMPTYINGIN NORMALSUBJECTS$IG$IS3CI n 2OBERTSON$2 2ENWICK!' 7OOD.$ ETAL4HEINmUENCEOFLEVODOPAONGASTRICEMPTYING INMAN"R*#LIN0HARMACOL n 'RITZ%2 )PPOLITI! *ARVIK-% ETAL4HEEFFECTOFNICOTINEONTHEDELAYOFGASTRICEMPTYING !LIMENT0HARMACOL4HERAP n 17. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJ, Hoes AW. Disturbed solid-phase GASTRICEMPTYINGINFUNCTIONALDYSPEPSIAAMETA ANALYSIS$IG$IS3CI n 4ALLEY.* ,OCKERD'2 ,AHR"$ ETAL&UNCTIONALDYSPEPSIA DELAYEDGASTRICEMPTYING AND IMPAIREDQUALITYOFLIFE'UT n 4ALLEY .* 6ERLINDEN - *ONES - #AN SYMPTOMS DISCRIMINATE AMONG THOSE WITH DELAYED ORNORMALGASTRICEMPTYINGINDYSMOTILITY LIKEDYSPEPSIA!M*'ASTROENTEROL n 4ALLEY.* 6ERLINDEN- 3NAPE7 ETAL&AILUREOFAMOTILINRECEPTORAGONIST!"4 TO RELIEVE THE SYMPTOMS OF FUNCTIONAL DYSPEPSIA IN PATIENTS WITH AND WITHOUT DELAYED GASTRIC emptying: a randomized double-blind placebo-controlled trial. Aliment Pharmacol Therapeut. n !RTS* #AENEPEEL0 6ERBEKE+ 4ACK*)NmUENCEOFERYTHROMYCINONGASTRICEMPTYINGAND MEAL RELATED SYMPTOMS IN FUNCTIONAL DYSPEPSIA WITH DELAYED GASTRIC EMPTYING 'UT n #HERIAN$ 3ACHDEVA0 &ISHER23 0ARKMAN(0!BDOMINALPAINISAFREQUENTSYMPTOMOF GASTROPARESIS#LIN'ASTROENTEROL(EPATOL n +ARAMANOLIS' #AENEPEEL0 !RTS* 4ACK*$ETERMINANTSOFSYMPTOMPATTERNINIDIOPATHIC SEVERELYDELAYEDGASTRICEMPTYINGGASTRICEMPTYINGRATEORPROXIMALSTOMACHDYSFUNCTION 'UT n (OOGERWERF7! 0ASRICHA0* +ALLOO!. 3CHUSTER--0AINTHEOVERLOOKEDSYMPTOMIN GASTROPARESIS!M*'ASTROENTEROL n 25. Harrell SP, Studts JL, Dryden GW, Eversmann J, Cai L, Wo JM. A novel classification scheme FOR GASTROPARESIS BASED ON PREDOMINANT SYMPTOM PRESENTATION * #LIN 'ASTROENTEROL n #AMILLERI- -ALAGELADA*2 "ROWN-, "ECKER' :INSMEISTER!22ELATIONBETWEENANTRAL MOTILITYANDGASTRICEMPTYINGOFSOLIDSANDLIQUIDSINHUMANS!M*0HYSIOL0T 'n +ERLIN 0 0OSTPRANDIAL ANTRAL HYPOMOTILITY IN PATIENTS WITH IDIOPATHIC NAUSEA AND VOMITING 'UT n

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#AMILLERI- "ROWN-, -ALAGELADA*22ELATIONSHIPBETWEENIMPAIREDGASTRICEMPTYINGAND ABNORMALGASTROINTESTINALMOTILITY'ASTROENTEROLOGY n -EARIN& #AMILLERI- -ALAGELADA*20YLORICDYSFUNCTIONINDIABETICSWITHRECURRENTNAUSEA ANDVOMITING'ASTROENTEROLOGY n 3HETLER+ .GUYEN, "UNKER3 0ARKER3 3NAPE7*2OLEOFPYLORICPRESSURESANDBOTULINUM TOXIN INJECTION IN THE TREATMENT OF DIABETIC AND IDIOPATHIC GASTROPARESIS 'ASTROENTEROLOGY ! ABSTRACT -ILLER,3 3ZYCH'! +ANTOR3" ETAL4REATMENTOFIDIOPATHICGASTROPARESISWITHINJECTIONOF BOTULINUMTOXININTOTHEPYLORICSPHINCTERMUSCLE!M*'ASTROENTEROL n %ZZEDDINE$ *IT2 +ATZ. 'OPALSWAMY. "HUTANI-30YLORICINJECTIONOFBOTULINUMTOXIN FORTREATMENTOFDIABETICGASTROPARESIS'ASTROINTEST%NDOSC n ,ACY"% #ROWELL-$ 3CHETTLER $UNCAN! -ATHIS# 0ASRICHA0*4HETREATMENTOFDIABETIC GASTROPARESIS WITH BOTULINUM TOXIN INJECTION OF THE PYLORUS $IABETES #ARE n "ROMER-1 &RIEDENBERG& -ILLER,3 &ISHER23 3WARTZ+ 0ARKMAN(0%NDOSCOPICPYLORIC INJECTION OF BOTULINUM TOXIN ! FOR THE TREATMENT OF REFRACTORY GASTROPARESIS 'ASTROINTEST %NDOSC n &RIEDENBERG&+ 0ALIT! 0ARKMAN(0 (ANLON! .ELSON$""OTULINUMTOXINAFORTHETREATMENT OFDELAYEDGASTRICEMPTYING!M*'ASTROENTEROL n !RTS* (OLVOET, #AENEPEEL0 ETAL#LINICALTRIALARANDOMIZED CONTROLLEDCROSSOVERSTUDYOF INTRAPYLORIC INJECTION OF BOTULINUM TOXIN IN GASTROPARESIS !LIMENT 0HARMACOL 4HERAPEUT n #OLESKI2 !NDERSON-! (ASLER7,&ACTORSASSOCIATEDWITHSYMPTOMRESPONSETOPYLORIC INJECTION OF BOTULINUM TOXIN IN A LARGE SERIES OF GASTROPARESIS PATIENTS $IG $IS 3CI n -ARANKI*, ,YTES6 -EILAHN*% ETAL0REDICTIVEFACTORSFORCLINICALIMPROVEMENTWITH%NTERRA GASTRIC ELECTRIC STIMULATION TREATMENT FOR REFRACTORY GASTROPARESIS $IG $IS 3CI n !NAND# !L *UBURI! &AMILONI" ETAL'ASTRICELECTRICALSTIMULATIONISSAFEANDEFFECTIVE A LONG TERM STUDY IN PATIENTS WITH DRUG REFRACTORY GASTROPARESIS IN THREE REGIONAL CENTERS $IGESTIONn n ,IN : 3AROSIEK ) &ORSTER * -C#ALLUM 27 3YMPTOM RESPONSES LONG TERM OUTCOMES AND ADVERSEEVENTSBEYONDYEARSOFHIGH FREQUENCYGASTRICELECTRICALSTIMULATIONFORGASTROPARESIS .EUROGASTROENTEROL-OTIL n !BELL4 -C#ALLUM2 (OCKING-ETAL'ASTRICELECTRICALSTIMULATIONFORMEDICALLYREFRACTORY GASTROPARESIS'ASTROENTEROLOGY n -USUNURU 3 "EVERSTEIN ' 'OULD * 0REOPERATIVE PREDICTORS OF SIGNIlCANT SYMPTOMATIC RESPONSEAFTERYEAROFGASTRICELECTRICALSTIMULATIONFORGASTROPARESIS7ORLD*3URG n

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Chapter 19

Gastroparesis from Other Causes Alia Dadabhai and Robert S. Fisher

Keywords 'ASTROPARESIS s 'ASTROESOPHAGEAL REmUX DISEASE s #ONNECTIVE TISSUE DISORDERSs-ALIGNANCYs6IRALINFECTIONS

Introduction 'ASTROPARESIS REFERS TO DELAYED STOMACH EMPTYING IN THE ABSENCE OF MECHANICAL OBSTRUCTIONOFTHEGASTRICOUTLET)TCANBEDUETOFAILURETOGENERATEANABORALPRESSURE GRADIENTWITHINTHESTOMACHIE PUMPFAILURE INADEQUATERELAXATIONOFTHEPYLORUS IE FUNCTIONALOBSTRUCTION ORANINAPPROPRIATEPRESSUREGRADIENTBETWEENTHEANTRUM ANDTHEDUODENUMCAUSEDBYANTRALHYPOMOTILITYORDUODENALSPASM4HEMAJORITY OFPATIENTSWITHGASTROPARESISCANBECATEGORIZEDASBEINGRELATEDTODIABETESMELLITUS TYPEORTYPE VAGUSNERVEMALFUNCTIONSECONDARYTOPRIMARYINJURYVAGOTOMY ORSECONDARYINJURYANTIREmUXORBARIATRICSURGERY HEART LUNGTRANSPLANTATION ORAS IDIOPATHIC"EFORECLASSIFYINGGASTROPARESISASBEINGIDIOPATHIC THEREAREANUMBER OFOTHERPUTATIVEETIOLOGIESTHATMUSTBECONSIDERED4ABLE19.1 4HESEOTHERPUTATIVE ETIOLOGIESARETHESUBJECTOFTHISCHAPTER

23&ISHER*) $EPARTMENTOF-EDICINE 4EMPLE5NIVERSITY(OSPITAL 0HILADELPHIA 0! 53! E MAILROBERTlSHER TEMPLEEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_19, © Springer Science+Business Media, LLC 2012

213

Table 19.1 #LASSIlCATION OFGASTROPARESIS

!$ADABHAIAND23&ISHER $IABETESMELLITUS Postsurgery 6AGOTOMY 6AGALINJURYn!NTIREmUX Bariatric Heart-lung transplant )DIOPATHIC h/THERvCAUSES 'ASTROESOPHAGEALREmUXDISEASE Functional dyspepsia (YPERTROPHICPYLORICSTENOSIS #ONSTIPATIONnGENERALIZEDDYSMOTILITY INTESTINALPSEUDOOBSTRUCTION #ONNECTIVETISSUEDISORDER Scleroderma Dermatomyositis !UTOIMMUNE Malignancy Paraneoplastic syndrome (IGH DOSECHEMOTHERAPY Stem cell transplantation 6IRALINFECTION %NDOCRINECAUSES (YPOTHYROIDISM Medication-induced Opioids !NTICHOLINERGICAGENTS Dopaminergic agents Neurologic disorders Multiple sclerosis Parkinson’s disease (OLLOWVISCERALNEUROPATHYORMYOPATHY #HAGASDISEASE 0SYCHIATRICDISORDERS #HRONICPANCREATITIS 2ENALFAILURE 4OTALPARENTERALNUTRITION

Gastroesophageal Reflux Disease 4HEPRESENCEOFGASTROPARESISINASIGNIlCANTNUMBEROFPATIENTSWITH'%2$WAS INITIALLYREPORTEDBY-C#ALLUMETAL;1=4HISASSOCIATIONWASINITIALLYCONTROVERSIAL BUTHASNOWBEENCONlRMEDBYOTHERINVESTIGATORS;2=4HEPATHOPHYSIOLOGIC EXPLANATION OF '%2$ RELATED TO GASTRIC HYPOMOTILITY IS STILL UNDER INVESTIGATION /NETHEORYISTHATGASTRICDISTENSIONASARESULTOFGASTRICSTASISMAYINCREASETHE FREQUENCYOFTRANSIENTLOWERESOPHAGEALSPHINCTERRELAXATIONSRESULTINGININCREASED

'ASTROPARESISFROM/THER#AUSES

215

GASTROESOPHAGEAL REmUX #ONTINUED BATHING OF THE DISTAL ESOPHAGUS IN ACIDIC OR BILIOUSGASTRICCONTENTSCANBESEENDURINGEXACERBATIONSOFGASTROPARESISLEADINGTO REmUX SYMPTOMS SUCH AS HEARTBURN OR ESOPHAGITIS ;2= !LTHOUGH FUNDOPLICATION MAYBEANOPTIONFORSYMPTOMATICRELIEFANDHEALING THEREAREALWAYSCONCERNSTHAT FUNDOPLICATIONCOULDEXACERBATETHEPROBLEMBYMAKINGGASTROPARESISWORSE

Hypertrophic Pyloric Stenosis )NTHEPEDIATRICPOPULATION CONGENITALHYPERTROPHICPYLORICSTENOSISUSUALLYPRESENTS WITHVOMITINGWITHINTHElRSTMONTHOFLIFE4HEPRIMARYCONDITIONISRARELYSEENIN ADULTS)NABILITYTORELAXTHEPYLORICSPHINCTERISASSOCIATEDWITHHYPERTROPHYOFTHE INNERCIRCULARMUSCLELAYERWHICHCAUSESDELAYEDGASTRICEMPTYING)NTERSTITIALCELLS OF#AJALALONGWITHNITRICOXIDECONTAININGINHIBITORYNERVESARELOST;3, =!SURGICAL OPTIONFORTREATMENTISPYLOROMYOTOMY2AMSTEDTPROCEDURE WHICHISOFTENSUCCESSFUL 2EVERSALOFTHEDEARTHININTERSTITIALCELLSOF#AJALANDANINCREASEINFREENITRICOXIDE HASBEENREPORTEDAFTERSURGERY(OWEVER THETONICITYOFTHEPYLORUSREMAINSHIGH WITHDIMINISHEDPYLORICPRESSUREWAVES0ASRICHAETALHASBEENABLETORESTORENITRIC OXIDEANDREVERSEGASTROPARESISINAMOUSEMODELOFGASTROPARESISBYPERFORMING STEMCELLTRANSPLANTATION;5].

Constipation-Associated Gastroparesis #ONSTIPATION ASSOCIATEDGASTROPARESISISPRESENTINnOFPATIENTSWITHCHRONIC IDIOPATHICCONSTIPATIONORIRRITABLEBOWELSYNDROMEWITHPREDOMINANTCONSTIPATION $URING ANTRODUODENAL MANOMETRY A HIGHER PREVALENCE OF BURST ACTIVITY HAS BEEN REPORTEDINTHEANTRUMANDDUODENUMINTHEFASTINGSTATEANDTHEPRESENCEOFABNORMAL PHASE))) LIKEACTIVITYDURINGTHEPOSTPRANDIALPHASESUGGESTINGNEURALDYSFUNCTION AFFECTINGTHEENTERICNERVOUSSYSTEMORTHEEXTRINSICPATHWAYS;6=/THERPOTENTIAL EXPLANATIONS FOR AN ASSOCIATION BETWEEN CONSTIPATION AND GASTROPARESIS INCLUDE UNINTENTIONALANDINTENTIONALDELAYSOFDEFECATIONWHICHCOULDCAUSEDYSREGULATION OFHORMONALGUTMEDIATORSANDCONSEQUENTCOLONICDISTENSIONWHICHMAYINHIBITTHE GASTROCOLICREmEX4HESEASSOCIATIONSARETHEORETICAL

Medication-Induced Gastroparesis -EDICATION INDUCED DELAYED GASTRIC EMPTYING HAS BEEN RELATED TO A NUMBER OF COMMONLYUSEDOVERTHECOUNTERANDPRESCRIPTIONDRUGS4ABLE19.2). Narcotics are THEMOSTCOMMONOFFENDERS4HEREARETHREEMAJOROPIOIDRECEPTORSINTHEHUMAN BODYDELTA KAPPA ANDMU4HESERECEPTORSOVERLAPINTHEIRDISTRIBUTIONANDFUNCTION

216

!$ADABHAIAND23&ISHER

Table 19.2 Medications ASSOCIATEDWITHIMPAIRED gastric emptying

Narcotics !NTICHOLINERGICMEDICATIONS 4RICYCLICANTIDEPRESSANTS #ALCIUMCHANNELBLOCKERS Clonidine Dopamine agonists ,ITHIUM Nicotine Progesterone

THROUGHOUTTHECENTRALANDENTERICNERVOUSSYSTEMSANDMAINTAINSOMESELECTIVITY FORENDOGENOUSOPIOIDS%XOGENOUSOPIOIDSPREFERENTIALLYACTIVATEP-opioid receptors. )NTHEHUMAN')TRACT THEPMU OPIOIDRECEPTORISPRIMARILYFOUNDINTHEMYENTERIC ANDSUBMUCOSALPLEXIOFTHESMALLANDLARGEINTESTINES;7="OTHENDOGENOUSAND EXOGENOUSOPIOIDSIMPAIRGASTROINTESTINALTRANSITBYALTERINGNEURONALEXCITABILITY ANDINHIBITINGTHERELEASEOFACETYLCHOLINEANDOTHERNEUROTRANSMITTERS)NVESTIGATORS INTHEEARLYSADMINISTEREDVARYINGDOSESOFMORPHINEANDHYDROMORPHONETO HEALTHYMALEVOLUNTEERSANDSTUDIEDTHEIRRESPONSES7HILEsegmental motor tone and contractility were increased, longitudinal propulsive peristaltic contractions wereDECREASED;8]. /RALNALOXONE ASYSTEMICOPIOIDANTAGONISTWITHLOWBIOAVAILABILITYOWINGTO lRST PASSHEPATICMETABOLISM HASBEENSTUDIEDFORITSTHEORETICALACCUMULATIONIN THEBOWELWITHOUTSYSTEMICLEVELSINTHEBLOODMAKINGITACANDIDATEFORTHETREATMENT OF OPIOID INDUCED CONSTIPATION 5NFORTUNATELY WHEN THIS HYPOTHESIS WAS TESTED ASIGNIlCANTNUMBEROFPATIENTSREPORTEDCENTRALSIDEEFFECTSANDPAINWHENSYSTEMIC OPIOIDSWEREWITHDRAWN;9=4HEDESIRETOMAINTAINANALGESIAWITHOUTCONSTIPATION HASLEDTOTHEINVESTIGATIONOFPERIPHERALLYACTINGOPIOIDANTAGONISTS SUCHASMETHYLNALTREXONEANDALVIMOPAN4HESEAGENTSSELECTIVELYANTAGONIZETHEPERIPHERALP MU OPIOIDRECEPTORWITHOUTDIMINISHINGOPIOIDEFFECTSONTHECENTRALNERVOUSSYSTEM 0RELIMINARY STUDIES USING METHYLNALTREXONE OR ALVIMOPAN TO TREAT OPIOID INDUCED GASTROINTESTINALSIDEEFFECTSHAVEBEENENCOURAGING;10]. /THERAGENTSHAVEBEENLESSWELLSTUDIEDINRELATIONSHIPTODELAYGASTRICEMPTYING !NTICHOLINERGICMEDICINES WHOSEPROPERTIESAREFOUNDINTHEMANYCOMMONPRESCRIPTIONS DO HAVE SOME RELATIONSHIP TO SLOWING MOTILITY !TROPINE BEING THE CLASSIC EXAMPLE OF AN ANTICHOLINERGIC MEDICINE HAS ALMOST CHOLINERGIC ANTAGONIST ACTIVITY WHILEOTHERMORECOMMONMEDICATIONS SUCHAS"ENADRYL HAVELESSTHAN EFFECTSANTICHOLINERGICACTIVITY4HEMECHANISMOFACTIONBEHINDTHEDELAYIN GASTRICEMPTYINGISINHIBITIONOFTHEPARASYMPATHETICNERVEIMPULSESBYSELECTIVELY BLOCKINGTHEBINDINGOFTHENEUROTRANSMITTERACETYLCHOLINETOITSRECEPTORSINNERVE CELLS.ERVOUSlBERSOFTHEPARASYMPATHETICSYSTEMARERESPONSIBLEFORTHEINVOLUNTARY MOVEMENTSOFSMOOTHMUSCLESPRESENTINTHEGASTROINTESTINALTRACT URINARYTRACT AND LUNGS ETC !NTICHOLINERGICS ARE DIVIDED INTO THREE CATEGORIES IN ACCORDANCE WITH THEIRSPECIlCTARGETSINTHECENTRALANDORPERIPHERALNERVOUSSYSTEMANTIMUSCARINIC AGENTS GANGLIONICBLOCKERS ANDNEUROMUSCULARBLOCKERS OFWHICHTHEANITMUSCARINICS


217

AREUSUALLYRELATEDTOGASTROINTESTINALDELAY&OREXAMPLE THETHERAPEUTICEFFECTOF METOCLOPRAMIDEFORPROKINESISISTHOUGHTTOBEMEDIATEDBYMUSCARINICACTIVITY D2RECEPTORANTAGONISTACTIVITY AND (4RECEPTORAGONISTACTIVITY;11].

Connective Tissue Disorders 4HE PREVALENCE OF DELAYED EMPTYING IN SCLERODERMA IS ESTIMATED TO BE n WHEREASTHERATESINPOLYMYOSITISnDERMATOMYOSITISANDSYSTEMICLUPUSERYTHEMATOSUS ARELOWER'ASTRICSTASISISDESCRIBEDINSMOOTHMUSCLEDISORDERS SUCHASMYOTONIC DYSTROPHYANDPROGRESSIVEMUSCULARDYSTROPHY;12]. Scleroderma 'ASTROINTESTINAL SCLERODERMA MOST COMMONLY AFFECTS THE ESOPHAGUS PRODUCING SYMPTOMS SUCH AS HEARTBURN REGURGITATION AND DYSPHAGIA ;13= 4HE SYMPTOMS OF SCLERODERMA RELATED GASTROPARESIS ARE INTERMITTENT WITH REMISSIONS OFTENLASTINGSEVERALMONTHS(EARTBURN DYSPHAGIA BLOATING NAUSEA ANDVOMITING ARECONSEQUENCESOFSMOOTHMUSCLEANDENTERICNEURONALDAMAGEOFTHEESOPHAGUS ANDSTOMACHINPATIENTSWITHSCLERODERMA#LINICALLY EVIDENCEOFSYSTEMICDISEASE INVOLVINGTHESKIN LUNGS ANDORTHEESOPHAGUSISUSUALLYPRESENTINPATIENTSWITH GASTRICORINTESTINALINVOLVEMENTDUETOSCLERODERMA;1=&OODREGURGITATEDFROM THESTOMACHMAYBECONFUSEDWITHFOODRETAINEDRETROSTERNALLYBECAUSEOFESOPHAGEAL DYSMOTILITYORADISTALESOPHAGEALSTRICTURE!POSSIBLEPATHOPHYSIOLOGICEXPLANATIONFORGASTRICSCLERODERMAISAUTOIMMUNE MEDIATEDINJURY)NONESTUDY HIGHTITER ANTIBODIESDIRECTEDAGAINSTMYENTERICNEURONSWEREDETECTEDINOFPATIENTS WITHSYSTEMICSCLEROSIS.ORMALCONTROLSOFPATIENTSWITHIDIOPATHICGASTROINTESTINAL DYSMOTILITY DID NOT DEMONSTRATE THESE ANTIBODIES ;15= 4HE PRESENCE OF #$ LYMPHOCYTESINTHEGASTRICMUCOSAASWELLASlBROSISHAVEALSOBEENNOTEDINDICATING AMUTIFACTORIALETIOLOGY;16].

Malignancy /FTENCANCERPATIENTSATTRIBUTENAUSEAANDVOMITINGTOTHEIRCANCERTHERAPYHOWEVER GASTROPARESISIS ONE OF THE MOST UNDERDIAGNOSEDDISORDERS RELATED TO MALIGNANCY 4HEGASTRICSLOWINGISTYPICALLYSEENINPATIENTSWITHUPPER')TRACTTUMORS SUCHAS GASTRIC PANCREATIC ESOPHAGEAL ORBILIARY"REASTANDLUNGCANCERHAVEALSOBEEN NOTABLYRELATED7HETHERMECHANICALTUMOR RELATEDOBSTRUCTION INlLTRATIONOFTHE CELIACPLEXUSORVAGUSNERVE POSTSURGICALRESECTION VIRALINFECTION ORPARANEOPLASTIC MEDIATEDCAUSESARETHEETIOLOGY TREATMENTCANBEDIFlCULTINTHESETTINGOFBASELINE NAUSEA FROM THE CHEMOTHERAPY ;17, 18= 0ATIENTS WITH MALIGNANCY ASSOCIATED GASTROPARESISHAVEDIFlCULTYWITHGASTRICEMPTYINGOFSOLIDS PARTICULARLYTHOSETHAT ARElBER RICH!MECHANICALGASTRICOUTLETOBSTRUCTIONMAYOCCURFROMTHESUBSEQUENT BEZOAR FORMATION ;19= )N ONE STUDY NAUSEA WAS THE MAJOR COMPLAINT IN OF THESEPATIENTSWITHGASTROPARESIS HADABDOMINALPAIN EXPERIENCEDEARLY SATIETY ANDVOMITINGOCCURREDIN;20]. In pancreatic cancer patients, as many

218


ASOFPATIENTSWHOHAVERECEIVEDTREATMENTCLINICALLYMANIFESTDELAYEDGASTRIC EMPTYING;21=$YSPHAGIAANDABNORMALSMALLBOWELMOTILITYWITHILEUSANDPSEUDO SMALLBOWELOBSTRUCTIONCANALSOBEEVIDENCEDINTHESECASES

High-Dose Chemotherapy and Stem Cell Transplantation 3TEMCELLTRANSPLANTATIONPOSESASIGNIlCANTRISKFORGASTRICMOTORFUNCTIONDISRUPTION ANDHASBEENNOTEDINUPTOONE HALFOFPATIENTSUNDERGOINGHEMATOPOIETICSTEMCELL TRANSPLANTATION(3#4 BOTHAUTOLOGOUSANDALLOGENEIC;22, 23=!VIRALPRECURSOR SUCHASCYTOMEGALOVIRUS#-6 ORHERPESSIMPLEXVIRUS HASBEENTHOUGHTTOBETHE INSTIGATING FACTOR ;16= (OWEVER THERE HAVE ALSO BEEN REPORTS OF GASTROPARESIS OR GENERALIZED GASTRIC MYOELECTRIC ACTIVITY HAS BEEN DOCUMENTED DISRUPTION WITHOUT EVIDENCE OF VIRAL INFECTION AMONG PATIENTS UNDERGOING HIGH DOSE CHEMOTHERAPY WITHAUTOLOGOUS(3#4;23=!LLOGENICSTEMCELLTRANSPLANTSCANALSOCAUSEGENERALIZED ANOREXIA NAUSEA AND VOMITING WITH OR WITHOUT GASTROPARESIS AS A FORM OF UPPER GASTROINTESTINALGRAFTVERSUSHOSTDISEASE;22].

Radiation Therapy 'ASTROPARESISISRARELYASSOCIATEDWITHRADIATIONTHERAPY2ADIATIONENTERITISCANBE SEENCAUSINGUPPER')SYMPTOMSSIMILARTOGASTRICMOTILITYIMPAIRMENT)FGASTRIC EMPTYING IS DELAYED A PRESUMED ETIOLOGY IS ENTERIC NERVOUS SYSTEM DAMAGE ;2 25=3CANTINFORMATIONONTHETOPICHASBEENPUBLISHED

Dysmotility and Paraneoplastic Syndrome Autoimmune and Paraneoplastic Gastrointestinal Dysmotility 4HEREISLIKELYANOVERLAPBETWEENAUTOIMMUNEMEDIATEDANDPARANEOPLASTICSYNDROMES!UTOIMMUNEGASTROINTESTINALDYSMOTILITYISANAUTOIMMUNEDYSAUTONOMIA THATCANOCCURINTHESETTINGOFANANATOMICALLYREMOTENEOPLASM MOSTCOMMONLY SMALLCELLLUNGCANCER4HESYMPTOMSMANIFESTASDELAYEDGASTRICEMPTYINGSOMETIMESACCOMPANYINGDELAYEDSMALLINTESTINALTRANSIT SLOWCOLONICTRANSIT ANDPELVIC mOORDYSSYNERGIA)NONEREPORT THEDIAGNOSISWASESTABLISHEDTHROUGHTHEPRESENCE OFPLASMAMEMBRANECATIONCHANNELAUTOANTIBODIES;26, 27=3OMEOFTHESEPATIENTS RESPONDEDTOIMMUNOTHERAPY 0ARANEOPLASTICGASTROPARESISHASBEENIDENTIlEDPRIMARILYINSMALLCELLLUNGCANCER (OWEVER INRARECASES OTHERTUMORSSUCHASBREAST OVARIANANDPANCREATICCANCER CARCINOID RETROPERITONEAL SARCOMA (ODGKIN LYMPHOMA AND CHOLANGIOCARCINOMA ;28n31=CANBEASSOCIATEDWITHAPARANEOPLASTICGASTROINTESTINALMOTILITYDISORDER )MMUNOmUORESCENCEASSAYCANDETECTTHEANTINEURONALNUCLEAR!..! ANTI (U


219

Table 19.3 0ARANEOPLASTICGASTROINTESTINALMOTORDYSFUNCTION Cancer !UTOANTIBODIES Breast cancer 0#! !..! (ODGKINLYMPHOMA 0#! 4R . TYPE#A!B /VARIANCANCER 0#! . TYPE#A!B Small cell lung cancer !..! 0#! TYPE 0URKINJE CELL CYTOPLASMIC ANTIBODY ALSO CALLED ANTI 9O!..!ANTINEURONALNUCLEARANTIBODYTYPE ALSOCALLED ANTI 2I0#! 4R0URKINJECELLCYTOPLASMICANTIBODYTYPE4R. TYPE #A!BANTINEURONALCALCIUMCHANNELANTIBODYOF. TYPESPECIlCITY !..! ANTINEURONAL NUCLEAR ANTIBODY TYPE ALSO CALLED ANTI (U$ATAFROM,EE (2 ,ENNON 6! #AMILLERI - 0RATHER #- 0ARANEOPLASTICGASTROINTESTINALMOTORDYSFUNCTIONCLINICALANDLABORATORYCHARACTERISTICS!M*'ASTROENTEROL

ANTIBODIESINTHESEPATIENTS;32=!SHAREDEPITOPEBETWEENTHESEAUTOANTIBODIESAND NEURONALCOMPONENTSOFTHEENTERICNERVOUSSYSTEMISTHEORIZEDASTHEEXPLANATION OFTHEGASTROPARESIS;33=4HETWOMOSTCOMMONAUTOANTIBODIESARE!..! AND . TYPEVOLTAGE GATEDCALCIUMCHANNELANTIBODIES/THERAUTOANTIBODIESASSOCIATED WITH PARANEOPLASTIC GASTROINTESTINAL DYSMOTILITY INCLUDE ANTINEURONAL ANTIBODIES TYPE!..! ORANTI 2I AMPHIPHYSINANTIBODY TYPE0URKINJECELLCYTOPLASMIC ANTIBODY0#! ALSOCALLEDANTI 9O 0#! 0#! 4R COLLAPSINGRESPONSEMODIlER PROTEIN#2-0 ANTIBODIESANDANTINEURONALCALCIUMCHANNELANTIBODIESOFTHE01 AND. TYPE4ABLE19.3 ;3]. !LTHOUGH THE EXACT MECHANISM FOR THE GASTROPARESIS HAS NOT BEEN ADEQUATELY DElNED STUDIESCONDUCTEDINPATIENTSWITHSMALLCELLLUNGCANCERANDGASTROINTESTINAL DYSMOTILITYHAVEDEMONSTRATEDIMMUNE MEDIATEDDESTRUCTIONOFTHEINTERSTITIALCELLS OF#AJALTHESO CALLEDINTESTINALPACEMAKERCELLS ;35=!NOTHERPROPOSEDTHEORYIS THATDYSMOTILITYRESULTSFROMAVISCERALNEUROPATHYOFTHEMYENTERICPLEXUSASSOCIATED WITH AN INlLTRATION WITH LYMPHOCYTES AND PLASMA CELLS AND SUBSEQUENT AXONAL DEGENERATIONWITHINTHEPLEXUS;36].

Celiac Plexus Injury $AMAGETOTHECELIACPLEXUSDUETOCANCERINlLTRATIONORACELIACPLEXUSNERVEBLOCK CANPRODUCEEFFECTSONGASTRICEMPTYING;37="OTHACCELERATEDANDDELAYEDGASTRIC EMPTYINGHAVEBEENREPORTED

Diffuse Gut Dismotility $IFFUSEDISORDERSOFGUTMOTILITY SUCHASCHRONICINTESTINALPSEUDOOBSTRUCTIONCAN PRESENT WITH GASTROPARESIS 0ATIENTS COMMONLY MANIFEST A WIDE RANGE OF CLINICAL FEATURES INCLUDING SMALL INTESTINAL BACTERIAL OVERGROWTH NUTRITIONAL DElCIENCIES BOWEL HABIT ABNORMALITIES AND PNEUMATOSIS INTESTINALIS 0RIMARY OR SECONDARY

220


AMYLOIDOSIS CAN CAUSE NEUROPATHIC OR MYOPATHIC INTESTINAL PSEUDOOBSTRUCTION 3TASISOFTHESTOMACHISFOUNDINnOFPATIENTSWITHCHRONICCONSTIPATIONOR CONSTIPATION PREDOMINANTIRRITABLEBOWELSYNDROMEANDHASBEENLINKEDWITHMEGARECTUM)NTESTINALPSEUDOOBSTRUCTIONCANALSOBERELATEDTOFAMILIALCAUSES OCCUR AFTERAVIRALPRODROME ORPRESENTASAPARANEOPLASTICPHENOMENONMOSTOFTENIN ASSOCIATIONWITHSMALLCELLLUNGCARCINOMA4HECLASSICINFECTIOUSCAUSEOFINTERRUPTEDGASTRICMOTILITYIS#HAGASDISEASE INWHICHTHEMYENTERICPLEXUSISDAMAGED BYTrypanosoma cruziINFECTION)NADDITIONTOPRODUCINGANACHALASIA LIKEPICTURE #HAGAS DISEASE MAY CAUSE GASTROPARESIS MEGADUODENUM AND CHRONIC INTESTINAL PSEUDOOBSTRUCTIONANDSEVERALEXTRAINTESTINALMANIFESTATIONS

Viral Infections 0UBLISHEDREPORTSHAVEDESCRIBEDTHEOCCURRENCEOFGASTRICSTASISINASSOCIATIONWITH PRIOR VIRAL INFECTION PARTICULARLY .ORWALK VIRUS AND ROTAVIRUS ;10, 15, 38= /THER VIRUSESWHICHMAYBEASSOCIATEDWITHISOLATEDCASESOFGASTROPARESISAREVARICELLA ZOSTER6:6 %PSTEIN "ARR%"6 #-6 ANDHUMANIMMUNODElCIENCYVIRUS()6 )THASBEENSPECULATEDTHATCERTAINVIRUSESMAYCAUSEEXTRINSICAUTONOMICDENERVATION;39, 0=!CASESTUDYOFSEVENPATIENTSSUGGESTEDTHATAMAJORITYOFPOSTVIRAL GASTROPARESIS CASES RESOLVED SPONTANEOUSLY WITHIN WEEKS TO MONTHS ;1]. &IVEOFSEVENPATIENTSINARETROSPECTIVESTUDYBY/HHETALHADCOMPLETERESOLUTION OFGASTROPARETICSYMPTOMSDURINGAMEANFOLLOW UPOFMONTHS4HETWOREMAINING SUBJECTSHADCONSIDERABLEIMPROVEMENTWITHINTHESTUDYTIMEFRAME;2=!NOTHER STUDY IN THE PEDIATRIC POPULATION INCLUDED POSTVIRAL DELAYED GASTRIC MOTILITY CASESALLHADRESOLUTIONOFSYMPTOMSINnMONTHSMEANMONTHS ;12]. 3YMPTOMATICGASTROPARESISIN#-6AND()6ARERARELYSEENINIMMUNOCOMPETENT WELL CONTROLLEDINDIVIDUALS#-6 ASSOCIATEDGASTROPARESISCANBECOMECLINICALLY RELEVANTAFTERORGANTRANSPLANT;3=5PTOONE THIRDOFPATIENTSWHODEVELOP#-6 INFECTION AFTER LIVER TRANSPLANTATION DEVELOP DYSPEPTIC SYMPTOMS (ISTOLOGICAL EVIDENCEOF#-6ISNOTEDONENDOSCOPICBIOPSIESFROMTHESTOMACH3IMILAROBSERVATIONSHAVEBEENMADEFOR()6INFECTION5PTOONE THIRDOFTHEPATIENTSWITH()6 INFECTIONHAVEDYSPEPTICSYMPTOMSWHICHMAYBEEXACERBATEDBYCONCOMITANT#-6 ORMYCOBACTERIUMAVIUM INTRACELLULAREINTHOSEINDIVIDUALSWHOARENOTWELLCONTROLLED -ANAGEMENTOFTHESEPATIENTSSHOULDEMPHASIZEANTIVIRALANDANTIRETROVIRALTHERAPY 2ECOVERYCANBEMAINTAINEDWITHMANAGEMENTOFTHEUNDERLYINGDISORDERS

Neurologic Disorders 'ASTRICSTASISORVOMITINGISCOMMONLYSEENWITHNEUROLOGICDISORDERS&IG19.1). 4HEVAGUSNERVEANDLOWERTHORACICSPINALSYMPATHETICOUTmOWWHICHREGULATETHE UPPERGUTSEXTRINSICNEURALCONTROLCANBEINVOLVEDINFORMULTIPLESCLEROSIS BRAIN STEMSTROKEORTUMOR DIABETICORAMYLOIDNEUROPATHY ORPRIMARYDYSAUTONOMIAS


221

Fig. 19.1 .EUROMUSCULARDISORDERSIMPAIRINGGASTRICMOTORFUNCTION#AMILLERI - AND0RATHER #-)N3LEISENGERAND&ORDTRANS'ASTROINTESTINAL$ISEASE THED &ELDMAN - 3CHARSCHMIDT "& AND3LEISENGER -(EDS 7"3AUNDERS 0HILADELPHIA P5SEDWITHPERMISSION

$EGENERATIVE DIFFUSENEUROLOGICPROCESSES SUCHASDIABETESMELLITUS ACQUIRED IMMUNEDElCIENCYSYNDROME!)$3 OR0ARKINSONSDISEASEWHERE,EWYBODIES HAVE BEEN NOTED IN MYENTERIC NEURONS CAN AFFECT THE MYENTERIC PLEXUS 'ASTRIC STASISMAYALSOBETHERESULTOFSEVERALMEDICATIONSUSEDTOCONTROLTHENEUROLOGIC DISEASEEG ANTICHOLINERGICS DOPAMINERGICS ETC

Psychiatric Disease 3YMPTOMSCOMMONLYASSOCIATEDWITHGASTRICSTASIS SUCHASNAUSEA VOMITING EARLY SATIETY ABDOMINALBLOATING ANDANOREXIA ARECOMMONLYPRESENTINPATIENTSWITH PSYCHIATRIC DISEASE INCLUDING DEPRESSION ANXIETY NEUROSIS AND EATING DISORDERS SUCH AS ANOREXIA NERVOSA BULIMIA PSYCHOGENIC VOMITING OR CAN BE DUE TO SIDE EFFECTSFROMAPSYCHOTROPICMEDICATION6OMITINGISNOTEDTOBETHEMOSTFREQUENT COMPLAINTINTHESEPATIENTS;=$OCUMENTATIONOFGASTROPARESISWITHGASTRICSCINTIGRAPHYORWIRELESSMOTILITYCAPSULEISESSENTIALINTHESECASESASVOMITINGMAYALSO BESELF INDUCEDINEATINGDISORDERS4REATMENTOFTHESEPSYCHIATRICDISORDERSASSOCIATED WITHGASTROPARESISSHOULDINCLUDEBEHAVIORALANDPSYCHIATRICAPPROACHESALONGWITH MEDICATIONMODIlCATION

222


Chronic Pancreatitis 'ASTROPARESIS HAS BEEN REPORTED WITH SOME CASES OF SMALL DUCT PANCREATITIS $ELAYEDGASTRICEMPTYINGMAYBEDIFlCULTTODIAGNOSEINTHESEPATIENTSASTHECLASSIC SYMPTOMS OF NAUSEAVOMITINGABDOMINAL PAIN PRECLUDE ITS MEASUREMENT )T IS REASONABLETOCHECKGASTRICEMPTYINGINPATIENTSWHOAREREFRACTORYTOMEDICATION AFTEROTHERANATOMICABNORMALITIESHAVEBEENRULEDOUT2ESTORATIONOFTHEGASTRIC MYOELECTRICALACTIVITYAFTERADMINISTRATIONOFPANCREATICENZYMESHASSHOWNSOME PROMISE;5].

Renal Failure $ELAYEDGASTRICEMPTYINGASSOCIATEDWITHRENALDIALYSISORMOREPARTICULARLYPERITONEAL DIALYSISHASBEENNOTEDINSEVERALPATIENTSWITHRENALFAILURE4HISISTHOUGHTTOBE RELATEDTOELECTROLYTEANDMACRONUTRIENTSHIFTSTHATLEADTOGENERALIZEDSLOWINGOFTHE GASTROINTESTINAL TRACT MOTILITY ;6= 0ATIENTS WHO HAVE RENAL FAILURE OFTEN MANIFEST NAUSEAVOMITINGWITHOUTGASTROPARESISBEINGPRESENTTHEREFORE THEDISORDEROFTEN GOESUNDIAGNOSED-AINTENANCESOFPROPERNUTRITIONANDELECTROLYTEBALANCESCANBE THEKEYTOCONTROLLINGTHEPATIENTSDYSPEPTICSYMPTOMS

Total Parenteral Nutrition 40.CANCAUSEHYPERGLYCEMIAWHICHMAYDECREASEANTRALCONTRACTILITY(YPERGLYCEMIA SLOWS THE ANTRAL PHASE ))) OF THE --# INCREASES PYLORIC CONTRACTIONS CAN CAUSE TACHYGASTRIA DECREASEGASTRICEMPTYING ANDMODIFYFUNDICRELAXATION;7=6IGILANT MANAGEMENTOFELECTROLYTEANDMACRONUTRIENTFORMULATIONSCANREVERSETHEEFFECTS OFTHE40. ASSOCIATEDGASTROPARESIS,IPIDCONTENTSINTHESOLUTIONCANALSODELAY GASTRICEMPTYING;8].

Conclusion 7HENCONFRONTEDWITHAPATIENTHAVINGSYMPTOMATICGASTROPARESIS THEREISATENDENCY TO CONSIDER DIABETES MELLITUS AND VAGAL INJURY SECONDARY TO SURGERY AS THE LIKELY CAUSE)FNEITHEROFTHESECONDITIONSISPRESENT MOSTOFTHETIME GASTROPARESISIS THOUGHTTOBEIDIOPATHIC4HEPURPOSEOFTHISCHAPTERISTOREMINDREADERSOFMANY OTHERPOSSIBLECAUSESORASSOCIATIONSFORGASTROPARESIS)NMANYCASES IFTHECAUSE ORASSOCIATIONISADDRESSED GASTROPARESISWILLIMPROVE


223

References -C#ALLUM27 "ERKOWITZ$- ,ERNER%'ASTRICEMPTYINGINPATIENTSWITHGASTROESOPHAGEAL REmUX'ASTROENTEROLOGYn 3TACHER' ,ENGLINGER* "ERGMANN( 3CHNEIDER# (OFFMAN7 7OLm' ETAL'ASTRICEMPTYING ACONTRIBUTORYFACTORINGASTRO ESOPHAGEALREmUXACTIVITY'UTn 6ANDERWINDEN* - ,IU( DE,AET- ( VANDERHAEGHEN* *3TUDYOFINTERSTITIALCELLSOF#AJAL ININFANTILEHYPERTROPHICPYLORISTENOSIS'ASTROENTEROLOGYn 6ANDERWINDEN* - -AILLEUX0 3CHIFFMAN3. 6ANDERHAEGHEN* * DE,AET- (.ITRICOXIDE SYNTHASEACTIVITYININFANTILEHYPERTOPHICSTENOSIS.%NG*-EDn -ICCI-! +AHRIG+- 3IMMONS23 3ARNA3+ %SPEJO .AVARRO-2 0ASRICHA0*.EURAL STEMCELLTRANSPLANTATIONINTHESTOMACHRESCUESGASTRICFUNCTIONINNEURONALNITRICOXIDESYNTHASE DElCIENTMICE'ASTROENTEROLOGY n %VANS02 "AK9 4 3HUTER" (OSCH2 +ELLOW*%'ASTROPARESISANDSMALLBOWELDYSMOTILITY INIRRITABLEBOWELSYNDROME$IG$IS3CI n 3TERNINI# 0ATIERNO3 3ELMER)3 +IRCHGESSNER!4HEOPIOIDSYSTEMINTHEGASTROINTESTINAL TRACT.EUROGASTROENTEROL-OTIL3UPPLn -C-ILLAN 3# !SSESSING AND MANAGING OPIATE INDUCED CONSTIPATION IN ADULTS WITH CANCER #ANCER#ONTROL3UPPL ,IU- 7ITTBRODT%,OW DOSEORALNALOXONEREVERSESOPIOID INDUCEDCONSTIPATIONANDANALGESIA *0AIN3YMPTOM-ANAGEn 9UAN#3 &OSS*& /#ONNOR- /SINSKI* +ARRISON4 -OSS* ETAL-ETHYLNALTREXONEFOR REVERSALOFCONSTIPATIONDUETOCHRONICMETHADONEUSEARANDOMIZEDCONTROLLEDTRIAL*!-! n 0ERKEL-3 -OORE# (ERSH4 $AVIDSON%$-ETOCLOPRAMIDETHERAPYINPATIENTSWITHDELAYED GASTRICEMPTYINGARANDOMIZED DOUBLE BLINDSTUDY$IG$IS3CI n -ADDERN'* (OROWITZ- *AMIESON'' ETAL!BNORMALITIESOFESOPHAGEALANDGASTRICEMPTYING INPROGRESSIVESYSTEMICSCLEROSIS'ASTROENTEROLOGYn -ADDERN'* (OROWITZ- *AMIESON#' ETAL!BNORMALITIESOFESOPHAGEALANDGASTRICEMPTYING INPROGRESSIVESYSTEMICSCLEROSIS'ASTROENTEROLOGY 7ESTON3 4HUMSHIRN- 7ISTE* #AMILLERI-#LINICALANDUPPERGASTROINTESTINALMOTILITY FEATURESINSYSTEMICSCLEROSISANDRELATEDDISORDERS!M*'ASTROENTEROL 3IGURDSSON, &LORES! 0UTNAM0% ETAL0OSTVIRALGASTROPARESISPRESENTATION TREATMENT AND OUTCOME*0EDIATR "ITYUTSKIY ,0 3OYKAN ) -C#ALLUM 27 6IRAL GASTROPARESIS A SUBGROUP OF IDIOPATHIC GASTROPARESIS CLINICAL CHARACTERISTICS AND LONG TERM OUTCOMES !M * 'ASTROENTEROL 92:1501. 3CHRAML&6 +RUEGER7(0RESENTATIONOFGASTRICCARCINOMAONARADIONUCLIDEGASTRIC EMPTYING STUDY#LIN.UCL-ED ,EUNG6+ +AN03 ,AI-3#HOLANGIOCARCINOMAPRESENTINGASPSEUDOACHALASIAANDGASTROPARESIS(ONG+ONG-ED* %MERSON!0&OODSHIGHINlBERANDPHYTOBEZOARFORMATION*!M$IET!SSOC (OOGERWERF7! 0ASRICHA0* +ALLOO!. 3CHUSTER--0AINTHEOVERLOOKEDSYMPTOMIN GASTROPARESIS!M*'ASTROENTEROL "ARKIN *3 'OLDBERG 2) 3FAKIANAKIS '. ,EVI * 0ANCREATIC CARCINOMA IS ASSOCIATED WITH DELAYEDGASTRICEMPTYING$IG$IS3CI "RAND2% $I"AISE*+ 1UIGLEY%- ETAL'ASTROPARESISASACAUSEOFNAUSEAANDVOMITING AFTER HIGH DOSE CHEMOTHERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION ,ANCET 352:1985. $I"AISE*+ "RAND2% ,YDEN% ETAL'ASTRICMYOELECTRICALACTIVITYANDITSRELATIONSHIPTOTHE DEVELOPMENTOFNAUSEAANDVOMITINGAFTERINTENSIVECHEMOTHERAPYANDAUTOLOGOUSSTEMCELL TRANSPLANTATION!M*'ASTROENTEROL "AERT$ "URVENICH0 ,AGAE* ETAL2ADIOTHERAPY INDUCEDGASTROPARESISANUNUSUALCOMPLICATION *#LIN'ASTROENTEROL


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Chapter 20

Pediatric Gastroparesis Miguel Saps and Carlo Di Lorenzo

Keywords 'ASTROPARESISs0EDIATRICSs0REMATURITYs&OODALLERGYs'ASTROENTERITIS s"REATHTESTINGs3CINTIGRAPHYs0ROKINETICs'ASTRICPACEMAKER

Etiology 4HE ETIOLOGY OF GASTROPARESIS IN CHILDREN VARIES WITH AGE )N PRETERM INFANTS gastroparesis is usually related to immaturityOFTHEGASTROINTESTINALTRACT'ASTRIC ELECTRICALACTIVITY NEUROMUSCULARCOORDINATION GASTRICEMPTYING THEDEVELOPMENT OF NUTRITIVE SUCKING AND FEEDING TOLERANCE ALL EXHIBIT GRADUAL MATURATION WITH GESTATIONALAGE4HEFREQUENCYOFNORMALLYCONlGUREDMIGRATINGMOTORCOMPLEXES --#S THEPROPORTIONOFANTRALCONTRACTIONSASSOCIATEDWITHDUODENALACTIVITYAND THESTRENGTHOFANTRALCONTRACTIONSALLINCREASEWITHAGE(UMANFETUSESSHOWINITIAL SWALLOWINGMOVEMENTSATAROUNDWEEKSOFGESTATIONWITHSUCKINGDEVELOPINGAT AROUNDnWEEKSOFGESTATION&ETALGASTRICEMPTYINGCANBENOTICEDASEARLYAS ATnWEEKSGESTATION.ORMALGASTRICELECTRICALRHYTHMOFPREDOMINANTCPM ACTIVITYANDMATUREPATTERNSOFLIQUIDEMPTYINGHASBEENREPORTEDTOOCCURASEARLY ASATWEEKSGESTATIONALAGE.ORMALGASTRODUODENALELECTRICALANDMOTORACTIVITIES AS WELL AS NUTRITIVE SUCKING ARE PRESENT AT WEEKS GESTATIONAL AGE AND PRETERM NEWBORNS EXHIBIT LITTLE DIFFERENCES IN GASTRIC ELECTRICAL ACTIVITY AND EMPTYING ON DIFFERENTRECORDINGDAYS 0OSTNATALMATURATIONOFGASTROENTERICMOTORFUNCTIONINPRETERMINFANTSCANBE AFFECTEDBYEARLYLIFEEXPERIENCES%NVIRONMENTALANDNOCICEPTIVEFACTORSAFFECTING THE AIRWAY AND DIGESTIVE TRACT MAY SLOW MATURATION #HILDREN WHO EXPERIENCED

M. Saps (*) $EPARTMENTOF'ASTROENTEROLOGY (EPATOLOGY AND.UTRITION .ORTHWESTERN5NIVERSITYS&EINBERG3CHOOLOF-EDICINE #HILDRENS-EMORIAL(OSPITAL #HICAGO ), 53! E MAILMSAPS CHILDRENSMEMORIALORG H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_20, © Springer Science+Business Media, LLC 2012

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M. Saps and C. Di Lorenzo

PROLONGED RESPIRATORY SUPPORT AND DELAYED INITIATION OF ENTERAL FEEDING ARE MORE LIKELYTOVOMITANDCOUGHWHENFEDSOLIDFOODSATMONTHSOFAGE!STUDYUSING IMPEDANCETOMEASUREGASTRICEMPTYINGRATEINFULLTERMNEONATESGIVENANONCALORIC LIQUIDMEALFOUNDAMEDIANGASTRICHALFEMPTYINGTIMEOFÕ MIN;1]. !STUDYININFANTSAGEDWEEKSTOMONTHS DEMONSTRATEDTHATGASTRICEMPTYING VARIESWITHTHECOMPOSITIONOFTHEMEAL4MEASUREDBYIMPEDANCEGASTROGRAPHY WASMINFORBREASTMILKANDMINFORINFANTFORMULA;2=0REBIOTICOLIGOSACCHARIDESCANMODULATEGASTRICEMPTYINGANDGASTRICELECTRICALACTIVITYINNEONATES .EWBORNSRECEIVINGFORMULAWITHPREBIOTICSHAVEMORECONSISTENTPROPAGATIONOF GASTRICELECTRICALACTIVITYANDFASTERGASTRICEMPTYING4HEREISEVIDENCETHATFACTORS AFFECTING GASTRIC EMPTYING IN PRETERM INFANTS DIFFER FROM ADULTS 7HILE INCREASES INOSMOLALITY ENERGYDELIVERYANDVOLUMESLOWSGASTRICEMPTYINGINADULTS STUDIES INnWEEKSPRETERMINFANTSSHOWEDTHATWHILEMODIFYINGEACHOFTHISFACTORS INDIVIDUALLYDOESNOTAFFECTGASTRICEMPTYING DECREASINGOSMOLALITYWHILEINCREASING VOLUMEACCELERATESEMPTYING;]. #HILDRENWITHCENTRALNERVOUSSYSTEMDISORDERS#.3 FREQUENTLYDEVELOPGASTRIC DYSRHYTHMIASANDFOREGUTDYSMOTILITY POSSIBLYRELATEDTOEITHERTHEINVOLVEMENTOF THEENTERICNERVOUSSYSTEMBYTHESAMEPROCESSAFFECTINGTHE#.3ORTOABNORMALITIES INMODULATIONOFTHEENTERICNERVOUSSYSTEMBYTHE#.3!STUDYCOMPARINGTHE GASTROINTESTINALFUNCTIONOFNEUROLOGICALLYIMPAIREDCHILDRENWITHHEALTHYCONTROL CHILDRENFOUNDASIGNIlCANTDELAYINGASTRICEMPTYINGINOUTOFNEUROLOGICALLY IMPAIREDSUBJECTSWITHAHISTORYOFVOMITING4HEREWASNOSIGNIlCANTDIFFERENCEIN GASTRICEMPTYINGBETWEENTHOSECHILDRENWITH#.3DISORDERSWHOHADNOHISTORYOF VOMITINGANDCONTROLS;4=/UTOFCHILDRENWITH#.3DISORDERSEVALUATED HAD GASTRIC DYSRHYTHMIA AND HAD BOTH GASTRIC DYSRHYTHMIA AND GASTROESOPHAGEAL REmUX'%2 $IETARYPROTEINALLERGYANDESPECIALLYCOWSMILKALLERGYSHOULDBE CONSIDEREDINTHEDIFFERENTIALDIAGNOSISOFPRETERMANDFULL TERMINFANTSWITHCHRONIC VOMITING)TWASREPORTEDTHATMORETHANOFINFANTSWITH'%2HADCOWSMILK ALLERGYASTHEUNDERLYINGCAUSEOFTHEIRSYMPTOMS3EVEREGASTRICDYSRHYTHMIASWITH DECREASED NORMOGASTRIA AND INCREASED BRADYGASTRIA ACTIVITY AND DELAYED GASTRIC EMPTYINGOCCURREDINAGROUPOFINFANTSDIAGNOSEDWITHCOWSMILKALLERGYFOLLOWING EXPOSURETOCOWSMILK)NSENSITIZEDCHILDREN DELAYEDGASTRICEMPTYINGMAYEXACERBATE'%2BYINDUCINGREmEXVOMITINGANDLEADINGTOFUNDICDISTENSIONANDTRANSIENT RELAXATIONSOFTHELOWERESOPHAGEALSPHINCTER!LTHOUGHTHEMECHANISMSARENOTYET CLEAR IN SENSITIZED PATIENTS IMMUNE ACTIVATION MAY RESULT IN POLYPEPTIDES AND PROINmAMMATORY CYTOKINES RELEASE THAT IN TURN RESULT IN ALTERATIONS OF THE ENTERIC NEUROMUSCULATURELEADINGTOABNORMALACTIVATIONANDSTIMULATIONOFGASTROINTESTINAL SMOOTHMUSCLECELLS

Postinfectious Gastroparesis 0OSTINFECTIOUSGASTROPARESISISONEOFTHEMOSTCOMMONPRESENTATIONSOFGASTROPARESIS INOLDERCHILDREN6IRUSESARETHEMOSTCOMMONPATHOGENICAGENTSBUTMYCOPLASMA

20

Pediatric Gastroparesis

Table 20.1 %TIOLOGY OFGASTROPARESISININFANTS ANDCHILDREN

227 Infants Immaturity/prematurity #OWSMILKPROTEINALLERGY Pyloric stenosis Duodenal atresia .ECROTIZINGENTEROCOLITIS Meconium ileus Children )NFECTIOUSACUTEANDPOSTVIRAL Surgery Drugs #HRONICINTESTINALPSEUDOOBSTRUCTION (IRSCHSPRUNGSDISEASE .EURODEVELOPMENTALDISORDERS &AMILIALDYSAUTONOMIA 3PINALCORDINJURY #YSTIClBROSIS Celiac disease (YPOTHYROIDISM !CIDOSISELECTROLYEABNORMALITIES $IABETES !NOREXIANERVOSA "ULIMIANERVOSA %OSINOPHILICGASTROENTEROPATHY #ONNECTIVETISSUEDISORDERS -USCULARDYSTROPHY #ROHNSDISEASE Caustic ingestion

INFECTIONSHAVEALSOBEENASSOCIATEDWITHGASTROPARESIS$ESCRIBEDVIRUSESINCLUDE %"6 VARICELLA VIRUS #-6 ;5= RESPIRATORY VIRUSES ROTAVIRUS AND THE .ORWALK AGENT0OSTVIRALGASTROPARESISUSUALLYPRESENTSWITHPERSISTENTVOMITING ABDOMINAL DISTENTION FULLNESS AND WEIGHT LOSS FOLLOWING AN ACUTE SELF LIMITING INTERCURRENT ILLNESS6OMITINGMAYCOINCIDEWITHTHEONSETOFOTHERACUTEGASTROINTESTINALOREXTRA GASTROINTESTINALSYMPTOMSORMANIFESTWEEKSTOMONTHSLATER!STUDYINCHILDREN ANDADULTSFOUNDTHATTIMETOREFERRALRANGESFROMWEEKSTOMONTHSAFTERTHE INITIALEPISODE;5="YTHETIMETHEPHYSICIANISINVOLVEDINTHEEVALUATION THEINITIAL ACUTEILLNESSHASUSUALLYRESOLVEDANDNOCAUSATIVEAGENTSCANBEIDENTIlED$IAGNOSIS ISBASEDONTHEHISTORYOFACUTEONSET INITIALSEVEREILLNESS DEMONSTRATIONOFDELAYED GASTRICEMPTYING ANDEXCLUSIONOFOTHERCAUSESOFPERSISTENTVOMITING4REATMENTIS SUPPORTIVEANDANTIVIRALTHERAPYOROTHERETIOLOGICTREATMENTSHAVENOTBEENSHOWN TOBEEFFECTIVE3YMPTOMSMAYPERSISTFORSEVERALMONTHSORYEARS4WOSTUDIESTHAT INCLUDED CHILDREN WITH POSTVIRAL GASTROPARESIS SHOWED RESOLUTION OF SYMPTOMS IN LESSTHANYEARSINALLCASES;5, 6]. /THER POSSIBLE CAUSES OF GASTROPARESIS IN CHILDREN ARE LISTED IN 4ABLE 20.1. )NPATIENTSWITHEOSINOPHILICGASTROENTEROPATHY THEDEPTHANDEXTENTOF')EOSINOPHILIC

228


INlLTRATION DETERMINES THE TYPE AND SEVERITY OF MANIFESTATIONS 6OMITING MAY BE PRESENTINCASESOFMUCOSALORTRANSMURALEOSINOPHILICINlLTRATION.OSTUDIESHAVE BEENCONDUCTEDEVALUATINGGASTRICEMPTYINGINPATIENTSWITHEOSINOPHILICGASTROENTEROPATHY(OWEVER ASTUDYOFCHILDRENWITHFUNCTIONALDYSPEPSIAINVESTIGATEDTHE ASSOCIATIONBETWEENANTRALINlLTRATIONBYEOSINOPHILSANDMASTCELLSWITHELECTROGASTROGRAPHYANDGASTRICEMPTYINGlNDINGS)TWASFOUNDTHATHIGHMASTCELLDENSITYWAS ASSOCIATEDWITHSLOWERGASTRICEMPTYINGANDPREPRANDIALTACHYGASTRIASUGGESTINGTHE EXISTENCEOFACAUSALRELATIONBETWEENANTRALINmAMMATIONANDGASTRICDYSFUNCTION;7]. 'ASTRIC EMPTYING STUDIES SHOW CONmICTING RESULTS IN PATIENTS WITH CYSTIC lBROSIS WITHSOMEAUTHORSREPORTINGNORMALRESULTS;8=WHILEOTHERSHAVESHOWNDELAYED GASTRICEMPTYING;9=#UCCHIARAETALFOUNDASIGNIlCANTLYPROLONGEDGASTRICEMPTYING TIMEINOUTOFCYSTIClBROSISPEDIATRICPATIENTSWHENCOMPAREDWITHHEALTHY CONTROLSUBJECTS!NELECTROGASTROGRAPHYSTUDYONCHILDRENWITHCYSTIClBROSIS ANDHEALTHYCONTROLS REVEALEDPOSTPRANDIALGASTRICARRHYTHMIASTHATWERETHOUGHT TOEXPLAINTHEPRESENCEOFDELAYEDGASTRICEMPTYING;10='ASTROPARESISSIGNIlCANTLY WORSENSAFTERLUNGTRANSPLANTATIONINALLPATIENTS POSSIBLYDUETODAMAGETOTHEVAGAL NERVESDURINGSURGERYORTOTHEUSEOFSOMEOFTHEPOSTTRANSPLANTMEDICATIONS %LECTROGASTROGRAPHICSTUDIESINCHILDRENWITHCHRONICINTESTINALPSEUDOOBSTRUCTION SHOWED PERSISTENT TACHYGASTRIA DURING FASTING PROBABLY RELATED TO THE LOSS OF INTRINSICINHIBITORYINNERVATION;11=!STUDYONFULL TERMINFANTSWITHAHISTORYOF pyloric stenosis, intestinal atresia, necrotizing enterocolitis, and meconium ileus FOUNDDELAYEDGASTRICEMPTYINGINALLPATIENTSANDDIFFERENCESINIMPEDANCEGASTRIC PHASICACTIVITYTHATRESOLVEDAFTERTHERESOLUTIONOFTHEPREDISPOSINGMEDICALCONDITION ;12= !LTHOUGH A COMMON CAUSE OF GASTROPARESIS IN ADULTS THE INCIDENCE OF GASTROPARESISINCHILDRENWITHDIABETESMELLITUSHASNOTBEENEXTENSIVELYINVESTIGATED !STUDYSHOWEDDYSPEPTICSYMPTOMSINOFDIABETICCHILDRENWITHAGERANGING BETWEEN AND YEARS ;1= )N THE FEW PUBLISHED PEDIATRIC STUDIES A COMMON THEMEISTHATGASTROPARESISMUSTBETAKENINCONSIDERATIONEVENINYOUNGDIABETIC PATIENTSWHOPRESENTWITHGASTROINTESTINALSYMPTOMS!STUDYMEASURINGTHEGASTRIC EMPTYINGTIMEANDGASTRICELECTRICALACTIVITYINCONSECUTIVECHILDRENWITHINSULIN DEPENDENTDIABETESMELLITUS)$$- WITHOUTAUTONOMICNEUROPATHYANDHEALTHY CONTROLSUBJECTSFOUNDASIGNIlCANTDIFFERENCEINGASTRICEMPTYINGTIMEANDASIGNIlCANTLYHIGHERPREVALENCEOFGASTRICELECTRICALDYSRHYTHMIASINCHILDRENWITH)$$- COMPAREDWITHCONTROLS;14=4HESTUDYSHOWEDTHATOFCHILDRENINTHE)$$- GROUPHADDELAYEDGASTRICEMPTYING4ACHYGASTRIAWASMOREPREVALENTINCHILDREN WITH)$$-WHILETHEREWASNOSIGNIlCANTDIFFERENCEINBRADYGASTRIABETWEENBOTH GROUPS%''WASSIMILARINDIABETICSUBJECTSWITHNORMALGASTRICEMPTYINGTIME ANDCONTROLSUBJECTS4HESTUDYFOUNDASIGNIlCANTCORRELATIONBETWEEN(B!CLEVELS ANDGASTRICEMPTYINGTIME4HEREWASALSOASIGNIlCANTCORRELATIONBETWEENBLOOD GLUCOSELEVELSMEASUREDMINAFTERMEALSWITHGASTRICEMPTYINGTIMEABNORMALITIES ! STUDY ON THREE ADOLESCENTS WITH )$$- WHO COMPLAINED OF NAUSEA VOMITING ABDOMINALPAIN ANDCONSTIPATIONREPORTEDIMPROVEMENTINGASTROINTESTINALSYMPTOMS GASTRIC EMPTYING AND GLYCEMIC CONTROL USING PROKINETIC TREATMENT ;15= 4HE STUDY SHOWED NORMAL ANTRAL AMPLITUDE CONTRACTIONS AFTER ERYTHROMYCIN INJECTION DURING FASTINGBUTTHEABSENCEOFPOSTPRANDIALANTRALCONTRACTIONSAFTERINGESTIONOFASOLID

20


229

MEAL7HITEETAL;16=DESCRIBEDTWOADOLESCENTSWITHSEVEREDIABETICNEUROPATHY DELAYEDGASTRICEMPTYING ANDPOORMETABOLICCONTROLTHATIMPROVEDTHEIRGASTROINTESTINALSYMPTOMSWITHIMPROVEDGLYCEMICCONTROL3TUDIESONCHILDRENWITHCYCLIC VOMITINGSYNDROME#63 PROVIDECONmICTINGRESULTS2EAL TIMEULTRASONOGRAPHY SHOWED NORMAL GASTRIC EMPTYING IN CHILDREN WITH #63 ;17= !NOTHER STUDY ON CHILDRENWITH#63SHOWEDABNORMAL%''WITHSIGNIlCANTTACHYGASTRIAIN OF CASES AND ABNORMAL GASTRIC EMPTYING IN OF THOSE CHILDREN SUGGESTING THATABNORMALGASTRICMYOELECTRICALACTIVITYISINVOLVEDINTHEPATHOGENESISOF#63 SYNDROME ;18= 0ATIENTS UNDERGOING SURGERY ARE EXPOSED TO MULTIPLE FACTORS THAT MAYRESULTINGASTRICDYSRHYTMIASANDMAYDELAYGASTRICEMPTYING3TUDIESINCHILDREN UNDERGOINGNONABDOMINALSURGERYHAVEDEMONSTRATEDTRANSIENT%''CHANGESASSOCIATEDWITHGENERALANESTHESIA4ACHYGASTRIAASSOCIATEDWITHNAUSEAANDVOMITING DEVELOPSIMMEDIATELYAFTERINDUCTION"RADYGASTRIAWASALSODESCRIBEDDURINGTHE lRSTHALFHOURAFTERGENERALANESTHESIA%''CHANGESRETURNTOBASELINEAPPROXIMATELY HAFTERREVERSALOFGENERALANESTHESIA;19=6AGALNERVEINJURYANDGASTROPARESIS MAYOCCURINCHILDRENUNDERGOINGUPPERABDOMINALSURGERY SUCHASFUNDOPLICATION OR BARIATRIC SURGERY 6AGAL NERVE INJURY IS ALSO FREQUENTLY REPORTED AFTER THORACIC SURGERY INCLUDINGLUNGANDHEARTSURGERY;20=0OSTSURGICALGASTROPARESISISFREQUENTLY TRANSIENTANDIMPROVESWITHTIME6AGALREINNERVATIONANDTHEABILITYOFTHEENTERIC NERVOUSSYSTEMTOADAPTMAYEXPLAINTHEREVERSALOFTHESESYMPTOMS!LONG TERM FOLLOW UP REPORT OF NEUROLOGICALLY IMPAIRED CHILDREN WHO UNDERWENT A .ISSEN FUNDOPLICATION FOUND THAT PREOPERATIVE DELAYED GASTRIC EMPTYING WAS ASSOCIATED WITHALESSFAVORABLESURGICALOUTCOME;21=4HEREISALSOEVIDENCETHATFUNDOPLICATIONMAYIMPROVEGASTRICEMPTYINGASSUGGESTEDBYASTUDYOFCHILDRENWITHDELAYED GASTRIC EMPTYING WHO UNDERWENT FUNDOPLICATION AND AN ANTROPLASTY AND HAD A SIGNIlCANTIMPROVEMENTINGASTRICEMPTYINGTIMEATMINFROMPREOPERATIVELY TO POSTOPERATIVELY ;22= !NOTHER STUDY MEASURED GASTRIC EMPTYING OF LIQUIDS BEFORE AND AFTER FUNDOPLICATION WITHOUT PYLOROPLASTY AND FOUND IT TO BE ACCELERATEDINALLBUTONEPATIENTAFTERTHESURGERY;2]. !DOLESCENTSWITHANOREXIANERVOSAOFTENEXPERIENCEDELAYINGASTRICEMPTYING ANDCONSTIPATION;24=)TREMAINSUNCLEARWHETHERTHESEABNORMALITIESAREPRIMARYOR SECONDARY 'ASTRIC ELECTROMECHANICAL ABNORMALITIES MAY INmUENCE REFEEDING AND WEIGHTRESTORATIONOFTHISGROUPOFPATIENTS3TUDIESONPATIENTSWITHBULIMIANERVOSA HAVESHOWEDDELAYEDGASTRICEMPTYINGASWELLASABNORMALGASTRICEMPTYINGCAPACITY ANDRELAXATION;25=)NVESTIGATIONSOFCHILDRENANDADULTSWITHUNTREATEDCELIACDISEASE HAVECONSISTENTLYSHOWNAMARKEDDELAYEDINGASTRICEMPTYINGTHATCORRECTSWITH GLUTENWITHDRAWAL;26, 27].

Diagnosis !SSESSMENTOFGASTRICEMPTYINGTIMETHROUGHSCINTIGRAPHICSTUDIESUSINGARADIOISOTOPE LABELEDSOLIDMEALISTHEGOLDSTANDARDFORTHEDIAGNOSISOFGASTROPARESISINADULTS ANDCHILDREN5NFORTUNATELY THEREARELIMITEDDATAONPEDIATRICSTANDARDSFORTHIS


DIAGNOSTICTECHNIQUEINCHILDRENOFDIFFERENTAGES-UCHLIKEITISDONEINADULTS CONVENTIONALTESTINGUSUALLYINCLUDESTHEUSEOFAM4CSULFURCOLLOIDLABELEDEGG SANDWICHFOLLOWEDBYIMAGINGAT ANDINSOMECASESH4ASTEANDMEAL PREFERENCESCANMAKEPERFORMINGAhSTANDARDvTESTINALLCHILDRENSOMEWHATPROBLEMATIC!PEDIATRICSTUDYONTHEPREFERENCEOFMEALSTOCONDUCTGASTRICEMPTYING SHOWEDALOWPREFERENCEFORSCRAMBLEDEGGONTOAST;28=4HESTUDY CONDUCTEDON HEALTHYCHILDRENnYEARSOFAGE FOUNDAMEAN4GASTRICEMPTYINGTIMEOF MINAFTERTHEINGESTIONOFGOFCHOCOLATECRISPYCAKECARBOHYDRATE FAT PROTEIN ENERGYCONTENTK* ;28="ECAUSE4VALUESOFGASTRIC EMPTYINGSEEMTOBELESSACCURATETHANTHEMEASUREMENTOFPERCENTAGESOFRETENTION ATlXEDTIMEPOINTS ANDDUETOTHELACKOFLARGESTUDIESINVESTIGATINGSTANDARDSAT lXEDTIMEPOINTSINNORMALCHILDREN PEDIATRICCENTERSHAVEINCREASINGLYADOPTEDTHE ADULT STANDARDS RECENTLY ENDORSED BY THE !MERICAN .EUROGASTROENTEROLOGY AND -OTILITY3OCIETYANDTHE3OCIETYOF.UCLEAR-EDICINE;29=4HEUSEOFSCINTIGRAPHY FORTHEASSESSMENTOFGASTRICEMPTYINGHASSOMEDISADVANTAGES)TREQUIRESEXPENSIVE GAMMACAMERASANDPATIENTSAREEXPOSEDTORADIATIONS AFACTORTHATMAYBEMORE CONCERNING IN YOUNG CHILDREN THAN IN ADULTS 4HIS HAS LED TO THE DEVELOPMENT OF ALTERNATIVETECHNIQUESOFEVALUATIONOFGASTRICEMPTYINGINPEDIATRICS 5LTRASONOGRAPHYISWIDELYAVAILABLEANDNONINVASIVE)TCANALSOPROVIDEDYNAMIC INFORMATIONONTHEVARIOUSAREASOFTHESTOMACHINRELATIONTOMEALS ALLOWINGSIMULTANEOUSMEASUREMENTOFGASTRICEMPTYINGANDGASTRICACCOMMODATION4HETECHNIQUE HASBEENUSEDINCHILDRENOFDIFFERENTAGESANDPATHOLOGICALCONDITIONS;0=4HE LARGESTPUBLISHEDSTUDYONASYMPTOMATICCHILDRENEVALUATEDSUBJECTSOFVARIOUS WEIGHTS ANDITSHOWEDASIMILARGASTRICEMPTYINGCURVEINNORMALWEIGHT OVERWEIGHT AND OBESE CHILDREN ;1= $ESPITE ITS MULTIPLE ADVANTAGES THIS TECHNIQUE HAS NOT BECOMEYETWIDELYUSEDFORROUTINECLINICALPURPOSES"REATHTESTINGEXCRETIONOF # LABELEDOCTANOICACIDORACETATEISANONINVASIVETECHNIQUEUSEDTOASSESSGASTRIC EMPTYINGOFLIQUIDSANDSOLIDS4HETECHNIQUEISEASYTOCONDUCT RELIABLE COST EFFECTIVE ANDDOESNOTINVOLVERADIATIONANDTHEEXPIREDAIRCANBECOLLECTEDINANY OUTPATIENTFACILITYANDMAILEDTOAREFERENCELABORATORY3TUDIESINCHILDREN USING EITHERACETATEOROCTANOICACIDLABELEDWITH# HAVESHOWNSIMILARRESULTSTOTHOSE OBTAINEDBYSCINTIGRAPHY;2=4HE#BREATHTESTSEEMSTOBEFEASIBLEANDRELIABLE ALSO IN NEUROLOGICALLY IMPAIRED PATIENTS ! STUDY ON HEALTHY CHILDREN GIVEN A STANDARDLIQUIDMEALFOUNDAMEDIAN4OFMINWITHARANGEOFnMIN USING # ACETATE BREATH TEST 4HE INTRAINDIVIDUAL VARIABILITY IN GASTRIC EMPTYING OBTAINEDBYTHISTECHNIQUEISCOMPARABLETOOTHERTECHNIQUES3INGLEPHOTONEMISSION COMPUTED TOMOGRAPHY 30%#4 IS A NONINVASIVE AND RELIABLE SCINTIGRAPHIC TECHNIQUE;=)TALLOWSTOASSESSGASTRICVOLUMEANDTHERELATIONBETWEENGASTRIC FUNCTIONS SUCHASACCOMMODATIONANDEMPTYING30%#4ISNOTUSEDFORCLINICAL PURPOSESINCHILDRENBUTHASBEENUSEDTOINVESTIGATEADOLESCENTSWITHFUNCTIONAL DYSPEPSIA;=.OSTUDIESHAVEBEENPUBLISHEDONPEDIATRICGASTROPARESISUSING30%#4 -EASUREMENT OF GASTRIC EMPTYING TIME BY THE 3MART0ILL® HAS A GOOD CORRELATION WITHGASTRICEMPTYINGMEASURESOBTAINEDBYSCINTIGRAPHYINADULTSALLOWINGDISCRIMINATIONBETWEENHEALTHYADULTSANDPATIENTSWITHGASTROPARESIS;4=3MART0ILLOFFERS AN ATTRACTIVE NONRADIOACTIVE NONINVASIVE AMBULATORY ALTERNATIVE TO SCINTIGRAPHY

20


BUTITHASNOTYETBEENAPPROVEDBYTHE&$!FORUSEINCHILDRENANDITSUTILITYAND SAFETY IN PEDIATRICS IS CURRENTLY BEING INVESTIGATED4HE SIZE OF THE CAPSULE IN THE 3MART0ILLISSIMILARTOTHATOFTHEENDOSCOPIC0ILL#AM ADEVICETHATHASBEEN&$! APPROVEDFORUSEINCHILDRENOLDERTHANYEARS

Treatment 4REATMENTISBASEDONDIETMODIlCATIONS LIFESTYLECHANGES USEOFMEDICATIONSAND WHEN POSSIBLE CORRECTION OF THE UNDERLYING CONDITIONS CAUSING GASTROPARESIS -EDICATIONSCURRENTLYBEINGUSEDSHOULDBEREVIEWEDTOUNCOVERDRUGSTHATCOULD CONTRIBUTE TO THE GASTRIC DYSFUNCTION 0ARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBLEANTICHOLINERGICEFFECTSOFPSYCHOTROPICMEDICATIONWHICHAREINCREASINGLY BEINGUSEDINTHETREATMENTOFCHILDRENWITHAUTISM ATTENTIONDElCITHYPERACTIVITY DISORDER OR OTHER PSYCHIATRIC DISEASES #HILDREN WITH GASTROPARESIS SHOULD BE MANAGED BY A MULTIDISCIPLINARY TEAM THAT INCLUDES AN EXPERIENCED NUTRITIONIST )N CHILDREN WITH SEVERE AND PROLONGED GASTROPARESIS CORRECTION OF ELECTROLYTE AND mUID IMBALANCES AND NUTRITIONAL OPTIMIZATION ARE THE MAINSTAY OF TREATMENT )NPATIENTSWITHMILDERFORMSOFGASTROPARESIS DIETARYMODIlCATIONSMAYBESUFlCIENTTOCONTROLTHESYMPTOMS3MALLVOLUMEANDMOREFREQUENTMEALSnTIMESA DAY ARERECOMMENDED"ECAUSELIPIDSDIMINISHANTRALPRESSURESANDINCREASEBASAL PYLORICPRESSUREFOODSWITHHIGHFATCONTENTSHOULDBEAVOIDED;5=-EALSWITHA HIGHCALORICCONTENTALSODECREASETHEGASTRICEMPTYINGRATE&IBERCONTENTSHOULDBE MINIMIZED #ARBONATED BEVERAGES SHOULD BE AVOIDED TO LIMIT GASTRIC DISTENTION 0OSTUREINmUENCESTRANSPYLORICmOWANDINTRAGASTRICDISTRIBUTIONOFLIQUIDS,IQUIDS EMPTY MORE SLOWLY IN THE DECUBITUS POSITION 0OSTPRANDIAL WALKING ACCELERATES gastric emptying. 0HARMACOLOGICTREATMENTMAYREQUIREACOMBINATIONOFDRUGSTARGETINGDIFFERENT PATHOPHYSIOLOGICALMECHANISMSANDSYMPTOMS0ROKINETICSARETHEDRUGSOFCHOICE FORTHETREATMENTOFGASTROPARESIS HOWEVER ASSYMPTOMSMAYNOTBEEXCLUSIVELY CAUSED BY A PROPULSIVE DYSFUNCTION OTHER DRUGS INCLUDING VISCERAL ANALGESICS FUNDICRELAXANTS ANDANTIEMETICSMAYNEEDTOBECONSIDERED0ROKINETICSCURRENTLY AVAILABLEINTHE53!INCLUDEDOPAMINERECEPTORANTAGONISTSANDMOTILINRECEPTOR AGONISTS$OPAMINERECEPTORANTAGONISTSAREDOMPERIDONE NOTCOMMERCIALLYAVAILABLEINTHE53! ANDMETROCLOPRAMIDETHATHASRECEIVEDAhBLACKBOXWARNINGvBY THE&$!$OPAMINERGICRECEPTORANTAGONISTSHAVEPROKINETICANDANTIEMETICPROPERTIESANDSTIMULATEPROXIMALGASTROINTESTINALMOTILITYLOWERESOPHAGEALSPHINCTER STOMACH AND PROXIMAL SMALL INTESTINE WITHOUT INCREASING GASTRIC SECRETIONS -ETOCLOPRAMIDEISACENTRALANDPERIPHERALANTAGONISTOFDOPAMINERGIC$RECEPTORS ANAGONISTOFPERIPHERALSEROTONERGIC (4RECEPTORS A (4RECEPTORANTAGONIST ANDHASINDIRECTCHOLINERGICEFFECTSBYRELEASINGACETYLCHOLINEFROMTHEMYENTERIC PLEXUS )N CHILDREN METOCLOPRAMIDE IS USUALLY ADMINISTERED ORALLY AT A DOSE OF n MGKGDOSE UP TO FOUR TIMES DAILY 3OME OF THE UNDESIRABLE EFFECTS OF METROCLOPRAMIDEINCLUDEEXTRAPYRAMIDALDYSKINETICREACTIONS FATIGUE DEPRESSION


AND GALACTORRHEA $OMPERIDONE HAS SIMILAR PERIPHERAL MECHANISMS OF ACTION TO METOCLOPRAMIDEBUTHASMINIMALPENETRATIONTHROUGHTHEBLOOD BRAINBARRIERLIMITING ITS CENTRAL EFFECTS ;6= $OMPERIDONE ENHANCES ACETYLCHOLINE RELEASE INHIBITS CHOLINESTERASEACTIVITY ANDANTAGONIZESADRENERGICALPHA RECEPTORS;7=!STUDY INCHILDRENFOUNDTHATORALDOMPERIDONEISASAFEANDEFFECTIVEPROKINETIC)NPEDIATRICS DOMPERIDONEISADMINISTEREDORALLYATADOSEOFnMGKGDOSEUPTOFOURTIMES DAILYMAXnMGKGDOSE $OMPERIDONEISCOMMERCIALLYAVAILABLEINMOSTOF THEWORLD)NTHE53! DOMPERIDONECANBELEGALLYPRESCRIBEDFORGASTROPARESISBY lLINGANINVESTIGATIONALNEWDRUGAPPLICATIONTOTHE&$!;8]. -OTILINISAPEPTIDEHORMONESECRETEDBYTHEENTEROCHROMAFlNCELLSOFTHESMALL INTESTINE%RYTHROMYCINISAMACROLIDEWHICHALSOACTSASAMOTILINRECEPTORAGONIST WITHPROVENPROKINETICEFFECTSINADULTS PRETERMINFANTS ANDCHILDREN!PLACEBO CONTROLLEDSTUDYONPRETERMINFANTSRANGINGFROMTOWEEKSWHORECEIVED ORALERYTHROMYCINMGKGEVERYHSHOWEDENHANCEMENTOFANTRALCONTRACTILITY ANDACCELERATIONOFWHOLEGUTTRANSITTIME;9=$UETOTHEIRDIFFERENTMECHANISMS OF ACTION ERYTHROMYCIN MAY BE COMBINED WITH METOCLOPRAMIDE )N CHILDREN THE PROKINETIC DOSE OF ERYTHROMYCIN IS n MGKGDOSE n MIN PRIOR TO MEALS %XPOSURETOERYTHROMYCININTHENEONATALPERIODHASBEENREPORTEDTORESULTINA SEVERALFOLDINCREASEINTHERISKOFDEVELOPINGHYPERTROPHICPYLORICSTENOSIS;40]. !NOTHERSTUDYFOUNDNOASSOCIATIONBETWEENMATERNALPRENATALERYTHROMYCINEXPOSURE ANDINFANTILEHYPERTROPHICPYLORICSTENOSIS;41=-ACROLIDESAREEXCRETEDINBREAST MILKBUTRESULTSOFAPROSPECTIVESTUDYSHOWEDTHATEXPOSURETOTHISGROUPOFDRUGS DURING BREASTFEEDING WAS NOT ASSOCIATED WITH AN INCREASED RATE OF HYPERTROPHIC PYLORICSTENOSISOROTHERSERIOUSADVERSEREACTIONS;42]. )NCHILDRENWITHPERSISTENTNAUSEAORVOMITING ANTIEMETICSCANBEADDEDTOTHE TREATMENTONANAS NEEDEDBASIS4HOSEINCLUDE (4RECEPTORANTAGONISTAGENT SUCHASONDANSETRON PROMETHAZINE ORPROCHLORPERAZINEINORALORSUPPOSITORYFORM !MONGTHESEDRUGS ONDANSETRONGIVENUPTOADOSEOFnMGKGDOSEEVERY nHONANAS NEEDEDBASISISTHEMOSTEFFECTIVETOOLTOCONTROLSEVEREVOMITINGIN CHILDREN!#OCHRANEREVIEWSHOWEDTHEUSEOFACUPOINTSTIMULATIONUSINGTHE0 ACUPUNCTUREPOINTPREVENTEDPOSTOPERATIVENAUSEAANDVOMITING;4=4HEREVIEW FOUNDNODIFFERENCEINEFFECTIVENESSBETWEENADULTSANDCHILDREN"OTULINUMTOXIN ACTS BY BLOCKING ACETYLCHOLINE RELEASE FROM EXCITATORY NERVE ENDINGS !LTHOUGH NO PEDIATRIC STUDIES HAVE BEEN CONDUCTED EVALUATING THE EFlCACY OF INTRAPYLORIC INJECTION OF BOTULINUM TOXIN FOR THE TREATMENT OF GASTROPARESIS BOTULINUM TOXIN INJECTIONSAREOCCASIONALLYUSEDFORTHETREATMENTOFTHISDISORDERS3TUDIESINADULT HAVE SHOWN DISAPPOINTING RESULTS IN THE TREATMENT OF GASTROPARESIS ;44]. Due to DIFFERENCE IN ETIOLOGICAL FACTORS INVOLVED IN GASTROPARESIS IN CHILDREN STUDIES IN PEDIATRICS ARE NEEDED BEFORE ANY CONCLUSIONS CAN BE DRAWN ON ITS EFlCACY IN THE younger age groups. 0ATIENTSWITHSEVEREGASTROPARESISMAYBENElTFROMGASTRICELECTRICALSTIMULATION 'ASTRIC ELECTRICAL STIMULATION USES AN INTRAMUSCULAR IMPLANTABLE DEVICE THAT IS PLACEDINTHESTOMACHATTHELEVELOFTHEGREATERCURVATURE CLOSETOTHEPYLORUSTO PROVIDELOWENERGYANDHIGHFREQUENCYELECTRICALSTIMULATION4HEDEVICEISBEING INCREASINGLYUSEDINADULTSANDCHILDRENFORTHETREATMENTOFGASTROPARESIS RELATED

20


SYMPTOMS4WOSTUDIESHAVEBEENPUBLISHEDINCHILDREN'ASTRICELECTRICALSTIMULATION WAS SHOWN TO BE SAFE AND SUCCESSFUL IN REDUCING SYMPTOMS AND OPTIMIZING NUTRITION IN A YEAR OLD TOTAL PARENTERAL NUTRITION 40. DEPENDENT CHILD WITH GASTROPARESIS ABNORMAL ANTRODUODENAL MANOMETRY POSTPRANDIAL VOMITING AND FAILURETOTHRIVESINCEBIRTHWHOHADDAILYNAUSEA VOMITING ANDINTRACTABLEVISCERAL PAINANDRETCHING/NEYEARAFTERTHEIMPLANTATIONOFTHEDEVICETHECHILDHADFEWER SYMPTOMSANDIMPROVEDNUTRITIONALSTATUSBUTCONTINUEDTOREQUIREJEJUNOSTOMY * TUBE FEEDINGS;45=!STUDYINCHILDRENWITHCHRONICNAUSEAANDVOMITINGWHO RECEIVED AN INITIAL TRIAL OF TEMPORARY STIMULATION FOLLOWED BY PERMANENT GASTRIC STIMULATIONDEVICESHOWEDASUSTAINEDBENElTINOFCHILDRENINSYMPTOMSAND IMPROVEMENTINQUALITYOFLIFEWITHOUTSIGNIlCANTELECTROGRAPHICORGASTRICEMPTYING CHANGES;46=4HERESULTSOFTHESTUDYAREINLINEWITHADULTSTUDIESTHATHAVESHOWN IMPROVEMENTINNAUSEA VOMITING ANDNUTRITIONALSTATUSWITHOUTACLEAREFFECTIN GASTRIC EMPTYING ;47= 4HE IMPROVEMENT OF SYMPTOMS EVEN IN PATIENT IN WHOM GASTRICEMPTYINGHASNOTIMPROVEDSIGNIlCANTLYCOULDBEPARTIALLYEXPLAINEDBYA REDUCTIONINVISCERALSENSITIVITY

References ,ANGE! &UNCH *ENSEN0 4HOMMESEN0 3CHIOTZ0/'ASTRICEMPTYINGPATTERNSOFALIQUID MEAL IN NEWBORN INFANTS MEASURED BY EPIGASTRIC IMPEDANCE .EUROGASTROENTEROL -OTIL 1997;9:55–62. 2IEZZO' )NDRIO& -ONTAGNA/ 4RIPALDI# ,AFORGIA. #HILOIRO- ETAL'ASTRICELECTRICAL ACTIVITY AND GASTRIC EMPTYING IN PRETERM NEWBORNS FED STANDARD AND HYDROLYSATE FORMULAS *0EDIATR'ASTROENTEROL.UTRn 2AMIREZ! 7ONG77 3HULMAN2*&ACTORSREGULATINGGASTRICEMPTYINGINPRETERMINFANTS *0EDIATRn 2AVELLI!- -ILLA0*6OMITINGANDGASTROESOPHAGEALMOTORACTIVITYINCHILDRENWITHDISORDERS OFTHECENTRALNERVOUSSYSTEM*0EDIATR'ASTROENTEROL.UTRn .AFTALI4 9ISHAI2 :ANGEN4 ,EVINE!0OST INFECTIOUSGASTROPARESISCLINICALANDELECTEROGASTROGRAPHICASPECTS*'ASTROENTEROL(EPATOLn 3IGURDSSON , &LORES ! 0UTNAM 0% (YMAN 0% $I ,ORENZO # 0OSTVIRAL GASTROPARESIS PRESENTATION TREATMENT ANDOUTCOME*0EDIATRn &RIESEN#! ,IN: 3INGH- 3INGH6 3CHURMAN*6 "URCHELL. ETAL!NTRALINmAMMATORY CELLS GASTRICEMPTYING ANDELECTROGASTROGRAPHYINPEDIATRICFUNCTIONALDYSPEPSIA$IG$IS3CI n #AVELL " 'ASTRIC EMPTYING IN INFANTS WITH CYSTIC lBROSIS !CTA 0AEDIATR 3CAND n #UCCHIARA3 2AIA6 -INELLA2 &REZZA4 $E6IZIA" $E2ITIS'5LTRASOUNDMEASUREMENTOF GASTRICEMPTYINGTIMEINPATIENTSWITHCYSTIClBROSISANDEFFECTOFRANITIDINEONDELAYEDGASTRIC EMPTYING*0EDIATRn 3CHAPPI-' 2OULET- 2OCHAT4 "ELLI$#%LECTROGASTROGRAPHYREVEALSPOST PRANDIALGASTRIC DYSMOTILITYINCHILDRENWITHCYSTIClBROSIS*0EDIATR'ASTROENTEROL.UTRn $EBINSKI(3 !HMED3 -ILLA0* +AMM-!%LECTROGASTROGRAPHYINCHRONICINTESTINALPSEUDOOBSTRUCTION$IG$IS3CIn ,ANGE ! &UNCH *ENSEN 0 3CHIOTZ 0/ 'ASTRIC DYSRHYTHMIA IN INFANTS WITH GASTROINTESTINAL DISEASESMEASUREDBYEPIGASTRICIMPEDANCE*0EDIATR'ASTROENTEROL.UTRn


"URGHEN '! -URRELL ,2 7HITINGTON ', +LYCE -+ "URSTEIN 3 !CID PEPTIC DISEASE IN CHILDRENWITHTYPE)DIABETESMELLITUS!COMPLICATINGRELATIONSHIP!M*$IS#HILD 718–22. #UCCHIARA3 &RANZESE! 3ALVIA' !LFONSI, )ULA6$ -ONTISCI! ETAL'ASTRICEMPTYING DELAYANDGASTRICELECTRICALDERANGEMENTIN)$$-$IABETES#AREn 2EID" $I,ORENZO# 4RAVIS, &LORES!& 'RILL"" (YMAN0%$IABETICGASTROPARESISDUETO POSTPRANDIALANTRALHYPOMOTILITYINCHILDHOOD0EDIATRICSn 7HITE.( 7ALTMAN32 +RUPIN4 3ANTIAGO*62EVERSALOFNEUROPATHICANDGASTROINTESTINAL COMPLICATIONS RELATED TO DIABETES MELLITUS IN ADOLESCENTS WITH IMPROVED METABOLIC CONTROL *0EDIATRn 4URCHETTI! 'UGLIELMI3 &OSSATI# -ATRUNOLA- #ORRADO''ASTRICEMPTYINGTIMEINCYCLIC VOMITINGSYNDROMEINCHILDREN%UR2EV-ED0HARMACOL3CIn #HONG3+%LECTROGASTROGRAPHYINCYCLICVOMITINGSYNDROME$IG$IS3CI3n3 #HENG7 #HOW" 4AM0+%LECTROGASTROGRAPHICCHANGESINCHILDRENWHOUNDERGODAY SURGERY ANESTHESIA*0EDIATR3URGn !U* (AWKINS4 6ENABLES# -ORRITT' 3COTT#$ 'ASCOIGNE!$ ETAL5PPERGASTROINTESTINAL DYSMOTILITYINHEART LUNGTRANSPLANTRECIPIENTS!NN4HORAC3URGn !LEXANDER& 7YLLIE2 *IROUSEK+ 3ECIC- 0ORVASNIK3$ELAYEDGASTRICEMPTYINGAFFECTS OUTCOMEOF.ISSENFUNDOPLICATIONINNEUROLOGICALLYIMPAIREDCHILDREN3URGERYn discussion 697–8. $UNN*# ,AI%# 7EBBER-- !MENT-% &ONKALSRUD%7,ONG TERMQUANTITATIVERESULTS FOLLOWING FUNDOPLICATION AND ANTROPLASTY FOR GASTROESOPHAGEAL REmUX AND DELAYED GASTRIC EMPTYINGINCHILDREN!M*3URGn 0ACILLI- 0IERRO! ,INDLEY+* #URRY*) %ATON3'ASTRICEMPTYINGISACCELERATEDFOLLOWING LAPAROSCOPIC.ISSENFUNDOPLICATION%UR*0EDIATR3URGn +AMAL. #HAMI4 !NDERSEN! 2OSELL&! 3CHUSTER-- 7HITEHEAD7%$ELAYEDGASTROINTESTINAL TRANSIT TIMES IN ANOREXIA NERVOSA AND BULIMIA NERVOSA 'ASTROENTEROLOGY n :IMMERLI %* 7ALSH "4 'USS *, $EVLIN -* +ISSILEFF (2 'ASTRIC COMPLIANCE IN BULIMIA NERVOSA0HYSIOL"EHAVn 0ERRI& 0ASTORE- :ICOLELLA! !NNESE6 1UITADAMO- !NDRIULLI!'ASTRICEMPTYINGOF SOLIDSISDELAYEDINCELIACDISEASEANDNORMALIZESAFTERGLUTENWITHDRAWAL!CTA0AEDIATR 89:921–5. 2OCCO! 3ARNELLI' #OMPARE$ DE#OLIBUS0 -ICHELI0 3OMMA0 ETAL4ISSUEGHRELINLEVEL AND GASTRIC EMPTYING RATE IN ADULT PATIENTS WITH CELIAC DISEASE .EUROGASTROENTEROL -OTIL 2008;20:884–90. 3INGH3* 'IBBONS.* "LACKSHAW0% 6INCENT- 7AKElELD* 0ERKINS!#'ASTRICEMPTYING OFSOLIDSINNORMALCHILDRENnAPRELIMINARYREPORT*0EDIATR3URGn !BELL4, #AMILLERI- $ONOHOE+ (ASLER7, ,IN(# -AURER!( ETAL#ONSENSUSRECOMMENDATIONSFORGASTRICEMPTYINGSCINTIGRAPHYAJOINTREPORTOFTHE!MERICAN.EUROGASTROENTEROLOGY AND -OTILITY 3OCIETY AND THE 3OCIETY OF .UCLEAR -EDICINE !M * 'ASTROENTEROL n #UCCHIARA 3 -INELLA 2 )ORIO 2 %MILIANO - !Z :EQEH . 6ALLONE ' ET AL 2EAL TIME ULTRASOUNDREVEALSGASTRICMOTORABNORMALITIESINCHILDRENINVESTIGATEDFORDYSPEPTICSYMPTOMS *0EDIATR'ASTROENTEROL.UTRn #HILOIRO- #AROLI- 'UERRA6 ,ODADEA0IEPOLI! 2IEZZO''ASTRICEMPTYINGINNORMAL WEIGHT AND OBESE CHILDREN n AN ULTRASOUND STUDY )NT * /BES 2ELAT -ETAB $ISORD n 'ATTI# DI!BRIOLA&& $ALL/GLIO, 6ILLA- &RANCHINI& !MARRI3)STHE# ACETATEBREATH TESTAVALIDPROCEDURETOANALYSEGASTRICEMPTYINGINCHILDREN*0EDIATR3URGn #HITKARA$+ #AMILLERI- :INSMEISTER!2 "URTON$ %L 9OUSSEF- &REESE$ ETAL'ASTRIC SENSORYANDMOTORDYSFUNCTIONINADOLESCENTSWITHFUNCTIONALDYSPEPSIA*0EDIATR 500–5.

20


+UO" -C#ALLUM27 +OCH+, 3ITRIN-$ 7O*- #HEY7$ ETAL#OMPARISONOFGASTRIC EMPTYINGOFANONDIGESTIBLECAPSULETOARADIO LABELLEDMEALINHEALTHYANDGASTROPARETICSUBJECTS !LIMENT0HARMACOL4HERn 3EIMON26 &ELTRIN+, -EYER*( "RENNAN)- 7ISHART*- (OROWITZ- ETAL%FFECTSOF VARYINGCOMBINATIONSOFINTRADUODENALLIPIDANDCARBOHYDRATEONANTROPYLORODUODENALMOTILITY HORMONE RELEASE AND APPETITE IN HEALTHY MALES !M * 0HYSIOL 2EGUL )NTEGR #OMP 0HYSIOL 2009;296:R912–20. *OLLIET0 .ION3 !LLAIN 6EYRAC' 4ILLOY &ENART, 6ANUXEEM$ "EREZOWSKI6 ETAL%VIDENCE OFLOWESTBRAINPENETRATIONOFANANTIEMETICDRUG METOPIMAZINE COMPAREDTODOMPERIDONE METOCLOPRAMIDE AND CHLORPROMAZINE USING AN IN VITRO MODEL OF THE BLOOD BRAIN BARRIER 0HARMACOL2ESn 4AKEDA+ 4ANIYAMA+ +UNO4 3ANO) )SHIKAWA4 /HMURA) ETAL#LEBOPRIDEENHANCES CONTRACTILITY OF THE GUINEA PIG STOMACH BY BLOCKING PERIPHERAL $ DOPAMINE RECEPTOR AND ALPHA ADRENOCEPTOR*0HARMACOL%XP4HERn !HMAD. +EITH &ERRIS* 'OODEN% !BELL4-AKINGACASEFORDOMPERIDONEINTHETREATMENT OFGASTROINTESTINALMOTILITYDISORDERS#URR/PIN0HARMACOLn #OSTALOS# 'OUNARIS! 6ARHALAMA% +OKORI& !LEXIOU. +OLOVOU%%RYTHROMYCINASA PROKINETICAGENTINPRETERMINFANTS*0EDIATR'ASTROENTEROL.UTRn -AHON"% 2OSENMAN-" +LEIMAN-"-ATERNALANDINFANTUSEOFERYTHROMYCINANDOTHER MACROLIDE ANTIBIOTICS AS RISK FACTORS FOR INFANTILE HYPERTROPHIC PYLORIC STENOSIS * 0EDIATR n #OOPER7/ 2AY7! 'RIFlN-20RENATALPRESCRIPTIONOFMACROLIDEANTIBIOTICSANDINFANTILE HYPERTROPHICPYLORICSTENOSIS/BSTET'YNECOLn 'OLDSTEIN ,( "ERLIN - 4SUR , "ORTNIK / "INYAMINI , "ERKOVITCH - 4HE SAFETY OF MACROLIDESDURINGLACTATION"REASTFEED-EDn ,EE ! &AN ,4 3TIMULATION OF THE WRIST ACUPUNCTURE POINT 0 FOR PREVENTING POSTOPERATIVE NAUSEAANDVOMITING#OCHRANE$ATABASE3YST2EV#$ &RIEDENBERG &+ 0ALIT ! 0ARKMAN (0 (ANLON ! .ELSON $" "OTULINUM TOXIN ! FOR THE TREATMENTOFDELAYEDGASTRICEMPTYING!M*'ASTROENTEROLn (YMAN0 3CHROPP+ 3AROSIEK) &ORSTER* ,IN: 'ERTKEN* ETAL&EASIBILITYANDSAFETYOF GASTRIC ELECTRICAL STIMULATION FOR A CHILD WITH INTRACTABLE VISCERAL PAIN AND GASTROPARESIS *0EDIATR'ASTROENTEROL.UTRn )SLAM3 6ICK,2 2UNNELS-* 'OSCHE*2 !BELL4'ASTRICELECTRICALSTIMULATIONFORCHILDREN WITHINTRACTABLENAUSEAANDGASTROPARESIS*0EDIATR3URGn 7ASEEM 3 -OSHIREE " $RAGANOV 06 'ASTROPARESIS CURRENT DIAGNOSTIC CHALLENGES AND MANAGEMENTCONSIDERATIONS7ORLD*'ASTROENTEROLn

sdfsdf

Chapter 21

Dietary Treatment for Gastroparesis Frank Duffy

Keywords 'ASTROPARESIS s $IGESTION s !BSORPTION s 5PPER GASTROINTESTINAL DYSFUNCTIONs-ALNOURISHMENTs$IETARYTREATMENTS

Introduction 0ROCESSINGOFINGESTEDFOODBYTHEUPPERGASTROINTESTINAL') TRACT WHICHPRIMARILY OCCURSINTHESTOMACHANDSMALLINTESTINE ISPARAMOUNTTOADEQUATEDIGESTIONAND ABSORPTIONOFNUTRIENTS4HECONSTELLATIONOFSYMPTOMSANDUPPERGASTROINTESTINAL DYSFUNCTION IN PATIENTS WITH GASTROPARESIS CAN CREATE A PROPENSITY FOR ACUTE OR CHRONICMALNOURISHMENTWHICHCANBEDEBILITATINGOREVENLIFE THREATENING-ANY PATIENTSWITHGASTROPARESISCONSUMEDIETSDElCIENTINCALORIES VITAMINS ANDMINERALS $IETARYTREATMENTISINDICATEDASAMEANSOFREDUCINGTHEIMPACTOFDELAYEDGASTRIC EMPTYINGONFOODPROCESSINGABSORPTIONANDISTAILOREDTOIMPROVESYMPTOMS MAKING ITIMPORTANTINTHETREATMENTOFTHEPATIENTWITHGASTROPARESIS 4HEGENERALAPPROACHTODIETARYTHERAPYFORGASTROPARESISINVOLVESANASSESSMENT OF THE PATIENTS NUTRITIONAL STATUS IDENTIlCATION OF EXISTENT OR RISK OF MALNUTRITION CORRECTIONOFACUTENUTRIENTDElCIENCIES COLLABORATIONWITHTHEPATIENTONANADEQUATE DIETARYREGIMEN ANDEDUCATIONONDIETARYPRINCIPLESINORDERTOPREVENTMALNUTRITION INTHEFUTURE)NTHISCHAPTER WEELABORATEONTHISAPPROACHFORTHEPATIENTWITHGASTROPARESIS AND THEN HIGHLIGHT CONCERNS SPECIlC TO GASTROPARESIS IN DIABETES AND RENAL FAILURE 2& WHERE DIETARY THERAPY IS ALTERED TO REmECT DIFFERING CLINICAL CONCERNS 7EMENTIONCOMPLEMENTARYTHERAPIESFORGASTROPARESIS WHICHSTRADDLETHEAREASOF NUTRITION MEDICINE AND LIFESTYLE INTERVENTION %DUCATIONAL TEMPLATES FOR USE WITH PATIENTSWITHGASTROPARESIS ASWELLAS)NTERNETRESOURCEINFORMATION AREPROVIDED F. Duffy (*) $EPARTMENTOF.UTRITION 4EMPLE5NIVERSITY(OSPITAL 3OUTHTH3TREET !PT 0HILADELPHIA 0! 53! e-mail: [email protected] H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_21, © Springer Science+Business Media, LLC 2012

237

238

F. Duffy

Nutrition Assessment 4HElRSTSTEPINDETERMININGTHENEEDOREXTENTOFDIETARYTHERAPYINTHEPATIENTWITH GASTROPARESISISANUTRITIONASSESSMENT WHICHINCLUDESTAKINGADIETARYHISTORYOF THEPATIENT WEIGHT HEIGHT ANDANTHROPOMETRICMEASUREMENTS ANDLABORATORYTESTS 4HE PATIENT MAY THEN BE CATEGORIZED AS EITHER AT LOW MODERATE OR HIGH RISK OF MALNUTRITION,OW RISKPATIENTSAREABLETOMAINTAINHEALTHYNUTRITIONALSTATUSWITH MINIMALINTERVENTIONANDSTANDARDEDUCATIONONGASTROPARESISANDDIET-ODERATERISK PATIENTSNEEDMOREEXTENSIVEDIETMANIPULATIONANDSUPPLEMENTATION WITHONGOING MONITORINGANDSUPPORTTOMAINTAINSTATUS(IGH RISKPATIENTSNEEDONGOINGMONITORING WITHMOREAGGRESSIVENUTRITIONSUPPORTREGIMENS INCLUDINGTHEPOSSIBILITYOF enteral nutrition.

Weight Assessment .UTRITION ASSESSMENT SHOULD BEGIN WITH AN ESTIMATION OF LEAN BODY MASS ,"- STATUS ! BODY WEIGHT "7 HISTORY WITH SUBJECTIVE REPORTS OF FOOD INTAKE AND STRENGTHLEVEL ALONGWITHVISCERALPROTEINSTATUSANDANTHROPOMETRICS CANCOMBINE TO ASCERTAIN ,"- STATUS AND RISK OF DEBILITATION AND SUBSEQUENT ILLNESS 7EIGHT ASSESSMENTISTHEMOSTCONVENIENTGROSSESTIMATEOFNUTRITIONALSTATUS5PONPRESENTATION ANYPATIENTIDEALBODYWEIGHTUSING(AMWIFORMULAOR"ODY-ASS )NDEXKGM2HASAHIGHRISKOFMALNUTRITION/BTAININGAWEIGHTHISTORYMAY ELUCIDATE A TREND TOWARD MALNUTRITION LOSS OF USUAL "7 OVER MONTHS OR LOSS IN MONTH INDICATES HIGH RISK ;1= &LUID STATUS MAY CONFOUND WEIGHT ASSESSMENTPATIENTSNEEDTOBEASSESSEDFORmUIDRETENTION$RYWEIGHTISUSEDFOR HEMODIALYSIS ANDPOSTPARACENTESISWEIGHTISUSEDFORPATIENTSWITHASCITES%DEMA CANBEANINDICATOROFDElCIENTPROTEINSTATUS!SCITICBUILDUPOFmUIDCANEXACERBATE GASTROPARESIS SYMPTOMS POSTPRANDIAL GASTRIC VOLUMES AND ACCOMMODATION ARE REDUCEDINPATIENTSWITHCIRRHOSISANDASCITES ANDREMOVALOFmUIDINCREASESFASTING GASTRICVOLUMES VOLUMESINGESTED ANDCALORICINTAKE;2=4HEREFORE SODIUMAND mUIDRESTRICTIONMAYBEWARRANTED

Patient Interview 0ATIENTREPORTINGONWEIGHTCHANGESANDDIETARYINTAKECANBEUSEDTOBOLSTERTHE WEIGHTANDNUTRITIONALASSESSMENTS!NYSIGNIlCANTWEIGHTLOSSFROMAPATIENTS REPORTEDHEALTHYWEIGHT ALONGWITHACONCOMITANTCOMPLAINTOFWEAKNESSFATIGUE INDICATES HIGH RISK $IET RECALL OR CALORIE COUNT CAN BE USED TO CORRELATE RECENT INADEQUATEINTAKEWITHOVERALLWEIGHTLOSS.ITROGENBALANCEMAYBEESTIMATEDIN ORDERTOASSESSADEQUACYOFPROTEININTAKE WHEREEXCESSOFURINARYNITROGENMAY REmECT SKELETAL MUSCLE CATABOLISM /THER AREAS TO SCREEN THE PATIENT FOR RISK

$IETARY4REATMENTFOR'ASTROPARESIS

239

INCLUDE ORAL FOOD INTOLERANCE FROM POOR DENTITION OR DYSPHAGIA LIQUID VERSUS SOLIDTOLERANCEPERCENTOFINGESTEDFOODVOMITEDAVOIDANCEOFCERTAINFOODSCYCLIC VS SPORADIC SYMPTOMS USE OF NUTRITIONAL SUPPLEMENTS AND BOWEL MOVEMENT PATTERNSCONSTIPATIONORDIARRHEA ;3]. 4HEAVERAGEPATIENTNEEDSACALORICINTAKEOFKCALKGDAYATREST!NYPATIENT NOT EATING OF THEIR DAILY NEEDS SHOULD BE CONSIDERED FOR ORAL LIQUID NUTRIENT SUPPLEMENTS TO INCREASE INTAKE EG %NSURE 0LUS (. HAS KCAL OZ CAN )NADEQUATEINTAKE SUCHASBEINGNILPEROS.0/ ORIMPAIREDEATINGORABSORPTION DAYS INDICATES HIGH RISK OF MALNUTRITION -ALNOURISHED PATIENTS WHO CANNOT tolerate oral supplements may need enteral or parenteral nutrition support.

Laboratory Assessment "IOCHEMICAL MARKERS OF VISCERAL PROTEIN STATUS CAN BE USED IN CONJUNCTION WITH WEIGHTANDINTAKEHISTORYTOFURTHERESTABLISHTHERISKOFMALNUTRITION

Albumin !LBUMINISAPROTEINSYNTHESIZEDINTHELIVERWHICHHASONCOTICANDCARRIERPROPERTIES INTHEBLOODSTREAM3ERUMALBUMIN ESPECIALLYWHENLOW CANBEUSEDASANOVERALL PROGNOSTICINDICATOR THOUGHLOWLEVELSMAYALSOINDICATEIMPAIREDHEPATICFUNCTION !LTHOUGH SERUM ALBUMIN ALONE DOES NOT CORRELATE WITH NUTRITIONAL STATUS IT IS A USEFUL BAROMETER FOR ANABOLISM OR INmAMMATION WHEN A CONCOMITANT # REACTIVE PROTEIN#20 LEVELISOBTAINED)NmAMMATIONCANINDUCECATABOLISMVIACYTOKINES EG INTERLEUKIN BYINHIBITINGPROTEINSYNTHESIS INCREASINGPROTEINHYDROLYSIS AND BREAKING DOWN MUSCLE PROTEIN )NmAMMATION MAY ALSO AFFECT ANOREXIA AND IMPACTTHE')SYSTEM ASWELLASAFFECTRESTINGENERGYEXPENDITURE;=!LOWSERUM ALBUMINLEVELOFGDLCONFERSMODERATERISKANDGDLHIGHRISKINAPATIENT WITHOTHERGLOBALINDICATORSOFMALNUTRITION&LUIDSHIFTSMAYCONFOUNDTHEACCURACY OFALBUMINLEVELANDNEEDTOBEACCOUNTEDFOR!NORMALALBUMINLEVELCANNOTRULE OUT RISK AS A CHRONIC HYPOCALORIC INTAKE MAY LEAD TO WEIGHT AND FUNCTIONAL LOSS WITHOUTACHANGEINHEPATICPROTEINPRODUCTION!LBUMINLEVELISNOTSENSITIVETO ACUTESTARVATIONDUETOITSBIOLOGICALHALF LIFEOFDAYSINADULTS!LBUMINLEVELHAS BEENREPORTEDTOINVERSELYCORRELATEWITHPROLONGEDGASTRICEMPTYINGOFSOLIDSIN IDIOPATHICGASTROPARESIS;5].

Prealbumin 3HORTER HALF LIFE VISCERAL BLOOD PROTEINS MAY INDICATE MORE ACUTE MALNUTRITION WHENADDEDTOTHEOVERALLASSESSMENTOFSTATUS0REALBUMINISACARRIERPROTEINFOR

F. Duffy

THYROXINE ANDRETINOL BINDINGPROTEIN ANDHASAHALF LIFEOFDAYS3ERUMPREALBUMIN LEVELSDROPINTHEACUTESTAGEOFSTARVATIONANDRETURNTONORMALASNUTRITIONALINTAKE BECOMESADEQUATE PRESUMABLYREmECTINGLIVERBIOSYNTHESISRATE;6=0REALBUMINIS ALSOLOWWITHCHRONICIMPAIRMENTOFLIVERFUNCTION0REALBUMINHASHIGHTRYPTOPHAN CONTENT4RYPTOPHANISAREGULATOROFPROTEINSYNTHESISTHISMAYINCREASETHESENSITIVITY OF PREALBUMIN LEVEL TO LOW PROTEIN INTAKE 3ERUM PREALBUMIN LEVEL MAY BE STRATIlEDINTOHIGHRISKGLMODERATEnANDLOW;7].

Other Laboratory Parameters 4RANSFERRINHASAHALF LIFEOFDAYS ANDASERUMLEVELMGDLCANCORRELATE WITHMALNUTRITION;8=(OWEVER THISMEASUREMENTMAYBECONFOUNDEDBYALTERED IRON &E METABOLISM AS &E DElCIENCY RAISES TRANSFERRIN LEVEL 2ETINOL BINDING PROTEINLEVELCANREmECTPROTEININTAKEBUTISNOTOFTENASSAYED!SWITHALBUMIN mUIDSTATUSANDINmAMMATIONMUSTBEACCOUNTEDFORINDETERMININGACCURACYWHEN ASSESSINGVISCERALPROTEINSTATUS /THER BIOCHEMICAL SERUM CORRELATES FOR MALNUTRITION INCLUDE CHOLESTEROL MMOLL WHICHMAYINDICATEHYPOCALORICINTAKE ANDTOTALLYMPHOCYTECOUNT 50% *EJUNOSTOMY Enteral feeding Infectious access, .UTRITIONALSUPPORT 4UBE RELATED /BSTRUCTION

NONRANDOMIZED 3UBJECTIVERELIEF N = 8, 18 OF3X IN 7EIGHTGAIN DC meds in 8/8 NONRANDOMIZED N = 2, 4 2ETROSPECTIVE N = 26

!LLSUBJECTIVE )MPROVEDNUTRITION $ECREASED3X )MPROVED Glycemic control

Table 30.2 /VERVIEWOFSURGICALTREATMENTMODALITIEShDElNITIVEvTHERAPY 4REATMENT Indication -ORBIDITY Studies RISKOF Case series (1) Eliminate $RAINAGE procedure) 2ETROSPECTIVE Pylorospasm, Pyloroplasty N = 2, 2, 4 Gastric continence Pyloromyotomy 'ASTROJEJUNOSTOMY

Outcomes 3UBJECTIVE IMPROVEMENT .OCHANGE .6

Resectional 4HERAPY Completion Gastrectomy

2EMOVEEND organ .EARTOTAL Gastrectomy

5PTO &REQUENT SUBSEQUENT Surgeries 194adm/33pts

RETROSPECTIVE N = 52, 60

SUBJECTIVE )MPROVEMENT IMPROVE Visick grade

Gastric electrical stimulation

Refractory gastroparesis

RISKOF procedure)

0ROSPECTIVE 2ANDOMIZED N = 33

~60% symptom 2EDUCTION $IABETICGROUP Greatest effect

HEALING ANDINCREASEDRISKOFPOSTOPERATIVEINFECTION&URTHERMORE PATIENTSWITH GASTROPARESIS MAY BE PRONE TO GASTROESOPHAGEAL REmUX RETAINED GASTRIC CONTENTS ANDEVENBEZOARSWHICHINCREASETHERISKOFPERIOPERATIVEASPIRATION 3URGICALINTERVENTIONISOFTENAIMEDATSUPPORTORSYMPTOMCONTROL3OYKANETAL FOUNDTHATOFPATIENTSSEENATATERTIARYMEDICALCENTERRECEIVEDNUTRITIONAL SUPPORTVIAENTERALORPARENTERALFEEDINGANDWERECONSIDEREDhNONRESPONDERSv TOPROKINETICTHERAPYANDEVENTUALLYUNDERWENTSURGICALINTERVENTION;3]. Surgical INTERVENTIONISOFTENCONSIDEREDFORREFRACTORYPATIENTSTOPROVIDEhSUPPORTIVEvTHERAPY INCLUDINGINTRAVENOUSORENTERALACCESS FORNUTRITIONALSUPPORTANDDECOMPRESSION 4ABLE30.1 )NSEVERALCENTERS SURGEONSPLACETHE%NTERRAÍGASTRICELECTRICSTIMULATOR FORELECTRICALSTIMULATIONTREATMENT/CCASIONALLY PATIENTSMAYBEEVALUATEDFOREITHER PALLIATIVETHERAPYAIMEDATAMELIORATINGSYMPTOMS SUCHASGASTRICDECOMPRESSION ANDORSURGICALDRAINAGEPROCEDURES ORhDElNITIVEvPROCEDURES SUCHASRESECTIVE SURGERY4ABLE30.2).

30(ARBISON

368

Supportive Intervention for Gastroparesis Intravenous Access: PICC Lines, CVC, Hickman Catheters, Infusaports 4HEREARENUMEROUSMETHODSOFESTABLISHINGCENTRALVENOUSACCESSIFTOTALPARENTERAL ALIMENTATIONISNEEDED4ABLE30.3 #ENTRALVENOUSCATHETERS#6#S MAYBEPLACED INTHEOPERATINGROOM ATTHEBEDSIDEORINANAPPROPRIATEAMBULATORYSETTING#ENTRAL CATHETERSCANBEDIVIDEDINTOTWOTYPESSHORTANDLONGTERM DEPENDINGUPONPATIENT NEEDSANDCONTRA INDICATIONS4ABLE30.3). .ONTUNNELED OR SUBCUTANEOUSLY TUNNELED SHORT TERM CATHETERS INTENDED TIME FRAMEFORUSEISFORAWEEKTOMONTH.ONTUNNELED#6#SAREPLACEDINTHESUBCLAVIAN OR INTERNAL JUGULAR VEINS WHILE TUNNELED #6#S ARE PERIPHERALLY INSERTED CENTRAL VENOUS CATHETERS 0)##S PLACED IN THE BASILIC CEPHALIC OR BRACHIAL VEINS 3HORT TERM#6#SMAYBEPLACEDATTHEBEDSIDECOMPLICATIONS SUCHASPNEUMOTHORAXAND HEMATOMAAREUNUSUAL OCCURINnOFCASESANDCANBEMINIMIZEDBYTHEUSE OFULTRASOUNDORmUOROSCOPYTOIMAGETHEVEIN.ONTUNNELED#6#SHAVEASLIGHTLY HIGHERINFECTIONRATEBECAUSEOFTHEPROXIMITYOFTHESKININSERTIONSITETOTHEVEIN CATHETER ASSOCIATED BACTEREMIA AND INFECTION OCCURS IN n OF CASES ;8]. 0ERIPHERAL #6#S BECAUSE OF THEIR ABILITY TO BE PLACED IN A SMALLER VEIN WITH A SUBCUTANEOUSTUNNELHAVEINCREASEDLONGEVITYANDLOWERSTHERATEOFINFECTION ,ONG TERMCATHETERSAREUSEDFOROUTPATIENTSREQUIRINGCENTRALVENOUSACCESSFOR PERIODSUPTOSEVERALMONTHSANDINCLUDE0)##S TUNNELED#6#S(ICKMAN AND TOTALLY IMPLANTABLE INTRAVASCULAR DEVICES 0ORTS )MPLANTABLE AND TUNNELED #6#S HAVETHELOWESTRATEOFINFECTIONBECAUSETHEPORTALOFENTRYFORBACTERIAISMINIMIZED BUTNOTELIMINATEDASUBCUTANEOUSORhPOCKETvINFECTIONMAYSTILLOCCUR0LACEMENT OFLONG TERM#6#SREQUIRESEITHERANOPERATIVEORINTERVENTIONALPROCEDURECOMPLICATIONSOFWHICHAREHEMATOMAANDPNEUMOTHORAXANDLESSTHAN;9]. "OTHSHORT ANDLONG TERM#6#SMAYBEASSOCIATEDWITHTHEMOSTTROUBLESOME ANDPOTENTIALLYDANGEROUSCOMPLICATIONINFECTION#ATHETER RELATEDINFECTION SITE INFECTION ORLINESEPSISSHOULDBECONSIDEREDINTHEPRESENCEOFSIGNSOFLOCALINFECTION OR BACTEREMIA 5NCOMPLICATED SITE INFECTIONS OR EVEN BACTEREMIA MAY BE TREATED WITHOUTREMOVINGTHE#6#DEPENDINGUPONSEVERITYANDCAUSATIVEORGANISMHOWEVER Table 30.3 )NTRAVENOUSANDCENTRALVENOUSCATHETERS #ATHETERTYPE Site 0ERIPHERALCATHETER SHORT &OREARM HAND .ONTUNNELEDPOLYURETHANE 3UBCLAVIAN INTERNALJUGULAR CVC FEMORALVEIN .ONTUNNELEDSILICONE#6# 3UBCLAVIAN INTERNALJUGULARVEINS 0ERIPHERALLYINSERTED#6# "ASILIC CEPHALIC ORBRACHIALVEINS (PICC) 4UNNELED#6#(ICKMAN 3UBCLAVIAN INTERNALJUGULARVEINS 4OTALLYIMPLANTABLEPORT 3UBCLAVIAN INTERNALJUGULAR

%XPECTEDDURATIONOFUSE Days $AYSTOWEEKS 7EEKSTOMONTH 7EEKSTOMONTHS -ONTHS -ONTHS

4HE')3URGEONAND'ASTROPARESIS

369

ELECTIVEREPLACEMENTISADVISEDIFONGOINGCENTRALACCESSISNEEDED-ORESERIOUS CATHETER SITE INFECTION CLINICAL SIGNS OF LINE SEPSIS OR IDENTIlCATION OF RESISTANT ORGANISMSMANDATEREMOVALOFTHECATHETERANDREPLACEMENTTOANEWSITE !NOTHERFREQUENTVENOUSACCESSCOMPLICATIONISCATHETER RELATEDTHROMBOSISTHAT MAYOCCURINnOFPATIENTSBASEDUPONCOMORBIDRISKFACTORS6ENOUSTHROMBOSIS PRESENTSASASWOLLENPAINFULARMANDSHOULDBETREATEDBYCATHETERREMOVALAND CONSIDERATIONOFTHROMBOLYTICTHERAPYORANTICOAGULATION -ANY OPTIONS ARE AVAILABLE FOR GASTROPARETIC PATIENTS REQUIRING INTRAVASCULAR ACCESS *UDICIOUS CONSIDERATION OF PATIENT NEEDS INCLUDING THE INDICATIONS AND POSSIBLECOMPLICATIONSOF#6#SALONGWITHTHEDELETERIOUSLONG TERMEFFECTSOF HYPERALIMENTATIONAREESSENTIALWHENCHOOSINGTHETYPEOFDEVICEANDPLACEMENTSITE

Gastrostomy $ECOMPRESSINGGASTROSTOMYTUBESHAVEBEENUTILIZEDTOPROVIDERELIEFOFNAUSEA VOMITING AND BLOATING BY VENTING OR SUCTIONING RETAINED GASTRIC LIQUID OR GAS 'ENERALLY GASTROSTOMYTUBESSHOULDNOTBEUSEDFORNUTRITIONALFEEDINGS ASPATIENTS HAVEDELAYEDGASTRICEMPTYING)NTHEGASTROPARETICPATIENTPOPULATION GASTROSTOMY TUBESMAYBEPAIREDWITHASEPARATEFEEDINGJEJUNOSTOMYTUBETOPROVIDESIMULTANEOUS ENTERAL ALIMENTATION /CCASIONALLY COMBINATION GASTROSTOMYJEJUNOSOTOMY ORTRANSGASTRICJEJUNOSTOMYTUBESAREUSED4HESEAREMULTILUMENTUBESDESIGNEDTO CONSOLIDATEBOTHDECOMPRESSIONANDENTERALFEEDINGINTOASINGLETUBEPLACEDINTO THEGASTRICLUMENANDFEDTHROUGHTHEPYLORUSWELLINTOTHEPROXIMALSMALLINTESTINE !DRAWBACKTOTHISTYPEOFTUBEISTHEFREQUENTMIGRATIONOFTHEJEJUNALTUBEBACK INTO THE STOMACH AND A TENDENCY TO INCREASED TUBE DYSFUNCTION AND CONSISTENTLY HIGHER INCIDENCE OF PERIOPERATIVE AND SHORT TERM TUBE RELATED COMPLICATIONS )N A PROSPECTIVE COMPARATIVE STUDY OF 0%' AND COMBINATION GASTROJEJUNOSTOMY TUBES WITH YEARFOLLOW UP THETUBESHADANEQUIVALENTLIFETIME%ARLYANDLATECOMPLICATIONSOCCURREDINOF0%'TREATEDVERSUSOFGASTROJEJUNALTUBETREATED patients [10=4HEADVANTAGEOFTWOSEPARATETUBESISPROVISIONOFDECOMPRESSIONOF THESTOMACHANDSIMULTANEOUSMAINTENANCEOFENTERALFEEDINGASANADJUNCTTOORAL INTAKEOREVENASAPRIMARYSOURCEOFNUTRITIONWITHALOWERINCIDENCEOFTUBE RELATED complications. 'ASTROSTOMYTUBESMAYBEPLACEDBYVARIOUSMETHODSnENDOSCOPICALLY mUOROSCOPICALLY ORSURGICALLYUTILIZINGEITHEROPENORLAPAROSCOPICTECHNIQUE4HEMOST WIDELY USED TECHNIQUE OF GASTROSTOMY PLACEMENT IS THE VARIOUS MODIlCATIONS OF THE h0%'v METHOD ORIGINALLY INTRODUCED BY 'AUDERER AND 0ONSKY IN ;11]. &ORPATIENTSWITHCONTRAINDICATIONSTOTHEPERCUTANEOUSENDOSCOPICAPPROACH SUCH ASPREVIOUSUPPERABDOMINALSURGERYORMORBIDOBESITY SURGICALGASTROSTOMY EITHER OPEN OR LAPAROSCOPIC IS AN ALTERNATIVE 4HIS METHOD IS ALSO USED FOR THOSE WHO REQUIRESIMULTANEOUSPLACEMENTOFFEEDINGJEJUNOSTOMYTUBES"OTHPERCUTANEOUS ANDSURGICALTECHNIQUESHAVEBEENESTABLISHEDASSAFEANDEFFECTIVEMEANSOFACCESSING THEGASTRICLUMEN

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$ECOMPRESSINGORVENTINGGASTROSTOMYHASBEENUTILIZEDEFFECTIVELYINPOSTSURGICAL ANDMALIGNANTMECHANICALOBSTRUCTION;12=,ESSWELLSTUDIEDINTHEGASTROPARETIC POPULATION THE TECHNIQUE HAS NEVERTHELESS BEEN IDENTIlED AS A SAFE AND EFFECTIVE PROCEDUREALTHOUGHLITTLEPROSPECTIVEDATAEXISTFOREFFECTIVEUSEFORPATIENTSWITH gastroparesis [13=.ONPROSPECTIVEDATAFROMONESTUDYOVERAFOLLOW UPPERIODOF UP TO MONTHS SUGGEST VENTING GASTROSTOMY QUALITATIVELY REDUCES SYMPTOMS OF NAUSEA VOMITING ANDBLOATINGANDALLOWSFORIMPROVEDNUTRITIONVIABOTHTHEORAL ANDTHEALIMENTARYJEJUNAL ROUTE;14=0ATIENTSEXPERIENCEDSYMPTOMIMPROVEMENT WEIGHTGAIN ANDWEREABLETORETURNTOWORKORSCHOOL 'ASTROSTOMY TUBES WHILE EASILY PLACED ARE NOT INNOCUOUS 0ROCEDURE RELATED MORTALITYISESSENTIALLYTHEANESTHETICRISKOFn/VERALL GASTROSTOMYCOMPLICATIONRATESFORTHELIFEOFTHEGASTROSTOMYTUBEFORBOTHPERCUTANEOUSANDSURGICAL TECHNIQUESARESIMILARANDHAVEBEENCITEDASn WITHnREGARDEDASBEING SERIOUSORLIFETHREATENING;15=4HESETUBE RELATEDCOMPLICATIONSAREOFTENINFECTIOUS WOUNDINFECTION FASCIITIS PERITONITIS ANDSTOMATITISFROMLEAKAGE BOWELPERFORATION ORlSTULA4HEOTHERCOMMONCATEGORYOFCOMPLICATIONISTUBEDYSFUNCTIONOCCLUSION FRACTURE DISLODGEMENT AND IRRITATIONEROSION INTO AN ADJACENT ORGAN OR ABDOMINAL WALL#ONVERSELY GASTROSTOMYHASBEENSHOWNTOBEADURABLETUBELIFETIMEINONE SERIESISCITEDASAMEDIANOFDAYSWITHARANGEFROMTO DAYSYEARS ;13]. )TISNOTABLETHATINSEVERALSERIES OVERALLMORTALITYRATEOFPATIENTSWITHGASTROSTOMY TUBESDURINGTHESTUDYPERIODOFUPTOYEARSWASSUBSTANTIAL CITEDFROMTO ANDWASRELATEDTOCOMPLICATIONSOFUNDERLYINGDISEASE MOSTOFTENDIABETES;13, 16]. 0ATIENTS WHO REQUIRE THIS TYPE OF SUPPORTIVE THERAPY OFTEN ARE PRESELECTED TO HAVE SIGNIlCANTCOMORBIDDISEASE'ASTROSTOMYTUBESAREAUSEFULADJUNCTINTHECAREOF GASTROPARETIC PATIENTS /NCE SAFELY PLACED TUBES SHOULD BE FOLLOWED CLOSELY AND MAINTAINEDBYTHEOPERATINGSURGEON GASTROENTEROLOGIST OREXPERIENCEDALLIEDHEALTH PROFESSIONALASAPPROXIMATELYONEINlVEPATIENTSEXPERIENCETUBE RELATEDDIFlCULTIES DURING THE LIFETIME OF THE TUBE ! PROPERLY MAINTAINED GASTROSTOMY CAN PROVIDE symptomatic relief for years.

Feeding Jejunostomy 0ATIENTS WITH GASTROPARESIS OFTEN ARE UNABLE TO TOLERATE ORAL INTAKE OR MEET THEIR NUTRITIONALNEEDS0ATIENTSWHONEEDNUTRITIONALSUPPLEMENTATIONGREATERTHANn WEEKSMAYBENElTFROMTHEPLACEMENTOFANENTERALFEEDINGTUBE%NTERALALIMENTATION USUALLY DENOTES JEJUNAL FEEDING IN GASTROPARETIC PATIENTS AS GASTRIC FEEDING IS FREQUENTLY NOT FEASIBLE !LIMENTARY NUTRITION OBVIATES THE COST COMPLICATIONS AND ADVERSENUTRITIONALSEQUELAEOFTOTALPARENTERALNUTRITION40. WHILEPROVIDINGTROPHIC BENElTS AND BETTER GLYCEMIC CONTROL ALL OF WHICH HAVE BEEN WELL DESCRIBED ;17]. &EEDINGJEJUNOSTOMYTUBESMAYBEPLACEDBYSEVERALMETHODSENDOSCOPICALLYOR SURGICALLYUTILIZINGOPENORLAPAROSCOPICTECHNIQUE%NDOSCOPICPLACEMENTREQUIRES EITHERCONVERSIONOFAPREEXISTINGGASTROSTOMYORPRIMARYPLACEMENTOFPERCUTANEOUS


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ENDOSCOPICJEJUNOSTOMYTUBE&RAUGHTWITHTECHNICALDIFlCULTYFORPLACEMENTAND PRONETOTUBE RELATEDDYSFUNCTION ENDOSCOPICALLYPLACEDTUBESARELESSOFTENUSEDIN THISPATIENTPOPULATION;18]. 3URGICALLY PLACED JEJUNOSTOMY USING EITHER OPEN OR LAPAROSCOPIC TECHNIQUE IS THEMORECOMMONMETHOD.EEDLECATHETERJEJUNOSTOMYHASBEENDESCRIBEDAND MAY BE PLACED mUOROSCOPICALLY HOWEVER THE SMALL BORE TUBE REQUIRED FOR THIS procedure renders it prone to occlusion and less useful for long-term enteral alimentation. 0ATIENTS ABILITY TO TOLERATE JEJUNOSTOMY FEEDINGS MAY BE PREDICTED CLINICALLY USING A TRIAL OF NASOJEJUNAL FEEDINGS PRECEDING DElNITIVE SURGICAL PLACEMENT OF A PERMANENTJEJUNOSTOMY3URGICALFEEDINGJEJUNOSTOMYCANBEACCOMPLISHEDUSING EITHEROPENORLAPAROSCOPICTECHNIQUEWITHEQUIVALENTPERIOPERATIVEMORBIDITY;19]. #AREMUSTBETAKENBYTHEOPERATINGSURGEONTOENSURETHATTHEACCESSEDJEJUNALLIMB ORTUBEISNOTUNDULYTWISTEDORANGULATEDANDTHATTHETUBEITSELFDOESNOTNARROW THEBOWELLUMEN3UCHTECHNICALERRORSCAUSEEARLYTUBEDYSFUNCTION OCCLUSION OR PROXIMALMECHANICALBOWELOBSTRUCTION 7ITHINHAFTERTUBEPLACEMENT FORMULAINFUSIONMAYBESAFELYINITIATEDATLOW INFUSIONRATESAPPROXIMATELYMLPERHOUR WITHDEXTROSEWATERORDILUTENUTRIENT ANDADVANCEDSLOWLYUNTILCALORICGOALISREACHED)FTOLERABLE NOCTURNALCYCLING OFFEEDINGPERMITSFREEDOMFROMANINFUSIONPUMPANDSOMEWHATMORENORMAL DAYTIME WORK AND FUNCTION 3IMILAR TO DECOMPRESSING GASTROSTOMY JEJUNOSTOMY FEEDINGTUBESAREFREQUENTLYUSEDFORNUTRITIONALSUPPORTINTHEGASTROPARETICPATIENT BUTHAVENOTBEENWELLSYSTEMATICALLYSTUDIED)TISCLEARTHATJEJUNOSTOMYTUBESAND FEEDINGAREASSOCIATEDWITHAHIGHINCIDENCEOFBOTHMAJORANDMINORMORBIDITY )NSTUDIESOFPATIENTSNOTABLETOTOLERATEORALFEEDINGBUTNOTRESTRICTEDTOGASTROPARESIS AUTHORS REPORTED OVERALL COMPLICATION RATES FOR PATIENTS GREATER THAN THROUGHOUTTHELIFEOFTHETUBE!DAMSETALREPORTEDCOMPLICATIONSINPATIENTS WITHNEUROLOGICDISEASE INCLUDINGSEVENDEATHS#OGANETALNOTEDCOMPLICATIONSINNURSINGHOMEPATIENTS;20, 21=)NHISSTUDYOFGASTROPARETICPATIENTS &ONTANADESCRIBEDOVERALLCOMPLICATIONSINPATIENTSWITHA YEARMORTALITY of 38% [19= #OMMON COMPLICATIONS INCLUDE INFECTIOUS EITHER TRACT OR WOUND INFECTION ORTUBEDYSFUNCTION SUCHASOCCLUSIONORDISLODGEMENT#LEARLY PATIENTS WHO REQUIRE JEJUNAL FEEDING HAVE SEVERE GASTROINTESTINAL DYSFUNCTION ASSOCIATED WITHMULTIPLEOTHERRISKFACTORS $ESPITESIGNIlCANTCOMPLICATIONSASSOCIATEDWITHTHEUSEOFFEEDINGJEJUNOSTOMY ITHASBEENSHOWNTOIMPROVEOVERALLNUTRITIONREDUCEHOSPITALIZATIONSANDSYMPTOMS SUCH AS NAUSEA AND VOMITING.[19= /VER OF THE PATIENTS IN &ONTANAS GROUP EXPERIENCEDIMPROVEDOVERALLHEALTH&ORPATIENTSWHOCANCONTINUESOMEORALINTAKE THETUBEACTSASA GOODBACK UPSYSTEMFORNUTRITION HYDRATION ANDMEDICATIONS !LTHOUGH OFTEN NEEDED BY PATIENTS WITH SEVERE GASTROPARESIS AND MULTIPLE OTHER COMORBIDITIESANDPRONETOFREQUENTTUBE RELATEDCOMPLICATIONS FEEDINGJEJUNOSTOMY ISANEXCELLENTADJUNCTFORNUTRITIONALSUPPORT0LACEDEQUALLYEFFECTIVELYBYSEVERAL METHODSJEJUNOSTOMYTUBESSHOULDBEFOLLOWEDCLOSELYBYTHETREATINGPHYSICIANOR EXPERIENCEDALLIEDHEALTHPROFESSIONAL

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Definitive Therapy Drainage Procedures: Pyloromyotomy, Pyloroplasty, and Gastrojejunostomy !NTRALHYPOMOTILITY PYLORICDYSFUNCTIONORPYLOROSPASMHAVEALLBEENIMPLICATED INGASTROPARESISASAWHOLEALTHOUGHPRIMARILYTHATOFDIABETICORIGIN)THASBEEN HYPOTHESIZED THAT ELIMINATING RELATIVE GASTRIC OUTLET RESISTANCE MIGHT ACCELERATE EMPTYINGANDIMPROVESYMPTOMSOFNAUSEAANDVOMITING!LESSINVASIVEhMEDICAL PYLOROPLASTYvISFEASIBLEBOTULINUMTOXIN APOTENTINHIBITOROFCHOLINERGICNEUROMUSCULARTRANSMISSIONHASBEENUSEDSUCCESSFULLYALBEITTEMPORARILYTOTREATSPASTIC DISORDERSOFSTRIATEDANDSMOOTHMUSCLEANDHASBEENINJECTEDLOCALLYINTOTHEPYLORIC SPHINCTER)NSEVERALSTUDIES OFDIABETICGASTROPARETICPATIENTSRECEIVINGBOTULINUM TOXINEXPERIENCEDSYMPTOMREDUCTIONLASTINGUPTOMONTHS;22, 23]. 3URGICALDRAINAGEPROCEDURES PYLOROMYOTOMY PYLOROPLASTY ORGASTROJEJUNOSTOMY MAYTHEORETICALLYPROVIDEPERMANENTRELIEFOFSYMPTOMSBYALLEVIATINGORBYPASSING THESAMECONTRIBUTORYFACTORS4ABLE30.2). Drainage procedures alter gastric emptying PRIMARILYTHROUGHPASSIVEMAINTENANCEOFGASTRICCONTINENCE"OTHTYPESOFDRAINAGE PROCEDURESRESULTINDECREASEDRESISTANCETOOUTmOWANDHAVELITTLETONOEFFECTUPON THECHANGEINGASTRICCONTRACTILEFORCE3TUDIESINNORMALPATIENTSHAVESHOWNDRAINAGE PROCEDURES THAT RESULT IN NORMAL TO INCREASED EMPTYING OF BOTH SOLIDS AND LIQUIDS ,ARGERSOLIDPARTICLESANDINDIGESTIBLEFOODTENDTOEMPTYPREMATURELYDUETOREDUCED OUTmOWRESISTANCE0YLOROPLASTYORPYLOROMYOTOMYTHUSMINIMALLYALTERSEMPTYINGOF SOLIDS WHILE LIQUID EMPTYING IS ONLY MILDLY ACCELERATED MOST LIKELY DUE TO PASSIVE DECREASEINOUTmOWRESISTANCE;24]. 'ASTROJEJUNOSTOMY DEPENDING UPON ITS LOCATION MAY PROVIDE MORE PROFOUND GASTRICEMPTYINGSIMPLYDUETOTHEEFFECTSOFGRAVITYTHEFUNCTIONALANDORMECHANICALGASTRICOUTLETOBSTRUCTIONISBYPASSED-OREEXTENSIVEDRAINAGEPROCEDURES SUCH ASTHOSEINVOLVINGA2OUX EN 9LIMB MAYACTUALLYIMPEDEGASTRICEMPTYINGFURTHER DUETOANTIPERISTALTICACTIVITYANDENTEROGASTRICREmUXFROMTHEJEJUNAL2OUXLIMB4HE ROLEOFSURGICALDRAINAGEPROCEDURESINTHETREATMENTOFGASTROPARESISISILL DElNED ANDHASBEENPOORLYSTUDIEDTHEREARENOSYSTEMATIC CONTROLLEDPROSPECTIVESTUDIES 4HE BENElTS OF SURGICAL DRAINAGE PROCEDURES FOR THE GASTROPARETIC PATIENT MUST BE MITIGATEDAGAINSTTHERISKOFSURGERYANDKNOWNLIMITATIONSOFTHEPROCEDUREANDTHEN UTILIZEDWITHTHEUTMOSTCARE

Resectional Therapy for Gastroparesis 2ESECTIONALTHERAPYFORSEVEREGASTROPARESISENTAILSNEARCOMPLETEREMOVALOFTHE OFFENDINGORGAN INTHISCASETHESTOMACH4HEINTUITIVENATUREOFTHETREATMENTREMOVAL OFTHEDYSFUNCTIONALORGANBELIESACOMPLEXSETOFCLINICALANDSURGICALISSUESWHICH


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RENDERTHEDECISIONTOPROCEEDWITHRESECTIONALTHERAPYFORGASTROPARESISDIFlCULT #OMPLETIONGASTRECTOMYHASBEENPROPOSEDANDPERFORMEDFORALLTYPESOFGASTROPARESIS BUT STUDIED IN A SYSTEMATIC WAY ONLY IN THE POSTSURGICAL POSTVAGOTOMY PATIENTPOPULATION)NTHEDIABETICGROUP COMPLETIONGASTRECTOMYHASBEENAPPLIED SUCCESSFULLYBUTSTUDIEDONLYINCASEREPORTORSMALLRETROSPECTIVEREVIEWSWITHFEW patients [25, 26=)THASBEENHYPOTHESIZEDTHATMULTIPLEFACTORSCAUSEGASTRICSTASIS INTHEPOSTSURGICALPATIENTFOREGUTANDGASTRICSURGICALPROCEDURESMAYINHERENTLY RESULTINDYSMOTILITYFROMTOOFPATIENTSEXPERIENCECHRONICGASTRICSTASIS FOLLOWING VAGOTOMY OR DISTAL GASTRIC RESECTION ;27= 'ASTRIC DYSMOTILITY MAY BE WORSENED IF A 2OUX EN 9 GASTROJEJUNOSTOMY WAS USED FOR RECONSTRUCTION OF THE GASTRICREMNANT)LL DElNEDMOTORABNORMALITIESINTHE2OUXLIMBITSELFHAVEBEEN implicated as an additional source of impaired gastric emptying [28=4HEPROPOSED SURGICAL PROCEDURE FOR PATIENTS WITH REFRACTORY POSTSURGICAL GASTROPARESIS IS THUS EXTENSIVESUBTOTALORNEARCOMPLETIONGASTRECTOMYAPPROXIMATELYnGASTRECTOMY LEAVINGASMALL APPROXIMATELYCMREMNANTOFPROXIMALSTOMACHCOUPLED WITHRECONSTRUCTIONUSINGALONGAPPROXIMATELYCM 2OUX EN 9LIMBTOPREVENT ENTEROGASTRICREmUX 4WOSTUDIES REVIEWINGANDPATIENTS RESPECTIVELY HAVEEXAMINEDSURGICAL THERAPYUSINGTHISTREATMENTMODALITY%CKHAUSERETALWEREABLETOFOLLOWUPOF PATIENTS WHO UNDERWENT COMPLETION GASTRECTOMY OVER MONTH PERIOD 4HEY USEDQUESTIONNAIRE BASEDOUTCOMEDATAANDDETERMINEDTHATOFPATIENTSSYMPTOMSHADIMPROVEDSINCESURGERYBUTPTS WERESYMPTOMATICALLYWORSE;29]. )TISALSONOTABLETHATTHISGROUPOFPATIENTSTENDEDTOHAVEMULTIPLEOPERATIONS SURGICALPROCEDURESWEREPERFORMEDINPATIENTS&ORSTNER "ARTBELLETALSTUDIED PATIENTS WHO HAD UNDERGONE COMPLETION GASTRECTOMY OVER AN YEAR PERIOD 4HEIRSTUDYGROUPHADAMEDIANOFFOURPRIOROPERATIONSANDOBJECTIVEEVIDENCEOF GASTRICSTASIS0ATIENTOUTCOMESWERERIGIDLYDETERMINEDUSINGTHE6ISICK GRADING SCALEPRE ANDPOSTOPERATIVELYsee4ABLE30.2) [30=0OSTOPERATIVELY NAUSEA VOMITING ANDPOSTPRANDIALPAINWEREALLREDUCEDBUTONLYEXPERIENCEDSYMPTOMRELIEF WHILE REMAINED AS 6ISICK GRADE OR WITHOUT SYMPTOMATIC RELIEF 0ATIENTS WEREFOUNDTOHAVENOCHANGEINCHRONICABDOMINALPAIN DIARRHEA ANDDUMPING /BJECTIVEMEASURES SUCHASNUTRITIONALSTATUSANDGASTRICEMPTYING WERENOTSTUDIED ANDALTHOUGHNUTRITIONALSTATUSWASREPORTEDASSTABILIZED PATIENTSREMAINEDON 40.AFTERTHEPROCEDURE;31]. #OMPLETION GASTRECTOMY IS A SIGNIlCANT UNDERTAKING WITH SUBSTANTIAL SURGICAL RISK ANDGOODCHANCEPATIENTSWILLNOTEXPERIENCEIMPROVEMENTASARESULT0ATIENTS OFTEN HAVE SEVERE UNDERLYING NUTRITIONAL AND MEDICAL COMORBID FACTORS 3URGICAL INTERVENTIONFORRESECTIONALTHERAPYCARRIESWITHITAHIGHRATEOFREOPERATIONEITHER FORONGOINGSURGICALISSUESORCOMPLICATIONSBOTHWITHINCREASEDRISKOFPERIOPERATIVE MORBIDITYANDMORTALITY"ASEDUPONTHESMALLAMOUNTOFEXISTINGDATA THISRADICAL APPROACHCANBECARRIEDOUTINWELL SELECTEDPATIENTSWITHANEXPECTATIONFORSYMPTOM IMPROVEMENTINnOFCASES4HEMODERATESUCCESSOFTHEPROCEDUREMUSTBE WEIGHED AGAINST THE MAGNITUDE OF THE INTERVENTION AND OFFERED TO WELL SELECTED WELL INFORMEDPATIENTS

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Gastric Electrical Stimulation !SUBSTANTIALGROUPOFPATIENTSWITHGASTROPARESIS UPTO EXPERIENCEADVERSE SIDEEFFECTSFROMPROKINETICTHERAPYORAREREFRACTORYTOTREATMENT;32]. In an effort TOTREATTHEUNDERLYINGCAUSEOFGASTROPARESIS ELECTRICALSTIMULATIONOFTHESTOMACH HASBEENINVESTIGATEDANDISNOWUTILIZEDWITHSOMESUCCESS3TUDIESINDOGSAND SUBSEQUENTLYINHUMANSHAVESHOWNTHATITISPOSSIBLETOUTILIZEHIGH ENERGY LOW FREQUENCYELECTRICALSTIMULATIONTHATENTRAINSANDEVENTUALLYPACESGASTRICMYOELECTRIC ACTIVITY;33, 34=5NFORTUNATELY THEEFFECTSOFGASTRICPACINGTENDTOBESHORT LIVED #URRENTLY GASTRIC ELECTRIC STIMULATION RATHER THAN PACING WITH %NTERRAÍ GASTRIC STIMULATOR HAS BEEN USED TO TREAT GASTROPARESIS WITH HIGH FREQUENCY LOW ENERGY STIMULATIONWITHSOMESUCCESS'ASTRICELECTRICALSTIMULATION'%3 HASBEENSHOWN TOIMPROVESYMPTOMS SUCHASNAUSEA VOMITING ANDABDOMINALPAIN ANDMODESTLY accelerate gastric emptying [35–37]. 4HE GASTRIC ELECTRIC STIMULATOR APPARATUS IS PLACED SURGICALLY UTILIZING EITHER OPENORLAPAROSCOPICTECHNIQUE4WOELECTRICALSTIMULATORLEADSAREPLACEDINTHE MUSCULARISOFTHEANTERIORGREATERCURVATUREOFTHESTOMACHCMAPARTANDCM PROXIMALTOTHEPYLORUS4HEPAIROFELECTRODESISCONNECTEDTOANEUROSTIMULATOR GENERATOR POSITIONED SUBCUTANEOUSLY IN THE ABDOMINAL WALL )NTRAOPERATIVELY THE ELECTRODESARETESTEDFORACCEPTABLEELECTRICALIMPEDANCEANDTHENEUROSTIMULATOR PROGRAMMED TO PRESET PARAMETERS )NTRAOPERATIVE UPPER ENDOSCOPY IS ROUTINELY PERFORMED TO CONlRM CORRECT PLACEMENT OF STIMULATOR ELECTRODES AS ACCEPTABLE ELECTRICAL IMPEDANCE BETWEEN THE TWO LEADS IS ESSENTIAL #ONTROLLED PROSPECTIVE DATA FROM SEVERAL SINGLE INSTITUTION STUDIES WITH SMALLER PATIENT POPULATIONS HAS METWITHPROMISINGRESULTS3UCCESSWITHTHISTECHNIQUELEDTOAMULTI INSTITUTIONAL PROSPECTIVERANDOMIZEDSTUDYINVESTIGATINGTHEEFlCACY SYMPTOMREDUCTION AND THEQUALITYOFLIFEFORPATIENTSTREATEDWITH'%34HESTUDY ENTITLEDTHE7ORLDWIDE !NTI 6OMITING %LECTRICAL 3TIMULATION 3TUDY 7!6%33 LED TO &$! APPROVAL OF '%3ASA(UMANITARIAN5SE$EVICE(5$ ;38=3HORTCOMINGSOFTHESTUDYINCLUDED A SMALL SAMPLE SIZE N AND THE FACT THAT -EDTRONIC )NC A MANUFACTURER OF NEUROSTIMULATORS COSPONSOREDTHESTUDY.EVERTHELESS THECLINICALSUCCESSOFTHIS STUDY HAS BEEN BORNE OUT PATIENTS UNDERGOING '%3 PLACEMENT REPORT SIGNIlCANT IMPROVEMENTINSYMPTOMATOLOGYASWELLASREDUCTIONINABDOMINALPAIN'ASTRIC EMPTYING HOWEVERASMEASUREDBYSCINTIGRAPHICMETHODS WASMODERATELYIMPROVED AFTER'%3PLACEMENT3YMPTOMREDUCTIONOCCURSINAPPROXIMATELYOFPATIENTS WITHDIABETICGASTROPARESISBUTWASSOMEWHATLESSEFFECTIVEFORPATIENTSWITHIDIOPATHICORPOSTSURGICALETIOLOGY;39=!DVANTAGESFORSURGICALPLACEMENTOF'%3ARE THATITISAPROCEDUREOFSIGNIlCANTLYLESSMAGNITUDEANDMORBIDITYTHANCOMPLETION GASTRECTOMY AND GASTROSTOMY ANDOR JEJUNOSTOMY TUBES MAY BE USED IN PARALLEL WITH'%3FORCONCOMITANTSUPPORTIFNEEDED!DVERSEEVENTSRELATEMAINLYTOSURGICAL PLACEMENTOF'%3ANDINCLUDESUBCUTANEOUSPOCKETINFECTION EROSIONOFLEADSOR GENERATOR ANDLESSOFTEN INCISIONALHERNIA"OWELOBSTRUCTIONCAUSEDBYTHELEADSIS POSSIBLEBUTHASRARELYOCCURRED#OMPLICATIONSRESULTINGINDEVICEREMOVALHAVE BEENNECESSARYINAPPROXIMATELYOFCASES;40='%3HASBEENPROMISINGINA


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WELL SELECTED GROUP OF PATIENTS WITH REFRACTORY GASTROPARESIS AND HAS AFFORDED ENCOURAGINGSUCCESSWITHMINIMALSURGICALMORBIDITY#ONTINUEDCONTROLLEDINVESTIGATIONISWARRANTEDANDONGOING

Conclusion #ONTINUEDBASICSCIENCEANDCLINICALSTUDIESHAVEEXPANDEDTHEUNDERSTANDINGOF GASTRIC MOTILITY AND ITS DISORDERS 'ASTROPARESIS HAS BEEN FOUND TO BE ASSOCIATED WITHAVARIETYOFNONSURGICALANDPOSTOPERATIVEETIOLOGIES0ATIENTSWHOSUFFERWITH THISCOMPLEXDISORDERFREQUENTLYREQUIRESURGICALINTERVENTIONATSOMETIMEDURING THECOURSEOFTHEIRDISEASE4HEVARIETYOFPOSSIBLESURGICALINTERVENTIONSFORGASTROPARESISSPANSTHEENTIRECONTINUUMOFMAGNITUDEANDRISK4HISREVIEWHASPROVIDED AN OVERVIEW OF CURRENT SURGICAL TREATMENT MODALITIES FOR GASTROPARESIS 3INCE THE ROLEOFSURGERYANDITSOPTIMALUSEREMAINILL DElNED THEGASTROENTEROLOGISTAND') SURGEON MUST THOUGHTFULLY WEIGH THE RISKS AND LIMITATIONS OF SURGERY AGAINST ITS POTENTIALBENElTS

References 2ABINE*# "ARNETT*,-ANAGEMENTOFTHEPATIENTWITHGASTROPARESIS*#LIN'ASTROENTEROL 0ARKMAN (0 (ASLER 7, &ISHER 23 !MERICAN 'ASTROENTEROLOGICAL !SSOCIATION MEDICAL POSITIONSTATEMENTDIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGY 1589–91. )BRARULLAH- -ITTAL"2 !GARWAL$+ ETAL'ASTRICEMPTYINGINPATIENTSWITHGALLSTONEDISEASE WITHORWITHOUTDYSPEPSIA%FFECTOFCHOLECYSTECTOMY!UST.:*3URGn 3UMMERS'% (OCKING-00REOPERATIVEANDPOSTOPERATIVEMOTILITYDISORDERSOFTHESTOMACH 3URG#LIN.! n /H** +IM#('ASTROPARESISAFTERAPRESUMEDVIRALILLNESSCLINICALANDLABORATORYFEATURES ANDNATURALHISTORY-AYO#LIN0ROCn 0ARKMAN (0 (ASLER 7, &ISHER 23 !MERICAN 'ASTROENTEROLOGICAL !SSOCIATION TECHNICAL REVIEWONTHEDIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGYn !BELL4,ETAL'ASTRICELECTRICALSTIMULATIONISSUPERIORTOSTANDARDPHARMACOLOGICALTREATMENT INREDUCINGHEALTHCARECOSTSANDHOSPITALSTAYSANDIMPROVINGQUALITYOFLIFEINPATIENTSWITH SEVEREUPPER')MOTORDISORDERS!M*'ASTROENTEROLS #RNICH #* -AKI $' 4HE PROMISE OF NOVEL TECHNOLOGY FOR THE PREVENTION OF INTRAVASCULAR DEVICERELATEDBLOODSTREAMINFECTIONPATHOGENESISANDSHORTTERMDEVICES#LIN)NF$IS n #RNICH #* -AKI $' 4HE PROMISE OF NOVEL TECHNOLOGY FOR THE PREVENTION OF INTRAVASCULAR DEVICESRELATEDBLOODSTREAMINFECTIONLONGTERMDEVICES#LIN)NF$ISn -ATHUS 6LIEGEN,-( +ONING(0ERCUTANEOUSENDOSCOPICGASTROSTOMYANDGASTROJEJUNOSTOMY ACRITICALREAPPRAISALOFPATIENTSELECTION TUBEFUNCTIONANDTHEFEASIBILITYOFNUTRITIONALSUPPORT DURINGEXTENDEDFOLLOWUP'ASTROINTESTINAL%NDOSC n 'AUDERER -7, 0ONSKY *, )ZANT *R 2* 'ASTROSTOMY WITHOUT LAPAROTOMY A PERCUTANEOUS ENDOSCOPICTECHNIQUE*0ED3URGn

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Chapter 31

Endoscopic Full-Thickness Gastric Biopsy for Evaluation of Patients Rukshana N. Cader, Mouen A. Khashab, and Anthony N. Kalloo

Keywords 'ASTROPARESIS s &ULL THICKNESS RESECTION s 'ASTRIC ELECTRIC STIMULATION s)NTERSTITIALCELLSOF#AJALs%LECTROGASTROGRAMs.ATURALORIlCETRANSLUMENALENDOSCOPIC SURGERYs3UBMUCOSALENDOSCOPY

Introduction 'ASTROPARESISISCHARACTERIZEDBYRECURRENTEPISODESOFPOSTPRANDIALNAUSEA VOMITING EPIGASTRICPAINANDFULLNESS EARLYSATIETY ANDBLOATINGINTHEABSENCEOFMECHANICAL OBSTRUCTION OF THE GASTRIC OUTLET OR THE PROXIMAL SMALL BOWEL ;1= 4HE COMMON ETIOLOGIESFORDELAYEDGASTRICEMPTYINGINCLUDEDIABETESMELLITUS POSTSURGICAL OFTEN ASARESULTOFDAMAGEOFTHEVAGUSNERVE ANDIDIOPATHICINCLUDINGDELAYEDGASTRIC EMPTYINGASARESULTOFAVIRALILLNESS ;2, 3=/THERLESSFREQUENTCAUSESINCLUDE COLLAGENVASCULARDISEASES NEUROLOGICPROBLEMS SUCHAS0ARKINSONSDISEASEAND MULTIPLESCLEROSIS INTESTINALPSEUDOOBSTRUCTION ENDOCRINOPATHIES MEDICATION RELATED ANDASAMANIFESTATIONOFAPARANEOPLASTICSYNDROME;2]. .ORMAL GASTRIC FUNCTION IS REGULATED BY A COMPOSITE INTERACTION BETWEEN THE NEUROHORMONAL MYOELECTRIC AND CONTRACTILE PROPERTIES OF THE STOMACH 'ASTRIC CONTRACTILITYISCONTROLLEDBYTHEGASTRICSLOWWAVESTHATORIGINATEFROMTHEINTERSTITIALCELLSOF#AJAL)##S ;4, 5=4HEELECTRICACTIVITYGENERATEDBYTHE)##SBEGINS ATTHEJUNCTIONOFTHEFUNDUSANDTHEBODYOFTHESTOMACHATARATEOFAPPROXIMATELY CYCLES PER MINUTE AND IS CONDUCTED CIRCUMFERENTIALLY AND DISTALLY TOWARD THE PYLORUS)##SARELOCATEDINTHEMYENTERICPLEXUSTHATISTUCKEDINTHEGASTRICSMOOTH MUSCLECELLS WHICHALSOAREINNERVATEDTHROUGHTHEENTERICNERVOUSSYSTEM;4, 5].

!.+ALLOO*) $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF-EDICINE 4HE*OHNS(OPKINS(OSPITAL .7OLFE3TREET "LALOCK "ALTIMORE -$ 53! E MAILAKALLOO JHMIEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_31, © Springer Science+Business Media, LLC 2012

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7HENEVERTHEREISPOSTPRANDIALSTIMULATIONOFTHESTOMACH SMOOTHMUSCLECELLSCAN ACHIEVE THE LEVEL OF DEPOLARIZATION FOR ELECTROMECHANICAL COUPLING TO OCCUR AND GENERATEANACTIONPOTENTIALLEADINGTOGASTRICCONTRACTILITYUPTOARATEOFTHREETIMES PERMINUTE WHICHEVENTUALLYRESULTSINGASTRICEMPTYINGOFNUTRIENTS4HISRESPONSE ALSOISMODULATEDBYINTESTINALPEPTIDESANDTHEVAGUSNERVE 5P TO ONE THIRD OF PATIENTS WITH GASTROPARESIS DO NOT RESPOND ADEQUATELY TO STANDARD MEDICAL TREATMENT WHICH INCLUDES DIETARY MODIlCATIONS AND A TRIAL OF ANTIEMETICS PROKINETICS ANDOR ANTIDEPRESSANTS ;3]. Gastric electric stimulation '%3 HASANIMPORTANTROLEINMANAGINGTHISDIFlCULT TO TREATGROUPOFPATIENTS;6, 7]. (OWEVER ONETHIRDOFPATIENTSWILLBENONRESPONDERSTO'%3;2=3ERIOUSLOSSOF )##SONFULL THICKNESSGASTRICBIOPSIESHASBEENSHOWNTOBEAPREDICTOROFPOOR RESPONSETO'%3;8]. 2ECENTLY THEREHASBEENGROWINGINTERESTINSTUDYINGGASTRICWALLHISTOPATHOLOGY IN PATIENTS WITH GASTROPARESIS ;9= 5NDERSTANDING THE HISTOLOGIC ABNORMALITIES IN THESEPATIENTSNOTONLYHELPSRECOGNIZETHEPATHOPHYSIOLOGYOFTHEDISEASE BUTMAY ALSOAIDINIMPROVINGTREATMENTANDINDIVIDUALIZINGTHERAPY4HEADVENTOFINTERVENTIONALENDOSCOPICACCESSORIESANDTECHNIQUESHASMADEITPOSSIBLETOOBTAINFULL THICKNESS GASTRIC BIOPSIES USING A TRANSLUMENAL APPROACH ;10, 11= 4HIS ADVANCE ALLOWSALESSINVASIVEMEANSASCOMPAREDTOSURGICALBIOPSIES TOOBTAINDEEPGASTRIC BIOPSIES4HISCHAPTERDISCUSSESGASTRICHISTOPATHOLOGYINGASTROPARESIS ENDOSCOPIC TECHNIQUESTOOBTAINFULL THICKNESSGASTRICBIOPSIES ANDTHEPOTENTIALOFUSINGBIOPSIES TOGUIDEINDIVIDUALIZEDTHERAPY

Gastric Histopathology in Gastroparesis 3EVERALSTUDIESHAVEASSESSEDTHENEUROMUSCULARPATHOLOGYINGASTROPARESISUSING FULL THICKNESSANTRALBIOPSIES(ARBERSONETALOBTAINEDFULL THICKNESSANTRALBIOPSIES FROMPATIENTSWITHREFRACTORYGASTROPARESISWITHDIABETICGASTROPARESISAND WITHIDIOPATHICGASTROPARESIS UNDERGOINGSURGICALLAPAROTOMYWITHPLACEMENTOFA '%3;9=4HESEBIOPSYSAMPLESWERECOMPAREDTOCONTROLSAMPLESOBTAINEDFROM EIGHTPATIENTSUNDERGOINGGASTRICRESECTIONFOROTHERREASONS(EMATOXYLINANDEOSIN ( % AND IMMUNOHISTOCHEMICAL STAINING WERE USED TO DETECT THE PRESENCE OF INmAMMATION GANGLIONCELLS AND)##S,YMPHOCYTICINlLTRATIONWASFOUNDINTHE MYENTERIC PLEXUS OF NERVES AND GANGLIA IN OF THE PATIENTS OF WHOM WERE DIABETIC BUTNONEOFTHEEIGHTCONTROLS4HEREWASAREDUCTIONINTHENUMBER OFGANGLIAPERHIGHPOWERlELDHPF INGASTROPARETICPATIENTSCOMPAREDTOCONTROLS )NADDITION THEREWASAREDUCTIONINTHENUMBEROFTOTALNERVECELLBODIESINTHE PATIENTSWITHGASTROPARESISCOMPAREDTOTHECONTROLSÕVSÕ RESPECTIVELY p # KITSTAININGWASUSEDTOIDENTIFY)##S4HEREWERESIGNIlCANT REDUCTIONSINTHEC KITSTAINING)##SINTHEMYENTERICPLEXUSINBOTHDIABETICPATIENTS Õ AND IDIOPATHIC GASTROPARESIS PATIENTS Õ COMPARED TO CONTROLS Õ 4HUS HISTOLOGICABNORMALITIESINGASTROPARESISWEREHETEROGENEOUSAND INCLUDED MYENTERIC INmAMMATION DECREASED INNERVATION AND REDUCTION OF )##S

%NDOSCOPIC&ULL 4HICKNESS'ASTRIC"IOPSYFOR%VALUATIONOF0ATIENTS

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(ARBERSON AND COLLEAGUES PROPOSED THAT THE INmAMMATION OR LOSS OF INNERVATION MAYRESULTININJURYTOTHE)##S WITHSUBSEQUENTREDUCTIONINTHENUMBEROF)##S ANDLOSSOFPACEMAKERACTIVITY;9=&ULL THICKNESSGASTRICBIOPSIESARE THUS CRUCIAL FORTHEFULLUNDERSTANDINGOFPATHOPHYSIOLOGYOFGASTROPARESIS

Correlation Between Gastric Histopathology and Gastroparetic Symptoms 4HELOSSORABSENCEOF)##SINPATIENTSWITHGASTROPARESISAPPEARSTOCORRELATEWITH CLINICAL lNDINGS AND MYOELECTRIC ACTIVITY &ORSTER ET AL STUDIED GASTROPARETIC PATIENTSDIABETIC IDIOPATHIC ANDPOSTSURGICAL FORWHOMSTANDARDMEDICAL THERAPYHADFAILEDANDWHOHADBEENTREATEDWITH'%3;8=0ATIENTSUNDERWENTFULL THICKNESSANTRALGASTRICWALLBIOPSYATTHETIMEOFSURGERY4HEBIOPSYSAMPLESWERE STAINEDWITHC KITANDSCOREDFORTHEPRESENCEOF)##S"ASELINEELECTROGASTROGRAM %'' RECORDINGS WERE OBTAINED IN THE FASTING STATE AND AFTER A TEST MEAL 4OTAL SYMPTOMSCOREWASCALCULATEDATBASELINEANDATMONTHSAFTER'%3PLACEMENT &IVEPATIENTSHADALMOSTNO)##SANDWERECOMPAREDWITHNINEPATIENTSWITH TONORMALCELLNUMBERS"OTHGROUPSDIDRESPONDSYMPTOMATICALLYTOGASTRICELECTRICAL STIMULATION(OWEVER PATIENTSWITHSEVERELYDEPLETED)##SHADLESSREDUCTIONINTHEIR SYMPTOMSASCOMPAREDTOTHEOTHERGROUPVS RESPECTIVELY )NADDITION PATIENTSWITHSEVERELYDEPLETED)##SHADSIGNIlCANTLYMORETACHYGASTRIAANDHAD SIGNIlCANTLYGREATERTOTALSYMPTOMSCORESATBASELINEANDAFTERMONTHSOF'%34HE AUTHORSOFTHISSTUDYCONCLUDEDTHAT)##SWEREABSENTINUPTOATHIRDOFPATIENTSWITH DIABETICORIDIOPATHICGASTROPARESIS ANDTHEABSENCEOFTHESECELLSWASASSOCIATED WITHABNORMALITIESOFGASTRICSLOWWAVES WORSESYMPTOMS ANDLESSIMPROVEMENT WITH'%3 ,INETALSTUDIEDTHEASSOCIATIONSBETWEENTHESTATUSOF)##SAND%''PARAMETERS GASTRIC EMPTYING AND SYMPTOMS IN PATIENTS WITH REFRACTORY GASTROPARESIS WHO WERESCHEDULEDTOUNDERGOSURGICALPLACEMENTOF'%3DIABETIC IDIOPATHIC AND POSTSURGICAL ;12= !LL PATIENTS UNDERWENT %'' RECORDINGS ASSESSMENT OF TOTAL SYMPTOMSCORES ANDA HGASTRICEMPTYINGSTUDYPRIORTOSURGERY&ULL THICKNESS ANTRALBIOPSIESOBTAINEDDURINGSURGERYWERESTAINEDWITHC KITTOASSESSTHENUMBER OF)##S&IFTEENPATIENTS HADSEVERELYDEPLETEDORNO )##S)##GROUP ANDPATIENTSHADNORMALORADEQUATE )##S)##GROUP %''RECORDINGSINTHE )##nGROUPEXHIBITEDSIGNIlCANTLYLESSNORMALSLOWWAVESTHANINTHE)##GROUP BOTHINTHEFASTINGANDFEDSTATES4ACHYGASTRIAOCCURREDMOREOFTENINTHE)##n GROUPCOMPAREDTOTHE)##GROUPVS RESPECTIVELY p 4HEREWAS NO STATISTICAL DIFFERENCE IN GASTRIC EMPTYING AND SYMPTOM SEVERITY BETWEEN BOTH GROUPS(OWEVER SEVERELYDEPLETED)##SDIDRESULTINSIGNIlCANTLYPOORERRESPONSE TO'%37HILEOFPATIENTSINTHE)##GROUPHADtSYMPTOMIMPROVEMENT YEAR AFTER '%3 ONLY OF PATIENTS IN THE )## GROUP EXPERIENCED SIMILAR IMPROVEMENT

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Endoscopic Gastric Full-Thickness Biopsy Techniques .ATURALORIlCETRANSLUMENALENDOSCOPICSURGERY./4%3 HASGAINEDAGREATDEAL OFATTENTIONFROMGASTROENTEROLOGISTSANDSURGEONSALLOVERTHEWORLDSINCEITSINTRODUCTIONIN;13="REACHINGTHEGASTROINTESTINALBOUNDARYOPENEDTHEREALMFOR NEW ENDOSCOPIC TECHNIQUES INNOVATIVE ENDOSCOPIC INSTRUMENTS AND PIONEERING DIAGNOSTICANDTREATMENTMODALITIES.UMEROUSMETHODSHAVEBEENDESCRIBEDFOR TRANSLUMENALEG TRANSGASTRIC TRANSCOLONIC ANDTRANSVAGINAL ACCESSSITECLOSURE AFTER./4%3PROCEDURES;14–17=-OSTPUBLISHEDREPORTSDESCRIBETHEUSEOFCLIPS ENDOSCOPICSTAPLERS THREADEDTAGS ANDSUTURINGDEVICES/THERAVAILABLEMETHODS INCLUDE THE USE OF PLUGS OR ADHESIVES 4HE ADVENT OF THESE CLOSURE DEVICES AND METHODSHASMADEITPOSSIBLETOPERFORMENDOSCOPICFULL THICKNESSBIOPSIES 2AJANETALINAPRECLINICALPORCINESTUDYEVALUATEDDIFFERENTENDOSCOPICTECHNIQUES FOROBTAININGDEEPGASTRIC MUSCLE WALLBIOPSYSPECIMENSANDDETERMINEDIFMYENTERIC GANGLIAWEREPRESENTINTHETISSUESAMPLES;18=4HElVESTUDIEDTECHNIQUESWERE %53 GUIDED TRU CUT BIOPSY JUMBO BIOPSY OF THE POSTENDOSCOPIC MUCOSAL RESECTION%-2 SITE JUMBOBIOPSYOFTHEGASTROSTOMYMARGIN SEROSAL SIDE BIOPSYTHROUGHAGASTROSTOMYAND DOUBLE%-2RESECTION%53 GUIDEDTRU CUT BIOPSYWASPERFORMEDUSINGA GAUGE4RU CUTBIOPSYNEEDLE1UICK #ORE#OOK %NDOSCOPY 7INSTON3ALEM .# 4HESECONDTECHNIQUEENTAILEDPERFORMING%-2 FOLLOWEDBYBIOPSYOFTHEEXPOSEDMUSCLELAYERUSINGA*UMBOFORCEPS/LYMPUS !MERICA #ENTER6ALLEY 0! 4HETHIRDTECHNIQUEWASPERFORMEDUSINGAlSTULOTOME TOCREATEAGASTROSTOMYTHROUGHTHEANTERIORGASTRICWALL!GUIDEWIREWASPASSED THROUGHTHETRACKWHICHWASTHENDILATEDUSINGANMMBALLOON"IOPSYSPECIMENS WERETHENOBTAINEDFROMTHEMARGINOFTHEGASTROSTOMYBYUSINGAJUMBOFORCEPS 4HEFOURTHTECHNIQUEENTAILEDOBTAININGBIOPSIESFROMTHESEROSALSIDEOFAGASTROSTOMY 4HE GASTROSTOMY WAS CREATED AS DESCRIBED ABOVE )T WAS FURTHER DILATED TO MM USING A BALLOON FOLLOWED BY PASSAGE OF AN ENDOSCOPE INTO THE PERITONEAL CAVITY"IOPSIESWERETHENOBTAINEDUSINGAJUMBOFORCEPSINARETROmEXEDPOSITION 4HE DOUBLE %-2 TECHNIQUE INVOLVED A SECOND %-2 THAT WAS PERFORMED ON THE MUSCLELAYERTHATWASEXPOSEDBYAlRST%-24HEDOUBLE%-2TECHNIQUEWASTHE ONLYTECHNIQUETHATYIELDEDGASTRICTISSUEWHICHINCLUDEDTHEMUSCULARLAYERSAND MYENTERICGANGLIA4HISTECHNIQUEMAYBEPERFORMEDEASILYBYEXPERIENCEDENDOSCOPISTS(OWEVER ITSMAINSHORTCOMINGISTHECREATIONOFANIMMEDIATEPERFORATION AFTER THE SECOND %-2 !LTHOUGH MULTIPLE STUDIES HAVE DESCRIBED VARIOUS CLOSURE DEVICESMAINLYINTHESETTINGOF./4%3 ARELIABLEMEANSOFCLOSUREMUST BE DEVELOPED BEFORE THE WIDESPREAD USE OF THE DOUBLE %-2 TECHNIQUE TO OBTAIN DEEPGASTRIC MUSCLE WALLBIOPSIES 2AJANANDCOLLEAGUESPROPOSEDTHATTHEOPTIMALDEEPGASTRIC MUSCLE WALLBIOPSY PROCEDURE WOULD SEAL THE GASTRIC WALL DEFECT BEFORE TISSUE RESECTION ELIMINATING THERISKOFPERITONITIS;19=4HISGROUPSTUDIEDATECHNIQUETHEYCALLEDhNOHOLEv FULL THICKNESSBIOPSYOFTHESTOMACH;19=4HISTECHNIQUEINVOLVEDTHEPERFORMANCE OF TWO CAP ASSISTED %-2S !N %-2 CAP ASSISTED RESECTION WAS PERFORMED lRST 3UBSEQUENTLY ASMALLERCAPWASATTACHEDTOTHETIPOFTHEENDOSCOPEANDANENDOLOOP


383

WAS POSITIONED AROUND THE ENDOSCOPE OUTER SHEATH 4HE MUSCULAR LAYER WAS THEN SUCTIONEDINTOTHECAPANDTHEENDOLOOPWASOPENEDANDRELEASEDFROMTHECAPAND THENTIGHTENEDWHILESUCTIONWASSTILLBEINGAPPLIED4HISRESULTEDINFORMATIONOFA PSEUDOPOLYPOFTHEEXPOSEDGASTRICMUSCULARLAYER!SECONDENDOLOOPWASPLACED TO TIGHTEN THE BASE OF THE POLYP 4 TAG TISSUE ANCHORS /LYMPUS !MERICA WERE PLACED ON EITHER SIDE OF THE PSEUDOPOLYP 4HE PSEUDOPOLYP WAS SUBSEQUENTLY RESECTED WITH SNARE ELECTROCAUTERY 4HE 4 TAGS WERE THEN PULLED CLOSE TOGETHER TO DECREASETHERISKOFPERFORATION&IG31.1 &ULL THICKNESSBIOPSIESWEREOBTAINED FROMSIXPIGSWITHOUTANYIMMEDIATECOMPLICATIONS4WOANIMALSWEREKILLEDWITHIN DAYSOFTHEPROCEDUREBECAUSEOFPERITONITISRESULTINGFROMDELAYEDPERFORATIONS BOTHANIMALSWEREFOUNDTOHAVEDISPLACED4 TAGSANDENDOLOOPS )KEDAETALPROPOSEDTWOMETHODSOFFULL THICKNESSGASTRICBIOPSYENDOSCOPIC FULL THICKNESS RESECTION WITH SUTURED CLOSURE ;20= AND THE CIRCUMFERENTIAL CUTTING METHOD;21=4HElRSTMETHODENTAILEDPERFORMING%-2USINGALIGATINGDEVICE;20]. "EFORE RESECTION TWO OR THREE STITCHES WERE PLACED IN THE DEEP MUSCULAR LAYER nMMOUTOFTHERESECTIONAREA4HEPOLYPOIDLESION INCLUDINGTHEMUSCULARIS PROPRIA WASRESECTEDWITHCONVENTIONALHOTSNARETECHNIQUEBYPLACINGTHESNARE BELOWTHERUBBERBAND4HESTITCHESPLACEDAROUNDTHERESECTEDSITEWERETHENTIED

Fig. 31.1 (a #AP ASSISTEDENDOSCOPICMUCOSALRESECTIONPERFORMEDWITHOUTAPROTECTIVESUBMUCOSAL CUSHION b %XPOSED MUSCLE LAYER SUCTIONED INTO THE CAP WHILE THE ENDOLOOP WAS GENTLY RELEASED AND TIGHTENED AROUND THE PSEUDOPOLYP c) Second endoloop and prototype T-tag tissue ANCHORSAREPOSITIONEDAROUNDTHEBASEANDADJACENTTOTHEPSEUDOPOLYP RESPECTIVELYd) Pseudopolyp RESECTEDBYSNAREELECTROCAUTERYe 2ESECTIONSITEFURTHERCLOSEDBYTIGHTENINGOPPOSING PROTOTYPE 4 TAGTISSUEANCHORS

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Fig. 31.1 (continued)

2.#ADERETAL

385

Fig. 31.1 (continued)

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TOGETHER USING A PROTOTYPE THREAD LOCKING DEVICE &ULL THICKNESS RESECTIONS WERE PERFORMEDSUCCESSFULLYINEIGHTPIGSWITHOUTCOMPLICATIONS(EALINGOFTHESUTURE SITEWASEVIDENTATFOLLOW UPENDOSCOPY4HESECONDTECHNIQUEDESCRIBEDBY)KEDA AND COLLEAGUES WAS THE CIRCUMFERENTIAL CUTTING METHOD ;21= ! CIRCUMFERENTIAL EXCISIONWASMADEUSINGANEEDLEKNIFE ASPHINCTEROTOMEANDASNAREWITHFORCEPS &IRST TWOSTITCHESWEREPLACEDONTHESIDESOFTHETARGETEDAREA!NEEDLEKNIFEWAS THENUSEDTOPUNCTURETHESTOMACHANDAGUIDEWIREWASPASSEDINTOTHEPERITONEAL CAVITY ! PROTOTYPE SPHINCTEROTOME BIDIRECTIONAL CUTTER WAS PASSED THROUGH THE WALLINTOTHEPERITONEUM BOWEDANDPULLEDBACK4HETARGETAREAWASCUTHALFWAY AROUND THESPHINCTEROTOMEREMOVED ANDASNAREWASPASSEDTHROUGHONEWORKING CHANNELANDAFORCEPSPASSEDTHROUGHTHEOTHERWORKINGCHANNELOFADOUBLECHANNEL ENDOSCOPE4HEFORCEPSWASUSEDTOPULLTHETISSUEINTOTHESNARE4HEN THESNARE WASCLOSED ANDTHETISSUEWASFULLYCUTANDRETRIEVED4HESUTURESWERESUBSEQUENTLY USEDTOCLOSETHEOPENING4WELVEDOMESTICPIGSWEREUSEDINSURVIVALANDNONSURVIVALSTUDIES&ULL THICKNESSGASTRICBIOPSIESWERESUCCESSFULLYOBTAINEDINALLPIGS ANDALLDEFECTSWERESUCCESSFULLYCLOSEDWITHOUTCOMPLICATIONS %LMUNZERETALEVALUATEDTHEFEASIBILITYOFAGRASP AND SNAREENDOSCOPICFULL THICKNESS RESECTION TECHNIQUE USING A NOVEL TISSUE LIFTING DEVICE THAT PROVIDED A SECURE TISSUE ANCHORING AND MANIPULATION ;22= ! DOUBLE CHANNEL THERAPEUTIC ENDOSCOPEWASUSEDWITHAPROTOTYPETISSUE LIFTINGDEVICETHROUGHONECHANNELAND ASNARETHROUGHTHEOTHERCHANNEL4HELIFTINGDEVICEWASADVANCEDTHROUGHTHEOPEN SNAREANDWASANCHOREDTOTHEGASTRICMUCOSA)TWASTHENPULLEDBACKTOWARDTHE ENDOSCOPE EVERTING THE MUCOSA INTO THE GASTRIC LUMEN AND THE SNARE WAS CLOSED AROUND THE EVERTED TISSUE ! BLENDED ELECTROSURGICAL CURRENT WAS SUBSEQUENTLY APPLIEDRESULTINGINAFULL THICKNESSBIOPSY)NTOTAL OFRESECTIONSRESULTEDIN FULL THICKNESSGASTRICBIOPSIES4HISSTUDYDIDNOT HOWEVER ADDRESSCLOSUREOFTHE LUMENALDEFECTSTHATWERECAUSEDBYTHEBIOPSY 3UMIYAMAETALSTUDIEDANOVELTECHNIQUEOFSUBMUCOSALENDOSCOPYWITHMUCOSAL mAPSAFETYVALVETOOBTAINFULL THICKNESSGASTRIC MUSCLE WALLRESECTIONANDACCESSTHE PERITONEALCAVITY;23=!DUALCHANNELENDOSCOPEWITHAN%-2CAPWASUSED(IGH PRESSURE SHORT BURSTS OF CARBON DIOXIDE #/2 WERE INJECTED INTO THE SUBMUCOSAL LAYERTHROUGHANINJECTIONNEEDLETOCREATEASUBMUCOSALGASCUSHION!MUCOSAL INCISIONWASMADEATONEMARGINOFTHECUSHIONWITHABIPOLARNEEDLEKNIFE" +NIFE :EON -EDICAL )NC 4OKYO *APAN ! BILIARY RETRIEVAL BALLOON /LYMPUS !MERICA WAS LATER INSERTED INTO THE SUBMUCOSAL LAYER FROM THE MUCOSAL INCISION AND WAS INmATEDTODISSECTTHECONNECTIVETISSUETOCREATEASPACETOEASILYINSERTTHEENDOSCOPEWITHTHEATTACHED%-2CAP4HEMUSCULARLAYEROPPOSITETOTHEMUCOSALENTRY POINTWASRESECTEDBYCAP%-24HEMUCOSALINCISIONWASCLOSEDBYMUCOSALAPPOSITIONWITHCLIPSOR IFTHATFAILED BYlXATIONOFTHEMUCOSALmAPONTOTHEMUSCULAR LAYERUSINGTISSUEANCHORS/LYMPUS/PTICAL#O ,TD 4OKYO *APAN ORMEDICAL ACRYLATEGLUE)NDERMIL4YCO(EALTHCARE .ORWALK #ONN "YUSINGTHEABOVENOVEL TECHNIQUE THE AUTHORS SUCCESSFULLY PERFORMED SUBMUCOSAL SPACE ENDOSCOPY AND DEEP LAYERGASTRIC WALLRESECTIONINFOURPIGS4HEMUCOSAOVERLYINGTHEDISSECTED SUBMUCOSALSPACESERVEDASASAFEmAPVALVE PREVENTINGPERITONEALLEAKAGE


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-ORERECENTLY &RASERANDCOLLEAGUESDESCRIBEDASIMPLETECHNIQUETOOBTAINGASTRIC FULL THICKNESSBIOPSIESINTHREEDOGSVIAAPERCUTANEOUS ENDOSCOPICALLYASSISTED APPROACH;24=$OGSUNDERWENTGASTROSCOPYANDABDOMINALSKINAREASWEREMARKED BASED ON APPROPRIATE ANTRAL INDENTATION BY EXTERNAL lNGER PRESSURE ! GAUGE BIOPSYNEEDLEWASTHENINTRODUCEDTHROUGHAMMINCISIONINTHEABDOMINALSKIN ANDBIOPSIESWEREOBTAINEDFROMEACHDOG WITHNOSUBSEQUENTCLOSUREINTERVENTIONS ANDWITHOUTANYCOMPLICATIONS(ISTOLOGICANALYSISOFTHEBIOPSIESREVEALEDALLLAYERS OFTHESTOMACH INCLUDINGENTERICNERVOUSSYSTEMELEMENTS

Use of Endoscopic Biopsies to Guide Therapy !SDISCUSSEDABOVE THELOSSOF)##SCORRELATESWITHDYSRHYTHMIASOFTHESTOMACH ANDAPOORERRESPONSETO'%34HUS KNOWLEDGEOFTHEHISTOPATHOLOGYOFGASTRIC MUSCULATURE AND STATUS OF )##S MAY BE OF IMPORTANCE IN SELECTING APPROPRIATE PATIENTSFOR'%34HEREISGROWINGEVIDENCETHATNEUROMUSCULARHISTOLOGICABNORMALITIESINTHESTOMACHANDOTHERPARTSOFTHEDIGESTIVETRACT ARERESPONSIBLEFORTHE PATHOPHYSIOLOGICDISTURBANCESOFTHEGASTROINTESTINALTRACT;25–28=&ULL THICKNESS BIOPSIESWILLHELPDIAGNOSESPECIlCABNORMALITIESINTHEDIGESTIVETRACT WHICHHOPEFULLY WILL GUIDE DIAGNOSIS AND SPECIlC TARGETED THERAPIES /UR UNDERSTANDING OF SEVEREMOTORDISEASESOFTHEGASTROINTESTINALTRACT SUCHASREFRACTORYGASTROPARESIS AND INTESTINAL PSEUDOOBSTRUCTION IS LIMITED 4HIS IS PART OF THE REASONS WHY THE CURRENTTHERAPYOFTHESEDISEASESISSUBOPTIMAL/BTAININGFULL THICKNESSBIOPSIES FORPATHOLOGICDIAGNOSISWILLHOPEFULLYIMPROVEOURUNDERSTANDINGANDTHERAPYOF REFRACTORYGASTROINTESTINALMOTILITYDISORDERS INCLUDINGGASTROPARESIS

Conclusion '%3HASANIMPORTANTROLETOIMPROVEGASTROPARETICSYMPTOMSANDTHEQUALITYOFLIFE INPATIENTSWITHSEVEREGASTROPARESISREFRACTORYTOMEDICALTHERAPY0ATIENTSELECTION IS KEY TO OBTAINING A GOOD RESPONSE TO GASTRIC STIMULATION 0ATIENTS WITH SEVERELY DEPLETED )##S RESPOND POORLY TO GASTRIC STIMULATION &ULL THICKNESS BIOPSIES MAY HELPDIAGNOSESEVEREDEPLETIONOF)##SANDOROTHERSPECIlCGASTRICABNORMALITIES WHICHHOPEFULLYWILLGUIDEDIAGNOSISANDSPECIlCINDIVIDUALIZEDTHERAPIES2ECENT ADVANCESINENDOSCOPICTECHNIQUESHAVEALLOWEDDEVELOPMENTOFNOVELENDOSCOPIC METHODSTOOBTAINFULL THICKNESSGASTRICBIOPSIES-OSTOFTHESETECHNIQUESARESTILL EXPERIMENTALWITHRISKSOFCOMPLICATIONS INCLUDINGLEAKAGE-ORERECENTLY SUBMUCOSAL ENDOSCOPY WITH MUCOSAL mAP SAFETY VALVE TO OBTAIN FULL THICKNESS GASTRIC MUSCLE WALLRESECTIONANDACCESSTHEPERITONEALCAVITYWASDESCRIBED&URTHERSTUDIES ARENEEDEDTOEXPLORETHESAFETYANDEFlCACYOFTHISANDOTHERPROMISINGTECHNIQUES

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2.#ADERETAL

Conflicts of Interest: 2UKSHANA #ADER HAS NO CONmICTS OF INTEREST TO DISCLOSE -OUEN +HASHAB HASNOCONmICTSOFINTERESTTODISCLOSE!NTHONY+ALLOOISAFOUNDING-EMBER EQUITY(OLDERAND CONSULTANTFOR!POLLO%NDOSURGERY

References 0ARKMAN (0 (ASLER 7, &ISHER 23 !MERICAN 'ASTROENTEROLOGICAL !SSOCIATION TECHNICAL REVIEWONTHEDIAGNOSISANDTREATMENTOFGASTROPARESIS'ASTROENTEROLOGYn 2EDDYMASU3# 3AROSIEK) -C#ALLUM273EVEREGASTROPARESISMEDICALTHERAPYORGASTRIC ELECTRICALSTIMULATION#LIN'ASTROENTEROL(EPATOLn 3OYKAN) 3IVRI" 3AROSIEK) ETAL$EMOGRAPHY CLINICALCHARACTERISTICS PSYCHOLOGICALAND ABUSEPROlLES TREATMENT ANDLONG TERMFOLLOW UPOFPATIENTSWITHGASTROPARESIS$IG$IS3CI n 3ANDERS+- /RDOG4 +OH3$ ETAL$EVELOPMENTANDPLASTICITYOFINTERSTITIALCELLSOF#AJAL .EUROGASTROENTEROL-OTILn /RDOG4 7ARD3- 3ANDERS+-)NTERSTITIALCELLSOF#AJALGENERATEELECTRICALSLOWWAVESIN THEMURINESTOMACH*0HYSIOL0T n !BELL4 -C#ALLUM2 (OCKING- ETAL'ASTRICELECTRICALSTIMULATIONFORMEDICALLYREFRACTORY GASTROPARESIS'ASTROENTEROLOGYn ,IN : 3AROSIEK ) &ORSTER * ET AL 3YMPTOM RESPONSES LONG TERM OUTCOMES AND ADVERSE EVENTS BEYOND YEARS OF HIGH FREQUENCY GASTRIC ELECTRICAL STIMULATION FOR GASTROPARESIS .EUROGASTROENTEROL-OTILn &ORSTER* $AMJANOV) ,IN: ETAL!BSENCEOFTHEINTERSTITIALCELLSOF#AJALINPATIENTSWITH GASTROPARESISANDCORRELATIONWITHCLINICALlNDINGS*'ASTROINTEST3URGn (ARBERSON* 4HOMAS2- (ARBISON30 ETAL'ASTRICNEUROMUSCULARPATHOLOGYINGASTROPARESIS ANALYSISOFFULL THICKNESSANTRALBIOPSIES$IG$IS3CIn +AEHLER'& ,ANGNER# 3UCHAN+, ETAL%NDOSCOPICFULL THICKNESSRESECTIONOFTHESTOMACH ANEXPERIMENTALAPPROACH3URG%NDOSCn +AEHLER' 'ROBHOLZ2 ,ANGNER# ETAL!NEWTECHNIQUEOFENDOSCOPICFULL THICKNESSRESECTION USINGAmEXIBLESTAPLER%NDOSCOPYn ,IN: 3AROSIEK) &ORSTER* ETAL!SSOCIATIONOFTHESTATUSOFINTERSTITIALCELLSOF#AJALAND ELECTROGASTROGRAMPARAMETERS GASTRICEMPTYINGANDSYMPTOMSINPATIENTSWITHGASTROPARESIS .EUROGASTROENTEROL-OTILnE +ALLOO ! +ANTSEVOY 36 3INGH 6+ ET AL &LEXIBLE TRANSGASTRIC PERITONEOSCOPY A NOVEL APPROACHTODIAGNOSTICANDTHERAPEUTICINTERVENTIONSINTHEPERITONEALCAVITY'ASTROENTEROLOGY ! VON2ENTELN$ 6ASSILIOU-# 2OTHSTEIN2)2ANDOMIZEDCONTROLLEDTRIALCOMPARINGENDOSCOPIC CLIPSANDOVER THE SCOPECLIPSFORCLOSUREOFNATURALORIlCETRANSLUMINALENDOSCOPICSURGERY GASTROTOMIES%NDOSCOPYn VON2ENTELN$ 3CHMIDT! 6ASSILIOU-# ETAL.ATURALORIlCETRANSLUMINALENDOSCOPICSURGERY GASTROTOMYCLOSUREWITHANOVER THE ENDOSCOPECLIPARANDOMIZED CONTROLLEDPORCINESTUDY WITHVIDEOS 'ASTROINTEST%NDOSCn "HAT9- (EGDE3 +NAUS- ETAL4RANSLUMINALENDOSURGERYNOVELUSEOFENDOSCOPICTACKS FORTHECLOSUREOFACCESSSITESINNATURALORIlCETRANSLUMINALENDOSCOPICSURGERYWITHVIDEOS 'ASTROINTEST%NDOSCn $ESILETS$* 2OMANELLI*2 %ARLE$" ETAL,OOP ANCHORPURSE STRINGVERSUSENDOSCOPICCLIPS FORGASTRICCLOSUREANATURALORIlCETRANSLUMINALENDOSCOPICSURGERYCOMPARISONSTUDYUSING BURSTPRESSURES'ASTROINTEST%NDOSCn 2AJAN% 'OSTOUT#* ,URKEN-3 ETAL%VALUATIONOFENDOSCOPICAPPROACHESFORDEEPGASTRIC MUSCLE WALLBIOPSIESWHATWORKS'ASTROINTEST%NDOSCn


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2AJAN % 'OSTOUT #* ,URKEN -3 ET AL %NDOSCOPIC hNO HOLEv FULL THICKNESS BIOPSY OF THE STOMACHTODETECTMYENTERICGANGLIA'ASTROINTEST%NDOSCn )KEDA + &RITSCHER 2AVENS ! -OSSE #! ET AL %NDOSCOPIC FULL THICKNESS RESECTION WITH SUTUREDCLOSUREINAPORCINEMODEL'ASTROINTEST%NDOSCn )KEDA+ -OSSE#! 0ARK0/ ETAL%NDOSCOPICFULL THICKNESSRESECTIONCIRCUMFERENTIALCUTTING METHOD'ASTROINTEST%NDOSCn %LMUNZER"* 4RUNZO*! -ARKS*- ETAL%NDOSCOPICFULL THICKNESSRESECTIONOFGASTRICTUMORS USING A NOVEL GRASP AND SNARE TECHNIQUE FEASIBILITY IN EX VIVO AND IN VIVO PORCINE MODELS %NDOSCOPYn 3UMIYAMA + 'OSTOUT #* 2AJAN % ET AL 3UBMUCOSAL ENDOSCOPY WITH MUCOSAL mAP SAFETY VALVE'ASTROINTEST%NDOSCn &RASER( .ESHEV% 3TORR- ETAL!NOVELMETHODOFFULL THICKNESSGASTRICBIOPSYVIAAPERCUTANEOUS ENDOSCOPICALLYASSISTED TRANSENTERICAPPROACH'ASTROINTEST%NDOSCn %JSKJAER .4 "RADLEY *, "UXTON 4HOMAS -3 ET AL .OVEL SURGICAL TREATMENT AND GASTRIC PATHOLOGYINDIABETICGASTROPARESIS$IABET-EDn (E#, 3OFFER%% &ERRIS#$ ETAL,OSSOFINTERSTITIALCELLSOF#AJALANDINHIBITORYINNERVATION ININSULIN DEPENDENTDIABETES'ASTROENTEROLOGYn ,YFORD', (E#, 3OFFER% ETAL0AN COLONICDECREASEININTERSTITIALCELLSOF#AJALINPATIENTS WITHSLOWTRANSITCONSTIPATION'UTn *ACKSON-7 'ORDON40 7ATERMAN3!$ISRUPTIONOFINTESTINALMOTILITYBYACALCIUMCHANNEL STIMULATINGAUTOANTIBODYINTYPEDIABETES'ASTROENTEROLOGYn

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Chapter 32

A Brief History and Future Directions for Permanent, Temporary, and Endoscopic GES Sumanth Daram and Thomas L. Abell

Keywords 'ASTRICELECTRICALSTIMULATIONs'ASTROPARESISs'ASTRICELECTRICALACTIVITY s %NTERIC NERVOUS SYSTEM s !UTONOMIC NERVOUS SYSTEM s %LECTROGASTROGRAPHY s#AJALCELLS

Introduction 'ASTRICELECTRICALSTIMULATION'%3 CURRENTLYRELIESONDEVICESTHATAREENDOSCOPICALLY OR SURGICALLY IMPLANTED AND WHICH FUNCTION MUCH AS DO CARDIAC PACEMAKERS BY UTILIZINGEXOGENOUSELECTRICALSTIMULUSTOHELPREGULATETHEWAVEACTIVITYNECESSARYTO HEALTHIERGASTRICMOTILITY'%3CANMITIGATETHEGASTROINTESTINALSYMPTOMSASSOCIATED WITH DRUG REFRACTORY GASTROPARESIS PARTICULARLY NAUSEA AND VOMITING AND SO CAN IMPROVESIGNIlCANTLYTHEQUALITYOFLIFEFORPATIENTSWITHTHISDISORDER4HEPRESENT CHAPTER BEGINS WITH A BRIEF HISTORY OF THE THERAPYS DEVELOPMENT AND MOVES TO A DISCUSSION OF TOPICS NOW UNDER INVESTIGATION IN GASTRIC MOTILITY LABORATORIES worldwide.

Background )N ELECTRICAL STIMULATION OF THE STOMACH WAS lRST REPORTED AS A THERAPY FOR POSTOPERATIVEILEUS;1=4HEPOSSIBILITYOFUSINGELECTRICALENERGYTOTREATDISORDERED GASTROINTESTINALFUNCTIONHADTANTALIZEDRESEARCHERSFORDECADES BUTTECHNICALOBSTACLES

4,!BELL*) $IVISIONOF$IGESTIVE$ISEASES 5NIVERSITYOF-ISSISSIPPI-EDICAL#ENTER .ORTH3TATE3TREET *ACKSON -) 53! E MAILTABELL UMCEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_32, © Springer Science+Business Media, LLC 2012

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DELAYEDANYREALPROGRESSUNTILTHES%ARLYWORKFOCUSEDONSURGICALAPPROACHES THAT MEASURED THE GUT ELECTRICAL ACTIVITY AS WELL AS THE APPLICATION OF ELECTRICAL CURRENTTOTHEGASTROINTESTINALTRACT#ONCURRENTWITHTHEPOSTOPERATIVEILEUSREPORT THElRSTCOMMERCIALLYAVAILABLEGASTRICELECTRICALSTIMULATOR THEh0ERI 3TART vBEGAN TOBEMARKETEDBYMedtronic#LINICALLYTESTEDBYAYOUNG4EXASSURGEON -ICHAEL DE"AKEY THIS DEVICE EVENTUALLY FELL OUT OF FAVOR LARGELY OWING TO AN ABSENCE OF CLEAREVIDENCETHATITCOULDIMPROVEPOSTOPERATIVEILEUS;2]. $ESPITETHESETBACK RESEARCHERSINTERESTEDIN'%3BEGANTOWORKOVERTHEFOLLOWING DECADEONWHATWOULDEVENTUALLYBECOMEKNOWNAShPACINGvOFTHEGUT-OSTOF THESEINVESTIGATORSTRACEDTHEIRORIGINTOONEORTWOCENTERS ANDPARTICULARLYTOTHE -AYOGROUP LEDINTHESBYSURGEON+EITH+ELLY4HESERESEARCHERSOWEDMUCH OFTHEIRINSPIRATIONTOSUCHPHYSIOLOGISTSAS#HARLIE#ODE WHOSECINERADIOGRAPHYOF THEALIMENTARYTRACTSIGNIlCANTLYINmUENCEDTHEDIRECTIONOFSUBSEQUENTRESEARCH #ODESTIMEATTHE-AYO#LINICOVERLAPPEDWITHTHATOFGASTROENTEROLOGIST7ALTER !LVAREZ WHO PRIORTOARRIVINGATTHE-AYOINTHELATES DESCRIBEDTHEELECTROGASTROGRAM%'' !LVAREZWORKEDAT(ARVARDINTHEEARLYTWENTIETHCENTURYWITH NOTED PHYSIOLOGIST AND FATHER OF GASTROINTESTINAL MOTILITY STUDIES 7ALTER #ANNON WHOSEEXPERIMENTALRADIOGRAPHICSTUDIES PERFORMEDALONGSIDEHISWORKINHOMEOSTASISANDTHEPOPULARIZEDhlGHTORmIGHTvRESPONSE PROVIDEDAFOUNDATIONFORTHE TWENTIETHCENTURYGASTROINTESTINALMOTILITYSTUDIES;3–5]. "Y THE S '%3 INVESTIGATORS SOUGHT TO INmUENCE GUT ELECTRICAL ACTIVITY DIRECTLY WITHTHEAIMOFIMPROVINGPHYSIOLOGICALFUNCTION#USTOMDEVICESPERMITTING THEDELIVERYOFENERGYATAWIDEVARIETYOFSETTINGSWERECONSTRUCTED ANDRELATIVELY HIGH ENERGY STIMULATION APPLIED TO THE SMALL BOWEL SO AS TO EFFECT FOR EXAMPLE CHANGESINABSORPTION!CANINEMODEL WITHIMPLANTEDELECTRODESANDSTRAINGAUGES WASCOMMONLYEMPLOYEDFORTHESESTUDIES

Experimental Studies "Y ANANIMALLABHADBEENREADIEDATTHE5NIVERSITYOF4ENNESSEE -EMPHIS TOSTUDYTHECAPACITYOFELECTRICALSTIMULATIONTOhCORRECTvDISORDEREDGASTROINTESTINAL FUNCTION ASMEASUREDBYELECTROGASTROGRAPHY%'' -EMPHISHADBECOMETHESITETO WHICH n NEW PATIENTS WITH SEVERE DISORDERS OF NAUSEA AND VOMITING WERE REFERREDEACHYEAR4HENEEDFOREFFECTIVETREATMENTSFORTHEIRSYMPTOMSWASTHE IMPETUSFORmOURISHINGRESEARCH5SINGACANINEMODELANDACUSTOMDEVICEFROM Empi AMULTIYEARSTUDYBY&AMILONI !BELL AND6OELLERWASUNDERTAKENTOEXAMINE VARIEDSTIMULATIONPARAMETERSANDTHEIREFFECTSONGASTROINTESTINALMOTILITY ESPECIALLY GASTRICMOTILITY4HEPRINCIPALlNDINGWASTHATTHECOMBINATIONOFMUCHHIGHERTHAN PHYSIOLOGICFREQUENCIESWITHVERYLOWENERGIESPRODUCEDTHEBESTMOTILITYRESPONSE 4HISAPPROACHWOULDBECOMETHEBASISFOR'%3!SMedtronic’s%NTERRA®HASBEEN THE ONLY COMMERCIALLY AVAILABLE DEVICE FOR '%3 TO DATE THE TECHNIQUE IS ALSO REFERREDTOAS%NTERRA®THERAPY

!"RIEF(ISTORYAND&UTURE$IRECTIONSFOR0ERMANENTx

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/VER THE SAME PERIOD OTHER INVESTIGATORS IN THE 53! NOTABLY IN &LORIDA AND 6IRGINIA WERE USING MUCH HIGHER ENERGIES AND CLOSER TO NORMAL FREQUENCIES FOR TRIALS ADDRESSING SIMILAR INDICATIONS SUCH AS THE NAUSEA AND VOMITING ASSOCIATED WITHDISORDEREDGASTRICEMPTYING3TUDIESFROMALLTHESEGROUPSWOULDBEPUBLISHED THROUGHOUTTHES

Investigational Work )NTHES THEGROUPAT-EMPHISDEMONSTRATEDTHEEFlCACYOFHIGH FREQUENCY '%3OVERLOW FREQUENCYPHYSIOLOGIC STIMULATIONINTHECANINESTOMACH;6]. Based ONASUCCESSFUL BUTEXPERIMENTAL USEOFTHISHIGH FREQUENCYLOW ENERGYAPPROACH INAPATIENTIN;7= APROPOSALFORANINVESTIGATIONALDEVICEEXEMPTION)$% WASSUBMITTEDTOTHE&$!)TSAPPROVALPERMITTEDAFORMAL53TRIALOFTHENEWPROTOCOL ANDTHETHEN AVAILABLE)TREL))DEVICEFROMMedtronic!TTHESAMETIME Medtronic ARRANGEDFORANUMBEROFSITESOUTSIDETHE53!TOCONDUCTASTUDYTHATEMPLOYEDAN ESSENTIALLY IDENTICAL PROTOCOL BUT WITHOUT STANDARDIZING SUCH MEASURES AS GASTRIC EMPTYING 4HIS INTERNATIONAL INVESTIGATION BECAME THE '%-3 STUDY WHICH WAS EVENTUALLYPUBLISHEDINDigestion;8]. 4HE'%-3STUDYMADEUSEOFTEMPORARYSTIMULATION WITHPLACEMENTOFTEMPORARYDEVICESEITHERVIAENDOSCOPYORLAPAROSCOPY PRIORTOPERMANENTDEVICEIMPLANTATION (OWEVER AS MORE THAN OF THE PATIENTS WHO PARTICIPATED HAD AN IMMEDIATE ANTI EMETICRESPONSETOTHETECHNIQUE ANOTHERSTUDYWASDESIGNEDIN WHICHPERMANENTSTIMULATORSWEREIMPLANTEDDIRECTLY 4HISNEWSTUDY ARANDOMIZED DOUBLE MASKEDPROTOCOL LIMITEDTOPATIENTSWITH DELAYEDGASTRICEMPTYING WASPERFORMEDATANUMBEROFSITESONTHREECONTINENTS In order to determine and standardize appropriate gastric emptying parameters, an INITIAL STUDY ON NORMAL VOLUNTEERS WAS CONDUCTED 4HIS PRELIMINARY INVESTIGATION WASLATERPUBLISHEDASTHELOW FATMEAL GASTRIC EMPTYINGPROTOCOLTHATISNOWUSED BYMOSTGASTROENTEROLOGISTS4HESTUDYWASCALLED7!6%33 ANDWOULDEVENTUALLY BEPUBLISHEDINGastroenterology;9=)NTHESPRINGOF BASEDONTHERESULTSOF THE'%-3AND7!6%33STUDIES THE53&$!APPROVEDTHEUSEOF%NTERRA® under THE HUMANITARIAN USE DEVICE DESIGNATION FOR PATIENTS WITH MEDICATION REFRACTORY GASTROPARESISOFTHEDIABETICANDIDIOPATHICTYPES;10].

Clinical Investigation and Application /VERTHEPASTYEARS SEVERALTHOUSANDPATIENTSWORLDWIDEHAVEBEENIMPLANTED WITH%NTERRA®4HEMAJORITYOFTHESEPATIENTSHAVEBEENPROVIDEDWITHTHISDEVICEIN THE 53! WHERE IT STILL HAS ($% DESIGNATION DESPITE ATTEMPTS TO OBTAIN THE FULL APPROVALTHATWOULDPERMITWIDESPREADUSE!RECENTREVIEWOFPUBLISHEDTRIALS

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FOUNDTHATALLOFTHESESTUDIESWEREPOSITIVEINATLEASTONEPARAMETERHOWEVER MOST WEREOPENLABELTRIALS4HUS MUCHRECENTFOCUSHASBEENONRANDOMIZEDBLINDED OR MASKED TRIALS REGISTERED WITH THE 53 CLINICALTRIALSGOV SITE WHICH CAN BE CLASSIlEDASEVIDENCE BASEDMEDICINE%"- 3UCH A RECENT CLINICAL TRIAL INVOLVING PERMANENT '%3 THE Enterra® Therapy Clinical Study HASBEENCOMPLETEDANDUPLOADEDONTHECLINICALTRIALSGOV7EBSITE !MULTICENTER INTERVENTIONAL RANDOMIZED CROSSOVERSAFETYEFlCACYSTUDY THISTRIAL INCLUDEDSUBJECTSWITHEITHERDIABETICORIDIOPATHICGASTROPARESIS0ARTICIPANTSWERE SURGICALLYIMPLANTEDWITHAN%NTERRA®DEVICE ANDAFTERWARDSUBJECTEDTOANINITIAL MONTHPERIODWITHTHEDEVICEh/.v3UBSEQUENTLY PARTICIPANTSWERECROSSED OVER TOA MONTHPERIODWITHTHEDEVICEh/&&v4HESTUDYDIDNOTSHOWASIGNIlCANT DIFFERENCE IN THE PRIMARY OUTCOME MEASURE PERCENT REDUCTION IN FREQUENCY OF WEEKLY VOMITING EPISODES WITH THE DEVICE /. AS COMPARED TO /&& (OWEVER A STATISTICALLY SIGNIlCANT IMPROVEMENT IN THE PERCENT REDUCTION FOR FREQUENCY OF WEEKLYVOMITINGEPISODESATMONTHSWASNOTEDINBOTHDIABETICANDIDIOPATHIC GASTROPARESIS PATIENTS ;11= 4HE APPARENT LACK OF BENElT IN TERMS OF THE PRIMARY OUTCOMEMEASUREMAYWELLHAVEBEENDUETOTHECARRYOVEREFFECTSFROMTHEINITIAL PERIODOFSTIMULATIONDURINGTHECOMMON/.PHASEBEFORERANDOMIZATION

Future Applications of GES !MONGTHEMANYQUESTIONSABOUT'%3THATAWAITADElNITIVEANSWER ATLEASTTHREE AREFOREMOST4HElRSTREQUIRESADETERMINATIONOFHOWBESTTODELIVERASPECIlCTYPE OFSTIMULUS4HESECONDINVOLVESIDENTIlCATIONOFOPTIMALSTIMULUSDELIVERYSITES 4HETHIRDCONCERNSTHESTIMULATIONPARAMETERSTOBEUSED7EADDRESSTHESEPRIMARY POINTS ANDTHENDISCUSSSUBSEQUENT RELATEDQUESTIONS

What Is the Best Way to Deliver Electrical Stimuli? 'ASTROINTESTINALELECTRICALSTIMULATIONCANBEDELIVEREDINONEOFTHEFOLLOWINGWAYS Continuous stimulation.!CONTINUOUSDELIVERYOFELECTRICALSTIMULATIONWHILETHEORETICALLYATTRACTIVE REQUIRESTHEDELIVERYOFAHIGHERGREATERVOLUMEOFENERGY POSING PRACTICAL TECHNOLOGICALCHALLENGES Cyclical Stimulation.%LECTRICALSTIMULATIONISDELIVEREDINCYCLES4HISMETHODIS CURRENTLYUSEDFOR'%3 Intermittent stimulation.%LECTRICALSTIMULATIONCOULDBECONTROLLEDBYTHEPATIENTOR A FEEDBACK MECHANISM THAT SENSES FOOD !LTHOUGH BOTH APPROACHES ARE CURRENTLY UNDER EXPLORATION AND DEVELOPMENT NEITHER HAS YET BEEN USED IN ANY FORMAL PUBLISHED&$!TRIAL


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Fig. 32.1 (a %NDOSCOPICVIEWOFTEMPORARYGASTRICSTIMULATORELECTRODEINSERTEDTHROUGHENDOSCOPE and screwed into gastric mucosa. (b %NDOSCOPICVIEWSHOWINGANCHORINGOFELECTRODEWITHCLIPS

Where Should Stimulation Be Delivered? '%3COULDBEDELIVEREDTOONEOFTHEFOLLOWINGSITES Mucosa.4HEGASTRICMUCOSAPROVIDESTHEMOSTEASILYACCESSIBLESITEFORELECTRODE PLACEMENT BUTITHASSOFARONLYBEENUSEDFORTEMPORARYSTIMULATION%LECTRODES CAN BE SITUATED EITHER THROUGH A PERCUTANEOUS ENTEROGASTROSTOMY 0%' SITE OR ENDOSCOPICALLY &IG32.1;12, 13].

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Serosa. !T PRESENT MOST '%3 IS DELIVERED VIA THE GASTRIC SEROSA WITH ELECTRODES PLACEDBYLAPARATOMYORLAPAROSCOPY Cutis.4RUEEXTERNALSTIMULATION AKINTOEXTERNALCARDIACSTIMULATION ISANATTRACTIVE IDEA#UTANEOUSSTIMULATIONHASBEENDEMONSTRATEDINANIMALS BUTNOTINHUMAN SUBJECTS

What Stimulation Parameters Should Be Used? 4HISQUESTIONISCRUCIALTOTHEAPPLICATIONOFELECTRICALSTIMULATIONINTHE')TRACT Low Energy.%NTERRA®ISDESIGNEDTODELIVERLOWENERGYWHILEUTILIZINGHIGHERTHAN PHYSIOLOGICFREQUENCIES High Energy.4HIS'%3APPROACHMAKESUSEOFNEAR PHYSIOLOGICFREQUENCIES)THAS BEENADVOCATEDFORUSEINATLEASTTWOTRIALS BUTHASYETTOUNDERGOFORMAL&$! APPROVAL

How Many Electrodes Are Needed to Deliver the Electrical Stimulus? One set of electrodes.#URRENTLY '%3MAKESUSEOFASINGLESETOFELECTRODES Multiple electrodes.4HEUSEOFMULTIPLEELECTRODESHASBEENTESTEDINANIMALMODELS BUTNOTINHUMANS Combination of multiple electrodes. 3EQUENTIAL ANDOR INTERMITTENT STIMULATION MAKESUSEOFACOMBINATIONOFELECTRODES-ULTICHANNELPACINGREQUIRESAFRACTION OFTHEENERGYOFSINGLE ELECTRODEPACING ANDHASIMPROVEDGASTRICEMPTYINGAND SYMPTOMSINEXPERIMENTALMODELSOFGASTROPARESIS ASWELLASINPATIENTSWITHDIABETIC GASTROPARESIS;14, 15].

How Can We Predict Which Stimulation Parameters May Work Best in an Individual Patient? ,OW ENERGY ELECTRICAL STIMULATION HAS BEEN SHOWN TO PRODUCE THE BEST CLINICAL RESULTSHOWEVER OUREXPERIENCEHASSUGGESTEDTHATASIGNIlCANTNUMBEROFPATIENTS BENElTBYHAVINGTHEIRSTIMULATIONPARAMETERSCHANGEDTOHIGHERENERGIESOVERA PERIODOFTIME4HISCLINICALEXPERIENCELEDUSTOSUGGESTANENERGYALGORITHMSEE &IG 32.2 FOR USE WITH PATIENTS WHO EITHER DID NOT IMPROVE OR WHO EXPERIENCED RECURRINGSYMPTOMSATLOW ENERGYSTIMULATIONSETTINGS;16]. It also led us to examine EFFECTSOFANINTRA OPERATIVEVARIATIONOFENERGYSETTINGS BASEDON%''PARAMETERS "ELOWWEDISCUSSTHEUSEOF%''DATAINPREDICTINGFAVORABLEOUTCOMESWITH'%3


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Start

Increased or No Sustained Decrease in SX

Increase current 5--->7.5--->10 mA

Improvement

No Improvement Increase “On” Time, Decrease “Off” Time 0.1/5--->1/4--->2/3

Improvement

No Improvement Increase Frequency 14--->28--->55 Hz

Improvement

No Improvement

Reasses Patient & Diagnosis

No Improvement

Consider Temp GES

Improvement

Re-Implant

Back to Steps 1&2

Fig. 32.2 !LGORITHM FOR '%3 ASSOCIATED SYMPTOM IMPROVEMENT 38SYMPTOMS M!MILLI!MPS (:(ERTZ '%3GASTRICELECTRICALSTIMULATION!DAPTEDFROM!BIDI. 3TARKEBAUM7, !BELL4,!NENERGYALGORITHMIMPROVESSYMPTOMSINSOMEPATIENTSWITHGASTROPARESISANDTREATED WITH GASTRIC ELECTRICAL STIMULATION .EUROGASTROENTEROL -OTIL n ! TYPOGRAPHICAL ERRORINTHEORIGINALALGORITHMHASBEENCORRECTEDINTHISADAPTATION

%ARLYRESULTSFROMANONGOINGSTUDYINOURGROUPAPPEARTOSUGGESTTHATINDIVIDUAL PATIENTSVARYSIGNIlCANTLYINTHESTIMULATIONPARAMETERSREQUIREDTOGENERATEOPTIMAL %''RESULTS7EARESTUDYINGTHEEFFECTSOFSUCHVARIEDSTIMULATIONPARAMETERSON CLINICALOUTCOMES;17].

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Can Less Invasive Methods Be Used to Predict Response to GES in an Individual Patient? 4HEPLACEMENTOFAPERMANENT'%3DEVICEINVOLVESCONSIDERABLECOSTANDPATIENT RISKS)TISTHEREFOREIMPORTANTTODElNEPREOPERATIVECHARACTERISTICSTHATMAYPREDICT OUTCOMESFORINDIVIDUALPATIENTS WHETHERTHESEPREDICTORSARERELATEDTOSYMPTOMS ORDERIVEDTHROUGHADDITIONALTESTING Symptom related.4HEDECISIONTOIMPLANTA'%3DEVICEMAYBEBASEDSOLELYON PATIENTSYMPTOMS!MONGTHEUSUALSYMPTOMSOFGASTROPARESISNAUSEA VOMITING EARLY SATIETY BLOATING AND ABDOMINAL PAIN PAIN HAS BEEN SHOWN TO BE THE LEAST LIKELY TO RESPOND TO '%3 0ATIENTS WHOSE PREDOMINANT SYMPTOM IS VOMITING ARE MORELIKELYTOBENElTFROM'%3;18]. GET based.2ESULTSRECENTLYOBTAINEDBYINVESTIGATORSIN&RANCEINDICATETHATPATIENTS WITH INITIAL DELAYS IN GASTRIC EMPTYING PARAMETERS OF PATIENTS DISPLAYED IMPROVEMENTS COMPARABLE TO THOSE SEEN IN PATIENTS WITH NORMAL '%4 4HESE RESEARCHERSCONCLUDEDTHATINDICATIONSFOR'%3SHOULDBEDETERMINEDCLINICALLY AND THATTHETECHNIQUEMAYBEUSEFULFORPATIENTSWITHNORMALGASTRICEMPTYING;19]. EGG based.%''ABNORMALITIESAREUSEDASABASISFORIMPLANTATIONOFTHE'%3 DEVICE;20]. Full thickness gastric biopsy based. !BNORMALITIES AT PATHOLOGIC EXAMINATION OF BIOPSYSPECIMENSMAYHELPDETERMINETHEAPPROPRIATENESSOF'%3DEVICEPLACEMENT 0ATIENTSWITHDECREASEDCOUNTSFORINTERSTITIALCELLSOF#AJALINFULLTHICKNESSANTRAL BIOPSIESARELESSLIKELYTORESPONDTO'%3;21]. ANS testing based.4HEDECISIONTOIMPLANTA'%3DEVICEISMADEONTHEBASISOF ABNORMALITIESSEENWITH!.3TESTING Other neurologic testing based.4HEDECISIONTOTRYA'%3DEVICEMAYBEBASEDON THEPRESENCEOFAKNOWNNEUROLOGICABNORMALITY SUCHASABNORMALlNDINGSONFULL THICKNESSBIOPSIES

Can We Determine Optimal Stimulation Parameters for Individual Patients? Mucosal EGG.7EHAVEPREVIOUSLYDEMONSTRATEDTHATALOW FREQUENCYAMPLITUDE RATIOAFTERTEMPORARY'%3CORRELATESWITHGREATERLIKELIHOODFORSYMPTOMIMPROVEMENTAFTERPERMANENT'%3DEVICEPLACEMENT;20]. Other parameters, in combination. !UTONOMIC AND ENTERIC PARAMETERS MAY BE EMPLOYEDTOPREDICTTHETYPEOF'%3NEEDED Intra-operative testing.!SDISCUSSEDEARLIER LOW ENERGYELECTRICALSTIMULATIONTYPICALLY RESULTS IN THE MOST FAVORABLE '%3 CLINICAL OUTCOME (OWEVER A SIGNIlCANT


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Fig. 32.3 &ROMLEFTTORIGHTa -ULTI ELECTRODEARRAYSAREPLACEDONTHEGASTRICSEROSAINTHEPOSITION INDICATEDb !CTIVATIONMAPOFATYPICALNORMALWAVE%ACHPOINTREPRESENTSANELECTRODE AND EACHCOLORBANDISOCHRONALBAND SHOWSTHEAREAOFSLOWWAVEPROPAGATIONPERSOFTIME!CTIVITY ISSHOWNTOARISENEARTHEGREATERCURVATUREANDTOPROPAGATEINITIALLYINALLDIRECTIONS4HEARROWS REPRESENTTHEVELOCITYMAGNITUDE WITHAHIGHERVELOCITYSHOWNINASSOCIATIONWITHTHEPACEMAKER origin. (c %XAMPLEHUMANGASTRICELECTROGRAMSCORRESPONDINGTOTHECOLUMNOFELECTRODESSECOND FROMRIGHTINMAPb SHOWINGSLOWWAVEACTIVITYSPREADINGPROXIMALLYANDDISTALLYFROMTHE pacemaker site

NUMBEROFPATIENTSREQUIREMODULATIONOFTHEIRENERGYSETTINGSTOHIGHERENERGIES EITHER SHORTLY AFTER '%3 PLACEMENT OR OVER A PERIOD OF TIME 7E HAVE THEREFORE ENDEAVOREDTOSTUDYTHEEFFECTSOFVARYINGENERGYSETTINGSON%''PARAMETERSINTRA OPERATIVELY AT THE TIME OF '%3 DEVICE PLACEMENT 4O LEARN WHETHER OR NOT THESE STUDY RESULTS TRANSLATE INTO MEANINGFUL CLINICAL OUTCOMES IS THE OBJECTIVE OF OUR CURRENTINVESTIGATIONS;17]. High-resolution Mapping. 3LOW WAVES COORDINATE GASTRIC MOTILITY THUS ABNORMAL SLOWWAVEACTIVITYMAYCONTRIBUTETOMOTILITYDISORDERS/'RADYETALHAVERECENTLY USED HIGH RESOLUTION MAPPING TO PROVIDE AN ACCURATE DEMONSTRATION OF HUMAN GASTRICSLOWWAVEACTIVITY4HEGASTRICPACEMAKERREGIONISASSOCIATEDWITHHIGH AMPLITUDE HIGH VELOCITYACTIVITY ANDMULTIPLEWAVEFRONTSPROPAGATESIMULTANEOUSLY 4HISINFORMATIONSERVESASABASELINEFORHIGH RESOLUTIONMAPPINGSTUDIESINGASTROPARESISSEE&IG32.3 )NTHEFUTURE PATIENT SPECIlCRESULTSFROMSUCHSTUDIESMAY HELPTOAIDOPTIMIZATIONOFSTIMULATIONPARAMETERS;22, 23].

How Is the Currently Available, Permanent GES Device (Enterra®) Implanted? $URINGSURGERYTOINITIATE'%3 TWOELECTRODESAREIMPLANTEDINTHESEROMUSCULARLAYER OF THE WALL OF THE STOMACH AT THE GASTRIC ANTRUMBODY JUNCTION 0REVIOUS ANIMAL AND HUMAN STUDIES PROVIDE EVIDENCE FOR PLACING THE ELECTRODES AT CM PROXIMAL TO THE PYLORUSONTHEGREATERCURVATUREOFTHESTOMACH4HELEADSARETYPICALLYPLACED CM APARTANDPARALLEL%LECTRODESMUSTNOTPENETRATETHEGASTRICMUCOSAUPONlNALPLACEMENT THEIR PROPER PLACEMENT SHOULD BE CONlRMED BY INTRA OPERATIVE ENDOSCOPY 0LACEMENT CAN BE ACHIEVED EITHER LAPARASCOPICALLY OR THROUGH LAPARATOMY 'IVEN THE REQUIREMENTFORCORRECTPLACEMENTOFLEADS LAPAROSCOPYCANBETECHNICALLYCHALLENGING

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New Technological Developments in GES Cutaneous placement of temporary GES electrodes (Percutaneous electrode system). 2ESEARCHERSFROM3WEDENHAVEDEVELOPEDANOVELMETHODFORPERMANENTIMPLANTATIONOFELECTRODESWITHOUTTHENEEDFORLAPARATOMYORLAPAROSCOPY!PLASTICCANNULA WITHANINTERNALNEEDLEISPERCUTANEOUSLYINTRODUCEDTHROUGHTHEABDOMINALWALL GASTRICSEROSA ANDMUSCULARISTOTHESUB MUCOSALPORTIONOFTHESTOMACH!SIMILAR APPROACHHASBEENPROPOSEDBYOTHERGROUPS;13=#AREISTAKENTOAVOIDLUMINAL PERFORATION!FTERUSINGASALINEINJECTIONTOCREATEAmUIDlLLEDSPACE ASELF ANCHORING ELECTRODEISLEFTINTHEANTRALSUB MUCOSALSPACE;24, 25]. Mucosal placement of temporary GES electrodes. 0LACEMENT OF TEMPORARY '%3 ELECTRODESENDOSCOPICALLY%.$/STIM ORTHROUGH0%'0%'STIM HASBEENSHOWN TOBEFEASIBLEANDEFFECTIVE;12, 26]. Wireless EGG.3IGNALACQUISITIONCANNOWBEACHIEVEDBYMEANSOFANAMBULATORY SYSTEMCARRIEDBYTHEPATIENT TOWHOMITISCONNECTEDTHROUGHSKINELECTRODES4HE ACQUIRED SIGNAL IS TRANSMITTED VIA "LUETOOTH TO A MOBILE PHONE WHERE DATA ARE STOREDINTHEMEMORYUNTILTRANSFERVIATHE'3-NETWORKTOAREMOTEPROCESSING ANDDIAGNOSTICUNIT;27]. Robotic Placement of permanent GES Electrodes. 'OULD ET AL HAVE RECENTLY DEMONSTRATEDTHATROBOTICPLACEMENTOFTHE'%3ELECTRODESISSAFEANDEFFECTIVE #OMPAREDWITHSTANDARDLAPAROSCOPICTECHNIQUES THEACCURATEINSERTIONANDANCHORINGOFLEADSHASBEENSHOWNTOBEMOREEFlCIENTLYANDCOMFORTABLYACCOMPLISHED WITHROBOTICTECHNIQUES4ODETERMINEWHETHERORNOTROBOTIC'%3ELECTRODEPLACEMENTWILLRESULTINSIGNIlCANTCLINICALADVANTAGESFORPATIENTSWILLREQUIRELONG TERM FOLLOW UP;28]. Miniature Wireless GES Devices. $EB ET AL HAVE DEVELOPED TWO NEW MINIATURE GASTRICSTIMULATORS/NEHASAWIRELESSLYRECHARGEABLEBATTERYTHEOTHERISWIRELESSLY POWERED ANDTHUSREQUIRESNOBATTERY0RELIMINARYTESTSOFTHESEMODELSHAVEBEEN PERFORMEDINAPORCINEMODEL)FEXPERIMENTALRESULTSCANBEDUPLICATEDINHUMANS ENDOSCOPICIMPLANTATIONOFPERMANENT'%3DEVICESMAYBECOMEFEASIBLE;29].

What Is the Future for GES? )NSPITEOFTHETECHNOLOGICALADVANCESFOR'%3THATHAVEBEENACHIEVEDTODATE NO CONSENSUS ON THE MECHANISM OF ACTION OF '%3 IN GASTROPARESIS HAS EMERGED 4HEORIESCURRENTLYPROPOSEDINCLUDETHEEFFECTSOFSTIMULATIONONGASTRICTONE GASTRIC EMPTYING FUNDALRELAXATION ANDACCOMMODATIONENTERICNERVOUSSYSTEMFUNCTION ANDCENTRALNEURONALPATHWAYS;30=!BETTERUNDERSTANDINGOFTHEMECHANISMOF ACTIONCANLEADTOIMPROVED'%3EFlCACY )N THE MEANTIME RESEARCHERS HAVE SUCCESSFULLY USED '%3 TO TREAT MEDICALLY REFRACTORYNAUSEAANDVOMITINGFORPATIENTSWITHNORMALGASTRICEMPTYINGSTUDIES


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AS WELL AS POSTSURGICAL GASTROPARESIS !BRAHAMSSON ET AL HAVE REPORTED THAT FOR PATIENTSWITHCHRONICINTESTINALPSEUDO OBSTRUCTIONANDMEDICALLYREFRACTORYVOMITING '%3SEEMSTOHAVEANANTIVOMITINGEFFECTSIMILARTOTHATSEENINPATIENTSWITHSEVERE DIABETICGASTROPARESIS;31=&URTHERMORE ANUMBEROF'%3PROTOCOLSHAVEPROVED EFlCACIOUSFORWEIGHTREDUCTIONINOBESITY #LINICALDILEMMASANDOUTCOMES ALONGSIDEINCREASINGEVIDENCEOFTHECOMPLEX INTERACTIONSANDPATHWAYSTHATMAYBEADDRESSEDBY'%3 HAVELEDTOANINCREASEIN QUESTIONSANDCONCERNSABOUTTHETECHNIQUESMECHANISMSANDUTILITY4HESEINQUIRIES INTURN HAVELEDTOINTENSIlEDRESEARCHEFFORTS%FFORTSTODEVELOPBOTHWIRED AND WIRELESS TEMPORARY DEVICES THAT CAN SERVE AS TRIAL STIMULATORS ARE UNDERWAY THOUGH NOT YET COMMERCIALLY AVAILABLE AND INTEREST IN THE AREA OF MULTICHANNEL PACINGDEVICESISGROWING4HEDELIVERYOF'%3ONLYATDETECTIONOFINTRINSICSLOW WAVESISALSOUNDERINVESTIGATION;32]. /FGREATINTEREST ,AMMERSETALHAVERECENTLYUSEDHIGH RESOLUTIONMAPPINGTO DElNETHEORIGINANDPROPAGATIONOFGASTRICARRHYTHMIAS AND/'RADYETALTOTRACK SLOW WAVE PROPAGATION ;23, 33= 4HE ROLE OF ARRHYTHMIAS IN THE PATHOGENESIS OF GASTROPARESIS ASWELLASTHEEFFECTOF'%3ONTHEM NEEDSTOBESTUDIED/VERTHE COMINGYEARS ITISHOPEDTHATGASTRICCONTRACTILITYANDFACTORSAFFECTINGITWILLBE BETTERUNDERSTOOD ANDSOHELPUSTODEVISENOVEL'%3PARAMETERSANDDEVICES;33]. )NADDITION THEINCREASINGRElNEMENTOFBATTERYTECHNOLOGIES THEDEVELOPMENTOF MINIMALLYINVASIVEMEANSOFELECTRODEIMPLANTATIONANDIMPROVEMENTSINTHESIZE OFSTIMULATORSWILLINCREASETHEPOTENTIALUTILITYANDFEASIBILITYOF'%3

Future Studies in GES )NVESTIGATIONSINTOGASTRICELECTRICSTIMULATIONAREINCREASING4HECLINICALRESPONSE TO%NTERRA®REMAINSACCEPTABLEABOUTOFPATIENTSHAVEATLEASTAREDUCTION IN SYMPTOMS AND ABOUT HALF OF THESE PATIENTS HAVE A MUCH GREATER REDUCTION IN SYMPTOMS(OWEVER '%3ISASIGNIlCANTLYEXPENSIVEMODALITYAND OWINGTOTHE SURGERY REQUIRED FOR IMPLANTATION CARRIES MEASUREABLE RISK 4O MITIGATE ADVERSE EVENTSANDCOST ITISIMPERATIVETHATWEIDENTIFYPREOPERATIVECHARACTERISTICSABLETO PREDICTIMPROVEDPATIENTOUTCOMES-UCHWORKTHUSREMAINSTOBEACCOMPLISHEDIN THISARENA.ONRESPONDERSTOSTANDARDHIGH FREQUENCYLOW ENERGY'%3SHOULDBE EVALUATEDWITHANINCREMENTALENERGYALGORITHM ASPREVIOUSLYREPORTED;16]. We are NOW INVESTIGATING THE EFFECTS OF SUCH INCREMENTAL ENERGY ON INTRA OPERATIVE %'' PARAMETERSTOHELPDEVELOPMETHODSFORDETERMININGOPTIMALENERGYPARAMETERSFOR INDIVIDUALPATIENTS;17]. !NUMBEROFCENTERSHAVEFOCUSEDONOTHERWAYSFORIDENTIFYINGTHELIKELIHOODOF OPTIMAL PATIENT RESPONSE TO '%3 0ROPOSED APPROACHES FOR THESE DETERMINATIONS INCLUDECLINICALPATIENTRELATEDFACTORS ASWELLASNONINVASIVEAUTONOMICNERVOUS SYSTEMMEASURES %'' MUCOSAL%'' ANDFULLTHICKNESSGASTROINTESTINALBIOPSIES 7EANDOTHERRESEARCHERSHAVEFOUNDTEMPORARY'%3 WHETHERPLACEDENDOSCOPICALLY ORVIA0%'ELECTRODES HELPFULINPREDICTINGAPATIENTSOUTCOMEWITHPERMANENT'%3

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!DDITIONALLY WEHAVEFOUNDTHATAYOUNGERAGE AHIGHERBASELINEVOMITINGSCORE ANDALOWFREQUENCY TO AMPLITUDERATIOON%''ATBASELINEAREINDEPENDENTLYASSOCIATEDWITHGREATERCHANCESFORSUCCESS;20=/THERRESEARCHERSHAVEREPORTEDTHAT DIABETICGASTROPARESISANDTHEABSENCEOFPREOPERATIVEOPIOIDDEPENDENCECANALSO HELPPREDICTBETTEROUTCOMESWITH'%3;18]. 4HE ESTABLISHMENT OF THE .)( 'ASTROPARESIS #LINICAL 2ESEARCH #ONSORTIUM '0#2# ALMOSTYEARSAGOHASRESULTEDINALARGEREGISTRYOFDATAONPATIENTSWITH GASTROPARESIS)TISHOPEDTHATTHISDATAMAYEVENTUALLYHELPINDETERMININGUSEFUL CRITERIATHROUGHWHICHTOPREDICTPATIENTRESPONSETO%NTERRAOROTHER'%3THERAPIES 4HE TECHNOLOGIES DESCRIBED ABOVE REQUIRE CONTINUED ASSESSMENT WHETHER BY THE &$! THE .)( OR OTHER AGENCIES FOR EXAMPLE THE !MERICAN 'ASTROENTEROLOGICAL !SSOCIATIONHASPROPOSEDAN/FlCEOF4ECHNOLOGY%VALUATIONTOHELPFACILITATETHE ASSESSMENTOFNEW'%3TECHNOLOGIESANDTOASSISTWITHTHEIRPROPERUSE

Summary 'ASTROINTESTINAL STIMULATION A PROMISING TECHNOLOGY FOR OVER A CENTURY NOW HAS OVERTHEPASTTWODECADESSEENAGREATINCREASEINITSCAPACITYTOBEOFBENElTTO PATIENTSWITHDRUG REFRACTORYGASTROINTESTINALMOTILITYDISORDERS'%3WILLCONTINUE TOEVOLVEOVERTHECOMINGYEARS ASQUESTIONSREGARDINGITSBESTUSEAREANSWERED ANDASNEWTECHNOLOGIESAREDEVELOPED'%3MAYEMERGEASANIMPORTANTCLINICAL TOOL FOR PATIENT CARE AND ONE THAT IS MORE UNIVERSALLY AVAILABLE FOR APPROPRIATE patients. Acknowledgments 4HE AUTHORS WOULD LIKE TO THANK $R 'REGORY /'RADY FOR HELPFUL MANUSCRIPTSUGGESTIONSASWELLASPRODUCINGANDPROVIDING&IG32.3FOREXCLUSIVEUSEINTHISCHAPTER AND*O!NNE&ORDHAMFORHELPWITHMANUSCRIPTPREPARATION

References "ILGUTAY!- ,ILLEHEI#7 7INGROVE2 'RIFFEN7/ "ONNABEAU2#'ASTROINTESTINALPACING ANEWCONCEPTINTHETREATMENTOFILEUS"IOMED3CI)NSTRUMn 1UAST$# "EALL!# $E"AKEY-%#LINICALEVALUATIONOFTHEGASTROINTESTINALPACER3URG'YN /BSn +ELLY+! #ODE#&$UODENAL GASTRICREmUXANDSLOWEDGASTRICEMPTYINGBYELECTRICALPACING OFTHECANINEDUODENALPACESETTERPOTENTIAL'ASTROENTEROLOGY n !LVAREZ 7# &UNCTIONAL DISEASES OF THE STOMACH AND COLON -ED #LIN .ORTH !M *AN#HICAGO.O n 3ZURSZEWSKI*(! YEARPERSPECTIVEONGASTROINTESTINALMOTILITY!M*0HYSIOL'ASTROINTEST ,IVER0HYSIOL 'n &AMILONI"/ !BELL4, .EMOTO$ 6OELLER' *OHNSON"%FlCACYOFELECTRICALSTIMULATION ATFREQUENCIESHIGHERTHANBASALRATEINCANINESTOMACH$IG$IS3CIn &AMILONI"/ !BELL4, 6OELLER' 3ALEM! 'ABER/%LECTRICALSTIMULATIONATAFREQUENCY HIGHERTHANBASALRATEINHUMANSTOMACH$IG$IS3CIn


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Chapter 33

Cell Transplantation for Gastroparesis Laren Becker and Pankaj J. Pasricha

Keywords %MBRYONICSTEMCELLSs)NDUCEDPLURIPOTENTSTEMCELLSs.EURALSTEMCELLS s%NTERICNEURALPROGENITORSs0ROGENITORSOFINTERSTITIALCELLSOF#AJAL

Introduction .ORMAL GASTRIC MOTOR FUNCTION REQUIRES COORDINATED INTERACTION AMONG CENTRAL NERVOUSSYSTEM#.3 ENTERICNERVOUSSYSTEM%.3 INTERSTITIALCELLSOF#AJAL)## ANDSMOOTHMUSCLECELLS3-#S .EUROMUSCULARDISORDERSRESULTINGINGASTROPARESIS ARE MULTIFACTORIAL IN ORIGIN INVOLVING DYSFUNCTION AT VARIOUS LEVELS OF THIS COMPLEXINTERACTION&OREXAMPLE THEPATHOGENESISOFDIABETICGASTROPARESISMAY INVOLVEVAGALDYSFUNCTION REDUCEDNEURONALNITRICOXIDESYNTHASEN./3 EXPRESsion in the myenteric plexus, smooth muscle abnormalities, and deficits in ICC networks [1–8]. Given this complexity, it is perhaps not surprising that our current THERAPIES WHETHER PHARMACOLOGIC OR DEVICE BASED ELECTRICAL STIMULATION FAIL TO REPAIRTHISFUNCTIONALINTERACTION!NIDEALAPPROACHWOULDBETOREPLACEORREPLENISH PERMANENTLYIMPAIREDCELLSWHILEMAINTAININGTHESPATIALANDTEMPORALFUNCTIONOF the network. With our recent insights in stem cell biology, such therapies seem promising. In this chapter, we discuss the progress that has been made discovering various STEMCELLPOPULATIONSANDEXPLORINGWHICHPOPULATIONMAYBEMOSTSUITABLEFORCELL BASEDTHERAPIES7EFOCUSONEMBRYONICSTEMCELLS%3#S ANDINDUCED PLURIPOTENT STEMI03 CELLS #.3 DERIVEDNEURALSTEMCELLS#.3 .3#S ENTERICNEURALPROGENITORS %.0S DERIVEDFROMTHEGUT ANDPROGENITORSOF)##S

P.J. Pasricha (*) $IVISIONOF'ASTROENTEROLOGYAND(EPATOLOGY $EPARTMENTOF-EDICINE 3TANFORD-EDICAL#ENTER 0ASTEUR$RIVE !LWAY"LDG - 3TANFORD #! 53! E MAILPASRICHA STANFORDEDU H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1_33, © Springer Science+Business Media, LLC 2012

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L. Becker and P.J. Pasricha

Embryonic Stem Cells and Induced Pluripotent Stem Cells %3#SREPRESENTAPLURIPOTENTSTEMCELLPOPULATIONCAPABLEOFDIFFERENTIATINGINTOALL THREEGERMLAYERS!MAJORADVANTAGEOFTHISSTEMCELLPOPULATIONISTHEIRABUNDANCE DUE TO EASE OF PROPAGATION AND EXPANSION (OWEVER THERE ARE BOTH ETHICAL AND SCIENTIlCCONCERNSASSOCIATEDWITHTHEUSEOF%3#4HUS ADRAWBACKOFPLURIPOTENCY IS AN INCREASED POTENTIAL TO FORM TERATOMAS AND DIFlCULTY OF DIFFERENTIATING TO A DESIREDCELLFATE;9]. Fortunately, “nudging” ESCs toward the desired lineage prior TOTRANSPLANTATIONAPPEARSTODECREASETUMORIGENICITYANDIMPROVEENGRAFTMENT;10]. 4HEREHASBEENSIGNIlCANTPROGRESSINDElNINGTECHNIQUESANDPROTOCOLSTOINDUCE ESCs toward a neural lineage [11–15]. More recently, several investigators have IDENTIlEDMETHODSOFINDUCING%3#STOWARDANEURALCREST.# PHENOTYPEFROM WHICHTHE%.3ISDERIVED;16–19=4HESE%3# DERIVED.#CELLSARECAPABLEOFCOLONIZINGEXPLANTEDGUTANDDIFFERENTIATINGINTONEURONALANDGLIALCELLTYPES;17, 18]. 7HETHERTHESE%3# DERIVED.#CELLSWOULDDEVELOPFUNCTIONALLYRELEVANTNEUROmuscular connections in vivo remains to be seen. 2ECENTDISCOVERIESTHATREPROGRAMMINGDIFFERENTIATEDCELLSWITHAMINIMALSETOF GENESCANGENERATEPLURIPOTENTSTEMCELLS TERMEDI03CELLS OFFERANEXCITINGNEW %3# LIKE POPULATION FOR CELL BASED THERAPIES ;20, 21= 4HIS I03 CELL TECHNOLOGY avoids the ethical controversy surrounding ESCs and provides an accessible source OFIMMUNOLOGICALLYCOMPATIBLESTEMCELLSFORAUTOLOGOUSTRANSPLANTATION!NINITIAL CONCERNOFINCREASEDCANCERRISKDUETOTRANSFECTIONOFTHEONCOGENE c-myc, and GENOMICINTEGRATIONOFRETROVIRALVECTORS;22=HASLESSENEDWITHEXCLUSIONOFc-myc FROMTHEGENECOCKTAILANDUSEOFALTERNATIVETRANSFECTIONMETHODSTHATAVOIDVIRAL vectors [23–25= ,IKE %3#S I03 CELLS WILL LIKELY REQUIRE hNUDGINGv TOWARD THE DESIREDLINEAGEPRIORTOTRANSPLANTATION4OTHISEND INVESTIGATORSHAVEFOUNDPROTOCOLSSIMILARTOTHOSEUSEDFOR%3#STODIFFERENTIATEI03CELLSTONEURALLINEAGE;26, 27]. 4ECHNIQUESTOINDUCEI03CELLSINTO.#CELLSHAVEALSOBEENIDENTIlED;28]. iPS cells HAVE BEEN SUCCESSFULLY TRANSPLANTED INTO A RAT MODEL FOR 0ARKINSONS DISEASE AND LEAD TO FUNCTIONAL IMPROVEMENT ;29] suggesting that a similar approach may be APPLICABLE FOR %.3 DISORDERS 2ECENTLY INVESTIGATORS HAVE BEEN ABLE TO DIRECTLY CONVERTlBROBLASTSTONEURONSBYTHEADDITIONOFTHREEGENES;30]. It remains unclear whether a similar approach can be used to directly generate enteric neurons.

Neural Stem Cells and Enteric Neural Progenitors .EURALSTEMCELLSAREAMULTIPOTENThADULTvSTEMCELLPOPULATIONTHATHOLDPROMISE FOR CELL BASED THERAPIES OF THE %.3 5NLIKE %3#S .3#S ARE POISED FOR A NEURAL LINEAGEANDTHUSDONOTREQUIREhNEURALINDUCTIONvPRIORTOTRANSPLANTATION4HEYALSO HOLDLOWERPOTENTIALFORTUMORFORMATION7HILEADULTSTEMCELLSMAYBEPROPAGATED IN VITRO THEY DO NOT DEMONSTRATE SIMILAR LONG TERM SELF RENEWAL AS %3#S AND EVENTUALLYUNDERGOSENESCENCEANDCRISISDUETOLACKOFTELOMERASEACTIVITY;31].

#ELL4RANSPLANTATIONFOR'ASTROPARESIS

407

Fig. 33.1 4RANSPLANTATIONOF#.3 .3#SINPYLORUSOFN./3 DElCIENTMICERESTORESGASTRICFUNCTION (a WEEKPOSTTRANSPLANTATION '&0 EXPRESSING.3#SHAVEENGRAFTEDINTOTHEHOSTSTOMACHAND can be seen expressing both neuronal (top) and glial (bottom) markers. (b .!.# INDUCEDRELAXATION OFPYLORICMUSCLEINRESPONSETO%&3WASSIGNIlCANTLYINCREASEDINnNOS−/− mice 1 week post TRANSPLANTATION OF #.3 .3#S COMPARED TO VEHICLE CONTROLS # nNOS−/− mice transplanted WITH#.3 .3#SDEMONSTRATEDINCREASEDGASTRICEMPTYINGOFLIQUIDSCOMPAREDWITHTHOSETRANSPLANTEDWITHVEHICLE&IGUREADAPTEDFROM-ICCI -! ETALGastroenterology 5SEDWITH permission

4HUS UNLIKE %3#S OR I03 .3#S REQUIRE AN ACCESSIBLE SOURCE TISSUE TO REPLENISH their stocks. #.3 .3#S HAVE BEEN IDENTIlED AND ISOLATED FROM SITES IN THE RODENT BRAINS particularly the hippocampus and subventricular zone [32=!LTHOUGHDERIVEDFROM THEBRAIN #.3 .3#SHAVEREMARKABLEPLASTICITYWHENTRANSPLANTEDTOOTHERTISSUES INCLUDINGTHEGUT4HEYARECAPABLEOFDIFFERENTIATINGINTON./3 EXPRESSINGNEURONS AKEYNEURONALSUBTYPEINTHE%.3 INVITROANDAFTERINJECTIONINTORODENTSTOMACH [33=7EHAVEALSODEMONSTRATEDTHAT#.3 .3#CANBENUDGEDTOWARDANENTERIC phenotype by coculturing in vitro with dissected longitudinal muscle and myenteric plexus (LM-MP) gut tissue [34=&INALLY WHEN#.3 .3#SWERETRANSPLANTEDINTO THESTOMACHOFN./3 DElCIENTGASTROPARETIC MICE;35], they partially restored GASTRICFUNCTIONAFTERWEEK&IG33.1) [36=(OWEVER FORUNCLEARREASONS THEREWAS NOTSUSTAINEDENGRAFTMENTWITHSIGNIlCANTCELLLOSSnWEEKSAFTERTRANSPLANTATION $ESPITETHEPLASTICITYOF#.3 .3#S THEREISEVIDENCETHATINTRINSICDIFFERENCES BETWEEN.3#POPULATIONSMAYINmUENCEPHENOTYPICFATEFOLLOWINGTRANSPLANTAtion [37, 38=2ECENTLY .3#SHAVEBEENISOLATEDDIRECTLYFROMTHEGUT;37–47].

408


Fig. 33.2 .EUROSPHERE CONTAINING %.0S CAN BE GENERATED FROM BIOPSY SPECIMENS OF POSTNATAL HUMANGUTMUCOSASIMILARTOTHOSEGENERATEDFROMHUMANEMBRYONICGUTTISSUEa, low power, and b HIGHPOWER 0HASE CONTRASTIMAGESOFEMBRYONICGUTTISSUEAFTERDAYSINCULTURESHOW characteristic neurospheres. (c, low power, and d HIGHPOWER !LTHOUGHSMALLERINSIZEANDLESS NUMEROUS SIMILAR NEUROSPHERES WERE GENERATED FROM BIOPSY SPECIMENS OF POSTNATAL GUT TISSUE AFTERDAYSINCULTURE&IGUREADAPTEDFROM-ETZGER-ETALGastroenterology 5SEDWITH permission

4HUS THISPOPULATIONOFSTEMCELLS TERMED%.0S MAYBEMOREAPPROPRIATEFOR REGENERATINGTHE%.3THAN#.3 .3#S%.0SISOLATEDFROMEMBRYONICANDPOSTNATAL GUTS IN RODENTS AND HUMANS ARE CAPABLE OF COLONIZING EXPLANTED GUT TISSUE AND DIFFERENTIATING INTO %.3 APPROPRIATE NEURONAL AND GLIAL SUBTYPES ;37–47]. While THESEGRAFT DERIVEDNEURONSANDGLIALCELLSHAVEBEENSHOWNTOINCREASECOORDINATED contractions and coordinated calcium waves in vitro [41= WHETHERTHEYFORMFUNCTIONALLYSIGNIlCANTNETWORKSINVIVOHASYETTOBEDEMONSTRATED!RECENTSTUDYBY -ETZGER ET AL DEMONSTRATED THAT %.0S COULD BE DERIVED FROM MUCOSAL BIOPSIES taken during endoscopy [43], which provides a readily accessible source should this POPULATION OF STEM CELLS PROVE CLINICALLY USEFUL &IG 33.2). It remains unclear WHETHERTHEREAREBEHAVIORALDIFFERENCESIN%.0SDEPENDINGONWHEREINTHEGUT THEY COME FROM AND WHERE THEY ARE TRANSPLANTED 4HESE QUESTIONS NEED TO BE EXPLOREDTOHELPCHARACTERIZETHEOPTIMALSUBSETOF%.0SFORTRANSPLANTATIONINTOTHE stomach.


409

Progenitors of Interstitial Cells of Cajal ,OSSOF)##HASBEENIMPLICATEDINTHEPATHOGENESISOFGASTROPARESIS;2, 5, 48–50]. 7HILETHEEXACTMECHANISMREMAINSUNCLEAR INTHECASEOFDIABETICGASTROPARESIS REDUCEDINSULININSULINGROWTHFACTOR SIGNALINGLEADSTODECREASEDSTEMCELLFACTOR 3#& A FACTOR NECESSARY FOR MAINTENANCE OF )##S ;3, 51= 7HILE RESTORATION OF THESE SIGNALING PATHWAYS MAY SERVE AS ONE APPROACH FOR TREATING GASTROPARESIS REGENERATIONOF)##NETWORKSBYTRANSPLANTATIONOF)##PROGENITORSMAYBEANOTHER Kit+MESODERMALPRECURSORSOF)##SHAVEBEENCHARACTERIZEDINEMBRYOSANDIN the immediate postnatal period [52–55=-ORERECENTLY PROGENITORSOF)##SHAVE BEENFOUNDINADULTGUTSOFRODENTSTHATARE+IT+ and express the adhesion marker CD34+ [56, 57]. Whether these progenitors can be isolated in human and represent APOPULATIONAMENABLEFORTRANSPLANTATIONREMAINSTOBESEEN

Conclusion 'IVENTHENUMBEROFCLINICALTRIALSUSINGSTEMCELLSINVARIOUSORGANS PHYSICIANS WILLLIKELYSTARTSEEINGCELL BASEDTHERAPIESASPARTOFTHEIRARSENALINTHENEARFUTURE )TISLIKELYONLYAMATTEROFTIMEBEFOREWElNDSTEMCELLPOPULATIONSTHATARESUITABLE CANDIDATESFORTREATINGNEUROMUSCULARDISORDERSOFTHESTOMACH(OWEVER SEVERAL obstacles remain with regard to clinical application [58]. What is the best method FOR DELIVERING STEM CELLS TO THE DISEASED TISSUE 7ILL THEY REQUIRE ENDOSCOPIC OR SURGICALTRANSPLANTATIONORCANTHEYREACHTHEAPPROPRIATESITEFOLLOWINGINTRAVENOUS INFUSION$OTHEYREQUIREIMBEDDINGINAPOLYMEROROTHERMATRIXPRIORTOTRANSPLANTATION 7ILL IMMUNOSUPPRESSIVE THERAPIES BE REQUIRED )S PROLONGED ENGRAFTMENT POSSIBLEORWILLREPEATTRANSPLANTATIONSBEREQUIRED/VERTIME WILLTHESESTEMCELLS BEPREDISPOSEDTOTUMORFORMATION$ESPITETHESEHURDLES NOVELCELL BASEDTHERAPIES FORTREATINGDEBILITATINGDISORDERS LIKEGASTROPARESIS WILLHOPEFULLYBEREALIZEDIN THENEARFUTURE

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Index

A Abdominal distension, 27 Abdominal pain, 28 Acetylcholinesterase inhibitors, 269 Acotiamide (Z–338), 269 Albumin, 239 American Neurogastroenterology and Motility Society (ANMS), 89 Amino acid assessment, 332 Amitriptyline, 308, 319 Anorexia nervosa, 307 Antidepressants and neuroleptic drugs, 284–285 Antiemetic treatment antidepressants and neuroleptic drugs, 284–285 benzodiazepine, 284–285 gastric emptying, 279 herbal remedy, 284–285 neurotransmitter control, nausea and vomiting, 279–280 prokinetic agents, 286 receptor antagonist cannabinoid CB1, 281, 283 dopamine D2, 281–282 histamine H1, 281 muscarinic M1, 281–282 neurokinin NK1, 281, 283 serotonin 5-HT3, 281–282 tricyclic antidepressant agent, 283–284 Antireflux surgery, 195–196 Antral contraction scintigraphy, 107 Antroduodenal manometry abnormal antroduodenal motility, 170 colonic inertia, 172

erythromycin, 168, 171 gastric emptying coordinated aboral contraction, 163 gastric and intestinal contraction, 165 gastrointestinal tract, 165 gut hormones, 166 ICC, 164 pyloric sphincter pressure, 164 gastroparesis, pathophysiology, 166–167 indications, 169–170 interpretation, 168–169 low-dose tricyclic therapy, 172 motility tracing, 167 octreotide, 171 partial bowel obstruction, 171 solid-state manometers, 167 water-perfused catheters, 167 wireless motility capsule (SmartPill), 168 Autonomic nervous system (ANS), 398

B Bariatric surgery, 196–197 Bethanechol, 268–269 Bicompartmental gastric emptying dyspeptic symptoms, 107 fundal dysmotility, 104, 107 intragastric distribution analysis, 106 primary antral dysmotility, 105, 107 Bloating, 27 Botulinum toxin injection, 232, 270–271 Bradygastria, 153, 157, 159, 160 Breath testing, 230 Bulimia nervosa, 307 Bupropion, 308

H.P. Parkman and R.W. McCallum (eds.), Gastroparesis: Pathophysiology, Presentation and Treatment, Clinical Gastroenterology, DOI 10.1007/978-1-60761-552-1, © Springer Science+Business Media, LLC 2012

413

414 C Cannabinoid CB1 receptor agonist, 281, 283 Carbamazepine, 296 Cell transplantation diabetic gastroparesis, pathogenesis, 405 ESCs and iPS, 406 gastric motor function requirements, 405 ICC, 409 NSCs CNS-NSCs, 407 multipotent “adult” stem cell, 406 postnatal human gut mucosa, 408 Cellular pathogenesis cellular degeneration enteric nervous system, 55 extrinsic nerves, 53–54 interstitial cells of Cajal, 56 smooth muscle, 55–56 cellular mechanisms afferent neural signaling, 52–53 cell deficit, 57–59 cell loss, 57 dihydropyridine-insensitive Ca2+ currents, 51 electro mechanical coupling, 51 ENS, 52 MLC18, 49 phasic contractions, 51 smooth muscle function, 52 tissue integrity and function, 59 gastric emptying, 48 Central nervous system (CNS) disorders, 226 Central venous catheters (CVCs), 368–369 Chronic pancreatitis, 222 Chronic uremia, 250 Cisapride, 89 Clarithromycin, 266 Classification, gastroparesis, 213–214 Clinical presentation GCSI, 31 physician assessment, 32–33 predominant symptom presentation, 29–30 psychological issues, 28–29 QOL measurement, 31–32 symptoms abdominal distension, 27 abdominal pain, 28 bloating, 27 early satiety, 27 emesis, 26 heartburn and regurgitation, 28 nausea, 26 patterns, 30 postprandial fullness, 27

Index satiation, 27 CNS-derived neural stem cells (CNS-NSCs), 407–408 Colonic transit time (CTT), 115 Complementary and alternative medicine (CAM) acupuncture, 329 antiemetics, 336–337 motility, 337–338 amino acid assessment, 332 amino acid blends, 334 Consortium of Academic Health Centers for Integrative Medicine, 330 essential fatty acids, 332–333 gastric emptying, 336 ginger, 336 glycemic control, 334 integrative therapies, 336 macronutrient and micronutrient status, 333 macronutrient dietary evaluation, 330 microflora colonies, 331 NCCAM, 330 smoothie recipe, 334, 335 systemic dysfunction, 334 University of Kansas Medical Center Program, 330 vitamin and mineral assessment, 331–332, 334 Connective tissue disorders, 217 Constipation-associated gastroparesis, 215 CVCs. See Central venous catheters (CVCs) Cyclic vomiting syndrome (CVS), 229

D Desipramine, 294 Diabetes mellitus, 81–83, 249 Diabetic gastroparesis, 15, 91–92 diabetes mellitus, 177 dietary therapy, 186 gastric electrical stimulation, 186 gastric emptying blood glucose concentration, 178 cystic fibrosis, 178 gastrointestinal symptoms, 183 glycemic control, 183 impaired nutrition, 184 postprandial hypotension, 184 hypo/hyperglycemia, 184 low-dose tricyclic antidepressants, 185 pathogenesis, 178–180 postprandial blood glucose regulation carbohydrate content, 180

Index erythromycin, 183 glycemic control, 180 incretin hormone GLP–1, 181 intraduodenal glucose infusion, 182 plasma insulin, 181 prokinetic therapy, 186 table isotope breath test, 185 Dietary treatment albumin, 239 anthropometric assessment, 240 avoidable foods, 248 complementary treatment, 248–249 diabetes, 249 dietary information list, 250–251 diet suggestion diabetic gastroparesis, 251–252 gastroparesis and renal failure, 251–253 gastric emptying, 247–248 malnourishment, 237 micronutrient deficiency calcium/vitamin D, 242–243 iron, 241–242 vitamin B12, 243–244 nutrition assessment, 238 nutrition support dietary components of food, 246–247 fat, 245–246 fiber, 246 hydration and electrolyte balance, 244 liquids and solids, 245 meal size, 245 nutritional counseling, 244 parameters, 240 patient interview, 238–239 prealbumin, 239–240 renal failure, 250 upper gastrointestinal dysfunction, 237 weight assessment, 238 Diethylenetriaminepentaacetic acid (DTPA), 98 Diffuse gut dismotility, 219–220 Dipeptidyl peptidase 4 (DPP–4), 259 Direct percutaneous endoscopic jejunostomy (DPEJ), 346–347 Dopamine D2 receptor antagonist, 281–282 Dopamine receptor antagonist domperidone (Motilium), 262–264 itopride, 264 metoclopramide (Reglan), 261–262 motor activity, stomach, 260 DPEJ. See Direct percutaneous endoscopic jejunostomy (DPEJ) Duloxetine, 295

415 Dysmotility and paraneoplastic syndrome, 218–219 Dyspepsia, 170, 171

E Early satiety, 27 Eating disorders, 306–307 Echo-planar imaging (EPI) sequence, 139 Electrogastrography (EGG), 392 electrocontractile abnormality, 160 gastric dysrhythmias, 159 gastric electrical stimulation, 160 gastric emptying, 158 gastric myoelectrical signal, 153 ICCs, 154 obstructive gastroparesis, 158 pacemaker region, 154 patient evaluation, 156–157 recording analysis, 155–156 recording procedure, 155 running spectral analysis, 158–159 slow waves, 154 tachygastrias, 159 Electronic radiotelemetry capsule, 113 Embryonic stem cells (ESCs), 406 Emesis, 26 EMR. See Endoscopic mucosal resection (EMR) Endoscopic full thickness gastric biopsy biliary retrieval balloon, 386 double-channel therapeutic endoscope, 386 electrogastrogram, 381 EMR, 382, 383 etiologies, 379 gastric function, 379 gastric histopathology, 380 14-gauge biopsy needle, 387 GES, 380 guide therapy, 387 ICCs, 379, 380 NOTES, 382 optimal deep gastric-muscle-wall biopsy procedure, 382 polypoid lesion, 383 preclinical porcine study, 382 sphincterotome, 386 submucosal endoscopy, 386 sutured closure and circumferential cutting method, 383 T-tag tissue anchors, 383–385 Endoscopic mucosal resection (EMR), 382, 383 Enteral nutrition (EN), 342

416 Enteric glial cells, 84 Enteric nervous system (ENS), 38, 52. See also Gut brain Enteric neural progenitors (ENPs). See Neural stem cells Enterra™ gastric stimulator, 374 Enterra® therapy, 94 cost reduction, 356 gastric dysrhythmia, 356 mechanisms, 356–357 nutritional status and quality of life, 355 stimulation parameters, 354–355 Epidemiology causes, 13 definitions, gastroparesis, 11–13 diabetic prevalence, 15 economic impact, 19 ethnicity effects, 14 etiology, 14 gastric emptying, 17 hospitalizations, 17–19 HRQOL, 19 hyperglycemia, 17 idiopathic gastroparesis, 15 incidence of, 16 influence of gender, 17 mortality, 20–21 Epigastric pain syndrome (EPS), 136 Erythromycin, 232 Essential fatty acids, 332–333 Exentilde, 259

F Fluoro-deoxy glucose positron emission tomography, 356 Fluoroscopic jejunal access, 348–349 Functional dyspepsia (FD), 12, 206

G Gabapentin, 295 Gadolinium tetraazacyclododecane tetraacetic acid (Gd-DOTA), 145 Gastric accommodation, 40–41 Gastric dysmotility antrum, 43 fundus, 42–43 gastric electrical dysfunction, 44 gastric motor function (see Gastric motor function) pylorus, 43–44 small bowel dysmotility, 44 Gastric electrical dysfunction, 44

Index Gastric electrical stimulation (GES), 200, 208, 233 ANS testing, 398 arrhythmias, 401 autonomic and enteric parameters, 398 clinical application, 353–354 clinical dilemmas and outcomes, 401 clinical investigation, 393–394 continuous stimulation, 394 cutis, 396 cyclical stimulation, 394 dual pulse GES, 360–361 EGG, 392, 398 electrodes, 396 enteric nervous system function, 400 Enterra® therapy, 392, 399 cost reduction, 356 gastric dysrhythmia, 356 mechanisms, 356–357 nutritional status and quality of life, 355 stimulation parameters, 354–355 full thickness gastric biopsy, 398 gastric contractions, 358 gastric dysrhythmia normalization, 357 gastric emptying, 358 gastric motility, 353, 392 gastric pacing, 357–359 gastric tone and accommodation effects, 358 gastrointestinal symptoms, 391 GEMS study, 393 GET, 398 GI surgeon, 374–375 GPCRC, 402 high resolution mapping, 399 IDE, 393 intermittent stimulation, 394 intraluminal catheter, 353 intra-operative testing, 398–399 low and high energy parameter, 396 Medtronic, 393 miniature wireless GES devices, 400 mucosa, 395 mucosal EGG, 398 multi-channel GES, 359–360 noninvasive autonomic nervous system, 401 ‘pacing,’ 392 percutaneous electrode system, 400 permanent GES electrodes, robotic placement, 400 postoperative ileus, 391 preoperative characteristics, 401

Index refractory nausea and vomiting, 400–401 serosa, 396 short-pulse stimulation and trains, 354 stimulation parameter prediction, 396–397 symptom related, 398 synchronized GES, 361–362 temporary GES electrodes, mucosal placement, 400 wireless EGG, 400 Gastric emptying, 17, 48. See also Bicompartmental gastric emptying blood glucose concentration, 178 breath tests nonradioactive isotope, 124 octanoate, 125 performance characteristics, 126 pitfalls and common artifacts, 126–127 spirulina, 125–126 coordinated aboral contraction, 163 cystic fibrosis, 178 gastric and intestinal contraction, 165 gastrointestinal symptoms, 183 gastrointestinal tract, 165 glycemic control, 183 gut hormones, 166 ICCs, 164 impaired nutrition, 184 patient management, 127 postprandial hypotension, 184 pyloric sphincter pressure, 164 radiation exposure, 123 scintigraphy, 123 Gastric emptying scintigraphy antral contraction scintigraphy, 107 DTPA, 98 dual-head SPECT cameras, 98 functional dyspepsia, 97 fundal relaxation, 108 gastric retention, 102, 104, 105 gastroesophageal reflux, 102, 106 GES, 97 imaging protocol and image analysis, 100, 101 intragastric distribution analysis, 106 lag phase, 104 patient preparation, 98–99 pediatric gastric emptying, 108–109 pressure gradient, 102, 103 radioisotope, 98 radiolabeled solids, 102 solid segregation, 101, 102 test meal, 99–100 whole gut transit, 102 Gastric emptying time (GET), 115

417 Gastric motility, 192. See also Magnetic resonance imaging electric slow waves, gut, 5–6 gastricemptying and intestinalmotility, 8 gastric sieving, 8 gastrointestinal contractions, 7 gastrointestinal tract flow measurement, 2–3 pressure measurement, 3–4 hunger contractions, 7 pacemaking system, 6–7 receptive relaxation, 8 reverse peristalsis, 8–9 rhythmic contractions, gut, 7 wall movements, 4 Gastric motility breath test (GMBT), 125 Gastric motor function ENS, 38 parasympathetic and sympathetic nervous systems., 38–39 peristaltic reflex, 39 physiology antrum, 41 fundic contraction, 40 fundic relaxation, 40–41 gastric emptying, 41–42 MMC cycle, 39 pylorus, 41 stomach muscle, 39–40 smooth muscle cells, 39 Gastric sieving, 8 Gastric strain rate imaging, 135–136 Gastric wall, 73 Gastroesophageal reflux disease (GERD), 214–215 gastric emptying scintigraphy, 102, 106 PSG, 191 Gastrointestinal (GI) surgeon characteristics, gastroparesis, 366 clinical symptoms, 365 definitive therapy, 367 delayed gastric emptying, 365 feeding jejunostomy, 370–371 gastrointestinal motility disorder, 366 gastrostomy, 369–370 GES, 374–375 PICC lines, CVC, Hickman catheters and infusaports, 368–369 pyloromyotomy, pyloroplasty and gastrojejunostomy, 372 resectional therapy, 372–373 supportive therapy, 367 surgical treatment, 366 treatment principles, 366

418 Gastroparesis cardinal symptom index (GCSI), 31, 88, 290 Gastroparesis Clinical Research Consortium (GPCRC), 402 Generalized auto-calibrating partially parallel acquisitions (GRAPPA), 142 GERD. See Gastroesophageal reflux disease (GERD) GES. See Gastric electrical stimulation (GES) Ghrelin receptor agonists, 271–272 GI surgeon. See Gastrointestinal (GI) surgeon Glucagon-like peptide–1 (GLP–1), 179 Gradient recall echo (GRE) sequence, 140 GSK962040 receptor agonist, 266 Gut brain, 38

H Half Fourier acquisition single-shot turbo spin echo (HASTE) sequence, 142–144 Health-Related Quality of Life (HRQOL), 19 Heartburn, 28 Heme-oxygenase–1, 179 Herbal remedies, 284–285 Histamine H1 receptor antagonists, 281 Histamine-secreting enterochromaffin-like cells, 74 5-HT receptor binding, 318 Humanitarian use device (HUD), 374 Hunger contractions, 7 Hyperglycemia, 17 Hypertrophic pyloric stenosis, 215

I Iberogast (STW 5), 270 ICC. See Interstitial cells of Cajal (ICC) Idiopathic gastroparesis (IGP), 15, 81, 92–93 functional dyspepsia, 206 gastric electrical stimulation, 208 impact, 208–209 intrapyloric botulinum toxin injection, 208 pathophysiology, 207 patient evaluation, 206 postinfectious gastroparesis, 205 psychological dysfunction, 206 symptoms, 207 Incretin hormone GLP–1, 181 Induced-pluripotent stem (iPS) cells, 406 Insulin-dependent diabetes mellitus (IDDM), 228 Interstitial cells of Cajal (ICCs), 178, 219 cell transplantation, 409 EGG, 154

Index endoscopic full thickness gastric biopsy, 379–381 gastric emptying, 164 pathology, 77 Intrapyloric botulinum toxin injection, 208 Intravenous phenotolamine, 298 Investigational Device Exemption (IDE), 393 iPS cells. See Induced-pluripotent stem (iPS) cells Irritable bowel syndrome (IBS), 319

J Jejunostomy tube feedings, 200 dietary effect, 341 EN, 342 gastric emptying scan, 349 major and minor complications, 350 nasoenteric tube access bedside and endoscopic nasoenteric tube passage techniques, 343 drag and pull method, 343 early complications, 342, 343 gastric feedings, 342 intravenous promotility agents, 343 over-the-guidewire-technique, 343–344 pharmacologic agents, 343 self-propelled NJ tube, 342 stylet-filled tube and corkscrew motion, 342 ultrathin endoscope, 344 PEG/J balloon internal bolster, 344 DPEJ, 346–347 fluoroscopic jejunal access, 348–349 intemittent gastric decompression, 345 management, 345 over-the-guidewire method, 344 retrograde migration/luminal dysfunction, 345 small bowel position, 344, 345 surgical jejunal access, 347–348 ultrathin endoscope, 344 refractory diabetic gastroparesis, 349 refractory patients, 341 retrospective anlaysis, 350 small bowel access, 342 weight loss, 341

K Kappa opioid agonist and asimadoline, 297 Ketamine, 299

Index L Levetiracetam, 321 Liver acquisition with volume acceleration (LAVA) sequence, 142–144 Longitudinal muscle and myenteric plexus (LM-MP), 407 Long pulse gastric electrical stimulation, 357–358

M Magnetic resonance imaging (MRI) 2D MR sequences, 141, 146 2D oblique coronal plane, time sequence, 146, 147 EPI sequence, 139 fiber-optic recording system, 149 Fourier coefficient, 146 gastric contractions analysis, 146, 148 gastric emptying assessment, 145–146 gastric motor functions gastric motility, evaluation, 140, 141 GRAPPA, 142 GRE, 140 HASTE, 140, 142 LAVA sequence, 142 SENSE technique, 142 SSFP, 140 gastric volumes assessment functional dyspepsia, 142 gastric secretion and emptying, 144 HASTE, 143 intragastric fluid and air, 142 postprandial change, 144 three-dimensional LAVA sequence, 143 intraluminal manometry, 146 pharmacological modulation and disease, 141, 146 phase shift plots, phase vs. location, 146 pylorus, 149 Major depressive disorder (MDD), 308–309 Malignant gastroparesis, 217–218 MAOs. See Monoamine oxidase inhibitors (MAOs) Medication-induced gastroparesis, 215–217 Methylnaltrexone, 297 Metoclopramide, 306, 321 Micronutrient deficiency calcium/vitamin D, 242–243 iron, 241–242 vitamin B12, 243–244 Migrating motor complex, 166–167, 192

419 Monoamine oxidase inhibitors (MAOs), 308–309 Motilin receptor agonists (motilides) azithromycin, 266 erythromycin, 264–266 mitemcinal (GM–611), 266 Muscarinic receptor agonists, 268–269, 281–282 Myoelectrical activity, 153

N Naltrexone, 307 National Center for Complementary and Alternative Medicine (NCCAM), 330 Natural history, patients clinical course, 88–89 clinical prevalence, 87 delayed gastric emptying, 87 diabetic gastroparesis, 91–92 gastric motility disorder, 88 hospitalizations, 89–90 idiopathic gastroparesis, 92–93 mortality, 90–91 post surgical gastroparesis, 93–94 symptoms, gastroparesis, 87 Natural Orifice Translumenal Endoscopic Surgery (NOTES), 382 Nausea, 26 Needle catheter jejunostomy (NCJ), 348, 371 Neural crest (NC), 406 Neural stem cells (NSCs) CNS-NSCs, 407 multipotent adult stem cell, 406 postnatal human gut mucosa, 408 Neurokinin NK1 receptor antagonist, 281, 283 Neurologic disorders, 220–221 Neuropathic pseudoobstruction, 169 Nitric oxide synthase (NOS), 79, 179 Nonadrenergicnoncholinergic nerves (NANC), 5 Nonradioactive isotope breath tests, 124 Non-steroidal anti-inflammatory drugs (NSAIDs), 293–294

O Octanoate breath test, 125 Octreotide, 269–270 Opioid bowel dysfunction, 297

420 P Pacemaking system, 6–7 Pain management abdominal pain characteristics, 291 differential diagnosis, 290 GCSI and PAGI-SYM, 290 NIH Gastroparesis Consortium, 291 PAGI-QOL, 291 pathogenesis, 292 acupuncture and biofeedback, 299 celiac and superior mesenteric ganglia, 298 clonidine, 297 functional dyspepsia, 289–290 gastric electric stimulation, 298 intravenous phenotolamine, 298 ketamine, 299 neurolytic celiac plexus blocks, 298 NSAIDs, 293–294 opiate analgesics, 296–297 pharmacotherapy, 293 prokinetic agents, 293 psychotropic agents antiepileptic agents, 295–296 chronic abdominal pain reduction, 294 SSRIs, SNRIs and SSNRIs, 295 TCAs, 294–295 visceral pain, 293 Pathology autoimmune, 82–84 diabetes mellitus, 81–83 duodenum, 73 enteric glial cells, 84 etiology, 80 gastric emptying patterns and scintigraphy, 73 gastric wall, 73 hematoxylin and eosin stain, 74–75 ICCs, 77 idiopathic gastroparesis, 81 immunohistochemical stain c-kit, 77–78 GFAP, 74, 76 NSE, 74–75 S100, 74, 76 immunomodulators, 77 infectious causes, 83–84 muscularis propria, 74 nonobese diabetic mice, 80 pathophysiology, 79 streptozotocin-induced diabetes, 79, 80 Patient assessment of GI quality of life (PAGI-QOL), 291

Index Patient assessment of GI symptoms (PAGI-SYM), 290 Pediatric gastric emptying, 108–109 Pediatric gastroparesis diagnosis, 229–231 etiology CNS disorders, 226 dietary protein allergy, 226 environmental and nociceptive factor, 225 gastrointestinal tract immaturity, 225 postinfectious gastroparesis, 226–229 gastric electrical stimulation, 233 5-HT3 receptor antagonist agent, 232 treatment, 231–241 Percutaneous endoscopic gastro/jejunostomy (PEG/J) balloon internal bolster, 344 DPEJ, 346–347 fluoroscopic jejunal access, 348–349 intermittent gastric decompression, 345 management, 345 over-the-guidewire method, 344 retrograde migration/luminal dysfunction, 345 small bowel position, 344, 345 surgical jejunal access, 347–348 ultrathin endoscope, 344 Peripherally inserted central catheters (PICC), 368 Positioning and orientation measurement (POM) transmitter, 132 Postinfectious gastroparesis, 205 CVS, 229 electrogastrographic study, 228 eosinophilic gastroenteropathy, 227–228 etiology, 227 functional dyspepsia, 228 gastric electromechanical abnormality, 229 IDDM, 228 postviral gastroparesis, 227 viruses, 226–227 Postprandial distress syndrome (PDS), 136 Postprandial fullness, 27 Postprandial hypotension, 184 Postsurgical gastroparesis (PSG) abdominal and thoracic surgery, 195 antireflux surgery, 195–196 bariatric surgery, 196–197 evaluation, 197–198 gastric motility and vagal function, 192–193 GERD, 191 heart/lung transplantation, 196

Index incidence, etiology, and mechanism, 193–194 management dietary, 198 GES, 200 medical therapy, 199 postoperative complications, 200 symptomatic, 198 tube gastrostomy, 199 postvagotomy, 194–195 vagal nerve injury, 201 Post traumatic stress disorder (PTSD), 307 Prealbumin, 239–240 Probiotics, 270 Prokinetic agents acetylcholinesterase inhibitors, 269 antiemetic treatment, 286 botulinum toxin injection, 270–271 cisapride (Propulsid), 267 delayed gastric emptying, 257 dopamine receptor antagonist domperidone (Motilium), 262–264 itopride, 264 metoclopramide (Reglan), 261–262 motor activity, stomach, 260 ghrelin receptor agonists, 271–272 GI tract contractility, 258 mosapride, 268 motilin receptor agonists (motilides) azithromycin, 266 erythromycin, 264–266 mitemcinal (GM–611), 266 muscarinic receptor agonists, 268–269 octreotide, 269–270 pathophysiology, 272 probiotics, 270 renzapride and prucalapride, 268 sympathetic agents, 270 symptomatic gastroparesis, 257 tegaserod, 267–268 treatment, 258–260 Prokinetics, 231 PSG. See Postsurgical gastroparesis (PSG) Psychiatric aspects gastroparesis adjustment disorders, 311 antiemetics, 312 benzodiazepine dependence, 311 chronic upper gastrointestinal symptoms, 303 clinical evaluation, 304–305, 312 definition and causes, 305 eating disorders, 306–307 epidemiology, USA, 305

421 MDD, 308–309 opioid dependence, 311 opioid withdrawal, 309–310 panic attacks, 309, 310 personality changes, 311 phobia to eat, 310 psychiatric comorbidities, 306 psychological dysfunction, 310 schizophrenia, 309 somatization disorders, 308 symptoms, diagnosis and treatment, 306 metoclopramide, 303 Psychiatric disease, 221 Psychological dysfunction, 206 Pylorospasm, 199

Q Quality-of-life (QOL), 31–32

R Radiolabeled solid and liquid meal, 98 Regurgitation, 28 Renal failure, 222, 250 Retching, 26 Reverse peristalsis, 8–9 Roux-en-Y anastomosis, 195

S Satiation, 27 Schizophrenia, 309 Scintigraphy, 123, 230 Scleroderma, 217 Selective norepinephrine reuptake inhibitors (SNRIs), 295 Selective serotonin reuptake inhibitors (SSRIs), 295, 308–310, 318 Sensitivity encoding (SENSE) technique, 142 Sensory dysfunction delayed gastric emptying, 65–66 therapeutic implications, 69 visceral hypersensitivity dyspeptic symptoms, 67, 68 functional dyspepsia, 68 physical/sexual abuse, 69 prevalence of, 67 Sensory neuromodulators action mechanism, 318–319 antiepileptic agents, 323 antisomatization effect, 317

422 Sensory neuromodulators (cont.) clinical evidence foregut functional disorder, 319, 320 IBS, 319 metoclopramide, 321 mirtazapine, 320 tachyphylaxis, 321 TCAs, 320 zonisamide and levetiracetam, 321 clinical symptomatology, 317 comorbid affective mood disorders, 321 delayed gastric emptying, 323–325 functional dyspepsia, 316 functional gastrointestinal disease, 322 imipramine and doxepin, 323 motor dysfunction, 316 nortriptyline, 323 nuclear medicine gastric emptying, 316 perceptive foregut symptoms, 326 pharmacotherapies, 317 psychiatric comorbidity, 322 side effects, 323 upper gut symptoms, 316, 321 Serotonin 5-HT4 receptor agonists, 267–268 Serotonin 5-HT3 receptor antagonist, 281–282 Serotonin-noradrenaline reuptake reuptake inhibitors (SNRIs), 318 Single photon emission computed tomography (SPECT), 230 Small bowel dysmotility, 44 Small bowel transit time (SBTT), 115 Somatostatin, 269 Spirulina gastric emptying breath test, 125–126 SSRIs. See Selective serotonin reuptake inhibitors (SSRIs) Steady state free precession (SSFP) sequence, 140 Stem cell factor (SCF), 409 Strain rate imaging (SRI), 135–136 STW–5 (Iberogast), 248

T Tachygastrias, 153, 157, 159, 160 Tachyphylaxis, 321 Total parenteral nutrition (TPN), 222, 370 Tramadol, 296 Tricyclic antidepressants (TCAs), 308, 318 antiemetic treatment, 283–284

Index clinical evidence, sensory neuromodulators, 320 psychotropic agents, 294–295

U Ultrasonography antral area, 133 antropyloroduodenal motility, 135 gastric emptying, 132–133 gastrointestinal motor function, 131 gold standard, 131 proximal stomach, 134–135 SRI, 135–136 transabdominal ultrasonography, 136 transpyloric flow, 135 two dimensional ultrasonography, 131

V Vagotomy, 192–193 Viral infections, 220 Visceral hypersensitivity dyspeptic symptoms, 67, 68 functional dyspepsia, 68 physical/sexual abuse, 69 prevalence of, 67

W Whole gut transit time (WGTT), 115 Wireless motility capsule (WMC) capsule technology, 113 clinical use and implication, 120 CTT and WGTT, 115 gastrointestinal tract, 113 gastrointestinal transit, 113 gastroparesis diagnosis, 116–117 GET definition, 115–116 physiologic parameters contractile activity, 117 contractions patterns and intraluminal pressure, 118 pH profile, 119 regional GI tract transit time, 118–119 SBTT, 115 SmartPill, 114, 168 test, 114

Z Zonisamide, 321

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