Wernicke encephalopathy as rare complication of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

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InternationalJournalofSurgeryCaseReports16(2015)29–32

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International

Journal

of

Surgery

Case

Reports

j o u r n al ho m e p a g e :w w w . c a s e r e p o r t s . c o m

Wernicke

encephalopathy

as

rare

complication

of

cytoreductive

surgery

and

hyperthermic

intraperitoneal

chemotherapy

Antonio

Macrì

_,

_Francesco

_Fleres

_,

_Antonio

_Ieni

_,

_Maurizio

_Rossitto

_,

Tommaso

Mandolfino

_,

_Salvatore

_Micalizzi

_,

_Francesco

_Iaropoli

_,

_Carmelo

_Mazzeo

_,

Massimo

Trovato

_,

_Eugenio

_Cucinotta

_,

_Edoardo

_Saladino

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received3August2015

Receivedinrevisedform28August2015 Accepted1September2015

Availableonline18September2015

Keywords: Gastriccancer Peritonealcarcinomatosis WernickeEncephalopathy HIPEC Complications

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BACKGROUND:Peritonealcarcinomatosisofgastric originisafrequent eventwithpoorsurvival.A

newpromisingapproachistheassociationoftheCytoreductiveSurgery(CRS)withtheHyperthermic

IntraperitonealChemotherapy(HIPEC),whichyetischaracterizedbyhighmorbidityandmortality.

Wereport,toourknowledge,thefirstcaseofWernickeEncephalopathy(WE)complicatingCRSplus

HIPEC.WE,causedbyadeficiencyofthiamine,ischaracterizedbyataxia,ocularmotorcranial

neu-ropathiesandchangesinconsciousness.

METHODS:Apatientaffectedbygastriccancerwithperitonealseeding,submittedtoCRSplusHIPEC,

in4thpost-operativedayhadmanifestedtheappearanceofflappingtremors,withpositive

manoeu-vreofMingazzini,impairedvisionandmentalconfusion.ThebrainMagneticResonanceImaging(MRI)

confirmedtheclinicalsuspicionofWE.Eventhoughtheappropriatetherapywaspromptlyapplied,the

patientdiedin10thpost-operativeday.

CONCLUSION:WEisanuncommonneurologicaldisorder.Only16%ofthesepatientsinadequatelytreated

recoverfully,withamortalityrateof10–20%.Weconsiderusefultoreportthiscase,becauseitisthe

firsttimethatWEiscorrelatedtoCRSplusHIPEC.

©2015TheAuthors.PublishedbyElsevierLtd.onbehalfofSurgicalAssociatesLtd.Thisisanopen

accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Peritonealcarcinomatosis (PC)of gastricoriginis a frequent event even in the earlyphase of the disease,but especially in advancedcases.PC,onceestablished,isassociatedwithpoor sur-vival as shown by many phase III trials that reported median survivalrangingfrom1to13.8months[1]andnosurvivorsatfive years[2].Investigatorsworldwidehavecontinuedtostudy poten-tialtreatmentoptionsforpatientswithgastriccancerwithlimited carcinomatosis,encouragedbytheresults,obtainedinasmallbut meaningfulnumberpatientswithcarcinomatosisofappendiceal andcolorectalorigin[3–5]withtheassociationofCytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).DespiteCRSplusHIPECareburdenedbyahigh

morbid-Abbreviations: WE,WernickeEncephalopathy;PC,peritoneal carcinomato-sis; MRI, magnetic resonance imaging; HIPEC, Hyperthermic Intraperitoneal Chemotherapy;CRS,CytoreductiveSurgery;CDDP,cisplatin;ICU,IntensiveCare Unit;BMI,bodymassindex;p.o.-day,pos-operativeday.

∗ Correspondingauthor.Fax:+390902212633. E-mailaddress:franz.fl[email protected](F.Fleres).

ity[6]WEhasneverbeenrecognizedamongcomplications.WE, anuncommonneurologicaldisorderdescribedforthefirsttime byCarlWernicke[7]iscausedbyadeficiencyofthiamineandis characterizedbyaclassicaltriadofsymptoms,consistingofataxia, ocularmotorcranialneuropathiesandchangesinconsciousness

[8,9].Wereport,toourknowledge,thefirstcaseofWE complicat-ingCRSplusHIPECusedastreatmentofperitonealcarcinomatosis ofgastricorigin.

2. Casehistory

A60year-oldmanwasreferredtoourinstitutionforapoorly dif-ferentiatedadenocarcinomaofthegastricbody.Hewasamoderate drinker(about0.5–1glassofwine/day)andnon-smoker.HisBMI was23.5.Hismedicalhistorywasnotcharacterizedbynothing rel-evant.Preoperativeoncologicalstagingrevealedtheinvolvement ofthegastricserosaland thepresenceofacleavageplanewith thepancreas.ThepatientwassubmittedtoaD2subtotal gastrec-tomyaccordingtoRoux.Alesionwhite-yellowish,foundonthe leftdiaphragmaticperitoneum,wasremovedanditsintraoperative histologicalexaminationdemonstratedthemetastaticorigin,while

http://dx.doi.org/10.1016/j.ijscr.2015.09.012

2210-2612/©2015TheAuthors.PublishedbyElsevierLtd.onbehalfofSurgicalAssociatesLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://

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30 A.Macrìetal./InternationalJournalofSurgeryCaseReports16(2015)29–32

Fig.1. Leftdiaphragmafterperitonectomy.

thecytological exam of peritoneal lavagewas negative. There-fore,thepatientwassubmittedalsotosubtotalleftdiaphragmatic peritonectomy(Fig.1)andHIPECwithclosedabdomentechnique with191mgof cisplatin(CDDP)plus25mgofMitomycinC for 60min.Histologicalexaminationofthestomachshowedan inva-sivemalignantproliferation,extensivelyulcerated,infiltratedthe gastric wallup tothe tunica serosa, characterizedby irregular glandswithhyperchromaticnuclei andnon-cohesiveindividual cellsinfiltratingthestroma.Morphologicalfeatureswere consis-tent withpoorly-differentiated gastric adenocarcinoma(Fig.2). Thepathologicalexaminationofthetwentyremovedlymphnodes demonstrated that two perigastric nodes were metastatic. The definitiveexamconfirmedtheneoplasticnatureoftheperitoneal nodule(Fig.3).Thepost-operativepathologicalstagingwas there-forepT4aN1M1.

After24hinIntensiveCareUnit(ICU),thepatientwas trans-ferredinsurgicaldepartment.In4thpost-operative(p.o.)-day,in absenceofothercomplications,occurredtheappearanceof flap-pingtremors, withpositive manoeuvreofMingazzini, impaired visionandmentalconfusion.Thepatientwassubmittedtoabrain MRI,thatshowed,in T2-weightedscans,a hyperintenseareain theperiaqueductalgraymatter;afterintravenous(i.v.) adminis-trationofGadoliniumwasdemonstratedthehighlightinvolvement ofthemammillarybodies.Thereforetheimaging,alsoatthelight

Fig.2. Histologicalexaminationofthegastriclesion.

ofclinicalpicture,allowedtoperformthediagnosisofWE.The patientwastransferredagaintotheICUandwassubmittedtothe treatmentwiththiamine100mg dailyi.v.Nevertheless,in 10th p.o.-day,hedied.

3. Discussion

Inliterature,CRSplusHIPECarecorrelatedwithmorbidityand mortalityratesthat rangesfrom12to57%andfrom0.9 to11%

[7]respectively.Comparingthevariousdataofthemajorrecords thathavecalculatedtheincidenceofgradesIII–IVevents,the prin-cipalcomplicationsareanastomoticleaks,digestiveperforations, biliaryfistula,pancreaticfistula,ileus/gastricstasis,intraperitoneal abscesses,pancreatitis,nausea/vomiting,smallbowelobstruction, urinarydisturbance,bleeding,respiratory distress[7].Inthe lit-eraturewe didnot findanycase of WE complicating CRSplus HIPEC.WEis anuncommonneurological disorderdescribed for thefirsttimein1881byCarlWernicke,characterizedbya clas-sicaltriadofsymptomsconsistingofataxia,ocularmotorcranial neuropathiesand changes in consciousness [8].A deficiency of thiamineis responsibleforthe complexsymptoms characteriz-ingthissyndrome.Infact,WEoccursprimarilyinthealcoholics while,inthe23%ofcases,it canbeassociated withsome non-alcoholicconditions(prolongedintravenousfeeding,hyperemesis gravidarum,anorexia, refeeding afterstarvation, thyrotoxicosis, regionalenteritis,malabsorptionsyndromes,hemodialysis, peri-tonealdialysis,uremia,HIV,malignancy,restorationstageofsevere acute pancreatitis, and gastroplasty with postoperative vomit-ing)[8]. Animal studiesshowed that alsotumor growthmight be related to the depletion of tissutal thiamine stores, appar-entlybecauseofincreasedthiamineutilization,andsomeclinical reportshaveunderlinedthatsecondary thiaminedeficiencycan beassociated withchemotherapy [9]. Alltheseconditions lead to decreased activation of thiamine pyrophosphate from thi-amine, that serves as a cofactor for three critical enzymes in theintermediatecarbohydratemetabolism:transketolase, ketog-lutarate dehydrogenase and pyruvate dehydrogenase complex

[10].

Actuallyacertaindiagnosisisperformedonlyin5–14%ofcases

[11].Thediagnosiscriteriarequire2ofthefollowing4signs:dietary deficiencies,oculomotorabnormalities,cerebellardysfunction,and eitheranalteredmentalstateormildmemoryimpairment,even ifonlyabout16%ofpatientshadtheclassicclinicaltriad,and19% hadnoclinicalsigns.ThegoldstandardinimagingisMRIwitha sensitivityof53%andaspecificityof93%[11].Actuallyonly16%of patientswithWEinadequatelytreatedrecoverfully,witha

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A.Macrìetal./InternationalJournalofSurgeryCaseReports16(2015)29–32 31

Fig.4. Thegraphshowscisplatin(CDDP)serumleveltrendswitherrorbarsasstandarddeviation.Ontherightarealsoreportedthevaluesofstandarddeviationinorder.

IntheX-axis(orabscissaaxis)thereisreportedthetimeindays.Thefirstthreevaluesarerespectivelyat0time,inthemiddleofperfusionandattheendofperfusion.

talityrateof10–20%[8].Thetreatmentconsistsintheimmediate administrationofintravenous(i.v.)thiamine.Theclinicalresponse afteradministeringthiamineisusuallystrikingandrapidenoughto bevirtuallydiagnostic.Hence,theprognosisofWEdependsonthe stageofdiseaseandpromptinstitutionoftherapywiththiamine

[10].

In our clinical case thediagnosis of WE was performed on the basis of the typicalclinical triad, characterized by positive Mingazzinimanoeuvre,impairedvisionandmentalconfusion.MRI documentedinT2-weightedscans,ahyperintenseareainthe peri-aqueductalgraymatterand,afteri.v.administrationofGadolinium, thehighlightinvolvementofthemammillarybodies.These instru-mental findings permitted to confirm the clinical diagnosis of WE,forwhichthepatientswastransferredinICU. Notwithstand-ingtheprompttherapies, thepatient,in 10thp.o.-day, died,in accordance with the data reported in other manuscripts [12], whichshowthat anumber ofpatientscandieevenifproperly treated.

Asourpatientwasnotheavydrinker,normalnourished,we believe,asreportedinliterature[9],thattheonsetoftheWEcanbe relatedtochemotherapyandtoprimarytumor,that,byincreasing metabolism,hadledtothedepletionofthiamine.

Thepeculiarityofourcaseistobeidentifiedinthe intraperi-tonealadministrationrouteofchemotherapy,whichshouldreduce thesystemiceffects.

We have already shown [13], that the serum level of cis-platin (Fig. 4). although intraperitoneally administered, peaks (6.52±1.61␮g/L)duringperfusion,remainshigh(1.79±0.76␮g/L) uptothe4th p.o.-day, and onlyin the7th p.o.-day,returnsto thebasalvalues(0.92±0.1␮g/L),wherebyalsotheHIPECmaybe responsibleforsystemiccomplications.

Inlightofthiscasereport,webelieveusefultoinclude,among potentialcomplicationsofCRSplusHIPEC,alsoWE.

Consent

Authorsdeclarethattheyhaveobtainedwritteninformed con-sent from the patient for publication of this case report and accompanyingimages.Acopyofthewrittenconsentisavailable forreviewbytheEditor-in-Chiefofthisjournalonrequest.

Conflictofinterest

Allauthorsdeclarethattheyhavenotanyconflictofinterest.

Funding

Theauthorsdeclaretherearenotanysponsorsinvolvement.

Ethicalstatement

Theauthorsdeclarethatallproceduresfollowedwerein accor-dancewiththeethicalstandardsoftheresponsiblecommitteeon humanexperimentation(InstitutionalandNational)andwiththe HelsinkiDeclarationof1975,asrevisedin2008(5).Informed con-sentwasobtainedfromthepatientforbeingincludedinthestudy.

Authorscontribution

Antonio Macrìstudy concept or design, data collection,data analysisorinterpretationandreviewer,writingthepaper.

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32 A.Macrìetal./InternationalJournalofSurgeryCaseReports16(2015)29–32

AntonioIenicontributor. MaurizioRossittocontributor. TommasoMandolfinocontributor. SalvatoreMicalizzicontributor. FrancescoIaropolicontributor. CarmeloMazzeocontributor. MassimoTrovatocontributor. EugenioCucinottacontributor.

EdoardoSaladinocontributor,reviewer.

Guarantor

AntonioMacrì. EdoardoSaladino. FrancescoFleres.

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