J. Coloproctol. (Rio J.) vol.37 número1

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w w w . j c o l . o r g . b r

Journal

of

Coloproctology

Review

Article

Colonic

Inertia:

approach

and

treatment

Ana

Sofia

Garcês

Ferreira

Soares

a,∗

,

Laura

Elisabete

Ribeiro

Barbosa

b a_Universidade_do_Porto,_Faculdade_de_Medicina,_Porto,_Portugal

b_Centro_Hospitalar_de_São_João,_Servic¸o_de_Cirurgia_Geral,_Porto,_Portugal

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received28April2016 Accepted15May2016 Availableonline9July2016

Keywords:

Constipation

Gastrointestinalmotility Gastrointestinaltransit

a

b

s

t

r

a

c

t

Objective:Revisionofthestateoftheartoftheknowledgeregardingpathophysiology, diag-nosisandtreatmentofColonicInertia,whichpredominantlyaffectsyoungwomenandhas asignificantsocio-economicimpact.

Methods:Asearchwasmadein“colonicinertia”,“coloninertia”and“slowtransit consti-pation”inPubMeddatabaseforarticlesofthelast5years,inPortugueseorEnglishwith availableabstractandfulltext.59articlesand2013guidelinesoftheAmerican Gastroen-terologicalAssociationonconstipationwereincluded.

Results:Thepathophysiologyisnotcompletelyelucidatedandthereductionofthe intersti-tialcellsofCajalisthemostconsistenthistologicalfinding.Diagnosisrequirestheexclusion ofsecondarycausesofconstipationandobstructeddefecationsyndrome,towhich con-tributeseveralcomplementarydiagnostictests.Giventhefrequencyoffailureofthemedical treatment,surgeryisoftentheonlypossibleoption.Sacralnervestimulationseemstobea promisingtherapeuticalalternative.

Conclusion: Adeeperinvestigationofthepathophysiologicalmechanismsisfundamentalto acquireamoreglobalandintegratedvision.Rigorouspatientselectionforeachtreatment andthediscoveryofnewtherapeuticaltargetsmayavoidtheuseofsurgicaltherapies.

Inércia

Cólica:

abordagem

e

tratamento

Palavras-chave:

Obstipac¸ão

Motilidadegastrointestinal Trânsitogastrointestinal

r

e

s

u

m

o

Objetivo:Revisãodoestadodaartedoconhecimentodapatofisiologia,diagnósticoe trata-mentodaInérciaCólica,queafetapredominantementemulheresjovensetemumimpacto socioeconómicosignificativo.

Métodos:Pesquisou-senabasededadosPubMedpor“colonicinertia”,“coloninertia”e“slow transitconstipation”porartigosapenasdosúltimos5anos,emportuguêsoueminglêscom resumoetextocompletodisponíveis.Incluíram-se59artigoseasrecomendaçõesde2013 daAssociaçãoAmericanadeGastroenterologiaparaaobstipação.

∗ _{Corresponding}_author_.

E-mail:[email protected](A.S.Soares).

http://dx.doi.org/10.1016/j.jcol.2016.05.006

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Resultados:Apatofisiologiaaindanãoestácompletamenteesclarecida,sendoquearedução dascélulasintersticiaisdeCajalconstituioachadohistológicomaisconsistente.O diag-nósticorequeraexclusãodecausassecundáriasdeobstipaçãoedesíndromedeobstrução defecatória,paraoqualcontribuemváriosexamescomplementaresdediagnóstico.Dada afrequênciadoinsucessodotratamentomédico,acirurgiaé,muitasvezes,aúnicaopção possível.Aestimulaçãonervosasagradapareceserumaalternativaterapêuticapromissora.

Conclusão:Éfundamentalumainvestigaçãomaisprofundadosmecanismospatofisiológicos envolvidosparaadquirirumavisãomaisglobaleintegrada.Aseleçãorigorosadepacientes paracadatratamentoeadescobertadenovosalvosterapêuticospoderãoevitarautilização deterapêuticascirúrgicas.

Introduction

Severe/intractablecolicinertiaorslowtransitconstipationis theinabilitythatthecolonhastomodifystoolconsistency,so astomakethemmovefromthececumtorectosigmoidatleast onceeverythreedays.Thereisasignificantdelayincolonic transit,notattributabletoanyothercause.1–4

Slowtransitconstipationisresponsibleforavariable per-centage (13–37% in recent studies) of cases of idiopathic chronicconstipation(lastingmorethan3months).This con-dition isclassified as a functional one according to ROME III criteria, contrary to the American Gastroenterological Association.5–11

Theconditionpredominantly affects young womenand hasasignificanteconomicimpact.6,11–14

Inaddition toconstipation,a lackofdesiretodefecate, abdominaldistension,abdominalpain,feelingofincomplete evacuation,nausea,anddecreasedfoodintakemayalsobe present.11,15

Thediagnosisisestablishedbyclinicalexaminationand ancillary diagnostic tests,including colonictransit studies; buttheseproceduresarenotsufficienttoselectpatientswith aviewtothemostappropriatetreatment.Thetreatmentof slow-transitconstipationis notstandardized, and the fail-ureofmedicaltreatment(whichoftenoccurs) isa surgical indication.Butsurgery,thoughwithpotentialgoodfunctional results,cannotsolveallthesymptoms.8,16,17

Onemustknowthepathophysiologyofthisentityinorder togivethebesttreatmentforeachpatient,withthehelpof complementarydiagnostictests.

Methods

ThesearchforthisreviewwasconductedinJulyandAugust 2015,andPubMedwasthedatabaseused.“Colonicinertia,” “coloninertia,”and“slowtransitconstipation”weresearched, alwaysusingasfilterstheabstractandfull-textavailability, articlesfromthelastfiveyears,andarticlesonlyinPortuguese and English. Seventeen, 11 (7 repeated) and 100articles (6 repeated)were obtained,respectively.Ofthese115articles, we did not haveaccess to one. After reading and analyz-ing these 114articles, 59 were selected for theirrelevance andimportancetothe subjectstudied.The2013American

GastroenterologicalAssociationrecommendationsfor consti-pationwerealsoincluded.

Pathophysiology

In order to have a normal bowel function, there must be integrityofthegut–brain–microbiomeaxis.Supposeif prob-lemscanoccuratanylevel,somemoregetlocalized(atthe colon wall level), other get more widespread. Manometric studieshaveshownthatcolonicmotoractivityisacomplex, intermittent,and variable intimeand space phenomenon, andthisoccursalsoamongdifferentsegmentsofthecolon.It isknownthatincasesofslowtransitconstipationthereisa changeofintestinalmotility,intermsoffrequency,amplitude and duration,but theunderlying mechanismsare notwell known.Variousexplanationsofpossibleetiologiesrelatedto myopathy,neuropathy(myentericplexus,changesinthe lev-elsofneuroendocrinetransmitters,centralneuropathy),ora reductionoftheinterstitialcellsofCajalhavebeenproposed, and seeminglythelatterpropositionisthemostconsistent histologicalfinding.Therehavebeenseveralobservationsthat supporteverypossibleetiology.8,16–19

Decreaseofspontaneoushigh-amplitudepropagating

sequences,aftermealsanduponwaking

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Asthecentralnervous systemappearstoplayarole in increasingthepropagationpressureaftermealsandin induc-ing their nocturnal suppression, a decreased or inhibited response to these stimuli, such as that found in cases of slowtransitconstipation,possiblysuggestsaneuropathy,or myopathy.Moreover,thisreducedresponsealsosuggeststhe possible involvement ofclock genes, which are central or peripheral(incolonicepitheliumandmyentericplexus)and, inturn,cancontroldirectlyorindirectlycolonicgenegroups thatregulatemotility.Inslowtransitconstipation,onecan alsoobserve adecreased responseto chemicalstimuli, for example,tobisacodyl,whichmayindicateaneuromuscular dysfunction;thiscandrawattention,morespecifically,toa changeofthemyentericplexus,inthecholinergicpathways, orincolonicandrectalneuralpathways.14,19,20,23

Decreaseinthenumberandfrequencyofcyclicmotor

patternsafterhigh-caloriemeals

Cyclicmotorpatterns areanothertypeobservedinhealthy subjects. These are repetitive propagating pressure events withacyclicfrequencyof2–6min−1_{(corresponding}_to_slow

waves)which,forthemostpart,areobservedinthesigmoid colonandwhichcanprogressinananterogradeorretrograde direction.Thesepatternsincreaseinnumberaftermeals.The retrogradecyclicmotorpatternsstandout;theirfunctionisto preventaprematurerectalfillingandprovidesufficienttimein ordertoallowthereabsorptionofwaterandelectrolytes dur-ingtheformationoffeces.Itisbelievedthattheinterstitial cellsofCajalarethesourceofthesepatterns,whichare mod-ulatedbyexcitatorystimuli.Therefore,theobservationofa decreasedpost-prandialresponsealsosuggeststheexistence ofanextrinsicneuropathy,namelyparasympathetic(extrinsic sympatheticstimuli inhibit theintestinal motility) neurop-athy.Anotherstudyfailedtogetaresponseafterapplyingan electricordistensiblestimulation,suggestingtheexistenceof aproblemintrinsictothecolonofthepatientsintheenteric nervoustransmission.20,21,24

Changingthespatial–temporalorganizationof

propagatingsequences

Thepropagatingsequencesareorganizedsoastoallowa con-tinuousflow. Slowtransitappearstobedocumented more frequentlyintheleftcolonthanintheascendingand trans-versecolon.Apan-colonic spatial–temporalmappingstudy usingmanometryevenshowedadecreaseinthepropagating extensionofthewavesoriginatingfromtheproximalcolon, andanincreaseofthefrequencyofretrogradepropagating sequences inthe proximal colon, suggesting the existence ofanadynamiczoneatthelevelofthesplenicangle, corre-spondingtothejunctionzoneoftwodifferentembryological segments and,therefore, possibly witha disruption ofthe innervationzone(probablymoreimportantinsubjectswith constipation at a very early age). It is assumed that the colonicvagalinnervationendsatthelevelofthesplenicangle. Theremainderofthecolonandtherectumreceivesensory innervationfrom pelvicnerves.Theabsence ofthe normal suppressionofnocturnalwavesalsosuggestsacentral neu-ropathiccause.7,14,20,22

DecreaseofinterstitialcellsofCajal

InterstitialcellsofCajalareconsideredasintestinal pacemak-ers, playingacriticalrole inthe regulationofspontaneous electrical activity (“slow waves and enteric transmission”). Thesecellscanbefoundparticularlyatthelevelofmucosa and myenteric plexus.Despite the frequent observationof their decrease in histologic findings in patients with slow transitconstipation,thereisstilldoubtwhetherthisisa pri-marycause,orifitisasecondarychange.Togetherwiththis decrease,areductioninentericnervesandhypoganglionosis arefindingsalsooftenobserved,suggestingtwopossibilities: theexistenceofafactorthatinducesbothdecreases,orthe decreasesinfluencetheirmutualsurvival.9,15,17,18

Otherobservations

Other changes have been observed in patients with slow transitconstipation.Theendocannabinoidsystemhasa con-troversial role in the regulation of intestinal motility and maybebidirectional.However,adecreaseinfattyacidamide hydrolase (FAAH)activity would leadtoanincreaseoftwo endocannabinoids:anandamideand2-araquidonilglicerol (2-AG)which,throughtheiractiononcannabinoidreceptortype 1 (CB1), would lead to a reduction ofintestinal motility.25

Thebrain-derivedneurotrophicfactor(BDNF)appearsto influ-ence the maintenanceand survival ofthe enteric nervous system, accelerating the colonic emptying and increas-ing the frequency of bowel movements. Studies in mice have suggested that a change of BDNF would lead to a changeintheneuralstructureoftheintestinalinnervation, with denervation, causing atrophy and secondary smooth muscledegeneration [withadecreaseinsmoothmuscle␣

-actin (␣-AML) expression] through the kinase tropomyosin

Breceptor-phospholipaseC/inositoltriphosphate (TrkB-PLC-IP3)pathway.Adecreaseofthisfactorinhumanpatientshas been demonstrated.26 _An _increase_in _the _number _of_intact

(not degranulated)mastcellsinthecolonofthesepatients wasalsoobserved,but itwassuggestedthatthiswouldbe apotentialcompensatorymechanism,inordertorepairany damagedneuroentericcircuits,takingintoaccountthatthey constitute asourceofnervegrowth factors.27 _Furthermore,

astudywithmicesuggestedthatmastcelldeficiencycould leadtoaninflammatoryconditionthatwoulddecreasemuscle contractilitybyreducingthereactivitytoacetylcholine(Ach), regardlessofthedecreaseinthenumberoftheinterstitialcells ofCajal.28_Apparently,_the_peptide_YY_(PYY)_is_increased_in_the

ascendingcoloninsomepatients,constitutingapossible eti-ologicalfactor,byleadingtoanincreasedabsorptionandto adecreasedsecretionofwaterandelectrolytes,andresulting inanincreaseoftheilealbrakeforceandintheinhibition ofintestinalmotility.29_The_{downregulation}_of_microRNA128

inthe colonofthesepatientsappearstoleadtoincreased numbers ofmacrophages,which couldleadtolossor dys-functionofthe interstitialcellsofCajal.9 _A_decrease_in_the

expressionofesmotelin,thatsupposedlyplaysarolein mus-clecontractileactivitybyinteractingwith␣-MLAintheouter

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Roleofprogesterone

Thereis evidencethat colonictransitis moreintense dur-ing the luteal phase of the menstrual cycle, and that the speed of propagation of phase III of the migrating motor complex isslowed in women. Althoughwomen with slow transitconstipationhavenormallevelsofprogesterone,there appears to be an overexpression of progesterone recep-torsinthe circular musclelayerofthe colon, which slows its contractility. Progesterone activates two nuclear recep-tors, A and B. The stimulation of A receptors increases muscle relaxation induced by vasoactive inhibitory pep-tides,whereasthestimulationofBreceptorsdown-regulates cyclooxygenase-1 (COX-1) and decreases thromboxane A2 (TXA2) andprostaglandin F2␣ (PGF-2␣)levels, whichwould

leadto musclecontraction. Thislatterreceptor appearsto beresponsibleforwhichnormalmusclecellswillrespondto physiologicalconcentrationsofprogesterona.31,32

Diagnosis

Clinicaldiagnosis

The initial approach of a chronically constipated patient consists in taking a comprehensive collection of medical historyandinathoroughphysicalexamination.Itis impor-tant that, as early as possible, warning symptoms and signs (weight loss, blood loss, and family history ofcolon carcinoma) and secondary causes (improper diet, lack of physicalactivity,useofpharmaceuticalagents,metabolic dis-eases,psychiatricorneurologicaldisorders,complicationsof perineal–pelvic–abdominalorobstetric–gynecologicsurgery) areexcluded.Itisparticularlyimportantthatmalignancyin olderpatientsisexcluded.2,17

Itmay beuseful toapply theWexnerconstipationscale thatsimplifiesandobjectifycomplaints,andtheConstipation SeverityInstrument(CSI)which,inadditiontoidentifyingthe varioustypesofconstipation,alsoscoresitsseverity;onthe otherhand,toassesstheimpactofconstipationonquality oflife,theSF-36questionnaireandtheConstipation-related qualityoflife(CRQOL)areusefultools.2,11,12,17,33_The_Rome_III

CriteriafortheDiagnosisofFunctionalConstipationandthe Bristolstoolscale(aclassificationbasedontheshapeoffeces) arealsoemphasized.2,7,11,34,35

Complementarydiagnostictests

In an initial approach, a complete blood count should be obtained;thereiscontroversyifbiochemicaltestswouldbe ofinterested.10,17,36

Colonoscopyandbariumenema

Colonoscopyallowsastructuralevaluationofthecolonand excludesanatomical/mechanicalcausesofconstipation.This testshouldbedone particularlyifthe patienthaswarning symptoms,showsasuddenonsetofconstipation,orifisaged over50andhaveneverdoneacolorectalcancerscreening.The colonoscopyalsoallowstheachievementofbiopsysamples

(ideallyreachingthemuscularlayer)toevaluatehistological changes.

Abariumenemamaybeindicatedincasesofadifficult bowelpreparationandofcolonictortuosity.1,10,17,36

Defecography,anorectalmanometryandballoonexpulsion test

Itwouldseemthatasignificantoverlapoccursbetweenslow transitconstipationand constipationcausedbypelvicfloor changes.Thedifferentialdiagnosis isessential todelineate anappropriatetherapeuticstrategy.

Defecography is a dynamic morphological radiological study that providesinformation about the anatomical and functional changes that occur in the anus and rectum at rest and during defecation. This test identifies several causes of failure in the evacuation (defecatory dyssyner-gia, defecatoryobstruction). Thepelvic dynamicMRI isan alternative.

Anorectal manometryisaveryuseful toolinthe inves-tigation ofanorectal physiology: it evaluatesthe sphincter pressure at rest, during contraction, and during a defeca-tioneffort.Theballoonexpulsiontestcanalsomeasurethe anorectal coordination during defecation. In analyzing the actionpotentialsofthepelvicmuscles,electromyography pro-videsfurtherinformation.1,2,4,37–39

Transitstudies

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A disadvantage of these methods is the higher radiation exposure.1,2,12,15,37,40–42

Colonmanometry

Colon manometry is of interest in the diagnosis and to thetherapeuticdecision-making,whichshouldnotbebased exclusivelyonradiologicstudies.Thistest showsthe daily motor patterns of bowel activity by measuring multiple regionsofthecolon,andchangesintheircharacteristicshelp to characterize dysmotility. This technique has undergone changeswhich mainlyconsistinincreasingthenumber of data-collectionsensors into the colon and in reducing the spacingbetween thesesensors,namely, the low-resolution manometry becomes a high-resolution test. Taking into accountthatthe motorpatterns arenot evenlydistributed throughoutthecolon,thisresultedinanincreaseinourpower tocorrectlyidentifythepropagatingeventsandtheirdirection andfrequency.Colonmanometryrevealsthatthereisa signif-icantpathophysiologicalheterogeneityamongpatientswith slowtransitconstipation,dividingthemintothreesubtypes basedonthreephysiologicalresponses:high-amplitude prop-agatingcontractions,gastrocolicresponse,andcolicresponse whenawakening.Iftwoofthesethreeresponsesareabsent, this suggests neuropathy(probablycausedby nervecircuit damage,withsecondarymuscledysfunction).Iftwoorthree responsesarepresent,but inanattenuated form(pressure activityless thantwostandarddeviationsfromthe normal motorresponse),thenthiswillsuggestmyopathy(probably causedby target organ or muscle damage,but withintact neural circuits). If the 3responses are present, or if there isaslightchangeofonlyoneoftworesponses,the mano-metricpatternisconsiderednormal.Arelationshipbetween thesepatternsandthe clinicalevaluationandtransit stud-ies has not been established. Thus, it can be concluded thatmanometryisparticularlyimportantforrefractoryslow transitconstipation,servingasaguideforsubsequent treat-ment;andthis technique mayalsopredict the therapeutic effectiveness.

Toassesscolonictoneandsensitivity,onecanconnecta barostatinthemanometer.Thisprocedureisusefulbecause studiesshowthat,inadditiontomotordysfunction,asensory dysfunction–orevenanisolatedsensoryneuropathy–may alsobepresent.However,thismayalsobeonlyaneffect,not acause.

Challengestudieswithbisacodylorneostigminemay be usefultotesttheresidualpropulsiveactivity,thushelpingin aproperselectionofpatientswithseverecolicinertiaorwith slowtransitconstipationforsurgery.8,17,19,42–44

Scintigraphyandcapsuleendoscopy

Scintigraphyandcapsuleendoscopyaremoreadvanced,but more expensive, methods, which limits their application. Thesemethodsallowmeasuringgastric,smallintestine,and colon transit times in a single test; thus, these tests are importanttoassess theregionaltransittimeandexcludea suspectedgastrointestinaldiffusedysmotility.This informa-tionmayhaveprognosticsignificanceinpredictingtheresults ofaggressivetherapies.2,40,45,46

Treatment

Conservativemeasures

Thefirstlineoftreatmentincasesofchronicconstipationis tochangebehavior,withmodificationofthelifestyleanddiet. Thesepatientsshouldbeadvisedtodiscontinuedrugsthat can cause secondaryconstipation,not topostpone defeca-tion whentheyfeelcomfortable,andtodefecateeveryday atthesametime,preferablyinthemorninguponwakingand aftermeals.Itisknownthatconstipationismorefrequent insubjects withasedentarylifestyle;thus theassumption thatincreasedexerciseimprovesintestinaltransittime.Such patientsshouldalsoincreasetheirfluidintake(1.5–2L/day) andfiber(25g/day).However,attemptstoobtainimprovement ofslowtransitconstipationwithfibersupplementsare usu-allyunsuccessful,despitemanystudiesthathavetestedthe useoffiberinthedietofsubjectswithchronicconstipation thatpointedintheoppositedirection.2,3,16,47,48

Medicaltherapy

Laxants

Formanyconstipatedpatients,theuseoflaxativesisa con-stantreality.Besidestheuseoffiberinthediet,severalstudies havealreadyproventheeffectivenessofosmoticand stim-ulantlaxativesinchronicconstipation,becausethesedrugs improvesomesymptomsandacceleratetheintestinaltransit. Whilelaxativeshaveasignificantimpactonthefrequencyand formofthestool,thesedrugshavelittleeffectonabdominal pain,senseofabdominaldistension,thefeelingofcomplete evacuation,andeffortsmadetodefecate(whichmaysuggest thepresenceofaconcurrentdefecatoryobstruction).

Typically, one begins the treatment with fiber and an osmoticlaxative(i.e.,magnesiumsaltorpolyethyleneglycol) and,ifnecessary,withtheadditionofastimulantlaxative(i.e. bisacodyl).16,35,47,48

Prokineticsandintestinalsecretagogues

Prokineticsandintestinalsecretagoguesareagentsthatcan restorethecolonfunctionincasesofconstipation.

Prokineticsaccelerate the colonictransitandhave laxa-tive potentialwhen inducingquick excitatorypostsynaptic potentials in intrinsic neurons, releasing excitatory neuro-transmitters,andactivatingsubmucosalneurons,whichleads toanincreasedmucosalsecretion.Thehighlyselective ago-nistsofthe5-HT4receptor(i.e.prucalopride,naronapride,and velusetrag),besidesbeingveryeffective,haveabettersafety profile,especiallyforcardiovascularsystem.

The use of prucalopride (so far the best-studied drug) shouldbeconsideredwhensymptomaticreliefisnotobtained afterthechangeoflifestyleandtheuseoflaxatives.However, anddespiteleadingtothegenerationofhigh-amplitude prop-agatingcontractionsinthecolon,itseffectontheslowtransit constipationisnotwhatisexpected.

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twodifferentways.Ontheonehand,type2intestinal chlo-ridechannelscanbeactivatedbypromotingsecretionoffluid (lubiprostone).Ontheotherhand,byactingontheguanylyl cyclasereceptorsofenterocytes,thesedrugspotentiatethe increaseinchlorideandbicarbonatesecretionintothe intesti-nallumen(linaclotide).6,7,13,16,47,48

Otherpharmaceuticals

Itmaybeadvantageoustotreatapossiblebacterialovergrowth withantibiotics,duetothereducedintestinaltransit.

Theeffects ofprobiotics inchronic idiopathic constipa-tionarenotwellknown,butitisthoughtthattheseeffects willmodestlydecrease theintestinal transitinconstipated patients.16,47,49

Nervestimulation

Neuromodulatortherapy, orsacralnerve stimulation,is an establishedtreatmentinurologicalpathology(incontinence andretention)andinfecalincontinence.Studiesthattested its applicability in slow transit constipation have shown promising results, as there is a direct involvement in the pathophysiologyofthedisease.Despitethis,theunderlying mechanismsarenotcompletelyunderstood,anditisbelieved that the action occurs in central, sensory and motor lev-els.Apparently,thistechniqueinducespan-colonicpressure waves(includingsequencesofretrogradepropagation,which atfirstmayseemcounterproductive).

Thegreatadvantageofthistechniqueisthatitallowsthe testingofresultsandtheeffectivenessofatemporary stim-ulation,pre-selectingpatientswhowillreceiveapermanent implant(a3-weektemporarystimulationappearstohavea highernegativethan positivepredictive value,but perhaps there is a need for a longer treatment, to obtain results). Strictselectioncriteriafortheapplicationofthis technique arenotestablished.Ingeneral,thetechniqueisappliedwhen the conventional therapy failed. Abetter understanding of thepathophysiologyallowsabetterselectionofpatientsand, therefore,betterresults(somestudiesreportthattheresults willbebetterinthepresenceofanisolatedorconcomitant defecatoryobstruction).

Thestimulationsitevariesfromthetranscutaneous stimu-lationtothedirectstimulationofspecificnerves.NormallyS3 isthestimulatednerve,butitisthoughtthatthestimulation ofposteriortibialnervefibers,bycontaining2ndand3rdnerve roots,willbeofpotentialinterest,thankstotheeasy acces-sibilityofthenerve.Thereisnoconsensusastotheoptimal stimulation.Oversensitivestimuluslevelsappeartobemore effective,butmorestudiesare neededtotestthe subsensi-tivestimulationthatwouldbemoretolerableand,therefore, moreattractivetopatients. Astudyindogsfoundthatthe useofpulsewaves,atechniqueusedinmostanimalstudies, willbemoreeffectivethan the useoflong isolated repeti-tivepulses,whichisthetechniquenormallyusedinhuman studies. A deepening of the knowledge related to meth-odsofdirectelectricalstimulation(intramuscular,serousor intraluminal)ofthe colon,and ofinterferentialtherapyfor treatmentofslow-transitconstipationinadults(stimulation

oftheparasympatheticfibersincreasesthecolonictransit)is required.14,16,33,47,50–57

Otheroptions

Other optionsthatshouldbeconsidered inrelieving symp-toms and that induce some improvements in chronic constipation are rectal/transanal irrigation (its advantages include: a less invasivetechnique versus surgery,it cleans the bowel more proximally versus enemas, it canbe done on anoutpatientbasis,and thepatientcandecide the fre-quencyandtimingoftheprocedure,allowingagreatercontrol ofsymptoms),oranterogradecolonenemas(whichshouldbe consideredforpatientswhoaresatisfiedwiththeresultsof therectalirrigation,butwhofinditinconvenient).47,58

Surgicaloptions

TheAmericanGastroenterologicalAssociationrecommends surgicalinterventionforpatientswithsymptomaticslow tran-sitconstipationwherethecolonicmotordysfunctionhasbeen appropriatelydocumented(manometry,barostat)andincases whoselongandaggressivetherapywithlaxatives,fiber,and prokinetic agents failed(proof of refractoriness tomedical treatment).10,36

Somestudiesclaimthatthefindingofmanometric char-acteristics ofneuropathy constitutes a surgical indication, whereasthisoptionshouldbediscouragedinpatientswitha normalcolonicmanometry,orawithmanometrysuggestive ofmyopathy.3,8,11,47

The twomain surgicaltreatments for slowtransit con-stipation are total colectomy with ileorectal anastomosis andsubtotalcolectomy.Asegmentalcolectomymayalsobe performed.1,11,59

Totalcolectomywithileorectalanastomosis

Thisisthesurgeryofchoiceforcolicinertia.Whenoneoptsfor atotalcolectomy,theanastomosisismadeatthesuperior rec-tumbylaparotomy,laparoscopyorhand-assistedlaparoscopy. Asmostofthepatientsareyoungandactive,theyaregood candidates foralaparoscopic surgery,with theadvantages associatedwiththisprocedure.

Aproperselectionofpatientsforthissurgeryresultsin excellentoutcomes(exceeding85–90%).However,other stud-iesshowthatpatientsatisfactionlevelsvarywidely(39–100%); itislikelythatthishastodowiththepossibilityofsomedegree ofpersistenceofsymptomsandmorbidity.Themostfrequent postoperativecomplicationisasmallbowelobstruction (by occlusionorneuropathicdysfunctionofthemyentericplexus, whichaffectsintestinalmotility).Themortalityofthissurgery isalsovariable.Somestudies reportlessthan 1%,whilein otherthemortalityrangesfrom0to15%.1,3,11,12,15,34,52,59–61

Subtotalcolectomy

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thistechniqueappearstobesimilartototalcolectomywith ileorectalanastomosis,withlowerratesofdiarrheaand post-surgicalincontinence.However,preservationoftheileocecal valveandcecumappearstoresultinahigherrateofrecurrent orpersistentconstipation.

Colonicreservoirsofdifferentsizesmay becreated,but there is still no consensus about what is the best option. However,itseemsthattheshorteningoftheascendingcolon portionabovetheileocecaljunctionresultsinabetter qual-ityoflife(lessdistentionofthececumandless abdominal pain).1,3,47,59–61

Segmentalcolectomy

Althoughanattractiveoption,itisdifficulttodetermine,by meansoftransitstudies,inwhichspecificpartofthecolon occursthedysmotility,orifitoccursthroughoutthecolon, whichmay lead torecurrence ofsymptomsand to persis-tentconstipation;also,anadditionalsurgicalresectionmay beneeded.Thesameproblemoccursinpatientstreatedwith subtotalcolectomy.1

Discussion

Investigationsandobservationsconductedonpatientswith colicinertialedtotheproposalofvariousetiologies, suggest-ingtheexistenceofmultiplecauses.However,todetermine ifsomeofthemarethecauseorconsequenceofthedisease isachallengingtask.Thisquestionisparticularlyrelevantin relationtothefindingsrelated tomyopathy,sincethevast majorityofstudiessuggesttheexistenceofneuropathy (lead-ingconsequentlytothebeliefthattheprimarycauseliesat thispoint).Itwouldbeimportanttohaveaconcatenated, com-prehensiveandintegratedviewofthemechanisms,inorderto clarifywhichchangesareoccurring,particularlyatthelevel ofentericnervoustransmission,regulationandmodulation withfoodintake,andapossibleroleofclockgenes.

Inviewofthepredominanceofcasesinyoungwomen,it wouldbeinterestingtoinvestigatethepossibleoccurrenceof avarietyofcomplaintswithmenstrualcycleanditsrelation withtheoverexpressionofprogesteronereceptors.Thismay projectanewfocusondifferenttherapeutictargets.

Despitethefactthattheevolutionofmanometryallowed anin-depthknowledgeofthepropagationcharacteristicsof thecolon,thereisstillnostandardizationofthetechnique, whichcanresultinapotentiallossofrelevantinformation.It wouldbeappropriatetoclarifywhethertheretrograde prop-agationsequenceshavesomeactiveetiologicalrole.

Asmentionedearlier,somestudiesstatethatneuropathic characteristicsobtainedwithcolonicmanometryconstitute anindicationforsurgery,whilepatientswithanormalcolonic manometry,oronesuggestiveofmyopathyarenotcandidates forsurgery.Onewhyisthis,becausepatientswithmyopathic featurescouldbenefitfromamorelocalizedintervention.

Standardization in the evaluation of the results of dif-ferent surgicalinterventions is very important,in order to obtain amore accurateassessment ofthe advantagesand disadvantages of each procedure, in the decision-making ofanindividualized therapeuticchoice.If the surgeon has tochooseasurgical treatment, theadvantageofferedby a

segmentalcolectomyisundeniable,becauseinthissituation this would allow the most conservative therapy possible. Therefore, wemust emphasizetheimportanceofthe vari-ouscomplementarydiagnostic studies,notonlytoconfirm the surgical indication but also for the exclusion ofother comorbiditiesthatcouldbeassociatedwithaworseoutcome. A broader understanding of the pathophysiology also allowsabetterselectionofpatientsforsacralnerve stimula-tion,whichisanattractivealternativetherapyversussurgery. Thestimulationofdifferentnerverootsandthedirect stimu-lationofthecolonwouldhelpcircumventthefactthatsacral nervestimulationseemstoproducebetterresultsinthecase ofdefecatoryobstructionorinpatientsinwhomthiscondition occurssimultaneouslywiththeslowtransitconstipation.

Conclusion

Althoughthemedicalcommunityhaswitnesseda consider-ableimprovementinunderstandingthepathophysiologyof colicinertiaoverthepastyears,thisisstillinsufficient.The evolutionofslowtransitconstipationasapathologyshouldbe furtherstudied,inordertoeventuallyfindpredictivemarkers ofitsprogression,aswellaswaystopreventtheworseningof thiscondition.

Itismandatorytoregisterthelinesofconductthatshould betakenintoaccountintheguidanceofthesepatients;and itisessentialtofindnewclinicaltargets,particularly consid-eringthatthis entityaffectsasignificant percentageofthe population,inwhomthemostaffectedindividualsareyoung people,andalsobecausetheendofthetherapeuticlineisa surgicalprocedure.

Morestudiesprovidingaglobalperspectivearewelcome. Amoreconsistentbetinrandomizedclinicaltrials,inorderto producehigher-valuescientificevidence,couldresultinmore effectivetherapeuticimplementations.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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