Materiale morbo di Hirschsprung

Casi Particolari

Alessio Pini Prato

Department of Pediatric Surgery, Giannina Gaslini Institute, Genoa, Italy

CISEF, Genova 15/05/2014

Sindrome di Down

Sindrome Down

• L’incidenza media dell’Hirschsprung nella Sindrome di Down è del 1%-3%

• L’incidenza media della Sindrome di Down nell’Hirschsprung è del 3% - 11%

Sindrome Down

Long-term clinical outcome in pat ients with Hirschsprung’sdisease and associated Down’s syndrome

Maria Menezes, Prem Puri*

Journal of Pediatric Surgery (2005) 40, 810–812

www.elsevier.com/locate/jpedsurg

Clinical features of Hirschsprung's disease associatedwith Down syndrome: a 30-year retrospectivenationwide survey in Japan



Sindrome Down

• L’estensione dell’aganglia intestinale è prevalentemente confinata al colon di sinistra

• Le forme estese a tutto il colon sono relativamente rare

Friedmacher and Puri. Ped Surg Int 2013Ieiri S, J Pediatr Surg, 2009

Sindrome Down

• L’incidenza preoperatoria di complicanze occlusive è sovrapponibile

• L’incidenza preoperatoria di enterocoliti è maggiore nei pazienti con Sindrome di Down

Friedmacher and Puri. Ped Surg Int 2013

Sindrome Down

“...è presumibile che le alterazioni innervative nella malattia di Hirschsprung dei pazienti con Sindrome di Down siano più complesse rispetto alla semplice assenza/presenza di gangli ma non cadono entro delle definizioni diagnostiche precise...”

Sindrome Down

• Maggior incidenza di enterocoliti ed incontinenza

• Sovrapponibile incidenza di stipsi

• Maggior mortalità (cardiopatie?)

Friedmacher and Puri. Ped Surg Int 2013

E dopo l’intervento?

Sindrome Down

• Stipsi persistente 20%• Diarrea con escoriazioni perineali 40%• Incontinenza fecale 87%• Reazioni avverse ai cibi 90%• Significativo miglioramento con l’età

Sindrome di Ondine

Sindrome di Ondine

Sindrome di Ondine

• E l’Hirschsprung?– Nel 15-20% dei pazienti con “polialanine”– Nel 90% dei pazienti con altre mutazioni

Le polialanine rappresentano l’85-90% delle mutazioni della sindrome di Ondine

Sindrome di Ondine

Sindrome di Ondine

Gestione delle apnee e delle problematiche di ventilazione:1) Tracheostomia2) Ventilazione non invasiva (maschera)3) Pace-maker diaframmatico (stimolazione del nervo frenico)

Sindrome di Ondine

• L’1,5% dei pazienti con malattia di Hirschsprung hanno la Sindrome di Ondine

• Rapporto fra maschi e femmine = 1:1

• Maggior estensione di malattia rispetto all’Hirschsprung isolato

• Maggior frequenza delle forme intestinali totali

• Frequenti anomalie associate

• Outcome dipende da estensione Hirschsprung, gravità della disventilazione ed anomalie associate

• Implicazioni cliniche

– Problema anestesiologico

– Impatto anomalie associate

– Impatto nutrizionale nelle forme estese a tutto

l’intestino

Sindrome di Ondine

DOI: 10.1542/peds.2011-3844; originally published online October 8, 2012; 2012;130;e1382Pediatrics

PourcyrousElizabeth M. Berry-Kravis, Teresa Santiago, Chukwuma Nnorom and Massroor Kelly L. Jones, Enikö K. Pivnick, Stacy Hines-Dowell, Debra E. Weese-Mayer,

Syndrome, and Hirschsprung DiseaseA Triple Threat: Down Syndrome, Congenital Central Hypoventilation

Ondine, Down e Hirschsprung...

Aganglia Colica Totale


... i gangli si fermano prima di raggiungere il colon ed il risultato

è una malattia estesa a tutto il colon e parte dell’ileo...


• Forma rara (ca 5 casi/anno in Italia)

• 2-13% di tutti i pazienti con Hirschsprung

• Distribuzione sovrapponibile fra i sessi

• Più frequente nelle forme familiari

• Più frequente in caso di mutazioni genetiche


• Manifestazione clinica neonatale

• Possibili manifestazioni subdole con diagnosi tardiva

• Ca. 15% dei pazienti diagnosticati dopo l’anno

• Difficile diagnosi

• Ridotta sensibilità di clisma opaco e biopsia rettale


• Cardini del trattamento:

– Diagnosi precoce

– Ileostomia con diagnosi di estensione (biopsie intraoperatorie)

– Chirurgia radicale dopo i 15-18 mesi di vita

– Escludere anomalie associate e/o mutazioni


Long-term clinical outcome in patients with total colonicaganglionosis: a 31-year reviewMaria Menezes, Alessio Pini Prato, Vincenzo Jasonni, Prem Puri �

Childrens Research Centre, Our Ladys Childrens Hospital, Dublin-12, IrelandGiannina Gaslini Institute, University of Genoa, Genoa, Italy



Long-term outcomes of Hirschsprung’s disease

Risto J. Rintala, MD, PhD, Mikko P. Pakarinen, MD, PhD

From the Section of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Finland.

Seminars in Pediatric Surgery (2012) 21, 336-343

Total colonic aganglionosis in Hirschsprung disease

Samuel W. Moore, MBChB, FRCS, MD(UCT)

From the Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, South Africa.

Seminars in Pediatric Surgery (2012) 21, 302-309


• Risultati a lungo termine:

– Ileostomia definitiva 6,5%

– Continenza normale o accettabile 60%

– Incontinenza e/o soiling 25%

– Mortalità 12%



• Per limitare le complicanze:

– Diagnosi di estensione attendibile (Patologo esperto)

– Ileostomia da mantenere il più a lungo possibile

– Preservazione del canale anale

– Centralizzazione delle cure

Aganglia Intestinale Totale


• Meno dell’1% dei pazienti con Hirschsprung

– Gangli assenti in tutto il colon e nella maggior parte del piccolo intestino

– In passato condizione invariabilmente fatale

– Miglioramento grazie a parenterale e posizionamento percutaneo dei Cateteri Venosi Centrali

– Casi totali descritti nella letteratura mondiale = 68*

*Ruttenstock e Puri, PSI, 2009


• Trattamenti ad oggi disponibili

– Trapianto intestinale 12 pz (mortalità 42%)

– Miotomia/miectomia sec. Ziegler 20 pz (mortalità 40%)

• Casistica IGG

– Totale pazienti seguiti 4 (moralità 25%)

• Ondine 1, isolati 3

• Trattamento conservativoRuttenstock e Puri, PSI, 2009


• Cardini essenziali del trattamento

– Team multidisciplinare (Chirurgo, Gastroenterologo, Nutrizionista, Stoma care, Ematologo, Infettivologo, Rianimatore)

– Nutrizione Parenterale con attento risparmio della funzionalità epatica

– Preservazione del patrimonio venoso

– Stomia con flusso, seppur molto alta, è meglio

Ruttenstock e Puri, PSI, 2009


• Trapianto

– Miglioramento delle tecniche chirurgiche e di immunosoppressione per il trapianto di intestino

• Terapia con cellule staminali

– Inoculazione diretta o libera in cavo peritoneale di cellule staminali adulte o da cordone o da liquido amniotico

– Inoculazione veicolata in nanosfere

• Ricerca di base

– Genetica molecolare, metagenomica, terapia genica

Prospettive future e ricerca clinica e di base

Altri casi particolari

• Sindrome di Mowat-Wilson

• Sindrome di Cat-Eye o 22q

• Sindrome di Bardet-Biedl

• Sindrome Smith-Lemli-Opitz

• Sindrome di Waardenburg-Saha

• Reinterventi

Panel

CISEF, Badia Benedettina della Castagna, 12 giugno 2015

Agenda del Panel (15:30 – 18:30)

• Diagnosi anatomopatologica (Nozza, Murgia) – 10’

• Diagnosi radiologica (Marzoli) – 10’

• Anomalie associate (CAKUT) (Piaggio) – 10’

• Preparazione all’intervento (Holm, Callegari) – 10’

• ... In Sala ... (Paravati, Bevilacqua, Razore) – 10’

• Anestesia e analgesia (Disma, Mameli) – 10’

• Intervento chirurgico (Sanfilippo, Mazzola) – 10’

• Continenza e QOL (Pini Prato) – 10’

• Ustioni del podice (Viglizzo) – 10

• Discussione (Jasonni, Mattioli, Masciavè)




































































































Problematiche gastroenterologiche dei bambini affetti da malattia di

Hirschsprung

Dott.ssa Serena ArrigoU.O. Gastroenterologia ed Endoscopia digestiva

IRCCS G.Gaslini

Problematiche gastroenterologiche

‐ Stipsi‐ Diarrea /incontinenza non ritentiva

‐ Enterocolite

‐ Disidratazione‐ Scarsa crescita

60%

*

*Dismotilità – stasi fecale – disordini dello sfintereanale

Diarrea Stipsi

• +/‐ incontinenza non ritentiva/dermatite

• Terapia: ispessenti fecali (tannato di gelatina, psyllium), loperamide, no succhi di frutta/bevande dolci

• +/‐ soiling • Terapia precoce: macrogol, al bisogno lassativi (senna; bisacodyl); lavaggi rettali; toilette training; fibre e acqua

Aganglia colica totale

• complicanze più comuni, soprattutto nel primo anno post‐intervento e nei lattanti

• > incidenza di ritardo di crescita

• > rischio di disidratazione in caso di gastroenterite/diarrea (mancanza del colon)

• > enterocolite


Disidratazione

‐ uso di soluzioni reidratanti orali a volontà‐ probiotici‐ antidiarroici (es. racecadotril, diosmectite) –“ispessenti” fecali (tannato di gelatina)

‐ in casi selezionati antibiotici per os (metronidazolo)‐ necessità di reidratazione ev

Enterocolite

• > incidenza (20‐50%), > ricorrenza ++ aganglia colica totale, sindromi associate, 1° episodio di enterocolite

• Diarrea, distensione addominale, febbre, vomito disidratazione, sepsi, shock

• Importante prevenire sintomi ostruttivi stasi fecale overgrowth batterico enterocolite

Enterocolite – “Profilassi”

1) RICONOSCERE PRIMI SINTOMI2) Sondaggi/ lavaggi rettali (10‐20ml/kg SF)3) trattamento dermatite:

‐ creme barriera‐ “ispessenti fecali” in caso di incontinenza/soiling

(psyllium, tannato di gelatina)3) probiotici non evidenza scientifica 4) antibiotici per os (decontaminazione intestinale)

non chiara indicazione

Decontaminazione intestinale

‐ ciclo di 7‐10 giorni ai PRIMI sintomi/segni‐ cicli di 7‐10 giorni di antibiotici a rotazione se elevata ricorrenza enterocoliti (prevenzione)/evidenza di overgrowth batterico (breath test glucosio)

attenzione selezione di ceppi resistenti!!

Ruolo della flora batterica disbiosi

Decontaminazione intestinale

Y. Avery Ching, MD et al. Children’s Hospital of Boston, Boston, Massachusetts Nutrition in Clinical Practice 22:653–663, December 2007

• trattamento dell’enterocolite dipende dalla gravità antibiotici per os/ev, idratazione per os/ev, lavaggi rettali, riposo intestinale

• se episodi ricorrenti di enterocoliti severe o se enterocolite cronica con malnutrizione/scarsa crescita nutrizione parenterale di supporto +/‐ileostomia

Enterocolite – Terapia


• In casi selezionati di diarrea cronica può essere di aiuto eseguire ileoanoscopia ileite terminale che può beneficiare di cicli di antibiotici + terapia locale con clismi a base di cortisone e antinfiammatori

Aganglia intestinale totale

• Molto rara, < 1%

• Coinvolgimento di colon e tenue e/o digiuno

• Dipendenza da nutrizione parenterale a lungo termine per la sopravvivenza nel 60‐80%

• Gastrostomia/digiunostomia gestione della

stomia, nutrizione enterale

Aganglia intestinale totale

• tentativo di migliorare la motilità intestinale e la tolleranza enterale farmaci procinetici (es. domperidone, eritrocina, augmentin, somatostatina)

• cicli di antibiotici per trattare sintomi da contaminazione intestinale

Nutrizione parenterale

• “alimentazione” artificiale attraverso un accesso venoso, che utilizza sacche contenenti tutti i nutrienti necessari

• può essere totale o di supporto

• scopo di prevenire o di correggere la malnutrizione in patologie acute e croniche garantire adeguata crescita e sopravvivenza

• Tra le numerose indicazioni alla NP: insufficienza intestinale cronica benigna, dovuta ad insufficiente assorbimento +/‐ alterazioni di transito:

‐ sindrome dell’intestino corto

‐ diarrea cronica intrattabile

‐ disordini della motilità intestinale:

POIC, Hirschsprung complicato/agangliaintestinale totale

Accesso venoso

• vaso centrale se NP a lungo termine differenti tipi di cateteri venosi centrali (CVC)

• gestione molto complessa da parte di personale esperto secondo protocolli standardizzati

• training di uno o più familiari in caso di prosecuzione della NP a domicilio (NP domiciliare)

Organizzazione della NP

• Scelta della sacca (standardizzata/personalizzata)

• Calcolo dei fabbisogni idrici, calorici e dei singoli nutrienti (glucidi, lipidi, aminoacidi, vitamine, oligoelementi) in base all’età ed allo stato nutrizionale

• Modalità di somministrazione: continua vs ciclizzata (10‐16 ore di NP)

Complicanze

• Correlate al CVC: infettive e meccaniche

• Vascolari: trombotiche

• Epatobiliari: epatopatia, calcolosi

Trombosi venoseprofonde

Sepsi ricorrenti

Indicazioni al trapianto di intestino/fegato

Epatopatia

Genetica Molecolare della malattia di Hirschsprung

Isabella Ceccherini UOC Genetica Medica, IGG

Badia Benedettina, 12.06.2015

http://www.gaslini.org/

Vagal NCCs Sox10/p75

Pre-enteric NCCs Sox10/p75±RET/Phox2b

ENCCs (progenitor cells) Sox10/p75/RET/Phox2b; EDNRB; Mash1

Neurons RET/Phox2b/PGP9.5/HuC-D/TuJ1±NOS; ±Calb; ±VIP; ±NPY; ± SubP; ±CGRP; ±5HT; ±ChAT; ±Calret

Glial cells Sox10/p75/Phox2b/B-FABP/S100β/GFAP

Non appena le ENCDCs migrano, esse proliferano estensivamente e dunque differenziano in neuroni e glia e si condensano in gangli a formare un network lungo tutto l’intestino. Tipi cellulari che esprimono sets variabili di marcatori riflettono diversi stadi di maturazione

Disordine congenito della motilità intestinale dovuto a mancanza di gangli in segmenti variabili del tratto gastro-intestinale distale

• - Segmento corto (80%: S-HSCR) • - Segmento lungo (15%: L-HSCR) • - Aganglia colica totale (5%: TCA) • Incidenza

da 15/100.000 a 28/100.000 a seconda della popolazione

Rapporto sessi (M:F) S-HSCR~ 4 L-HSCR/TCA~ 1.5

Familiarità principalmente simplex (80%)

Adapted from Heanue & Pachnis, Nat. Rev. Neurosci. 2007

RET pathway

• Migrazione

• Proliferazione

• Differenziazione

EDNRB pathway

• Migrazione

• Differenziazione prematura

•KBP pathway

• Differenziazione

Combinazioni di varianti comuni, rare o private causano la malattia di Hirschsprung

Fenotipo HSCR + + +

* *

*

Malattia multigenica/complessa :

*

*

* *

opp opp opp

Eterogeneità genetica :

*

Malattia monogenica/semplice :

*

Coinvolgimento di geni multipli

Alta proporzione di casi sporadici

(80-90%)

Rapporto sessi sbilanciato (M:F = 4:1)

Espressività variabile e penetranza ridotta

FENOTIPO

+ + +

* *

*

Malattia multigenica/complessa :

*

*

* *

opp opp opp

Eterogeneità genetica :

*

Malattia monogenica/semplice :

*

Progenitori delle creste neurali

Neuroni sistema nervoso periferico

Melanociti

Gangli enterici

Cellule C della tiroide

Rene Placche del Peyer Testicoli

Malattia di Hirschsprung (HSCR)

Neoplasia endocrina multipla di tipo 2 (MEN2)

Disordine congenito della motilità intestinale

Mutazioni : perdita di funzione

del gene RET

Sindrome neoplastica ereditaria

Mutazioni: acquisto di funzione del gene RET

Mutazioni “loss of function” del gene RET si rinvengono in eterozigosi in <20% dei casi sporadici e in circa 50% di quelli familiari

SP

P20LS32L

L40PR57W

P64L

R77CG93S

C142SC157W

F174S

R180PC197Y

R231HE251K

R287Q

E289QR313Q

R330QV331M

R360W

F393LN394KP399L

R475QC570W

D584GC609W/Y

C620R/S/WC618R/S

Q626K

A654TS690P

T729AE762Q

S765P

S767R

T791PS795R

R813QR873Q

E884DF893L

R897QK907E

M918T

E921K

R972GP973LM980T

P1039L

L1061P

E136XR180X

IVS5+9G>AS365X

c.1120delGc.1204delC

IVS6-5C>T

c.1483ins6CAGGCCIVS7-2A>G

C541Xc.1677dup21ins16;

1699del15c.1836-1842del7CCCTGAG

IVS10+1G>AIVS10+2T>AIVS10+5G>C

IVS10as+62C>TIVS10as+68G>A

IVS11+5C>TIVS12+13C>TIVS12+19C>TIVS12-2A>G

c.2379delC

IVS14+5G>Ac.2675delA

E921Xc.2793delAA

W942X

c.2864insTIVS17+5G>A

c.3118del4CTGG

N1059del

CAD CYS rich TM TK

C611F

C634R/T/G

L790F

E768D

V804L/M

A884FP921L

Class I Class II Class III Class IVHSCRmutations Reduced RET to

cell membraneReduced transport to cellmembrane / constitutive

dimerization

Abrogated/reduced kinase

activity

Compromisedadaptor protein

interaction

Spettro mutazionale di RET : mutazioni molte rare che colpiscono tutti i domini proteici

In ogni genoma vi sono

diversi milioni di posizioni,

su tre miliardi, che

mostrano contenuto

variabile (polimorfico) nella

popolazione (SNPs)

SNP–1 SNP–5

SNP 2

promoter exon2

A C A

exon1

Alleli specifici di varianti introniche

La combinazione di varianti A-C-A è parte di un aplotipo del gene RET

predisponente ad HSCR (62% di pazienti HSCR vs 22% individui di

controllo (p<0.00001))

“RET+3” è una variante localizzata in una sequenza conservata non codificante (intron 1) con putativa funzione di regolazione dell’espressione di RET

Freq. in Caucasici = 24% Freq. in Cinesi = 45%

-1

-5

14

13 15

19

2

aplotipo protettivo definito dallo SNP 14

G G T C C

aplotipo predisponente definito dagli SNPs –5, -1 e 2

A C A

Genere

Familiarità

Lunghezza aganglia

Il rischio verso HSCR varia a seconda di:

Come si distribuiscono le mutazioni/varianti di RET in rapporti ai diversi fattori di rischio?

cad cys rich TM TK1 TK2

P20L

S32L

L40P

P64L

G93S

C142S

R231H

E251K

R330Q

R475Q

C609Y

S609P E762Q

S767R

S765P

C609W

C618R

C620R

K907E

M980T

P1039Q

M1064T

E921K

-27 C/G E136X R180X

1120delG

S365X

1453ins6

C541X

167dup21ins16; 1699del15

1063+9G/A 2013del7

2285+19C/T

2397delC

2675delA

E921X

2939+5G/A

2864insT

W942X

R972G

P973L

P399L

F393L

R897Q

R873Q

F893L

Mutazioni della sequenza codificante (CDS) << 1%

Allele variante dell’enhancer dell’introne 1 (NCDS) ~ 24%

International HSCR Consortium diversi effetti fenotipici di mutazioni codificanti

e non del gene RET in HSCR

Familiarità

Lunghezza segmento Genere

Rare mutazioni della regione codificante di RET

e polimorfismi comuni dello stesso gene hanno effetti complementari in

HSCR, ciascun tipo di mutazione essendo

predominante in una diversa classe fenotipica:

femmine, lungo, familiare vs

maschi, corto, sporadico

Simplex Segmento corto

Maschi

Multiplex Segmento lungo

Femmine

Mutazioni rare regione codificante

Mutazioni comuni regione non codificante

Garcia-Barcelo et al., PNAS 2009

genome-wide association (220 trios) ed uno studio replicativo (429 trios) hanno rivelato una seconda variante NCD prossimale a RET e alleli NCDs sul cromosoma 7, entro il cluster genico delle semaforine di classe 3

Studi in vivo e screeening di mutazioni hanno confermato che il ruolo delle semaforine 3C/3D si è conservato durante l’evoluzione per lo sviluppo dell’ENS, e che la dis-regolazione di SEMA3 è causa di aganglionosi enterica

UNO, il rischio HSCR è altamente significativo in individui con tre o piu’ alleli di rischio

DUE, possedere uno solo o nessun allele di rischio protegge significativamente dalla malattia

TRE, individui con due alleli di rischio non sono nè protetti nè suscettibili verso lo sviluppo di HSCR

La penetranza (probabilità di essere affetti dato un certo genotipo) varia tra ∼1/20 000 nati vivi per la più bassa classe di rischio (allele count 0) e ∼1/800 nati vivi per la più alta classe di rischio (allele count 5 or 6)

Osservate tre classi di individui:

La natura complessa della genetica dell’HSCR isolato rende difficile individuare tutti i fattori che contribuiscono alla sua insorgenza

Mutazioni rare di RET sono causative (con penetranza incompleta) mentre varianti comuni possono giocare un ruolo predisponente

Altri geni sono coinvolti, specialmente con varianti di predisposizione o di dosaggio

Le nuove tecnologie di sequenziamento stanno contribuendo alla ricomposizione del puzzle di geni coinvolti in HSCR

La consulenza genetica è da raccomandarsi in ogni caso

Acknowledgements

Tiziana Bachetti

Eleonora Di Zanni

Paola Griseri

Alice Grossi

Alessandra Lo Sardo

Ivana Matera

Marta Rusmini

Francesco Caroli

Marco Di Duca

Andrea Santamaria

Prof Roberto Ravazzolo

UOC Genetica Medica

Chirurgia Pediatrica, Istituto G Gaslini

Tutte le chirurgie pediatriche che

hanno segnalato pazienti affetti da

HSCR e inviato campioni biologici

Pazienti e le loro famiglie

Y

A

Cec

GGa

b

a

ARAA

KCCPP

1

dr

p

ir

a

G

h1

ARTICLE IN PRESSG ModelDLD-2884; No. of Pages 5

Digestive and Liver Disease xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Digestive and Liver Disease

jou rna l h om epage: www.elsev ier .com/ locate /d ld

limentary Tract

one-like resection, fistulectomy and mucosal rectal sleeve partialndorectal pull-through in paediatric Crohn’s disease with perianalomplex fistula

irolamo Mattioli a,b,∗, Luca Pioa,b, Serena Arrigoa, Alessio Pini Pratoa,iovanni Montobbioa, Nicola Massimo Dismaa, Arrigo Barabinoa

Giannina Gaslini Institute, Genoa, ItalyDINOGMI, University of Genoa, Italy

r t i c l e i n f o

rticle history:eceived 24 February 2015ccepted 6 May 2015vailable online xxx

eywords:omplex fistulaone-like resectionaediatricerianal Crohn’s

a b s t r a c t

Background: Perianal abscesses and fistulae have been reported in approximately 15% of patients withpaediatric Crohn’s disease and they are associated with poor quality of life. Several surgical techniqueswere proposed for the treatment of perianal Crohn’s disease, characterized by an elevated incidence offailure, incontinence, and relapse.

Aim of our study was to present the technical details and results of our surgical technique in case ofrecurrent, persistent, complex perianal ano-rectal destroying Crohn’s disease not responding to medicaltreatment.Methods: Data of patients who underwent surgical treatment (cone-like resection, fistulectomy, sphincterreconstruction, endorectal advancement sleeve flaps like in Soave endorectal pull-through) for com-plicated high-level trans, inter or suprasphincteric fistulae between January 2009 and June 2014 wereretrospectively reviewed.Results: 20 surgical procedures were performed in 11 patients (males 72.7%) with transsphincteric (n = 5),intersphincteric (n = 4) and suprasphincteric (n = 2) fistulae. Three patients needed a second treatment.
Two patients needed more than 2 surgeries and one temporary colostomy. No patient presented analincontinence at 15 months’ median follow-up.Conclusions: Although several procedures may be required to obtain a complete remission of perianallesions, in our series the proposed surgical technique seemed effective and safe, preserving anal conti-nence in all treated cases and reducing the need of faecal diversion.
Gast
© 2015 Editrice
. Introduction

Paediatric Crohn’s disease (PCD) accounts for 20–25% of totaliagnosis of this inflammatory bowel disease, with an incidenceanging from 0.2 to 9.5:100.000 children in the United States.

Perianal disease has been reported in 8–15% of paediatricatients [1,2].

Complex fistula can have transsphincteric, suprasphincteric,ntrasphincteric and extrasphincteric perianal localization [3] and

Please cite this article in press as: Mattioli G, et al. Cone-like resectionthrough in paediatric Crohn’s disease with perianal complex fistula. D

epresents a challenge for paediatric surgeons.In recent years, magnetic resonance imaging (MRI) has become

n important instrument to evaluate complex fistula severity and

∗ Corresponding author at: Paediatric Surgery Unit, Istituto Giannina Gaslini, Largo. Gaslini 5, 16147 Genoa, Italy. Tel.: +39 010 56362217; fax: +39 010 3075092.

E-mail address: [email protected] (G. Mattioli).

ttp://dx.doi.org/10.1016/j.dld.2015.05.003590-8658/© 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All

roenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

pelvic anatomy, providing indications for the correct type of sur-gical intervention. However, many false negative results and poorsensitivity of this tool have been reported [4,5].

Different approaches have been described for the treatment ofcomplex fistula in children, including simple drainage, mobilizationof tissue flaps, seton placement, fistulotomy, anus-sparing procto-colectomy, and defunctioning ileostomy [6–8]. However, the riskof complications remained high, with more than one procedure forrecurrence in 29–50% of cases [8–10].

Aim of this study was to report on the surgical technique usedin our institution, describing surgical details and main results.

2. Materials and methods

, fistulectomy and mucosal rectal sleeve partial endorectal pull-ig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.05.003

2.1. Study population

All patients with diagnosis of perianal PCD admitted to ourInstitute for complex fistula (defined according to Bell criteria)

rights reserved.

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mailto:[email protected]

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IN PRESSG ModelY

2 d Liver Disease xxx (2015) xxx–xxx

wtp

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Fig. 1. Illustration of cone-like resection and rectal sleeve. IS, internal sphincter;ES, external sphincter; IF, intersphincteric fistula; TF, transsphincteric fistula; SS,

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ith recurrent/persistent, anorectal involvement not respondingo medical treatment, between January 2009 and June 2014 wererospectively included in a database.

Patients with simple fistula (subcutaneous fistula) werexcluded from the study.

This study was performed according to national ethical guide-ines and informed consent was obtained for surgical treatment andata collection from parents or guardians. Data including demo-raphics, previous surgical and medical treatments, surgical detailsf interventions, and clinical follow-up were retrospectively ana-yzed.

All patients were studied with pre-operative MRI. All patientsere continent before surgical procedures.

.2. Cone-like resection technique (CLR)

Peri-operative antibiotic prophylaxis with metronidazole wasdministered. Patients were placed in the lithotomy position undereneral anaesthesia without preoperative bowel preparation. Arobe was inserted through the fistula to measure the distance from

ts internal opening. The fistula tract was completely mobilized en-loc with the granulation tissue reaching the normal fatty tissueear the pelvic floor. A cone-like excision of skin and perianal tis-ue was performed with the cone base in the perineum includinghe anal canal if affected, and the cone apex in the rectal wall wherehe fistula opened (Figs. 1 and 2).

Exposure of levator ani was needed to completely remove theffected tissue, including also rectal wall and anal sphincters ifnvolved.

The second step of this surgical approach was to recreate thenal canal. The rectal sleeve was prepared proximally to the inter-al opening of the rectum. We used Soave endorectal pull-through


ERPT), pulling the normal rectal mucosa to the anal skin and sutur-ng the sphincters to recreate anal ring normal shape. The perianalkin was always left open in order to reduce infection risks. No morehan two areas were treated simultaneously (Figs. 2 and 3).

ig. 2. The chronic Crohn’s granulation tissue involves skin, fatty tissue, anal sphincter anreatment, therefore the inflamed tissue should be completely removed before completereviously placed seton.

suprasphinteric fistula; R, rectum; RS, rectal sleeve; CLFR, cone-like fistulectomyresection.

2.3. Endpoints

The primary endpoint was clinical recurrence, defined symp-tomatic recurrence requiring surgical treatment.


Secondary endpoints were definition of 30-day post-operativecomplication rate using Clavien-Dindo classification [11], assess-ment of post-operative faecal incontinence using Yamataka score

d rectal wall. In selected cases, when there is recurrence despite adequate medical destruction of sphincter activity due to risk of sepsis. The blue arrow indicates the

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Fig. 3. Cone-like resection includes removal of ano-rectal canal and perianal tis-sue (skin and subcutaneous) macroscopically involved by Crohn’s granulomatosisreaching the normal muscle of the perineum (levator ani, blue arrow). The secondstep includes restoration of normal continuity of the ano-rectal canal and sphincteractivity (yellow arrow). The proximal rectal mucosa is pulled down to the perianalskin. The anal ring is recreated by suturing the normal muscle. The skin is left open.Ts

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Table 1Overall patient population characteristics (n = 11).

Characteristic N (%)

Males 8 (72.7)Median age (years) 12 (range 5–19)Transsphincteric fistula 5 (45.4%)Intersphincteric fistula 4 (36.4%)Suprasphincteric fistula 2 (18.2%)Median PDAI 5 (range 3–12)Previous surgery

Seton 4 (36.4%)Abscess drainage 6 (54.5%)Fistulotomy 1 (9.1%)

Median operative time (min) 40 (range: 20–80)Median hospital stay (days) 4 (range: 3–7)Median FLACC score 0Median number of procedures 1 (range: 1–5)Complications 0

gical procedures.

he aspect of resection is cone-like, the apex is in the rectum and the base is thekin of the perineum.

12], and analysis of post-operative pain using Faces, Legs, Activity,ry, and Consolability (FLACC) score [13].

Follow-up was performed with clinical evaluation.

.4. Statistical analysis

Continuous variables are reported as means and standard devi-tion or median and range and were compared using Student’s tests; categorical variables are reported as n (%) and were comparedsing Chi-squared tests or Fisher’s test. Possible risk factors as aget presentation, type of previous surgical treatment, pre-operativer post-operative medical treatment were analyzed with statisticalignificance defined as p < 0.05.

. Results

From January 2009 to June 2014, 11 patients were treated (72.7%ales, median age at surgery 12 years, range: 5–19 years).In two patients perianal disease appeared after diagnosis of

rohn’s disease (after 1 and 8 years), during immunosuppres-ive therapy (azathioprine) and on mesalazine. In the other cases,rohn’s disease was diagnosed during the evaluation of perianalisease. Location was ileocaecal (n = 7), ileocolic (n = 3), and panen-eric (n = 1).

At preoperative endoscopy, rectal inflammation was presentnly in 2 cases (18.2%). One girl, previously followed for syndromiciarrhoea by home parenteral nutrition, presented with perianalectal Crohn’s-like disease involvement. Median Perineal Diseasectivity Index (PDAI) was 5 (range: 3–12).

Diagnosis and classification of perineal disease were made byhe surgeon with evaluation under anaesthesia with pelvic MRI.

Four subjects were initially treated at another hospital (3 withimple drainage and seton placement, 1 with fistulotomy). Oneatient presented a gluteus abscess and drainage with seton place-ent was performed along with prolonged antibiotic treatment.


fter abscess resolution, complex fistula persisted. The other patients underwent simple drainage before CLR (54.5%). In 2ases, patients were receiving medical treatment with biologics,

PDAI, Perineal Disease Activity Index; FLACC, Faces, Legs, Activity, Cry and Consola-bility score.

azathioprine and thalidomide (18.2%); in the other 9 cases onlyantibiotics were administered.

The locations of the fistulae are shown in Table 1; transsphinc-teric location was present in 5 patients (45%).

Median surgery duration was 40 min (range 20–80 min) andmedian hospital stay was 4 days (range 3–7 days; Table 1).

Anti-TNF therapy was started in all patients within 10 days post-operatively, for a minimum of 12 months. No significant adverseeffects were observed. Clinical and endoscopic follow-up was per-formed, post-operative MRI was performed in complex cases withmore than two recurrences requiring repeated surgery or to rule outabscess. Step down to thiopurines was performed only in patientswith sustained clinical and endoscopic remission. Median follow-up was 15 months (range 11–56 months).

A total of 20 CLRs with rectal sleeve were performed. In 6 casescomplete remission was obtained after the first operation (54.5%).The remaining 5 required subsequent surgeries for relapses or newlocalizations. Three patients needed a second intervention, one athird procedure. One patient needed five treatments (Supplemen-tary Table S1) and required colostomy for the recurrence of complexfistula, despite biological treatment. Colostomy was closed after 12months and the patient underwent clinical follow-up.

The median number of procedures to obtain fistula healing was1 (range: 1–5).

Evidence of wound healing by second intention was providedin the first month of follow-up (Fig. 4), and at the end of surgicaltreatment all eleven patients healed with complete restitutio adintegrum. No other minor recurrences were observed.

Age at surgery, absence of previous surgical treatments, type ofmedical treatment before surgical procedure were not statisticallyrelated with recurrence. Post-operative pain was easily controlledwith elastomeric pump (chirocaine plus clonidine) for the first twodays and with non-steroidal anti-inflammatory drugs on day threeevery 8 h. Daily FLACC score was 0 for all patients.

No major complications nor anal incontinence were observed(Table 1).

4. Discussion

Complex fistula is a debilitating condition for paediatricpatients. Several treatments have been proposed, however the riskof recurrence remains high with a long history of medical and sur-


Very few studies on major surgical treatments for paediatriccomplex fistula are available in the literature. Current NASPHGANguidelines [6] recommend surgeons not to perform advancement

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4 G. Mattioli et al. / Digestive and Live

Fig. 4. Healing by second intention with normal stool retention, sensory function,ai

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[6] De Zoeten EF, Pasternak BA, Mattei P, et al. Diagnosis and treatment of perianal

nd continence. The cosmetic aspect is not objectively evaluated but scar retractions limited and anal shape is normal.

aps or major surgery for high risk of failure, suggesting colostomyr ileostomy in case of severe or recurrent perianal Crohn’s dis-ase, especially in case of refractory infectious complications (suchs recurrent abscess). Fistulectomy and other major surgical pro-edures did not gain popularity in the treatment of complex fistulaor the risk of sphincter injury and incontinence.

In our opinion, it is better to completely remove perianal chronicnflammatory tissue, obviously only in case of persistent, recurrentomplex disease not responding to medical treatment.

The purpose of this study was to use cone-like resection to reachomplete removal of granulation tissue (fistulectomy) and recreatehe ano-rectal canal. Sphincteric activity was restored using ERPTith rectal sleeve as main surgical technique in complex fistula

n order to reach primary healing, low recurrence rate, and mini-al risk of sphincter injury when sphincteric section was necessary

o remove all inflammatory tissue. ERPT allows the restoration ofearly normal perineal shape and limited scar retractions.

In our series of 11 patients with complex fistula, cone-likestulectomy with rectal sleeve was a safe and well-tolerated pro-edure. Fistula healing rate was 54.5% with no case of faecalncontinence after the first surgical procedure and 100% after max-mum 5 procedures.

In accordance to Arroyo et al. [14] our series confirms that fis-ulectomy with sphincteric surgery is a procedure with limited riskf faecal incontinence.

The role of faecal diversion for complex fistula remains unclearn the literature. In adult patients, the reported incidence is about1% [15], while in children the incidence of faecal diversion waseported in few articles, and in the largest series, 23% of cases hadefunctioning ileostomy with 38% of stoma-related complications7].

Though faecal diversion is an accepted major invasive treat-ent for complex fistula, in addition to stoma complications the

hild’s quality of life must also be considered. In adult patients sometudies on quality of life of have been published [16–18], to ournowledge, there is only one reported study on this topic in theaediatric population [19].

In our series, CLR was used as first major surgical procedurend faecal diversion was associated with fistulectomy only in oneatient (9%) with recurrent complex fistula and high risk of sepsis.


he introduction of biologic agents has dramatically changed theherapeutic strategy for IBD in children. The first evidence-basedractical guidelines on medical management in paediatric-onset

PRESSr Disease xxx (2015) xxx–xxx

Crohn’s disease have recently been published. Among the recom-mended biologics, anti-TNF agents are the treatment of choice inactive perianal fistulising disease in combination with appropriatesurgical intervention [20].

Combined anti-TNF therapy and surgery showed improvedhealing and lower recurrence of fistulae compared with surgeryalone in paediatric patients [21]. Combined treatment was also suc-cessful in adult patients with faster and prolonger fistula healing asdescribed by Sciaudone et al. [22].

Hukkinen reported a 70% healing rate in 13 patients and setonswere kept for 8 months [23]. In our series, all patients recov-ered from complex fistula and wounds healed by second intentionwithin one month.

NASPHGAN guidelines also suggested seton placement for treat-ment of paediatric complex fistula but as reported by Langer et al.[6,7], in some cases up to 7 placements with multiple anaesthe-sia procedures can be required. Furthermore, reported healing ratereported is low.

CLR is characterized by a low number of surgical interventionsand consequently of anaesthesia procedures in children. CLR alsoallows an easy post-operative pain management: morphine is notrequired and patients may be discharged only with non-steroidalanti-inflammatory drugs.

In our experience, CLR is a safe and well-tolerated techniquewith high primary healing and low recurrence rates, without risk ofsphincter injury and faecal incontinence when performed by expe-rienced surgeons. In some cases multiple procedures are required,and adequate medical treatment with biologics is needed to con-solidate remission. CLR could be considered as a primary majorsurgical technique in children with complex fistula, in associationwith biologics, reserving enterostomy only for very difficult non-responder cases.

However, as reported by Pellino et al. [24], other surgical treat-ments like fibrin glue or adipose tissue-derived stem cell injectionhave shown promising preliminary results and further studies arerequired to improve surgical outcomes for the treatment of com-plex fistula.

Conflict of interestNone declared.

Acknowledgements

We thank Anna Capurro for her help in revising the manuscript.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.dld.2015.05.003

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[2] Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinicalcharacteristics of children with newly diagnosed inflammatory bowel dis-ease in Wisconsin: a statewide population-based study. Journal of Pediatrics2003;143:525–31.

[3] Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in-ano. BritishJournal of Surgery 1976;63:1–12.

[4] Essary B, Kim J, Anupindi S, et al. Pelvic MRI in children with Crohn’s diseaseand suspected perianal involvement. Pediatric Radiology 2007;37:201–8.

[5] Toma P, Granata C, Magnano G, et al. CT and MRI of paediatric Crohn’s disease.Pediatric Radiology 2007;37:1083–92.


Crohn’s disease: NASPGHAN clinical report and consensus statement. Journalof Pediatric Gastroenterology and Nutrition 2013;57:401–12.

[7] Seemann NM, Elkadri A, Walters TD, et al. The role of surgery for children withperianal Crohn’s disease. Journal of Pediatric Surgery 2015;50:140–3.

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[8] Strong SA. Perianal Crohn’s disease. Seminars in Pediatric Surgery2007;16:185–93.

[9] Short SS, Dubinsky MC, Rabizadeh S, et al. Distinct phenotypes of chil-dren with perianal perforating Crohn’s disease. Journal of Pediatric Surgery2013;48:1301–5.

10] Keljo DJ, Markowitz J, Langton C, et al. Course and treatment of perianal dis-ease in children newly diagnosed with Crohn’s disease. Inflammatory BowelDiseases 2009;15:383–7.

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14] Arroyo A, Perez-Legaz J, Moya P, et al. Fistulotomy and sphincter reconstructionin the treatment of complex fistula-in-ano: long-term clinical and manometric


results. Annals of Surgery 2012;255:935–9.15] Hong MK, Craig Lynch A, Bell S, et al. Faecal diversion in the management of

perianal Crohn’s disease. Colorectal Disease 2011;13:171–6.16] Lim SH, Chan SW, Lai JH, et al. Journal of Advanced Nursing 2014,

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17] Prieto L, Thorsen H, Juul K. Development and validation of a quality of lifequestionnaire for patients with colostomy or ileostomy. Health and Quality ofLife Outcomes 2005;3:62.

18] Person B, Ifargan R, Lachter J, et al. The impact of preoperative stomasite marking on the incidence of complications, quality of life, andpatient’s independence. Diseases of the Colon and Rectum 2012;55:783–7.

19] Bray L, Sanders C. Preparing children and young people for stoma surgery.Paediatric Nursing 2006;18:33–7.

20] Ruemmele FM, Veres G, Kolho KL, et al. Consensus guidelines of ECCO/ESPGHANon the medical management of Paediatric Crohn’s disease. Journal of Crohn’sand Colitis 2014;8:1179–207.

21] Barabino A, Castellano E, Gandullia P, et al. A girl with severe fistulizing Crohn’sdisease. Digestive and Liver Disease 2000;32:792–4.

22] Sciaudone G, Di Stazio C, Limongelli P, et al. Treatment of complex perianalfistulas in Crohn’s disease: infliximab, surgery or combined approach. CanadianJournal of Surgery 2010;53:299–304.

23] Hukkinen M, Pakarinen MP, Piekkala M, et al. Treatment of complex perianal


of Crohn’s and Colitis 2014;8:756–62.24] Pellino G, Selvaggi F. Surgical treatment of perianal fistulizing Crohn’s disease:

from lay-open to cell-based therapy—an overview. Scientific World Journal2014;2014:146281, http://dx.doi.org/10.1155/2014/146281.

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Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]

1

Journal of Crohn's and Colitis, 2015, 1–7doi:10.1093/ecco-jcc/jjv065

Original Article

Original Article

Paediatric Ulcerative Colitis Surgery: Italian SurveyG. Mattioli1,2, A. Barabino3, M. Aloi 4, S. Arrigo3, T. Caldaro5, M. Carlucci1,2, S. Cucchiara4, P. De Angelis5, G. Di Leo6, M. T. Illiceto7, P. Impellizzeri8, L. Leonelli1,2, G. Lisi9, G. Lombardi7, S. Martelossi6, M. Martinelli10, E. Miele10, A. Randazzo11, C. Romano11, C. Romeo8, E. Romeo5, F. Selvaggi12, S. Valenti11, L. Dall’Oglio5

1DINOGMI, University of Genova, Genova, Italy 2Pediatric Surgery Unit, G. Gaslini Children’s Hospital-IRCCS, Genova, Italy 3Pediatric Gastroenterology Unit, G. Gaslini Children’s Hospital-IRCCS, Genova, Italy 4Department of Pediatrics, Sapienza University of Rome, Rome, Italy 5Surgery and Digestive Endoscopy Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy 6Gastroenterology Unit, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy 7Department of Pediatrics, Unit of Pediatric Gastroenterology and Digestive Endoscopy – Ospedale Civile Spirito Santo, Pescara, Italy 8Pediatric Surgery Unit, Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy 9Pediatric Surgery Unit, ‘G. d’Annunzio’ University of Chieti, Chieti Italy 10Department of Translational Medical Science, Section of Pediatrics, University of Naples ‘Federico II’, Naples, Italy 11IBD Unit Pediatric Department,University of Messina, Messina, Italy 12Unit of General Surgery, University of Naples ‘Fedrico II’, Naples, Italy

Corresponding author: Marcello Carlucci MD, Pediatric Surgery Unit, G. Gaslini Children Hospital-IRCCS, Genova, Italy. Tel: +39 01 05 63 6217; fax: +39 01 03 07 5092; E-mail: [email protected]

Abstract

Background and Aims: Recent epidemiological studies showed an increase in ulcerative colitis among children, especially in its aggressive form, requiring surgical treatment. Although medical therapeutic strategies are standardized, there is still no consensus regarding indications, timing and kind of surgery. This study aimed to define the surgical management of paediatric ulcerative colitis and describe attitudes to it among paediatric surgeons.Methods: This was a retrospective cohort study. All national gastroenterology units were invited to participate. From January 2009 to December 2013, data on paediatric patients diagnosed with ulcerative colitis that required surgery were collected.Results: Seven units participated in the study. Seventy-one colectomies were performed (77.3% laparoscopically). Main surgical indications were a severe ulcerative colitis attack (33.8%) and no response to medical therapies (56.3%). A three-stage strategy was chosen in 71% of cases. Straight anastomosis was performed in 14% and J-pouch anastomosis in 86% of cases. A reconstructive laparoscopic approach was used in 58% of patients. Ileo-anal anastomosis was performed by the Knight–Griffen technique in 85.4% and by the pull-through technique in 9.1% of patients. Complications after colectomy, after reconstruction and after stoma closure were reported in 12.7, 19.3 and 35% of cases, respectively.Conclusions: This study shows that there is general consensus regarding indications for surgery. The ideal surgical technique remains under debate. Laparoscopy is a procedure widely adopted for colectomy but its use in reconstructive surgery remains limited. Longer follow-up must be planned to define the quality of life of these patients.

Key Words: Paediatric ulcerative colitis; IBD; surgery

Journal of Crohn's and Colitis Advance Access published May 14, 2015

http://www.oxfordjournals.org/

mailto:[email protected]?subject=

1. Introduction

Inflammatory bowel diseases include idiopathic disorders associated with chronic inflammation of the gastrointestinal tract and include Crohn’s disease and ulcerative colitis (UC). The definition of UC is a chronic relapsing inflammatory condition of the colon, extend-ing continuously from the rectum proximally to a varying degree, clinically appearing with bloody diarrhoea, tenesmus, abdominal pain, weight loss, vomiting and fatigue. Acute severe exacerba-tions (ASCs) of UC are a medical emergency and are defined by a Pediatric Ulcerative Colitis Activity Index (PUCAI) of at least 65 points (maximum PUCAI score 85 points).1 Recent epidemiological studies suggest that the incidence of UC has increased in the pae-diatric population, being diagnosed before the age of 20 years in 20% of cases; the incidence of UC is reported to be between 1 and 4/100 000/year in American and European studies.2–4 Moreover, UC appears to manifest more aggressively in childhood and 60–80% of all cases present with pancolitis, a frequency that is approximately 2-fold higher than that seen in adults. Because of the increased sever-ity of UC in children, even the colectomy rate 10 years after onset is higher when compared with adult data (40 and 20% respectively).3–6 Additionally, no changes in the colectomy rate have been observed during the last 20 years7 and, although significant progress has been made in the medical treatment of UC, the colectomy rate in children with steroid-refractory disease is still high (60%).8 It was also reported that delayed surgical treatment in cases refractory to medical therapy is associated with an increased risk of postoperative complications.9

Although the medical management of UC, even in its critical phases, has been standardized1,3,4 with well-characterized pharmaco-logical treatment steps, surgical treatment needs to be further defined in the absence of uniformity and consensus. Several studies have tried to identify factors associated with progression to colectomy but there is still no general agreement on the surgical indication, timing and techniques.10–14 Children with active UC are at particular risk of delayed growth and puberty, and correct surgical treatment is necessary to guarantee a better quality of life.

The aims of the study were to define the surgical management of paediatric patients affected with UC in the major national cen-tres for paediatric gastroenterology, focusing on details of surgical technique, postoperative complications and quality of life, and to describe and compare attitudes among paediatric surgeons.

2. Methods

We conducted a retrospective cohort observational multicentre national study from January 1, 2009 to December 31, 2013. All SIGENP (Italian Society of Pediatric Gastroenterology Hepatology and Nutrition) centres were invited to participate in the study through the society’s mailing list and journal. All patients younger than 18 years who had undergone operation for UC in one of the partici-pating centres were included in the study. The diagnosis of inflamma-tory bowel disease was established on the basis of clinical, endoscopic, radiological and histological data according to the Porto criteria.15

Every responsible referent from each centre collected data on demographics, date of UC onset, indication for surgery, PUCAI before surgery, therapy and age of the patient at the time of the first operation, details about staged surgery, operative technique and other technical aspects, postoperative complications and functional results in terms of number of evacuations, daytime and night-time soiling and incontinence at 3 and 12 months of follow-up. The dead-line for data collection was set as January 31, 2014. All data that

were collected were added to a database according to the National Data Protection Act and analysed by a team of two physicians.

2.1. Statistical analysisDescriptive statistics were reported as percentages with the 95% confidence interval (CI), when appropriate, for categorical variables. Median and range were used for age, given the wide variability in our series. Differences in the frequencies of each categorical vari-able were evaluated by the χ2 test. Comparison of continuous data was performed using the two-tailed unpaired t-test. For scant data or non-normal distribution, a non-parametric test (Mann–Whitney) was used. A p value lower than 0.05 was considered statistically sig-nificant. Analyses were performed using Stata for Windows (release 9.0, Stata Corporation, College Station, TX).

3. Results

Seven gastroenterology units participated in the study. A total of 71 cases were collected (37 males and 34 females; male:female ratio 1.08), all of which progressed at least to colectomy. Median age at diagnosis was 9.41 years (SD 4.27). Sixty-seven patients (94.3%) had available data on preoperative medical therapy (Table 1). In 11 cases (16.4%) the therapies were not specified and 5 patients (7.4%) were out of therapy at the time of surgery. Surgical indica-tions were side effects of steroid therapy in 7 cases (9.8%), ASC in 24 cases (33.8%) and UC not responsive to medical therapy in 40 cases (56.3%). The PUCAI index prior to surgery was evaluated in 70 patients; it was <40 in 12 (17.1%), between 41 and 64 in 34 (48.6%) and ≥65 in 24 (34.3%); the median value was 65 (range 20–80). Surgery was performed by a paediatric surgeon in 52 cases (76.4%) and by a general adult surgeon in 16 cases (23.6%); in 3 cases the surgeon’s specialty was unknown.

All patients underwent total colectomy; it was performed by laparoscopy in 51 patients (77.3%) and by laparotomy in 15 cases (22.7%); this information was not reported for 5 patients. Median age at colectomy was 12 years (SD 4.84, range 1.8–17.5) and the operation was performed a median of 2.58 years (SD 2.51, range 0–10.2) after the diagnosis of UC. Twenty-eight patients (39.4%) needed surgery in the first month after diagnosis. Nine patients (12.7%) received only colectomy at the end of the study period without any reconstructive step, 6 laparoscopically and 2 open (data were missing for 1 patient); of these, 4 patients had reconstructive surgery after the study deadline and data were not included. In 1 case reconstructive surgery was delayed beyond the study deadline because of a second operation due to stoma complication. In 4 cases there were insufficient data to determine the cause of the delay in reconstructive surgery.

Sixty-two patients received reconstructive surgery and surgical technical details were reported in 58 cases (93.5%). Only 3 of the participating centres performed mini-invasive surgery at the time of reconstruction and 81.8% of laparoscopic proctectomies and ileo-anal anastomoses were performed at a single centre. A single-stage operation was performed in 1 case (1.6%) and a two-stage opera-tion in 15 (24.2%). A three-stage operation was planned in 46 cases (74.2%) and this was completed with stoma reversal in 36 cases (58%). A laparoscopic approach for reconstructive surgery was cho-sen in 33 patients (57.9%). Nineteen patients (26.8%) still had an ileostomy at the end of the study period; of these patients, 9 did not receive a reconstructive operation, 7 had a reconstructive procedure close to the study deadline and 3 had insufficient data. The stoma was maintained after laparoscopic or open reconstructive surgery in

2 G. Mattioli et al.

7 and 3 cases, respectively. Ileo-anal anastomosis was performed at a median time of 4.7 months (SD 5.7) from colectomy; an ileal pouch was constructed in 50 cases (86.2%) and a straight anastomosis in 8 (13.8%), while 4 patients had insufficient surgical details. Data on ileo-anal anastomosis were reported for 55 of 62 reconstructions: a double-stapled anastomosis according to Knight–Griffen technique was performed in 47 patients (85.4%) and a pull-through anasto-mosis in 5 (9.1%). Three patients who had a pouch constructed had mucosectomy of the anal channel (5.4%). The surgical approach was laparoscopic in 33 cases (56.8%), open in 23 (39.6%) and transanal in 2 (3.4%). After three-stage surgery was completed, ileostomy was closed at a median time of 2.85 months (range 0–12) after the recon-structive operation. Medical therapies were required in 31 patients (55.4%) after stoma closure; probiotics were used in 23 (74.2%), fae-cal thickening agents in 18 (58.1%), steroids or non-steroidal anti-inflammatory agents in 6 (19.3%), immunomodulators in 1 (3.2%), anti-kinetic agents in 4 (12.9%) and other minor therapies in 2 (6.4%). Information on complications after each surgical stage was collected. Postcolectomy complications occurred in 11.2% of cases (8 of 71 procedures), postreconstructive complications in 19.3% (12 of 62 procedures) and postcanalization complications in 26.9% (14 of 52 patients with no stoma); reoperations were required in 2 cases (Table 2). After reconstructive surgery, anastomotic leak was reported in 2 straight procedures (3.2%) and not observed in J-pouch operations (p = 0.01); 1 patient receiving a straight procedure had a single-stage and 1 had a three-stage operation. Anastomotic stenosis was observed in 4 cases (6.4%): 3 patients with straight anastomosis and 1 with a J-pouch (p = 0.006); the patient with a pouch had a three-stage operation. Among patients from the straight group, the patient who had a single-stage procedure and anastomotic leak also presented a stenosis; the other 2 patients had a two-stage and three-stage operation, respectively. Bowel obstruction after reconstructive surgery occurred in 3 cases (4.8%), 2 after a straight procedure and 1 after pouch anastomosis (p = 0.04), all performed by three-stage open surgery. Intestinal occlusion after stoma reversal occurred in 1 patient (1.9%) with a pouch anastomosis. Perianal skin lesions were all described in straight anastomosis procedures (3.8%, 2 versus 0,

p = 0.01), while 2 patients in the straight group and 1 in the J-pouch group had an anastomotic stenosis after stoma closure (5.7%, p = 0.04). Major complication after colectomy refers to patients who present cardiorespiratory failure requiring medical therapy with inotropes, tracheostomy and prolonged total parenteral nutrition. Reoperations were necessary in 2 cases (2.8%). One of these patients presented a bowel obstruction after laparoscopic colectomy because of internal hernia on the stoma site; a second laparoscopic operation was performed, the hernia was reduced and a stoma was recreated. The second patient required the creation of a second stoma because of adhesions between the terminal ileum and uterus after straight anastomosis and stoma closure; anal anastomosis was delayed and a J-pouch anastomosis was performed. Rectal bleeding because of a short tract of affected mucosa was reported in 2 cases (3.8%) but insufficient surgical details were collected.

Clinical follow up-was performed 3 and 12 months after stoma closure, reporting evacuation frequency, daytime and nocturnal soil-ing and incontinence (Table 3). Among patients with stoma rever-sal, follow-up data were collected on 47 cases (90.4% of patients with bowel continuity). After 3 months of follow-up, patients in the pouch anastomosis group had a median of 7 daily evacuations (range 3–20, IRQ 5), while patients in the straight anastomosis group had a median of 10 daily evacuations (range 7–30, IRQ 5). Among these 47 patients, 11 (23.4%) had more than 10 daily evacu-ations (3 patients in the straight group and 8 in the J-pouch; dif-ference not significant). At 12 months of follow-up, patients with a pouch anastomosis had a median of 5 daily evacuations (range 3–10, IRQ 3) while those in the straight anastomosis group had a median of 8.5 daily evacuations (range 5–12, IRQ 6.5). Four patients (8.5%) with more than 10 daily evacuations had follow-up data at 12 months (3 patients with a straight and 1 with a J-pouch anasto-mosis, p = 0.006). Twelve patients (25.5%) reported daytime soiling after 3 months of follow-up (3 in the straight group and 9 in the J-pouch group; difference not significant); the number of cases with daytime soiling decreased to 4 (8.5%) after 12 months of follow-up (3 in the straight group and 1 in the J-pouch group; p = 0.006). After 3 months of follow-up, nocturnal soiling was reported by 13 patients (27.6%, 6 with a straight and 7 with a J-pouch anastomosis, p = 0.0009); nocturnal soiling decreased to 3 and 1 cases, respec-tively (p = 0.006) after 12 months of follow-up (when these patients constituted 8.5% of the overall follow-up population). Incontinence was observed in 10 cases (21.2%) at 3 months of follow-up (3 in the straight and 7 in the J-pouch group; difference not significant) and in 3 J-pouch cases after 12 months of follow-up (6.3%, not significant). Data on pouchitis were collected for 19 of 40 patients with a J-pouch and stoma closure (47.5%). Among these 19 patients, inflammation of the J-pouch was observed at 6 months of follow-up in 3 cases (15.7%) and at 12 months in 1 case (5.2%).

4. Discussion

The increased options for second-line therapy due to advances in the medical treatment of UC in children reduced the need for colec-tomy, despite its curative results. As reported by several studies, the rate of colectomy for UC exacerbations decreased from 40% dur-ing the 1990s to 9% during the 2000s, and in the latest published series the figure was 2.7%.8,10,16 Moreover, the standardization of pharmacological management and the development of an interna-tional approved clinical scoring system (PUCAI) and international guidelines have contributed to the success of the medical therapy of paediatric UC.1,3,4,17 However, surgical treatment is still needed but

Table 1. Medical therapies used in children with UC at surgery. To-tal number of patients on 5-aminosalicylic acid (5-ASA) agents was 6 (9%), on steroid therapy 22 (32.8%), on immunomodulators 29 (43.2%) and on biological agents 13 (19.4%).

Medical therapy Number of patients %

5-ASA agents 2 2.8Steroids 7 9.8Immunomodulators 11 15.5Biological agents 11 15.55-ASA agents + steroids 2 2.8Immunomodulators + biological agents

1 1.4

Steroids + immunomodulators 12 16.9Immunomodulators association 2 2.85-ASA agents + immunomodulators 2 2.8Steroid + immunomodulators + biological agents

1 1.4

Biological agents + immunomodu-lators

1 1.4

Steroids + biological agents 1 1.45-ASA agents + steroids + biological agents

1 1.4

5-ASA agents + biological agents 2 2.8

Paediatric Ulcerative Colitis Surgery: Italian Survey 3

Tab

le 2

. C

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: 71

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t.


no standardization of surgical management has been proposed and indications for surgery, timing and surgical technique still depend on the surgeon’s professional opinion.

4.1. Indications for and timing of surgerySurgery is indicated in cases of ASC not responding to medical ther-apy or in cases of toxic megacolon; these could represent indica-tions for urgent colectomy. Indeed, it is well know that severe and extensive colitis is the main presentation of UC in children.3–6 Other indications for elective colectomy include prolonged steroid therapy complications (growth retardation, osteoporosis, cataract) and poor or absent response to second-line medical therapies.3,4 Moreover, the increased risk of developing colorectal cancer on long-term follow-up may also be an indication for colectomy. Ekbom et al.18 dem-onstrated an incidence of cancer of 5% at 20–years and 40% at 35 years in children with UC diagnosed before 14 years of age; simi-larly, Griffiths et al.19 estimated that children affected by UC had an 8% of risk of cancer 10–25 years after UC diagnosis. Two retrospec-tive studies in a large series from McAteer et al.10 and Kelley-Quon et al.12 identified factors associated with progression to colectomy in children, stressing the importance of disease severity and associated comorbidities when assessing the need for colectomy (malnutrition, hypoalbuminaemia, total parenteral nutrition, electrolyte imbalance, Clostridium difficile colitis, anaemia requiring blood transfusion, sepsis, family history of UC, use of advanced medical therapies). In our series the main indication for colectomy was failure of medical therapy (56%), followed by ASC (34%) and side effects of medi-cal therapy. Nine patients (20%) not responding to medical therapy had colectomy because of the development of ASC. These results are consistent with recent data showing that the main indications for colectomy in children are the failure of second-line medical therapies

and ASC.8 No data on previously reported risk factors were collected in this study, so no negative prognostic factors could be identified. Regarding the timing of surgery, there is still a lack of consensus. A study of adult patients from the UK suggested that delayed sur-gery is associated with an increased risk of complications9; moreover, a large series of paediatric patients from the USA reported an 8% increased risk of colectomy for each successive admission after the primary diagnosis of UC.10 In this study colectomy was executed at a median interval of 2.5 years after diagnosis, being performed in the first month after diagnosis in almost 40% of cases. This could explain the low rate of complications reported in this series, similar to those reported in the studies mentioned above.

4.2. Surgical techniqueThe benefits of laparoscopic procedures are well known in term of cosmesis, pain control and fast-track principles. Regarding colec-tomy, almost 80% of patients in this study had the operation per-formed by mini-invasive surgery. Decisions regarding laparoscopic or open approach to colectomy are completely dependent on the surgical team’s preferences and skills and no significant differences were reported in major complications between the two approaches.

Although in the past ileo-anal straight anastomosis has been the procedure of choice, nowadays restorative proctocolectomy and ileal J-pouch–anal anastomosis are the most frequently used operations, although there are few paediatric data to support this. As reported by the ECCO and ESPGHAN guidelines,3,4 straight anastomosis is associated with a higher failure risk, perianal sepsis and higher stool frequency. It is still debated whether straight anastomosis should be performed in female patients, because of the lower risk of associated reduced fecundity.20–22 This global trend is also evident in our series, as 86% of patients had restorative proctocolectomy and J-pouch

Table 3. Clinical follow-up 3 and 12 months after surgery, comparing patients who received a straight anastomosis with those who received an ileal J-pouch anastomosis (p < 0.05 was considered statistically significant). Overall, 52 patients had a stoma reversal or one-stage sur-gery but 5 were lost to follow-up. Percentages were calculated for the 47 patients with 12 months of follow-up. Pouchitis percentages refer to 19 of 40 patients who received a pouch anastomosis and were checked by endoscopy on follow-up at 6 and 12 months.

Follow-up Number of patients (%) 95% CI Straight versus pouch p

Number of evacuations per day at 3 months1–6 15 (31.9) 20.4–46.1 0 versus 15 (0 versus 31.9%) ns6–10 16 (34) 22.1–48.3 4 versus 12 (8.5 versus

25.5%)ns

>10 11 (23.4) 13.6–37.2 3 versus 8 (6.3 versus 17%) nsNumber of evacuations per day at 12 months1–6 32 (68) 53.8–79.6 2 versus 27 (4.2 versus

57.4%)ns

6–10 12 (25.5) 15.2–39.5 3 versus 9 (6.3 versus 19.1%) ns>10 4 (8.5) 3.3–19.9 3 versus 1 (6.3 versus 2.1%) 0.006Daytime soiling3 months 12 (25.5) 15.2–39.5 3 versus 9 (6.3 versus 19.1%) ns12 months 4 (8.5) 3.3–19.9 3 versus 1 (6.3 versus 2.1%) 0.006Nocturnal soiling3 months 13 (27.6) 16.9–41.7 6 versus 7 (12.7 versus

14.8%)0.0009

12 months 4 (8.5) 3.3–19.9 3 versus 1 (6.3 versus 2.1%) 0.006Incontinence3 months 10 (21.2) 11.9–34.9 3 versus 7 (6.3 versus 14.8%) ns12 months 3 (6.3) 2.1–17.1 0 versus 3 (0 versus 6.3%) nsPouchitis6 months 3 (15.7) 5.5–37.5 - -12 months 1 (5.2) 0.9–24.6 - -

ns, not significant.


ileo-anal anastomosis. The cases treated by straight pull-through were mostly reported at the beginning of the study period; this could be explained by a shift in surgeons’ preferences towards ileal pouch anastomosis because of the advantages of this procedure.

It was reported that ileo-anal anastomosis could be performed with hand-sewn or stapled sutures.23,24 Mechanical sutures make it possible to reduce anal manipulation and the need for mucosectomy, which can be difficult because of the inflamed mucosa; moreover stapled suturing is associated with a shorter hospital stay.25 The intrinsic limitation of this procedure is that it leaves a few centime-tres of inflamed mucosa. Otherwise, in hand-sewn anastomosis proc-tectomy is accomplished by endorectal mucosectomy, permitting a lower anastomosis, just above the columns of Morgagni, avoiding disease recurrence and preserving continence. Some authors have proposed a combined approach, using endorectal mucosectomy prior to mechanical anastomosis.26 In our opinion, although muco-sectomy permits radical treatment of UC, it carries a significant risk of leaving islets of inflamed mucosa in situ, which could be diffi-cult to follow up by endoscopic examination. Moreover, it has not been proved that mucosectomy reduces the risk of dysplasia and malignancies.27 The results of this series highlight the preference for performing a lower anastomosis by a double-stapled technique; although it leaves a few centimetres of affected mucosa with a cer-tain degree of inflammation (cuffitis), it could be easily controlled by medical therapy (systemic or local) and checked periodically by endoscopy. Mucosectomy was performed in only 3 cases from 1 cen-tre, thus reflecting the general opinion that it is not a recommendable procedure because the risk of recurrence that could be difficult to evaluate by endoscopy. Pull-through procedures represent a minor-ity in this series (9%); these data confirm the technical difficulties represented by mucosectomy. Moreover, in pull-through procedures islets of inflamed mucosa could be retained and hidden by the pulled through ileum.

There is still a lack of general consensus among surgeons about the staging of operations. Single-stage procedures have been pro-posed only for selected cases with no risk factors. Both two- and three-stage surgeries are used more often in emergency surgery than in elective surgery. Data from this series showed that most (70%) surgeons preferred the three-stage approach; this could be explained by the high incidence of colectomy performed for ASC, after pro-longed steroid therapies or because of failure of second-line medical therapies. Two-stage surgery was performed mostly in elective sur-gery; in this study group a single-stage operation was executed only in 1 case, in which the surgical approach was combined with lapa-roscopic and transanal straight pull-through. This patient reported postoperative complication, again confirming that a single-stage approach must be reserved strictly for selected cases. A two-stage operation could represent the best indication in patients treated other than in an emergency situation and with minimal risk factors.

The feasibility, safety and benefits of the laparoscopic approach are well demonstrated in the literature.11,14 In this series the laparo-scopic approach to reconstructive surgery was used in 58% of cases and more than 80% of these were treated in one centre. These data reflect the need for a learning curve in performing proctectomy and ileo-anal anastomosis by laparoscopy and lead us to speculate about the need to centralize care in specialized centres in order to guaran-tee the benefits of a full laparoscopic treatment for these patients. Laparoscopic reconstructive surgery was performed mostly after laparoscopic colectomy, but in 6% of cases it was performed after open colectomy and no complications were reported, demonstrating the feasibility and safety of this procedure even after open surgery.

Complications after reconstructive surgery were not significantly different between open and laparoscopic procedures or between pull-through and Knight–Griffen operations. However, there was a significant difference in the complication rate between straight and pouch procedures; anastomotic leak, anal stenosis and bowel occlu-sion occurred more frequently in patients in the straight anastomosis group compared with those who underwent the pouch procedure. The lack of association with postoperative complications represents another point in favour of pouch procedures. When surgery was per-formed in three stages, the only significant differences, after ileos-tomy closure, concerned perianal lesions and anal stenosis, both of which were increased in the straight anastomosis group. These data support the advantages of pouch procedures. Similarly, no differ-ences among surgical techniques were demonstrated in terms of the need for medical therapies after surgery.

4.3. Follow-upWhen analysing data on continence and frequency of evacuation, no differences were found at 3 months of follow-up between the pouch and straight procedure groups, except for night-time soiling, which was higher in patients in the straight anastomosis group. At 1 year of follow-up there was a general decrease in daily evacuation, daytime and night-time soiling and incontinence. When comparing these data on the basis of surgical treatment received at 1-year of follow-up, the straight anastomosis group showed a higher frequency of daytime and night-time soiling than the pouch group, and had more than 10 daily evacuations. These data support the advantages of the J-pouch reservoir in terms of quality of life, which is inversely related to the number of evacuations and incontinence and is in accordance with data from a meta-analysis on 306 paediatric patients.28 However, a multicentre study on 112 paediatric patients showed that the dif-ference in stool frequency was less evident with longer follow-up.29 Pouchitis is the most common complication of pouch anastomosis, occurring with a frequency varying from 30 to 75%.3 Data from our series showed a lower rate of pouch inflammation, because we focused on immediate postoperative complications and short-term follow-up (12 months). As pouchitis can occur several months after surgery, we speculate that the frequency reported in our series might have been higher with longer follow-up. It appears that these patients must be observed for a longer period in order to better define the real outcome of different surgical options in terms of quality of life.

5. Conclusion

This study is the first survey of paediatric patients with UC in Italy and focused on the surgical management of this population. After evaluating the attitude of each referring centre, we found a general consensus regarding indications for surgery, in accordance with the guidelines proposed by ECCO-ESPGHAN. The ideal surgical technique remains debatable, although most of the centres partici-pating in the study performed restorative proctocolectomy with ileal J-pouch–anal anastomosis. Centres using a straight anasto-mosis at the beginning of this study progressively moved towards pouch surgery. Laparoscopy is a procedure widely adopted for colectomy, but its use in reconstructive surgery remains limited to a few centres because of the technical skills required at this stage. Centralization of specialized centres should be considered in order to provide these patients with the benefits of a laparoscopic approach. Longer follow-up must be planned in order to precisely define the advantages of the ileal J pouch in terms of continence and evacuation frequency.


AcknowledgementsThe authors thank the staff of all the medical and surgical units participating in the study.

Conflict of interest

The authors have no relevant financial support or conflicts of inter-est to disclose. There are no funding sources to disclose.

Author contributions

All authors contributed equally to the realization of the study.

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4. Turner D, Travis SPL, Griffiths AM et al. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint state-ment from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol 2011;106:574–88.

5. Gower-Rousseau C, Dauchet L, Vernier-Massouille G et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009;104:2080–8.

6. Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a sys-tematic review. Inflamm Bowel Dis 2011;17:440–9.

7. Benchimol EI, Guttmann A, To T et al. Changes to surgical and hospitali-zation rates of pediatric inflammatory bowel disease in Ontario, Canada (1994–2007). Inflamm Bowel Dis 2011;17:2153–61.

8. Turner D, Walsh CM, Benchimol EI et al. Severe pediatric ulcerative colitis: inci-dence, outcomes and optimal time for second line therapy. Gut 2008;57:331–8.

9. Randall J, Singh B, Warren BF et al. Delayed surgery for acute severe colitis is associated with increased risk of postoperative complications. Br J Surg 2010;97:404–9.

10. McAteer JP, Larison C, Wahbeh GT et al. Total colectomy for ulcerative colitis in children: when are we operating? Pediatr Surg Int 2013;29:689–96.

11. Flores P, Bailez MM, Cuenca E et al. Comparative analysis between lapa-roscopic (UCL) and open (UCO) technique for the treatment of ulcerative colitis in pediatric patients. Pediatr Surg Int 2010;26:907–11.

12. Kelley-Quon LI, Jen HC, Ziring DA et al. Predictors of proctocolectomy in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 2012;55:534–40.

13. Mattioli G, Guida E, Pini-Prato A et al. Technical considerations in chil-dren undergoing laparoscopic ileal-J-pouch anorectal anastomosis for ulcerative colitis. Pediatr Surg Int 2012;28:351–6.

14. Mattioli G, Pini Prato A, Barabino A et al. Laparoscopic approach for children with inflammatory bowel diseases. Pediatr Surg Int 2011;27:839–46.

15. IBD Working Group of the European Society for Paediatric Gastroenterol-ogy, Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis—the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41:1–7.

16. Turunen P, Ashorn M, Auvinen A et al. Long-term health outcomes in pediatric inflammatory bowel disease: a population based study. Inflamm Bowel Dis 2009;15:56–62.

17. Tomomasa T, Kobayashi A, Ushijima K et al. Guidelines for treatment of ulcerative colitis in children. Pediatr Int 2004;46:494–6.

18. Ekbom A, Helmick C, Zack M et al. Ulcerative colitis and colon cancer: a population based study. N Engl J Med 1990;323:1228–33.

19. Griffiths AM, Sherman PM. Colonoscopic surveillance for cancer in ulcer-ative colitis: a critical review. J Pediatr Gastroenterol Nutr 1997;24:202–10.

20. Cornish JA, Tan E, Teare J, et al. The effect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy and delivery: a systematic review. Dis Colon Rectum 2007;50:1128–38.

21. Waljee A, Waljee J, Morris AM, et al. Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcera-tive colitis. Gut 2006;55:1575–80.

22. Mortier PE, Gambiez L, Karoui M, et al. Colectomy with ileorectal anas-tomosis preserves female fertility in ulcerative colitis. Gastroenterol Clin Biol 2006;30:594–7.

23. Martin LW. Current surgical management of patients with chronic ulcera-tive colitis. J Pediatr Gastroenterol Nutr 1993;17:121–31.

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analysis. J Pediatr Surg 2009;44:1410–7.


Paolo FioreUOSD Centro NutrizionaleIstituto Giannina Gaslini

Assorbimento Intestinale

– Inizia dallo stomaco e termina a livello del colon

– Nel colon vengono assorbiti il 90% dei fluidi

– Na e K, Vit K

– SCFA

Endorsed by the American Academy of Pediatrics and the American Hearth Association Circulation 2005;112:2061-2075

Dramatic Change in Food Sources During the First 2 Years

Individuare la dieta adatta nel MH

– Una corretta alimentazione rappresenta uno fattori fondamentali per la riabilitazione. I problemi nutrizionali …

– ripercussioni sulla qualità della vita

– ripercussioni sullo stato di nutrizione e sull’accrescimento

Problemi Principali

– Stipsi

– Diarrea

– Meteorismo

– Adeguati apporti nutrizionali ? …

La dieta deve essere bilanciata (12-15% proteine, 25% lipidi, 60-65% glucidi)

Sostanzialmente non differisce dalle raccomandazioni e linee guida della popolazione generale

Importante il ruolo dei nutraceutici

Nel lungo termine, non esiste un alimento proibito, in quanto cibi che danno problemi ad un soggetto possono non darli ad un altro

Nei momenti “critici“ si raccomanda aggiungere gradualmente nuovi alimenti alla dieta, allo scopo di osservare la risposta personale all'alimento

Se un cibo causa problemi, sospenderne temporaneamente la somministrazione e riprovare dopo qualche giorno o settimana (processo adattativo)

E’ importante mangiare lentamente e masticare bene

Introdurre liquidi in quantità sufficiente

In caso di diarrea:

- Aumentare ulteriormente l’apporto di liquidi - Frazionare ulteriormente i pasti - K e Na- Prebiotici e probiotici

Problemi Nutrizionali Principali

Nel lattante Nel divezzamento

Nel bambino in attesa di intervento Nel bambino operato Nel bambino stomizzato Nel bambino con importanti resezioni

La genetica clinica

“In passato il genetista era come un “allibratore”, qualcuno che forniva la probabilità che un dato evento potesse accadere. Oggi il genetista partecipa all’azione, cioè alla diagnosi e alla terapia, ha cambiato il suo ruolo in quello di colui che è in grado di offrire certezze”.(Roy D. Schmickel)

La genetica clinicaL’obiettivo più importante della genetica medica

sarebbe prevenire e/o evitare l’insorgenza di malattia. Fondamentali per questo scopo:

la diagnosi presintomatica, la consulenza genetica, l’utilizzo di programmi di screening genetici e la diagnosi prenatale.

Definizione

La consulenza genetica è, secondo quanto definito dal Comittee on Genetic Counselling of the American Society of Human Genetics nel 1974, “… un procedimento informativo relativo a problemi associati alla comparsa o al rischio di ricorrenza in una famiglia di una malattia genetica”.

Consiste nell’aiutare l’individuo o la famiglia a conoscere atti medici (diagnosi, storia naturale e terapia), a comprendere come l’eredità contribuisca alla malattia e a capire il rischio genetico.

Strutturazione e Specializzazione

Consulenza genetica prenatale Consulenza genetica per la diagnosi

prenatale invasiva Consulenza genetica neonatale Consulenza genetica riproduttiva Consulenza genetica teratologica Consulenza genetica nei tumori Consulenza genetica associata a test

genetici di screening Consulenza genetica nelle sindromi

malformative

Punti salienti della consulenza genetica

Non accettare mai per valida una diagnosi riferita ma valutare sempre il paziente in prima persona

Raccolta anamnesi familiare Esame obiettivo del probando e dei collaterali Richiesta di esami specifici Valutazione degli esami effettuati Collaborazione e discussione collegiale con i

colleghi

Raccolta della storia familiare (1)

Rilevare i dati riguardanti la malattia che interessa il probando

Chiedere informazioni su malattie ad insorgenza precoce e prevenibili

Chiedere informazioni sui parenti di primo grado Chiedere informazioni sui parenti che risultano

informativi

Raccolta della storia familiare (2)

Segnalare il gruppo etnico di appartenenza

Chiedere informazioni sulla consanguineità

Effettuare visite di follow-up

L’esame obiettivo in genetica medica

Come nelle altre aree della medicina è una parte essenziale nella valutazione del paziente. Malgrado i rapidi progressi nella ricerca di mutazioni, la diagnosi di molte malattie genetiche si basa ancora su un attento esame obiettivo.

Esame Obiettivo e Anomalie Associate

Le anomalie congenite sono una causa di mortalità e di morbosità nel periodo infantile.

Malformazioni congenite importanti vengono diagnosticate nel 2-3% dei neonati ed in più del 5% dei bambini di 2 anni.

La genetica nella HSCR

First International Workshop on Hirschsprung disease and related Neurocristopathies.Sestri Levante (Genova) 17-19 Marzo 1994Director Prof. Giovanni Romeo

Malattia di Hirschsprung (HSCR)

L’incidenza di HSCR è approssimativamente di 1:5000 nati vivi e varia tra differenti gruppi etnici:

Nord Europa 1,5:10.000 nati vivi Afro-Americani: 2,1:10.000 Asiatici: 2,8:10.000

HSCR da anomalie cromosomiche

Anomalie cromosomiche : un’anomaliacromosomica è presente approssimativamente nel12% degli individui con HSCR (array-CGH)

La più frequente è la trisomia 21 (S. Down) checompare nel 2%-10%

Altre anomalie cromosomiche includono delezioniche comprendono geni associati a HSCR:

del 13q22 (EDNRB) del10q11.2 (RET) del2q22 (ZFHX1B)

HSCR da mutazione genica

Mutazioni di un singolo gene che causanomalattie monogeniche e sono ereditatesecondo un modello di tipo : autosomicodominante, autosomico recessivo, X-linked recessivo.

Possono essere sindromiche o non sindromiche.

Forme Sindromiche

monogeniche di HSCR

Forme non sindromiche di HSCR

HSCR con Anomalie Congenite da causa non nota

Strategia

Esame clinico-dismorfologico per ricerca segni anche minimi che potrebbero indirizzare a forme monogeniche sindromiche

Dettagliata storia familiare Se la causa monogenica non sembra plausibile e se sono

presenti anomalie multiple, ritardo di crescita ,ritardo cognitivo: effettuare cariotipo

Se HSCR monogenica non sindromica è confermata o plausibile: effettuare analisi genetico molecolare per gene RET

Consulenza genetica e rischio ricorrenza

HSCR senza una chiara eziologia è considerata un disordine poligenico con penetranza incompleta, espressivitàvariabile, e con un rapportomaschi:femmine di 4:1

Rischio ricorrenza- HSCR non sindromica AD

Genitori di un probando In una significativa proporzione di individui affetti, la mutazione

identificata nel probando è stata rilevata anche in un genitore sano. In pochi casi documentati, la presenza di due mutazioni in geni

differenti correlati a HSCR in un probando sono state proposte causative della malattia, e ciascun genitore ha trasmesso un singolo allele mutato (ereditarietà digenica)

Un probando con HSCR AD non sindromica può avere la malattia come risultato di una mutazione genica de novo.

N.B.: molti individui con HSCR AD non sindromica hanno un genitore non affetto con la mutazione causativa; la storia familiare spesso appare negativa a causa della penetranza incompleta e dell’espressività variabile.

Rischio ricorrenza- HSCR non sindromico AD

Fratelli di un probando

Il rischio per fratelli di un probando dipende dallo stato genetico dei genitori.

Se un genitore del probando è affetto e/o presenta la mutazione causativa della malattia, il rischio per i fratelli di ereditare la mutazione è pari al 50%. In virtù della penetranza incompleta e dell’espressività variabile, non è possibile predire se il bambino

manifesterà i segni clinici di HSCR.

Rischio ricorrenza HSCR non sindromico etiologia sconosciuta : Rischio empirico

Il rischio empirico complessivo per fratelli di un probando è pari al 4%

Il rischio è più alto per fratelli di probandi con malattia a segmento lungo e dipende dal sesso del probando e del fratello

Il rischio per fratelli di un probando con malattia a segmento corto è più basso.

Rischio empirico di ricorrenza

Rischio ricorrenza- HSCR non sindromico AD

Prole di un probando

Ciascun figlio di un individuo affetto con HSCR AD non sindromica ha una probabilità pari al 50% di ereditare la mutazione.

A causa della penetranza incomplerta, la prole che ereditata l’allele mutato può non sviluppare i sintomi della malattia, e per coloro che sviluppano la malattia non è possibile predirne la gravità

Rischio ricorrenza HSCR non sindromico etiologia sconosciuta : Rischio empirico

La prole presenta un rischio di ricorrenza aumentato rispetto alla popolazione generale, ma non quantificabile.

HSCR E DPN

Se la mutazione causativa è stata identificata nella famiglia, la DPN per gravidanze a rischio aumentato è possibile mediante l’analisi del DNA fetale estratto da amniociti o villi coriali.

A causa della penetranza incompleta e dell’espressività variabile, non è possibile predire se il feto svilupperà i segni clinici dela malattia.

Grazie per l’attenzione !

Malattia di Hirshsprung: dalla parte del bambino – 2 ed12-13 Giugno 2015 CISEF Germana Gaslini, Genova

Michela BevilacquaAntonella ParavatiBarbara Razore

Dip. Cardio-Toraco-Addominale e Trapianti

Il percorso del bambino in Sala Operatoria

Carta diritti del bambino

Articolo 7

Articolo 8

Articolo 14

FAMILY CENTERED CARE

Riconoscere la centralità della famiglia nel bambino con problemi di salute e l'inclusione del contributo e del coinvolgimento della famiglia nel piano assistenziale

Obiettivi

Illustrazione ambienti e operatori della Sala Operatoria

Accoglienza al paziente e alla famiglia

Informazione

Arrivo nel blocco operatorio

Accoglienza e vestizione da parte del personale di supporto

Camera di preanestesia

Accoglienza Incontro con infermiere e

anestesista

Interazione con bambino e genitori

Informazioni generali sull'intervento

Giusta preparazione all'anestesia

Prepararsi all'anestesia: opzioni

Presenza di uno dei due genitori al momento dell'induzione

Somministrare la premedicazione per bocca o per via endorettale

Se c'è un accesso venoso, induzione incameretta con i genitori

In Sala Operatoria

Tutto il personale si “prende cura” del bambino

Per tutta la durata dell'intervento si garantisce:- posizione corretta e sicura- temperatura corporea adeguata

Durante l'intervento chirurgico

Attenzione continua al bambino

Monitoraggio continuo dei PV

Controllo del dolore

Finito l'intervento chirurgico

Risveglio Trasferimento in recovery room- presenza di un infermiere dedicato- monitoraggio PV- valutazione, controllo e trattamento dolore- presenza di un genitore Dopo valutazione anestesiologica rientro in

reparto

Bibliografia

Wong D., Hockenberry M., Nursing care of infants and children, 2003 Mosby

Smith L., Coleman V., Bradshaw M., L'assistenza centrata sulla famiglia, 2008 EdiSES Napoli

Kain Z. N., Mayes L. C., O'Connor T. Z., Cicchetti D. V., Preoperative anxiety in children. Predictors and outcomes, Arch Pediatr Adolesc Med, 1996; 150:1238-45

Documents

Materiale morbo di Hirschsprung