Advances in Anorectal Function Testing: Current Status and Future Directions

1. 2nd London Masterclass 2016FUNCTION TESTING – WHERE ARE WE NOW AND WHERE ARE WE GOING? Testingrectalsensoryandbiomechanicalfunction Mark Fox MD, MA, FRCP (London) • Professor, Zürich NGM Group, University HospitalZürich, Switzerland • Lead Physician, Abdominal Center: Gastroenterology, St. Claraspital, Basel • Chair, International Working Group forDisordersof GI MotilityandFunction

2. COI Research & Educational Funds Medtronic, MMS, Sandhill ReckittBenckiser, Almirrall Advisory Role Mui Scientific (manufacturersof RBB pump)

3. Content Background Ano-rectalfunction Whatareaimsofphysiologicalinvestigations Rectal Motor andSensoryFunction Balloon vs. Barostat Studies Standard vs. Rapid BarostatStudies Anal SphincterFunction Standard vs. HR-ARM EUS, Defecography

4. Background: anorectalfunction • Effective anorectal function is like • effective use of a tube of toothpaste • It has got to be full… • You have to know it is full… • You have got to squeeze it and take the lid off… • You have got to put the lid back on when finished! • Courtesy of Anton Emmanuel

5. Background: anorectalfunction • Continence requires both: • Rectum • Fecal Reservoir • Evacuation • Sensation (distension) • Anal Sphincter • Stoolretention • Sensation • Thereis an importantimbalance in ourknowledge! # Pubmed Publications Balloon RectalBarostat Anal Manometry

6. Background: physiologyoffecalcontinence Rectoanal InhibitioryReflex Anorectal Perception Voluntary ExternalSphincter Contraction • Internal SphincterRelaxation „Sampling Reflex“ Mass Movement Rectal Distension

7. Small and / or Non-compliant Rectal Reservoir Weak Sphincter Function Abnormal Sensitivity Background: causesofimpairedcontinencefunction

8. Background - • Stoolconsistency • Diarrhea with high volumes of loose stool is the single most important cause of fecal incontinence • Diarrhea OR ~53 • Obstetric Injury OR ~ 4 • Identify treatable causes of chronic diarrhea Bharucha et al. Gastroenerol. 2010 Camilleri et al. NGM 2014; Walters et al. CGH 2013

9. History& Clinical Examination Endoscopy Proctoscopy / Endoscopy Endoluminal Ultrasound Imaging ConventionalRadiology Transit Studies Defecography Physiological Measurements Manometry / HR-Manometry Endo-FLIP RectalFunction (Balloon, Barostat) PNTML, EMG Continence Test Background: Evaluation ofanorectalsymptoms !?

10. Background: needforphysiologicaltesting Endoscopy and/or conventional radiology Necessary to exclude anorectal neoplasia, inflammation, etc… but often normal in patients with either incontinence or constipation and rarely identify causes of symptoms Would you investigate cardiac function at rest?! We need exercise tests for anorectal function!

11. Small Bowel Caecum Hepatic Flexure Splenic Flexure Sigmoid Colon Normal Colorectal Motility & Function ‘Mass Movement” High Amplitude Peristaltik Contractions (HAPC) Defecation Absorption Bampton et al. Am J Gastroenterology 2000; Dinning et al., Gastroenterology 2004

12. Propagated pressure wave sequences preceding defecation Propagating pressure wave (mean amplitude mmHg) Propagating sequence frequency (per 15 minutes) Dinning et al Gastroenterology 2004;127:49-56

13. High-resolution anorectal manometryMR Defecography Rest Squeeze

14. High-resolution anorectal manometryMR Defecography 30ml Strain Rest RAIR Defecation Positive Pressure Gradient

15. Background: physiologyofvoluntarydefecation Normal anorectal activity documented by MRI Gadolinium Defecography A - at rest B - On contraction of the sphincter C- On straining • Consciousawarenessofneedtodefecate • Colorectalcontractionanddistention • RAIR „Sampling Reflex“ • Coordinatedevacuationofstool • Increase in abdominal pressure • Relaxation ofpuborectaliswithopeningofrectoanal angle • Relaxation oftheanorectalsphincterallowingpassageofstool

16. Background: Indication for physiological tests Tests of rectalas well as anal physiology indicated if patient symptoms persist on conservative therapy: Colonic Motility and Transit Rectal Capacity, Compliance and Sensitivity Anal Sphincter Function Anorectal Coordination Continence Testing

17. Anal SensitivityTesting Sensitivity of anoderm essential for discriminating solid, liquid and gas • Mucosal stimulation • Electrosensory thresholds • Frey hairs • Thermal (heat) thresholds Kamm & Lennard-Jones. Dis Colon Rectum 1990 Chan et al. Dis Colon Rectum 2003

18. Assessment of rectalfunction Current Elastic Balloon (clinical) Barostat Bag (research) New Advance Rapid Barostat Bag assessment

19. Background: aimsofphysiologicaltesting Identify the patho-physiologic basis of disease Provide a meaningful explanation for anorectal dysfunction and symptoms (Urgency, Incontinence, Outlet Obstruction, etc.) Establish definitive diagnosis Guide rational treatment Improvequalityoflife

20. Assessment ofrectalfunction Balloondistension • Elastic balloon • syringe inflated ( air/ water) • rate of ~1 ml/sec • record thresholds volumes • first constant sensation • urge / defecatory desire • maximum tolerated Farthing & Lennard-Jones. Gut 1978 Diamant et al. Gastroenterology 1999

21. Balloondistension: Limitations • Large intersubjectvariation, poor inter-observerreproducibility • Does not measurerectalcapacity • Poor performanceformeasurementofcomplianceandsensation • Measurementsreflectpropertiesofballoonmorethanrectum • Recentstudies • Little ornocorrelationbetweenbarostat/ balloon • Little correlationbetweenfindingsandsymptoms… except at extremes Whitehead et al. Digestive Diseaseand Sciences1997 Scott et al. GastroenterolClin Am 2008 Felt-Bersma et al. Dis Colon Rectum 2000 Sauter/Heinrich et al, Neurogastro and Motil 2014

22. Alternative methods • Mucosal stimulation • electrosensory thresholds • thermal (heat) thresholds • Barostat Method • Measures volume change while maintaining stable pressure within an oversized air-filled bag or vice versa • Rectal capacity, tone, compliance, sensitivity and response Kamm & Lennard-Jones. Dis Colon Rectum 1990 Chan et al. Dis Colon Rectum 2003

23. Assessment ofrectalfunctionRectal Barostat Volume:PressureRelationship Oversized Bag fills Rectum Barostat Pump

24. 500 „Rectalcapacity“ Late (slower) rectalexpansion Maximal Active Relaxation Expansion against ‚Passive resistance‘ 400 300 Early (rapid) rectalexpansion Expansion into potential space, then „activerelaxation“ / „accommodation“ 200 100 0 0 10 20 30 40 Rectal Barostat: Volume:PressureRelationship • Compliance assessed at maximum slope pressure-volume curve. • Capacity assessed at supra-physiological distension pressure (e.g. 40mmHg) Compliance „Distensibility“ Barostat volume (ml) MDP (mmHg) Barostat pressure (mmHg) Fox et al. DCR 2006

25. Difference Compliance p<0.001 400 350 300 Compliance 22 ml/mmHg 250 200 Volume (ml) Compliance 16 ml/mmHg 150 Distensible 100 50 Stiff 0 0 10 20 30 40 Rectal Barostat: Compliance and Capacity • Compliance highly variable on repeated measurement • Rectal capacity stable as determined by rectal structure not function • Similar findings comparing slow and rapid distension protocols Difference Capacity p>0.05 Volume @ 40 mmHg Index 378 ml Conditioning 363 ml Index Conditioning Fox et al. DCR 2006 Intra-balloon pressure (mmHg)

26. Patient #1 Capacity 500ml Patient #2 Capacity250ml Rectal Barostat: Capacity, Compliance, Sensation • Rectal Capacity @ 40mmHgvaries 200-500ml in health (for 700ml bag) • Compliance assessed at maximum slope pressure-volume curve. Measurement closely associated with rectal capacity. 500 Compliance 24ml/mmHg 400 Compliance 12ml/mmHg 300 Barostat volume (ml) 700ml barostat bag 200 #1 100 #2 0 0 10 20 30 40 Barostat pressure (mmHg) Fox et al. DCR 2006 Fox et al. Digestion 2010

27. >90% Capacity Patient #1 Capacity 500ml Compliance 24ml/mmHg Patient #2 Capacity 250ml Compliance 12ml/mmHg Discomfort Rectal Barostat: Capacity, Compliance, Sensation • Sensory thresholds can be assessed as absolute volume and also in terms of distension volume relative to rectal capacity (i.e. percentage filling). • “Normalization by volume” allows direct comparison between patients. Similar performance but more informative than current results 500 ~60-80% Capacity 400 ~20% Capacity 300 Barostat volume (ml) 200 #1 100 #2 0 0 10 20 30 40 First perception Urgency Barostat pressure (mmHg) Fox et al. DCR 2005 Fox et al. Digestion 2010

28. Rectalcapacity Rectalcompliance Rectal sensitivity EffectofAnoRectalFunction on FecalContinence in Health N= 42 Healthy Controls Fox et al. Digestion 2010 Rectal Barostat Internal sphincter / RestingPressure Externalsphincter / SqueezePressure Anal Manometry Continence Test

29. resting pressure rectal capacity squeeze pressure • EffectofAnoRectalFunction on • FecalContinence in Health N= 42 Healthy Controls Fox et al. Digestion 2010 5 4 p=0.001 3 Strength of association (t-values of co-variable) p=0.01 2 p=0.05 1 0 First awareness Urge to defecate First incontinence DuringContinence / Rectal Infusion Test

30. hyper- hypo- • Hypocompliant(‘stiff’): urgency / urge incontinence • Chan, Scott, Williams, Lunniss. Dis Colon Rectum 2005 • Hypercompliant(‘lax’): rectal evacuatory disorder • +/- passive incontinence • Gladman, Dworkin, Williams, Lunniss, Scott. Am J Gastroenterol 2005 Clinical Relevance Rectal Compliance 400 normal volume (ml) 200 Compliance 0 pressure (mmHg) 10 40 • Extreme measures have clinical impact Felt-Bersmaet al. DCR 2000

31. Clinical Relevance Rectal Sensitivity 20-30% hyposensitive Passive incontinence (also constipationand „overflow“) 48 40 30-40% normosensitive Often severe combined sphincter weakness or Diarrhea (high volume stool) 32 Rectal pain threshold (mmHg ) 24 30-40% hypersensitive Often Urge Incontinence (associated with IBS) 16 8 Controls IBS Functional Constipation Incontinence Gladman et al. Dis Colon Rectum 2003 Bouin M, et al Gastroenterology 2002;122:1771–7

32. Measurement of rectal function in clinical practice • Electronic Rectal Barostat measurements: • Best established investigation of rectal physiology • capacity, compliance, sensation • Repeated, pressure or volume guided inflations (computerized electronic pump) • Superior to measurements by elastic balloon • However • Fullmeasurementprotocoll time - consuming(>1h) • Clinical relevanceofmeasurements (compliance, pressurethresholds) not intuitive / well-understood • expensive equipment, availableonly in specialistcenters • not used in routine clinical practice

33. Rapid Barostat Bag (RBB) measurement of rectal function • Insightsfromcontinencestudiessuggestmeasurementsofrectalcapacityplus sensationbased on normalizedvolumethresholdsmaybesufficient in clinicalpractice • Short studyduration (capacityhighlystablemeasurement) • Intuitive results. (i) RectalCapacity. (ii) Relative Sensation as %filling relative to capacity allow comparison between patients • Cheapequipment, Simple protocol Mui Scientific Instruments

34. Assessment ofrectalfunctionin clinicalpractice • Clinical study compared results of measurements obtained by Electronic Barostat vs. Rapid Barostat Bag (RBB) • Healthy Volunteers (N=26) underwent both procedures in randomized order • RBB much quicker (~6 vs. 60min), easier and cheaper than full electronic barostat method • Good agreement for rectal capacity and sensation Sauter, Heinrich et al. NGM 2014

35. Clinical Relevance Rectal Capacity and Sensitivity Patients referred for anorectal investigation (n=124) EAS = external anal sphincter IAS = internal anal sphincter Updated from Heinrich et al. DDW 2015 abstract 7 with Urge Incontinence had either reduced rectal capacity (n=4) and/or rectal hypersensitivity (n=4). 13 with Passive Incontinence had:either reduced rectal capacity (n=6) and/or rectal hyposensitivity (n=10) Many other patients had combined anal and rectal pathology

36. Rapid Barostat Bag (RBB) Mui Scientific Instruments

37. Conclusion • Physiological testsofcontinencefunctionrequire a multimodal approach • Anal sphincterfunction, evenbyHR Manometry, is not sufficient! • Rectalcapacity, complianceandsensitivityare an integral partofthecontinencesystem. • Measurementscanexplainsymptoms in patientswith normal anal manometry • Importantinsightsandrecentadvances • Barostat Bag not Balloons! • Methodologicaladvancesimproveeaseofuse in clinicalpractice, withoutimportantlossofaccuracy

38. Thankyouforyourattention ! International GI Motility and Function Working Group Esophageal Motility: Kahrilas, Pandolfino, Omari, Rommel Reflux / TLESR: Roman, Gyawali, Savarino, Bredenoord Anorectal Physiology: Carrington, Scott, Knowles, Altomare, Rao Hands-On Training: SerhatBor, Jutta Keller, Mark Scott www.iDigest.ch/