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Week 24: Combination Therapies in IBD: Assessing the Evidence for and Against Stephen B. Hanauer, MD, FACG September 3, 2020 at Noon EDT

Week 23: The Role of Endoscopy in the Management of Pancreatic DisordersVanessa M. Shami, MDAugust 27, 2020 at Noon EDT

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Disclosures:

Satish S.C. Rao, MD, PhD, FACGAdvisory Board / Consultant: Progenity, Ironwood Pharmaceuticals, Takeda Pharmaceuticals, In Control Medical, Vibrant, Quin-Tron, Valeant Pharmaceuticals, Neurogut, Inc.

Research Grant: Progenity, Valeant Pharmaceuticals, Vibrant.

Sarah B. Umar, MDSpouse is a stockholder in Hygieacare.

Virtual Grand Roundsuniverse.gi.org

Fecal Incontinence: Innovations in Clinical Assessment, Diagnosis and

Treatment

Fecal Incontinence: Innovations in Clinical Assessment, Diagnosis and

Treatment

Satish SC Rao, MD, PhD, FACGJ. Harold Harrison, MD, Distinguished University Chair

in Gastroenterology, Professor of MedicineDirector, Neurogastroenterology/Motility

Director, Digestive Health Clinical Research CenterMedical College of Georgia

Augusta University, Augusta, GA

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OBJECTIVESOBJECTIVES

Epidemiology

Pathophysiology

Novel Diagnostic approaches

Treatment options Conservative measures

Role of drugs

Biofeedback Therapy

Others


Case StudyCase Study

PW, 54 yrs, Secretary C/O: Fecal Incontinence Intermittent loose stools 7 Yrs Bloating and increased flatus

Unaware of stool coming out but feels wetness in her groin or stool dripping down the legs

Symptoms worse with loose stools Changes 2 pads daily Prescribed psyllium; little change but flatus

incontinence has increased

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Case Hx – Contd.Case Hx – Contd.

Past Hx: Hemorrhoidectomy, Hysterectomy, Mastectomy, Osteoarthritis

Obstetric Hx: Gravida 3, Para 3, Vaginal deliveries, Forceps delivery x 1

Psychological issues and QOL: Threat of job loss, Stopped socializing and does not go out to eat

Medications: Aspirin, Metamucil, Imodium

O/E: Clinical & neurological evaluation was unremarkable.

Digital rectal exam: Impaired anocutaneous reflex (Rt) Weak resting & squeeze tone


Prevalence of Fecal Incontinence: Fast FactsPrevalence of Fecal Incontinence: Fast Facts

Prevalence in men: 7.4%

Prevalence in women: 9.1%

Prevalence in individuals aged ≥70 years: 17.5%

*Data from NHANES 2005/2006 and 2009/2010 surveys. N=52,195.Ditah I et al. Am J Gastroenterol. 2012;107:S717. Abstract 1762.

Menees S, Chey W et al. Gastroenterol. 2018;154:1672-81

14.4%

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Fecal incontinence- A Multifactorial ProblemFecal incontinence- A Multifactorial Problem

AgingDiarrhea/Urgency Bharucha et al Gastro 2010

0 20 40 60 80 100

Other

Poor rectalcompliance

Impaired rectalsensation

Pudendalneuropathy

Sphincterdysfunction

%

80% > one abnormality-Rao et al Am J Gastro1997;92:469-75

S.C. InjuryPudendal Neuropathy Fecal

Impaction


FECAL INCONTINENCE - HISTORYFECAL INCONTINENCE - HISTORY

Establish rapport & Overcome social stigma

Onset & Precipitating events

Duration, Severity & Timing

Coexisting problems/Surgery/ Urinary Incontinence

Obstetric Hx-Forceps, Tears, Presentation, Repair

Drugs, Caffeine, Diet

Clinical Subtypes & Grading

Rao SS, Am J Gastroenterol 2004;99:1585-604

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Tools for improved understanding of symptoms

Tools for improved understanding of symptoms

Rao SSC, et al. Am J Gastroenterol. 2005;100:1605.

Constipation APP Incontinence APP


Incontinence APP - DiaryIncontinence APP - Diary

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Components of FI Stool Diary APP

Components of FI Stool Diary APP Investigator Use

Patient/Clinician Use


Validation of Paper vs Electronic Diary APP-FIValidation of Paper vs Electronic Diary APP-FI

Electronic (n=10) Paper (n=10) ICC PNumber of FI episodes 12.6 ± 2.7 15.0 ± 3.8 0.812 0.001Use of Pads 24.2 ± 9.9 16.3 ± 9.6 0.849 0.004Stool frequency 31.7 ± 8.9 36.5 ±11.0 0.981 <0.001Number of BMs with Urgency (%) 69 ± 6 75 ± 8 0.714 0.04Mean Stool Consistency -BSFS 5.3 ± 0.4 5.3 ± 0.4 0.783 0.028

Type 1-2 1.2 ± 0.6 2.1 ± 0.8 0.457 0.186Type 3-5 8.9 ± 3.7 10.6 ± 4.9 0.924 <0.001Type 6-7 21.6 ± 8.0 23.9 ± 9.4 0.987 <0.001

What are you doing when leakage occurred?

Sitting or Resting (%) 37 ± 9 28 ± 9 0.355 0.267Household Chores (%) 17 ± 5 18 ± 6 0.504 0.173Working (%) 24 ± 11 29 ± 13 0.735 0.036Traveling (%) 3 ± 1 4 ± 2 0.836 0.006Eating / Drinking (%) 3 ± 2 7 ± 3 0.259 0.321Exercise (%) 0 ± 0 9 ± 7 0 0.5Other (%) 16.5 ± 10 5 ± 2 0.013 0.508

Yan Y, Rao et al APDW 2019

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Rao S. Am J Gastroenterol 2018;112:635-38

DRE video: Available on Amazon


Yan Y, Rao SSC et al. DDW 2019

DRE: Expert vs Junior or Senior Traineen=137 patients

DRE: Expert vs Junior or Senior Traineen=137 patients

Kappa statistics (95% CI)

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FECAL INCONTINENCE - EXAMINATION

General & Neurospinal Exam Perineal Inspection:

» Chemical dermatitis» Rectal prolapse / Gaping anus» Excessive perineal descent» Hemorrhoids» Fistula / ScarsRectal Exam:

» Anocutaneous reflex» Resting & Squeeze tone» Puborectalis» Attempted defecation

Rao SS, Am J Gastroenterol. 2004;99:1585-604

Fecal Incontinence - Clinical Subtypes

Passive Incontinence Involuntary discharge of feces or flatus

without awareness

Urge IncontinenceDischarge of rectal contents in spite of

active attempts to retain

Fecal Seepage Involuntary seepage with otherwise

normal evacuation

Rao, ACG Guidelines, Am J Gastro 2004

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Tests of Anorectal FunctionTests of Anorectal Function

Anorectal High Resolution Manometry

Anorectal 3D-High Definition Manometry

Anal Endosonography

Rectal Compliance Test

Translumbosacral Anorectal magnetic Stimulation (TAMS) test

Balloon expulsion test

Defecography/MR Defecography

Modified from Rao, ACG Guidelines, Am J Gastro 2004


Anal Sphincter Function & Morphology in FIAnal Sphincter Function & Morphology in FI

Normal

HDMAUS

Incontinent

Squeezerest

EAS

IAS

rest

defectdefect

Squeeze

defectdefect

Nguyen M, Rao S et al, DDW 2011

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Clinical Utility of ARM in Fecal Incontinence

Clinical Utility of ARM in Fecal Incontinence

Incontinence Pts

Diagnosis Confirmed 95%

New Information 98%

Influenced Treatment 84%

Normal Study 2%

Not Helpful 14%

Rao et al. Am J Gastro 1997;92:469-75

Translumbosacral AnorectalMagnetic Stimulation (TAMS)

Test

Translumbosacral AnorectalMagnetic Stimulation (TAMS)

Test

1

2

3

4

Rao SS, Tantiphlachiva K et al Dis Colon Rectum 2014;57:645-52

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TAMS testVideo

Demonstration

TAMS testVideo

Demonstration


Tantiphlachiva K, Rao SS et al DDW 2008

Case vignette: Incontinent vs HealthyCase vignette: Incontinent vs Healthy

Healthy

Patient

LEFT RIGHT

Sacro-anal MEPs

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p<0.001p<0.001 p<0.001

Clinical Utility of TAMSFI=152, Mixed=68, LAS=31

Clinical Utility of TAMSFI=152, Mixed=68, LAS=31

Yan Y, Rao S, et al DDW 2019

• FI= Fecal Incontinence

• Mixed= FI and Constipation

• LAS= Levator AniSyndrome


Pharmacological Treatment of Incontinence

Pharmacological Treatment of Incontinence

Fiber SupplementationLoperamideDiphenoxylate/atropine (Lomotil®)Cholestyramine/colestipolAmitriptylineValproic acidClonidine

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Effects of loperamide in F. IncontinenceRCT, n=26

Effects of loperamide in F. IncontinenceRCT, n=26

Placebo Loperamide P

24-hr stool weight (g) 144 (0-466) 72 (0-467) <0.001

Bowel movements

per week13 (0-54) 7 (1-44)

<0.001

% unformed stools

per week62 (0-100) 29 (0-100)

<0.001

Episodes of urgency

per week3 (0-27) 0 (0-7)

<0.001

Read M, et al. Dig Dis Sci 1982


Effects of Cholestyramine (2- 6 g) in F. Incontinence, n=42

Effects of Cholestyramine (2- 6 g) in F. Incontinence, n=42

0

1

2

3

4

5

6

7

INCONTINENCE EPISODES PER WEEK

Nu

mb

ero

fin

co

nti

ne

nc

eep

iso

de

spe

rwe

ek

(Me

an

±S

EM

)

Baseline 3 months Baseline 3 months

*

* p < 0.05 vs baseline

CholestyramineCholestyramine ControlsControls

*

0

1

2

3

4

5

6

7

INCONTINENCE EPISODES PER WEEK

Nu

mb

ero

fin

co

nti

ne

nc

eep

iso

de

spe

rwe

ek

(Me

an

±S

EM

)

Baseline 3 months Baseline 3 months

*

* p < 0.05 vs baseline

CholestyramineCholestyramine ControlsControls

*

Remes-Troche J, Rao SS et al. Int J Colorectal 2007

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Cochrane Review of Medical Therapy - 2013Cochrane Review of Medical Therapy - 2013

16 trials (11 cross over), n=558

11 Trials of F. Incontinence + Diarrhea

7 tested antidiarrheals, 6 enhance anal sphincter function (Phenylephrine, valproic acid), 2 tested Lactulose, 1 zinc aluminum

Small studies, short F. up, meta-analysis not possible

Risk of bias unclear

Conclusions:

Focus of most therapy was diarrhea not incontinence

Little evidence to guide clinicians, Larger well designed trials are required

Omar et al, Cochrane Database Systematic Rev 2013


Goals of Biofeedback Training for Fecal Incontinence

Goals of Biofeedback Training for Fecal Incontinence

Biofeedback Therapy (Neuromuscular Training)Strengthen anal sphincter muscle Endurance + Strength

Improve rectal sensation/sensory delay

Rectoanal coordination training Isolation of anal muscles

Control of Accessory Muscles

Training for improving Dyssynergia & evacuation


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Biofeedback-Incontinence - Before TherapyBiofeedback-Incontinence - Before Therapy

Anal Canal

Rectum

Courtesy of Rao SS


Biofeedback-Incontinence - After TherapyBiofeedback-Incontinence - After Therapy

Rectum

Anal Canal

Courtesy of Rao SS

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BF

PFE

BF

PFE

0

10

20

30

40

50

60

70

80

90

100

Intention-to-Treat,n=108 Per Protocol, n=93

Percent Reporting Adequate

Relief

Biofeedback vs Non-digital assisted squeezes-Incontinence: Primary Outcome

Biofeedback vs Non-digital assisted squeezes-Incontinence: Primary Outcome

* P < 0.001

**

Heymen S, Whitehead W et al, Dis Colon Rect 2008


Dextranomer Injection - Step by stepDextranomer Injection - Step by step

lighted anoscope

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Significantly higher responder rates in Dextranomergroup at 6 months (Responder50)

53.2%

30.7%

0

20

40

60

80

Solesta Sham

Proportion responders

50(%

)

p ‐value = 0.004p ‐value = 0.004

All 3 pre‐specified success criteria at 6 and 12 months were

met

Graf et al, Lancet 2011;377:997–1003

Efficacy of Dextranomer in F. Incontinence: RCT


Mellgren A et al, NGM 2014

Long Term Efficacy of NASHA

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Post- Dextranomer Injection:Anal ultrasound & Colonoscopy views


Surgical Treatment of IncontinenceSurgical Treatment of Incontinence

Sphincteroplasty

Anterior repair

Rectal Augmentation

SECCA procedure

Sacral nerve stimulation

Maloney-ACE procedure

Colostomy

Long term=50%


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Long Term DataLong Term Data

Glasgow, Lowry DCR 2012

SPHINCTEROPLASTY long term results

SPHINCTEROPLASTY long term results


Sacral Nerve Stimulation for Incontinence

4-6 needles, bilaterally, S2-S4, Temporary –14 days, later Permanent

Rao SS, Am J Gastroenterol 2004;99:1585-604

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3

FIGURE 1.Sacral Nerve Stimulation - Effects on Weekly Incontinence Episodes, n=120Sacral Nerve Stimulation - Effects on Weekly Incontinence Episodes, n=120

Wexner et al. Ann Surg 2010

SNS with Sphincter Defects

SPHINCTER LESIONS

Defect size (degree)

Melenhorst et al [204] 2008 20 22.6 8.3 1.4 ns ns EAS: 17–33

Jarrett et al [257] 2008 8 26.5‡ 5.5 1.5 15‡ 9.5‡ EAS: 30–150

Vitton et al [258] 2008 5 14‡ ns ns 15‡ 6‡ EAS: 45–180

Chan et al [259] 2008 21 12 13.8 5 15.7 1 EAS: 90–120

Boyle et al [260] 2009 15 nr 7.5‡ 1.5‡ 12 9 EAS: 90–180

Ratto et al [261] 2010 10 33 25.6 0.8 18 10 IAS: 60–180 EAS: 30–170

Dudding et al [262] 2010 8 46 9.9 1 ns ns IAS defect

Brouwer et al [100] 2010 20 20 ns ns 15‡ 7‡ EAS, extent nr

Authors (ref) Year No. of patients

Follow-up

(months)

Incontinence episodes per week Incontinence

Score (CCIS*)

Before SNS

(base-line)

SNS

(last FU)

Before SNS

(base-line)

SNS

(last FU)

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New devices for Fecal IncontinenceNew devices for Fecal Incontinence

Role of anal/vaginal plugs & Devices: Fenix®, Renew®, Vaginal insert (Pelvalon®)

Home vs Office Biofeedback Therapy: RCT

A prescriptive biofeedback device for male and female urinary and fecal incontinence that combines muscle & electrical stimulation with voice-guided exercises for patient use at home

Xiang X, Sharma A, Rao SS. ACG 2017

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ACG 2018October 5‐10Philadelphia, PA

Primary Outcome Responder: ≥50% decrease in the weekly FI episode in the final week compared with baseline period.

P=0.78

Sharma A, Xiang X, Rao SS. ACG 2018

non-responder

responder

What is Neuromodulation?What is Neuromodulation?

Definition: The modulation or alteration of nerve function through targeted delivery of magnetic, electrical or chemical stimulus

Goal: Normalize or restore neuronal function

Principle: Neuroplasticity - Body’s natural biological response


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What is Neuroplasticity?Neuro=Nervous system, Plasticity=Plastos (Gk)=Moldable/Adaptable

Introduced by Ernest Lugaro in 1906

What is Neuroplasticity?Neuro=Nervous system, Plasticity=Plastos (Gk)=Moldable/Adaptable

Introduced by Ernest Lugaro in 1906

• “The ability of neuronal systems to LEARN, ADAPT & RECOVER” Alter function in response to changes in input, both

physiological and pathophysiological”

• Neuroplasticity can be driven by neurostimulation• Repetitive stimulation drives NEW neuronal

connectivity• Improved Connectivity is Improved Functionality


Translumbosacral Neuromodulation Therapy for Fecal Incontinence: Randomized Frequency

Response Trial

This study was supported by NIH R21 (5R21 DK104127-02)


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Translumbosacral Neuromodulation Therapy (TNT)Translumbosacral Neuromodulation Therapy (TNT)

Rao SSC et al Am J Gastroenterol 2020

Six weekly sessions, 600 stimulations/site, Total=2400 stimulations/visitDuration: 20 (15 Hz) to 60 minutes (1 Hz)


Effect of TNT on FI episodes

P<0.01

P<0.03

P<0.01

Rao SSC et al. Am J Gastroenterol 2020Virtual Grand Rounds

universe.gi.org

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TNT Efficacy: Primary Outcome Measure TNT Efficacy: Primary Outcome Measure

50% reduction in FI episodes compared to baseline

Rao SSC et al. Am J Gastroenterol 2020Virtual Grand Rounds

universe.gi.org

1 Hz 5 Hz 15 Hz

MEP siteBaseline

Post-treatment

BaselinePost-

treatmentBaseline

Post-treatment

LeftLumbo-anal 5.1±0.5 3.8±0.3* 6.1±0.6 5.6±0.6 5.4±0.8 4.0±0.6*

Lumbo-rectal 3.1±0.3 2.7±0.2 4.5±0.53.4±0.3

3.8±0.4 4.0±0.3

RightLumbo-anal 5.3±0.4 3.9±0.3* 6.1±0.5 5.2±0.5 5.9±0.7 4.4±0.4*

Lumbo-rectal 3.9±0.4 3.0±0.2* 4.6±0.7 3.9±0.3 3.7±0.3 3.8±0.3

LeftSacro-anal 4.8±0.4 3.8±0.3* 6.0±0.5 5.0±0.4 4.9±0.6 4.4±0.7

Sacro-rectal 3.3±0.3 3.0±0.2 5.3±0.5 4.1±0.4 4.0±0.4 3.7±0.5

RightSacro-anal 5.3±0.5 3.7±0.4* 5.7±0.6 4.5±0.4* 5.7±0.6 4.7±0.5

Sacro-rectal 3.8±0.3 3.3±0.2 5.0±0.8 3.4±0.2* 4.7±0.5 3.6±0.4

Effects of TNT on Spino-anorectal axisRectal and Anal Motor Evoked Potential (MEP) latency (ms)

mean ± SEM

Rao SSC et al NGM 2019Evidence for NeuroplasticityVirtual Grand Rounds

universe.gi.org

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ConclusionsConclusions

TNT at 1Hz was superior to 5 and 15Hz frequency in FISignificant Improvement in FI symptoms & QOL

Significant, multidimensional, mechanistic improvement (neuropathy & anorectal sensori-motor function)

Neuromodulation therapy with LOW frequency TNT appears to be safe and efficacious for FI

Sham controlled and longer duration studies are needed to establish the efficacy, durability & safety of TNT

Rao S, et al Am J Gastroenterol 2020


EBM – Incontinence – 2020EBM – Incontinence – 2020

Treatment Modality Level RecommendationPharmacological

Loperamide II C

Diphenoxylate/atropine II C

Lactulose II D

Fiber supplements II B

Clonidine II D

Topical Therapy

Zinc Aluminum II C

Estrogen II C

Phenylephrine I D

Biofeedback Therapy I A

SNS I B

TENS/PTNS I D

Dextranomer (NASHA Dx) I A

Rao SSC, Sleisenger & Fordtran, 9th edition, 2020; pp Virtual Grand Rounds

universe.gi.org

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F. incontinence/Biofeedback ProgramF. incontinence/Biofeedback Program

n NIDDKn Patientsn Shaheen Hamdyn Thoru Yamadan Amol Sharma� Jose Remes Troche� E.Coss Adame� A.Attaluri� A.Erdogan� T.Patcharatrakul� K.Rattanakovit� Xuelian Xiang� Yun Yan

� Jessica Valestin� Anne Dewitt� Arie Mack� A.Schmeltz� R.Parr� T.Karunaratne� A.Eubanks� H.Smith

I salute you all from the bottom of my heart

� NIH FIT Trial� U01-115572� A. Bharucha� W.Whitehead� A.Lowry� W.Chey� A.Markland

� NIDDK, TNT Trial� R01DK121003� B.Kuo� K.Staller� S.Hamdy

(Manchester, UK)


Take Home PointsTake Home Points

Fecal incontinence is multifactorial Detailed History, Physical & DRE important FI Stool diary APP could help management ARM, A. Ultrasound, MRI, TAMS Tests are

complementary and facilitate optimal therapy Lifestyle measures, antidiarrheals are helpful Biofeedback Therapy remains mainstay Home Biofeedback appears to be effective

Dextranomer injection-selected cases Selected cases - Surgery or SNS TNT (Neuromodulation) is efficacious & safe


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Questions?

Satish S.C. Rao, MD, PhD, FACG

Sarah B. Umar, MDVisit gi.org to learn more


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Documents

Visit gi.org to learn more€¦ · Week 24: Combination Therapies in IBD: Assessing the Evidence for and Against Stephen B. Hanauer, MD, FACG September 3, 2020 at Noon EDT Week 23: