FUNCTIONAL DYSPEPSIA Rome III Definition

DYSPEPSIA OR GASTROPARESIS Update 2015

J. TACK, M.D., Ph.D. TARGID University of Leuven Leuven, Belgium

www.targid.eu DYSPEPSIA OR GASTROPARESIS Clinical case

A 22 year old preschool teacher sees a gastroenterologist with marked early satiety with postprandial epigastric pain, nausea and fullness.

Symptoms started with an acute gastroenteritis while on holiday on a Greek island. Diarrhea disappeared rapidly but since then she remained intolerant to food. In total she lost 4 kgs over the last 5 months.

Upper endoscopy with biopsies, laboratory testing and abdominal ultrasound are negative. FUNCTIONAL DYSPEPSIA Rome III definition

Functional dyspepsia: one or more of bothersome  Postprandial fullness, or  Early satiety, or  Epigastric pain, or  Epigastric burning No evidence of organic disease that is likely to explain the symptoms; and Symptoms present during the last 3 months with onset at least 6 months before diagnosis Overlap with GERD and IBS is common and does not exclude the diagnosis.

Tack et al., 2006 DYSPEPSIA OR GASTROPARESIS Clinical case

Proton pump inhibitors are not helpful.

A psychiatrist ruled out an eating disorder.

A CT scan of the abdomen was normal

Would you do a gastric emptying test? DYSPEPSIA EPIDMIOLOGY Prevalence and health care impact

141 (33.8%)

D+R+

1608 417 4 (1.0%) D+R- D-R- 237 35 (56.8%) (8.4%)

P < 0.001 P < 0.001 P < 0.001 100% 100% 100% 90% 90% 90% 80% 80% 80% 70% 70% 70% 60% 60% 60% No No No 50% 50% 50% Yes Yes Yes 40% 40% 40%

30% 30% 30%

Medication (% of patients)Medicationof (%

Investigationspatients)of (%

Doctor's visit (% of patients) Doctor's (% visit 20% 20% 20%

10% 10% 10%

0% 0% 0% GERD+FD+ GERD-FD+ GERD-FD- GERD+FD+ GERD-FD+ GERD-FD- GERD+FD+ GERD-FD+ GERD-FD- 5 Doctor’s visits, Investigations, Medications Piessevaux et al., NMO 2010 MEAL-RELATED DYSPEPSIA Prevalence of delayed gastric emptying

Study n Delayed emptying Normal emptying

Jian 1989 23 59% 41% Wegener 1989 48 30% 70% Wegener 1989 50 42% 58% Klauser 1993 69 35% 65% Scott 1993 75 28% 72% Stanghellini 1996 343 33% 67% Maes 1997 344 30% 70% Perri 1998 304 33% 67% Sarnelli 2003 392 23% 77% Overall 1648 30% 70% GASTROPARESIS Definition

• Delayed gastric emptying in the absence of a mechanical obstruction of the stomach.

• Symptoms: – Postprandial fullness – Early satiety – Nausea and vomiting – Bloating – Epigastric pain

Parkman et al., Neurogastroenterology and Motility 2010 GASTROPARESIS Causes

Pseudo-obstruction Anorexia nervosa 5% 3%

Collagen-vascular disease 5% Idiopathic 33% Parkinson’s disease 5%

Miscellaneous 6%

Postgastric surgery 19%

Diabetes mellitus 24% GASTROPARESIS Diagnosis

• Gastric emptying test • Rule out mechanical obstruction • Upper g.i. endoscopy • Small bowel x-ray / CT GASTROPARESIS Gastric emptying test

• Scintigraphy • Breath test • (Ultrasound) • (Magnetic resonance imaging) • (Paracetamol absorption test) • (Solid markers radiography) • (Gastric aspiration tests) GASTROPARESIS Scintigraphy

• 99mTc-containing meal • Scan at 0,1, 2 and 4 hours

100 Tlag 75 Gastric retention (%) 50 T1/2 25

0 0 60 120 180 240 300 360 Time after the meal (min) GASTROPARESIS Breath test

• Standardized meal: caloric content, % CH and fat – Scrambled egg and water – Substrate: degraded immediately after emptying from stomach; appearance of labeled CO2 in breath; empyting is rate-limiting step • 13C- or 14C-octanoic acid • 13C- or 14C-glycin • 13C-acetate • 13C-spirulina DYSPEPSIA OR GASTROPARESIS Reasons to do a gastric emptying test

Would enter the patient into or would exclude the patient from a different diagnostic category: Gastroparesis

 Is it present in a subset of patients?

 Is it stable over time?

 Does it explain symptoms (better?)

 Does it determine choice of therapy?

 Does it determine long-term prognosis? FUNCTIONAL DYSPEPSIA Rome III definitions

Functional Dyspepsia

Postprandial distress Epigastric pain syndrome (PDS): syndrome (EPS): Meal-related FD Meal-unrelated FD Early satiation Epigastric pain Postprandial fullness Epigastric burning

Tack et al., Gastroenterology 2006; 130(5):1466-79 FUNCTIONAL DYSPEPSIA Subgroups

20 Tack and Talley, NRGH 2013 FUNCTIONAL DYSPEPSIA Subgroups

21 Tack and Talley, NRGH 2013 MEAL-RELATED FUNCTIONAL DYSPEPSIA Putative pathophysiological mechanisms

Perception Perception

Visceral hypersensitivity

Fasting Accommodation Emptying Gastric acid secretion Hormone secretion Hormone secretion Duodenal bicarbonate secretion Impaired Gastric Disordered gastric Accommodation emptying 22 MEAL-RELATED DYSPEPSIA Impaired accommodation

Presence

Health FD Impaired accommodation

Troncon et al., 1994 Hausken et al., 1996 Tack et al., 1998 Boeckxstaens et al., 2002 Kim et al., 2001 ……… MEAL-RELATED DYSPEPSIA Prevalence of impaired accommodation

Impaired Normal Author Method n accommodation accommodation Scott 1993 Scintigraphy 75 31% 69%

Tack 1998 Barostat 40 40% 60%

Thumshirn 1999 Barostat 17 70% 30%

Kim 2001 SPECT 32 41% 59%

Boeckxstaens 2001 Barostat 42 40% 60%

Piessevaux 2003 Scintigraphy 40 50% 50%

Bredenoord 2003 SPECT 151 43% 57% Overall 397 44% 56% GASTROPARESIS Scintigraphy

• 99mTc-containing meal • Scan at 0,1, 2 and 4 hours

100 Tlag 75 Gastric retention (%) 50 T1/2 25

0 0 60 120 180 240 300 360 Time after the meal (min) MEAL-RELATED DYSPEPSIA Prevalence of delayed gastric emptying

Study n Delayed emptying Normal emptying

100%

80%

60% Normal sensitivity Hypersensitivity 40%

20% Prevalence (% patients) of (% Prevalence

0% Control Organic Functional dyspepsia dyspepsia Mertz et al., 1998 Tack et al., 2001 Rhee et al., 2001 Boeckxstaens et al., 2002 …….. FUNCTIONAL DYSPEPSIA Rome III definitions

Functional Dyspepsia

Postprandial distress Epigastric pain syndrome (PDS): syndrome (EPS): Meal-related FD Meal-unrelated FD Impaired accommodation 45% Delayed emptying 30% Visceral hypersensitivity 40% …

Tack et al., Gastroenterology 2006; 130(5):1466-79 MEAL-UNRELATED FUNCTIONAL DYSPEPSIA Putative pathophysiological mechanisms

CNS Non-acid reflux dysfunction

Atypical NERD

H. pylori Duodenal acid infection exposure Duodenal lipid Gastric hypersensitivity arrhythmia’s Small bowel dysmotility

32 IDIOPATHIC GASTROPARESIS Overlap with FD

Idiopathic gastroparesis N= 243

Overlapping FD: 86% PDS: 91%

Parkman et al., Neurogastroenterology and Motility 2010 DYSPEPSIA OR GASTROPARESIS Reasons to do a gastric emptying test

 Is it present in a subset of patients?

 Is it stable over time? FUNCTIONAL DYSPEPSIA Reproducibility of emptying rate

350

300

250

200

150

100 Half emptying Half emptying time (min)

0 Baseline 1 month Measurement of gastric emptying

Arts et al., 2005 IDIOPATHIC GASTROPARESIS Tegaserod and emptying rate

25%

Baseline (%) hours

4 4 20% 8 weeks (%)

15% * “normal”

postmeal 10% gastric retention rate

% retention% at 5% at 4 hours is 6.3% 0% 24 18 12 6 Placebo Tegaserod daily dose

Tougas et al DDW 2003 DYSPEPSIA OR GASTROPARESIS Reasons to do a gastric emptying test

 Is it present in a subset of patients?

 Is it stable over time?

 Does it explain symptoms (better?) FUNCTIONAL DYSPEPSIA Symptoms and delayed emptying

100

90 Normal emptying (77%) * Delayed emptying (23%) 80

70 *

60 50 * 40

Prevalence Prevalence (% of patients) 20

0 Fullness Bloating Pain Early Nausea Belching Weight Epigastric Vomiting satiety loss burning Sarnelli et al., 2003 ROME II DYSPEPSIA AND GASTROPARESIS Symptom patterns

100% 90% 80% 70% 60% Absent or Functional dyspepsia 50% mild 40% Relevant or severe 30%

Prevalence (% (% ofpatients) Prevalence 20% 10% 0% FullnessBloating Pain Early satietyNausea BelchingWeight EpigastricVomiting loss burning 100% 90% 80% 70%

60% Absent or mild Idiopathic gastroparesis 50% Moderate = severely delayed emptying 40% or severe on at least 2 occasions 30%

Prevalence (%of (%of patients) Prevalence 20% 10% Tack et al., 2005 0% FullnessBloating Pain Early Nausea Belching WeightEpigastric Vomiting Karamanolis et al., 2007 satiety loss burning ROME II DYSPEPSIA AND GASTROPARESIS Symptom patterns

100 Dyspepsia normal emptying 90 Dyspepsia delayed emptying Idiopathic gastroparesis 80

20 Prevalence (% patients)(% of Prevalence

0 Fullness Bloating Pain Early Belching Nausea Epigastric Weight Vomiting satiety burning loss Sarnelli et al., 2003 Karamanolis et al., 2007 IDIOPATHIC GASTROPARESIS Symptom severity and emptying rate

10 Symptom Symptom severity score

0 100 120 140 160 180 200 220 240 260 280 300 Solid half emptying time (min) Karamanolis et al., 2007 IDIOPATHIC GASTROPARESIS Symptom severity and gastric sensitivity

10 Symptom Symptom severity score 5

0 0 5 10 15 20 25 Discomfort pressure (mm Hg above MDP) Karamanolis et al., 2007 DYSPEPSIA OR GASTROPARESIS Reasons to do a gastric emptying test

 Is it present in a subset of patients?

 Is it stable over time?

 Does it explain symptoms (better?)

 Does it determine choice of therapy? FUNCTIONAL DYSPEPSIA Management algorithm (in the West)

Chronic dyspeptic symptoms Endoscopy 70% Functional Organic dyspepsia dyspepsia

Eradicate if H.pylori positive

POSTPRANDIAL EPIGASTRIC PAIN DISTRESS SYNDROME SYNDROME (PDS) (EPS)

44 FUNCTIONAL DYSPEPSIA Response to proton pump inhibitors

Patient subgroup Risk ratio (95% c.I.)

0.76 (0.66, 0.88) GERD: Reflux group

EPS: Epigastric pain group 0.85 (0.79, 0.92)

PDS: Dysmotility group 1.02 (0.92, 1.13)

0.65 1 1.55 Risk ratio

Favors PPI therapy Favors placebo No dose-response effect Moayyedi et al., 2004 FUNCTIONAL DYSPEPSIA Treatment options

Acid suppression (PPI)

Helicobacter pylori eradication

Camilleri and Tack, 2013 48 FUNCTIONAL DYSPEPSIA Response to H. pylori eradication

Blum

Froehlich Limitations: Gisbert

Hsu - Majority in the West are HP negative Koelz - High NNT Koskenpato - Therapeutic gain efffect is late, reaching Malfertheiner significance at 6-12 months McColl

Miwa

Talley

Varannes

van Zanten 0.93 (0.87, 0.973) TOTAL OR 0.92; 95% c.i. 0.88 – 0.97 Moayyedi et al., 2004 0 0.5 1 1.5 2 FUNCTIONAL DYSPEPSIA Treatment options

Acid suppression (PPI)

Helicobacter pylori eradication

Prokinetic drugs

Camilleri and Tack, 2013 FUNCTIONAL DYSPEPSIA Response to prokinetic therapy

Study

Al-Quorain Champion Chung Cisapride QT prolongation De Nutte Francois Metoclopramide CNS Hannon Domperidone QT prolongation Hansen Mosapride Kellow Itopride Rosch Clebopride Yeoh Alizapride Wood Renzapride Holtmann De Groot Bekhti

Overall 0.52 (0.37 – 0.73)

0.05 1 1.55 Risk ratio

Favors Prokinetics Favors placebo Moayyedi et al., 2003 5-HT4 RECEPTOR AGONISTS Efficacy in functional dyspepsia

20 Responders (% Responders(% of patients)

0 PBO 30 mg 60 mg PBO 30 mg PBO 10 mg 20 mg 22.5 mg PBO 12 mg PBO 12 mg

Champion De Groot Hallerback Vakil

Cisapride Mosapride Tegaserod IDIOPATHIC GASTOPARESIS Improvement in emptying and symptoms

Janssen et al., Am. J. Gastroenterol. 2013 FUNCTIONAL DYSPEPSIA Management algorithm (in the West)

Chronic dyspeptic symptoms Endoscopy 70% Functional Organic dyspepsia dyspepsia

Eradicate if H.pylori positive

POSTPRANDIAL EPIGASTRIC PAIN DISTRESS SYNDROME SYNDROME (PDS) (EPS)

Prokinetic Acid suppressive

Antidepressant if refractory Psychotherapy 53 FUNCTIONAL DYSPEPSIA Treatment options

Acid suppression (PPI)

Helicobacter pylori eradication

Prokinetic drugs

Centrally acting agents

Camilleri and Tack, 2013 ROME I/II FUNCTIONAL DYSPEPSIA Response to psychotropics

Hojo et al., 2005 FUNCTIONAL DYSPEPSIA Venlafaxine in functional dyspepsia

Improvement in symptom score Proportion of asymptomatic patients (%)

18 50 16 45 14 40 12 35 30 10 25 8 20 6 15 4 10 2 5 0 0 Venlafaxine 75 → 150 mg Placebo Venlafaxine 75→ 150 mg Placebo

n = 160 8 weeks treatment Completion 59% and 74% resp. Per protocol 43% and 37% symptomfree (NS)

Van Kerkhoven et al., 2008 DYSPEPSIA/GASTROPARESIS Efficacy of antidepressants

Talley et al., Gastroenterology 2015: in press DYSPEPSIA/GASTROPARESIS Efficacy of antidepressants

Talley et al., Gastroenterology 2015: in press FUNCTIONAL DYSPEPSIA Antidepressants in functional dyspepsia

Talley et al., Gastroenterology 2015: in press FUNCTIONAL DYSPEPSIA Management algorithm (in the West)

Chronic dyspeptic symptoms Endoscopy 70% Functional Organic dyspepsia dyspepsia

Eradicate if H.pylori positive

POSTPRANDIAL EPIGASTRIC PAIN DISTRESS SYNDROME SYNDROME (PDS) (EPS)

Prokinetic Acid suppressive

Antidepressant if refractory 61 GASTROPARESIS Medical costs

Wang et al., 2008 GASTROPARESIS Treatment

• Treatment of the underlying condition • Nutritional and dietary treatment • Prokinetic drugs • Centrally acting agents • Botox injection • Feeding tube • Surgery IDIOPATHIC GASTROPARESIS Hypothesis

Inflammation Dyspeptic symptoms Intrinsic Delayed gastric neuropathy emptying, no ICC mechanical cause deficiencies - (Bezoar Autonomic - formation) neuropathy Prokinetic drug treatment GASTROPARESIS Heterogeneity of prokinetic drugs

Proposed foregut effects Primary Gastric Visceral Antral mode(s) Antiemetic Fundic emptying sensitivity motility accommodation of action D antagonist Metoclopramide 2 5HT4 agonist  ↑ ↓ ↑ 5HT agonist Cisapride 4 5HT3 antagonist ↑ ↑ ↑

5HT agonist Tegaserod 4 ↑ ↑ ↑

5HT agonist Mosapride 4 5HT3 antagonist  ↑ ↑

D antagonist Domperidone 2  ↑ ↓

D2 antagonist Itopride Cholinesterase  ↑ ↑ inhibitor

D antagonist Levosulpiride 2  ↑ ↓ ↑

Erythromycin Motilin agonist ↑ ↑ ↑ ↓ GASTROPARESIS Heterogeneity of prokinetic drugs

5HT agonist Tegaserod 4 ↑ ↑ ↑

5HT agonist Mosapride 4 5HT3 antagonist  ↑ ↑

D antagonist Domperidone 2  ↑ ↓

D2 antagonist Itopride Cholinesterase  ↑ ↑ inhibitor

D antagonist Levosulpiride 2  ↑ ↓ ↑

Erythromycin Motilin agonist ↑ ↑ ↑ ↓ 5-HT4 RECEPTOR Classes of agonists

Benzamides Metoclopramide

Cisapride Clebopride

Mosapride Renzapride

Naronapride (ATI-7505) 5-HT4 RECEPTOR Classes of agonists

Carbazimidamides Tegaserod

Velusetrag

Benzofuran carboxamides: prucalopride IDIOPATHIC GASTROPARESIS Tegaserod and emptying rate

25%

Baseline (%) hours

4 4 20% 8 weeks (%)

15% * “normal”

postmeal 10% gastric retention rate

% retention% at 5% at 4 hours is 6.3% 0% 24 18 12 6 Placebo Tegaserod daily dose

Tougas et al DDW 2003 SYMPTOMS OF GASTROPARESIS Revexepride dose-finding study

133 Tack et al., submitted 2015 GASTROPARESIS Heterogeneity of prokinetic drugs

5HT agonist Tegaserod 4 ↑ ↑ ↑

5HT agonist Mosapride 4 5HT3 antagonist  ↑ ↑

D antagonist Domperidone 2  ↑ ↓

D2 antagonist Itopride Cholinesterase  ↑ ↑ inhibitor

D antagonist Levosulpiride 2  ↑ ↓ ↑

Erythromycin Motilin agonist ↑ ↑ ↑ ↓ DIABETIC GASTROPARESIS Influence of domperidone

Reddymasu et al., Am J Gastroenterol 2007 FUNCTIONAL DYSPEPSIA Itopride GASTRIC EMPTYING IN HEALTH AND DIABETES Influence of itopride

Placebo Itopride 100 mg Itopride 200 mg

140

120

100

Solid half (min) Solid emptying time 20

Health Diabetes

No significant enhancement of gastric emptying Choung et al., 2007 Stevens et al., 2007 GASTROPARESIS Heterogeneity of prokinetic drugs

5HT agonist Tegaserod 4 ↑ ↑ ↑

5HT agonist Mosapride 4 5HT3 antagonist  ↑ ↑

D antagonist Domperidone 2  ↑ ↓

D2 antagonist Itopride Cholinesterase  ↑ ↑ inhibitor

D antagonist Levosulpiride 2  ↑ ↓ ↑

Erythromycin Motilin agonist ↑ ↑ ↑ ↓ PROKINETIC DRUGS Erythromycin in diabetic gastroparesis

180

160

140

120

100 * Placebo 80 * Erythromycin 60

Half emptying time (min) time emptying Half 40

0 Solid gastric emptying Liquid gastric emptying

Janssens et al., 1992 IDIOPATHIC GASTROPARESIS Erythromycin

Placebo Erythromycin

30 Placebo 140 Erythromycin

120 25 *

100 20 80 15 60 P < 0.05 10

40 Symptom score 5

20 Cumulative Cumulative symptom score 0 0 0 50 100 150 200 Fullness Belching Bloating Nausea Pain Burning Solid gastric emptying t1/2 (min) Arts et al., 2004 CAMICINAL IN GASTROPARESIS Patient flow

Enrollment Number screened (n=204) Four weeks of treatment Once daily Qualified by symptoms (n=116) GCSI Daily diary

Qualified by gastric emptying (n=80) Breath test and smartpill day 1 Allocation Randomize (n=79) and day 28

Placebo (n=21) Camicinal 10 mg (n=18) Camicinal 50 mg (n=18) Camicinal 125 mg (n=22) Withdrawn from study (n=3): Withdrawn from study (n=2): Withdrawn from study Withdrawn from study Protocol deviation (n=1) Protocol deviation (n=0) (n=0) Lost to followup (n=1) (n=1) Total completed Total completed Withdrew consent (n=1) Withdrew consent (n=18) (n=22) Total completed (n=18) (n=1) Total completed (n=16)

Kuo et al., submitted 2015 CAMICINAL IN GASTROPARESIS Symptom evaluations

Kuo et al., submitted 2015 CAMICINAL IN GASTROPARESIS GCSI diary scores and responders

GCSI-DD: 14 questions Responder: improvement of at least 1 point from the weekly average at baseline

Kuo et al., submitted 2015 CAMICINAL IN GASTROPARESIS Gastric emptying

Breath test

Capsule

Kuo et al., submitted 2015 GASTROPARESIS Heterogeneity of prokinetic drugs

5HT agonist Tegaserod 4 ↑ ↑ ↑ 5HT agonist Mosapride 4 5HT3 antagonist  ↑ ↑

D antagonist Domperidone 2  ↑ ↓

D2 antagonist Itopride Cholinesterase  ↑ ↑ inhibitor

D antagonist Levosulpiride 2  ↑ ↓ ↑ Erythromycin Motilin agonist ↑ ↑ ↑ ↓ TZP-102 Ghrelin agonist ↑ ↑ ↓ IDIOPATHIC GASTROPARESIS Influence of ghrelin

Saline Ghrelin

p<0.05 Saline Ghrelin 250

200 200 180 * * 160 150 p<0.01 140 120 100 100 80 60 50 40 20

0 0 Cumulative symptom score symptom Cumulative Half empting time (min) time empting Half Solid Liquid 0 20 40 60 80 100 120 140 160 180 200 Half emptying solids (t1/2)

Tack et al., 2006 TZP-102 IN DIABETIC GASTROPARESIS Symptomatic response

McCallum et al., NMO 2013: 25: e705-17 TZP-102 IN DIABETIC GASTROPARESIS Symptomatic response

McCallum et al., NMO 2013: 25: e705-17 DIABETIC GASTROPARESIS Prokinetic drugs: Relamorelin (RM131)

154 Camilleri et al., 2013 DIABETIC GASTROPARESIS Ghrelin agonist: relamorelin

Composite symptom score Vomiting episodes Placebo RM-131 10 ug Placebo RM-131 10 ug 0 0

-1 -1 -1 -0,8 -2 -2 -1,4 -2 -3 -3 -3,62

-4 -3

Change Change from baseline Change Change from baseline -4 -5 -4,75 -3,5 -5,25 -4 * -6 -5 -4,3 -6,36 * -7 * -5 All Vomiting subgroup All Vomiting subgroup

Lembo et al., DDW 2014 GASTROPARESIS Treatment

Placebo (n=65) Idiopathic gastroparesis (n=130)

Nortriptyline 20 mg (n=66)

2 weeks 12 weeks

Baseline Treatment period

Assessments: • Questionnaires (GCSI, PAGI-SYM, CGPIn GSRS, overall relief questionnaire, BDI, STAI, PHQ) • Electrogastrograph, nutrient challenge test Parkman et al., JAMA 2013: 310: 2640-9 IDIOPATHIC GASTROPARESIS Nortryptiline study

Parkman et al., JAMA 2013: 310: 2640-9 DYSPEPSIA/GASTROPARESIS Efficacy of antidepressants

Gastric emptying test

Talley et al., Gastroenterology 2015: in press FUNCTIONAL DYSPEPSIA Antidepressants in functional dyspepsia

Talley et al., Gastroenterology 2015: in press FUNCTIONAL DYSPEPSIA Management algorithm (in the West)

Chronic dyspeptic symptoms Endoscopy 70% Functional Organic dyspepsia dyspepsia

Eradicate if H.pylori positive

POSTPRANDIAL EPIGASTRIC PAIN DISTRESS SYNDROME SYNDROME (PDS) (EPS)

Prokinetic Acid suppressive

Gastric emptying test

Normal

Delayed: experimental Antidepressant 162 gastroparesis therapy GASTROPARESIS Treatment

• Treatment of the underlying condition • Nutritional and dietary treatment • Prokinetic drugs • Centrally acting agents • Botox injection • Feeding tube • Surgery GASTROPARESIS Botulinum toxin controlled trial

Botulinum toxin control Botulinum toxin 1 month Saline control Saline 1 month

30 25 20

15 GCSI 10 5 0 0 20 40 60 80 100 120 140 Solid half emptying time (min)

Arts et al., 2007 DIABETIC GASTROPARESIS Gastric electrical stimulation

• N = 55

McCallum et al., CGH 2010; 8: 947-54 REFRACTORY GASTROPARESIS Feeding tubes

 Several case series in literature  Fontana and Barnett, 1996 – 26 refractory diabetic gastroparesis patients – Jejunostomy placement – One related death – Improvement in most patients (nausea/vomiting, nutritional status, less hospitalizations) – Mean duration of tube use 20 months (f.u. 47) REFRACTORY GASTROPARESIS Surgery

 Published case series with mixed results  Watkins et al., 2003 – 7 refractory diabetic gastroparesis patients – 70% gastric resection with Roux-en-Y jejunal anastomosis – Excellent result in 6  Own experience – Referral of “disasters” – 3 refractory gastroparesis patients – Subtotal gastrectomy with Roux-en-Y jejunal anastomosis – Severe dumping and persisting low body weight GASTROPARESIS Prucalopride and upper GI in health

Kessing et al., 2014 GASTROPARESIS Prucalopride and upper GI in health

Kessing et al., 2014 PRUCALOPRIDE IN GASTROPARESIS Controlled cross-over study

– 34 gastroparesis patients – 28 idiopathic, 6 diabetic – Mean age 46, 26 women – Run-in of 2 weeks – Two 4 week treatment periods, prucalopride 2 mg daily or placebo – Gastric emptying, GCSI at baseline and end of each treatment PRUCALOPRIDE IN GASTROPARESIS Controlled cross-over study

Prucalopride in gastroparesis Baseline Placebo Prucalopride 160

140

120 *

100

Gastric solid half emptying Gastric solid half emptying time (min) 20

0 Half emptying time Tack, unpublished PRUCALOPRIDE IN GASTROPARESIS Controlled cross-over study

Prucalopride in gastroparesis Run-in Placebo Prucalopride 4,00

3,00

2,00 *

* GCSI GCSI subscale score 1,00

0,00 Nausa/vomiting Fullness/satiety Bloating/distension Tack, unpublished GASTROPARESIS Prucalopride in idiopathic gastroparesis

Prucalopride in idiopathic gastroparesis Prucalopride in idiopathic gastroparesis Baseline Placebo Prucalopride Baseline Placebo Prucalopride 160 4,0

140

120 3,0

100

80 2,0

60 GCSI GCSI subscale score 40 1,0

Gastric solid half emptying Gastric solid half emptying time (min) 20

0 0,0 Half emptying time Nausea/vomiting Fullness/satiety Bloating

Tack, unpublished DYSPEPSIA OR GASTROPARESIS Reasons to do a gastric emptying test

 Is it present in a subset of patients? yes

 Is it stable over time? no

 Does it explain symptoms (better?) no

 Does it determine choice of therapy? in advanced cases

 Does it determine long-term prognosis? no FUNCTIONAL DYSPEPSIA Long-term follow-up

Weight loss Worsened 7 13% Disappeared 6 17% 5

0 Weight loss at presentation (kg) presentationatlossWeight

50 Depression 42 40

30 28

Improved 20 Unchanged 39%

31% 10 History (%) of depressionHistory 0

60 Trait anxiety 50

30 253 patients, follow-up 5.8 years

20 STAI scoresSTAI trait 10

0 FUNCTIONAL DYSPEPSIA Management algorithm (in the West)

Chronic dyspeptic symptoms Endoscopy 70% Functional Organic dyspepsia dyspepsia

Eradicate if H.pylori positive

POSTPRANDIAL EPIGASTRIC PAIN DISTRESS SYNDROME SYNDROME (PDS) (EPS)

Prokinetic Acid suppressive

Gastric emptying test

If delayed: experimental Antidepressant if refractory 184 gastroparesis therapy Psychotherapy IDIOPATHIC GASTROPARESIS Rome II framework

Postprandial fullness Rome II FD with Early satiation normal emptying Epigastric pain Rome II Epigastric burning Functional Negative dyspepsia Gastric Belching endoscopy emptying test Idiopathic Nausea gastroparesis

Vomiting IDIOPATHIC GASTROPARESIS Rome III framework

Postprandial fullness Negative endoscopy Early satiation Rome III Functional Epigastric pain dyspepsia

Epigastric burning Rome III nausea and vomiting

Negative disorders with investigations Rome III normal emptying Nausea nausea & vomiting Vomiting disorders Gastric emptying test Idiopathic Rome III gastroparesis Belching belching Negative disorders investigations TARGID Methusalem research group

Human Animal GA, Esophagus Mucosal Enteric GI PET/FMRI human , visceral permeability nervous hormone studies food intake sensitivity system studies

PhD