FUNCTIONAL AND MOTOR DISORDERS

1
FUNCTIONAL AND MOTOR DISORDERS
J. TACK, M.D., Ph.D. Department of
Gastroenterology University Hospitals, K.U.
Leuven Leuven, Belgium
2
FUNCTIONAL AND MOTOR DISORDERS

• Presumed refractory GERD

3
GERD CLASSICAL ALGORITHM
PPI therapy for GERD
Persisting symptoms
Double dose of PPI
Resolution maintenance GERD treatment
No improvement endoscopy, 24 h pH monitoring on
PPI
Positive tests more intense treatment or surgery
Negative tests not GERD-related
4
GERD EVOLUTIONS Overlapping manifestations
Bloating
Constipation
Belching
Chronic Constipation (CC)
Dyspepsia
Discomfort
IBS
GERD
Abdominal pain
Heartburn
Regurgitation
Locke et al, Neurogastroenterol Motil 2004 16
1 Corazziari, Best Pract Res Clin Gastroenterol
2004 18 613 Talley at al, Am J Gastroenterol
2003 98 2454
5
GERD EVOLUTIONS Pathophysiological concept
Stress Anxiety Sleep
Psychiatric co-morbitity Somatization
Symptoms
Lesions
Barrier Failure Hiatal hernia Hypotensive
sphincter TLESRs

• Dilated intercellular spaces
• Nociceptor expression
• Dietary fat

Acid Pepsin Bile Food
6
REFRACTORY GERD Classical algorithm
PPI therapy for GERD
Persisting symptoms
Double dose of PPI
Resolution maintenance GERD treatment
7
GERD management Double or switch PPI in treatment
failure
Heartburn
Regurgitation
Pain
0
-10
-20
Esomeprazole 40
Change in symptom severity score
-30
Lansoprazole 60
-40
-50
-60
Fass et al., 2006
8
REFRACTORY GERD Classical algorithm
PPI therapy for GERD
Persisting symptoms
Double dose of PPI
Resolution maintenance GERD treatment
No improvement endoscopy
9
GERD management Endoscopy in treatment failure
Grade 4
9
Grade 3
2
Grade 2
6
Grade 1
20
Non-erosive
n 347
63
Karamanolis, Vanuytsel et al., 2008
10
REFRACTORY GERD Classical algorithm
PPI therapy for GERD
Persisting symptoms
Double dose of PPI
Resolution maintenance GERD treatment
No improvement endoscopy, 24 h pH monitoring on
PPI
Positive tests more intense treatment or surgery
Negative tests not GERD-related
11
ESOPHAGEAL PH MONITORING Explanation of treatment
failure
100
90
80
70
60
QD PPI
Pathological pH monitoring ( of patients)
50
BID PPI
40
31
30
30
20
7
10
1
0
Charbel et al., 2005
Typical
Atypical
12
REFRACTORY GERD pH and Bilitec monitoring
9.5 mm
3 mm
453 nm
2 mm
13
REFRACTORY GERD Symptoms on PPI - pH and Bilitec
monitoring
pathological
pathological
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
Half dose
Full dose
Double dose
Half dose
Full dose
Double dose
n 353
Karamanolis, Vanuytsel et al., 2008
14
GERD EVOLUTIONS New pathophysiological concepts
Acid reflux
Non-acid reflux
Swallow
TLESR with reflux
Pharynx
Manometry
22
LES
pH
Impedance
pH
78
12 GERD patients 478 reflux events SUPINE
POSTPRANDIAL
10 s
Vela et al., 2001
15
Impedance monitoring symptom association




S
R
S
R
150108
080848
125504
event102
1
A 3812.75
1
A 5197.05
heartburn
1
A 3554.35
heartburn
event
heartburn

6
S 497.00
S 1017.69
S 497.56
2
A 1732.35
2
A 2631.49
2
A 2112.04
S 234.00
S 605.03
S 234.93
3
A 1170.72
3
A 2831.88
3
A 1376.39
S 186.00
S 699.42
S 186.54
4
A 896.50
4
A 1381.66
4
A 675.01
S 92.00
S 381.44
S 92.60
5
A 580.09
5
A 980.87
5
A 669.74
S 98.13
S 319.12
S 98.13
7
A 4.60
7
A 5.90
7
7
S 0.66
S 1.00
pH
pH
65 sec
100 sec
1
1
Heartburn, no reflux
Heartburn, acid reflux
Heartburn, non-acid reflux
16
PH AND IMPEDANCE MONITORING Symptoms on PPI
Persistent Sx on PPI
(n 63 )
Failed acid suppression
Successful acid suppression
( n 13 )
( n 19 ) (40)
increased number pH-MII GER
increased number pH-MII GER
positive SI with non-acid GER
positive SI with acid GER
Mainie et al, 2006
17
REFRACTORY GERD Proposed algorithm
Persisting symptoms during PPI therapy for GERD
Switch PPI
Increase to b.i.d. PPI
Positive response
Negative response
Reflux testing off PPI (pH metry) OR Non-acid
reflux testing on PPI
18
PH AND IMPEDANCE MONITORING Predictors of outcome
Persistent Sx on PPI Evaluated with MII pH
(n 200 )
Surgery in 19 18 with positive symptom
association 1 with negative symptom association
Unfavorable outcome 1/1 with negative
association 1/17 with positive association
Favorable outcome 16/17 with positive association
Mainie et al, 2006
19
19 patients with refractory GERD
18 positive SAP
1 negative SAP
16 success after surgery
2 symptomatic after surger
Mainie et al, 2007
20
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough

21
Impedance monitoring reflux related cough
1
A 7854.90
S 2970.06
2
A 2979.54
S 799.62
Impedance
3
A 5455.45
S 1231.65
4
A 3129.83
S 654.80
5
A 1795.63
S 684.73
6
A 2444.28
S 330.31
esophagus
pH
stomach
9
A -11.00
S 19.40
10
A -7.00
Manometry
S 13.17
11
A 76.00
S 31.45
12
A 10.00
S 9.89
10 sec
48 sec
Cough
Blondeau et al. 2006
22
Impedance monitoring reflux related cough
Total N cough 647
Reflux cough n97
WA n36
Cough associated with reflux
acid
Cough reflux
Cough not associated with reflux
Blondeau et al, 2006
23
Impedance monitoring reflux related cough
5 acid
10 patients SAP reflux cough
22 patients
3 Weakly acidic
2 Acid weakly acidic
Blondeau et al, 2006
24
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry

25
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry
• Dysphagia

26
HIGH RESOLUTION MANOMETRY Catheter
27
HIGH RESOLUTION MANOMETRY Data analysis and
presentation
Clouse et al., 2000
28
HIGH RESOLUTION MANOMETRY Data analysis and
presentation
Clouse et al., 2000
29
HIGH RESOLUTION MANOMETRY Dysphagia patterns
Fox and Bredenoord, 2007
30
HIGH RESOLUTION MANOMETRY Dysphagia patterns
Fox and Bredenoord, 2007
31
HIGH RESOLUTION MANOMETRY Rationale
Higher number of closer spaced manometry ports
More detailed information
Improved assessment of motility Increased
diagnostic yield

32
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry
• Dysphagia high resolution manometry

33
EOSINOPHILIC ESOPHAGITIS
34
EOSINOPHILIC ESOPHAGITIS Fluticasone therapy
Teitelbaum et al., 2007
35
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry
• Dysphagia high resolution manometry
• Dysphagia eosinophilic esophagitis
• Constipation

36
BIOFEEDBACK FOR DYSSYNERGIC DEFECATION
Rao et al., 2007
37
BIOFEEDBACK FOR DYSSYNERGIC DEFECATION
Rao et al., 2007
38
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry
• Dysphagia high resolution manometry
• Dysphagia eosinophilic esophagitis
• Dyssynergic defecation biofeedback
• Irritable bowel syndrome

39
IRRITABLE BOWEL SYNDROME Bifidobacterium infantis
10
9
8
Composite score
7
6
Placebo
5
Lacto
Bifido
4









3
2
1
0
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
Week
OMahony et al., 2005
40
IRRITABLE BOWEL SYNDROME Bifidobacterium infantis
N360 Primary Care
Whorwell et al., 2006
41
IRRITABLE BOWEL SYNDROME Response to antibiotics
Lin et al., 2003 Pimentel et al., 2006
42
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry
• Dysphagia high resolution manometry
• Dysphagia eosinophilic esophagitis
• Dyssynergic defecation biofeedback
• Irritable bowel syndrome ??pro- or antibiotics??
• New drugs

43
Tegaserod in functional dyspepsia
Vakil et al., 2008
44
Tegaserod in functional dyspepsia
Vakil et al., 2008
45
FUNCTIONAL DYSPEPSIA Acotiamide (Z-337)
Acotiamide 300 mg
No PPI response
Acotidamide 600 mg
Acotiamide 900 mg
Placebo
PPI open label
PPI response end of study
Endoscopy BRAVO wireless pH monitoring
4 weeks
2 weeks
2 weeks
12 weeks
Treatment free interval
Baseline
PPI therapy
46
Acotiamide in functional dyspepsia
Tack et al., DDW 2008
47
Acotiamide in functional dyspepsia
Tack et al., DDW 2008
48
Acotiamide in functional dyspepsia
Tack et al., DDW 2008
49
Prucalopride in chronic constipation
subjects with an average of 3 SCBM per week
over 12 weeks







Placebo Pru 2mg Pru 4mg
p lt 0.005 vs. placebo
Camilleri et al., in press Tack et al., UEGW 2007
SCBM spontaneous complete bowel movements
50
Prucalopride in chronic constipation
subjects with an increase of gt 1 SCBM per week
over weeks 1-12







Placebo Pru 2mg Pru 4mg
p lt 0.001 vs. placebo
Camilleri et al., in press Tack et al., UEGW 2007
51
TD-5108 in chronic constipation
ACG 2007
52
TD-5108 in chronic constipation
ACG 2007
53
GI MOTOR AND SENSORY DISORDERS Chloride secretion
as a therapeutic target
Linaclotide
Crofelemer
Guanylin or uroguanylin
E. Coli or Yersinia enterotoxin
LUMEN
Cl-
Cl-
Lubiprostone
GC
CFTR
EC cell
CCl2
GTP
cGMP
PKG II
K
ATP
Cl-
Cl-
Na K 2Cl-
K
Na
54
CHRONIC CONSTIPATION Effect of lubiprostone
Johanson and Ueno, 2007
55
FUNCTIONAL AND MOTOR DISORDERS

• Refractory GERD pH impedance monitoring on PPI
• Refractory cough pH impedance manometry
• Dysphagia high resolution manometry
• Dysphagia eosinophilic esophagitis
• Dyssynergic defecation biofeedback
• Irritable bowel syndrome ??pro- or antibiotics??
• New drugs