Disease Management PointofCare Program for Irritable Bowel Syndrome and Migraine Headache

1
Disease Management Point-of-Care Program for
Irritable Bowel Syndrome andMigraine Headache
2
The LEAP Program

• Improve Treatment Outcomes Patient Specific
  Oligoantigenic Diet for IBS and Migraine
• Novel Point-of-Care System For Physician to
  Implement Recommended Clinical Guidelines
• Based on Patented Technology For Detection of
  Abnormal Proinflammatory Proalgesic Mediator
  Release Due to Lost Oral Tolerance
• An Effective and Safe Program Based Strictly on
  The Literature IBS and Migraine Symptom
  Management Where No Program Has Existed

3
The LEAP Program provides

• Simple Guidelines for Pt. Selection
• Simple Tool for Outcome Assessment
• Multidisciplinary, Patient Specific,
  Self-Directed Oligoantigenic Diet and Stress
  Management Plan (IBS Plan)
• Eliminates Guesswork involved in Lifestyle Change
  of IBS and Migraine

4
American Gastroenterological Association Position
Statement Irritable Bowel Syndrome Treatment

• Education and Reassurance
• Dietary and Lifestyle Modifications
• Symptom Monitoring
• Symptom Directed Medication PRN
• Psychological Treatment (HT, CBT)

Current Clinical Guidelines for IBS Diagnosis and
Treatment National Guidelines Clearinghouse www.g
uideline.gov
5
Lifestyle Eating and Performance Provides the
Specific Missing Tools In a Patient Specific
Point of Care Program to Meet Published Clinical
Guidelines and Enhance Outcomes

• Education and Reassurance
• Dietary and Lifestyle Modifications
• Symptom Monitoring
• Symptom Directed Medication PRN
• Psychological Treatment (HT, CBT)

Current Clinical Guidelines for IBS Diagnosis and
Treatment National Guidelines Clearinghouse www.g
uideline.gov
6
Trial and Error Diet Plans- Frustrating.
Ineffective.
Doctors do not advocate a particular diet to
manage symptoms
But through Trial and Error many people find
they feel better when they stop eating certain
foods. These foods cause the intestines to
contract, which can aggravate IBS in people who
have diarrhea as their main symptom. Nicholas
Talley, MD., Patrice Burgess, MD
from Controlling I.B.S. With Diet Healthwise
Information Library
7
"Recently Food Intolerance was found to be
responsible for symptoms of some patients with
the Irritable Bowel Syndrome, confirmed by
double-blind food challenge. An increase in
rectal Prostaglandin levels was noted when a
reaction occurred (other mediators found
during in vivo studies include Plasma PGE-2 ,
PGF2, TNF-alpha, IFN gamma, IL-4, IL-10, GM-CSF,
and more)
Physiologic Basis for Mediator Release Testing
and LEAP Develops
From The Merck Manual of Diagnosis and Therapy,
Page 1051

• PGE2 and PGF2a contract longitudinal muscle.
• PGE's and PGF's stimulate water movement into
  intestinal lumen.
• Wide array of proinflammatory and proalgesic
  mediators involved.

Physiologic Basis for Mediator Release Testing
and LEAP Set Forth In Merck Manual
8
IBS is not a distinct entity but merely a
collection of disorders ...
Physiologic Basis for Mediator Release Testing
and LEAP Described
I.B.S. is organic. That is, all sufferers will
eventually be found to have measurable, unique
pathologic defects. When that happy day
arrives, the term IBS will no longer be used
and each patient will receive a more precise
diagnosis. Until then, it is sufficient to
appreciate that Food Intolerance represents an
important proportion of the conditions which
together make up I.B.S.
John Hunter, MD, FCRPDirector or
Gastroenterology Addenbrookes HospitalCambridge,
United Kingdom From Food Allergy and Food
Intolerance Brostoff Challacombe, Second
Edition, 2002
9
Why have Diet Plans typically failed to make
much difference in most IBS or Migraine patients?
Diet Plans not based on the known immunologic,
non- allergic causes of GI and global symptoms
in these conditions, use of Possibility and
Guesswork
10
Why have Diet Plans typically failed to make
much difference in most IBS or Migraine patients?

• Oral Tolerance Immune Mechanisms and Loss of
  Oral Tolerance not well understood and not
  considered in approach to treatment of IBS and
  Migraine Symptoms.

11
Why have Diet Plans typically failed to make
much difference in most IBS or Migraine patients?

• Cell Mediated Inflammatory Reactions in IBS and
  Migraine not seen nor considered until recently
  if at all. The mechanisms run counter to the
  Prevailing Paradigms of Putative Pathogenesis or
  Provocation

12
Why have Diet Plans typically failed to have
much impact on IBS or Migraine Outcomes before?
Studies of systemic release of mediators, food
and additive provocation, and the causal effects
of these mediators on symptoms of IBS and
Migraine were studied in Europe, from a different
perspective. Work has often been viewed, in
error, as not relevant.
13
Why have Diet Plans typically failed to make
much difference in most IBS or Migraine patients?
Overestimating the role of enzymatic-deficiency
intolerance or endogenous chemical intolerance
mechanisms when providing dietary planning
instructions (lactose intolerance, fructose
intolerance, etc).
14
Why have Diet Plans typically failed to make
much difference in most IBS or Migraine patients?
The discovery of the INTESTINAL Allergy
mechanism (vs. classic IgE food allergy ) has not
been incorporated into IBS Diagnosis and
Management. This, and Migraine related
cell-mediated hypersensitivity reactions, are not
seen nor treated. Symptoms addressed after the
fact rather than prophylactically, drugs not
effective for global symptoms.
15
Why have Diet Plans typically failed to make
much difference in most IBS or Migraine patients?
Lack of an in vitro assay which could quantify
cell-mediated reactions to foods or additives
allergy assays (antibody assays) are of little
value in IBS and Migraine no circulating
antibodies to provoking foods are seen.
16
SUMMARY
Why No Specific Diets Have Had Much Impact
Overall

• Guesswork and Trial-and-Error often ineffective
• Loss of Oral Tolerance not understood, not
  considered.
• Cell Mediated Inflammatory Reactions in IBS and
  Migraine misunderstood.
• Persistent Prevailing Paradigms of Putative
  Pathogenesis
• Studies overlooked due to European origin or
  publication.
• Overestimating role of lactose, fructose, other
  intolerance
• INTESTINAL allergy mechanisms recent discovery,
  not disseminated nor considered in Dx and Tx
• Allergy (antibody) of little or no value in IBS
  or Migraine.
• Lack of an in vitro assay which could quantify
  the recently confirmed cell-mediated intolerance
  reactions to specific foods or additives on a
  patient by patient basis

Physiologic Basis for Mediator Release Testing
and LEAP Established 1994-1999
17
Physiologic Basis for Mediator Release Testing
and LEAP Established 1994-1999
Mediator Release with Symptom Onset Follows
Direct Food Provocation In Closed Jejunum Absent
Antibodies
1994
SEGMENTAL INTESTINAL PERFUSION A NEW
TECHNIQUE FOR HUMAN STUDIES (Lakartidningen
1994 May 1191(19)1941-6 Swedish) Allergy
Center, Sahlgrens Medical University Hospital
Goteborg Sweden Intralumenal release in the
proximal jejunum of proinflammatory mediators was
confirmed by closed segmental food provocation
with multi-lumen catheter. Subjects met Rome
Criteria and were test-negative for food allergy
(no circulating antibodies to the challenge
positive foods were detectable). Il-4,
IFN-gamma, CD3, CD4, CD8 were all isolated in
jejunum following non IgE mediated Food
Intolerance Induced reaction per Professor Ulf
Bengtsson, MD, Immunologist and Investigator
18
Staple Foods Provoke Mediator Release and
Diarrheic IBS Symptoms in Jejunum Term
Intestinal Allergy First Used to Describe Loss
of Oral Tolerance to Foods
1996
Double Blind, Placebo Controlled Food Reactions
Do Not Correlate to IgE Allergy in the Diagnosis
of Staple Food Related Gastrointestinal
Symptoms. Bengtsson, Hansen, et al Gut, 1996
Jul39(1)130-5In adult patients with staple
food induced gastrointestinal symptoms,
objectively verified by double blind placebo
controlled food challenge (via jejunal
isolation), there were no indications of IgE
mediated allergy to the relevant foods,
suggesting other mechanisms.
Physiologic Basis for Mediator Release Testing
and LEAP Established 1994-1999
19
Mucosal Allergy Role of Mast Cells and
Eosinophilic Granulocytes in the Gut.Baillieres
Clin Gastroenterol 1996 Sep10(3)443-59Bischoff
SC.Division of Gastroenterology and Hepatology,
Medical School of Hanover Intestinal
Allergic reactions may be different from
classical IgE-mediated reactions because patients
with intestinal allergy often have negative skin
tests and low levels of serum IgE. such
reactions should be considered in the
differential diagnosis of unclear intestinal
inflammation and Irritable Bowel Syndrome.
1996
Physiologic Basis for Mediator Release Testing
and LEAP Established 1994-1999
20
Abnormal Systemic Lymphocyte Activation Response
via Mediator Release to Food Challenge Described
T CELL IMMUNITY TO ORAL ANTIGENS MacDonald TT,
Dept. of Pediatric Gastroenterology, St
Bartholomews Hospital, the Royal London School of
Medicine. London Current Opinions in Immunology
1998 Dec10(6)620-7 An important discovery is
that food antigens have major systemic effects on
T cells, similar in many ways to those seen
following intravenous injection of soluble
antigens It is the type of food antigens seen
in the gut which dictates the types of
proinflammatory responses observed.
1998
Physiologic Basis for Mediator Release Testing
and LEAP Established 1994-1999
21
Mediator Effects on Brain-Gut Axis Are Well
Known
EFFECTS OF INFLAMMATORY MEDIATORS ON GUT
SENSITIVITY. Canadian Journal of
Gastroenterology, 1999 Mar13 Suppl
A42A-46A Over the past decade, attention has
been paid to the role of visceral sensitivity in
the pathophysiology of functional bowel
disorders, especially Irritable Bowel Syndrome.
Visceral Hypersensitivity is the most widely
accepted mechanism responsible for both motor
alterations and abdominal pain. Among the
structures activated by inflammatory mediators
and prone to release proalgesic substances,
mast cells and platelets play a crucial role.
Other Immunocytes such as macrophages and
neutrophilsare also candidates.
1999
Physiologic Basis for Mediator Release Testing
Clearly Established 1999
22
Cellular Inflammation Discovered In IBS Jejunum
(4) Years After First Evidence of Intestinal
Allergy
HISTOPATHOLOGICAL FINDINGS IN JEJUNUM OF PATIENTS
WITH SEVERE IRRITABLE BOWEL SYNDROME Tornbloom
H, Lindberg, G, Nyberg B, Veress presented at
DIGESTIVE DISEASE WEEK, MAY 21-24, 2000, San
Diego, Ca. Patients with documented severe IBS
met all ROME IBS Symptom Criteria were
laparoscopized to the level of the jejunum.
Jejunal biopsy revealed inflammatory
infiltration of lymphocytes in the myenteric
plexus. The lymphocytes were situated in
periganglionic and intraganglionic locations.
2000
Physiologic Basis for Mediator Release Testing
Established since 1999
23
Physiologic Basis for Mediator Release Testing
and LEAP known since 1999
Relation Between Food Provocation and Systemic
Immune Activation in Patients with Food
Intolerance. Jacobsen MB, Aukrust P, et al,
Section of Gastroenterology, Rikshospitalet,
University of Oslo, NorwayLANCET 2000 Jul 29
356 (9227) 400-1 We have found that food
provocation in Food Intolerant patients was
characterized by a general and systemic immune
activation accompanied by an increase in systemic
symptoms. an increase in both T Helper cell
related (IFN-gamma) and T Helper 2 cell-related
(IL-4) cytokines was found after food
provocation. striking increase in TNF-alpha
indicates that monocytes are also activated Our
findings might be important for the understanding
of the mechanisms involved in the pathogenesis of
Food Intolerance.
2000
24
In the last (2) years the abnormal inflammatory
process in the upper bowel of Diarrheic component
IBS Subjects has been fully described
A ROLE FOR INFLAMMATION IN THE IRRITABLE BOWEL
SYNDROME Gut 2002 Jul51 Suppl 1i41-4 Abnormal
neuroimmune interactions may contribute to the
altered GI physiology and hypersensitivity that
underlies I.B.S. INFLAMMATION, INFECTION AND
IRRITABLE BOWEL SYNDROME From Digestive Disease
Week Program, 2002, Ringel, Drossman, et
al Studies of mucosal biopsies have shown
increased inflammatory cells and Inflammatory
Mediators in patients with IBS. Recent studies
have shown proximity between nerve trunks and the
inflammatory cells, suggesting a local
neuroimmune interaction that may contribute to
the pathogenesis of IBS.
2002
Physiologic Basis for Mediator Release Testing
and LEAP Complete
25
2002 Digestive Disease Week
Irritable Bowel Syndrome Physiology and
Management Nicholas J. Talley, MD, PhD
 Clinical Subtyping of IBS By Inflammation
Type  Dunlop and colleagues4 also evaluated 76
patients with IBS and 40 healthy controls,
applying immunohistochemical staining for lamina
propria and intraepithelial lymphocytes,
enteroendocrine (serotonin-containing) cells, and
mast cells. They subdivided their patients into 3
groups, those with (1) postinfectious IBS (2)
constipation-predominant IBS and, (3)
nonconstipated, non-postinfectious
IBS   (continuednext slide)
Physiologic Basis for LEAP...
26
2002 Digestive Disease Week
Clinical Subtyping continued
These investigators found that cell counts in
constipation-predominant IBS were not
significantly different from that of controls.
 In contrast, patients with diarrhea, but
without a postinfectious history, showed
increased CD3 and lamina propria lymphocytes, in
addition to mast cells, whereas patients with
postinfectious IBS had increased enteroendocrine
cells, CD3, and lamina propria lymphocytes.
(continued)
Physiologic Basis for Mediator Release Testing
and LEAP Complete
27
Digestive Disease WeekSubtyping continued
These findings suggest that subgrouping of IBS
by bowel symptoms may identify distinct
histomorphic phenotypes within IBS, which in turn
suggests that treatment may need to be tailored
to symptom subgroups. In view of the increasing
evidence of histologic abnormalities in
IBS... ...might intervention to reduce the
inflammation have utility? If such an
intervention was able to prevent the development
or progression of IBS then this would be of major
clinical importance.
2002
LEAP Isolate and Avoid Foods and Additives
Provoking Inflammation
28
SUMMARY of Interactive Mechanisms of
Gastro-Neuro-Immune Response Mechanisms in
Diarrheic-Component IBS
Food Hypersensitivity and Irritable Bowel
Syndrome S. Zar, D. Kumar, M. J.
Benson Alimentary Pharmacology and Therapeutics
2001, April Vol. 15, Issue 4 Page 439
29
Role of Lost Oral Tolerance in Migraine?

• Medical Hypotheses. 1992 Oct39(2)168-74.
• The Cytokine Theory of Headache.Smith
  RS.Immune cell cytokines are proposed as the
  common mediators of headache. This unifying
  concept can not only account for headache, but
  also the prostaglandins, leukotrienes, platelet
  activating and vasoactive substances linked with
  headache, the varied symptoms associated with
  headache and the high incidence of headache with
  depression, infectious disease, trauma and in
  premenopausal women.
• This hypothesis provides a unified mechanism to
  explain headache triggered by food, infectious
  disease or trauma

Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
30
Is there Evidence of Food Induced Immune Response
in Specific Migraine Patients?
1979
Oligoantigenic Diet for Migraine has been shown
to be effective if properly implemented since at
least 1979
60 migraine patients completed elimination diets
after a 5-day period of withdrawal from their
normal diet. ...there was a dramatic fall in the
number of headaches per month, 85 of patients
becoming headache-free. ... Both immunological
and non-immunological mechanisms may play a part
in the pathogenesis of migraine caused by food
intolerance. Lancet. 1979 May 51(8123)966-9
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
31
Is there Evidence of Food Induced Immune Reaction
in Migraine?
1983
Oligoantigenic Diet for Migraine has been shown
to be Effective again and againbut is very
difficult to implement clinically.
93 of 88 children with severe frequent migraine
recovered on Oligoantigenic Diets. The
causative foods were identified by elimination
and sequential reintroduction, and the role of
the foods provoking migraine was established by a
double-blind controlled trial in 40 of the
children. Many foods were involved, suggesting
an immunologic rather than an idiosyncratic
(metabolic) pathogenesis(continued next slide)
32
Is there Evidence of Food Induced Immune Response
in specific Migraine Patients?
1983
Oligoantigenic Diet for Migraine has been shown
to be effective many timesstandard protocol very
difficult to implement clinically.
(continued) Associated symptoms which improved
in addition to headache included abdominal pain,
behaviour disorder, asthma, and eczema. In
most of the patients in whom migraine was
provoked by non-specific factors, such as blows
to the head, exercise, and flashing lights, this
provocation no longer provoked migraine while
they were on the Oligoantigenic Diet.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
33
Evidence of Food Induced Mediator Release in
Specific Migraine Patients
Food Allergy Is Not Involved (NO Immunoglbulins).
It is Another Immunologic Mechanism.
1983
Sera were collected from 208 adults 74 with
dietary migraine, 45 with non-dietary migraine,
29 with cluster headache and 60 controls. No
significant differences were identified between
any of the groups in IgE nor IgG food
antibodies. ...no evidence that the food
intolerance often associated with migraine
headaches is associated with a conventional food
allergic mechanism. Food Related Antibodies in
Headache Patients.J Neurol Neurosurg Psychiatry
1983 Aug 46 (8)738-42
34
Evidence of Food Induced Mediator Release in
Specific Migraine Patients
Food Intolerance Induced Migraine Treated With
Immunomodulator During Food Challenge
1984
Lancet 1984 Sep 292(8405)719-21 The patients
were given either sodium cromoglycate or placebo
orally in a double-blind manner, in combination
with foods previously identified as
provocative. Sodium cromoglycate exerted a
protective effect, thus confirming that it can
prevent a hypersensitivity mechanism as well as
the symptoms of migraine. Immune complexes were
not produced in those patients who were protected
by sodium cromoglycate. These observations
confirm that a food-sensitivity reaction is the
cause of migraine in this group of patients.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
35
Evidence of Food Induced Mediator Release in
Specific Migraine Patients
Food Intolerance Induced Migraine Confirmed By
Fasting Type Oligoantigenic Diet
1985
Annals of Allergy 1985 Jul 55 (1) 28-32 A
nutritionally supported fast week followed by
conventional food sensitivity management achieved
major improvement for 80 of a migraine panel.
This procedure gave a reliable (0.8 correlation
coefficient) prognosis on the substantial value
of this approach for selection of the treatment
of migraine. The study gave two lines of
evidence which indicate that migraine has an
etiology of food sensitivity.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
36
Evidence of Food Induced Mediator Release in
Specific Migraine Patients
Evidence of Aberrant Immune Response To Foods in
Migraine Continues to Accumulate
1989
38 of 41 migraine subjects have been treated
with elimination diet... 25 (65.7) obtained a
significant improvement of migraine. 24 of 25
(96) of oral challenged patients were affected
by food intolerance and only (1) one by food
allergy. Migraine and Food Recenti Prog Med
1989 Feb 80 (2)53-5
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
37
Evidence of Food Induced Mediator Release in
Specific Migraine Patients
Evidence of Abnormal Immune Response To Foods in
Migraine Continues to Accumulate
Headache 1989 Nov29(10)664-7 Evidence For an
Immune-Mediated Mechanism in Food-Induced
Migraine from a Study on Activated T-cells, IgG4
subclass, anti-IgG Antibodies and Circulating
Immune Complexes.
1989
IgG4 and anti-IgG antibodies values showed no
variation... Total T-cells (OKT3) showed a
marked increase at T4 and a subsequent decrease
at T72. T-activated cells (4F2 and TAC)
showed a parallel trend at T4 and a subsequent
decrease at T72 only for the Tac cells. K and
NK cells (H366) showed an early increase at T4,
all of which suggest an aberrant cell-mediated
immune response to the food antigen challenge.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
38
Evidence of Food Induced Mediator Release in
Specific Migraine Patients
Evidence of Aberrant Immune Response To Foods in
Migraine Continues to Accumulate
Acta Neurol (Napoli) 1991 Oct13(5)448-56 T
cells Expressing IL-2 Receptor in Migraine
1991
We studied a group of migraine patients for
circulating immune complexes, lymphocyte
subpopulations, IgG4 and anti-IgG antibodies,
before, after 4 hours and after 72 hours a
specific challenge test ...Total T cells showed
a marked increase after food challenge test. The
most important finding was the presence of
T-activated cells. Also K and NK cells showed an
early increase after the challenge. It must be
stressed that the evidence of early lymphocyte
activation after the challenge test indicates an
involvement of interleukin-2 related receptor in
food-induced migraine.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Develops
39
Breakthrough Evidence of Food Induced Mediator
Release in Migraine
Headache Center in Rome Quantifies Food Challenge
Induced Mediator Release In Migraine
1993
Headache. 1993 Nov-Dec 33 (10)
524-7. Disruption of the Immunopeptidergic
Network in Dietary Migraine.Headache Centre,
Rome University La Sapienza, Italy.This
investigation is devoted to the study of the
time-course of a cytokines panel (IL-4, IL-6,
IFN-gamma, GM-CSF) in plasma samples from
migraine patients. The data obtained during
challenged migraine crises was compared to the
baseline values. Time-data series analysis showed
a fall after a challenge test for IL-4 and IL-6
plasma levels and an increase in plasma levels
for IFN-gamma and GM-CSF levels.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Confirmed
40
Ongoing Evidence of Food Induced Mediator Release
Discovered
More Studies Published Showing Food provoked
Cytokine Responses in Migraine
1995 to 1998
Allergy 1995 50 (20 Suppl)78-81 Mechanisms in
Adverse Reactions to Food The Brain.Anderson
JA. Division of Allergy Clinical Immunology
Henry Ford Hospital, Detroit, Michigan Headache.
1998 Jun38(6)465-7. Cytokines and Migraine
Increase of IL-5 and IL-4 Plasma LevelsMunno
I, Centonze V, Marinaro M, Bassi A, Lacedra G, et
al Department of Immunology and
Allergy Universita di Bari, Italy.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Confirmed
41
Ongoing Evidence of Systemic Food Induced
Mediator Release
Most Recent Studies Confirm Food Provoked and
Consistent Cytokine Responses in Migraine
2000 to 2003
Headache. 2001 Sep41(8)764-7. Immunological
Aspects in Migraine Increase of IL-10 Plasma
Levels During Attack. Interestingly, we
observed low to undetectable IL-5 and IL-4
levels, whereas HIGH IL-10 levels were seen in
52.2 of the patients leads us to speculate that
a preferential enhancement of TH2-type cytokine
production may contribute to the pathogenesis of
migraine.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Confirmed
42
Ongoing Evidence of Systemic Food Induced
Mediator Release
Most Recent Studies Also Link Migraine and
Depression Comorbidity To Cytokine Release
2001 to 2003
Comorbidity of Migraine and Depression
Investigating Potential Etiology and
Prognosis.Breslau N, Lipton RB, Stewart WF,
Schultz LR, Welch KM.Departments of Psychiatry
and Biostatistics and Research Epidemiology,
Henry Ford Health System, Detroit, and Department
of Psychiatry, University of Michigan School of
Medicine Major depression increases the risk
for migraine, and migraine increases the risk for
major depression. This bidirectional
association, with each disorder increasing the
risk for first onset of the other, was not
observed in relation to other severe headaches.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine Confirmed
43
Ongoing Evidence of Systemic Food Induced
Mediator Release
Studies Also Link Depression To Cytokine
ReleaseOften Migraine Comorbid and IBS Comorbid
2001 to 2003
Psychopharmacology (Berl). 2003 Aug
30 Increased Serum Tumor Necrosis Factor-alpha
Levels and Treatment Response in Major Depressive
Disorder.Tuglu C, Kara SH, Caliyurt O, Vardar
E, Abay E.Department of Psychiatry, Trakya
University, School of MedicineOver the last 15
years, an increasing body of evidence has
suggested a causal relationship between
depression and the immunological activation and
hypersecretion of pro-inflammatory cytokines,
such as interleukin-1, interleukin-6 and tumor
necrosis factor-alpha (TNF-alpha) (continued
next slide)
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine ? Depression?
44
Ongoing Evidence of Systemic Food Induced
Mediator Release
Studies Also Link Depression To Cytokine
ReleaseOften Migraine Comorbid and IBS Comorbid
2001 to 2003
(continued from previous slide) On admission,
serum TNF-alpha and leukocyte count were
significantly higher in MDD patients compared to
controls... Comparison of pre- and
post-treatment measurements revealed that
TNF-alpha, CRP, and leukocyte count decreased to
levels comparable with those of the control
subjects ... The results emphasized that some
immunological parameters, such as CRP, leukocyte
count and TNF-alpha, are significantly involved
in the clinical course and treatment response in
Major Depressive Disorder. TNF-alpha in
particular could be considered as a potential
state marker in MDD.
Physiologic Basis for Mediator Release Testing
and LEAP for Migraine? Depression?
45
Detect the Common End-Point of ANY Reaction...
With Over 100 Possible Mediators Involved, What
to Test?
1997 Invented
2000 Patented
Basic Principal of Mediator Release Testing V1
V2 V3 V3 K
V3
V2
V1
BEFORE REACTION AFTER REACTION
Common End Point Detection Covers All Possible
Non-IgE Mediator Release from Food or Additives
Signet Diagnostic Corporation Awarded U.S. Patent
No. 6114174 (9/5/2000) U.S. Patent No. 6200815
B1 (3/13/2001) for Mediator Release Test
46
Detect the Common End-Point of ANY Reaction...
With Over 100 Possible Mediators Involved, What
to Test?
Basic Principal of Mediator Release Testing V1
V2 V3
V3
V2
V1
BEFORE REACTION AFTER REACTION
V3 Total Mass is constant in vitro (immunocyte
plasma) V1 Immunocyte Mass including
intracellular mediators formed or
synthesized V2 Extracellular compartment
(plasma)
47
Detect the Common End-Point of ANY Reaction...
With Over 100 Possible Mediators Involved, What
to Test?
V3
V2
V1
BEFORE REACTION AFTER REACTION
Normal immunocyte response to food challenge is
NO Mediator Release. This is ORAL TOLERANCE
mechanism. Loss of Oral Tolerance is seen in
IBS and Migraine patients and results in Mediator
Release from patient specific foods and
additives. Detection is V1 decreasing after in
vitro challenge and V2 increasing.
Signet Diagnostic Corporation Awarded U.S. Patent
No. 6114174 (9/5/2000) U.S. Patent No. 6200815
B1 (3/13/2001) for Mediator Release Test
48

• Excerpt from a LEAP patient Mediator Release
  Testing Result, total panel is 150 foods and
  chemical additives
•  
• Green Range indicates minimal to no reaction.
  Tolerance high.
• Yellow Range reflects modest reaction at the
  challenge dose, some Loss of Tolerance.
• Red Range indicates significant volume movement
  from affected immunocytes. Suggestive of
  significant Loss of Oral Tolerance to that food
  or additive.
• Thus, LEAP Diet is Patient Specific

49
Signet STS 100 Mediator Release Test Instrument
Signet Diagnostic Corporation Awarded U.S. Patent
No. 6114174 (9/5/2000) U.S. Patent No. 6200815
B1 (3/13/2001) for Mediator Release Test
50
Mediator Release Test Confirmed Effective in a
Controlled Trial conducted by an Independent
Allergy Center. Published in Peer Reviewed
Journal.
...M.R.T. method will be useful in identifying
cell-mediated food intolerance and
hypersensitivity reactions.
Kaczmarski Maciej MD, Sawicka Ewa MD,
Werpachowska Irena MD .III Children Allergy
Clinic, University of Bialystok Medical School.
Pediatric Review, 1997, Supplement 1,
61-65   THE MRT TEST A NEW GENERATION OF TESTS
FOR FOOD HYPERSENSITIVITY IN CHILDREN AND
ADULTS
51
An assessment of the diagnostic usefulness of
the new Mediator Release Test (MRT) for isolating
staple food intolerance/sensitivity reactions was
performed on subjects confirmed milk protein
reactive. The Mediator Release Test yielded a
sensitivity of 94.5 percent. Through analysis of
the data stream report, it was demonstrated that
differentiated cell types were involved in
reactions to antigen challenge with the following
frequency Lymphocytes 38.5 Granulocytes
47.5 mixed reaction (combination of
Lymphocytes and Platelets) 14. These results
suggest that the M.R.T. method will be useful in
identifying cell-mediated food intolerance/hyperse
nsitivity reactions and implementing dietary
modifications based on the results. (Kaczmarski
Maciej MD, Sawicka Ewa MD, Werpachowska Irena MD)
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What is the LEAP Disease Management Approach?
Summary

• LEAP is the Only Program Available which includes
  ALL the Lifestyle Elements Recommended in The
  Current Literature and Clinical Guidelines for
  Effective Management of Irritable Bowel Syndrome
• A Patient Specific Oligoantigenic Diet Plan for
  Doctor to Provide Patient for Self-Implementation
• A Self-Directed Stress and Anxiety Reduction (HT)
  Compact Disc developed by a Gastroenterologist
  and Clinical Psychologist
• Physician Tools for Patient Selection and Outcome
  Assessment
• Places the Primary Responsibility For Success on
  the Patient where it belongs, not the Physician,
  and provides access to added R.D. support if
  required.

53
Degree of Symptom Reduction After Just 30 Days on
the LEAP Program reported by A LEAP Affiliate
Primary Care Provider on 80 of his patients with
These Symptoms.
54
Why Will LEAP Produce Better Results?

• LEAP A SIMPLE Blueprint For Success.
• Developed over 3 years by a team of
  Immunologists, Allergists, Primary Care
  Physicians and Dietitians
• Turnkey Protocol

• Full Customer Support of Implementation Into Any
  Practice
• Full Staff In-Servicing
• Program Guide Books and Staff Training
• Assistance with Office Integration
• Front Office System Assistance
• Billing Guidance
• Specimen Collection and Handling Supplies
  Provided
• Marketing Assistance For the Practice Seeking to
  Promote LEAP Within the Community to Target
  Populations

55
For more information

• Contact your LEAP Consultant at the number
  provided, OR
• If You Do Not Have a Consultant, Contact Signets
  Professional Services Director toll free
  nationwide at
• 1-888-NOW-LEAP