Adjunct Asst. Prof of Psychiatry – Indiana University School of Medicine Department of

PsychiatryChild, Adolescent, Adult, Functional

Neuropsychiatry – Evansville, Indiana

4rth Annual MMH CONFERENCE – Chicago, IL.Saturday, September 21, 2013

New Adventures in Food Allergy Testing

Louis B. Cady, MD – CEO & Founder – Cady Louis B. Cady, MD – CEO & Founder – Cady Wellness Institute Wellness Institute

Continuing Medical Education Commercial Disclosure Requirement for Louis B. Cady, M.D.

I, Louis B. Cady, MD, have the following commercial relationships to disclose:•Speaker honoraria received from:

• Immunolaboratories, Great Plains Diagnostic Labs, LABRIX

•Speaker’s bureaus (active) for:• Forest Pharmaceuticals, Sunovion, Shionogi

•Historical data – speaker’s bureau for Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith Kline, Janssen, McNeil, Pfizer-Roerig, Sanofi!~aventis, Sepracor, Shire, McNeil, Takeda, Janssen, Searle, Shire, Takeda, Wyeth-Ayerst

IMMUNOLOGY

The forgotten component of “workups”

"What is food for one, is to others bitter poison.”

Lucretius – 099? B.C. – 055? A.D. De rerum natura.

“The Three Little Ig’s & Three Stories”

•Ig E

• Ig G

•Ig

xciting

oing along

norant

IgE Antibodies: catastrophic reactions vs. sneezes and itching (checked via skin tests or RAST)

http://pathmicro.med.sc.edu/ghaffar/skintest.jpg

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/MastCell.gif

www.souzaoenterprises.com/Allergiescomp.jpg

CELLULAR immunity

This model of human IgG1 was created by E. A. Padlan -- "Anatomy of the Antibody Molecule." Molecular Immunology 31:169 (1994)

HUMORAL Immunity

“Globulin molecules capable of attacking the invading agent.” [Guyton]

Actions and downstream effects

• Direct action of antibodies:– Agglutination, precipitation, neutralization,

lysis

• Downstream effects: complement activation:– Lysis, opsonization/phagocytosis, chemotaxis,

agglutination, neutralization of viruses, INFLAMMATORY EFFECTS

The Classical Pathway of Complement Activation http://www.youtube.com/watch?v=gNvHLStz-VA

It can therefore be hypothesized that all the components of the circulatory humoral system are participating in this reaction and that Type II, the cytotoxic, and Type III, the immune-complex type of immunologic reaction, are the major contributors in the production of symptoms.

It can therefore be hypothesized that all the components of the circulatory humoral system are participating in this reaction and that Type II, the cytotoxic, and Type III, the immune-complex type of immunologic reaction, are the major contributors in the production of symptoms.

Trevino RJ. Laryngoscope. 1981 Nov;91(11):1913-36.

De Weck Al. Ann Allergy. 1984 Dec;53(6 Pt 2):583-6.De Weck Al. Ann Allergy. 1984 Dec;53(6 Pt 2):583-6.

“antigen-IgG complexes generating anaphylatoxins…”

ADHD Diagnosis DSM-IV (TR)

–SIX Symptoms present before age 7 years

–Impairment from symptoms present in 2 or more settings

–Significant social, academic, or occupational impairment

–Exclude other mental disorders

DSM-V–Symptoms rewritten slightly

• FIVE only required for adults

From:

www.patientmedia.com

(used with permission of William Esteb)

Food Allergies and ADHD in the Literature

• Get “THE THINKER” illustration•Food allergies presumed to be related to ADHD•Before 1976 – No known relationship between FA and ADD•1976 – IgE reactivity + food allergies = decreased IQ•1985 – d/c of antigenic foods = ADHD improvement •1993 – more confirmation •1994 – some kids that got better on diet did NOT have IgE reactivity•2003 – evidence mounting for non-IgE sensitivities related to food allergies]•2002 – 2011 Pelsser LM et al – SIX published papers (European and Dutch literature, cf: www.pubmed.gov). •73 papers, at present – 8/03/2013

Millman, et al – the groundbreaking article

• “Allergy & Learning Disabilities in Children” – Annals of Allergy, 1976 [36:3, 149-160.]

• “The allergic tension-fatigue syndrome observed by Speer”– “A symptom complex accepted by many allergists.”

• Food allergies established by scratch testing or intradermal injections

• Positive correlation between [IgE] food allergies and IQ scores.

–The more the food allergies, the lower the IQ scores.

Oligoantigenic diet (w/o testing)

• “Controlled trial of oligoantigenic treatment in the Hyperkinetic Syndrome.” Egger et al. Lancet, March 9, 1985, 540-545.

• No testing performed• Children empirically placed on restrictive diet.

– Two meats, two carb sources, two fruits, one vegetable, water, calcium, vitamins.

• No food allergy symptoms were provoked; ADHD improved.

The crossover study – no distinguishing between IgE and IgG

• “Effects of a few foods diet on ADD.” Carter et al, Archives of Disease in Childhood, 1993;69:564-568.

• “Few foods” elimination diet– 59 of 78 children improved.

• “This trial indicates that diet can contribute to behavior disorders in children and that this effect can be shown in a double blind, placebo controlled trial.”

• “The ways in which [this] diet worked remain unclear. Toxic pharmacological, or allergic mechanisms could be involved, and the physiological effects of different foods may vary.”

Profound cautions

• “Effects of a few foods diet on ADD.” Carter et al, Archives of Disease in Childhood, 1993;69:564-568 (cont.)

• “The treatment, as applied in this study, has disadvantages. It is a difficult and exacting regimen, which puts a considerable strain on the whole family. It is not yet clear whether modified diets can also be effective…. It may therefore be possible to devise a less restricted diet with similar levels of success.”

• Cady impression: “Shooting in the dark is dangerous.”

The appearance of IgG

• “Foods and additives are common causes of ADHD in children.” Boris, et. al. Annals of Allergy, vol.. 72, 1994, 462-468.

• “DBPCF” - “double blind placebo controlled food challenge test”

• 4/19 children who showed improvement with removal of offending foods were non-atopic.

Pelsser publishes - 2002• “few foods diet” – {rice, turkey, pear &

lettuce} in 40 children– 36 boys, 4 girls; 3-7 years of age, all dx with

ADHD}

• Results:– 25 patients (62%) improved behavior >/= 50%– 10 (25%) had improved parent/teacher ratings. – 9 (23%) withdrew from study

Pelsser LM, Buitelaar JK. Favourable effect of a standard elimination diet on the behavior of young children with attention deficit hyperactivity disorder (ADHD): a pilot study. Ned Tijdschr Geneeskd. 2002;146(52):2543–2547

“IgE and Non IgE Food Allergy”

• Sabra, et al. Annals of Allergy, Asthma, and Immunology 2003;90 (Suppl 3)71-76.

• “The gastrointestinal tract serves not only a nutritive function but also is a major immunologic organ. Although previously thought to be triggered primarily by an IgE mediated mechanism of injury, considerable evidence now suggests that non-IgE mechanisms may also be involved in the pathogenesis of FA (“food allergy”).

Pelsser publishes (again)- 2011• “Impact of Nutrition Study on Children with ADHD”• 100 children, 4-8 years of age with ADHD

– Open label phase – 5 weeks of a restricted elimination diet (“diet group”) OR healthy control diet (50 kids each)

– THEN – 4 week double-blind crossover challenge of “diet group” responders

• Challenge responders:– With either HIGH or LOW IgG reactivity (per testing):

• increase of 20.8 point on ADHD [ARS] rating scale (p<0.0001)• 11.6% increase of a Conner’s score (p<0.0001)

• After challenge – 63% of children relapsedPelsser LM, Frankena K, Toorman J, et al. Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder

(INCA study): a randomised controlled trial. Lancet. 2011;377(9764):494–503

What does a 20.8 point increase in ARS mean???

Number crunching:•9 symptoms of inattentiveness & 9 of hyper/impuls = 18.•Lichert scale {0 – 3}•Max score = 18 *3 = 54 points

•20.8 points = 39% of range.

• Assume little Johnny has dropped from 45 to 18 in phase II of study (40% drop which was required.)

• Increase from 18 +20.8 points = 39 points = 2.16 X increase in sxs.

• Drug examples:– Fluoxetine at 80 mg (max dose) gets

increased to 172.8 mg– LiCO3 gets increased from 1200 mg/d to

2,592mg of Li+/day– LIPITOR – goes from 80 mg to 172.8 mg

Well, what does a 2.16 X effect mean?

• My favorite: a speeding ticket for 75 mph in a 70 mph zone gets increased to going 162 mph!!

FROM HYPERNESS TO HEADACHES…and joint pains, migraines, brain fog, irritable bowel syndrome, asthma, fatigue, misc. aches and pains

www.pubmed.com search August 2, 2013Correlations found between food allergy & :

• ADHD (73 citations)• Depression (80 citations)• Anxiety (109 citations)• Acute psychosis (1 citation)• Autism (43 citations)• Schizophrenia (20 citations)

Mechanisms of behavioral, atopic, and other reactions to artificial food colors in children

[Stevens LJ et al. Nutr. Rev. 2013 May; 71(5):268-81]

• “… a subgroup of children (with or without ADHD) react adversely to challenges with AFC’s.”

• “Children with ADHD show EXCESS inattention, impulsivity, and hyperactivity.”

• “Studies using at least 50 mg of AFC’s showed a greater % of children who reacted to the challenge.”

Neltner, T. JAMA Internal MedicineAugust 7, 2013Neltner, T. JAMA Internal MedicineAugust 7, 2013

In a previous study, Neltner and his colleagues estimated that about 43 percent of the 10,000 or so additives allowed in food were on the FDA's GRAS list, with other additives approved through other means or not submitted to the FDA. Manufacturers made their own safety determinations for about 1,000 additives without ever notifying the agency.

In a previous study, Neltner and his colleagues estimated that about 43 percent of the 10,000 or so additives allowed in food were on the FDA's GRAS list, with other additives approved through other means or not submitted to the FDA. Manufacturers made their own safety determinations for about 1,000 additives without ever notifying the agency.

Millichap & Yee. Vol 129, no. 2 Feb 1 2012 – pp 330-337

Full article: http://pediatrics.aappublications.org/content/129/2/330.long

• Diets reviewed:– Sugar restricted. Additive/preservative free,

elimination diet and FATTY ACID SUPPLEMENTS

• NOTABLE: “ADHD-associated Western diet”high in fat and refined sugars

• ADHD-free [sic] healthy diet: {fiber, folate, and omega 3 fatty acids.

• Multiple cits. on + results with IgG elimination

Millichap & Yee. Loc. Cit.

• Other findings:– Strong results with Omega 3 & 6 supplementation.

• (doses of 300 – 600 omega 3 and 30-60 mg Omega 6/d)

– Benefits of zinc supplementation • (optimal dose of d-amphetamine was 37% lower with zinc

than with placebo)

– Children are more sensitive to reactive hypoglycemia than adults: AVOID SUGAR LOAD.

– Unusually low ferritin levels {18.4ng/ml, mean} correlated with baseline inattention, hyperactivity and impulsivity.

• Also correlated with dose of d-amphetamine required.

Association of atopic and non-atopic asthma with emotional symptoms in school children

• Cross sectional data on asthma and allergic diseases at 10 year follow-up of two birth cohorts. – Atopic = “asthma ever and + IgE test” – Non-atopic = “asthma ever and NEGATIVE IgE”

• “Non atopic asthma was associated with about 3-fold higher likelihood of emotional symptoms compared to children with no asthma.” [OR = 2.90, CI 95% = 1.46-5.73]

• Atopic asthma – not associated with emotional symptoms [OR 1.35]

Kohlboeck G et al. Pediatr Allergy Immuno. 2013 May; 24(3):230-6

Serological tests in gluten sensitivity (nonceliac gluten intolerance)

• “Gluten sensitivity” noted to be recently identified as a new clinical entity included in spectrum of gluten-related disorders.

• Study - Sera from 78 patients with GS + 80 patients with celiac disease was retrospectively analyzed for:

– immunoglobulin (Ig)G/IgA antigliadin antibodies – IgG deamidated gliadin peptide antibodies – IgA tissue transglutaminase antibodies (tTGA)– IgA endomysial antibodies (EmA)

Volta U, et al. J Clin Gastroenterol. 2012 Sep;46(8);680-5.

Serological tests in gluten sensitivity (nonceliac gluten intolerance)

• Patients with GS had intestinal and extraintestinal symptoms– Abdominal pain, bloating, diarrhea, constipation

– “foggy mind,” tiredness, eczema/skin rash, headache, joint/muscle pain, numbness of legs/arms, depression, and anemia

• NORMAL or MILDLY ABNORMAL small intestinal mucosa

• CONCLUSIONS: “The serological pattern of GS is characterized by IgG AGA positivity in more than half of the cases.”

Volta U, et al. J Clin Gastroenterol. 2012 Sep;46(8);680-5.

“Is a subtype of autism an allergy of the brain?”

Theoharides, TC. Clin Ther. 2013 May; 3595):584-91.

• Methods – PubMed search since 1995: associations between autism/ASD’s and “allergy, atopy, brain, corticotropin-releasing hormone, cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, mast cells, mitochondria”… [etc.]

• “Children with ASD…present with food and skin allergies that involve mast cells (IgE).”

“Is a subtype of autism an allergy of the brain?”

Theoharides, TC. Clin Ther. 2013 May; 3595):584-91.

• “Activation of brain mast cells by allergic, environmental, immune, NEUROHORMONAL, stress, TOXIC TRIGGERS, especially in those areas associated with behavior and language, lead to focal brain allergies and subsequent focal encephalitis.”

Food allergy and autism spectrum disorders: is there a link?

Jyonouchi H. Curr Allergy Asthma Rep. 2009 May;9(3):194-201

• “ Our previous studies indicated a high prevalence of non-IgE mediated FA in young children with ASD’s.”

• “…non-IgE-mediated FA may account for some but not all GI symptoms observed in children with ASDs.”

Anxiety & depression in patients with self-reported food hypersensitivity

• 130 consecutive patients and 75 random healthy volunteers– Completed the Hospital Anxiety and Depression Scale

(HADS)

• 57% of patients fulfilled a DSM-IV criteria for at least one psychiatric disorder. – Anxiety disorders – 34%

– Depression – 16%

• Food hypersensitivity rarely confirmed by provocation tests. (Non IgE)

• 81% of patients had irritable bowel syndrome

Lillestol K et al. Gen Hosp Psychiatry. 2010 Jan-Feb; 32(1):42-8.

IgG food allergies in IBS• 150 outpatients with IBS randomized to diet

excluding all IgG reactive items or a sham diet (excluding the same number of foods but not the ones to which they had antibodies)– 25% reduction in IBS symptoms in fully compliant

patients– 10% reduction in moderately compliant

• “Food elimination based on IgG antibodies may be effective in reducing IBS symptoms and is worthy of further medical research.”

Atkinson, W et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.

Gluten – one of the ultimate “bad boys” in food sensitivities

• Headaches

• Tearing up your gut

• Depression

• Suicide*– * Untreated celiac

disease and attempted suicide. Lancet, September 1995. Pelligrino et al

Gluten and neurologic disease

• “More recent studies have emphasized that a wider spectrum of neurologic syndromes may be the presenting extraintestinal

manifestation of gluten sensitivity with or without intestinal pathology.”– -Bushara, KO. Neurologic presentation of

celiac disease – Gastroenterology. 2005 Apr; 128(4 Suppl 1):592-7.

“UBO’s on MRI” – the gluten connection

• 10 patients – had headaches. – MRI– UBO’s

• 6 – unsteady, 4 gait ataxia

• 90% response rate to gluten free diet.

Observant pediatricians and depressed parents – with celiac dz

Corvaglia, et al 1999

• 3 adult patients found with undiagnosed/untreated celiac disease

• Found by pediatricians who noted family history when child’s medical history obtained.

• Celiac disease diagnosis was MADE in childhood, but diet was stopped due to no more GI symptoms.

• In all three patients, depressive symptoms improved with gluten free diet.

Does it have to be celiac/gluten to mess up your head?

“According to the results obtained, serum IgG antibodies to common food should be investigated in patients with migraine.”

“According to the results obtained, serum IgG antibodies to common food should be investigated in patients with migraine.”

Jonez, HD Calif Med. 1953 November; 79(5): 376–380.

• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1521914/pdf/califmed00209-0035.pdf

Practicum

Photos deleted for syllabus materials. The presenter has permission to use the patient’s

photos during the live presentation only.

Criticality of removing IgG antigens (+ complete, holistic approach)

RX: dairy free diet (+IgG test); D3 5000 IU/d; Armour thyroid, Testosterone cypionate 100 mg IM q wk, MVI, Zinc, DHEA 50 mg SR, CoQ10 400mg

(photo shot 15 months after tx)

(permission granted to use photos & data)

Photos deleted for syllabus materials. The presenter has permission to use the patient’s

photos during the live presentation only.

Photos deleted for syllabus materials. The presenter has permission to use the patient’s

photos during the live presentation only.

Just one more: Rusty- 6/28/11 “The kid that wouldn’t poop.”

• 11 year old male 5th grader with dx of ADHD and Speech Apraxia; problems with reading, writing, oral expressive language, math, sequencing

• Medical:– Hx of “lazy bowel”

• “He doesn’t go more than once in two weeks.”• Dietary: likes cheese, chicken nuggets, ice cream, Coke, pizza.

Used to like cottage cheese.

– GI sxs refractory to pediatric interventions• Dx 1: ADD: 6/9 sxs of inattentiveness ON RX.• Dx 2:“Probable severe IgG food sensitivity with

obvious stool retention problems”

Dairy IgG sensitivity suspected. Testing/Results:

• Pediatrician ordered IgE RAST = NEGATIVE

• 7/25/11 – no change. 2 BM’s in one month.– IgG Testing previously ordered. (Mom resistant

and delayed due to cost. Finally done after this appt). RESULTS……

Milk = 5+

“The kid who wouldn’t poop.”

The kid that wouldn’t poop, concl.

• 8/15/11 – milk/wheat stopped.

• Constipation and fecal retention totally eliminated within 1 week.

• Follow-up: “He won’t follow the diet.” Mom wimped out. Now constipated again.

What to be looking for…• Obvious GI problems• Meds not working.• Chiro adjustments don’t

“hold.” • Atypical presentations• KNOWN associations

(autism)• Symptoms varying with diet• Excess ABX use (candida) • Lack of normal progression

in treatment

Diagnostic challenges & IgG food sensitivities - opportunities exist

• “Tough cases”• Weird, multiple symptoms• Headaches• GI symptoms, food cravings, or both• ADHD and “bipolar” type symptoms• Processing issues (no pills available!)• Headaches resistant to standard

chiropractic and medical tx• Fatigue, “brain fog”, temper fits

Personal collection - Louis B. Cady, M.D.

Louis B. Cady, M.D. www.cadywellness.com www.facebook.com/cadywellness www.tms-relief.comOffice: 812-429-0772 E-mail: lcady@cadywellness.com 4727 Rosebud Lane – Suite F ~ Interstate Office Park Newburgh, IN 47630 (USA) TWITTER FEEDS: @LouisCadyMD @TMS4depression

Once more…. Where to “get the slides” -

Syllabuswww.slideshare.net/lcadymdCady Wellness Institute app.