EURIMM European Institute of Molecular Medicine Chronic Fatigue

EURIMM European Institute of Molecular Medicine Chronic Fatigue Immune Dysfunction Syndrome A Model for a Paradigm-change in the Diagnosis and Therapy of Chronic Diseases Arnold Hilgers, M. D. , EURIMM, Düsseldorf

EURIMM European Institute of Molecular Medicine Anamnesis 30 -criteria-score (Hilgers et al. , 1996) Immune Balance Check Humoral Trigger Factors Infections Food Environment Cellular Activation Autoimmune Cytokines Genetic predisposition Endocrine/Metabolism Anti-oxidant capacity Hormones Metabolic enzyme activity PUFA’s Cardiovascular disease Neurotransmitters Risk for enhanced suppressor cell activity Treatment Trigger Factor Elimination Immunomodulation

EURIMM European Institute of Molecular Medicine Anamnesis 30 -Criteria-Score Arnold Hilgers and Johannes Frank. Journal of Chronic Fatigue Syndrome, 1996, Vol. 2 (4). Ø 45 criteria from Centers for Disease Control (CDC) definition of chronic fatigue syndrome + 17 additional criteria Ø 385 patients (according CDC) were compared with 53 healthy controls Ø The first 30 symptoms that were significantly different between the two groups led to the 30 -Criteria-Score Major criterium (fatigue/exhaustion) + 3 minor criteria High probability of disturbed immunebalance

EURIMM European Institute of Molecular Medicine 30 -Criteria-Score Rank Symptom 1 fatigue/exhaustion 16 dryness of eye/mouth 2 lack of concentration 17 visual disorders 3 memory disorders 18 allergy 4 sleep disorders 19 nausea 5 myalgia 20 paresthesia 6 swings of mood 21 hair loss 7 headache 22 lymphadenopathia 8 respiratory infections 23 skin alterations 9 depression 24 dyscoordination 10 palpitation 25 chest pain 11 dizziness 26 personality changes 12 pharyngitis 27 skin rashes 13 dyspepsia 28 general infections 14 nocturnal sweat 29 muscle twitching 15 arthralgia 30 urinary infections

EURIMM European Institute of Molecular Medicine Immune Balance Check ØCellular Leukocyte subsets Lymphocyte subsets ØHumoral Electrophoresis, Ig. G Complement activity ØActivation Activated T-cell Humoral factors ØAutoimmune Auto-antibodies ØCytokines in plasma Intracellular cytokines

EURIMM European Institute of Molecular Medicine Trigger Factors Factor Appearance Detection Infection Viruses Intracellular bacteria Serology PCR Antigen detection Lymphocyte Transformation Test Food components (f. e. cow milk) Food additives (f. e. glutamate) Lymphocyte Transformation Test (Type-IV allergy) Environmental factors Metals (incl. dental metals) Fungi Lymphocyte Transformation Test (Type-IV allergy)

EURIMM European Institute of Molecular Medicine Genetic predisposition Determination of Single Nucleotide Polymorphisms (SNP’s) ØLack of anti-oxidant capacity ØRisk factors for cardiovascular disease ØRisk for enhanced suppressor cell activity ØMetabolic disturbances

EURIMM European Institute of Molecular Medicine Neuro-endocrine/Metabolic Factors Hormonal dysregulation - modulates immune balance - GH-axis, HPA-axis, sex hormones, … Poly Unsaturated Fatty Acids (PUFA’s) and other lipids - anti-oxidants - direct influence on immune balance - effect on brain neurotransmitters Neurotransmitters - modulates immune balance - serotonin, tryptophan and metabolites

EURIMM European Institute of Molecular Medicine Neuro-endocrine/Metabolic Factors Anti-oxidant capacity Oxidative stress - lipid peroxidation - neutrophil function: oxidative burst Anti-oxidants - Zn, Se - carnitine, gluthation, co-enzyme Q 10 - Vit C, E, B 6 - taurine, tyrosine, tryptophan

EURIMM European Institute of Molecular Medicine Treatment Elimination of trigger factors - Food (diet) - Environment (eventual change environment) - Antiviral/Antibacterial therapy Immunomodulation - Products of B- and T-cells - Anti-oxidants to repair macrophage function Restoring Th 1/Th 2 -balance Nutriceuticals - Substances to counteract genetic predisposition - PUFA’s, 5 HTP, …

EURIMM European Institute of Molecular Medicine Paradigm change Classical Medicine Psychic Disease Psychiatrist Doctor 1 Organic Doctor 2 Doctor 3 … Treatment: symptomatic therapy

EURIMM European Institute of Molecular Medicine New Paradigm to Diagnose and Treat Psychoneuroimmunological and Other Chronic Diseases New Medicine Universal 30 -Criteria-Score Disturbed Immune Balance 1. Check immune balance 2. Find trigger factor 3. Restore immune balance 4. Eliminate trigger factor Treatment = Causal therapy

EURIMM European Institute of Molecular Medicine Patient 1 Ø Patient suffered from several CFS episodes and presented (together with parents) with severe psychotic episode (Nov. 1995) Ø Previous diagnosis was depression. Patient was due to be admitted to psychiatric hospital. Ø Laboratory findings - stimulated immune system(CD 8+CD 38+) with leukopenia, reduced NKCA, elevated s. IL-2 R and TNF-alpha - abnormal B-cell function - Helicobacter, Candida, and viral (EBV, HVZ) infection - Type IV-allergy to many food supplements, fungi and dental metals. - auto-antibodies to serotonin, gangliosides, phospholipids and keratin Ø Treatment - immunoglobulin i. v. with anti-oxidant infusion - antiviral therapy (Zovirax) - antibacterial therapy (standard triple therapy against Helicobacter)

EURIMM European Institute of Molecular Medicine Patient 1 (Ctd. ) Ø After treatment (Jan. 1996) - patient recovered from psychosis and chronic fatigue - patient started working again Ø In Oct. 1996, patient presented again with CFS. elimination of trigger factors: diet and avoiding Aspergillus Patient was also treated again for Helicobacter infection Patient recovered Ø Patient subsequently suffered form recurrent chronic fatigue, but was able to work. Every time there were recurrent viral infections and auto-antibody elevations. Patient had a lot of allergies to food supplements and environmental factors.

EURIMM European Institute of Molecular Medicine Patient 1 (Ctd. ) Ø Nov. 2002 Patient presented with new severe psychotic episode Now, laboratory findings were: - no stimulated immune system, no auto-antibodies - viral infections (EBV, HHV-6) and Chlamydia pneumonia infection - high levels of IL-8 (>7500 pg/ml) and IL-6 Ø Treatment - anti-bacterial treatment for Chlamyidia infection - immunoglobulin i. v. Ø Patient is now recovered from psychotic episode and chronic fatigue.

EURIMM European Institute of Molecular Medicine Summary Patient 1 Typical example of chronic disease due to disturbed immune balance and leading to severe psychiatric symptoms Trigger factors (infections, food, environment) Chronic stimulated immune system Severe psychiatric symptoms Chronic fatigue

EURIMM European Institute of Molecular Medicine Patient 2 Ø Patient (age 34) presented in Aug. 2002 Ø Symptoms: chronic fatigue, panic attacks, stomach problems and depressive episodes. Ø Previous diagnosis: somatoform depression. Ø Laboratory findings - normal leukocyte number and function ongoing infections: CMV, EBV, Chlamydia, Candida, Helicobacter, Borrelia, Yersinia, Mycoplasma - auto-antibodies: gangliosides, serotonin Ø Treatment - immunoglobulin i. v. - anti-oxidants - anti-Helicobacter therapy

EURIMM European Institute of Molecular Medicine Patient 2 (Ctd. ) Ø Outcome (Nov. 2002) - reduction of auto-antibodies - remission of helicobacter infection - still ongoing Borrelia-infection Ø Further investigation showed reduced IGF-1 levels. Ø Further treatment with growth hormone restored IGF-1. Patient subsequently recovered from Borrelia infection. Ø LTT showed Type-IV allergy to lamb meat and mollusc. This is the probable cause of the stomach problems.

EURIMM European Institute of Molecular Medicine Summary Patient 2 Ø After doctor- and clinic Odyssey, without any positive results and even worsening of the situation, present condition is significantly improved in association with reduced Borrelia load.

EURIMM European Institute of Molecular Medicine Patient 3 Ø Patient (age 55) presented in May 1996. She was previous diagnosed as having psychosis. Ø Findings Chronic Fatigue Syndrome with: - humoral immunodeficiency (Ig. G < 3 g) - anti-phospholipid syndrome - chronic re-activating infections (Herpes viruses) - reduced gluthation-S-transferase reduction - pathological polymorphism of gluthation-S-transferase - TNF-alpha elevation

EURIMM European Institute of Molecular Medicine Patient 3 (Ctd. ) Ø Treatment: Immunoglobulin i. v. Improvement of symptoms and reduction of auto-antibodies No alleviation of viral infections Ø Additional treatment: Antiviral therapy: Cymeven 5 mg, which had to be increased to 10 mg Elimination of viral infections (trigger factor)

EURIMM European Institute of Molecular Medicine Summary Patient 3 Ø Recovery after therapy so significant, that patient could resume position as chief journalist of a newspaper, after having been unable to carry out any work for one and a half year.

EURIMM European Institute of Molecular Medicine Patient 4 Ø Patient was previously a healthy student from a family with high social-economic status. He was very intelligent with high grades at school and a good sportsman. Ø When the patient went to boarding-school, he developed a depressive-like syndrome with lack of concentration, fatigue and cognitive dysfunction. His room was in an 300 -year old building, with probably high humidity. Previous diagnosis was depression, but treatment failed.

EURIMM European Institute of Molecular Medicine Patient 4 (Ctd. ) Ø Laboratory findings: - high TNF-alpha level - auto-antibodies to serotonin - elevated Ig. E and ECP - LTT showed Type-IV allergy to 5 different fungi Ø Treatment: - immunoglobulins and anti-oxidants - change of living environment (room in new building) Ø Patient recovered from depressive symptoms and fatigue, and is doing better in his studies. Summary: Patient healed.