Excerpts from: “Lyme Borreliosis Complex: Evaluation and Preparation, Treatment, and Recovery” Joseph G Jemsek MD, FACP Presented at University of South Florida, January 19, 2008

Cousins: Lyme Disease & Syphilis Chromosome + 21 plasmids 132 lipoproteins genes More genetic material 90% genes unrelated to any other known bacteria Only 22 lipoproteins genes Borrelia burgdorferi Syphilis Syphilis is dumb cousin J Clin Invest Mar;107(6): Review Perhaps the most complex bacteria known

Example of Tropism Lyme bacteria “love” brain tissue! Neuroborreliosis > Memory loss Severe mood disorders Lack of concentration Sleep disturbance Anxiety Word retrieval difficulty Headaches Microbes Infect Nov-Dec;8(14-15): Emerg Infect Dis Jul;12(7): Infect. Immun Jan;76(11): Epub 2007 Nov 5.

Proposed Mechanisms of Borrelia burgdorferi Persistence Active Immune Suppression Immune Evasion Innate: Complement inhibition Induction of anti- inflammatory cytokines Tolerization of monocytes Adaptive: Induction of anti- inflammatory cytokines Tolerization of lymphocytes Complement inhibition Immune complex sequesterization Phase and antigenic variation: Gene conversion Variable expression of antigens Physical seclusions: Intracellular Extracellular Cysts Immunologically privileged sites Microbes Infect Mar;6(3):312-8 ….Borrelia & friends bypass the immune system

Borrelia Blebs  Sheds antigenic “decoys” from the spirochete membrane  Self aggregate to form a pearl or tube chain  Causes increased B cell proliferation and response - Spending “Immune Capital”  Can contain Bb plasmids  Possible survival mechanism - Not necessarily a degenerative response as seen with E. coli Antimicrob Agents Chemother May;39(5): Bleb pearl strand Can form under antibiotic pressure Lack a cell wall Are osmotically fragile Can survive during beta-lactam treatments Reforms the cell wall upon reversion back to the spirochete Could be transitional form to cyst Borrelia L-Forms Przegl Epidemiol. 2002;56 Suppl 1: Infection May-Jun;24(3): Infection May-Jun;26(3):

Borrelia > Survival Mechanism Borrelia entering human B cell where it destroys the cell instead of the cell destroying the Borrelia as it is supposed to do. (mag.~13,700)‏ Dr. David W. Dorward, NIH Rocky Mountain Labs, MT Slide courtesy of LDA

Basic Tenets > Successful treatment Regain & Maintain Immunologic Control Reduce the impact of co-pathogens by means of sophisticated use of antimicrobials Multiple immunosuppressive infections in play acting as a barrier to Immunologic Control and Stability……antimicrobials may ‘even the field’ Find and treat the “ringleaders” (co-pathogens) leading to the LBC syndrome: “Pathogenic Hierarchy” not fully established and nothing is certain;We do not yet know which one is most damaging Dormancy is likely dominant paradigm > What reactivates dormant infections? - Life Stressors - Other physical illness, including new/recurrent TBIs

Basic Tenets > LBC and immune dysfunction - Synergy by pathogens in immunosuppression – Co-Pathogenicity - Markers ill-defined, largely wanting - Primarily a TH1 suppressive event with significant B cell dysfunction - “Immunologic triggers” allow other opportunistic events, chronic illness syndromes – regards host immunologically predisposed - LBC is an immunologically labile and frail condition - Appreciate wide spectrum of “stressors” or trauma, e.g. biologic, environmental, emotional, hormonal - LBC is a different paradigm from HIV/AIDS, but similar conceptually as a form of immunologic surrender

Basic Tenets > Lyme Borreliosis Complex (LBC) > Summary Most evidence suggests LBC reflects: Chronic Acquired Immunodeficiency Clinical State with a High Degree of Dysfunction – primarily a TH1 event - e.g. lab markers (depressed null cell measurements, IgG levels, and CD8 levels), clinical hypersensitivities, etc. LBC is often associated with Co-morbid Conditions: - One hypothesis would be that the immunosuppressive nature of LBC is ‘permissive’ in the expression of other chronic illness syndromes, e.g. Crohn’s, RA, MS…..?? Direct involvement as etiology There are multiple clinical patterns: - We hypothesize a fluid spectrum of clinical states with most “in waiting” or “waxing / waning” unless a ‘tipping point ’ Advanced disease is profoundly life altering without fluidity: - Without hope of spontaneous remission …”immunologic surrender”

Trigger Mechanisms for LBC > The ‘Tipping Point’ Any immunostimulating event with the impact to “Tip” the immunologic balance. May be : - Biologic - Environmental - Hormonal - Physical or psychological

Definition of LBC > Clinical Triad > Chronic/Relapsing LBC I. ENCEPHALOPATHY – One or more of the following Sx: - Inflammatory, as in headache / sensory aversion - Sleep disturbances - Mood alterations - Cognitive changes II. ARTHRITIC Symptoms – inflammatory and non-inflammatory - Generally migratory - Overlap with several rheumatologic syndromes III. POLYNEUROPATHY / MONONEURITIS MULTIPLEX - Primarily symmetrical sensory (C fiber) ‏ - Cord (myelitis) - Ganglionitis - Motor neurologic Sx Assumption is that the above qualifiers are chronic or relapsing and otherwise unexplained

Selected Head and Neck Clinical Findings in LBC Scalp: hair loss, recurrent ulcerations Throat: recurrent ulcerations Ear: pain (carotidynia), tinnitus, hearing loss or distortion Mouth: gingival and dental decay, dryness, altered taste Carotidynia Trigger point tenderness Eye: dry eyes, iritis, scleritis, papillitis, saccades, anisocoria Cranial neuropathies common, 7 th N or Bell’s Palsy, particularly when bilateral, pathognomonic “Pre-auricular Tap”: 5 th Nerve Irritability Thyroid: nodules (most TPO+)‏

Support for Polymicrobial Concept of Illness > Co-Pathogenicity Model  Specific clinical signs & pathologic correlation associated with co-infections - Key players are Babesia sp. and Bartonella sp.  Animal data to support this concept  Clinical experience revealing  Supporting laboratory serology and other markers

Clinical Approach to LBC > Three Critical Phases I. Evaluation and Preparation - Requires 0-12 weeks (or more) ‏ II. Treatment - Multidisciplinary…immunologic support - Sophisticated and individualized use of antibiotic combination - Pulse and sequencing combination therapies… - Induction phase weeks or more (tolerance dependant) ‏ III. Recovery - Goal of maximum immunologic control and tissue repair - Maintenance antimicrobial therapies…minimalist schedule

I. Evaluation and Preparation > Know the ELF E →Essential L → Life F → Functions Must gain control of the unruly elf!

Ia. Evaluation and Preparation > Learn Your P O E M S P → Pain O → Other - family support, access to care issues E → Endocrine/Metabolic M → Mood/Psychiatric S → Sleep Critical Instability in any POEMS Category precludes clinical success POEMS Categories equate to Life Stressors capable of immunosuppressive consequences

II. Treatment > Goals > Assist the dysfunctional immune system > M anage stressors > nutritional/psychiatric/hormonal/ life adjustments/sleep/pain Decide on best means of administration > Based on multiple factors > - Tolerance - Drug-to-drug interactions - Optimal route for bioavailability to diseased tissue (CSF penetration, limited GI absorption issues, etc.) Immunologic blockade by pathogens - (i.e.) Babesia co-infection up-regulates Borrelia infection - Address Babesia early as patients reach “sticking point” if not addressed - Extremely variable clinical responses Adequate duration is key! - Serious Babesia co-infections may require 8-12 weeks of treatment Pitfalls >

IIa. Treatment > Antimicrobials Combination Rx – Most effective programs and combos are based on the treating physician’s experience Antibiotic therapy design based on these principles: - Bb has multiple strains, life forms & locations - Synergizing co-infections ALWAYS present in LBC -- Highly genomically replete microbial pathogens capable of immune evasion, immunosuppression and antimicrobial resistance - No practical retrieval and strain/species definition of pathogens, and no practical or reliable antimicrobial sensitivity testing - Slow replication characteristics of all targeted pathogens (allows for pulse approach in therapy) ‏ - Rest periods or treatment holidays allows for cellular repair and detoxification Persistence of Bb & other pathogens despite Rx is assumed - The Goal of Rx becomes immunologic control Therapy designed to address essential issues - Bb multiple life forms & locations - Major co-infections - The immunosuppressed patients with co- morbidities

III. Recovery/Maintenance > Keys  Minimalist Approach  “Stun and Kill” Approach - Prominent Herxheimer is a bad sign on maintenance  Once past induction, anticipate months on maintenance program - Without markers, best measure is response to intense life stressors After induction, continued therapy with a step-down oral treatment program using a pulsed schedule in various combinations. Rationale for Maintenance - There is still immune building and tissue repair to be done! Goal is to restore optimal levels of immune capital and immunologic control. Maintenance program should contain - - Core combination Rx - Periodic imidazole - Progressive extension of holiday periods until goal of 1 week per month is attained - QOD dosing for core is acceptable

Modern Medicine in the US: Change is Needed in Health Insurance Industry  Epidemic chronic illness in the world - Estimated at 90 million in the US alone consuming 75% of the health care dollar  24 of 25 top world illnesses with “no known cause”  Average routine visit time with Internist is 7 minutes  Doctors must fight for their patients - The patients must feel we are in their corner  US health care change for the better - Patients will lead changes - Doctors limited in ability to affect change for many reasons

A New Paradigm > What LBC May Teach Us LBC, when fully expressed, is a debilitating, progressive immunosuppressive, multisystemic disorder in which multiple pathogens with a variety and range of tropisms work in synergy to frustrate and exhaust the host immune system. The manifestations of illness are a reflection of the inflammatory quotient and subsequent tissue damage/disturbance at a given site in the host. Once the host is in a state of immunologic surrender due to LBC, there is no hope for clinical improvement without epic intervention Are we on the threshold of a new paradigm for chronic illness based on improved understanding of immunologic profiles and risk for disease, immunologic capital and control, and the role of the interplay of a whole host of dormant, pathogenic and potentially reactivated microbial organisms?