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. 2001 Mar;107(6):651-6. 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. 2006 Nov-Dec;8(14-15):2832-40. Emerg Infect Dis. 2006 Jul;12(7):1051-7. Infect. Immun. 2008 Jan;76(11):298-307. 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. 2004 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. 1995 May;39(5):1127-33

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 1:57-67. Infection. 1996 May-Jun;24(3):218-26Infection. 1998 May-Jun;26(3):144-50.

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, NIHRocky 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

antimicrobialsMultiple 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 Statewith 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

Triggerpointtenderness

Eye: dry eyes, iritis, scleritis, papillitis,saccades, anisocoria

Cranial neuropathies common, 7th N or Bell’s Palsy, particularly when bilateral, pathognomonic

“Pre-auricular Tap”: 5th 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 12-24 weeks or more (tolerance

dependant)

III. Recovery - Goal of maximum immunologic control and tissue repair - Maintenance antimicrobial therapies…minimalist schedule

http://www.sevenoaksart.co.uk/gnomes.htm

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

http://office.microsoft.com/clipart

II. Treatment > Goals >Assist the dysfunctional immune system >

Manage 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 18-24 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?