1. Current Status of Lyme Disease and Co-Infections Sam T Donta MD Infectious Diseases Professor of Medicine (ret)

2. Introduction/Overview Diagnosis of Lyme Disease Clinical Aspects Stages of Lyme Disease Differential Diagnosis of Lyme Disease Laboratory Diagnosis Routine Bloodwork Lyme Serologic Testing Adjunctive Studies MRI Brain SPECT scan Treatment of Lyme Disease

3. Stages of Lyme Disease Early Lyme Disease Early Disseminated Lyme Disease Late or Chronic Lyme Disease

4. Early Lyme Disease Tick Bite Rash Typical Erythema Migrans (EM) Atypical Rash(es) Diagnosis Clinical Serology

5. Treatment of Tick Bite Empiric vs waiting for tick results Double dose doxycycline? 2-3 weeks of doxycycline or amoxicillin? What to do if tick bite, but no tick Wait to see if symptoms develop? Any value to serologic testing? Double dose doxycycline? 2-3 weeks of doxycycline or amoxicillin?

6. Early Disseminated Lyme Disease Clinical Rash “Flu-like” Symptoms Diagnosis Clinical Serology

7. Late Lyme Disease Early/Late LD Symptoms/Signs Bell’s Palsy Meningitis Carditis Arthritis-Oligoarthritis Encephalopathy Diagnosis

8. Chronic Lyme Disease Clinical Major Criteria Fatigue MusculoSkeletal Neurocognitive Minor Criteria

9. “Minor” Symptoms & Signs Headaches Eye Symptoms Ear Symptoms Jaw/Tooth Pain Bell’s Palsy Dysequilibrium Dyspnea Chest/Rib Pains Palpitations Paresthesias Tremors GI Symptoms GU Symptoms Fevers/Sweats

10. Spectrum of Lyme Disease Generalized Symptoms Neurologic Symtoms/Manifestations Rheumatologic Symptoms/Signs

11. Chronic Fatigue Syndrome Definition: New Onset Severe, Unexplained Fatigue >6mo Other Symptoms (4 of 8) Memory or Concentration Sore Throat Tender Lymph Nodes Muscle Pain Multijoint Pain New Pattern Headache Unrefreshed Sleep Postexertional Malaise>24hrs

12. Fibromyalgia Definition: Pain in fibrous tissues & muscles Specific Symptoms: Pain (widespread)-myalgias, stiffness Fatigue Sleep Disorder Mental Concentration problems Mood Changes Headaches Abdominal Pain/Diarrhea Paresthesias (Numbness, Tingling, Itching Dizziness Facial Rashes Urinary Urgency Fluid Retention

13. Gulf War Veterans’ Illness Definition: New Onset Fatigue, Musculoskeletal, and/or Neurocognitive symptoms (2/3) arising after deployment to the Persian Gulf, and persisting >6mo Specific Symptoms HeadachesSleep DisorderParesthesias FatigueAbdominal PainSore Throat ArthralgiasDiarrheaCough MyalgiasWeight GainChest Pain MemoryShortness of BreathSweats, fevers ConcentrationDecreased LibidoLymph Nodes IrritabilityDepressionRashes, sores

14. Chronic Lyme and Lyme-like Illnesses SymptomLyme CFS Fibro GWI Fatigue + + + + Myalgias + + + + Arthralgias + + + + Memory + + + + Confusion + + + + Mood Changes + + + + Headache + + + + Paresthesias + ? + + Sore Throat + + ? + Lymph Nodes + + ? + Sleep Disorder + + + + Abd pain/Diarrhea + ? ? + Urinary Frequency + ? ? ? Fevers/Sweats + + ? + Palpitations + ? ? + Rashes/Sores + ? ? + Weight Gain + + ? +

15. Etiology of Chronic or “Post-Treatment” Lyme Disease Persisting Infection Autoimmunity Post-infectious sequelae

16. Pathogenesis of Symptoms Infection Where do bacteria go? Do they persist? How do you know if they’re gone? Mechanisms Neurotoxicity? Borrelia/Host Interaction? Auto-Immunity Cross-reaction between bacteria and neural gangliosides? Need for continuing infection? Damage Other ?, Disease Tolerance

17. Laboratory Issues Serologic Tests EIA, ELISA Western Blot IgM vs IgG in early vs chronic disease- ?dysregulation of IgM vs IgG response Numbers of bands vs specificity of bands Specific bands: 23,31,34,39,83/93 Lymphocyte Stimulation PCR-DNA Culture Spinal Fluid

18. Serologic Testing CDC Criteria Surveillance vs Clinical Diagnosis Two-step testing EIA/ELISA Western Blot-IgM, IgG

20. Imaging Studies MRI 15% T2 Signals Brain SPECT Scan 75% perfusion defects

21. Brain SPECT Scans in Patients with Chronic Lyme Disease

22. Issues Regarding Treatment of Chronic Lyme Disease In vitro antibiotic sensitivities Antibiotic treatment studies Beta-lactam antibiotics Tetracyclines Macrolides Others

24. Klempner/Steere Treatment Trial of Chronic Lyme Disease Assumptions Equivalence of Doxycycline and Ceftriaxone Duration of Treatment Conclusions No analysis of Other Treatment Options ?No need for further Treatment Trials

25. Doxycycline v Tetracycline Dose differences 200mg/d v 1500mg/d Protein Binding differences 90+ protein bound v 40% protein bound

26. Ceftriaxone Questions Duration of Treatment 1 months v 3-6 months Mechanism of Action Reconciling in vitro v in vivo observations Antibiotic v Glutamate Receptor Upregulation

27. Macrolide Antibiotics in Treatment of Lyme Disease In vitro activities Resolving lack of in vivo efficacy

28. Macrolide MICs of B.burgdorferi

29. Cell Trafficking

30. Maurin M, Benoliel AM, Bongrand P, and Raoult D. Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm. J Infect Dis 1992, 166:1097-102.

31. Inhibition of Acidification

32. Macrolide Therapy of Chronic Lyme Disease

33. Prior Symptom Duration vs Outcome of Rx CURE IMPROVEMENT FAILURE PRIOR Sx DURATION <1 YR 33 (28%)78 (67%) 6 ( 5%) 1-3 YR 9 (15%)45 (75%) 6 (10%) >3 YR 7 (11%)43 (70%) 11 (18%)

34. Gender vs Outcome CURE IMPROVEMENT FAILURE MALE 27 (32%) 51 (61%) 6 ( 7%) FEMALE 22 (14%) 115 (75%) 17 (11%)

35. Other Treatment Issues Vitamin Supplements B Vitamins Vitamin C Mineral Supplements Hyperbaric Oxygen Heat

36. Questions/Future Directions Is there persistent/latent infection? Where are the bacteria in chronic disease? Where were the bacteria before treatment? Evidence points to intracellular reservoir Identification of Lyme-specific products for diagnosis and monitoring treatment Development of New Vaccines Controlled Clinical Treatment Trials Validation or refutation of other treatment regimens Importance of duration of treatment

37. Ixodes Tick Co-Infections Babesiosis Clinical Aspects Laboratory Diagnosis Ehrlichia/Anaplasma Clinical Aspects Laboratory Diagnosis Bartonella Clinical Aspects Laboratory Diagnosis