1. What we Know and Don’t Know About Lyme Disease Sam T Donta MD Infectious Diseases Professor of Medicine (ret)

2. Historical Aspects A mysterious illness in children An unusual rash following a tick bite Swollen joint(s), other symptoms Initial considerations Form of juvenile rheumatoid arthritis Discovery of the cause Dr Burgdorfer, Dr Barber

3. Etiology and Pathogenesis Transmission of Lyme Disease From Ixodes to target hosts Any other form of transmission? Pathogenesis of Lyme Disease Course of infection Cause of symptoms/signs

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

5. Diagnosis of Lyme Disease Early vs Late vs Chronic Illness Clinical Issues Laboratory Issues Imaging Studies Treatment Trial as Diagnostic Tool

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

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

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

9. Chronic Lyme Disease Major Criteria Fatigue MusculoSkeletal Neurocognitive Cognitive-Memory, Concentration Mood Minor Criteria

10. “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

11. Chronic Fatigue Syndrome (Systemic Exertion Intolerance Disease) 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 + + ? +

16. 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

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

19. Western Blot vs EIA in Chronic Lyme Disease M+G+ M+G- M-G+ M-G- EIA POSITIVE 28 (57%) 7 (14%) 11 (22%) 3 (6%) NEGATIVE 28 (20%) 49 (35%) 18 (12%) 47(33%)

20. Western Blots Pre and Post Rx of Chronic Lyme Disease SYMPTOMATIC ASYMPTOMATIC IgG 4/64 ( 6%) 17/32 (53%) IgM 23/64 (36%) 3/32 ( 9%) IgG+IgM 37/64 (58%) 5/32 (16%) None 7/32 (22%)

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

22. Brain SPECT Scans in Patients with Chronic Lyme Disease

23. Brain SPECT scan pre- and post-antibiotic treatment

24. Pathogenesis of Symptoms Infection Where do bacteria go? Do they persist? Antibiotic Tolerance? 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

25. Management Issues Symptom-based Treatments Helpful but not curative Antibiotic Treatments Efficacy of different antibiotics Need for Intracellular penetration? Is Blood-Brain Barrier an issue? Non-antibiotic effects? Gender response differences

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

28. 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

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

30. 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

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

32. Macrolide MICs of B.burgdorferi

33. Cell Trafficking

34. 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.

35. Inhibition of Acidification

36. Macrolide Therapy of Chronic Lyme Disease

37. 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%)

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

39. Treatment of Early Lyme Disease Early Lyme Disease Doxycycline-100mg bid, or Amoxicillin-500mg bid, or Cefuroxime-500mg bid for 3-4 wks Continue treatment if still symptoms until symptoms resolve

40. Treatment of Chronic Lyme Disease Chronic Lyme Disease Tetracycline-1500mg/day for 3+ months, or Macrolide Antibiotic Clarithromycin-500mg bid, or Erythromycin-500mg bid, or Azithromycin-500-600mg qd + Hydroxychloroqine (Plaquenil)-200mg bid for 3+ months Continue treatment if still symptoms until symptoms resolved (and have not reappeared for at least 1 month). May need to alternate above 2 regimens every 6 months for 18-24 months in illness> 1-2 yrs

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

42. Future Directions Identification of Lyme-specific Products for Diagnosis and Monitoring Treatment Controlled Clinical Treatment Trials Development of Vaccines