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

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

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

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

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

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

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

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

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

“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

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

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

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

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 + + ? +

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

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

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%)

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%)

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

Brain SPECT Scans in Patients with Chronic Lyme Disease

Brain SPECT scan pre- and post-antibiotic treatment

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

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

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

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

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

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

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

Macrolide MICs of B.burgdorferi

Cell Trafficking

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:

Inhibition of Acidification

Macrolide Therapy of Chronic Lyme Disease

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%)

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

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

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 mg 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 months in illness> 1-2 yrs

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

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