What we Know and Dont Know About Lyme
What we Know and Don’t Know About Lyme Disease Sam T Donta MD Infectious Diseases Professor of Medicine (ret)
Historical Aspects n A mysterious illness in children n Initial considerations n n An unusual rash following a tick bite Swollen joint(s), other symptoms Form of juvenile rheumatoid arthritis Discovery of the cause n Dr Burgdorfer, Dr Barber
Etiology and Pathogenesis n Transmission of Lyme Disease n n n From Ixodes to target hosts Any other form of transmission? Pathogenesis of Lyme Disease n n Course of infection Cause of symptoms/signs
Spectrum of Lyme Disease n n n Generalized Symptoms Neurologic Symptoms/Manifestations Rheumatologic Symptoms/Signs
Diagnosis of Lyme Disease n n n Early vs Late vs Chronic Illness Clinical Issues Laboratory Issues Imaging Studies Treatment Trial as Diagnostic Tool
Early Lyme Disease n n Tick Bite Rash n n n Typical Erythema Migrans (EM) Atypical Rash(es) Diagnosis n n Clinical Serology
Early Disseminated Lyme Disease n Clinical n n n Rash “Flu-like” Symptoms Diagnosis n n Clinical Serology
Late Lyme Disease n Early/Late LD Symptoms/Signs n n n Bell’s Palsy Meningitis Carditis Arthritis-Oligoarthritis Encephalopathy Diagnosis
Chronic Lyme Disease n Major Criteria n n n Fatigue Musculo. Skeletal Neurocognitive n n n Cognitive-Memory, Concentration Mood Minor Criteria
“Minor” Symptoms & Signs n n n n Headaches Eye Symptoms Ear Symptoms Jaw/Tooth Pain Bell’s Palsy Dysequilibrium Dyspnea n n n n 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 >6 mo Other Symptoms (4 of 8) n Memory or Concentration n Sore Throat n Tender Lymph Nodes n Muscle Pain n Multijoint Pain n New Pattern Headache n Unrefreshed Sleep n Postexertional Malaise>24 hrs
Fibromyalgia Definition: Pain in fibrous tissues & muscles Specific Symptoms: n Pain (widespread)-myalgias, stiffness n Fatigue n Sleep Disorder n Mental Concentration problems n Mood Changes n Headaches n Abdominal Pain/Diarrhea n Paresthesias (Numbness, Tingling, Itching n Dizziness n Facial Rashes n Urinary Urgency n 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 >6 mo Specific Symptoms Headaches Sleep Disorder Paresthesias Fatigue Abdominal Pain Sore Throat Arthralgias Diarrhea Cough Myalgias Weight Gain Chest Pain Memory Shortness of Breath Sweats, fevers Concentration Decreased Libido Lymph Nodes Irritability Depression Rashes, sores
Chronic Lyme and Lyme-like Illnesses n n n n n Symptom 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 Lyme + + + + + CFS + + + + ? ? + Fibro + + + + ? ? ? GWI + + + ? + +
Laboratory Issues n Serologic Tests n n EIA, ELISA Western Blot n n n n Ig. M vs Ig. G in early vs chronic disease? dysregulation of Ig. M vs Ig. G 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 n CDC Criteria n n Surveillance vs Clinical Diagnosis Two-step testing n n EIA/ELISA Western Blot-Ig. M, Ig. G
Western Blot vs EIA in Chronic Lyme Disease M+G+ M+G- M-G+ M-G- EIA POSITIVE 28 (57%) 7 (14%) NEGATIVE 28 (20%) 49 (35%) 11 (22%) 3 (6%) 18 (12%) 47(33%)
Western Blots Pre and Post Rx of Chronic Lyme Disease SYMPTOMATIC Ig. G Ig. M Ig. G+Ig. M None 4/64 ( 6%) 23/64 (36%) 37/64 (58%) ASYMPTOMATIC 17/32 (53%) 3/32 ( 9%) 5/32 (16%) 7/32 (22%)
Imaging Studies n MRI n n 15% T 2 Signals Brain SPECT Scan n 75% perfusion defects
Brain SPECT Scans in Patients with Chronic Lyme Disease
Brain SPECT scan pre- and post-antibiotic treatment
Pathogenesis of Symptoms n n n Infection n Where do bacteria go? Do they persist? n Antibiotic Tolerance? n How do you know if they’re gone? n Mechanisms n Neurotoxicity? n Borrelia/Host Interaction? Auto-Immunity n Cross-reaction between bacteria and neural gangliosides? n Need for continuing infection? Damage
Management Issues n Symptom-based Treatments n n Helpful but not curative Antibiotic Treatments n Efficacy of different antibiotics n n Need for Intracellular penetration? Is Blood-Brain Barrier an issue? Non-antibiotic effects? Gender response differences
Issues Regarding Antibiotic. Treatment of Chronic Lyme Disease n n In vitro antibiotic sensitivities Antibiotic treatment studies n n Beta-lactam antibiotics Tetracyclines Macrolides Others
Klempner/Steere Treatment Trial of Chronic Lyme Disease n Assumptions n n n Equivalence of Doxycycline and Ceftriaxone Duration of Treatment Conclusions n n No analysis of Other Treatment Options ? No need for further Treatment Trials
Doxycycline v Tetracycline n Dose differences n n 200 mg/d v 1500 mg/d Protein Binding differences n 90+ protein bound v 40% protein bound
Ceftriaxone Questions n Duration of Treatment n n 1 months v 3 -6 months Mechanism of Action n n Reconciling in vitro v in vivo observations Antibiotic v Glutamate Receptor Upregulation
Macrolide Antibiotics in Treatment of Lyme Disease n n 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: 1097 -102.
Inhibition of Acidification
Macrolide Therapy of Chronic Lyme Disease
Prior Symptom Duration vs Outcome of Rx CURE IMPROVEMENT FAILURE <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%) PRIOR Sx DURATION
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 n n n n Doxycycline-100 mg bid, or Amoxicillin-500 mg bid, or Cefuroxime-500 mg bid for 3 -4 wks Continue treatment if still symptoms until symptoms resolve
Treatment of Chronic Lyme Disease n n Tetracycline-1500 mg/day for 3+ months, or Macrolide Antibiotic n n n Clarithromycin-500 mg bid, or Erythromycin-500 mg bid, or Azithromycin-500 -600 mg qd n n n + Hydroxychloroqine (Plaquenil)-200 mg 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
Other Treatment Issues n Vitamin Supplements n n n B Vitamins Vitamin C Mineral Supplements Hyperbaric Oxygen Heat
Future Directions n n n Identification of Lyme-specific Products for Diagnosis and Monitoring Treatment Controlled Clinical Treatment Trials Development of Vaccines
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