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 Headaches Specific Symptoms Sleep Disorder Paresthesias Fatigue Arthralgias Myalgias Abdominal Pain Diarrhea Weight Gain Sore Throat Cough Chest Pain Memory Concentration Irritability Shortness of Breath Decreased Libido Depression Sweats, fevers Lymph Nodes Rashes, sores

Chronic Lyme and Lyme-like Illnesses                   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

    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 IgM 4/64 ( 6%) 17/32 (53%) 23/64 (36%) IgG+IgM 37/64 (58%) 3/32 ( 9%) 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, 166:1097-102.

Inhibition of Acidification

Macrolide Therapy of Chronic Lyme Disease

Prior Symptom Duration vs Outcome of Rx

CURE IMPROVEMENT PRIOR Sx DURATION <1 YR 1-3 YR >3 YR 33 (28%) 9 (15%) 7 (11%) 78 (67%) 45 (75%) 43 (70%) FAILURE 6 ( 5%) 6 (10%) 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-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

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