2.  Controversial  Suboptimal diagnostic testing  Transmitted by Ixodes ticks ◦ May also transmit Babesia and Anaplasma  Variable disease presentation ◦ Cutaneous ◦ Cardiac ◦ Rheumatologic ◦ Neurologic  Treatment is longer than for other spirochetal illnesses

3.  1883 – Buchwald, degenerative skin d/o  1902 – Herxheimer, ACA  1909 – Afzelius, EM rash post tick bite described  1913 – Lipschutz, ECM rash described  1921 – Afzelius case reports, associates Ixodes ticks  1930 Hellerstrom, links EM and lymphocytic meningitis  1941 – Bannwarth, lymphocytic meningoradiculitis  1946 – Svartz, PCN for ACA

4.  1948 – Lenhoff, spirochetes on EM  1950 – Hellerstrom, ECM with meningitis treated with PCN  1955 – Binder, 355 cases of ECM treated with PCN  1968 – Scrimenti, first case of EM in US reported  1975 – Murray (Lyme resident) reports cases in relatives and friends in area  1975 – Steere identifies cases as “Lyme arthritis”

5.  1997 – Steere, defines more complete case description (cardiac, rheum, neuro)  1980 – Steere, rx with PCN or tetracycline  1982 – Burgdorfer, discovers spirochetes in blood, CSF, skin lesions of Lyme patients  1997 – genome sequenced  1999 – vaccine marketed

6.  Borrelia burgdorferi has has at least 132 functional genes (c/w about 22 for T pallidum)  Most plasmids of any bacteria identified to date  Antigenic variation/quorum sensing to evade immune response  Dormancy? Cyst structures form in vitro

12.  Ixodes scapularis (east and midwest)  Ixodes pacificus (west) Deer / blacklegged tick, Ixodes scapularis Western blacklegged tick (Ixodes pacificus)

14. From left to right: The deer tick (Ixodes scapularis) adult female, adult male, nymph, and larva on a centimeter scale.

19.  Most common tick-borne disease in US and Europe.  Affects 50 nations worldwide  Nymphal ticks are primarily responsible for Lyme transmission to humans.  Tick must feed for ~ 48 hours and become engorged before risk of transmission becomes substantial.  Risk of infection after a deer tick bite in a highly endemic area is ~1.4%.

20.  Obtaining Lyme serology at the time of tick bite is not recommended.  Prophylactic one time use of 200 mg doxy can be considered if: ◦ 20% or more of local ticks are Bb+ (this is generally true in East only) ◦ The patient presents within 72 hours of Ixodes bite ◦ The tick was attached for 36 hours or more. ◦ No contraindication to doxy  Analysis of ticks to determine whether they are infected is not recommended.

21.  Early local infection ◦ Skin - EM ◦ CNS  Early disseminated infection ◦ Skin  Multifocal EM  Lymphocytoma cutis (Europe) ◦ Heart  Heart block ◦ Musculoskeletal ◦ Nervous System ◦ Ocular  Conjunctivitis  Late stage infection ◦ Skin ◦ Musculoskeletal  Oligoarticular arthritis ◦ Nervous system ◦ Eye  uveitis

22.  EM: ◦ Erythema migrans appears 3-30 (usually 7- 10) days after tick bite, commonly on thigh, groin, axilla. ◦ EM recognized in 70% of patients with objective evidence of B. burgdorferi infection. ◦ Early symptoms may include fever, malaise, headache, myalgias, arthralgias, meningismus.

23.  Erythema migrans ◦ Clinical diagnosis – testing not indicated ◦ Annular or macular ◦ History of tick bite in only 25% of cases ◦ Location: Skin/folds and creases ◦ By definition at least 5 cm in size (controversial) ◦ Lesions may grow 2-3 cm/day ◦ Multiple EM reflective of disseminated disease (hematogenous)

26.  Multiple EM 3-5 weeks after tick bite.  Cranial nerve palsies (especially facial nerve— can be bilateral).  Aseptic meningitis.  Carditis 5% (AV block).  Myalgias, arthralgias, headache, fatigue.

27.  Lyme Lymphocytoma ◦ May be associated with EM lesion

28.  80% of untreated patients will develop some manifestation of late disease  Arthritis (mono- or oligoarticular, affecting large joints, especially the knee).  Encephalitis/encephalopathy.  Polyradiculopathy.

29.  Early local infection (<30 days) ◦ EM with CNS seeding (HA, stiff neck, cognitive difficulties) ◦ Flu like syndrome with CNS seeding  Early disseminated infection (<3 mo) ◦ Aseptic meningitis ◦ Meningoencephalitis (acute cerebellar ataxia, acute myelitis) ◦ Cranial nerve palsy (facial) ◦ Acute painful radiculoneuritis

30.  Late persistent infection (>3 mo) ◦ Encephalopathy ◦ Chronic axonal polyradiculoneuropathy ◦ Chronic encephalomyelitis

31.  4-10% of Lyme Disease patients develop carditis  AV block ◦ 40% Wenkebach ◦ 50% complete  Myocardial involvement

32.  Emerges in 60% of untreated EM within 6 months average  Intermittent attacks  Asymmetrical  Usually large joints especially the knees  May involve the TMJ

33.  No formal definition: persistent (predominantly neurologic) subjective symptoms that date to initial Lyme disease illness  Most likely heterogeneous and multifactorial causes involved ◦ Persistent infection ◦ Post infectious immune/inflammatory syndrome ◦ Co infection ◦ Reinfection ◦ Fixed deficits ◦ Alternative diagnosis ◦ Hypochondriasis  Most patients do not respond to antibiotics  Medical Clinics of NA 2002;86(2)

34.  Erythema migrans is the only manifestation of Lyme sufficiently diagnostic to be clinically diagnosed without lab testing  Serology (ELISA) ◦ Only 30-40% of patients with EM have a positive serology. ◦ IgM antibodies appear in 3-4 weeks, may persist despite treatment. ◦ IgG antibodies appear in 6-8 weeks, usually remain detectable for many years. ◦ 2-4 weeks after acute reaction 70-80% are positive  Western blot ◦ Indicated for positive or equivocal ELISA. ◦ IgM is only diagnostic within the first month of illness.

35. Up-To-Date 2004

36.  False positive ◦ Other spirochete (syphilis) ◦ Cross reaction with other bacterial heat shock protein (RMSF, Ehrlichia) ◦ RA ◦ SLE ◦ Mononucleosis

37.  IFA: At least as sensitive and specific as the ELISA  Immune assays of CSF ◦ ELISA

38. TESTSENSITIVITYSPECIFICITY ELISA/IFA (early)59%93% ELISA/IFA (late)95%81% ELISA/IFA + WB (early + late) 50-75%99-100%

39.  Cultivation ◦ Barbour-Stoenner-Kelly (BSK) broth medium ◦ Sensitive for detection of early-phase infection (EM) ◦ Limited value for detection of infection during late stages ◦ Very few places can do this ◦ Skin biopsy or blood taken within first 2-3 weeks of infection

40.  Histology ◦ Numbers of B. burgdorferi in tissues is low ◦ Very hard to find on specimens ◦ Silver stain  PCR ◦ Limited places are able to do this ◦ Urine PCR is available but there is insufficient evidence of its accuracy, predictive value, or its significance ◦ Unclear of benefit of this test

41.  Early localized ◦ Doxycycline 100 bid or amoxicillin 500 tid or Cefuroxime 500 mg po bid x 14-21 days.  Early disseminated ◦ Isolated facial nerve palsy/mild carditis: doxy/amoxicillin. ◦ Meningitis/severe carditis: ceftriaxone 2gm qd x 14-28 days.  Late disease ◦ Arthritis: doxycycline or amoxicillin or ceftrixaone or IV PCN x 28 days. ◦ Recurrent arthritis: ceftriaxone. ◦ CNS disease: ceftriaxone or IV PCN. ◦ Facial palsy alone: oral meds may be enough

42.  Cardiac ◦ 1 st degree AV block: oral meds ◦ High degree AV block: Ceftriaxone for 14-21 days or IV PCN for 28 days