Clinical Manifestations of Lyme
Disease
Michael T. Melia, MD
Assistant Professor of Medicine
Division of Infectious Diseases
June 2013
1
Disclosures
• Michael T. Melia, M.D.
– No financial interests or relationships to
disclose
June 2013
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Unapproved/Off-Label Use
• Ceftriaxone
• Doxycycline
June 2013
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Objectives
• By the conclusion of this presentation, the
audience will be able to:
– Describe the spectrum of erythema migrans
eruptions
– Discuss the clinical manifestations of early
localized, early disseminated, and late Lyme
disease
– Define post-treatment Lyme disease syndrome
– Understand some of the ongoing controversies in
the fields of Lyme disease and tick-borne
infections
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Common tick vectors
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http://facstaff.cbu.edu/~seisen/IxodesSpp.htm
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Reported Cases of Lyme Disease,
U.S., 2002-2011
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www.cdc.gov
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Reported Cases By County of
Residence, 2011
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www.cdc.gov
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Notifiable Diseases U.S. 2010
June 2013
Disease
Reported Cases
1. Chlamydia
1,307,893
2. Gonorrhea
309,341
3. Salmonellosis
54,424
4. Syphilis
45,834
5. HIV/AIDS
35,741
6. Lyme disease
30,158
7. Pertussis
27,550
8. Giardiasis
19,811
9. S. pneumoniae
16,569
10. Varicella
15,427
MMWR 2012;59(53):1-111
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Notifiable Diseases MD 2010
Disease
Reported Cases
1. Chlamydia
26,192
2. Gonorrhea
7,413
3. Lyme disease
1,617
4. HIV/AIDS
1,259
5. Salmonellosis
1,086
6. Meningitis, aseptic
650
7. Campylobacteriosis
532
8. Strep pneumoniae, invasive
526
9. Strep Group B, invasive
430
10. Mycobacteriosis (non-TB)
360
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MMWR 2012;59(53):1-111
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Natural History of Untreated Lyme
Disease
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Morrison C et al. J Am Board Fam Med 2009;22:219-222
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Clinical Manifestations
• Early Lyme Disease, localized
– Days-weeks
– Erythema migrans (EM)
• No symptoms other than rash in 20-30%
– Flu-like symptoms (70-80%)
• Headache = meningitis-like
– Flu-like syndrome without rash
• Uncommon
– Many unaware of tick bite
June 2013
Wormser GP et al. Clin Infect Dis
2006;43:1089–134
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Case 1
• 42F gardener
• Asymptomatic
– Growing rash over 5-7d
– Husband “worried”
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Erythema Migrans: Homogenous
Rash Most Common
No Central Clearing
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1d later following abx
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Typical Erythema Migrans
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Multiple erythema migrans
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Early Localized Lyme: Clinical
Manifestations and Diagnosis
• Erythema migrans
– At tick bite site, 7-14d average
– >5 cm = secure diagnosis
• Unsure? Observe for expansion
• Characteristic rash + epidemiology = Lyme
– Clinical diagnosis sufficient: no need for lab testing
– Serology insensitive for early disease
– Uncertain: Observe and obtain acute +
convalescent (4-6 wk) serology
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Wormser GP et al. Clin Infect Dis 2006;
43:1089–134
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Early Lyme Disease
• Early disseminated Lyme
– Weeks-months
– Multiple erythema migrans
• Usually with flu-like symptoms, fever
– Neurologic (Bell’s palsy, radiculopathy, meningitis)
• Rash may occur simultaneously
– Musculoskeletal (arthritis, tendonitis, bursitis)
– Cardiac (AV block, rare carditis)
• Objective symptoms PLUS serology or
erythema migrans history
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Wormser GP et al. Clin Infect Dis 2006;
43:1089–134
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Case Presentation
• 53-year-old man awoke drooling on the
morning of today’s urgent office visit
– 4-7 days earlier, he had slight flu-like
symptoms and headache that resolved
– No rash
– Golfer
– Resident of Rockingham County
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Diagnosis – Facial Palsy
• Up to 25% due to B. burgdorferi
– Long Island
• Serology may take 4-6 wks to turn positive
– If untreated, recheck if initially negative
• Lumbar puncture optional
• 99% recover without antibiotic therapy
– Main role of abx: prevent late disease
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Halperin JJ et al Neurology 1992; 42:1268. Clark JR et al Laryngoscope
1985;95:1341. Wormser GP et al. Clin Infect Dis 2006; 43:1089–134.
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Early Disseminated Lyme Disease:
Neurologic Manifestations
•
•
•
•
•
CN palsies
Radiculoneuritis
Mononeuritis multiplex
Meningitis
Encephalomyelitis
(rare)
• Optic Neuritis
– children >> adults
• Possible associations
– Hearing loss
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• Usually afebrile
• CSF
– <10% PMNs
– May be confused with
viral meningitis
• Most seropositive at
presentation
• Other tests:
– Helpful: CSF index,
intrathecal Ab production
– Not helpful: PCR
Wormser GP et al. Clin Infect Dis 2006;
43:1089–134
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Clinical Manifestations of Late
Infection (Months-to-Years Later)
• Arthritis
– Usually large weight
bearing joint
– Almost 100% have knee
involvement
• Others: hip, ankle, TMJ
– 100% seropositive IgG
• including WB
– Synovial fluid
• >2000-25,000 WBC
• May have positive PCR if
not previously treated
• ~10% antibiotic refractory
June 2013
Wormser GP et al. Clin Infect Dis 2006;
43:1089–134
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Neurologic Manifestations of Late
Infection
• Less common now compared with initial reports from
1970’s-1980’s
• Encephalopathy
–
–
–
–
Objective cognitive findings
CSF may be normal
Non-infectious?
Rare: 7 pts dx in 5 yrs by IDSA panel members
• Encephalomyelitis
– MRI abnormalities
– Rare in US: 1 pt dx in 5 yrs by IDSA panel members
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Wormser GP et al. Clin Infect Dis 2006;
43:1089–134
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More Neurologic Manifestations of
Late Infection
• Peripheral Neuropathy
–
–
–
–
–
CSF normal
Stocking/glove paresthesia
Sensory findings
Intermittent radicular pain
Rare (9 patients in 5 years by IDSA Lyme panel
members)
• All late Neuroborreliosis: expect positive serology and
CSF antibodies
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Wormser GP et al. Clin Infect Dis 2006;
43:1089–134
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Neurologic Manifestations of Late
Infection
• Caveats
– MRI reports often include Lyme disease in
the differential diagnosis
• Treat as unlikely unless proven otherwise
• Consider other diagnosis if Lyme serology
negative
– Intrathecal antibody production may persist
for years despite antibiotic therapy
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Lyme disease: Antibiotics
• Antibiotic-responsive illness
– 10-21d for early infection: oral doxycycline/amoxicillin
– 14-28d for late infection: orals or ceftriaxone IV
– Rare second courses of treatment needed
• Late manifestations from untreated infection
• Subjective symptoms may persist after abx
– More common in women
– Increased with longer duration of untreated infection
– No convincing evidence of persistent infection after abx
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Wormser GP et al. Clin Infect Dis
2006;43:1089-1134
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Recommended antimicrobial regimens for treatment of patients with Lyme disease.
Wormser G P et al. Clin Infect Dis. 2006;43:1089-1134
© 2006 Infectious Diseases Society of America
Recommended therapy for patients with Lyme disease.
Wormser G P et al. Clin Infect Dis. 2006;43:1089-1134
© 2006 Infectious Diseases Society of America
Lyme Disease Issues
• Diagnosis
– Unlike most bacterial infections, diagnosis is clinical
• Bacteria hard to detect by culture, PCR, microscopy
• Serological tests = laboratory diagnostic standard
– Up to 60-70% early Lyme (EM) seronegative
– EM is only characteristic finding
• Absent or unrecognized in 10-30%?
• Treatment: Late lyme arthritis
– ~10% have persistent arthritis unresponsive to abx
• Fatigue after early Lyme Disease
– 25% at 3 months; ≥5% (?) after 1 year
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Why is Lyme Disease
Controversial?
1.
2.
3.
4.
Subjective symptoms
Serologic testing
Syndrome bigotry
The internet
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Lyme Disease: Expectations
• Subjective symptoms post-treatment
– Prospective studies (treated erythema migrans)
• 24% with mild symptoms at 3 months
– Fatigue, aches, neurocognitive symptoms
• 5-17% with symptoms at 6-12 months
• Culture confirmed LD (n = 96)
– 81 f/u (mean 5.6 yrs): 10% with symptoms
– 4% with symptoms at every visit
June 2013
Wormser et al. Ann Intern Med 2003; 138: 697. Nowakowski et al.
Am J Med 2003; 115:91.
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Symptoms 6-24 mos post abx
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A. Marques 2011 in Lyme Disease: An Evidence-based Approach,
Halperin Ed, 2011
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Symptoms in General Populations
•
•
•
•
Fatigue complaints
Arthritis
Serious pain
Fibromyalgia
20-30%
21.5%
3.72-12.1%
2%
• Background problems in average population make
difficult interpretation of non-specific subjective
symptoms
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Ann Int Med 1995; 123:81. Ann Intern Med 2001; 124:838.
MMWR 2005;54:484. J Rheumatol 1993;20:710. Arthritis Rheum,
1995;38:19.
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Lyme Is Not Unique for
Causing Post-infectious Fatigue
• Bacterial
– Coxiella burnetti (Q
fever)1
– Brucella2
• Viral
– EBV3
– Viral hepatitis4
– Viral Meningitis5
• Parasitic
– Toxoplasmosis6
• Toxin
– Toxic Shock
Syndromes7
• Sepsis8
1QJM
1998; 91:105, 2JAMA 1934;103:665, 3Brit J Gen Prac 2002; 52:844,
4J Viral Hepat 1995; 3:133, 5J Neurol Neurosurg Psych 1996; 60:495, 6Prin Prac ID; Chap 257 1995
7Ann Intern Med 1982;96:865 8Crit Care Med 2000; 28:3599
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788 “Lyme” Patients Presenting to
a Lyme Center
• Active Lyme disease: 23%
• Prior Lyme disease: 20%
• Not Lyme disease: 57%
• Implication: Serology has poorpredictive value in patients without
objective signs and symptoms
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Steere AS, et al. JAMA 1993;269:1812
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Lyme Serology: Two-Tier Testing
• First: ELISA/EIA/IFA Screen (Total AB)
• Second: Western blots (immunoblots)
– IgM:
• Need 2/3 bands: 23,39,41 kDa
• Caution: Use only for illness < 1 month
– Positive IgM WB alone = frequent false (+) Lyme
diagnosis
– Cross reactive with other bacterial and non-bacterial
antigens
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MMWR 1995;44:590
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Lyme Serology
• Western blot
– IgG: Need 5 of 10 potential bands
• 18,23,28,30,39,41,45,58,66 or 93 kDa
– More reliable test
– Usually positive by wk 4-6 of infection
– Only use this test for sx > 6 wks.
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MMWR 1995;44:590
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Lyme testing: False Positives
• Non-specific sx
• Westchester NY
– 50/182 false (+) IgM
immunoblot
– 78% unnecessary
antibiotics
June 2013
Seriburi V et al. Clin Microbiol Infect 2012; 18: 1236–1240
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Lyme Serologies
• Immunological test
– Host response to infection
– Does NOT detect actual bacteria
• Tests do NOT distinguish between
active or inactive disease
– 40-60% seropositive 25 years after initial infection
– No reason to follow titers routinely
June 2013
Clin Infect Dis. 2001 Sep 15;33(6):780-5
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Common Clinical Scenarios with
Improper Use of Serology
1) EIA only, no Western Blot (WB)
2) WB only (without EIA/IFA)
–
>50% population reactive to 1 or more antigens
3) Using the IgM WB alone for symptoms >1 mo
–
Usually false positive
4) Serology at time of erythema migrans
5) Treating tests that “stay positive”
6) Testing samples by WB other than serum
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MMWR 1995;44:590
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Longer-term Antibiotic Courses Do Not
Influence Outcomes
• Evidence: Prospective trials, shorter term
outcomes – longer therapy without benefit
– Early Lyme disease1
(n=108: PCN, TCN, erythromycin)
– Erythema migrans2
(n=180: 10d doxy +/- CTX v 20d doxycycline)
– Late Lyme disease3
(n=143: 14d vs. 28d CTX)
1Ann
Intern Med 1983;99:22. 2Ann Intern Med 2003. 138:697.
3Wien Klin Wochenschr 2005; 117:393.
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Persistent Symptoms – Controlled Trial
Antibiotic Treatment v. Placebo
• Two studies of patients with clinical Lyme Disease
– 78 pts seropositive (IgG antibodies); 51 seronegative
• Entry criteria
– Well-documented Lyme disease
– Prior antibiotic treatment
– Persistent musculoskeletal pain, neurocognitive symptoms
(>70%), dysesthesia, fatigue (90%)
– Average duration of symptoms: 4 years
• Ceftriaxone 2 gm IV q24h x 30d, then doxycycline
200 mg x 60d vs. matched placebos
• Primary outcome: SF-36 scale measuring healthrelated quality of life at day 180
June 2013
Klempner M, et al. NEJM 2001; 345:85
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Overall Outcomes d180 SF-36
100%
90%
80%
70%
60%
Improved
Unchanged
Worse
50%
40%
30%
No significant statistical
difference
20%
10%
0%
Antibiotic
Placebo
*No evidence of persistent infection
B. burgdorferi by Cx or PCR in blood, CSF
June 2013
(700 samples in 129 patients)
Klempner M, et al. NEJM 2001; 345:85
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Cognitive Function: Lyme disease
• Companion study, n=129
• Used cognitive objective testing, mood scores
• >70% gave cognitive dysfunction as
complaint at study entry
– Patients had normal baseline neuropsych testing
– Suggests symptom report ≠ objective evidence
• No significant differences between groups
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Kaplan RF, et al. Neurology 2003;
60:1916
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RCT Scorecard: Long-term Antibiotics
and persistent symptoms after Lyme disease
treatment
Long-term abx v.
placebo
Antibiotics, Durable & Antibiotics without
Significant Effect
efficacy
Subjective sx OR
Encephalopathy after
initial treatment
4
1.
2.
3.
4.
0
4
Klempner M, et al. NEJM 2001; 345:85
Krupp, LB, et al. Neurology 2003;60:1923
Oksi J et al, Eur J Clin Microbiol Infec Dis 2007; 26:571
Fallon BA, et al. Neurology 2008; 70:992
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Lyme Terminology
• Favored (IDSA &
others)
– Late Lyme disease
• Not Favored
– Chronic Lyme disease
• Objective findings
– Neuroborreliosis
– Late arthritis
– Post-Lyme Disease
Syndrome
– Chronic Lyme disease
• Subjective symptoms
– Fatigue
– Musculoskeletal sx
– Neurocognitive sx
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Post-Lyme Disease Syndrome
Definition
• Lyme disease defined by CDC criteria
• Concluded appropriate antibiotic course
• 6 months after diagnosis or treatment
–
–
–
–
Fatigue
Widespread musculoskeletal pain
Cognitive problems
Substantial reduction in functional status
–
–
–
–
Co-infection
Prior CFS/fibromyalgia or undiagnosed similar problems
Other medical explanation
Active infectious Lyme disease (e.g., neuroborreliosis,
persistent Lyme arthritis)
• Exclusions:
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Wormser GP, et al. Clin Infect Dis
2006;43:1089-134
49
Case Presentation #2
 41F resident of Maryland’s Eastern Shore
 Ovoid rash R upper thigh late June with fever,
headache, myalgia – resolved in 2-3 days
 July 4: Onset of L facial palsy, otherwise well
 Lyme serology negative
 Doxycyline given, improved within 48h
 Now worried about “co-infections”
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Science: How likely > 1 microbe?
• Depends on
geography
– Nymph I. scapularis
ticks 2-5%
– Adults 1-28%
• Usually B.
burgdorferi + other
• I. scapularis does
not transmit:
–
–
–
–
E. chaffeensis
Bartonella spp.
Mycoplasma spp.
Rickettsia spp.
– A. phagocytophilum
– B. microti
June 2013
Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.
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Coinfection Prevalence
June 2013
Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.
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Lyme Information: Internet
June 2013
Cooper JD, Feder HM Jr. ,Pediatr Infect
Dis J. 2004;12:1105
53
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Reliable Resources
•
American Lyme Disease Foundation: http://www.aldf.com/
–
–
•
Centers for Disease Control: www.cdc.gov/lyme/
–
–
•
Helpful clinical information, photos, statistics
Excellent FAQ section
Feder HM Jr, et al. N Engl J Med 2007;357:1422-30.
–
–
–
–
•
Patient and physician information
Help with physician referral to evidence-based physicians
A critical appraisal of “chronic Lyme disease”
Reviews data and critiques the use of this term and diagnosis
Helpful physician advice
Appendix available electronically
Wormser GP, et al. Clin Infect Dis 2006;43:1089-1134.
– IDSA Guideline
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