June 20131

Clinical Manifestations of Lyme Disease

Michael T. Melia, MD

Assistant Professor of Medicine

Division of Infectious Diseases

Disclosures

• Michael T. Melia, M.D.– No financial interests or relationships to

disclose

June 2013 2

Unapproved/Off-Label Use

• Ceftriaxone• Doxycycline

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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

June 2013 http://facstaff.cbu.edu/~seisen/IxodesSpp.htm

Reported Cases of Lyme Disease, U.S., 2002-2011

June 2013 7www.cdc.gov

Reported Cases By County of Residence, 2011

June 2013 8www.cdc.gov

Notifiable Diseases U.S. 2010

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

June 2013 9MMWR 2012;59(53):1-111

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

June 2013 10MMWR 2012;59(53):1-111

Natural History of Untreated Lyme Disease

June 2013 11Morrison C et al. J Am Board Fam Med 2009;22:219-222

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 12Wormser 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 1d later following abx

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Typical Erythema Migrans

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Multiple erythema migrans

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Wormser GP et al. Clin Infect Dis 2006; 43:1089–134

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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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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.

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

• 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

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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

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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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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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Wormser GP et al. Clin Infect Dis 2006;43:1089-1134

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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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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. Subjective symptoms

2. Serologic testing

3. Syndrome bigotry

4. 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 33Wormser et al. Ann Intern Med 2003; 138: 697. Nowakowski et al. Am J Med 2003; 115:91.

Symptoms 6-24 mos post abx

June 2013 A. Marques 2011 in Lyme Disease: An Evidence-based Approach, Halperin Ed, 2011

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Symptoms in General Populations

• Fatigue complaints 20-30%• Arthritis 21.5%• Serious pain 3.72-12.1%• Fibromyalgia 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.

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 19957Ann Intern Med 1982;96:865 8Crit Care Med 2000; 28:3599

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Steere AS, et al. JAMA 1993;269:1812

788 “Lyme” Patients Presenting to a Lyme Center

• Active Lyme disease: 23%• Prior Lyme disease: 20%• Not Lyme disease: 57%

• Implication: Serology has poor-predictive value in patients without objective signs and symptoms

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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

June 2013 38MMWR 1995;44:590

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.

June 2013 39MMWR 1995;44:590

Lyme testing: False Positives

• Non-specific sx• Westchester NY

– 50/182 false (+) IgM immunoblot

– 78% unnecessary antibiotics

June 2013 40Seriburi V et al. Clin Microbiol Infect 2012; 18: 1236–1240

Clin Infect Dis. 2001 Sep 15;33(6):780-5

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

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MMWR 1995;44:590

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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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 TrialAntibiotic 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 health-related quality of life at day 180

June 2013 44Klempner M, et al. NEJM 2001; 345:85

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Antibiotic Placebo

ImprovedUnchangedWorse

Overall Outcomes d180 SF-36

*No evidence of persistent infection

B. burgdorferi by Cx or PCR in blood, CSF

(700 samples in 129 patients)

No significant statisticaldifference

June 2013 45Klempner M, et al. NEJM 2001; 345:85

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

June 2013 46Kaplan RF, et al. Neurology 2003; 60:1916

RCT Scorecard: Long-term Antibioticsand persistent symptoms after Lyme disease treatment

Long-term abx v. placebo

Subjective sx OR Encephalopathy after initial treatment

Antibiotics, Durable & Significant Effect

Antibiotics without efficacy

4 0 4

1. Klempner M, et al. NEJM 2001; 345:852. Krupp, LB, et al. Neurology 2003;60:19233. Oksi J et al, Eur J Clin Microbiol Infec Dis 2007; 26:5714. Fallon BA, et al. Neurology 2008; 70:992

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Lyme Terminology

• Favored (IDSA & others)– Late Lyme disease

• Objective findings– Neuroborreliosis– Late arthritis

– Post-Lyme Disease Syndrome

• Subjective symptoms– Fatigue– Musculoskeletal sx– Neurocognitive sx

• Not Favored– Chronic Lyme disease

– Chronic Lyme disease

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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

• Exclusions:– Co-infection– Prior CFS/fibromyalgia or undiagnosed similar problems– Other medical explanation– Active infectious Lyme disease (e.g., neuroborreliosis,

persistent Lyme arthritis)

June 2013 49Wormser GP, et al. Clin Infect Dis 2006;43:1089-134

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– A. phagocytophilum– B. microti

• I. scapularis does not transmit:– E. chaffeensis– Bartonella spp.– Mycoplasma spp.– Rickettsia spp.

June 2013 Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.

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Coinfection Prevalence

Swanson SJ et al. Clin Microbiol Rev 2006;19(4):708.

Lyme Information: Internet

June 2013 53Cooper JD, Feder HM Jr. ,Pediatr Infect Dis J. 2004;12:1105

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Reliable Resources

• American Lyme Disease Foundation: http://www.aldf.com/– Patient and physician information– Help with physician referral to evidence-based physicians

• 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.– 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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