1. Less is More: Lyme Disease and NOT Lyme Disease Eugene D. Shapiro, MD Nothing to Disclose

7. LYME DISEASE 1.Caused by the spirochete Borrelia burgdorferi 2.Transmitted by Ixodes scapularis (deer tick) and other Ixodes species 2. Pathogenesis, ecology and epidemiology are well described 3. Antimicrobial treatment is very effective 4. Complications are rare

8. LYME DISEASE Overview 1.Lyme Disease 2.Advances in Treatment a. Surgical procedure useful in routine management of patients with Lyme disease 3.Diagnostic testing 4. NOT Lyme Disease 5. Medically Unexplained Symptoms 6.Research: Pilot study of an intervention 7. Questions

9. LYME DISEASE Clinical Manifestations 1.80-90% have a characteristic rash, erythema migrans a. Localized disease: single erythema migrans (75%) b. Disseminated disease: multiple erythema migrans (25%)

10. Lyme Disease Erythema Migrans

12. Lyme Disease Multiple Erythema Migrans

13. LYME DISEASE Clinical Manifestations 2.Early Disseminated disease (25%) a. Multiple erythema migrans (20%) b. Neurologic (5%): cranial nerve palsy, meningitis c. Cardiac (<1%): carditis, syncope 3. Strain specificity a. Likelihood of dissemination b. Differences in Europe and Asia

14. LYME DISEASE Clinical Manifestations 4.Late Disseminated disease (7%) a. Arthritis—knee especially b. Neurologic: extremely rare, especially in children

15. SEROLOGIC TESTS FOR LYME DISEASE 1.Two-tier procedure 2.First a quantitative test, usually enzyme-linked immunosorbent assay (ELISA) 3. If ELISA is positive or equivocal (only if), confirm specificity with a Western immunoblot 4. Original tests use sonicated whole bacteria (laboratory strains)

16. LYME DISEASE Positive Result of Serology (2 tier) 1.Positive (or borderline) quantitative test result AND Positive western immunoblot a. IgM: 2 of 3 Bands b. IgG: 5 of 10 Bands 2. Misinterpretation of results common

17. LYME DISEASE C6 ELISA 1.Measures antibodies against C6 peptide of the variable-major protein-like sequence expressed lipoprotein (C6VlsE) 2. Hope was to replace 2-tier test with single ELISA 3.Sensitivity comparable to or better than standard whole-cell ELISA, but specificity not as good as 2-tier testing 4.Has been used as 2 nd tier test

18. LYME DISEASE Antibodies in Other Sites 1.Joint Fluid a. Worthless test b. Many false-positive results 2.CSF a.Can be useful b.CSF index

19. LYME DISEASE Polymerase Chain Reaction Assay 1.CSF and Blood a.Very poor sensitivity b.Caution about false-positive results 2.Joint Fluid a. Can be useful b. Positive result does not mean live spirochetes

20. Notice to Readers: Caution Regarding Testing for Lyme Disease CDC Home Share Notice to Readers: Caution Regarding Testing for Lyme Disease Weekly February 11, 2005 / 54(05);125 CDC and the Food and Drug Administration (FDA) have become aware of commercial laboratories that conduct testing for Lyme disease by using assays whose accuracy and clinical usefulness have not been adequately established. These tests include urine antigen tests, immunofluorescent staining for cell wall--deficient forms of Borrelia burgdorferi, and lymphocyte transformation tests. In addition, some laboratories perform polymerase chain reaction tests for B. burgdorferi DNA on inappropriate specimens such as blood and urine or interpret Western blots using criteria that have not been validated and published in peer-reviewed scientific literature. These inadequately validated tests and criteria also are being used to evaluate patients in Canada and Europe, according to reports from the National Microbiology Laboratory, Public Health Agency of Canada; the British Columbia Centres for Disease Control, Canada; the German National Reference Center for Borreliae; and the Health Protection Agency Lyme Borreliosis Unit of the United Kingdom. In the United States, FDA has cleared 70 serologic assays to aid in the diagnosis of Lyme disease. Recommendations for the use and interpretation of serologic tests have been published previously (1). Initial testing should use an enzyme immunoassay (EIA) or immunofluorescent assay (IFA); specimens yielding positive or equivocal results should be tested further by using a standardized Western immunoblot assay. Specimens negative by a sensitive EIA or IFA do not need further testing. Similar assays and recommendations are used in Canada (2). In the European Union, a minimum standard for commercial diagnostic kits is provided by Conformité Européene (CE) marking; application and interpretation guidelines appropriate for Europe have been published (3,4).1 Health-care providers are reminded that a diagnosis of Lyme disease should be made after evaluation of a patient's clinical presentation and risk for exposure to infected ticks, and, if indicated, after the use of validated laboratory tests. Patients are encouraged to ask their physicians whether their testing for Lyme disease was performed using validated methods and whether results were interpreted using appropriate guidelines. References 1.CDC. Recommendations for test performance and interpretation from the Second National Conference on SerologicCDC. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR 1995;44:590--1. 2.Consensus Conference on Lyme Disease. Can Dis Wkly Rep 1991; 17:63--70. 3.Wilske B, Zöller L, Brade V, et al. MIQ 12 Lyme-Borreliose. Qualitätsstandards in der mikrobiologisch- infektiologischen Diagnostik. Munich, Germany: Urban & Fischer Verlag; 2000;1--59. Guidelines available in English at http://nrz-borrelien.lmu.de/miq- lyme/index.html. at http://nrz-borrelien.lmu.de/miq- lyme/index.html. 4.Robertson J, Guy E, Andrews N, et al. A European multicenter study of immunoblotting in serodiagnosis of Lyme borreliosis. J Clin Microbiol 2000;38:2097--102. Disclaimer All MMWR HTML versions of articles are electronic conversions from ASCII text into HTML. This conversion may have resulted in character translation or format errors in the HTML version. Users should not rely on this HTML document, but are referred to the electronic PDF version and/or the original MMWR paper copy for the official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices. Morbidity and Mortality Weekly Report (MMWR) MMWR A-Z Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z # ABCDEFGHIJKLMNOPQRSTUVWXYZ# http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5405a6.htmhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm5405a6.htm[6/11/2014 10:15:43 PM]

21. LYME DISEASE SEROLOGY Myth 1.There are many false-negative antibody test results for Lyme disease (i.e., sensitivity is poor) a. True….but…. b.80-90% of patients with Lyme disease have single or multiple erythema migrans (EM) c. EM usually develops 1-2 weeks after infection d. Antibodies detectable 3-4 weeks afterinfection e. Sensitivity poor in early Lyme disease—but not needed because of rash; Do not order f. Sensitivity excellent in late Lyme disease (100% of patients with Lyme arthritis positive)

22. LYME DISEASE SEROLOGY Myth 1.Early treatment with antimicrobials may lead to false-negative serology a. True….but…. b. Reason is that treatment kills the bacteria (and the antigenic stimulus to produce antibodies) c. Cannot argue that a patient has on-going symptoms from active infection but negative serology because of previous treatment

23. LYME DISEASE Serologic Tests 1. IgM Antibodies to B. burgdorferi a. False-positive results common 1. Multiple binding sites for antibody (less specific) 2. Criteria for positive W. blot too liberal a. Only 2 of 3 bands = positive b. One study found majority of adults referred to Lyme clinic had false-positive IgM Western blot c. True-positive result may persist even after successful treatment and cure of disease 2. Western immunoblot does not = “truth” a. Cannot be interpreted without an ELISA b. False-positive results not uncommon

24. LYME DISEASE Symptoms of Lyme Disease? 1.NONE 2.None of the symptoms associated with Lyme disease (headache, fever, arthralgia, fatigue, etc) sufficiently specific by itself to make it likely symptom is due to Lyme disease 3.Unless accompanied by more specific SIGNS

26. Rev. Thomas Bayes (1702-1761)

27. LYME DISEASE Serologic Tests 1.Tests for antibody should not be used for screening or for proving negative result in someone with lowprobability of Lyme disease 2.Order only when prior probability (“pre-test” probability) of Lyme disease is reasonably high 3.Do we need better serologic tests?

28. LYME DISEASE Diagnosis of Lyme Disease? 1.Based on history and typical rash 2.If no rash, then diagnosis often based on results of serologic tests 3.Thomas Bayes: Bayes’ Theorem

29. TEST FOR ANTIBODIES AGAINST B. BURGDORFERI 1. Sensitivity95% 2. Specificity90% 3. Pre-test probability of Lyme disease 1% Population of 10,000

30. TEST FOR ANTIBODIES AGAINST B. BURGDORFERI LymeNo TestDisease DiseaseTotal Positive 95 9901,085 Negative 5 8,9108,915 Total 100 9,900 10,000 False-Positives = 990 = 91% 1085 Positive Predictive Value = 9%

31. Prevalence50%5%0.5%0.05% Sensitivity90% Specificity95% Pos Pred Value94.7%48.6% 8.3%0.9% Neg Pred Value90.5%99.4%99.9%99.99% Diagnostic Accuracy 92.5%94.8%95% PREVALENCE OF DISEASE: EFFECT ON POS AND NEG PREDICTIVE VALUE

32. LYME DISEASE Clinical Situation 1. Patient with non-specific, vague symptoms not likely to be Lyme disease a. Antibody to B. burgdorferi: Negative Diagnosis: Not Lyme disease b. Antibody to B. burgdorferi: Positive Diagnosis: Not Lyme disease 2. Moral: Don’t order Lyme titers

33. LYME DISEASE Nonspecific (Chronic) Symptoms 2. Rarely if ever the ONLY manifestation of Lyme disease a. Nonspecific (subjective) symptoms accompany OBJECTIVE signs of Lyme disease 3. There is no evidence that “chronic Lyme disease” exists and substantial scientific evidence that it does not (N Engl J Med 2007;357:1422-30)

34. LYME DISEASE Post-Treatment Lyme Disease Syndrome 1.Patients who report non-specific symptoms (e.g., fatigue, arthralgia, myalgia, problems with memory, etc) after documented Lyme disease 2.If symptoms last <6 months or, if longer, not functionally disabling, termed post-Lyme disease symptoms 3.If symptoms last >6 months and disabling termed post- Lyme disease syndrome (PLDS) a. Unclear how common or whether more common after Lyme disease than in general population b. Clinical trials of long-term antibiotics in this group: No efficacy; substantial adverse side effects

35. LYME DISEASE Advances in Treatment 1.Surgical procedure useful in routine management of patients with Lyme disease An Internet-ectomy

36. A REAL CASE 1.Jennifer: 15 y.o. girl. Adopted, parents now divorced; A’s and B’s in school. Diagnosed with strep throat 3 years ago. 2.August, 2014: insomnia, then epigastric pain/nausea. Diagnosed with gastric ulcers and treated with antibiotics. 3.Developed shooting pains arms, legs, jaw, back; impaired short-term memory; night sweats; temperature intolerance; headaches; irregular menses; increased urinary frequency; rash upper eyelid and arm.

37. A REAL CASE 4.Retrobulbar micturalgia? 5.Appointments with endocrinology, nephrology, neurology, infectious diseases, rheumatology, cardiology (chest pain w/breathing) 6.Missed school most days past few months 7.Diagnostic tests: Upper GI endoscopy, EKG, nuclear scan of gall bladder, MRI brain, renal and abd ultrasounds, Chest X-ray, food allergy profile, many other blood tests

38. A REAL CASE 8.Saw a holistic medicine practitioner, suggested it might be Lyme disease, so came to see me. 9.Child was completely normal on exam. Mom (a piece of work), did all the talking. 10. Not unusual story. Less extreme cases far more common in general pediatric practice. 11. Majority of new referrals to Pedi ID Clinic.

39. LYME DISEASE Alternate Universe 1. There is an alternate universe that we are about to enter in which Lyme disease is something altogether different

40. The Chronic Lyme Disease Community

42. “CHRONIC” LYME DISEASE Definition 1. There is none!! This complicates studies of this entity 2. Definition essentially is that someone (often a “Lyme-literate” doctor) says patient has it 3. Often patients themselves conclude they have chronic Lyme disease and seek provider who will confirm and treat them

43. “CHRONIC” LYME DISEASE Definition (ILADS) “For the purpose of the ILADS guidelines, ‘chronic Lyme disease’ is inclusive of persistent symptomatologies including fatigue, cognitive dysfunction, headaches, sleep disturbance and other neurologic features, such as demyelinating disease, peripheral neuropathy and sometimes motor neurone disease, neuropsychiatric presentations, cardiac presentations including electrical conduction delays and dilated cardiomyopathy and musculoskeletal problems.” ILADS: International Lyme and Associated Diseases Society

44. Fatigue Low grade fevers, “hot flashes” or chills Night sweats Sore throat Swollen glands Stiff neck Migrating arthralgias, stiffness and frank arthritis Myalgia Chest pain and palpitations Abdominal pain, nausea Diarrhea Sleep disturbance Poor concentration and memory loss Irritability and mood swings Depression Back pain Blurred vision and eye pain Jaw pain Testicular/pelvic pain Tinnitus Vertigo Cranial nerve disturbance ( facial numbness, pain, tingling, palsy or optic neuritis) Headaches Lightheadedness Dizziness ILADS Symptoms of Lyme Disease http://www.ilads.org/lyme_disease/treatment_guidelines_summary.html

46. REPORTED CASES OF LYME DISEASE - 2011 http://www.cdc.gov/lyme/stats/maps/map2011.html

47. http://www.lymenet.org/SupportGroups/ DISTRIBUTLLLION OF LYME DISEASE SUPLYME DISEASE SUPPORT GROUPS PORT GROUPSLYME

48. “CHRONIC” LYME DISEASE Magnitude of the Problem 1.In 2012 about 3 million tests for Lyme disease ordered in the U.S. a. 30,000 reported cases, 90% EM for which serologic testing NOT recommended 2.Testing and treatment driven in part by misunderstanding among patients and MDs, by patient advocate groups and the media

49. MEDICALLY UNEXPLAINED SYMPTOMS 1. Medically unexplained symptoms (MUS) are physical symptoms with little or no basis to attribute toan underlying medical disease 2. When a medical condition does exist, symptoms inconsistent with or out of proportion to the illness 3.People with MUS are not necessarily abnormal 4.Many people exhibit MUS but seldom seek care 5. MUS become problem when lead to frequent healthcare-seeking for feared but nonexistent physical illness

50. MEDICALLY UNEXPLAINED SYMPTOMS 6.Among patients seeking medical care, prevalence of MUS of any type is in the range of 50 percent, pain being most common 7.For the 80 percent of patients with mild symptoms, treatment is simple reassurance, symptomatic medications, good provider-patient relationship 8. Laboratory tests should be avoided in these patients with short-term, often stress-related physical symptoms that typically resolve in a week or two 9. More troublesome are the remaining 20 percent whose symptoms are chronic and more severe, and may result in physical/psychological disability

52. CHRONIC LYME DISEASE “Soldier’s Heart” 1.Da Costa’s Syndrome (during Civil War) a. Cardiac neurosis, chronic asthenia, effort syndrome, functional cardiovascular disease, neurocirculatory asthenia, primary neurasthenia, subacute asthenia and irritable heart. b. Really PTSD (post-traumatic stress disorder)

53. MEDICALLY UNEXPLAINED SYMPTOMS 1.Each subspecialty has its own: a. ID: Chronic Lyme disease; chronic mono; chronic fatigue syndrome; candida connection b. Rheumatology: Fibromyalgia; chronic pain syndromes c. GI: Irritable bowel syndrome; chronic abdominal pain d. Cardiology: Palpitations; non-cardiac chest pain e. Gyn/Urology: Chronic pelvic pain; interstitial cystitis f. Pulmonary: Chronic cough g. Neurology: Chronic headaches; migraines h. Endocrine: Hypothyroidism i. ENT: Globus pharynges; dysphonia j. Orthopedics: Back pain

54. TAXONOMY 1.Are these one entity or multiple different entities, each with a different pathophysiology? 2.Or something else? 3.Study of 315 subjects (wide variety) 4. DSM-III-R self-report somatization questionnaire 5. Correlations between all of the 26 non-gender specific MUS

55. TAXONOMY 6. People tend to be serial somatizers 7.Principal-components analysis: general factor contributed to about 40% of the mean variances of the individual symptoms 8.Structural equation model

56. 56 Editorial Fig. 2. Structural equation model of some common medically unexplained symptoms and syndromes. Redrawn from Kirmayer et al. [11]. Ellipses contain latent traits. Numbers adjacent to arrows between ellipses and individual symptoms represent the strength of relationship between manifest and latent vari- ables. The extreme right hand column represents unique sources of variance for each symptom. The numbers adjacent to curved lines on the left of the figures are the correlation coefficients among the la- tent variables.

57. TAXONOMY 8. Structural equation model indicates correlations among the five latent traits universally positive and fairly strong; much of the variance that appears to be attributable to specific syndromes is actually shared

59. TAXONOMY 9.Higher order principal component analysis shows that much of the variance of individual symptoms is attributable to a general latent variable (MUS) rather than the individual syndromes 10. Bottom line: These syndromes have a lot in common, although clearly we don’t understand why patients develop a specific syndrome or constellations of somatic symptoms

60. CHRONIC LYME DISEASE Medically Unexplained Symptoms 1. Psychosocial factors propel amplification of symptoms a. Belief that one has a serious disease b. Expectation that one's condition is likely to worsen c. “Sick role,” including the effects of litigation and compensation d. Portrayal of the condition as catastrophic and disabling 2.Patients often strongly assertive; sense of embattled advocacy for their etiologic suppositions 3.Patients often devalue and dismiss medical authority and evidence that conflicts with their beliefs

61. CHRONIC LYME DISEASE Medically Unexplained Symptoms 4. Complicated by: a. Sensationalized coverage in the media b. Internet (chronic Lyme disease: 4.6 million hits) c. Profound suspicion of medical expertise and of physicians f. Clinical approach that overemphasizes biomedical and ignores psychosocial factors

62. CHRONIC LYME DISEASE Unconventional Treatments 1.Prolonged (years of) treatment with antimicrobials 2.Stem cell transplantation 3.Heavy metal therapy (deaths from Bismuth Rx) 4.IVIG 5.Anal or vagina infusion of ozone 6.Hyperbaric oxygen 7.Rife machines

63. MEDICALLY UNEXPLAINED SYMPTOMS Fibromyalgia

65. “CHRONIC” LYME DISEASE Managing the Problem 1.Doctors are part of the problem 2.Good at treating “diseases” (diagnoses); Poor at managing symptoms without a diagnosis 3.Large literature on “medically unexplained symptoms” and “functional somatic syndromes” 4.Saying it is not Lyme disease does not solve the problem 5.Stigma associated with medically unexplained symptoms (“it’s all in your head”) 6.Doctors may have negative feelings about such patients that influence their management

66. “CHRONIC” LYME DISEASE Managing the Problem 7. Medically unexplained symptoms are common and should be treated seriously a. Patients are experiencing these symptoms and seeking affirmation/sympathy/concern (parents) 8.Explanations should integrate psychological and biological factors and provide patients with a model for managing the problem 9. Associated organic pathology is rare and rarely missed; psychological problems are common and often missed a. Depression and/or anxiety often present

67. “CHRONIC” LYME DISEASE Managing the Problem 10. Paradigm for many other functional syndromes 11. Focus on symptoms, not diagnosis a. Trusting relationship important b. Exercise, counseling, improve sleep, in some instances medications (e.g., antidepressant) c. Get patients back to work, school, up and going 12. Primary care docs need to be trained how to manage patients with MUS that do not need to be referred 13. More research needs to be done

68. S L I D E 68 Current Research: Mindfulness/Chronic pain Mindfulness Interventions and Chronic Widespread Pain in Adolescents (NIH/NCCIH K23, PI Ather Ali, ND) –Also for functional somatic syndromes NIH/NCCIH: “A type of meditation that focuses attention on breathing to develop increased awareness of the present. The intent is to reduce stress and control emotion in order to improve health.”

69. Mindfulness-based stress reduction (MBSR) Standard protocol (Kabat-Zinn/UMass) – mindfulness meditation, patient education, and group support – 8-week group session x 2.5 hr/wk; 4 hr retreat – Home practice: 30-45 min/day JAMA Intern Med. 2014 Jan 6.

70. MBSR – Results in progress Development of the Intervention: – Translating adult program to teens Two cohorts so far (n=11) – Cohort 3: September – November 2015 Positive effects (small numbers) in functioning, symptoms, anxiety, QOL (teens and parents), perceived stress Dose-response?

71. Quotes “I had no idea that there would be a way for someone with symptoms like the people in my group and myself had…. I didn't think that it would ever work, and I didn't think it could be used to work in that way, so it was really cool. It's like a different way of dealing with something or helping to deal with something.” “I see a different behavior at home. She seems to be able to handle stress within the household in a better fashion. We haven't had any outbursts… When she runs into difficulty now, a difficult situation, she calls her mom instead of not calling her mom.”

72. “CHRONIC” LYME DISEASE and MUS Summary 1.This is a very difficult problem 2. Many of these patients ARE suffering 3. Teaching doctors to manage medically unexplained symptoms without a diagnosis is a major challenge 4.Getting patients and the media to accept a diagnosis of “medically unexplained symptoms” is an even greater challenge! 5.We are trying!!

73. Reported Cases LD (total U.S.)