Transcript Less is More - Middlesex Hospital

Less is More: Lyme Disease
and NOT Lyme Disease
Eugene D. Shapiro, MD
Nothing to Disclose
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
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
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%)
Lyme Disease
Erythema Migrans
Lyme Disease
Erythema Migrans
Lyme Disease
Multiple Erythema Migrans
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
LYME DISEASE
Clinical Manifestations
4. Late Disseminated disease (7%)
a. Arthritis—knee especially
b. Neurologic: extremely rare,
especially in children
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)
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
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 2nd tier test
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
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
Notice to Readers: Caution Regarding Testing for Lyme Disease
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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).
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 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.
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 after infection
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)
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
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
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
Rev. Thomas Bayes (1702-1761)
LYME DISEASE
Serologic Tests
1. Tests for antibody should not be used
for screening or for proving negative
result in someone with low probability
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?
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
TEST FOR ANTIBODIES
AGAINST B. BURGDORFERI
1. Sensitivity
95%
2. Specificity
90%
3. Pre-test probability
of Lyme disease
1%
Population of 10,000
TEST FOR ANTIBODIES
AGAINST B. BURGDORFERI
Lyme
Test
Disease
Positive
95
Negative
5
Total
100
No
Disease
990
8,910
9,900
Total
1,085
8,915
10,000
False-Positives = 990 = 91%
1085
Positive Predictive Value = 9%
PREVALENCE OF DISEASE: EFFECT
ON POS AND NEG PREDICTIVE VALUE
Prevalence
50%
5%
0.5%
0.05%
Sensitivity
90%
90%
90%
90%
Specificity
95%
95%
95%
95%
Pos Pred Value
94.7%
48.6%
8.3%
0.9%
Neg Pred Value
90.5%
99.4%
99.9%
99.99%
Diagnostic
Accuracy
92.5%
94.8%
95%
95%
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
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)
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 postLyme 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
LYME DISEASE
Advances in Treatment
1. Surgical procedure useful in routine
management of patients with Lyme disease
An Internet-ectomy
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.
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
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.
LYME DISEASE
Alternate Universe
1. There is an alternate universe that we
are about to enter in which Lyme
disease is something altogether
different
The Chronic Lyme Disease Community
“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
“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
ILADS
Symptoms of Lyme Disease
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
http://www.ilads.org/lyme_disease/treatment_guidelines_summary.html
REPORTED CASES OF LYME DISEASE - 2011
http://www.cdc.gov/lyme/stats/maps/map2011.html
DISTRIBUTLLLION OF LYME DISEASE
SUPLYME DISEASE SUPPORT GROUPS
PORT GROUPSLYME
http://www.lymenet.org/SupportGroups/
“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
MEDICALLY
UNEXPLAINED SYMPTOMS
1. Medically unexplained symptoms (MUS) are
physical symptoms with little or no basis to
attribute to an 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
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
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)
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
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
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
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.
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
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
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
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
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
MEDICALLY UNEXPLAINED SYMPTOMS
Fibromyalgia
Table 1. The prev alence of chronic w idespread pain in the general population
P rev alen ce %
Study
Country
Patients, n
Wo men, %
Croft et al. [6]
Macfarlane et al. [7]
United Kingdom
United Kingdom
2034
1953
57.3
57.2
White et al. [8]
Buskila et al. [9]
Wolfe et al. [11]
Bergman et al. [13]
Canada
Israel
United States
Sweden
3395
2210
3006
2425
61.6
60
N/A
52.7
N/A—nonapplicable.
Table 1. The prev alence of chronic w idespread pain in the general population
Study
Country
Patients, n
Wo men, %
P rev alen ce %
Age range, year s
Ov erall
Female
M ale
Croft et al. [6]
Macfarlane et al. [7]
United Kingdom
United Kingdom
2034
1953
57.3
57.2
18–85
18–65
11.2
12.9
15.6
14.7
9.4
10.5
White et al. [8]
Buskila et al. [9]
Wolfe et al. [11]
Bergman et al. [13]
Canada
Israel
United States
Sweden
3395
2210
3006
2425
61.6
60
N/A
52.7
18+
18–86
18+
20–74
7.3
9.9
10.6
11.4
N/A
14
N/A
15.3
N/A
3.3
N/A
7.5
N/A—nonapplicable.
Age range, year s
Ov erall
Female
M ale
18–85
18–65
11.2
12.9
15.6
14.7
9.4
10.5
18+
18–86
18+
20–74
7.3
9.9
10.6
11.4
N/A
14
N/A
15.3
N/A
3.3
N/A
7.5
“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
“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
“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
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.”
S L I D E 68
•
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.
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?
Change in FIQR vs. Total Minutes Practiced
Change in FDI vs. Total Minutes Practiced
50.00
50
40
R² = 0.30725
40.00
30
30.00
R² = 0.20002
20
20.00
10
0
10.00
-10
0.00
-20
-10.00
-30
-40
0
500
1000
1500
2000
-20.00
0
500
1000
1500
2000
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.”
“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!!
Reported Cases LD (total U.S.)