Amsterdam NL

Problems with Diagnostic Testing

To Test or Not to Test? That is the

Question…

Horowitz, R.I. et al. Clin Microbiol & Infection, 10 October 2017

10

Testing for Lyme Disease: Inaccurate

◼ The mean sensitivity for all tests and for all samples
was 59.5% and 53.7% when the two-tier
methodology was used (Puri, Cook)

◼ The two-tier test generated over 500 times more
false-negative results than two-stage HIV testing

◼ Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy. Cook, MJ, Puri,
BK. Int J Gen Med. 2016 Nov 18;9:427-440

◼ Application of Bayesian decision-making to laboratory testing for Lyme disease and comparison with
testing for HIV. Cook, MJ, Puri, BK. Int J Gen Med 2017:10 113-123

◼ Serology changes over time:

◼ Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates
exposed to Borrelia burgdorferi by tick feeding. Embers, M. et al. PLoS ONE 12(12): e0189071.
https://doi.org/10.1371/journal.pone.0189071

Percentage of Patients with EM

Rashes & Positive Lyme Testing

Horowitz, R., Freeman P. International Journal of General Medicine 2019:12 101–119

Problems with Diagnostic Testing

◼ 1)Intra & Inter-laboratory Variation

Marangoni J Med Microbiol 2005: 3 different commercial Elisa tests showed discrepant results.
Sensitivity for the same sera 36,8% to 70.5%
De Marteno Med Mal Infect 2007: Compared 14 Elisa test kits for the diagnosis of neuro Lyme.
Sensitivity varied from 20.9% -97.7%

◼ 2) Different species of Borrelia:

Rudenko FEMS Microbiol Letter 2009 ; Lopes de Carvalho Clin Rheumatol 2008

◼ 3) Problems w/ 2 -Tiered Testing in Early
Lyme: CDC two tiered testing missed up to 55%

of positive Lyme cases

Coulter,et al.,J Clin Microbiol 2005;43:5080-5084. CDC correspondance with NYS DOH

◼ 4) Sensitivity/Specificity of Commercial Two-
Tier Testing for Lyme Disease=56%/99%

Stricker and Johnson BMJ 2007; 335:1008; The mean sensitivity for all tests and for all
samples was 59.5% and 53.7% when the two-tier methodology was used (Puri, Cook)

What Are Other Problems w/ Testing?

Immune Complexes/Immune Evasion

◼ 5. Failure to detect Antibodies: Circulating immune

complexes, ↓ ability to find AB’s in the spinal fluid of Lyme
patients w/ significant CNS dx.

Coyle, et al. Detection of Bb antigens in CSF. Neurology 1993;43:1093-1097; Schutzer SE et al.
Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease.
Lancet. 1990 Feb 10;335(8685):312-5;

◼ 6. Borrelia subverts a B cell response (which produces

antibodies), leading to T cell independence: Baumgarth et al. PLoS

Pathog 7(5): e1002066. doi:10.1371/journal.ppat.1002066

◼ 7. Bb Has the Ability to Evade The Immune System:

Long replication time, changes outer surface proteins, cloaking→ Bb
surrounds itself w/ the body’s lymphocytic proteins, ↓ immune
recognition: Dorward, et al. Jounal of Clin Microbiol 1991;29:1162-70; Berndtson, Review of

evidence for immune evasion and persistent infection in Lyme disease. International Journal of General
Medicine 2013:6 291–306

Problems with LD Two-Tiered Testing

◼ Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J. Sequestration of antibody to
Borrelia burgdorferi in immune complexes in seronegative Lyme disease. Lancet. 1990
Feb 10;335(8685):312-5;

◼ Marangoni, A. et al. Comparative evaluation of three different ELISA methods for the
diagnosis of early culture-confirmed LD in Italy. J. Med. Microbiol. 54, 361-367 (2005);

◼ Ang, C.W.,et al. T. Large differences between test strategies for the detection of anti-
Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur. J.
Clin. Microbiol. Infect. Dis. 30, 1027-1032 (2011).

◼ Cook MJ, Puri BK. Commercial test kits for detection of Lyme borreliosis: a meta-analysis
of test accuracy. Int J Gen Med. 2016 Nov 18;9:427-440. eCollection 2016.

◼ Cook MJ, Puri BK. Application of Bayesian decision-making to laboratory testing for Lyme
disease and comparison with testing for HIV. Int Jnl of Gen. Medicine 2017:10 113–123

◼ Embers ME, et al. (2017) Variable manifestations, diverse seroreactivity and post-
treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick
feeding. PLoS ONE 12(12): e0189071.

◼ Horowitz, R.I., Freeman PR. Precision Medicine: retrospective chart review and data
analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-
treatment Lyme disease syndrome: part 1. International Journal of General Medicine
2019:12 101–119

False Positive and Negative Tests

◼ Variation in antibody responses to Borrelia are
known, where even post EM, seroneg. is possible

◼ 2 patients with early-disseminated LD were
misdiagnosed with mono based on false + EBV tests

◼ ? Use biofilm busters to improve detection by PCR

◼ Embers ME, et al. (2017) Variable manifestations, diverse seroreactivity and post-treatment persistence
in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS ONE 12(12): e0189071.

◼ Early Disseminated Lyme Disease Causing False Positive Serology for Primary Epstein-Barr Virus
Infection - Report of 2 Cases. Pavletic AJ, et al. Clinical Infectious Diseases, online first, 2017 Apr 4.

◼ Biofilms busters to improve the detection of Borrelia using PCR. Lacout A, et al. Med Hypotheses 2018
Mar;112:4-6

◼ Baumgarth et al. PLoS Pathog 7(5): e1002066. doi:10.1371/journal.ppat.1002066

Current Limitations of Most Lab
testing for Lyme Disease

◼ Most commercial labs only use the B31 lab strain of Bb
(specificity can be as low as 40%) Other strains, i.e., 297
strain can ↑ specificity & sensitivity (IgeneX W. blot)

◼ Borrelia sensu lato strains can all cause disease, & are
not picked up on most commercial assays (IgeneX
Immunoblot tests for sensu lato spp.)

◼ Most labs do not use recombinant proteins, or report
OspA (31) or OspB (34) bands (IgeneX W Blot’s do)

◼ Some labs include the VlsE recombinant antigen to
improve sensitivity (Coppe labs)

◼ Shah, J. et al. Pilot Study of Immunoblots with Recombinant Borrelia burgdorferi Antigens for
Laboratory Diagnosis of Lyme Disease, August 2018. Healthcare 6(3):99

Diagnostics: Key Points

◼ Clinical diagnosis: How do you make it? It is a
multisystemic illness. Use the HMQ as a first step to
evaluate patients, paying attention to the number
and type of symptoms. Do a broad differential
diagnosis to rule out other diseases

◼ Need for a reliable blood test: There are problems
with the sensitivity of the Elisa (? do the C6 instead)

◼ Consider using laboratories that expand the
number of strains of borrelia on the Western Blot (ie

add 297 to B31, ? Add others based on local strains)

◼ Horowitz R, et al. To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis. Clin
Microbiol Infect. 2017 Oct 10. pii: S1198-743X(17)30528-1.

Diagnostics: Key Points

◼ Panel Approach is best. Do Indirect & Direct tests
after establishing a clinical diagnosis (HMQ score)

◼ Indirect tests: IFA, ELISA, C6 ELISA, W. Blot,
Immunoblot (IgeneX),LTT [Elispot], iSpot, Spirotest

◼ Direct tests: PCR, FISH [RNA], culture, Nanotrap

◼ Key: Look for borrelia specific bands on the W. Blot:
23 kda (Osp C), 31 (Osp A), 34 (Osp B), 39, 83-93 kda. 1-2
borrelia specific bands in the right clinical setting
helps make the diagnosis

◼ Sedegah M. The Ex Vivo IFN-γ Enzyme-Linked Immunospot (ELISpot) Assay Methods Mol Biol.
2015;1325:197-205; Sapi E, et al. Improved Culture Conditions for the Growth and Detection of Borrelia
from Human Serum. Int J Med Sci 2013; 10(4):362-376.

Panel Approach: Indirect Tests for

Lyme Disease

ELISA Test WESTERN IFA (Immunofluorescence LTT (ELISPOT) & C6 ELISA
Blot/Immunoblot Test Assay) SPIRO Test
Detects IgM and/or IgG
antibodies Detects IgM & IgG antibodies Detects IgM, IgG & IgA antibodies Spirotest is being evaluated at Sensitivity – 88%
W blot (IgeneX): 297. B31 Columbia; based on work at Johns
Immunoblot: B sensu lato spp. Hopkins

Most commonly used screening Generally more sensitive & Antibodies are detected 2-3 weeks Soloski MJ, Crowder LA, Lahey LJ, Wagner Standard ELISA
test for primary diagnosis, specific than ELISA after infection CA, Robinson WH, et al. (2014). PLoS ONE Sensitivity - 52%
despite significant limitations 9(4):
e93243.http://doi.org/10.1371/journal.pone
.0093243

Many ins providers require Lab may be able to report if May remain elevated for a long time Sensitivity – 84% Performance of United States Serologic
these tests to be ordered first findings are consistent with in some patients Specificity -- 94% Assays in the Diagnosis of Lyme
early, late, persistent and/or Borreliosis Acquired in Europe
Unreliable as screening test recurrent disease (Lehman PV et al.: Unique Strengths of ELISPOT Clinical Infectious
for T Cell Diagnostics. In: Kalyuzhny AE. Diseases (2013) 57 (3): 333-340 John A.
Handbook of ELISPOT: Methods and Protocols, Branda, Franc Strle, Klemen Strle, Nikhil
Methods in Molecular Biology, Vol. 792. 2nd Ed: Sikand, Mary Jane Ferraro, Allen C. Steere

Springer; 2012: 3-23)

Misses 35% of culture proven 20-30% of acute culture- LTT already being used in
Lyme Disease proven Lyme disease remain clinical practice
seronegative on western blot
52% of patients with chronic sampling
Lyme disease are negative by
ELISA but positive by Western Including highly specific bands
blot 31 and 34, which are not
generally reported by
commercial labs

www.niaid.nih.gov

Direct Tests for Lyme Disease

Lyme PCR LDA/Lyme Dot Blot Assay CULTURE Test &
NANOTRAP Test
Detects the genomic & plasmid DNA of the Detects antigens of Lyme bacteria in urine
Lyme bacteria samples & cerebral spinal fluid/CSF

Can be performed on whole blood, serum, urine, Can be useful when initial Lyme panel tests on NANOTRAP is urine antigen test
breast milk, skin & CSF blood samples are negative (including PCR) but
symptoms for Lyme disease are present

Increased specificity to ID unusual strains of B. Cross reactions may occur with other non-Lyme Application of Nanotrap technology for high sensitivity
burgdorferi antigens so use caution measurement of urinary outer surface protein A
carboxyl-terminus domain in early stage Lyme borreliosis.
Test can often be negative due to the Magni et al. J Transl Med (2015) 13:346. DOI
bacteria’s ability to “hide” behind biofilms 10.1186/s12967-015-0701-z

Standard PCR generally not sensitive enough due . Sapi E, et al. Improved Culture Conditions for the
Growth and Detection of Borrelia from Human
to the low numbers of bacteria present
Serum. Int J Med Sci 2013; 10(4):362-376

Multiple sample types (blood & serum) improve
sensitivity of test

Newer Markers of Human Lyme Disease
Activity: Immunoblots

◼ The Lyme ImmunoBlot (IgeneX) IgM & IgG has
better specificity than the traditional Western Blot
(98% for IgM and 98.7 for IgG): appx 1 year old

◼ Detects antibodies to major B. burgdorferi sensu
lato specific antigens (N. America & European strains):

B. burgdorferi B31, B. burgdorferi 297, B. californiensis, B.
mayonii, B. afzelii, B. garinii, B. spielmanii, B. valaisiana

◼ Direct testing: ? LymeSeq (RNA testing)

◼ Casselli T, et al. MicroRNA and mRNA Transcriptome Profiling in Primary Human Astrocytes Infected
with Borrelia burgdorferi. PLoS One. 2017 Jan 30;12(1):e0170961.

Newer Markers of Early & Late Human
Lyme Disease Activity: Chemokines

◼ Chemokine signatures are associated with the early
stages of infection: (CXCL9, CXCL10, CCL19)

◼ Acute phase proteins (CRP and serum amyloid A)
are also seen in early disease

◼ CXCL13 is a biomarker of acute neurological Lyme

◼ CCL19 has also been identified in late Lyme

◼ Soloski MJ, Crowder LA, Lahey LJ, Wagner CA, Robinson WH, et al. (2014). PLoS ONE 9(4):
e93243.http://doi.org/10.1371/journal.pone.0093243

◼ Aucott JN, et al. 2016. CCL19 as a chemokine risk factor for posttreatment Lyme disease syndrome: a
prospective clinical cohort study. Clin Vaccine Immunol 23:757–766.

◼ Karrasch, M. et al. Neuroborreliosis and acute encephalopathy: The use of CXCL13 as a biomarker in CNS
manifestations of Lyme borreliosis. Ticks and Tick-borne Diseases11 December 2017

Newer Tests for Human Lyme Disease
Activity: Nested PCR’s

◼ There is a need to detect of all known species of
bacteria causing tick borne borreliosis in the US,
including Borrelia burgdorferi sensu lato, Borrelia
miyamotoi, B. lonestari, B. hermsii & B. mayonii

◼ Nested PCR: amplicons generated in the first
primary PCR are being reamplified, w/↓ inhibitors

◼ Real time PCR & nested PCR: comparable: NYSDOH

◼ Kingry LC. et al. Surveillance for and Discovery of Borrelia Species in US Patients Suspected of Tickborne
Illness. Clin Infect Dis. 2017 Dec 20; Hong G, et al. A Novel Low Temperature PCR Assured High-Fidelity
DNA Amplification. International Journal of Molecular Sciences. 2013; 14(6):12853-12862. Private
Correspondence between SH Lee and Ronald J. Limberger, Ph.D, Wadsworth Laboratory, NYS, Dec 2017;

Understanding Laboratory Testing TBD’s

Overview:

1. Lyme Disease is a CLINICAL DIAGNOSIS. The
laboratory only helps to support that clinical
diagnosis.

2. An EM rash is definitive evidence of Lyme
Disease, and DOES NOT require laboratory
confirmation to make the diagnosis

3. Patients are often seronegative if tested too
early, or if antibiotics have been used early in the
course of the disease, which may abrogate the
immune response

Laboratory Testing in TBD’s

4. The 2 tiered protocol of an Lyme ELISA followed
by a Western Blot misses approximately 1/2 of the
patients: Consider C6 ELISA, IFA…+ Immunoblot

5. The utility of the Western Blot is based on
understanding specific bands which reflect
exposure to Bb: 23, 31, 34, 39, 83-93

6. PCR testing is an important diagnostic tool for
seronegative patients, but many require multiple
sets over time. Other tests may be helpful to
confirm the diagnosis (LTT (Elispot), Nanotrap,
Lyme Dot Blot, culture, RNA testing..)

Casselli T, et al. MicroRNA and mRNA Transcriptome Profiling in Primary Human Astrocytes Infected
with Borrelia burgdorferi. PLoS One. 2017 Jan 30;12(1):e0170961

Understanding Laboratory Testing in

TBD’s

7. 10-20% of the Borrelia presently in ticks in the
Northeastern United States are genetically related
to Borrelia miyamotoi, the agent of relapsing fever
(RF) in Japan. These organisms will not test
positive by ELISA, Western Blot, or PCR assays for
Lyme Disease. ? Cause of Lyme-like syndromes

8. Other tick-borne diseases such as Babesia and
Bartonella are similarly unable to be reliably
diagnosed using standard screening procedures.

Aliota MT, et al. The prevalence of zoonotic tick-borne pathogens in Ixodes scapularis collected in the
Hudson Valley, New York State. Vector-Borne Zoonot. Dis. 2014; 14:245–250.

Check For Common Co-infections:

Laboratory, Symptom Complexes

◼ Expand Babesia testing: Use a panel approach (IFA,

FISH (IgeneX), PCR) including a Babesia WA-1 (duncani)

◼ Expand the “net” for other TBD’s, i.e. rickettsial

infections (Q-fever, RMSF, Typhus), Ehrlichia/Anaplasma,
Bartonella, Mycoplasma species, Tularemia, Brucella & tick
borne viral infections (POWV). Some of these can be fatal

◼ Take the HMQ & evaluate the risk for LD/Bab

◼ Curcio Sabino R., et al. Seroprevalence of Babesia microti in Individuals with Lyme Disease Vector-Borne and Zoonotic
Diseases. October 2016. doi:10.1089/vbz.2016.2020; Rickettsia Parkerii: Journal of Medical Entomology, 2017, 1–7 doi:
10.1093/jme/tjx138;

◼ Horowitz, R.I.; Freeman, P.R. Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating
Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2. Healthcare 2018, 6,
129.

Are Your Symptoms Due to Lyme
Disease? Take the Horowitz Lyme-

MSIDS Questionnaire (HMQ)

This is a validated screening tool to determine the
probability of having Lyme and associated tick-borne
illness (without an EM rash). Patients can have up to
16 different reasons why they stay ill. I call this
multifactorial diagnostic and treatment model MSIDS

Empirical Validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for
Suspected Lyme Disease. Maryalice Citera1¶*, Ph.D., Phyllis R. Freeman2¶, Ph.D., Richard I. Horowitz2¶,
M.D., International Journal of General Medicine 2017:10 249–273

Empirical Validation of the Horowitz MSIDS

Questionnaire for Suspected Lyme Disease

Citera M, Freeman PR, Horowitz RI. International Journal of General Medicine 2017:10 249–273.
http://www.ncbi.nlm.nih.gov/pubmed/28919803

Validation of the MSIDS Questionnaire

Citera, Freeman, Horowitz, RI. International Journal of General Medicine 2017:10 1–25

◼ Purpose of this study: evaluate the HMQ designed
by Dr. Richard Horowitz as an initial screening tool
for Lyme and other tick borne co-infections. Is it
reliable and valid?

◼ Data were collected from two independent
samples: 1600 patients from medical practices
specializing in treating Lyme and healthy
individuals recruited through email and social
media to complete an online survey

The Horowitz Multiple Systemic Infectious

Disease Syndrome Questionnaire (HMQ)

Section 1: The Symptom Checklist: 38 symptoms

rated from 0 (none) to 3 (extremely frequent)

Section 2: The Lyme Incidence scale: items

related to the likelihood of having Lyme,
& migratory symptoms

Section 3: The Healthy Days Scale:

contains 2 items about the individual’s overall health
(physical and mental health) over the last 30 days

Section 4: The Common Lyme Score: awards points for the most

common Lyme symptoms

◼ A score > 63: high likelihood of exposure
◼ Especially if “migratory” pain is present

Differential Diagnosis Migratory Pain

Horowitz et al: International Journal of General Medicine 2017:10 1–25
See: Table 11 MSIDS differential diagnosis of migratory pain

◼ Acute Rheumatic ◼ Reactive Arthritis
Fever: ASO, anti-DNAase Ab (Salmonella, Yersinia,
Chlamydia species…,
◼ Crohn’s HLA B 27+): Reiters triad
Disease/Inflammatory
Bowel Disease: ◼ SLE (Lupus): dsDNA, Smith Ag

colonoscopy, calprotectin (IBD).. ◼ Lyme Disease: this is
the only disease with
◼ Gonococcal Arthritis: migratory nerve pain!

Check for triad: suppurative arthritis,
tenosynovitis and dermatitis

◼ Hepatitis (A, B, C, D, E):

check viral Abs’, PCR, RNA

Cardio/ Neuropathy
Respiratory

Dysautonomia HMQ Cognitive
Factors Dysfunction

Fatigue Musculo-skeletal
Pain

Validation of the MSIDS Questionnaire

◼ 5 factors consistent with LD: fatigue, flu like symptoms,
joint stiffness, tingling, concentration problems (1600
individuals, 3 medical practices)

◼ Migratory joint/muscle/nerve pain was significant!

◼ Demonstrated convergent and divergent construct validity,
as well as predictive validity. Discriminant analysis showed
we could accurately classify the Lyme Status: 87% accuracy

◼ Conclusion: A score > 63 on the HMQ confers a high
probability of LD; Between 45-62 (probable), 25-44
(possible). Healthy individuals scored below 24

◼ Q’s 1 +22 on the HMQ indicate possible co-inf w/ Babesia

◼ Empirical Validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for
Suspected Lyme Disease. Maryalice Citera, Ph.D., Phyllis R. Freeman, Ph.D., Richard I. Horowitz, M.D.,
International Journal of General Medicine 2017:10 249–273

Discriminant analysis also showed we
could accurately classify the Lyme
Status of individuals using their HMQ
scores: Overall accuracy was 87.6%

12.4

87.6

Correctly Classified Not Correctly Classified



Lyme-MSIDS Questionnaire: HMQ

See symptom differential diagnoses» How Can I Get Better? An Action
Plan for Treating Resistant Lyme & Chronic Disease. Pgs 50-65

◼ 1. Fever, sweats (day and night), chills

◼ 2. Unexplained weight change (loss or gain)

◼ 3. Fatigue, tiredness

◼ 4. Unexplained hair loss

◼ 5. Swollen glands

◼ 6. Sore throat

◼ 7. Testicular pain/Pelvic pain

◼ 8. Unexplained menstrual irregularity

◼ 9. Unexplained breast milk production/pain

◼ Horowitz, R. How Can I Get Better? St Martins Press 2017; Empirical Validation of the Horowitz Multiple Systemic Infectious Disease
Syndrome Questionnaire for Suspected Lyme Disease. Maryalice Citera, Ph.D., Phyllis R. Freeman, Ph.D., Richard I. Horowitz, M.D.,
International Journal of General Medicine 2017:10 249–273

Lyme-MSIDS Questionnaire: HMQ

◼ 10. Irritable bladder or bladder dysfunction
◼ 11. Sexual dysfunction/loss of libido

(↓ Testosterone)
◼ 12. Upset stomach (children ↑ )
◼ 13. Change in bowel function

(constipation/diarrhea)
◼ 14. Chest pain or rib soreness
◼ 15. Shortness of breath/unexplained cough

(especially seen with Babesiosis)

Lyme-MSIDS Questionnaire: HMQ

◼ 16. Heart palpitations, heart block
◼ 17. History of heart murmur or valve prolapse
◼ 18. Joint pain or swelling in one or several joints

(? Migratory…Pain is more common than swelling)
◼ 19. Stiffness of the neck or back (cracking..)
◼ 20. Muscle pain or cramps (? Migratory)
◼ 21. Twitching of the face or other muscles
◼ 22. Headaches
◼ 23. Neck cracking or neck stiffness

Lyme-MSIDS Questionnaire: HMQ

◼ 24. Tingling, numbness, burning, or stabbing
sensations (neuropathy, ? migratory)

◼ 25. Facial paralysis (Bell’s palsy)
◼ 26. Eyes/Vision: Double, blurry (accommodation

problems, symptoms may come and go..)
◼ 27. Ears/Hearing: Buzzing, ringing, ear pain (rare

red swollen ear lobes=lymphocytoma)
◼ 28. Increased motion sickness, vertigo

Lyme-MSIDS Questionnaire: HMQ

◼ 29. Lightheadedness, poor balance, difficulty
walking (? Neurotoxins…)

◼ 30. Tremors
◼ 31. Confusion/difficulty thinking
◼ 32. Difficulty with concentration or reading
◼ 33. Forgetfulness, poor short term memory
◼ 34. Disorientation: getting lost, going to the wrong

places

Lyme-MSIDS Questionnaire: HMQ

◼ 35. Difficulty with speech or writing (word finding
problems, reversing letters & numbers, unable to
remember commonly used names or phone
numbers..)

◼ 36. Mood swings: irritability, depression, anxiety

◼ 37. Disturbed sleep: insomnia w/ inability to fall
asleep, frequent awakening, too much
(hypersomnolence) or too little sleep. Often
resistant to standard sleep medications

◼ 38. Exagerated symptoms with ETOH

MSIDS: Frequent Constellation of
Symptoms

◼ Fatigue, tiredness

◼ Headaches, with neck and back stiffness/cracking

◼ Pain in the joints & muscles ? swelling ? migratory

◼ Tingling, numbness, burning sensations (? migrate)

◼ Confusion, difficulty thinking & conc., distraction,
poor short term memory, prob’s speech/writing

◼ Insomnia: Too little or too much sleep, frequent
awakening, unrefreshed sleep

◼ Key point: Always take a proper history and do a
differential diagnosis

The 3 I’s in Chronic Disease

◼ The common denominator underlying various
etiologies on the MSIDS map: multiple sources of
inflammation (infections, environmental toxins): ↑
inflammation→ A.I. reactions, damages cells

◼ These agents create inflammation through various
pathways (NFK-B, NO, MCA): ↑ IL-1, IL-6, TNF-α, IL-
17, histamine, leucotrienes… This creates free
radicals and oxidative stress which damages cell
membranes, mitochondria, nerve cells

◼ Anaya JM, et al (2016) The Autoimmune Ecology. Front. Immunol. 7:139.

◼ Borgermans, L., Relevance of Chronic Lyme Disease to Family Medicine as a Complex Multidimensional Chronic Disease
Construct: A Systematic Review Intl Jnl Fam Med, Volume 2014 (2014)

◼ Nicolson G., et al. Neurodegenerative and Fatiguing Illnesses, Infections and Mitochondrial Dysfunction: Use of Natural
Supplements to Improve Mitochondrial Function. Functional Foods in Health and Disease 2014; 4(1):23-65

The 3 I’s in Chronic Disease

◼ Some infectious agents also produce neurotoxins
(Quinolinic Acid..) and other toxic by-products

◼ Autoimmunity may also result from antibodies
produced against these agents that cross react with
our own tissue antigens (molecular mimicry) + TLR-
2 activation by bacteria ↑ TNF-alpha, IL-17

◼ The same biological effects are seen in multiple
disease processes: Lyme Disease, CFS/M.E., FM, E.I.,

ASD, Alzheimer’s Disease and AI disorders (SLE, RA, MS),

◼ Allen HB, et al (2015) Autoimmune Diseases of the Innate and Adaptive Immune System including
Atopic Dermatitis, Psoriasis, Chronic Arthritis, Lyme Disease, and Alzheimer’s Disease. Immunochem
Immunopathol 1: 112;

◼ Alaedini, A., et al. “Antibodies against OspA epitopes of Borrelia burgdorferi cross- react with neural
tissue.” J Neuroimmunol 159 (2005): 192–95

“Wisdom is the marriage of knowledge and
experience bound by compassion.”