What it is What it isnt Marianne J. Middelveen, Mdes Raphael B. - - PowerPoint PPT Presentation

Morgellons Disease: What it is What it isn’t

Marianne J. Middelveen, Mdes Raphael B. Stricker, MD

When you hear hoof beats think . . . .

Horses Zebras Unicorns

Disclosure Statement

Speaker: Marianne J. Middelveen, Mdes

Consultant Microbiologist Atkins Veterinary Services

Has completed commercial bias disclosure forms and does not have any conflicts of interest.

Definition

Morgellons disease (MD) is a dermatologic condition associated with spirochetal infections – mostly Borrelia

• spp. – and other co-infections. It is

characterized by spontaneously- appearing, slowly-healing, ulcerative, filamentous skin lesions, that may be accompanied by stinging or crawling

• sensations. The key diagnostic criterion

is the presence of colored filaments (mostly white, blue or red) that protrude from or are embedded in skin.

• 1643 – Sir Thomas Browne’s

monograph described an illness, in which coarse black hairs emerged from the skin.

• 1544 to 1884 – Kellet summarized

Browne’s and other historical accounts – scientists debated if “hairs” were animate or inanimate.

1682 – drawing by

• Dr. Michel Ettmuller

“Inanimate, Levenloos”

Father of Microbiology

History

Sir Thomas Browne

History

• 1894 – Thibierge – case

studies of “acarophobia”, erroneous and unshakeable beliefs of skin infestation by parasites.

• 1902 to 1938 – sporadic

cases of “parasitophobias” or “dermatological hypochondriasis”.

History (continued)

• 1935 – French physician, Vié reported

6/8 subjects in his case studies had syphilis.

• 1938 – Dr. Karl Ekbom – published

seminal studies of delusionary parasitosis – patients had movement sensations and false belief of insect

• infestation. Ekbom reported that 3/7

subjects had syphilis, and mentioned self-collected specimens with “sand” and “little hairs”.

• 1946 – Wilson and Miller, coin term

“delusions of parasitosis” (DOP) for such cases.

Treponema pallidum spirochetal agent

• f syphilis
• Dr. Karl-Axel Ekbom

History (continued)

• 2001 – Biologist Mary Leitao, saw fibers in

her son’s skin, named the condition MD based on similarity to Browne’s description.

• 1983 – Lyell named the presentation of

specimens “the matchbox sign”.

• 2005 – Leito teamed up with

sympathizers, founded MRF (defunct).

• 2009 – Delusional Infestation (DI)

proposed for MD.

• 2006 – CEHMDF founded.
• 2001 – to date: Polarized view of

MD etiology: delusion vs. infection.

1st Conference CEHMDF Cindy Casey Holman RN, Charles E Holman Matchbox and skin specimens Mary Leitao with her children

fakenews.com

Morgellons disease (MD) proposed etiologies

Hypotheses Supportive evidence

Delusional disorder/Textile fibers. Peer-reviewed medical literature. Infectious etiology/ Biofibers of human origin. Peer-reviewed medical studies. Infectious etiology/ Filamentous organisms i.e. molds, insects, worms. Speculation, no evidence. Extraterrestrial origin/ Mystery fibers. Fantasy, no evidence. Bioengineering by nanites etc. / Man-made filaments. Fantasy, no evidence. Toxins/Filaments of silicone, dental adhesive, chemtrails, GMOs, mercury etc. Fantasy, no evidence.

ucmp.berkeley.edu mst3k.wikia.com

Infection

The dark horse

Delusion

The favorite

• Caused by mental illness
• Lesions self-inflicted
• Fibers are textile
• Claim patients have fixed

delusional belief of parasite or fiber infestation

• Caused by infection
• Lesions spontaneous
• Fibers are biofibers
• Neuropsychiatric

symptoms occur, but are secondary to infection VS

• Review article
• History of DOP and MD
• Examines evidence supporting Infectious etiology
• Refutes evidence supporting the DOP hypothesis

Borrelia spirochetes MD skin section

Over 50 articles support delusional parasitosis (DP) or delusional infestation (DI) etiology of MD

• Case studies: ~18 studies, diagnose delusional mental illness contrary

to the American Psychiatric Association’s DSM-5, used inappropriate case definitions, inadequate laboratory analysis, none of the studies used methods appropriate to find borreliosis.

• Original research: 4 key studies, 3 retrospective analyses by the Mayo

Clinic, and 1 collaborative study by Centers for Disease Control and Prevention (CDC) and Kaiser Permanente (KP), all failed to perform lab analysis to detect spirochetes/borreliosis, all had flawed case definitions; fiber analysis was flawed and included analysis of contaminating cotton fibers.

• Opinion articles: ~27 articles that are opinion-

based and that offer little or no original research evidence.

PubMed search 2009-2018:

Image: healthymind.com

• false beliefs
• incorrect

interpretation of external reality

• firmly held despite

what most others believe to be true

• maintained

despite incontrovertible and obvious proof to the contrary, even to the point

• f being absurd

Delusions

Delusions are:

• true
• bservation

s

• overvalued

ideas

• mistaken

beliefs Delusions are not: Delusional disorder somatic type should not be diagnosed when there is an underlying medical conditions such as an infection.

Studies that support an infectious etiology

PubMed search 2009-2018:

• ~13 articles total
• 3 are reviews, 2 of which present

new previously unpublished evidence

• 6 original research, 5 of which

involve larger cohorts

• 4 opinion

Borrelia burgdorferi1,2,3,4,5,6,7 Borrelia garinii 1,4 Borrelia miyamotoi1 Borrelia hermsii 1,4

• 1. Australian Biologics, Sydney
• 2. University of New Haven
• 3. Oklahoma State University
• 4. IGeneX Reference Laboratory
• 5. Mount Allison University
• 6. Perkin Elmer
• 7. McClains

Borrelia Spirochetes

• Most consistent pathogens found
• Borrelia burgdorferi sensu stricto and sensu lato strains
• Also Relapsing Fever Borrelia spp.
• 7 labs detected DNA using 3 methodologies

• Cohort of 25 subjects
• Visual, antigenic, and genetic confirmation
• f borrelial spirochetes
• Detection directly in skin and in cultures

from skin and fluid (detected viable

• rganisms)
• Different detection methods from

independent laboratories provided corroborative evidence

• Evidence suggests causality

Evidence of Spirochetal infection Electron Microscopy:

• Samples for scanning electron

microscopy (SEM) and transmission electron microscopy (TEM) were forwarded to the Electron Microscopy Facility, Department of Materials Science and Engineering, Clemson University, Anderson, South Carolina.

• Spirochetes were detected in

submitted samples – both in tissue and cultures.

SEM – skin culture

TEM – callus section

Spirochetes (dark brown/black) detected in Dieterle-stained histological sections of Morgellons tissue

• Warthin-Starry and Dieterle stains are

standard silver nitrate stains used to detect spirochetes.

• Skin and/or culture specimens were

fixed and processed for silver nitrate staining at Interscope Laboratories, Canoga Park, CA (ISL) and McClain Clinical Laboratories, Smithtown, NY (MCL).

• Subjects that have more severe

lesions have larger spirochetal load.

Silver Nitrate Stains

Dieterle-stained cultured spirochetes

McClain Labs

Borrelia immunostaining – skin tissue and culture

Helical spirochete MD histological section – callus Helical spirochete MD vaginal culture Immunostain MD callus section.

University of New Haven

Single spirochete Immunostain MD skin culture.

Photos: Divya Burugu, University of New Haven

Bb immunostaining controls

Human psoriasis skin

Human skin with normal bacterial flora

Positive control Bb B-31 in human plasma Gram-negative coliforms Gram-positive cocci Not detected in skin without MD pathology

PCR

• Skin from asymptomatic

healthy people

• Normal human foreskin
• Normal skin from Morgellons

patients

• Cultures from normal healthy

controls

• Distilled water

Negative controls Experimental specimens

• 29 positive specimens (skin

and cultures) from 20 subjects

• 5 positive skin cultures
• 13 dermatological

specimens

• 15 confirmatory sequences

Molecular Probes: Bb DNA Hybridization Culture and tissue

Top – MD tissue Fla B probe. Bottom – MD tissue Probe 740.

• Probe FlaB – derived from the Bb

flagellin B gene, and Probe 740 – derived from a Bb inner cell membrane protein.

• Nucleotide Basic Local Alignment

Search Tool (BLASTn) disclosed no matches to either probe other than those of corresponding Bb gene sequences.

Probes donated by Dr Alan MacDonald

Staining, MCL

• Visual confirmation of the

presence of Borrelia DNA in tissue with Morgellons pathology, but not in controls

DNA Detected in Morgellons samples by PCR and confirmed by sequencing,

Treponema denticola1,3 Bartonella henselae3,4 Helicobacter pylori 2,3

• 1. Australian Biologics, Sydney
• 2. University of New Haven
• 3. Oklahoma State University
• 4. IGeneX Reference Laboratory

5 Mount Allison University

OTHER PATHOGENS

https://www.researchgate.net www.igenex.com

Rickettsia spp. 5

Filaments

Blue Red Key diagnostic criterion MD filaments are biofibers of human origin, composed of structural proteins.

Filament Composition and Origin

Filaments are nucleated at the base of attachment and are continuous with surrounding cells. Nuclei are stained blue. Gömöri trichrome stain – filaments are collagen and keratin produced by epithelial cells; they are not textile fibers. Keratin is stained red and collagen is stained green.

Collagen

Nucleation at base

Fiber Coloration

Blue Red

Fontana Masson stain Positive for melanin

Fontana Masson stain Negative for melanin Prussian blue stain Negative for iron

Color origin unknown

Independent Analysis Blue Fibers

Hair-like strands

Shawkey M. University of Akron. Department of Biology. 2013-2014. Personal communication (SEM) MD filament Cuticular scaling

Photo: Liliana D’Alba

(TEM) MD fiber cross section Irregular medulla Melanin granulation

Photo: Liana D’Alba

Raman spectroscopy relevant peaks indicative of melanin aromatic rings

Some blue fibers are very small hairs!

Abnormal keratinization

• Comedo-like keratinized

plugs that form within a pore.

• Can have attached

unusual filamentous growths.

• Filaments that form

within a confined space can be tightly wound into a wad.

• These plugs indicate a

defect of follicular keratinization.

• Sand-like particles

• Hyperkeratotic

follicular casts around a hair bulb or follicle.

• Can have downward

growing hairs.

• Can have unusual

filamentous attachments.

• Filaments that form

around sheath within a confined space can be tightly wound into a wad.

• Sectioned – contains

keratin (red) and collagen (green).

Borrelia association demonstrated in studies

• Savely VR, Stricker RB. Clin Cosmet Investig Dermatol. 2010 May 13;3:67-78.
• Middelveen MJ, et al. BMC Dermatol. 2015 Feb 12;15:1.
• Fesler MC, Middelveen MJ, Stricker RB. Clinical evaluation of Morgellons disease

in a cohort of North American patients. Dermatol Reports. 2018; 24;10(1):7660.

Morgellons Study Cohort size % with LD Methodology Savely & Stricker, 2010 122 96.8 Serology and clinical diagnoses Middelveen et al, 2015 25 100 Culture and detection in tissue/fluids – visual, DNA, and antigen detection Fesler et al, 2018 60 100 Serology Fiber section

Immunostained borrelial spirochetes

Spirochetes are visibly associated with fibers

6% of Lyme disease patients have

• r develop

Morgellons disease

6 % Morgellons

4-31% 5-10% 30-80 % 50% 60-70% 54%

https://www.lymedisease.org/lyme-basics/lyme-disease/symptoms/ https://www.sciencedirect.com/science/article/pii/S1201971212012672

1. 2.

Fesler MC, et al. Clinical evaluation of Morgellons disease in a cohort of North American patients. 2018; 24;10(1):7660.

Distribution of Morgellons?

Distribution of B. hermsii Distribution of human Lyme disease cases

• Geographic area of infection may differ

from area where symptoms develop

• Symptoms may develop long after infection
• Secondary factors implicated
• Multiple Borrelia species implicated
• Bias in voluntary reporting
• Distribution maps are not accurate
• Reported canine Lyme cases differ

• A skin condition

analogous to Morgellons was reported in 9 dogs.

• The dogs had

borreliosis and colored collagen skin fibers.

• An analogous condition

in animals strengthens evidence of a causal relationship.

Filament formation associated with spirochetal infection: a comparative approach to Morgellons disease Similarity to an animal disease, bovine digital dermatitis (BDD), provided clues and suggested a spirochetal etiology.

Middelveen MJ, Stricker RB. Clin Cosmet Invest Dermatol. 2011; 4: 167-177.

Lesions on heel bulb have unusual keratin

• projections. Treponemes are abundant in

diseased tissue. Experimental infection of calves with pure cultured treponemes caused disease.

Spirochetes

Keratin filaments

Infections causing keratin proliferation

• 1. EBV – oral hairy leukoplakia.
• 2. Cholesteatoma of the ear –

probable multiple bacteria and inflammation.

http://www.entnet.org/content/cholesteatoma

Luana et al. Int J Dent. 2017

• 1. Georgilis K, Peacock M, Klempner MS. J

Infect Dis. 1992;166(2):440–444.

• 2. Klempner MS, Noring R, Rogers RA.. J Infect
• Dis. 1993;167(5):1074–1081.
• 3. Chmielewski T, Tylewska-Wierzbanowska
• S. 2010;59(3):157–160.
• Borrelia spirochetes can invade

both keratinocytes and fibroblasts

• Intracellular infection increases

resistance to antibiotics and contributes to immune evasion

Borrelia co-cultured with fibroblasts induces an upregulation of collagen and growth factor mRNA.

Collagen in MD skin Most MD fibers are collagen

• New multisystem illness (skeletal, neurological and cardiac systems)

associated with a bull’s eye skin rash was reported.

• Geographic clustering, rural setting, suggested arthropod vector.
• 3 positive spirochetal cultures from skin, blood, and CSF from 142

samples taken from 56 subjects.

• 2 positive cultures from 110 ticks Ixodes dammini (I. scapularis).
• Serologic evidence – 40 patients with EM rash 90% IgM positive; 95

patients with later illness 94% IgG.

• Cultures characterized by immunostaining, no DNA evidence.
• Concluded that the spirochete was the etiologic agent.

Allen C. Steere, MD

The Obvious Horse

• Relapsing Fever is a neglected disease, that occurs

in temperate and tropical countries, causing illness in five out of seven continents. Estimated number of cases are unknown.

http://myvirtualcontent.me/

• Over 300,000

people in the USA are diagnosed with Lyme disease each year.

• More than 360 000

cases of Lyme disease have been reported in Europe

• ver the last two

decades.

Is the Dark Horse

We are not delusion al!

Acknowledgements

• Thanks to Cindy Casey and all at the Charles E. Holman Morgellons

Disease Foundation, and Dr. Carsten Nicholas and all at the BCA- Augsburg.

• Thanks to my co-authors and collaborators including: Dr. Raphael

Stricker, Melissa Fesler, Dr. Eva Sapi and her research group at University of New Haven, Jennie Burke and all at Australian Biologics, and Dr. Peter Mayne.

• Thanks to Dr. Jyotsna Shah and IGeneX labs, and Dr. Vett Lloyd and

Julie Lewis at Mt Allison University, for collaboration and helpful discussion.

• Thanks to Drs. Virginia Savely and Randy Wymore for their pioneering

work on this disorder.

• Thanks to all the Morgellons patients who generously provided

samples and shared their knowledge of Morgellons disease.

1. Aberer E, Surtov-Pudar M, Willfinger D, et al. Arch Dermatol Res . 2018. 310(2):117-126 2. Chmielewski T, Tylewska-Wierzbanowska S. Pol J Microbiol. 2010;59(3):157–160. 3. Ekbom KA. Acta Psychiatr Scand. 1938;13:227–259.

• 4. Fesler MC, Middelveen MJ, Stricker RB. Dermatol Reports. 2018 Apr 24;10(1):7660.
• 5. Freudenmann RW, Lepping P, Clin Microbiol Rev. 2009; 22(4): 690-732. doi:
• 6. Georgilis K, Peacock M, Klempner MS. J Infect Dis. 1992;166(2):440–444
• 7. Greenhalgh T. BMJ.1997;315
• 8. Kellett CE. Ann Med Hist. 1935;7:467–479.
• 9. Klempner MS, Noring R, Rogers RA. J Infect Dis. 1993;167(5):1074–1081.
• 10. Lloyd V. Mount Allison University. Personal Communication. 2017.
• 11. Lopez JE, Krishnavahjala A, Garcia MN, Bermudez S. Vet Sci. 2016 Sep; 3(3):
• 16. Published online 2016 Aug 15
• 12. Luana et al. Int J Dent. 2017
• 13. Mayne PJ. Int J Gen Med. 2014 Dec 23;8:15-26

References

References

• 13. Mayne P, English JS, Kilbane EJ et al. F1000Research 2013, 2:118 Middelveen
• 14. Middelveen MJ, Stricker RB. Clin Cosmet Invest Dermatol. 2011; 4: 167-177.
• 15. Middelveen MJ, Rasmussen EH, Kahn DG, Stricker RB. 2012; J Clin Exp Dermatol Res

3:140.

• 16. Middelveen MJ, Mayne PJ, Kahn DG, Stricker RB. Clin Cosmet Invest Dermatol.

2013; 6: 1–21.

• 17. Middelveen MJ, Poruri A, Mayne PJ, et. al . 2013; J Invest Med. 2013; 61(1): 225.
• 18. Middelveen MJ, Burugu D, Poruri A et al. F1000Research. 2013 2:25.
• 19. Middelveen et al. BMC-Dermatology. 2015; 15:1
• 20. Middelveen MJ, Stricker R. Int J Gen Med. 2016;9:349-352.
• 21. Middelveen MJ, Rotaru GM, McMurray JL et al. J Vet Sci Med Diagn Vol: 5 Issue: 6.
• 22. Savely VR, Stricker RB. Clin Cosmet BInvestig Dermatol. 2010; 3:67-78.
• 23. Savely VR, Leitao MM, Stricker RB. Am J Clin Dermatol. 2006;7(1):1-5.
• 24. Shah JS. 9th Annual Medical-Scientific Conference on Morgellons Disease; April

30–May 1, 2016; Austin, TX.

References

• 25. Steere AC, Grodzicki RL, Kornblatt AN, et al.N Engl J Med. 1983. Mar 31;308(13):733-40.
• 26. Stricker RB, Middelveen MJ: Psychosomatics. 2012; 53(5): 504-505.
• 27. Stricker RB, Johnson L. BMJ. 2000;335(7628):1008.
• 28. Talagrand-Reboul E, Byer PH, Bergström S, Vial L, Boulanger N. Front Cell Infect
• Microbiol. 2018 Apr 4;8:98.
• 29. Wymore R, Saylor-Hefley C, Charles E. Holman Foundation Conference on Morgellons
• Disease. Austin, TX. March 2015.

http://lymediseaseguide.net/maps-of-us-lyme-disease-cases https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6403a3.htm http://www.vetfolio.com/infectious-disease/how-global-warming-may-affect-the-prevalence-of- lyme-disease http://www.life.umd.edu/classroom/bsci424/BSCI223WebSiteFiles/KochsPostulates.htm https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589117/ http://cmr.asm.org/content/9/1/18.full.pdf+html http://www.entnet.org/content/cholesteatoma

Web References