Dr. Shoemaker: Deficits In Cognitive Functioning

Discussion in 'Fibromyalgia Main Forum' started by Khalyal, Apr 17, 2009.

  1. Khalyal

    Khalyal New Member

    Dr Ritchie Shoemaker made a brilliant presentation at the 2009 IACFS/ME conference in Reno, which basically lays out the fundamentals. No more guesswork.
    When C4A complement Activation factor shoots through the roof after a known exposure to mold toxins, unrestrained cytokine response is now a measurable
    immune abnormality.

    Now it remains for "CFS researchers" to take an interest in those of us who have always been interested in "The Mold Connection to Illness".

    Background: Our understanding of the pathophysiology of human illness acquired following exposure to the interior environment of water-damaged buildings (WDB-illness) has been transformed over time by advancements in unveiling the role of innate immune mechanisms contributing to human illness (1, 2, 3, 4). Initial emphasis on mycotoxins alone as causative agents of WDB-illness has given way to recognition that multiple members of the indoor microbial world make toxins and other antigenic compounds that initiate inflammation and cause illness (5, 6). Recognition of the “chemical stew” that exists as a unique ecosystem inside WDB, with multiple elements capable of initiating multiple interacting cascades of host responses through differential gene activation and activation of innate immune responses following pattern recognition of microbial antigens now dominates current literature on WDB-illness.

    Fundamental to the ultimate target of the research effort to define WDB-illness is a need to explain (i) the genetic basis of differential susceptibility to initial illness (ii) absence of recovery following removal from exposure and (iii) accentuated inflammatory responses (“sicker, quicker”) seen in those previously ill but then re-exposed to WDB. Results of research in WDB-illness now implicate physiologic mechanisms including capillary hypoperfusion and chronic inflammatory response syndromes (CIRS) demonstrated in affected patients but not in controls (7). Understanding the basis of capillary hypoperfusion and CIRS has already led to better understanding, treatment and prevention (primary and secondary) of WDB-illness (8).

    Previously presented data on WDB-illness supported the role of capillary hypoperfusion induced by innate immune responses as a basic physiologic mechanism in the illness (8). Application of the recognition of capillary hypoperfusion could provide data to support use of diagnostic markers for impaired executive cognitive function using magnetic resonance spectroscopy measurements of lactate, and the ratio of glutamate to glutamine (G/G) in the selected areas of the brain. Prior work from this site (8, 9) marked CIRS by the near-universal deficiency of regulatory neuropeptides melanocyte stimulating hormone (MSH) and vasoactive intestinal polypeptide (VIP), as well as reduction of ADH response to hyperosmolality and reduction of VEGF which in turn is correlated with low VO2 max seen on pulmonary stress testing. Elevated levels of C4a; MMP9 and autoimmune markers of antigliadin and anticardiolipins in CIRS have been identified. Clotting abnormalities are not uncommon in CIRS. This occurrence may correlate with commonly observed clinical problems of hemoptysis and epistaxis in cases.

    TGF beta-1 has provided a new window of opportunity to study abnormal T-regulatory cell function and autoimmunity in this illness as well as the unexplained occurrence of unusual rheumatologic syndromes often seen in WDB-illness (9). The newer understanding of innate immune responses is bringing salutary new therapies to patients previously disabled by WDB-illness. Here we present a database on 1000 consecutive patients (850 WDB-illness cases; 150 controls) seen since 2007 at one site.

    Methods: Our first major hypothesis was (1) the same differences documented previously between symptoms, VCS, HLA, MSH, ADH/osmolality, ACTH/cortisol, MMP9 between cases and in controls would be replicated; our second major hypothesis was (2) elements of activated innate immune response known to reduce capillary perfusion, i.e. low VEGF, high C4a and high TGF beta-1 would be enhanced in cases compared to controls. Our minor hypothesis predicts (2a) differences between cases and controls would be highly associated with HLA DR haplotype. If (2b) TGF beta-1 were elevated, we would see evidence of abnormal T regulatory cell function as manifested by increased presence of autoimmunity. Finally, minor hypothesis (2c), if C4a were elevated, we would see the same elevation of lactate in frontal lobes and hippocampus and reduction of G/G ratios as seen on MR spectroscopy previously that in turn would correlate with symptoms of executive cognition impairment recorded on a severity scale of 0 to 4, with zero being absent and 4 being severe.

    1000 consecutive adult patients seen at a single medical clinic site signed IRB- approved HIPAA waivers (Copernicus IRB, Cary, NC) that permit use of baseline data in research studies. Patients were labeled as being a case if they met a restrictive, two-tiered case definition for WDB-illness published previously (2). Controls were identified as patients coming to the site for well adult physical exam without known untreated acute or chronic illness. Data was extracted from charts retrospectively including symptoms (individual, from a roster of 37; and total); visual contrast sensitivity testing (VCS); lab studies: HLA DR by PCR, MSH, VIP, leptin, ADH/osmolality, ACTH/cortisol, MMP9, PAI-1, CBC, CMP, CRP, ESR, lipid profile, testosterone, DHEAS, androstenedione, GGTP, VEGF, erythropoietin, ACLA (IgA, IgM, IgG), AGA (IgG, IgA), TGF beta-1, C3a, C4a, IgE, TSH, von Willebrand’s (vWF) profile; and deep aerobic nasal culture were also compared for cases compared to controls. MR spectroscopy data on N-acetyl aspartate, choline, creatinine, myoinositol, lactate and ratio of glutamate and glutamine (G/G) measured in left and right frontal lobes and hippocampus were also analyzed. Individual measurements and test results were compared using two-sample T-test.

    Patients were excluded from the data set if they had untreated, active alcohol abuse with abnormal liver functions, ongoing cocaine use, uncontrolled diabetes, anemia, active hepatitis, occupational exposure to hydrocarbons, petrochemicals, metal fumes and metal dusts as well as undiagnosed neurologic conditions. Individuals requiring acute intervention for illness other than that acquired from WDB were excluded.

    Results: There was no difference between groups in gender, age or ethnicity. Mean total symptoms were 21.4 in cases and 2.6 in controls. 37 individual symptoms were assessed in all patients (N= 1000); results for all symptoms were all different in cases compared to controls except for sinus congestion (p=.137) and tremor (p=0.0064). VCS was different in cases from controls in all frequencies tested, as shown by multivariate analysis; visual acuity was no different. Six HLA DR haplotypes were present in cases compared to controls with relative risk > 2.0 for 4-3-53; 7-2-53; 11-3-52B; 13-6-52A; 14-5-52B; and 17-2-52A. Labs with no differences (p > 0.001; N=1000) between cases and controls were leptin, PAI-1, CBC, CMP, CRP, ESR, lipid profile, testosterone, DHEAS, androstenedione, GGTP, erythropoietin, C3a, IgE, TSH. Labs with differences (p <0.001; N=1000) were MSH, VIP, ADH/osmolality, ACTH/cortisol, MMP9, VEGF, ACLA, AGA, TGF beta-1, C4a, vWF and presence of multiply antibiotic resistant, biofilm-forming coagulase negative staphylococci (MARCoNS) in deep aerobic nasal spaces. von Willebrand’s profiles were abnormal in 67% of patients compared to < 5 % of controls (p <0.001). There were statistically significant differences (p < 0.001) between cases (N=759) and controls (N=86) for lactate and G/G ratio, averaging a total of 5.2 abnormalities in eight measurements (added four each for lactate and G/G) in cases and 0.9 in controls. A weighted symptoms score (out of 24 possible) for six symptoms of executive cognitive function showed an average of 23, 20, 16 and 13 for the highest to lowest C4a quartile. NB: results table not presented.

    Discussion: Our major and minor hypotheses were confirmed.
    (1) Total and 35/37 individual symptoms, and VCS are again shown to be markedly different in cases compared to controls, with results essentially identical to prior published findings (1, 2, 3, 8, 9).
    (2) Markers of capillary hypoperfusion (C4a, TGF beta-1 and VEGF) from innate immune activation are present in cases but not in controls.
    (2a) Finding relative risk > 2.0 for haplotypes of patients, found in a total of 24% of well patients, replicates earlier published relative risks.
    (2b) TGF beta-1 elevation was associated with autoimmunity
    (2c) C4a elevation was associated with impairment of executive cognitive function.

    The result of untoward innate immune activation is systemic capillary hypoperfusion that can be measured directly in brain using CNS lactate and indirectly in lung using VO2 max and anaerobic threshold. It remains likely that the underlying reason for ongoing dysregulated innate immune response is deficiency of regulatory neuropeptides MSH and VIP, a finding seen in > 90% of cases (10). In control patients who invariably had normal MSH and normal VIP, increased TGF beta, high C4a or low VEGF is rarely seen. Deficiency of both MSH and VIP was not seen in controls but was common in cases. Given the not-infrequent history of epistaxis and hemoptysis in this cohort of WDB-illness patients the abnormal vWF findings are consistent with a similar acquired coagulopathy commonly seen in systemic inflammatory illness due to endotoxemia (12).

    Persistent elevation of C4a, an otherwise short-lived anaphylatoxin, suggests ongoing activation of mannose binding lectin pathway of complement activation, thought to be due to ongoing autoactivation of the enzyme MASP2 (14), continuing despite absence of an environmental source of antigenic stimulus of the MBL pathway.

    Studies of WDB-illness patients have noted neurologic symptoms (5), but other than hyperacute trials of re-exposure, in which rising C4a correlates with increasing cognitive dysfunction (7, 8), no studies have been published that document a mechanism of illness acquisition. Finding the clear link between peripheral inflammation (i.e. rising C4a) and central metabolic disturbances (elevated lactate) provides a plausible mechanism of hypoperfusion to explain cognitive impairment. Unpublished studies presented previously confirm that reduction of C4a alone, using low dose erythropoietin injections, simultaneously resolves the CNS hypoperfusion and cognitive symptoms (13).

    Conclusions: These results are consistent with the hypothesis that WDB-illness is a CIRS with ongoing capillary hypoperfusion. Symptoms taken as a whole create a distinct cluster that classifies cases accurately without providing mechanisms. Lab results show a dense, unregulated innate immune inflammatory response without yielding symptoms. Linking labs and symptoms, especially when linked together with VCS, a neurotoxicologic measure; provides a landscape approach to a definable illness seen repeatedly in WDB-illness patients.

    Treatment of this complex syndrome will involve sequential (1) removal from exposure; (2) correction of toxin carriage, using VCS monitoring to assess endpoints; (3) eradication of biofilm-forming MARCoNS; (4) correction of elevated MMP9; (5) correction of ADH/osmolality; (6) correction of low VEGF; (7) correction of elevated C4a (8) reduction of elevated TGF beta-1 and (9) replacement of low VIP. Each of these steps using FDA-approved medications is available to practicing physicians.

    1. Shoemaker R, House D. A time-series of sick building syndrome; chronic, biotoxin-associated illness from exposure to water-damaged buildings. Neurotoxicology and Teratology 2005; 27(1) 29-46.
    2. Shoemaker R, Rash J, Simon E. Sick building syndrome in water-damaged buildings: Generalization of the chronic biotoxin-associated illness paradigm to indoor toxigenic fungi; 5/2005; Pg 66-77 in Johanning E. Editor, Bioaerosols, Fungi. Bacteria, Mycotoxins and Human Health.
    3. Shoemaker R, House D. SBS and exposure to water damaged buildings: time series study, clinical trial and mechanisms. NTT 2006; 28: 573-588.
    4. Janeway, C. Approaching the Asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symposia on Quantitative Biology. 1989; Vol LIV: 1-13.
    5. Government Accountability Office 08-980; 10/08 Better coordination of Research on Health Effects and More Consistent Guidance Would Improve Federal Efforts
    6. Rao C, Riggs M, Chew G, Muilenburg M, Thorne P, Van Sickle D, Dunn K, Brown C. Characterization of airborne molds, endotoxins, and glucans in homes in New Orleans after Hurricanes Katrina and Rita. Applied and Environmental Microbiology 2007; 73(5): 1630-1634
    7. AIHA continuing education program Round Table, Minneapolis 6/2/08; R Shoemaker, S Vesper, G Boothe, G Cormier, K Lin co-panelists. Integrating Field, Laboratory and Clinical data for the IAQ investigation. Comparison of indices of human health and building healthy: SAIIE meets ERMI.
    8 Shoemaker R. Sequential upregulation of innate immune responses during acute acquisition of illness in patients exposed prospectively to water-damaged buildings. ASTMH 11/07, Philadelphia, Pa
    9. Shoemaker R. ASTM International, Section D22, Boulder Colorado 7/27/06. “Defining causality of a biotoxin-associated illness by exposure to water-damaged buildings: a case control series.”
    10. Vignali D, Collison L, Workman C. How regulatory T cells work. Nature Reviews Immunology 2008; 8: 523-532.
    11. Brozska T, Luger T, Maaser C, Abels C, Bohm M. Melanocyte stimulating hormone and related tripeptides; biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune–mediated inflammatory disease
    12. Rittirsch D, Flieri M, Ward P. Harmful molecular mechanisms in sepsis. Nature Reviews Immunology 2008; 8: 776-787.
    13. Shoemaker R. Correction of central nervous system metabolic abnormalities, deficits in executive cognitive functioning and elevated C4a: a clinical trial using low dose erythropoietin in patients sickened by exposure to water-damaged buildings. 1/14/07 IACFS, Fort Lauderdale, Florida.
    14. Wallis R, Dodds A, Mitchell D, Sim R, Reid K, Schwaeble W. Molecular interactions between MASP-2, C4, and C2 and their activation fragments leading to complement activation via the lectin pathway. J Biol Chem 2007; 282: 7844-51.
  2. Khalyal

    Khalyal New Member

    to take away from this is that there is a measurable immune abnormality, and that Dr. Shoemaker believes this to be important to the CFS community.

  3. TeaBisqit

    TeaBisqit Member

    I'm surprised doctors don't take mold seriously. Mold spores can do alot of bad things. People always forget about what happened when archeologists opened King Tut's tomb and they all ended up dying from mold spore poisoning. But it wasn't fast. They found that it lingered in their systems for up to a year and a half.

    I do get worse if mold is around. When I have to do my laundry in the basement of my apartment building, it flares me up like crazy. And I no longer go to a library. The public library is so full of moldy old books, I just die if I walk in there.
  4. Khalyal

    Khalyal New Member

    Trichothecene mycotoxins are able to activate immunological pathways in the human brain-capillary endothelial cells (HBCEC).
    Continuous exposure keeps these pathways open on a constant basis, which can compromise the integrity of the blood-brain barrier
    (BBB). The BBB is a cellular structure in the central nervous system (CNS) that alters the permeability of brain capillaries, keeping
    various chemicals, bacteria, and other microscopic substances from passing between the blood stream and actual neural tissue.

    A damaged BBB would then allow other harmful agents to pass. This may make a mold-toxin victim more susceptible to Lyme disease
    and other unwanted invaders, and increase the risk of neural damage due to the constant activation of immune response.

    Astrocytes are cells in the brain and spinal cord. They perform many functions, one of which is biochemical support of endothelial cells.
    Endothelial cells are the cells that form the BBB. Astrocytes also provide nutrients to the nervous tissue.

    Once the HBCECs are damaged by the T2 toxins, the toxins and other agents would come into contact with astrocytes. The effects of
    toxins on astrocytes can lead to the cell-death of the astrocytes.

    The toxins then have direct contact with the neural tissue. This kicks off another increase in immune-response
    activity. Without the protection of the astrocytes, neurons can enter programmed cell-death.

    The immune system has two types of cells, T helper cells 1 and 2. Th1 works against intra-cellular pathogens (i.e. pathogens that work
    inside the cell) such as virus, cancer, yeast and intra-cellular bacteria like mycoplasma and chlamydia pneumonia. Th2 works against
    extra-cellular pathogens in blood and other fluid, such as allergens, toxins, parasites and bacteria (normal extra-cellular bacteria).

    'CFS' causes a switch in the immune system, away from Th1. Th1 cells are suppressed and Th2 cells are activated. 'CFS' patients
    have more Th2 cells than Th1 cells. They also typically have low natural killer (NK) cells, the weapons of the Th1 system, and high
    white cells and antibodies, the weapons of the Th2 system. In other words, the anti-viral immune system is suppressed, while the
    antibody-mediated anti-bacteria, anti-allergen etc, system is activated. So CFS patients over-respond to allergens, toxins etc, and
    under-respond to viruses etc.
  5. simonedb

    simonedb Member

    what has worked for you?

    Also, I know this probably isnt the appropriate tests, but I had the tests that de merleirer and i think peterson recommend, the redlabs, and the interesting thing was my elastase, nkc and immunobilian were all problematic showing immune problems but the thing that measure inflammation, ugh brain dead today, what was that, interleukins maybe? was relatively normal, which my local doc thought was weird, he expected to see inflammation along with the other abnormalities.
    do you know if that has relevence for the inflammation being talked about in shoemakers theory?
    Is there anywhere that breaks this down in laymen's terms better, my brain is so tired of trying to read and decipher and then incorporate new ideas in its compromised state, what a quandry!
    [This Message was Edited on 04/18/2009]
  6. Forebearance

    Forebearance Member

    Thanks for sharing this!

  7. Khalyal

    Khalyal New Member

    Dr. Shoemaker says:

    Treatment of this complex syndrome will involve sequential
    (1) removal from exposure;
    (2) correction of toxin carriage, using VCS monitoring to assess endpoints;
    (3) eradication of biofilm-forming MARCoNS;
    (4) correction of elevated MMP9;
    (5) correction of ADH/osmolality;
    (6) correction of low VEGF;
    (7) correction of elevated C4a
    (8) reduction of elevated TGF beta-1 and
    (9) replacement of low VIP. Each of these steps using FDA-approved medications is available to practicing physicians.

    Note that removal from exposure is the first step. That's essential. For the rest, Dr. Shoemaker is the man, and one thing you can do is find a local doctor who will work with Dr. Shoemaker. But Removal From Exposure is the biggest thing you can do for yourself.

    Dr. Shoemaker has a website at http://www.chronicneurotoxins.com/

    What I did was really extreme, but then again so was my illness. I gave up on trying to live in or remediate the house. Cleaning up mold, replacing moldy construction, really doesn't matter once the toxins have been released. The toxins are independent of the life cycle of the mold. They are not dead, so you cannot kill them. They bind at a submolecular level, so cleaning is ineffective. They take years to denature.

    Trying to live with that was impossible for me. I moved, got rid of almost everything, put the rest in storage, and keep a vehicle for escaping whatever area I'm in if a mold plume blows through.

    I'm not offering that as advice. I'm just saying what worked for me, and continues to work if I'm careful. Beats being bedridden.

  8. simonedb

    simonedb Member

    I would bet money tht I dont have black mold in my house, but did have a little water exposure in basement last year after heavy rains and lots of snow in winter melted, the water came up thru the floor of concrete cus area so saturated. didnt get on any wood or drywall. so I assumed that shouldnt have caused a big problem? it did get some of my lp records damp though and i put them upstairs to dry cus couldnt bear to part with them (I mean like original t.rex, beatles, clash, red hot chili peppers....what are ya gonna do?) but I am reconsidering my attachment to material things if its possibly hurting my health. tough one to decide. I admire your committment, but money is a factor too, do you have a trust fund or something? Perhaps I will get rid of or sell my junk, rent my house.......hmmm but couldnt keep part time job unless found a place to live and in areas where it snows and get cold you have to be indoors---whats the safest sort of envmt inside for that to avoid mold?
    [This Message was Edited on 04/19/2009]
  9. Khalyal

    Khalyal New Member

    lol! No, no trust fund. I'm broke. Gave up my house, cars, everything to make this happen. As I said, I'm not giving advice. Bought a $500 car that was clean and pristine, pay rent to someone to let me live in their house, got rid of almost everything else.

    I chose my living arrangement carefully, making sure I had the desert at my back for instant escapes. I sleep in the car in the desert sometimes, when a wind pushes a mold plume through. My commitment is simple. I just wanted to stop feeling like crap, really badly.

    The problem with mold toxins is that they have little to do with the lifespan of the actual mold. You don't necessarily have to have black mold in your house to be sick from it. Your neighbor might have it, for instance. The toxins travel away from the mother colony on spores, but even more important, for every spore there are 500 plus microparticulates, equally as toxic. That's dust, and it can spread or become airborne easily. The toxins are carried and whatever the particulates land on is fair game. The toxins quite easily separate from the particulates and bind at a submolecular level to whatever they land on.

    It's a tough concept, and one that has nothing to do with mold allergies or the actual presence of visible mold. But it's becoming more and more common as sick buildings pop up all around us, and as formaldehyde, pesticides, and other toxins become staples in the diet of the mold itself.
  10. QuayMan

    QuayMan Member

    Haven't had a chance to read the whole thread yet but found the Shoemaker presentation fascinating.
  11. mezombie

    mezombie Member

    Once more, you rock Khaly!

    Bumping this for others to read.
  12. skeptik2

    skeptik2 Member

    this is amazing information, khalyal. It was hard to get thru but when I got to the results and how abnormal they were, I cheered! forgive me; I was just so happy that your mold illness was so strongly validated!

    Are you going to be able to get the care Dr. Shoemaker recommends? How I hope so!

    You summarized the treatment plan beautifully, as usual..

  13. Khalyal

    Khalyal New Member

    Thank you guys! I appreciate the encouragement. Shoemaker obviously felt that this information was relevant to the CFS community, as he gave this presentation at the IACFS/ME conference. My personal feeling on it is that the mold toxins, for an extreme reactor anyway, enable reactivation of whatever latent viral intrusions we carry, whether it be hhv6-a, ebv, or perhaps cytomegalovirus..

    I hope to be able to get this care. I am working with my local GP, who admits to knowing nothing of this, but is very amenable to working with Shoemaker to make things happen. It actually encourages me that she freely admits her lack of knowledge but expresses no skepticism whatsoever, only willingness to learn.

    In the meantime, learning biological warfare-type evasion tactics has helped tremendously!