Transcript of videotape of Dr Ritchie Shoemaker MD
Thank you Dr Cosama and good afternoon. It certainly is a pleasure to be here at the B B Lewes Center . The Delaware Medical Society, in association with the Thomas Jefferson Medical School was kind enough to allow me to talk about one of my favorite topics: this is new, emerging problems that we see routinely in our primary practices. This talk could have been, "It's a long way from Pocomoke" and in a way it has been. Four years of experience for a country family practice physician to learn what it's like with the big boys such as we have here today: sitting down, going one on one with people from the CDC and the NIH. It's interesting to see how much we have all learned about what is involved in the primary care world. It's fascinating to me that when we looked at the recent review from the National Health and Environmental Effects research lab - this is a US EPH facility down in North Carolina - that the reviewers suggest that the recent work that Dr Ken Hudnell who's a neurotoxicologist and I had been doing, if confirmed, was "perhaps the most significant ever to come out of a neurotoxicology lab." From Pocomoke and getting your toes in the mud, to the highest levels of peer review has been quite a ride.
When I look back on the last four years, my involvement started when some patients and friends started saying that they were getting sick, after they had been exposed to fish that had funny sores. The word Pfiesteria started creeping into the newspapers on a daily basis. How could so many people have symptoms that involved so many different organ systems at the same time? They did not get better, and the symptoms were so unusual and changed from day to day. What was going on? It turned out that Pfiesteria was just the window to a much larger field: the study many organisms that make neurotoxins that make us sick. I want to introduce you to the fact that you are seeing them every single day in your practice in one way or another. The difficulty in this field is that each new topic that comes up seems to me more controversial than the one the night before.
In this brief talk, I would like to take you on a quick tour of the diagnosis and treatment of neurotoxic mediated illnesses; I want to give you a little bit of environmental chemistry at the risk of speaking in front of Dr Werther and Dr Richards; I want to talk about a distinct grouping of symptoms that characterize these illnesses; I want you to know about a new biomarker, one that is at the bedside, that I want you to start using on a routine basis; I want to go on to talk about how to treat these neurotoxic illnesses quickly and efficiently. Finally, I want to take you to the world of super-family of nuclear receptors and introduce you to how to use PPAR-gamma to our great benefit: medicines that are now used to treat diabetes such as Actos and Avandia actually have many effects on PPAR-gamma, including down-regulation of cytokines like tumor necrosis factor alpha and, indeed, the receptor for tumor necrosis factor alpha. If I can make the pitch today to show you how we need to think differently, then I can work in a discussion of some of the antibiotics that we use routinely. Macrolides, in addition to being antibiotics, are also anti-inflammatory, not by acting on cyclo-oxygenase pathways but by an entirely new mechanism. Practising medicine involves learning something new every day, and often we have to throw out what we knew before and say "that was wrong".
Perhaps what I am telling you today, that is considered the cutting edge of neurotoxicology, will be thrown out next week or next year when we know more. It is a very fast-moving field.
The neurotoxins we talk about are not speculative: we know what they are. They are very small molecular-weight compounds. The Shiga toxins you may hear about from hamburgers that were not cooked well enough in the "jack-in-the-box" routine are 55,000 kilo-Daltons (KD). How about the Botulinum toxin, three times at large at 155,000 KD. The toxins I work with on a daily basis are much smaller, at 200-1000 KD. The small size and the molecular structure of these compounds allow them to move from cell to cell to cell, a property we call being an ionophore. As such, they have the capability of perpetual fat soluble distribution throughout our body. They are extravascular so that our immune response is cloaked and blood tests become unreliable for diagnosis. We therefore have to use the biochemical and biological effects of neurotoxins to show the presence. The critical issue in these NTS that I hope to show you is that they are the link between control of synthesis of inflammatory cytokines - not just TNF but interleukin-1, interleukin-1 beta, and interleukin-6 - and the balance of these redundant, mutually-overlapping communicating systems for cells talking to cells is fairly new. The first reference and landmark article on tumor necrosis factor alpha was published in 1989. Since then, in the past five years, there have been 10,000 references to TNF in the Index Medicus. This is a fast moving field, and no family physician or primary-care doctor can afford not to know about cytokines. What we have in the nucleus of a cell is a cloaked pistol, if you will, a compound called nuclear factor KB (NFKB) is held in abeyance as it is bound by a protein IKA. When a cell is exposed to a lipo-polysaccharide from a gram-negative rod or neurotoxin or some other compound, there can be a phosphate group put on to IKA which splits it off, releasing the nuclear factor to migrate to the nucleus. There it can bind to a switch, a factor that controls synthesis and transcription of a variety of genes. These genes are the cytokine, or pro-inflammatory cytokine genes. Following activation of the cytokine nuclear receptor, we can find increased levels of tumor necrosis factor mRNA adjacent within twenty minutes. What a spectacularly precise mechanism, in biology, to signal a local cell response to a local perturbation.
We'll also see just how important PPAR-gamma is. PPAR-gamma opposes the cytokine nuclear receptor. Sure, it controls production of glucose-transport proteins 1 and 4 -and we use that to improve insulin-resistance - but it also controls transcription of at least three different uncoupling proteins. Two weeks from now I will be in Denver presenting a paper on how to use activation of uncoupling proteins in the treatment of obesity that is refractory to any other therapy in insulin-resistant patients, just by turning on PPAR. We also need to use this to control TNF and TNF-receptors. Fascinating that we are practising genetic manipulation as our therapy at the bedside.
There are additional mechanisms of toxicity from these toxins. They can disrupt intracellular potassium gradients as an ionophone transports potassium against the gradient inside a cell, disrupting normal electrical function of nerve and muscle. They can disrupt the control of putting a phosphate onto one molecule or another. They can disrupt totally how the body uses glycogen. Individuals exposed to blue-green algae toxins will have their protein-phosphatases 1 and 2a disrupted. As you can imagine, people will be tired if they cannot mobilize glycogen. More importantly, these blue-green algae toxins are well-known tumor promoters. The concern about recurrent and chronic exposure to Microcystin and Cylindrospermopsis in Florida is not just about getting sick like the alligators and pelicans do in Lake Apopka and Lake Griffin; it's about what happens when you drink this contaminated water over and over again. Are we going to be like the people in China who are well-documented as having huge rises in liver cancer, because we are ignoring the physiological effects of blue-green algae toxins? Or shall we begin to recognize these effects early? That is what I want to show you today.
All of the biological toxins that I speak of have the curious feature, in three dimensions. of rings of oxygen, nitrogen or sulfur contained almost inside the oil and vinegar, if you will, of a small molecule, with the fat-soluble part on the outside and the water-soluble parts on the inside. [Examples are cyclic peptides in blue-green algae, carboxylic acid in fungi, and polycyclic ethers in dinoflagellates.] Curiously, in all cases a molecular glove or dipole is created, with an ionic radius of 1.4 Angstroms. I found this amazing: why would blue-green algae, a fungus, a dinoflagellate, and a spirochete all have an ionic radius in three dimensions of a structure that was so different in other ways? Possibly it is due to the ionic radius of potassium being 1.43Å. The benefit from Cholestyramine as a therapeutic agent is, I suspect, due to Cholestyramine having a positive charge as opposed to the sharing of negative charges in these molecular dipoles, and it has an ionic radius of 1.45Å. I think it may have something to do with something more basic in biology: the ionic radius of water is 1.40Å, exactly the same size as the polar in these compounds.
The family physician may not be talking about Angstrom units in his daily practice, but I want the practising doctor to be aware of what goes on in patients exposed to these toxins. I want you to take a couple more minutes when recording a history, to look for symptoms: fatigue is very common, unusual neurologic events, tingling in non- anatomic distributions, funny kinds of pain. things that you don't see routinely but are in association with weakness, headache, sensitivity to bright light, abdominal pains that have already been worked up for irritable bowel disease (and don't ever say fibromyalgia again, please, until you have asked for a neurotoxin history).
Let me teach you how to do it. It is quicker than taking a depression history and you can be helping your patients instead of just giving them an anxiolytic or antidepressant and sending them out the door. Ask about environmental exposures. They are real, you will see them; it is part of medicine. The syndromes for neurotoxin patients before I get to see them include: fibromyalgia, irritable bowel disease, chronic fatigue syndrome, depression, stress, age-related memory loss, lack of physical fitness, obesity from out of the blue, and diabetes from out of the blue. I find it very hard to accept that age 50 is one at which memory loss due to age is an acceptable diagnosis. Don't buy into that - ask! The interesting thing about cytokines produced following exposure to neurotoxins is that they directly disrupt the normal functioning of insulin binding to an insulin receptor, and with that disruption they artificially create insulin resistance.
So when you have a diabetic showing up with no family history, and he's gained fifteen pounds for no reason since he was down in Florida eating a Ciguatera-contaminated fish, ask if there is a TNF disruption of the insulin-receptor and you will find an environmental acquisition of diabetes and obesity. These illnesses are exploding across our country: sick-building syndrome is said to affect 20% of office buildings with recycled and recirculated air are full of indoor fungal species with mycotoxins. They cause the same disruption of insulin receptors. Fifteen percent of our schools, according to OSHA, are contaminated with the same kind of organisms. We have looked at the explosion of diabetes and obesity, and are we really supposed to believe that it is because we have become sedentary and drive our cars to the supermarket? Or are we missing something that is much more common?
A simple list covers some twenty organisms that Dr Hudnell and I have shown to produce neurotoxins that we can detect with a special test that I will show you, called visual contrast sensitivity. The test can be performed at the bedside, is non-invasive and takes five minutes. The test looks at the optic nerve as a binary-output system. We eliminate near vision and far vision; we eliminate static and motion; we eliminate peripheral vision and color vision; and we are left with the ability to separate black from gray from white. Believe it or not, people with neurotoxins have had a big divot taken out of what they should be able to see. We will get to the diagnosis in just a minute. For organisms like Pfiesteria, I have seen some hundreds of patients, though the CDC announced at the October 2000 meeting that in their surveillance they found no cases of possible estuarine- associated syndrome. The moderator chuckled as he introduced Dr Hudnell, because he and I were going to introduce 37 cases of possible estuarine-associated syndrome. Who was right? Are we making this up? No, we have the data and now we are having a big switch. In the Environmental Health Perspectives for May 2001, you will see a Grand Rounds in Environmental Medicine presenting these concepts at the highest level of peer-reviewed academic journals. It is not just some fantasy; it is real. Why should we be worried about Stachybotrys ; law suits like crazy for the sick-building and the black fungus that you see. Well, the biggest study on Stachybotrys is one building with this fungus and children with pulmonary hemorrhaging and some deaths in Cleveland, and twelve patients. Dr Hudnell and I have 34 buildings and 222 patients. We take patients in and out of the building. We control environmental factors and compounding variables. We see these repeatedly. What we are looking for is academic surety of a diagnosis in the absence of having a blood test, and in the absence of having a toxin in the bottle. Why should we be worried about Cylindrospermopsis? Who can spell it? Who has heard of it? In Australia, this blue-green algae is sensitive to copper, and if you see this algae growing in your reservoir and you dump in copper sulfate, you kill the algae and release toxins; you could kill animals and make people sick. In Brazil, the organism is resistant to copper. There was a hemodialysis unit that had nearly fifty unexplained deaths. Where did the deaths come from? Toxins produced by Cylindrospermopsis or hepatotoxins, neurotoxins. A cup-sized sample of water from a lake in central Florida should contain between 40 and 100 species of algae; now it contains just one, Cylindrospermopsis, not found before 1995. Now it is 95% of all algae biomass. We see unexplained deaths of pelicans and alligators, found swimming aimlessly round and not avoiding things. We see sick patients, and what are we supposed to do? Here's a report on drinking water; the Peace River. Here's West Palm Beach. What could be the cause? The levels of blue-green algae are four times the level that the WHO would recommend. What are the long-term effects of drinking water from reservoirs contaminated with these organisms? Our data show clearly that we can identify the sick patients, and treat them, and eliminate the question of cancer down the road.
I want to talk briefly about Lyme disease. If people thought Pfiesteria was controversial, and the millions of dollars lost when people were afraid to go into the water or eat crabs or fish in 1997-98, then look at the controversy that Lyme disease brings. How shall we treat it? Three weeks of antibiotics only, says one group. Treat it for years, with IV antibiotics, says another group. I say: identify those patients with exposure to ticks or tick bites, with symptoms refractory to antibiotics, who have the visual contrast deficit, and who have symptoms: those are the patients with Lyme, and that is neurotoxic Lyme. They are all around you, and don't let the next doctor say to you, "I did a Lyme ELISA test and that was negative, so you don't have Lyme." Nonsense.
Oh, Pfiesteria caused a lot of hysteria. That's for sure. Who could imagine a life form that can change its genetic make up in four hours? Deprive Pfiesteria of its sustenance of blue-green algae and Cryptomonads as it creeps along the bottom of a river, and within a few short hours it changes from being like an Ameba, engulfing chloroplasts to grow to a fairly large size. It changes to being a free-swimming motile organism, that releases toxin into the water that does two things: it hurts fish and people, but more importantly it is a chemo-attractant for other Pfiesteria motile forms, and in this motile zygote form, this is the time for Pfiesteria to feed and breed. So why should we be worried about this thing doing things to people? If we can recognize and treat the illness, as we have documented we can, why should we be so worried about it? Because, in a way, it shows the likelihood that we are changing our environment through chemicals. Some esteemed scientists are certain this is due to nutrients. Radicals like me say we are overlooking what happens when you poison important aspects of predator-prey relationships. Perhaps the answer is a combination of the two, but the new organisms I see, in relation to chemicals, invariably end up making their own toxins. Whoever heard of a water-borne fungus - Aphanomyces invading fish? It does, and is resistant to copper. Whoever heard of Lyngbya wollii in the reservoirs of High Point, North Carolina? It's resistant to copper. Whoever heard of Pfiesteria growing in the copper sulfate treated ponds on Tony Mazzacarro? There it is [on a fish]. Is there a relationship? It would be interesting to find out. Pfiesteria does do some dramatic things. We know that a lot of other organisms attack fish. Once you breach the protective mucus lining, other organisms can invade.
We, humans, have the mucus lining to the stomach. [Tangent relating to Helicobacter and ulcers] We have got good proton-pumping medications and these neurotoxic illnesses - like, I find that Previcid does do a better job than Priolosec. Is the stomach a parallel to the mucus layer of a fish? Both are full of lysozyme, which is an interesting idea. Do the H pylori bacteria breach the mucus membrane, leading to an invasion of stomach acids? Are we looking at commonalties in biology? Nor did the hysteria about Pfiesteria stop when this fellow walked into my office [photo of face]. He was the first of many. Unusual skin lesions were thought to be the marker early on. If you biopsy those lesions in the first twenty four hours, you will find hyper intense infiltration of eosinophils. In the first death, associated with repeated exposure to Pfiesteria, no obvious cause on pathology. Look again please! State Medical Examiner of Maryland. Above the larynx of this man, who had sudden onset of upper airway obstruction and sudden death, hyper intense infiltration of the eosinophils Very unusual. Is this the cause? We don't know for sure, we do know that if there are people exposed to these neurotoxins, then the idea should not be dismissed as crazy. Don't take it for granted that the disease is self-limited. The State of Virginia thought they had no problem with Pfiesteria, but this fellow showed up at my office [photo of lesion].
Do not be deceived, in this case by State agencies that sampled and biopsied from the wrong places. Here in Florida, a young man had a six-month old illness, from exposure to Cryptoperidiniopsis in the Indian River inlet near the St Lucie River. How should we biopsy this lesion [photo of leg]? Should we biopsy three inches away? I don't think so.
It is interesting to look at the distribution of Pfiesteria attacks on NHS Big Bay [map]. They are clustered around one spot, so if we want to find Pfiesteria, let's look where it is. Let's look at the leading edge of the incoming tide, where the salt wedge meets the downstream flow. Let's look at the areas where there is the right salinity. Let's look at the deposition side of silty loams; don't look on the dig sides or the deep areas. Look where we know the Pfiesteria habitat to be. Same thing with sick-buildings. Do you want to sample dust on someone's desk? Or do you want to get the black mould that's hidden behind the paneling where you can't see? You have got to go where the organism is to show it.
Rashes get to be quite impressive in other diseases caused by neurotoxins [photo of shoulder with rings of rash]. I would imagine no one here could possibly mistake that this is a target lesion or bull's eye rash of Lyme disease. But how many would diagnose this as a Lyme disease rash [photo of oval pink patch]? We knew that Pfiesteria rashes could change totally. Who would call this a Lyme disease rash [photo of linear dark patch]? It is biopsy-proven. Who would call angioedema like this a Lyme rash [photo of dark pink elbow]? It is, and if we are deceived by looking into our old knowledge about Lyme disease, for example, just as with Pfiesteria we are going to make mistakes and patients will suffer. Here's a trick slide [photo of calf]: the interesting point feature here is that this fellow has both a Pfiesteria rash and a Lyme rash. One of my toughest cases of all is a fellow who lives alongside Lake Apopka, and the breeze containing neurotoxins from Cylindrospermopsis comes across his front porch; he's got Lyme disease that he got in Georgia (remember the CDC said until two years ago that there was no such thing as Lyme in the south, but there sure is); and he works in a sick building. Which of these toxins makes him tired?
I want you to look at symptoms in categories:
General
Muscle
General & Muscle
Psychiatic
Neuotoxic patients will have at least four different organ systems represented. Why? These fat-soluble ionophores move from nerve, to muscle, to brain, to eye, to synapse, to lung, to GI tract, to joint, to skin, and they keep on moving. How do we get rid of them? It looks like there is a transport protein. The multi-specific organic anion protein transporter that is in bile canaliculi, that preferentially will secrete these compounds into bile. If they don't undergo liver metabolism and are not excreted into urine, how is the body going to get rid of them? Putting it back into store makes sense, except there is re-absorption: the intra-hepatic circulation of these toxins, further down the ileum. So we have chronic illnesses. Now if you just happen to have some Cholestyramine, with no food and no other medicines hooked onto it, at the sphincter of Oddi in the duodenum when this little neurotoxic comes past, you can bind it, prevent re-absorption, and down the toilet it goes. You deplete the body burden, one by one by one. We can use our test of visual contrast to follow how all of this happens. We can see change in intensity of symptoms, the day to day recirculation that is such a constant feature will begin to disappear. We have looked at this in relation to Pfiesteria:
With Pfiesteria there are immediate effects: [slide of symptoms: skin burning, conjunctional injection, cough, wheeze, sore throat]. Mucus membrane involvement? No. With Pfiesteria you don't get it from eating the fish, but you do with Ciguatera, a different dinoflagellate illness. And, by the way, although we are not in the tropics here, there are other micro-organisms - the dinoflagellate called Prorocentrum minimus that has been shown to make a Ciguatoxin-like compound. Even though some may say we don't have Ciguatera here, we may have something else doing the same thing. Shortly after exposure [to Pfiesteria] we will see muscle involvement, headache and early onset of memory impairment [slide of 3 hours]. What is going on here? There is circulation through fat-soluble tissue and the brain is a target organ. When you see someone coming in with new onset of a psychiatric abnormality, rage reaction, attention deficit, depression, be sure to ask about the associated findings; because you will see all of the findings from neurotoxin. One of my best examples of blue-green algae patient got sick in the Sassafras River last year in the middle of an algal bloom and presented with mad-depressive psychosis. Treated with anti-psychotics, what was his problem? He had a neurotoxin. The first case of mania I've treated successfully with Cholestyramine. Non-absorbable anion-binding resin.
In patients who have been sick for longer, you will see additional organ systems recruited [slide of 24 hour symptoms]: abdominal pain and cramping should not be surprising, given the distribution; neurocognitive effects can be quite dramatic. [slide of 2 month symptoms] Be sure and check for symptoms, in general, fatigue and weakness. Ask about headaches: this is the Pfiesteria salute [grasps both sides of his head]. If you have someone with a pounding bifrontal headache like that, ask them if they are tired; ask about their eyes being sensitive to bright light; ask about unusual pains, ice-pick pains behind the eyes. The Lyme patients stop me with the most unusual symptom of all, a pain that feels like a lightning bolt, that shoots deep into a muscle group and explodes. This is not in my medical textbook. It is in Desperation Medicine, and if you have not read this book, get it from the library. The Lyme patients will teach you what the doctors didn't. It's new knowledge. If they have Lyme, then you got your diagnosis. Be very careful when people present with refractory enthesopathies, the extensor epicondylitis that doesn't come from running a floor hammer. Be very curious when people have difficulty assimilating new knowledge: they don't remember the newspaper, or have difficulty in word finding. Ask someone quickly, "What's 7 divided into 91?", and if they have difficulty handling numbers abstractly, let them do it with pencil and paper.
They will be able to do it on paper but not in their head, and that lag between abstract and concrete mathematics is very specific. The skin is another target organ. People may tell you about sensitivity when they take a hot shower: "Doctor, it feels like pins and needles on my skin." Bizarre, but the patient is not crazy. We are the ones that are crazy when we don't ask for the rest of the syndrome.
The sensitivity to bright light can be just night-blindness from headaches. It is not a reaction to halogen lamps. Red eyes, shedding tears, and blurred vision are all symptoms to ask about.
In our paper on residential and recreational acquisition of Pfiesteria in the estuaries around my home town of Pocomoke Maryland, Dr Hudnell and I were able to show that the CDC definition of finding memory confusion - and other symptoms such as headache, rash, burning skin, eye irritation, upper respiratory problems, muscle cramps and gastro- intestinal insults - was a small fraction of the syndrome [slide of Chesapeake symptoms]. The CDC made their opinion from a very small number of patients. We need to expand the definition of PEAS (possible estuarine-associated syndrome), not by saying Pfiesteria but by including others. Look at the patients who were tired, with muscle aches, with weakness, with abdominal pain, with cough: we need to continue to think in a system approach.
This is from the paper I presented to the American Society for Tropical Medicine and Hygiene on Ciguatera [slide]. It shows the same grouping of chronic symptoms: fatigue, muscle ache, burning dysesthesias, headache, more memory loss, cough, diarrhea, skin itching. Ask the question. Here's a case of people who all had negative tests for Lyme disease, and never would have been diagnosed with Lyme disease by the usual tests. They were all diagnosed with visual contrast, and with toxin-binding therapy were shown to be improved. Look at their symptoms: fatigue, headache, muscle ache, neurologic complications, shortness of breath, sensitivity to bright light. memory impairment, small-joint pain, large-joint pain. Over and over again. There is no relationship of time following exposure to number of symptoms. One Lyme patient, sick for fifteen years, reports fourteen symptoms [slide]. Another Lyme patient, sick for three months, reports thirteen symptoms [slide]. Why do they have so many? Ongoing circulation [of toxins], primarily extra-vascular.
If we look at the definition of diagnostic testing for a neurotrophic bacterium such as the spirochete Borrelia burgdorferi - of which we have many different strains in the US - some of the commercial lab tests will target only one strain. If all blood tests are negative, do they look for the other strains? Usually not. Do remember to look for neurotoxicity: all these cases had tick bites, all had symptoms. One or two had a distinctive rash, a couple had Bell's palsy. None of them had a positive ELISA test. CDC said that we were supposed to order this first. I disagree; I find that a waste of time. Sixty percent are false negatives; sixty percent false positives. How can we possibly interpret a test like that? How about getting Western blots? It depends which lab you use. If I want a positive test, I'll use lab A. If I want a positive test, I'll use lab B. It is better to use the visual contrast [holds up frame]. If acute Lyme disease, the patients we are working with now, we see the deficit occurring within 36 hours in over 80% of patients who have the illness. We see it persistent for years despite antibiotics. When people say, "I have been taking my Biaxin, my doxycycline for six weeks and I feel much better, Doctor, and three weeks after stopping I feel much worse. Does that mean I still have live bacteria? No, it means that macrolides and tetracyclines stabilize that NFKB and prevent transcription of TNF. So remember that anti-inflammatory aspects of antibiotics must be kept in mind.
By the way, it turns out that all these people, including one lady who was blind in one eye and one lady who was deaf at age 15, had been diagnosed by very competent physicians, tertiary card specialists at Johns Hopkins, got better with Cholestyramine - some needed longer on antibiotics in the neurologic cases. But look at the diagnoses: optic neuritis, Meniere's disease, fibromyalgia, neuroborrelliosis (at least there they had the diagnosis right), another fibromyalgia, sero-negative rheumatoid arthritis [slide]. No, simple Lyme, and trying to convince the rheumatologist - good luck! Start showing the rheumatologists how to do visual contrast, and they won't need the blood test. A case of fibromyalgia for fifteen years; gone in six weeks. The test of visual contrast was first developed by Dr Ken Hudnell for patients exposed to Pfiesteria, in 1998. He took a commercially-available test, the Functional Acuity Contrast Test (FACT), available from Stereo Optical, whose (US) phone number is 0800 344 9500. Ask for the "near" card, which is not expensive and will last for ever. What you will see with this bedside test is representation of visual contrast. With the lights on in this room, it is difficult to see. But at the low-frequency presentation of 1.5 cycles per degree of visual arc, we can see the dark lines gradually reducing in intensity by 0.3 log units as we go from box A to B to C to D [slide of zebra pattern], and then we increase the frequency, so in a way what we are doing is a five-tone hearing test for the eyes. The mid frequency, row C which is 6 cycles per degree of arc, drops out like crazy with people who have neurotoxins.
You need to eliminate confounding variables. Look out for people who have exposure to solvents, heavy metals and some pesticides on an occupational basis. Not just using a little fungicide in your back yard, though do be careful with such products as the active ingredient is usually copper and we've got too much of that anyhow. But once you eliminate confounding variables, start looking at a simple protocol for how to do visual contrast tests. The vision has got to be 20:50 or better, the patient cannot have any confounding neurologic problems, and cannot be an alcoholic after drinking. But if you can see the deficit, recognize it with symptoms and with environmental exposure.
This sounds too simplistic. How can I document that the changes in blood flow, at the capillary level in the retina and the neural rim of the optic nerve pad, really are causing the problems? It's a nice theory, with TNF and all this stuff binding to endothelial cells and endothelial cells releasing adhesin which holds small neutrophils in place. It's all fun. How can we prove it? Take a hundred thousand dollar laser device, a Heidelberg Retinal Flowmeter [slide, but "Fourier" not "Fournier" transform], and start measuring velocity of flow in the retina. Measure velocity of flow in capillaries, not arterials. This is not an arteriogram. We can see, in a two second exposure of this laser-doppler device, clear evidence of hyper- perfusion that starts changing 12 hours after we start treating with Cholestyramine. The flow rates in this HRF treatment are not affected by age, alcohol, cigarettes or caffeine. This has the potential to be a fantastic diagnostic device. Unfortunately, this is not a machine that everyone has access to.
What about Cholestyramine? How did I start using it? I got lucky. My first Pfiesteria patient had terrible secretory diarrhea that didn't get better with Pepto Bismol or Kaopectate or Fluoroquinolones or whatever else we used. I said, "Well, we can use Cholestyramine to treat bile salt malabsorption and associated diarrhea. Boy, I love the old Chole bar for diarrhea; you just give the guy this stuff and you pull him right up. The lady came back two days later and said, "Doctor I want to thank you. I feel so much better. My diarrhea's gone, and so has my cough. My headache's gone and my memory's better." That was a little bizarre, and in the last four years I have been looking at disease differently and listening to skepticism from my peers. I don't mind being called a kook any more, because I've got the NIH and you guys can argue with them now. Many different species of organisms make neurotoxins, and Cholestyramine is well documented to bind these [slide]. This is now some craziness. The mechanism makes sense. We have seen it with radioactive-labeled ochratoxin in fungal syndromes. It is easy to take in the normal dose you use to treat cholesterol problems [slide of protocol]. The FDA issued me a letter of exemption when I petitioned about this in 1999: they saw no reason for increased risk of side-effects in this group of patients compared to those they had studied for 35 years [slide, chemical structure of Questran]. It turns out that the side effects are the ones we already know about: a little bloating, a little constipation, a little reflux. Tell the patient what is going to happen, and expect them to have some problems. Get ready for the clever things they are going to call it - "that's sawdust", but I've heard worse. Cholestyramine is the key friend; it fits right into that glove, in that core [slide of ring structure] and prevent re-absorption. The side chain of Cholestyramine looks quite complicated. It actually is not. If we look down in three dimensions at this circle of oxygens or nitrogens and sulfurs making their little molecular glove, look how the side chains can directly fit into this compound [slide]. This is called an 18-crowned 6-ether. That's not in the family practice textbook, but it's going to be. Another way of looking at these compounds, in 3-D, is this glove with negative charges holding the positive charge, Monensin in this case. Monensin, by the way, is widely used and is a polycyclic ether antibiotic; it doesn't leave the human body, but it does get added to chicken feed and hog feed to prevent Eimeria that would prevent the little hogs from growing right. If you put white blood cells from a normal person in a test tube and add Monensin, you turn those cells into ones that function as if they were diabetic. We can create insulin resistance with Monensin in the test tube. We are eating much more chicken to replace beef nowadays; I wonder if we are taking in too much Monensin, creating this extra diabetes and obesity in the US?
Here is another 3-D structure: Okadaic acid [slide]. OA is well known to bind to the cytokine nuclear receptors, a well-known stimulator of NFKB. It has been well studied, and if you eat too many Sea-fans out of the Pacific you may go sick with it. Look what happens in 3-D with OA [slide]. Look at all the black circles, which are oxygens creating their little groups, separating themselves like oil and vinegar from the lipid layer on the outside. Here we have Monensin and a fungal toxin [slide], a carboxylic acid ether - you don't need to know the structures, just know they are there. Other people have worked out the chemistry, which is 1.4A in the central pore. We can look at other fungi found in water-borne organisms - it's not just in buildings. Here we have more polycyclic ether compounds of a variety of shapes; they all do the same thing. If we look at Ochratoxin, which is well studied, radioactive labeled; this compound is well known for creating illness among investigators working on a problem of new, unusual illnesses at a plant nursery in central Florida, where fungicides had been used and resistant organisms had developed. It is a long-lasting syndrome.
Wortmannin is made by Fusarium, not too different in structure from zearaleneone. zearalenone was in the news recently. It was thought to be part of the reason that the blue-grass country had such trouble with the mare reproductive-loss syndrome. Caterpillars, cherry trees, cyanide - lots of different ideas. But if it is a fungal toxin - and this would not be surprising - it is easily diagnosed, easily treated, saving millions of dollars of horses, not to mention people.
Two different toxins from blue-green algae micro systems: one is thought to be more a liver toxins, nodularin?! more a nerve toxin [slide]. They all create the same 3-D ring. These compounds are all out there, and if you don't ask your patients about exposures, you will be missing an easily-treated illness. Ciguatoxin is made by many different species; there is increasing knowledge of these, and there are at least eight different Ciguatoxins. If you take in enough - because we can metabolise Ciguatoxins - we call it dinophysosystin and it creates another illness.
If we look at the Visual Contrast Sensitivity scores of people exposed in the estuary: the lower end are the people exposed to PEAS; the top are the normal non-control- quite a significant difference between the two in Dr Hudnell's very small study. I did the same study with a group of watermen that I knew were exposed in the Pocomoke River, who had no confounding variables. Look again at the normal height of the normal curve, especially in row C, and look how dramatically it falls off. The difference is highly statistically significant (p<0.001). These people all get better, having been sick for months or years. It takes about two weeks. We did a double-blind placebo-control clinical trial. We took patients as they were when they came in and gave them placebo: no improvement in their VCS. We took some and gave them active drug, and they returned to the level of controls, again within two weeks. We gave those treated with placebo the active drug, and once again they went back to the normal range. This one guy was exposed in cold weather - the line on the left [of the slide] corresponds to December and that on the right to February - when water temperature is quite cold and we are not supposed to have a problem. But in the placebo-control trial, we do nothing to him because he's about to have rehab knee surgery and feels fine, having been given pre-op clearance. But three weeks after surgery, we start on the Cholestyramine and see nice improvement. He goes back to the estuary and catches a nice bass with some lesions, and once again, same abnormality. Did he get a little worse the second time? Yes. Do I worry about kids with re-exposure in schools? Yes. Am I concerned about Acquired Learning Disability in children? Absolutely. Should we test every 3rd-grader in a school that is old, that might have fungal toxins? Absolutely. We make them take MSPAP standardized test and then we blame the teachers when their reading scores do not improve. Perhaps the child can't see the difference between "b" and "d"; perhaps they can't keep focus long enough, and perhaps they have delayed assimilation of new knowledge. It would not be surprising, but what do we do? We give them something for Attention Deficit - I don't think that's right.
Chronic or acute illness - it doesn't really matter. The patient on the left [of the slide] had been sick for six months; look at her scores on the bottom. The one on the right had been sick for two days. With treatment, back to the normal curve they go.
In the cohorts that we had in the recreational-acquisition study - and this will be in *Environmental Health Perspectives* as well, in the CDC Pfiesteria supplement - we took people with no exposure to the estuary, and look at their scores at the top. It is a wonderful control group of 87 patients. We took 77 exposed to the estuary where they had been exposed to the estuary where there had been fish-kill, though they had no exposure to fish-kill. We grouped these 77 patients and we see the difference in the groups, which were very different although these folks thought they were healthy when coming to see me. "Oh yes, my memory's getting bad because I'm a little older. I always have sinus problems. My muscle aches; my doctor says I have fibromyalgia. I have Irritable Bowel disease. I smoke and that's why I cough." Ask the questions, because they didn't. On this graph [slide], the bottom line shows the 37 patients who had criteria to meet the CD definition of PEAS, compared to score for the whole group. We treat the PEAS patients and they return to the normal range. They thought they were well, so this is just another example of before and after treatment. This is a treatable disease if the doctor recognizes it. (Actually, it does not have to be a physician. I was giving a tour of the Pocomoke nature trail and one lady came up to me in the middle of the forest - she had sunglasses on because the light was bothering her eyes so much, and she asked, "Could I have that Pfiesteria disease?" I said it was pretty likely, and it turned out that she met the criteria, but she is not in this study.)
With Ciguatera we see the same change in [VCS] scores before and after treatment. The same thing at Lake Griffin, Florida (possible Cylindrospermopsis exposure), where there are now 360 alligators dead in two years, and you will not find a living bass in this "fishing paradise" nor a living blind shrimp. Look what happens with people with residential or recreational acquisition [slide]. While some people are worried about drinking water, I am just worried about having a breeze blow across toxic contaminated water. Is this just hype and hysteria? No. Fact defeats fear. Recognize the illness and treat the syndrome. Don't say it isn't real.
With Lyme disease, we have a thousand patients we are about to bring to publication. One trial will be to document a demonstration of the benefit of a drug called Actos that is another PPAR-gamma agonist. We can actually block TNF transcription, and we can block the terrible Herxheimer-like reactions that patients get when they take antibiotics. Even worse, if you give a Lyme patient who has been sick for more than six months Cholestyramine, they will get even worse. That Herxheimer reaction, that I call the intensification, will show dramatic onset of symptoms. The Visual Contrast test shows a distinct fall [slide]. The people on the bottom line of this graph had known Lyme disease; they had positive blood test, good rash, indisputable history, 7.9 symptoms per patient. The people on the line above would not have been diagnosed with Lyme: they had no rash, no blood test; all they had were symptoms after a tick bite or exposure to an area where others had tick bites, with symptoms refractory to antibiotics and the Visual Contrast Deficit. When there are no confounding factors but environmental exposure, we treat them and both groups returned to the normal levels on the curve that you should recognize by now. Maybe this is just repeat testing? Well no. With our stair step testing, there is no improvement over time [slide]. Nor it related to Cholestyramine and cholesterol, as a group of high-cholesterol patients show no change in VCS over time [slide].
Ciguatera and Lyme are simply examples of a generalization of this syndrome. In the post-Lyme cases I have talked about, marked deficit in the patients before and after treatment, and these people had seen good doctors. When I talked about casting out false knowledge, our knowledge of Lyme disease still relies on criteria that are now indefensible, based on what we know about the neurotoxic aspects of Lyme. What we have as a mechanism is that toxins turn on cytokine receptors; the cytokine receptors turn on TNF; TNF has local effects, neighbor effects and distant effects; and it sets off a cascade of many reactions. We know that TNF will produce hypoperfusion, and if you don't give enough oxygen or nutrient to a muscle cell or brain cell, how well does it work? We know that we can clear those symptoms, avoiding the cytokine storm, by using things like Actos in Lyme disease with Cholestyramine. We find a rise of TNF and mRNA within twelve hours of treating a Lyme patient with a non-absorbent ionic-binding resin. How can that possibly be true? If we interrupt the balanced-equilibrium dissociation of toxin from its receptor, we enhance more dissociation, push the equation to the right, and have greater symptoms.
I want to finish up by telling you about the dueling nuclear receptors. I think it is going to be mandatory that practice physicians become acquainted with what we are looking at here. When you hear about diabetes, and you want to use a glitazone such thiazolidinedione, you must realize that that drug will turn on a whole string of genes. You are turning on uncoupling protein, and you can help that patient to lose weight, provided you don't let them eat the starches that will bring insulin out to combat the effects of the thiazolidinedione. It gets a little complicated, but look for that in the appropriate literature. We know that we can turn on TNF prevention, and we know that these drugs do good things. We know that we can block matrix metalloproteinases. We know that we can turn off the effect of excessive progesterone and estrogen as pro-inflammatory hormones. We can turn on enhanced androgen effects, down-regulating TNF, down- regulating interleucin-6. We know we can do many things at the bedside.
We must recognize that we are in an era when we will be seeing new organisms. This one happens to be Chattonella in the Roosevelt inlet last August 11; a huge red tide with eleven million cells per liter. You can see the redness in the picture [aerial view]. People exposed to that were exposed to Brevetoxin; the literature says that Brevetoxin is a self-limited compound which does not make people sick. That is actually not the case. Today, I am reporting seven patients in a handout. They had an average of 7.9 symptoms before treatment, and 0.4 afterwards. They had on average seen four doctors each, who unfortunately had missed the persistent syndrome from Brevetoxin. Recently, we have documented the same dinoflagellate organism active in the St Martin’s River in Maryland, looking right at the Ocean City with its tourist attractions. Six people are sick; Maryland investigated and put up a big sign warning against swimming and boating. Fortunately they were treated. My message today is to be sure to get a baseline Visual Contrast test. Dr Bruce Richards of the Center for Inland Bays did that for his staff, and he'll be ready to treat their illnesses should they occur.
I want you to be ready as well. Thank you very much.
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