In his search for answers, over the next few years he became intimately familiar with the habits and neurotoxic illnesses of fresh water and sea animals including fish, birds, alligators, turtles and pelicans. He studied basic and esoteric subjects, including predator-prey relationships of aquatic invertebrates; plants; phytoplankton; the pathology of invertebrate organisms in marine and estuarine environments; pesticide physiology; and the study of the rhizosphere, the interface between a root and its immediate environment.

He consulted experts in fields such as pathology; toxicology; biochemistry; geochemistry; physiology; estuarine limnology; and even membrane ionophore chemistry, the study of the passage of organisms and molecules in aqueous solutions across membranes. He learned how pesticides degrade in air, water and subsoils.

Given the intense political controversy that an environmentally acquired illness like Pfiesteria created, he needed this knowledge to piece together a mystery: Was there a link between the fish kills and the illnesses his patients were suffering? Why didn't the body rid itself of these toxins naturally? Do bacteria, fungi, algae and other tiny organisms manufacture toxins that linger on in the human body, long after the organisms themselves are dead?

Eventually, Shoemaker figured out that his patients had a new illness, originally named Pfiesteria human illness syndrome in his 1997 article in the Maryland Medical Journal. The CDC renamed the illness "Estuarine-Associated Syndrome" in 1998, and "Possible Estuarine-Associated Syndrome" (PEAS) in 2000.

It took Shoemaker a few more years to put together his "chronic neurotoxin-mediated illness" theory and some time after that to gather the data to tell him his theory was sound. In the end, he believes he and Hudnell have discovered a new brand of illness and a new way for pathogens to make people sick. The two have continued to gather data fleshing out the theory with more clinical and molecular information.

In the meantime, Shoemaker built up his medical practice, winning the 2000 Maryland Family Doctor of the Year Award and being named one of five finalists for the National Family Practice Doctor of the Year Award in 2002. At the same time, he battled state and local bureaucrats who continued to tell people, "the river is safe," despite evidence to the contrary.

When Shoemaker went to the press with his theory and his data during the outbreak in Maryland in 1997, the bureaucrats did everything they could to ruin his reputation. One state official quoted in the local newspapers accused him of "scientific malpractice," and claimed he was "out of his field" when it came to the sciences.

Their refusal to see -and say -the truth simply drove him to work harder. When residents near the St. Lucie River near Stuart on Florida's East Coast suffered a rash of dinoflagellate illnesses in 1998, they listened to Shoemaker's theories of copper toxicity. Copper binds to pesticides, giving them easier entrance into organisms. If predators of dinoflagellates are more susceptible to the copper-pesticide toxicity than dinoflagellates, a decrease in the predator population could result in an increase in the dinoflagellate population. Also, if prey of dinoflagellates are killed at lower exposure levels than dinoflagellates, this might put pressure on the dinoflagellates to produce and release toxins in order to kill fish for a food source.

Then Florida officials earmarked $30 million to build lagoons that filter runoff from copper-laden citrus groves, bought wetland farms to restore them and dredged contaminated sections of the St. Lucie. They levied a three-year, one percent sales tax to pay for these improvements.

The CSM treatment proved just as effective in Florida as it did in Maryland. About 15 residents and investigators working on the St. Lucie became ill with multiple systems symptoms and suffered a VCS deficit. They responded well to CSM therapy given by four local Florida physicians.

But like the guy who discovered that a bug causes ulcers, Shoemaker found the medical community in Maryland reluctant to applaud his new theory. In fact, it was met with active resistance, he said. For example, the head of ophthalmology at the University of Maryland School of Medicine dismissed the value of visual contrast testing in helping to diagnose Lyme disease by simply saying, "I don't think so."

In his spare time, Shoemaker also wrote four books: Gateway Press, in Baltimore, Md., published Pfiesteria: Crossing Dark Water, a 360-page tally of the outbreak in the waters of the Pokomoke, in 1997; Weight Loss and Maintenance: My Way Works, a 325-page explanation of a weight loss mechanism with maintenance rates that exceed 70 percent, in 1998; and Desperation Medicine, the 519-page saga of his findings that neurotoxins are responsible for many chronic illnesses, in 2001.
His latest book, Lose the Weight You Hate, is a 454-page update of his earlier diet primer which adds recipes, an explanation of how neurotoxic illnesses contribute to obesity and diabetes, and a discussion of the importance of genes and how they effect weight loss.

The test

Despite the disbelief, Shoemaker and Hudnell can point to data, accumulated since the mid-60s, that visual contrast sensitivity deficits exist in diseases like Type 1 diabetes, multiple sclerosis, and in Alzheimer's and Parkinson's disease.

In fact, experts suspect that many diseases involve deficits in visual perception, but there's little research relating toxic
exposures to differences in visual function before diagnosing disease. Visual contrast sensitivity testing assesses the quality of vision. It differs from typical visual acuity testing in that it simulates "real-world" circumstances, while routine visual acuity
testing measures eyesight under the best possible conditions.

"That's why measuring visual contrast sensitivity in patients who report difficulty with their vision, yet see well on the conventional visual acuity eye chart, is particularly useful," says Hudnell. The test is performed by showing the patient a series of stripes or bars that slant in different directions. The patient must identify which way each series of stripes is tilted. As the test progresses, the bars become thinner and lighter. People with excellent contrast sensitivity can discern the orientation of even very light, thin bars; patients with neurotoxic damage cannot.

After chronic exposure to many organic solvents, VCS is the most sensitive indicator of effects from many toxins, either because the visual system is highly susceptible to neurotoxins or because even small deficits can be measured, according to Hudnell.

"The visual system is the ideal place to look for evidence of neurotoxicity," he says. "The retina is a microcosm of the brain; it contains most of the cell types and biochemicals that are in the brain. So the retina is as susceptible as the rest of the brain to
neurotoxic effects."

According to Hudnell, this "piece of brain," being near the front of the face, is in close contact with the environment. Chemicals may be directly absorbed from the air into the retina, so the potential for exposure to neurotoxins is greater in the retina than in the brain. But unlike the brain, he points out, the visual system has few functional outputs (pattern and motion detection, or color discrimination, for example) and we can easily measure them. The VCS test measures the least amount of stimulation needed to detect a stationary pattern.

"As neurologic function decreases due to toxicity, more and more stimulation is needed to see the patterns," he explains.

The effect can be huge; the Pfiesteria cohort in one of Shoemaker and Hudnell's studies showed a 60 percent loss of VCS on average relative to controls.

"When we see VCS drops like this following exposure, and see it recover following treatment to eliminate the toxins, we're seeing an indication of how strongly the toxins may be affecting the entire nervous system," says Hudnell. "Of course, biotoxins don't just affect the nervous system. They trigger release of inflammatory agents in the body that can inflame almost any organ and cause multiple-system symptoms."

The theory

And that's where Shoemaker and Hudnell's theory begins, with biotoxins in the body that some people - as many as 10 million Americans - cannot naturally eliminate, resulting in many chronic illnesses.

The two men believe these poisonous chemical compounds continually circuit the human body, shuttling from nerve to muscle to brain to sinus to G.I. tract and other organs, triggering the familiar symptoms.

These symptoms are similar to those caused by infectious agents, and so is the effect they have on nerve, muscle, lung, intestines, brain and sinus, say the researchers.

Shoemaker and Hudnell say the compounds are manufactured by a growing number of microorganisms that thrive in our ecosystem due to changes in the human habitat.

"New biotoxins or toxin-forming organisms are being identified all the time," notes Hudnell.

Some, like the deer tick that passes along Lyme disease, do so directly. Toxin-forming bugs such as the fungi (Stachybotrys and others) that cause "sick-building syndrome" and the blue-green algae (Cylindrospermopsis and Microcystis) that poison people and animals in most of the lakes in Central Florida, do their work by releasing their toxins into air or water.

And although the pathogens differ, Shoemaker and Hudnell say the biotoxins they produce all do their damage by setting off a similar "exaggerated inflammatory response" in humans. While hiding out in fatty tissues where blood-borne disease-fighters can't get at them, they trick the body's immune system into launching attacks against joints, muscles, nerves and brain.

There is increasing evidence to show these attacks are carried out by a newly discovered group of molecules, the "pro-inflammatory cytokines," and that the destruction they cause is linked to recent surges in the rates of heart disease, obesity and diabetes. Illnesses once blamed solely on diet and life-style choices are now being shown to have an inflammatory basis.

And while infections cause a cytokine response from white blood cells, especially macrophages, the cytokine response to neurotoxins comes from fat cells.

"The body can turn off the macrophage cytokine response, so that the achiness, fever, headache and fatigue of a cold will go away, but there's no negative feedback that stops the cytokine response from fat cells," says Shoemaker. "So the illness doesn't self-heal." The team's research found that through typing of immune response genes, the HLA DR, they can show that individual susceptibility to particular neurotoxins is associated with particular genetic factors not found in others with a different neurotoxic illness or in controls. In other words, they're beginning to crack the code to show that some people are genetically predisposed to get certain chronic fatiguing illnesses.

But the research that links these things - the exaggerated inflammatory response, which may also involve an autoimmune response by a process called "molecular mimicry" -and its link to heart disease, for example, is in its infancy, so the medical community remains skeptical.

Nonetheless, Shoemaker thinks these provocative discoveries will eventually require researchers to confront the grim possibility that these organisms have learned how to skew immune responses by using powerful toxins to decimate the body's disease protection system. The diagnosis According to Shoemaker, a diagnosis of chronic, biotoxin-induced illness is based on biotoxin exposure potential, multiple system symptoms, the VCS deficit discovered by Dr. Hudnell, and no
other reasonable explanation for the illness. "As opposed to illnesses which have no supporting tests or biomarkers like
fibromyalgia, CFS, depression, irritable bowel disease, or just getting older, our approach gives the physician readily obtained hard data to use as a marker and, more importantly, as a monitor that changes dynamically with response to treatment," says Shoemaker. Hudnell points out that new tests for cytokine levels, hormone levels and blood flow in the microvasculature of the retina help characterize how biotoxins induce chronic illness. The new HLA genotype tests (the DNA PCR assays -not the serology or transplant tests) also help identify people who are at risk for developing chronic illness from particular biotoxins because they're unable to eliminate those toxins.

"Patients must have a compatible history, the deficit in VCS, the HLA genotype, an abnormal cytokine response, and the abnormal effects of cytokines on hypothalamic hormones, especially melanocyte stimulating hormone (MSH)," said Shoemaker. "All CFS patients should have the MSH test done."

Shoemaker and Hudnell's data show that there's a group of CSM treatment-resistant CFS patients who are coagulase negative Staph (CNS) positive and who have high leptin levels. Leptin is a hormone made by fat cells that signals the satiety center in the hypothalamus that a person is no longer hungry.

Leptin stimulates the production of alpha melanocyte stimulating hormone (MSH), which in turn controls production of endorphins (the body's natural "opiates") and melatonin (which regulates sleep) in the hypothalamus. CFS patients rarely have much MSH. Eradicating CNS does nothing to the high leptin and low MSH levels in patients with "end-stage CFS," says Shoemaker, but it certainly does in patients who are diagnosed acutely and treated aggressively, preventing irreversible damage to the MSH-manufacturing pathway.

"We must recognize that the process by which CFS develops may include an acute neurotoxic event which includes upper respiratory symptoms," says Shoemaker.

Shoemaker believes that the secondary cytokine damage from neurotoxic exposure changes the mucus membranes in the nose, allowing biofilm-forming, slow-growing CNS to release hemolysins (once called delta toxins) that in turn activate a powerful cytokine response. The boost in cytokines disrupts the leptin-MSH production link. This classic, positive feedback system increases cytokines and CNS and reduces MSH.

"While the data is certainly compatible with this model, I haven't asked for volunteers to put CNS in their noses to watch for
subsequent development of CFS," says Shoemaker jokingly. But the team has found particular genotypes of the immune response genes in HLA-DR that show marked consistency within a diagnosis group and marked disparity in other diagnostic groups.

Shoemaker won't yet say that the HLA DR genes or the abnormalities in the leptin/MSH pathway are the "Holy Grail" of CFS research, but will admit that there are unique HLA genes in his CFS patients; that his Sick Building Syndrome patients have at least three unique triplets of gene biomarkers; his Post-Lyme patients have two; and that these gene-types are quite different from each other. Is CFS an illness that includes a genetic susceptibility to particular neurotoxins, which trigger cytokines associated with carrying CNS, that produce nerve, hormone and immune system dysfunction in the ventromedial nucleus of the hypothalamus? Maybe, says Shoemaker.

"If our study shows that replacement of MSH improves many (or most!) of the abnormalities of CFS, I'll believe that," says Shoemaker. That study will be done after the animal studies required by the FDA are completed. They hope it will establish an effective MSH dose and the most effective method of MSH delivery, as well as confirm that symptoms reoccur when MSH is stopped, and then again show benefit when an effective does is reinstituted.

They'll do baseline VCS tests and MSH levels first, and will attempt to show that high levels of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha and leptin improve after treatment.

A longer trial is planned, pending initial results. That study, which will be done when funds are obtained, will also attempt to show that high levels of PAI-1 and leptin improve after treatment. Shoemaker believes PAI-1 is likely to be responsible for the extra clotting and vascular disease frequently found in CFS patients, and that once leptin levels fall, CFS patients who have gained weight will be able to lose it.

The website

Before you can take the CS exam at Dr. Shoemaker's web site (http://www.chronicneurotoxins.com), you have to register and get a log-in identity and password, as well as answer symptom and medical history questionnaires. Then you can buy a VCS test for $8.95, or a package with several tests and treatment protocols for $49.95. The preliminary test (a free questionnaire) assesses the symptoms commonly associated with biotoxin-induced illness, as well as your potential for exposure.

"Many symptoms of and potential exposures to biotoxins are not yet well known by physicians," says Shoemaker, "So they're easily overlooked."

After you take the test, your results are available immediately. They can also be sent to your physician. If your physician isn't familiar with the theory or protocol, the website mentions a list of referral physicians across the nation, or you can request to see Dr. Shoemaker in his Pokomoke City office. (A second part to this article will detail the author's diagnostic and treatment experiences at Dr. Shoemaker's clinic.)

The treatment protocol

Cholestyramine (CSM) is an FDA-approved medication which has been used to safely lower elevated levels of cholesterol for more than 20 years. It isn't absorbed; if it's not taken with food, it binds cholesterol, bile salts and biological toxins from bile in the small intestine, and then the CSM-toxin complex is excreted harmlessly. Science - or Shoemaker and Hudnell -doesn't have definitive answers yet as to exactly how or why CSM clears neurotoxins from the body, but a double-blind, placebo-controlled, cross-over clinical trial of eight Pfiesteria patients positive for biotoxins showed that those who took a placebo remained ill, but improved following CSM treatment. Data from 30 others he's gathered since matches the original study data.

Shoemaker says while some patients notice immediate improvements, Lyme disease patients who've been sick for more than five years usually require toxin-binding therapy for 4-8 weeks, he says. "Most patients improve in two weeks, some with complete abatement of symptoms, but depending on the amount of toxin in your body, it may take longer," says Shoemaker.

He believes the response of these patients to CSM therapy shows the underlying common theme of neurotoxin-mediated illness, and that the proof that toxins were responsible for the illness is found when patients recover, i.e., have no symptoms following treatment with his protocol.

"The proof of neurotoxin effect comes from watching the biomarkers change with treatment and relapse with re-exposure," says Shoemaker. "There's very strong evidence, especially in the Sick Building Syndrome patients." Hudnell agrees.

"The best evidence that biotoxins are causing the illnesses comes from cases with repeated illness," says the toxicologist. "When you see patients with chronic illness recover vision as symptoms resolve while being treated with a drug that can do nothing but remove compounds from circulation, then see vision plummet and symptoms return following re-exposure to sources of toxins, and finally see re-recovery with re-treatment, sometimes for three or four cycles, you become convinced that it's the toxins causing the illness."

In another study of 51 post Lyme disease patients treated with CSM after a tick bite, both those who tested positive and those who tested negative to Lyme had the same number of symptoms after treatment as matched controls. Shoemaker says that data from more than 500 other patients he's seen since matches the study data. Prior to treatment, the chronic Lyme disease patients had a statistically significant VCS deficit. Following treatment, all patients' clinical syndrome was gone; and their VCS scores and the number of symptoms were the same as that of the controls.

Some of these Lyme disease patients, especially those who'd been sick longer then three years, suffered what Shoemaker calls "a symptom intensification reaction" early in CSM therapy, similar to, but more intense than, the Herxheimer reactions experienced previously during antibiotic treatment. The reaction was reduced with pioglitazone (Actos) therapy or prevented by pretreatment with Actos, which downregulates proinflammatory cytokine production by fat cells. Patients who weren't reexposed to another tick bite didn't relapse, though follow-up was stopped at 18 months.

There are other diagnoses- chronic Ciguatera seafood poisoning, Possible Estuary Associated Syndrome, brown recluse spider bites and mycotoxicosis-that were thought to involve biotoxins, but for which there was no known, effective treatment. Shoemaker has treated patients with these illnesses successfully with cholestyramine, too. Over the years Hudnell has done studies that linked environmental exposure to neurotoxicants like airborne solvents and metals to adverse neurologic effects in humans, including VCS deficits. But there was no treatment for it.

"There was nothing I could do to help them, and the impairments were permanent," he said. "So I was ecstatic when we found that a simple treatment, taken for a short period of time, could benefit so many people who had suffered severe chronic illness due to biotoxins." News spreading Others have gotten excited about this research: Paul Cheney has used the VCS test and a modified version of the protocol to treat patients at his Bald Head Island Clinic in North Carolina.

Chuck Lapp, director of the Hunter Hopkins Center in Charlotte, NC, also plans to put one of the machines in his office. "A number of my patients have complained that I wear loud, patterned clothing, and that it bothers their vision when I wear a patterned tie, so I think there may be something to this," he said.

There are also almost 50 physicians in a nationwide referral network who are familiar with the VCS test and the treatment protocol; for more information, contact the website for the name and number of the doctor nearest you.

Recent advances

In June, Hudnell and Shoemaker presented data from their latest studies on Sick Building Syndrome and Post Lyme Syndrome at the 8th International Symposium on Neurobehavioral Methods and Effects in Occupational and Environmental Health in Brescia, Italy, where Dr. Hudnell chaired a session on biotoxins. Shoemaker co-chaired. Next, they plan to conduct human studies that will more definitively characterize the proinflammatory cytokine basis of chronic, biotoxin-induced illness, and describe the permanent damage that they think has occurred in the hypothalamic-pituitary-adrenal (HPA) axis of those who had the highest exposure levels for the longest periods of time.

They also want to do the animal studies and human trials needed for FDA approval of hormone replacement therapy that they think will help those with permanent damage. To that end, Dr. Shoemaker has established a not-for-profit corporation, the Center for Research on Biotoxin Associated Illness (CRBAI).

"If the research is to get done, CRBAI needs to raise funds through grants and donations from private organizations and individuals because there is virtually no Federal funding of research in this area," said Shoemaker.

In the meantime, he still sees patients every day in his Market Street office, many suffering from chronic, neurotoxic illnesses.
Both Shoemaker and Hudnell routinely get calls from all over the world asking for advice on toxic outbreaks and how to treat them. New patients are still taking the tests on the website and beginning CSM treatment.

So as physician William Osler advocated long before the advent of the biotoxin-mediated illness theory, to find the proper diagnosis, Ritchie Shoemaker listens to the patient.

"Recognizing the pattern of a neurotoxic illness is as subtle as being run over by a steamroller, once you learn how to ask the right questions," he says.

Physicians need to learn to ask the patient a few more questions in a new order-in essence, take an organized neurotoxin history, he says. "All our biomarkers and all our data and all our nice molecular models simply provide an academic foundation for what the bedside physician already knows to be true," insists Shoemaker. "The toxins did it."