Mycotoxins and Tick-Borne Disease: Increasingly Common Causes of Unexplained Chronic Pain

In the modern medical system, the search for the cause and cure for chronic pain often begins and ends with the consideration of a structural lesion as the sole etiology. Although these structural causes may be identifiable targets for intervention in many cases, there is a growing number of patients with chronic pain syndromes caused by environmentally acquired illnesses. Exposure to some infections and environmental toxins cause pain through unique biochemical pathways. Two of the most common (and increasingly seen) causes of chronic pain among the environmentally acquired illnesses are Lyme disease and mycotoxin exposure from contact with toxic mold species.

Lyme Disease

History

“Lyme arthritis” was first identified in Lyme, Connecticut, in 1975 after a cluster of cases of what was thought to be juvenile rheumatoid arthritis was reported.¹-² It was subsequently noted that additional symptoms were often present in patients with this disorder including a characteristic rash, neurologic signs and symptoms, and other constitutional symptoms such as fever, headache, fatigue, and myalgias. For this reason, the disorder eventually became known as “Lyme disease.” A few years later, investigators discovered³ that the cause of Lyme disease was infection with the spirochete, Borrelia burgdorferi, and improvement was seen in some patients with antibiotic treatment.⁴

Lyme disease (“Borreliosis”) was not a new' phenomenon, however. Tick-borne disease has been well-described in the world medical literature since the early part of the 1900s. In 2011, National Geographic published⁵ an article detailing findings of the autopsy the 5300-year-old mummy, Otzi. The article notes that Borrelia burgdorferi DNA was found in his tissue.

Epidemiology

Currently, the Centers for Disease Control (CDC) note that there are about 30,000 cases of Lyme disease reported yearly, although conservative estimates⁶ indicate that this might reflect underreporting with the true number of cases being about 10-fold higher. Once thought to be a disease entity confined only to the Northeastern United States, current reports from the CDC indicate that Lyme disease has been reported in every state except Hawaii.⁷ Lyme disease has also been reported in over 50 countries.⁸ Recently, researchers have compiled borrelial DNA data⁹ from over 11 million tick samples from the 48 contiguous United States and have used these data along w'ith information on forestation and topography to compose a map (called a Bayesian model), to help provide a risk forecast for pet owners which would predict the risk of Lyme disease transmission to pets based upon current location. As expected, the risk is greatest in the northeastern United States and in Michigan, but the maps show some southern and western spread in contiguous areas with some isolated high-prevalence areas noted in the western United States. As with human testing, it is difficult to tell w'ith tick testing whether current numbers reflect true epidemiological differences in prevalence versus biases due to under-reporting or under-testing.

Pain as a Clinical Presentation

Lyme disease is traditionally described as having three forms: early localized Lyme disease (3-30 days from the bite), early disseminated Lyme disease (3-5 weeks from the bite), and late Lyme disease.⁸ In early localized Lyme disease, patients may present with (or without) a known tick bite and a characteristic rash (erythema migrans). They may also have some constitutional symptoms such as a headache, myalgias, neck stiffness, and a fever. In the early disseminated form, patients may have multiple erythema migrans rashes, cranial nerve palsies (like bell’s palsy), carditis wfith cardiac arrhythmia, or meningitis. Conjunctivitis is seen as well. In late Lyme disease, patients often develop monoarticular arthritis of a large joint. Even after treatment with antibiotics, some patients with Lyme arthritis continue to have pain. It has been proposed that an autoimmune mechanism is responsible.¹⁰ Encephalitis, encephalopathy, and polyneuropathy may be seen as well. The original paper" describing these entities notes the fact that patients may improve with antibiotics and that later the symptoms may reoccur. It is the pattern of persistent, multi-system, and recurring symptoms in some patients w'hich has resulted in Lyme disease being called “the great imitator.”

Longitudinal studies of patients with confirmed Lyme disease indicate that these patients are 35% more likely to have complaints of chronic joint and muscle pain as well as other constitutional symptoms.¹² Because Lyme disease has such a varied clinical presentation and diagnosis is challenging (see below), patients may be diagnosed with a plethora of other conditions including depression, cognitive impairment, chronic fatigue syndrome, and fibromyalgia.

Molecular Mechanisms of Pain in Lyme Disease

Molecular mechanisms for pain as a result of infection with Borrelia have been studied previously in patients with Lyme neuroborreliosis.¹³ Pain is due to chemokines from Borrelia which stimulate an inflammatory response. Elevated levels of IL-6, IL-8, chemokine ligand 2, and CXCL13 and white blood cell pleocytosis have been noted in this same group of patients.¹⁴ Lymphokines from liberated T-cells may also contribute to inflammation and pain.¹⁵

Diagnosis of Lyme Disease

The definitive diagnosis of Lyme disease can be daunting for several reasons. As mentioned previously, the clinical manifestations can be varied in timing and may involve multiple bodily systems. The presence of a classical erythema migrans rash following a tick bite is considered pathognomonic, but the rash may vary in appearance. About 70-80% of patients develop this rash, but the appearance may vary, and it is recognized that only about 10% of patients with erythema migrans get a classic “target lesion.”¹⁶ The incubation between tick bite and the lesion may be as long as 30 days. It is also well known that only 50-70% of patients recall being bitten by a tick prior to diagnosis.¹⁷

Laboratory diagnosis of Lyme disease is also challenging. The Borrelia spirochete is notoriously hard to culture, may take 6 weeks to recover, and results of the culture process are fair at best.⁸ There are several reasons for this. First, the Lyme spirochete is only present in the bloodstream transiently.¹⁸ Skin biopsy of the periphery of the erythema migrans lesion recovers spirochetes in 80% of cases with 100% specificity but is rarely used since special culture media (Barbour-Stoenner-Kelly medium) and prolonged culture observation are required.¹⁸

The most common method currently used to support the diagnosis of Lyme disease involves measuring antibodies to Borrelia using some combination of ELISA or IFA testing and Western Blot testing (IgM and IgG).¹⁸ The current testing sequence recommended by the Centers for Disease Control (CDC) in the United States starts with an ELISA test or IFA test. These tests are reportedly very sensitive but not specific. In addition, the timing of testing may alter the sensitivity of the testing. The CDC recommends no further testing if the IFA or ELISA are negative. If positive, the CDC recommends Western Blot IgG and IgM testing for confirmation. Like IFA and ELISA testing, the sensitivity of the Western Blot tests can be affected by the timing of the test and other factors. A large meta-analysis on the subject of Lyme testing accuracy¹⁹ found that the current “two-tier” testing approach demonstrated a sensitivity of 57% across all stages of Lyme disease. This number increased to a sensitivity of about 99% for stage 3 Lyme disease detection. Specificity for the detection of Borellia burgdorferi was close to 99% for the commercially available IgG and IgM Western Blot. Other tests are available from various specialty laboratories which have higher sensitivities (from 70 to 90%) including immunoblot testing, PCR, and C6 peptide testing. Often, if patients have a positive IgM for Lyme and the exposure to the tick bite has been more than 30 days prior, the test is labeled a “false positive” and the patient is told they do not have Lyme disease. However, the peer-reviewed infectious disease literature confirms persistent positivity of the IgM antibody test for as long as 10-20 years in at least 10% of patients with proven Lyme disease.²⁰ Further complicating testing is the fact that the two-tiered test was originally designed for population surveillance of the disease and was not intended to be used as the sole criteria to make a diagnosis.²¹ The ability of current two-tier testing to detect newer species of Borrelia is unknowm.²² The most current Testing and Diagnostics Subcommittee’s Report to the Tick-Borne Disease Working Group²³ from the U.S. Department of Health and Human Services reiterated the fact that some patients fail to make antibodies in high enough titers to be measured by current testing.

Antibiotic Treatment of Lyme Disease

As difficult as testing for Lyme disease is, treatment may be even more challenging. As previously mentioned, patients with Lyme disease have varied clinical presentations as w'ell as varied periods from initial infection to discovery of the disease. Oral antibiotic therapy is used for most Lyme patients. Initial recommendations from the Infectious Disease Society of America (IDSA)²⁴ include doxycycline or a penicillin such as amoxicillin or cefuroxime. The recommended duration of treatment is 14-21 days. Intravenous antibiotics are recommended in cases of neuroborreliosis and for cardiac manifestations of the disease. There have been concerns, however, about the IDSA process for professional guideline development for Lyme disease diagnosis and treatment.²⁵ Among the concerns is the fact that persistence of symptoms is often seen after discontinuation of antibiotic treatment.²⁶ The conventional viewpoint is that these symptoms either do not occur or are immunologic phenomena unrelated to the persistence of infection. Researchers at Johns Hopkins have recently published an article²⁷ affirming the occurrence of “post-treatment Lyme disease syndrome” (PTLDS). In addition, studies have found that this persistence of infection can occur.²⁸-²⁹ It has also been shown that Lyme spirochetes have various mechanisms of immune evasion including the production of cystic forms and microcolonies.³⁰ For this reason, Lyme patients may require treatment with several antibiotics concomitantly or for prolonged periods of time.³¹ In this way, Borrelia is very similar to tuberculosis, for which multi-drug therapy is now' routine.

The International Lyme and Associated Disease Society (ILADS) is a literature-based organization composed of physicians, researchers, and other clinicians who study and treat Lyme disease. ILADS has been at the forefront of advances in the diagnosis and treatment of Lyme disease and tick-borne co-infections. ILADS favors diagnosis and treatment based upon clinical responses and advocates individualizing treatment. The organization has published evidence-based diagnostic and treatment guidelines.³²

Herbal Treatment of Lyme Disease

Various products are commercially available for herbal treatment of Lyme disease. There is grow'ing evidence for the efficacy of herbal preparations for treatment.³³-³⁵ Efficacy for these compounds has been demonstrated through in vitro studies. These products are still not considered first-line therapies by most physicians, as efficacy in patient populations (in vivo) has not been formally studied.

A Note on Co-Infections

It is well-known that co-infections of ticks with various pathogens including Babesia, Bartonella, and ehrlichiosis occur.³⁶ The CDC has listed several other co-infections and Borrelia variants on their website.³⁷ It is interesting to note that the CDC acknowledges that variant strains of Borrelia, such as Borrelia miyamotoi, Borrelia hermsii, B. parkerii, and B. turicatae, are not identified by current two-tier testing. The presence of co-infections often causes differences in clinical presentation and laboratory testing and may make treatment of the patient more challenging. Additional antimicrobials or a longer period of treatment is often required.