Lyme disease

Lyme disease
Specialty	Infectious diseases, dermatology, neurology, cardiology

Lyme Disease is caused by the spirochete spiral-shaped bacteria (spirochete) named "Borrelia burgdorferi", and is transmitted to humans by the bite of infected blacklegged ticks, (Ixodes scapularis), aka. deer ticks. Early manifestations of infection include fever, headache, fatigue, and a characteristic skin rash called erythema migrans. Left untreated, late manifestations involving the joints, heart, immune, and nervous system can occur.

Lyme Disease, or borreliosis, is an emerging infectious disease caused by at least three species of bacteria from the genus Borrelia. Infection is acquired from the bite of hard ticks belonging to several species of the genus Ixodes. Borrelia burgdorferi is the predominant cause of Lyme disease in the U.S., whereas Borrelia afzelii and Borrelia garinii are implicated in most European cases.

The disease presentation varies widely, and may include a rash and flu-like symptoms in its initial stage, then musculoskeletal, arthritic, neurologic, headaches,psychiatric and cardiac manifestations. In a majority of cases, symptoms can be eliminated with antibiotics, especially if diagnosis and treatment begins early in the course of illness. Late, delayed, or inadequate treatment can lead to "late stage or chronic" Lyme disease that can be disabling and difficult to treat. Controversy over diagnosis, testing and treatment has led to two different standards of care.

Cases of Lyme Disease has been documented in all 50 states in the US per the Centers for Disease Control(CDC).

Symptoms

The Lyme disease bacterium can infect several parts of the body, producing different symptoms at different times. Not all patients with Lyme disease will have all symptoms, and many of the symptoms can occur with other diseases as well. If you believe you may have Lyme disease, it is important that you consult your health care provider for proper diagnosis.

The first sign of infection is usually a circular rash called erythema migrans or EM. This rash occurs in approximately 70-80% of infected persons and begins at the site of a tick bite after a delay of 3-30 days. A distinctive feature of the rash is that it gradually expands over a period of several days, reaching up to 12 inches (30 cm) across. The center of the rash may clear as it enlarges, resulting in a bull's-eye appearance. It may be warm but is not usually painful. Some patients develop additional EM lesions in other areas of the body after several days. Patients also experience symptoms of fatigue, chills, fever, headache, and muscle and joint aches, and swollen lymph nodes. In some cases, these may be the only symptoms of infection.

Untreated, the infection may spread to other parts of the body within a few days to weeks, producing an array of discrete symptoms. These include loss of muscle tone on one or both sides of the face (called facial or "Bell's palsy), severe headaches and neck stiffness due to meningitis, shooting pains that may interfere with sleep, heart palpitations and dizziness due to changes in heartbeat, and pain that moves from joint to joint. Many of these symptoms will resolve, even without treatment.

After several months, approximately 60% of patients with untreated infection will begin to have intermittent bouts of arthritis, with severe joint pain and swelling. Large joints are most often affected, particularly the knees. In addition, up to 5% of untreated patients may develop chronic neurological complaints months to years after infection. These include shooting pains, numbness or tingling in the hands or feet, and problems with concentration and short term memory.

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Common bullseye rash pattern associated with Lyme Disease.

Characteristic "bulls-eye"-like rash caused by Lyme disease.

The acute phase of Lyme disease infection may, but not always present a reddish "bulls-eye" rash, with accompanying fever, malaise, and musculoskeletal pain (arthralgia or myalgia). The characteristic reddish "bull's-eye" rash (known as erythema migrans) may be seen in some early stage Lyme disease patients, appearing anywhere from one day to a month after a tick bite. The rash does not represent an allergic reaction to the bite, but a skin infection caused by the Lyme bacteria, Borrelia burgdorferi sensu lato. Not all individuals develop this rash and there is no clinical or scientific findings to prove that one must have the EM rash to have Lyme Disease.

The incubation period from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (days), or much longer (months to years). Symptoms most often occur from May through September because the nymphal stage of the tick is responsible for most cases. Asymptomatic infection exists but is found in less than 7% of infected individuals in the United States. Asymptomatic infection may be much more common among those infected in Europe.

Other, less common findings in acute Lyme disease include cardiac manifestations (up to 10% of patients may have cardiac manifestations including heart block and palpitations), and neurologic symptoms (neuroborreliosis may occur in up to 18%). In addition, simple altered mental status as the sole presenting symptom has been reported in early neuroborreliosis. Patients have been known to get Baker's cysts.

Chronic Symptoms

Cases may progress to a chronic form most commonly characterized by meningoencephalitis, cardiac inflammation (myocarditis), and frank arthritis. It should be noted, however, that chronic Lyme disease can have a multitude of symptoms affecting numerous physiological systems: the symptoms appear heterogeneous in the affected population, which may be due to innate immunity or variations in Borrelia bacteria. Late symptoms of Lyme disease can appear months or years after initial infection and often progress in cumulative fashion over time. Neuropsychiatric symptoms often develop much later in the disease progression, much like tertiary neurosyphilis.

In addition to the acute symptoms, chronic Lyme disease can be manifested by a wide-range of neurological disorders, either central or peripheral, including encephalitis or encephalomyelitis, muscle twitching, polyneuropathy or paresthesia, and vestibular symptoms or other otolaryngologic symptoms, among others. Neuropsychiatric disturbances can occur (possibly from a low-level encephalitis), which may lead to symptoms of memory loss, sleep disturbances, or changes in mood or affect. In rare cases, frank psychosis has been attributed to chronic Lyme disease effects, including mis-diagnoses of schizophrenia and bipolar disorder. Panic attack and anxiety can occur, also delusional behavior, including somatoform delusions, sometimes accompanied by a depersonalization or derealization syndrome similar to what was seen in the past in the prodromal or early stages of general paresis.

Cause

Main article: Lyme disease microbiology

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Borrelia bacteria, the causative agent of Lyme disease. Magnified 400 times.

Lyme disease is caused by Gram-negative spirochetal bacteria from the genus Borrelia. At least 37 Borrelia species have been described, 12 of which are Lyme related. The Borrelia species known to cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, and have been found to have greater strain diversity than previously estimated.

Until recently it was thought that only three genospecies caused Lyme disease: B. burgdorferi sensu stricto (predominant in North America, but also in Europe), B. afzelii, and B. garinii (both predominant in Eurasia). However, newly discovered genospecies have also been found to cause disease in humans. "There are over 300 strains of Borrelia world wide". It is presently unknown how many of these cause lyme, but some of them may.

Transmission

Ixodes scapularis, the primary vector of Lyme disease in eastern North America.

Hard-bodied ticks of the genus Ixodes are the primary vectors of Lyme disease. The majority of infections are caused by ticks in the nymph stage, as adult ticks are more easily detected and removed as a consequence of their relatively large size.

In Europe, the commonly known sheep tick, castor bean tick, or European castor bean tick (Ixodes ricinus) is the transmitter.

In North America, the black-legged tick or deer tick (Ixodes scapularis) has been identified as the key to the disease's spread on the east coast. Unfortunately, only about 20% of persons infected with Lyme disease by the deer tick are aware of having had any tick bite, making early detection difficult in the absence of a rash. Tick bites often go unnoticed due to the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. The lone star tick (Amblyomma americanum), which is found throughout the southeastern U.S. as far west as Texas, has been ruled out as a vector of the Lyme disease spirochete Borrelia burgdorferi[citation needed], though it may be implicated with a clinical syndrome southern tick associated rash illness (STARI), which resembles the skin lesions of Lyme disease.

On the west coast, the primary vector is the western black-legged tick (Ixodes pacificus). The preponderance of this tick species to feed on host species that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West.

While Lyme spirochetes have been found in insects other than ticks, reports of actual infectious transmission appear to be rare. Sexual transmission has been anecdotally reported; Lyme spirochetes have been found in semen and breast milk, however transmission of the spirochete by these routes is not known to occur.

Congenital transmission of Lyme disease can occur from an infected mother to fetus through the placenta during pregnancy, however prompt antibiotic treatment appears to prevent fetal harm.

Diagnosis

Lyme disease is a clinical diagnosis.

Lyme disease is diagnosed based on symptoms, objective physical findings (such as erythema migrans, facial palsy, or arthritis), and a history of possible exposure to infected ticks. Validated laboratory tests can be very helpful but are not generally recommended when a patient has erythema migrans.

When making a diagnosis of Lyme disease, health care providers should consider other diseases that may cause similar illness. Not all patients with Lyme disease will develop the characteristic bulls-eye rash, and many may not recall a tick bite. Laboratory testing is not recommended for persons who do not have symptoms of Lyme disease.

Laboratory Testing

Several forms of laboratory testing for Lyme disease are available, some of which have not been adequately validated. Most recommended tests are blood tests that measure antibodies made in response to the infection. These tests may be falsely negative in patients with early disease, but they are quite reliable for diagnosing later stages of disease.

CDC recommends a two-step process when testing blood for evidence of Lyme disease. Both steps can be done using the same blood sample.

1) The first step uses an ELISA or IFA test. These tests are designed to be very "sensitive," meaning that almost everyone with Lyme disease, and some people who don't have Lyme disease, will test positive. If the ELISA or IFA is negative, it is highly unlikely that the person has Lyme disease, and no further testing is recommended. If the ELISA or IFA is positive or indeterminate (sometimes called "equivocal"), a second step should be performed to confirm the results.

2) The second step uses a Western blot test. Used appropriately, this test is designed to be "specific," meaning that it will usually be positive only if a person has been truly infected. If the Western blot is negative, it suggests that the first test was a false positive, which can occur for several reasons. Sometimes two types of Western blot are performed, "IgM" and "IgG." Patients who are positive by IgM but not IgG should have the test repeated a few weeks later if they remain ill. If they are still positive only by IgM and have been ill longer than one month, this is likely a false positive.

CDC does not recommend testing blood by Western blot without first testing it by ELISA or IFA. Doing so increases the potential for false positive results. Such results may lead to patients being treated for Lyme disease when they don't have it and not getting appropriate treatment for the true cause of their illness. For detailed recommendations for test performance and interpretation of serologic tests for Lyme disease, please speak to your physician.

Other Types of Laboratory Testing

Some laboratories offer Lyme disease testing using assays whose accuracy and clinical usefulness have not been adequately established. These tests include urine antigen tests, immunofluorescent staining for cell wall-deficient forms of Borrelia burgdorferi, and lymphocyte transformation tests. In general, CDC does not recommend these tests. Click here for more information. Patients are encouraged to ask their physicians whether their testing for Lyme disease was performed using validated methods and whether results were interpreted using appropriate guidelines.

Testing Ticks

Patients who have removed a tick often wonder if they should have it tested. In general, the identification and testing of individual ticks is not useful for deciding if a person should get antibiotics following a tick bite. Nevertheless, some state or local health departments offer tick identification and testing as a community service or for research purposes. Check with your health department; the phone number is usually found in the government pages of the telephone book.

Due to the difficulty in culturing Borrelia bacteria in the laboratory, diagnosis of Lyme disease is typically based on the clinical exam findings and a history of exposure to endemic Lyme areas. The EM rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when serologies are negative. Serological testing can be used to support a clinically suspected case but is not diagnostic. Clinicians who diagnose strictly based on the U.S. Centers for Disease Control (CDC) Case Definition for Lyme may be in error, as the CDC explicitly states that this definition is intended for surveillance purposes only, and is "not intended to be used in clinical diagnosis."

Importantly, virtually no controlled studies of late Lyme encephalopathy have been performed, and the CDC diagnostic criteria were not formulated for use on this entity. Once Lyme disease is well established in the brain, it can occur as a very disabling diffuse encephalopathy which however is difficult to diagnose using standard serological or intrathecal testing for reasons outlined below . Lyme is a deep tissue infection and by the time encephalopathy is established, few if any CSF antibodies can be detected, and PCR is unreliable. Seronegative disease can occur for the same reason that this phenomenon occurs in neurosyphilis, with incomplete or intercurrent antibiotic treatment abrogating the serum antibody response, but not eliminating the infection.

It is in this context that advanced imaging studies like SPECT or PET can provide objective evidence of global brain dysfunction. Resort is often made to neuropsychological testing, but a normal result does not rule out the illness, which can be very subtle and manifest as a disabling mood disorder accompanied by massive and debilitating fatigue, with few objective signs.

Diagnosis of late-stage Lyme disease is often difficult due to the multi-faceted appearance which can mimic symptoms of many other diseases. For this reason, Lyme has often been called the new "great imitator". Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome (CFS), or other autoimmune and neurodegenerative diseases.

Tick Borne Co-Infections

Commonly called co-infections ticks that transmit Lyme Disease also carry several other parasitic diseases. Babesia infection is becoming more commonly recognized, especially in patients who have Lyme Disease. Ehrlichiosis is another common infection found among people with Lyme Disease. (Anaplasma phagocytophila, Human Granulocytic Ehrlichiosis HGE, Human Monocytic Ehrlichiosis HME ) It is also said that Bartonolla is another common co-infection

In fact the CDC's emerging infections diseases department did a study in rural New Jersey as follows;[1]

To assess the potential risk for other tick-borne diseases, we collected 100 adult Ixodes scapularis in Hunterdon County, a rapidly developing rural county in Lyme disease–endemic western New Jersey. We tested the ticks by polymerase chain reaction for Borrelia burgdorferi, Babesia microti, and the rickettsial agent of human granulocytic ehrlichiosis (HGE). Fifty-five ticks were infected with at least one of the three pathogens: 43 with B. burgdorferi, five with B. microti, and 17 with the HGE agent. Ten ticks were coinfected with two of the pathogens. The results suggest that county residents are at considerable risk for infection by a tick-borne pathogen after an I. scapularis bite.

Serology

The serological laboratory tests most widely available and employed are the Western blot and ELISA. A two-tiered protocol is recommended by the CDC: the more sensitive ELISA is performed first, if it is positive or equivocal, the more specific Western blot is run. The reliability of testing in diagnosis remains controversial, however studies show the Western blot IgM has a specificity of 94–96% for patients with clinical symptoms of early Lyme disease.

Erroneous test results have been widely reported in both early and late stages of the disease. These errors can be caused by several factors, including antibody cross-reactions from other infections including Epstein-Barr virus and cytomegalovirus, as well as herpes simplex virus.

Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. PCR tests are susceptible to false-positive results from poor laboratory technique. Even when properly performed, PCR often shows false-negative results with blood and CSF specimens. Hence PCR is not widely performed for diagnosis of Lyme disease. However PCR may have a role in diagnosis of Lyme arthritis as it is highly sensitive in detecting ospA DNA in synovial fluid. With the exception of PCR, there is no currently practical means for detection of the presence of the organism, as serologic studies only test for antibodies of Borrelia. High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to Borrelia antigens indicate disease, but lower titers can be misleading. The IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years.

Western blot, ELISA and PCR can be performed by either blood test via venipuncture or cerebrospinal fluid (CSF) via lumbar puncture. Though lumbar puncture is more definitive of diagnosis, antigen capture in the CSF is much more elusive; reportedly CSF yields positive results in only 10-30% of patients cultured. The diagnosis of neurologic infection by Borrelia should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.

New techniques for clinical testing of Borrelia infection have been developed, such as LTT-MELISA, which is capable of identifying the active form of Borrelia infection (Lyme disease). Others, such as focus floating microscopy, are under investigation. New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.

Imaging

Single photon emission computed tomography (SPECT) imaging has been used to look for cerebral hypoperfusion indicative of Lyme encephalitis in the patient. Although SPECT is not a diagnostic tool itself, it may be a useful method of determining brain function.

In Lyme patients, cerebral hypoperfusion of frontal subcortical and cortical structures has been reported. In about 70% of chronic Lyme disease patients with cognitive symptoms, brain SPECT scans typically reveal a pattern of global hypoperfusion in a heterogeneous distribution through the white matter. This pattern is not specific for Lyme disease, as it can also be seen in other central nervous system (CNS) syndromes such as HIV encephalopathy, viral encephalopathy, chronic cocaine use, and vasculitides. However, most of these syndromes can be ruled out easily through standard serologic testing and careful patient history taking.

The presence of global cerebral hypoperfusion deficits on SPECT in the presence of characteristic neuropsychiatric features should dramatically raise suspicion for Lyme encephalopathy among patients who inhabit or have traveled to endemic areas, regardless of patient recall of tick bites. Late disease can occur many years after initial infection. The average time from symptom onset to diagnosis in these patients is about 4 years. Because seronegative disease can occur, and because CFS testing is often normal, Lyme encephalopathy often becomes a diagnosis of exclusion: once all other possibilities are ruled out, Lyme encephalopathy becomes ruled in. Although the aberrant SPECT patterns are caused by cerebral vasculitis, a vasculitide, brain biopsy is not commonly performed for these cases as opposed to other types of cerebral vasculitis.

Abnormal magnetic resonance imaging (MRI) findings are often seen in both early and late Lyme disease. MRI scans of patients with neurologic Lyme disease may demonstrate punctuated white matter lesions on T2-weighted images, similar to those seen in demyelinating or inflammatory disorders such as multiple sclerosis, systemic lupus erythematosus (SLE), or cerebrovascular disease. Cerebral atrophy and brainstem neoplasm has been indicated with Lyme infection as well.

Diffuse white matter pathology can disrupt these ubiquitous gray matter connections and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status. White matter disease may have a greater potential for recovery than gray matter disease, perhaps because neuronal loss is less common. Spontaneous remission can occur in multiple sclerosis, and resolution of MRI white matter hyper-intensities, after antibiotic treatment, has been observed in Lyme disease.

Prevention

Attached ticks should be removed promptly. Protective clothing includes a hat and long-sleeved shirts and long pants that are tucked into socks or boots. Also, light-colored clothing makes the tick more easily visible before it attaches itself. Also people should use special care in handling and allowing outdoor pets inside homes as they can bring ticks into your house.

A more effective, community wide method of preventing Lyme disease is to reduce the numbers of primary hosts on which the deer tick depends such as rodents, other small mammals, and deer.

Another approach that has bee suggested is to reduce the deer population which over time helps break the reproductive cycle of the deer ticks and their ability to flourish in suburban and rural areas. Please see below.

The Connecticut Agricultural Experimentation published a Tick Management Handbook supported through a cooperative agreement with the Centers for Disease Control and Prevention (CDC). It is well researched and written. A link can be found below.

[2]

Management of host animals

Lyme and all other deer-tick borne diseases can be prevented on a regional level by reducing the deer population that the ticks depend on for reproductive success. This has been effectively demonstrated in the communities of Monhegan, Maine and in Mumford Cove, CT. The black-legged or deer tick (Ixodes scapularis) depends on the white-tailed deer for successful reproduction.

By reducing the deer population back to healthy levels of 8 to 10 per square mile (from the current levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates), the tick numbers can be brought down to very low levels, too few to spread Lyme and other tick-borne diseases.

Vaccination

A vaccine, called Lymerix, against a North American strain of the spirochetal bacteria was approved by the United States FDA on December 21, 1998. It was produced by GlaxoSmithKline (GSK) and was based on the outer surface protein A (OspA) of B. burgdorferi. OspA causes the human immune system to create antibodies that attack that protein.

A group of patients who took Lymerix developed arthritis, muscle pain and other troubling symptoms after vaccination. A class-action lawsuit against GSK was filed on December 14, 1999. Cassidy v. SmithKline Beecham, No. 99-10423 (Ct. Common Pleas, PA state court) (common settlement case). On February 26, 2002, GSK, citing poor sales, need for frequent boosters, the high price of the vaccine, and the exclusion of children, decided to withdraw Lymerix from the market. Some people believe that the actual reason was that the vaccine was neither safe nor effective. This was in addition to the numerous financial settlements made due to the vaccine.

While Lymerix was initially being marketed, it was learned that patients with the genetic allele HLA-DR4 were susceptible to T-cell cross-reactivity between epitopes of OspA and lymphocyte function-associated antigen in these patients causing an autoimmune reaction.

New vaccines are being researched using outer surface protein C (OspC) and glycolipoprotein as methods of immunization.

Removal of ticks

Many urban legends exist about the proper and effective method to remove a tick, however it is generally agreed that the most effective method is to pull it straight out with tweezers, making sure not to squeeze the tick or break it' head off. Another method is to wrap dental floss around the tick and then pull up to remove it. Gently pinch the tick and drag. Complete removal of the tick head is important; if the head is not completely removed, local infection of bite location may result. Data have demonstrated that prompt removal of an infected tick, within approximately 36 hours, reduces the risk of transmission to nearly zero percent ; however the small size of the tick, especially in the nymph stage may make detection difficult. Others however strongly disagree with this conclusion including thousands of individuals who have contracted Lyme Disease.

Treatment

Antibiotics are the primary treatment for Lyme disease, but the most appropriate antibiotic treatment varies from patient to patient and with the stage of the disease. The antibiotics of choice are doxycycline (in adults), amoxicillin (in children), and ceftriaxone. Alternative choices are cefuroxime and cefotaxime. Macrolide antibiotics have limited efficacy when used alone. Many physicians who treat chronic Lyme disease have noted that combining a macrolide antibiotic such as clarithromycin (biaxin) with hydroxychloroquine (plaquenil) is especially effective in treatment of chronic Lyme disease. This is suggested as being due to the hydroxychloroquine raising the pH of intracellular acidic vacuoles in which B. burgdorferi may reside; raising the pH is thought to activate the macrolide antibiotic, allowing it to inhibit protein synthesis by the spirochete.

Persons who remove attached ticks should be monitored closely for signs and symptoms of tick-borne diseases for up to 30 days. A three day course of doxycycline therapy may be considered for deer tick bites when the tick has been on the person for at least 12 hours. Patients should report any Erythema migrans over the subsequent two to six weeks. If there should be suspicion of disease, then a course of Doxycycline should be immediately given for ten days without awaiting serology tests which yield positive results only after an interval of one to two months.

Results of a recent double blind, randomized, placebo-controlled multicenter clinical study, done in Finland, indicated that oral adjunct antibiotics were not justified in the treatment of patients with disseminated Lyme borreliosis who initially received intravenous antibiotics for 3 weeks. The researchers noted the clinical outcome of said patients should not be evaluated at the completion of intravenous antibiotic treatment but rather 6-12 months afterwards. In patients with chronic post-treatment symptoms, persistent positive levels of antibodies did not seem to provide any useful information for further care of the patient.. However, this study has been criticized by ILADS, on the grounds that 1) treatment over years is often necessary to produce noticeable improvement in chronic Lyme patients and 2) the antibiotics used were cell wall antibiotics which may act relatively slowly against Lyme disease.

In later stages, the bacteria disseminate throughout the body and may cross the blood-brain barrier, making the infection more difficult to treat. Late diagnosed Lyme is treated with oral or IV antibiotics, frequently ceftriaxone, 2 grams per day, for a minimum of four weeks. Minocycline is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier.

Therapies for "post-Lyme syndrome"/"chronic Lyme disease"

Further information: Lyme disease controversy

Some Lyme disease patients who have completed a course of antibiotic treatment continue to have symptoms such as severe fatigue, sleep disturbance, and cognitive difficulties. It is currently unclear whether persisting symptoms following antibiotic treatment result from continuing low-level B. burgdorferi infection or from residual effects of the infection prior to treatment. Currently there are two sets of peer-reviewed published guidelines in the United States. The International Lyme and Associated Diseases Society (ILADS) advocates extended courses of antibiotics for chronic Lyme patients in light of evidence of persistent infection following "standard" antibiotic treatment of some Lyme disease patients. In contrast, the Infectious Diseases Society of America, which favors the term "post-Lyme syndrome" to describe the condition in these patients, does not believe persisting symptoms following standard antibiotic treatment results from chronic infection and does not recommend additional antibiotic treatment.

Three double-blind, placebo-controlled trials of long-term antibiotics for chronic Lyme have produced mixed results. In all three studies, the subjects had persisting symptoms despite being treated with a standard course of antibiotics for Lyme disease. The first published study failed to detect any benefit of a 90-day course of antibiotics. However, the patients enrolled in the study may have been unusually difficult to treat as suggested by their previous multiple antibiotic treatment failures and their lengthy illness prior to the study; hence the results may not be generalizable to others with post-Lyme syndrome. Further, the study has been criticized for failing to run the antibiotic treatment over a long enough period to take into account the very gradual improvement of chronic Lyme patients seen over many months or even years on antibiotics. The second clinical trial, which used slightly different enrollment criteria and outcome measures, noted improvement in disabling fatigue that was sustained for six months following antibiotic therapy. The most recent trial was published by a group known to favor prolonged treatment with antibiotics. They found that subjects with post-treatment cognitive impairment exhibited some improvement following intravenous cefriaxone treatment for 10 weeks. However, the cognitive gains were lost when the subjects were examined 14 weeks following treatment. There is disagreement with the interpretation of the data. ILADS believes that the relapse observed following the termination of antibiotic therapy is consistent with persistent infection with B. burgdorferi, whereas the lack of lasting improvement is cited in the editorial accompanying the article as evidence that prolonged antibiotic treatment is not helpful.

A controversial new guideline developed by the American Academy of Neurology, finds conventionally recommended courses of antibiotics are highly effective for treating nervous system Lyme disease. They find no compelling evidence that prolonged treatment with antibiotics has any benefit in treating symptoms that persist following previous standard antibiotic therapy. The new guideline was touted as independent corroboration of the IDSA guideline and was quickly endorsed by the IDSA. However ILADS has accused AAN of simply repackaging the IDSA guidelines as three coauthors of the new guideline, including the lead author, were also coauthors of the IDSA Lyme guideline. There is significant disagreement with this guideline (www.ilads.org).

Antibiotic-resistant therapies

Antibiotic treatment is the central pillar in the management of Lyme disease. In the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment. Lyme arthritis which is antibiotic resistant may be treated with hydroxychloroquine or methotrexate. Experimental data are consensual on the deleterious consequences of systemic corticosteroid therapy. Corticosteroids are not indicated in Lyme disease.

Antibiotic refractory patients with neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study. The immunomodulating, neuroprotective and anti-inflammatory potential of minocycline may be helpful in late/chronic Lyme disease with neurological or other inflammatory manifestations. Minocycline is used in other neurodegenerative and inflammatory disorders such as multiple sclerosis, Parkinsons, Huntington's disease, rheumatoid arthritis (RA) and ALS.

Alternative therapies

A number of other alternative therapies have been suggested, though clinical trials have not been conducted. For example, the use of hyperbaric oxygen therapy (which is used conventionally to treat a number of other conditions), as an adjunct to antibiotics for Lyme has been discussed. Though there are no published data from clinical trials to support its use, preliminary results using a mouse model suggest its effectiveness against B. burgdorferi both in vitro and in vivo. Anecdotal clinical research has shown potential for the antifungal azole medications such as diflucan in the treatment of Lyme, but has yet to be repeated in a controlled study or postulated a developed hypothetical model for its use.

Alternative medicine approaches include bee venom because it contains the peptide melittin, which has been shown to exert inhibitory effects on Lyme bacteria in vitro; no clinical trials of this treatment have been carried out, however.

Prognosis

For early cases, prompt treatment is usually curative. However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, simultaneous infection with other tick-borne diseases including ehrlichiosis, babesiosis, and bartonella, and immune suppression in the patient.

A meta-analysis published in 2005 found that some patients with Lyme disease have fatigue, joint and/or muscle pain, and neurocognitive symptoms persisting for years despite antibiotic treatment. Patients with late stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.

In rare cases, Lyme disease can be fatal.The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11.

Ecology

Urbanization and other anthropogenic factors can be implicated in the spread of the Lyme disease into the human population. In many areas, expansion of suburban neighborhoods has led to the gradual deforestation of surrounding wooded areas and increasing "border" contact between humans and tick-dense areas. Human expansion has also resulted in a gradual reduction of the predators that normally hunt deer as well as mice, chipmunks and other small rodents -- the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission to Lyme residents has greatly increased. Researchers are also investigating possible links between global warming and the spread of vector-borne diseases including Lyme disease.

The deer tick (Ixodes scapularis, the primary vector in the northeastern U.S.) has a two-year life cycle, first progressing from larva to nymph, and then from nymph to adult. The tick feeds only once at each stage. In the fall, large acorn forests attract deer as well as mice, chipmunks and other small rodents infected with B. burgdorferi. During the following spring, the ticks lay their eggs. The rodent population then "booms." Tick eggs hatch into larvae, which feed on the rodents; thus the larvae acquire infection from the rodents. (Note: At this stage, it is proposed that tick infestation may be controlled using acaricides (miticide)).

Adult ticks may also transmit disease to humans. After feeding, female adult ticks lay their eggs on the ground, and the cycle is complete. On the west coast, Lyme disease is spread by the western black-legged tick (Ixodes pacificus), which has a different life cycle.

The risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. New research suggests that eliminating deer from smaller areas (less than 2.5 ha or 6.2 acres) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots".

Epidemiology

Lyme disease is the most common tick-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States. Of cases reported to the United States Center for Disease Control (CDC), the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.

Although Lyme disease has now been reported in 49 of 50 states in the U.S, about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central). Charts and tables for Lyme disease statistics in the U.S. can be found at the CDC website. New 2008 CDC (Center for Disease Control) Lyme case definition guidelines are used to determine confirmed CDC surveillance cases. (online, http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm.) Effective January 2008, the CDC gives equal weight to laboratory evidence from 1) a positive culture for B. burgdorferi; 2) two-tier testing (ELISA screening and Western Blot confirming); or 3) single-tier IgG (old infection) Western Blot. Previously, the CDC only included laboratory evidence based on (1) and (2) in their surveillance case definition. The case definition now includes the use of Western Blot without prior ELISA screen.

The number of reported cases of the disease have been increasing, as are endemic regions in North America. For example, it had previously been thought that B. burgdorferi sensu lato was hindered in its ability to be maintained in an enzootic cycle in California because it was assumed the large lizard population would dilute the prevalence of B. burgdorferi in local tick populations, but this has since been brought into question as some evidence has suggested that lizards can become infected. Except for one study in Europe , much of the data implicating lizards is based on DNA detection of the spirochete and has not demonstrated that lizards are able to infect naive ticks feeding upon them . As some experiments suggest lizards are refractory to infection with Borrelia, it appears likely their involvement in the enzootic cycle is more complex and species-specific .

While B. burgdorferi is most associated with deer tick and the white tailed mouse, Borrelia afzelii is most frequently detected in rodent-feeding vector ticks, Borrelia garinii and Borrelia valaisiana appear to be associated with birds. Both rodents and birds are competent reservoir hosts for B. burgdorferi sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement pathway of various host species may determine its reservoir host association.

In Europe, cases of B. burgdorferi sensu lato infected ticks are found predominantly in Norway, Netherlands, Germany, France, Italy, Slovenia and Poland, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at Eurosurveillance website.

B. burgdorferi sensu lato infested ticks are being found more frequently in Japan, as well as in Northwest China and far eastern Russia. Borrelia has been isolated in Mongolia as well.

In South America tick-borne disease recognition and occurrence is rising. Ticks carrying B. burgdorferi sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of Borrelia has not yet been defined. The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo. B. burgdorferi sensu stricto antigens in patients have been identified in Colombia and in Bolivia.

In Northern Africa B. burgdorferi sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.

Lyme disease in sub-Saharan is presently unknown but evidence indicates that Lyme disease may occur in humans in this region. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa. In East Africa, two cases of Lyme disease have been reported in Kenya.

In Australia there is no definitive evidence for the existence of B. burgdorferi or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease. Cases of neuroborreliosis have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.

To date, data shows that Northern hemisphere temperate regions are most endemic for Lyme disease.

Controversy and politics

Main article: Lyme disease controversy

Most clinicians agree on the treatment of early Lyme disease infections. There is, however, considerable disagreement regarding prevalence of the disease, diagnostic criteria, treatment of late-stage Lyme disease, and the likelihood of chronic, antibiotic-resistant infections. Some authorities contend that Lyme disease is relatively rare, easily diagnosed with available blood tests, and most often easily treated with two to four weeks of antibiotics, while others propose that the disease is under-diagnosed, available blood tests are unreliable, and that extended antibiotic treatment is often necessary.

The majority of public health agencies such as the U.S. Centers for Disease Control maintain the former position. Published studies involving non-randomized surveys of physicians in endemic areas found physicians evenly split in their views, with the majority recognizing seronegative Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease, suggesting that there is much disagreement and confusion on this topic.

Some of the scientists involved in formulating what have become controversial Lyme diagnostic tests and treatment guidelines have been involved in both commercial vaccine and diagnostic test development, which some view as a conflict of interest. In response to these and other concerns expressed by the expanding national community of patients, Richard Blumenthal, the Attorney General of Connecticut has launched an investigation exploring possible conflicts of interest.

To date, federal research aimed at developing treatments for chronic Lyme disease is roughly $30 million, as contrasted to a $22 billion budget for military biodefense. Some scientists involved in Lyme treatment and diagnostic testing policy in the United States have a well publicized history in biodefense research. Several Lyme disease investigators, including Mark Klempner of Boston University, Jorge Benach of the State University of New York, and Alan Barbour of UC Irvine have recently received biodefense grants for BSL-3 and BSL-4 Labs where, critics contend, Lyme treatment research lacks transparency, accountability and focus on treatment research, though, it should be pointed out, that labs obtaining such grants are required to make their research findings publicly available via publication and focus their studies on issues pertinent to human health . Most people familiar with the field contend that the new grants and centers stimulate research by bringing together experts in the field and providing a stable source of funding.

The selection of leading Lyme researchers for such senior posts in biodefense and emerging infectious disease research has fueled conspiracy theories that suggest Lyme disease is clandestinely connected with biological warfare. Such lines of thought overlook the fact that the majority of infectious disease research is supported by the U.S. government via National Institutes of Health grants, and therefore the funding of Lyme disease research does not appear to be unusual.

In recent years, of a number of documents referring to the study of Lyme disease at facilities that also have BSL-4 (Biosafety Level 4) labs, the highest level of biocontainment which is reserved for highly infectious and deadly disease agents, has only served to stoke suspicion further. An example of one such document, which leads to this confusion, is a section on biocontainment in a 2003 letter from the director of a California Health Department concerning a bid for a biodefense grant, where possible research at a new lab is discussed. The mixture of infectious disease work from BSL-1 to BSL-4 level agents at such facilities appears to be the source of confusion on this issue - the biosafety level that research on a pathogen is conducted at remains relatively constant.

Consistently, disagreement on the exact guidelines for diagnosis and treatment of Lyme disease has been a source of controversy and high emotions. In October 2006, further controversy erupted with the release of updated diagnosis and treatment guidelines from the Infectious Diseases Society of America (IDSA). The new IDSA recommendations are more restrictive than prior IDSA treatment guidelines for Lyme, and now require either an EM rash or positive laboratory tests for diagnosis; seronegative Lyme disease is no longer acknowledged (except incidentally in early Lyme disease). The authors of the guidelines maintain that chronic Lyme disease does not result from persistent infection, and therefore treatment beyond 2-4 weeks is not recommended, even in late stage cases. An opposing viewpoint has been expressed by the International Lyme and Associated Disease Society (ILADS), which proposes extended antibiotic treatment beyond four weeks for both early and late Lyme disease. Hopefully future research will provide clarity on this issue.

On May 1st 2008, Connecticut Attorney General Richard Blumenthal announced news of a settlement in a landmark antitrust investigation into the Lyme Disease Treatment Guidelines Process of the Infectious Diseases Society of America (IDSA).

Blumenthal said "My office uncovered undisclosed financial interests held by several of the most powerful IDSA panelists, The IDSA's guideline panel improperly ignored, or minimized, consideration of alternative medical opinion and evidence regarding chronic Lyme disease, potentially raising serious questions about whether the recommendations reflected all relevant science."

"The IDSA guidelines have sweeping and significant impacts on Lyme disease medical care. They are commonly applied by insurance companies in restricting coverage for long-term antibiotic treatment or other medical care and also strongly influence physician treatment decisions."

"Insurance companies have denied coverage for long-term antibiotic treatment relying on these guidelines as justification. The guidelines are also widely cited for conclusions that chronic Lyme disease is nonexistent."

This finding forces a complete review of the IDSA guidelines by a new panel free from conflicts of interest, specifically excluding previous panel members. This panel will consider a range of scientific evidence in a public forum broadcast live over the internet and will be overseen by a specialist in financial conflicts of interest in medicine.

Connecticut Attorney General's-Official Press Release Attorney General's Investigation Reveals Flawed Lyme Disease Guideline Process, IDSA Agrees To Reassess Guidelines, Install Independent Arbiter [3]

Advancing immunology research

Long term persistence of T cell lymphocyte responses to B. burgdorferi as an "immunological scar syndrome" was hypothesized in 1990. The role of Th1 and interferon-gamma (IFN-gamma) in borrelia was first described in 1995. The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.

Inflammation

Further information: Innate immune system and Cell signaling networks

Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory immune process. This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation. These studies have shown a significant decrease in cytokine output of (IL-10), an upregulation of Interleukin-6 (IL-6), Interleukin-12 (IL-12) and IFN-gamma and disregulation in TNF-alpha predominantly.

These studies suggest that the host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. IFN-gamma alters gene expression by endothelia exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils.

Studies also suggest suppressors of cytokine signaling (SOCS) proteins are induced by cytokines, and T cell receptor can down-regulate cytokine and T cell signaling in macrophages. It is hypothesized that SOCS are induced by IL-10 and B. burgdorferi and its lipoproteins in macrophages, and that SOCS may mediate the inhibition of IL-10 by concomitantly elicited cytokines. IL-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators.

Researchers are also beginning to identify microglia as a previously unappreciated source of inflammatory mediator production following infection with B. burgdorferi. Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis. This effect is associated with induction of nuclear factor-kappa B (NF-KB) by Borrelia.

Disregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in Borrelia infected patients. IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease.IL-6 is also significantly indicated in cognitive impairment.

Neuroendocrine

Further information: Signal transduction

A developing hypothesis is that the chronic secretion of stress hormones as a result of Borrelia infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically glucocorticoids and catecholamines, the major stress hormones. This process is mediated via the Hypothalamic-pituitary-adrenal axis. Additionally Tryptophan, a precursor to serotonin appears to be reduced within the CNS in a number of infectious diseases that affect the brain, including Lyme. Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric disorders developing in some patients with borreliosis.

Antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a psycho-neuroimmunological process. Antidepressants have also been shown to suppress Th1 upregulation.These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal pharmacotherapy of antibiotic refractory Lyme patients.

New developments

New research has also found that chronic Lyme patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells. The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from Borrelia.

The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the Borrelia bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern. This interpretation must however be considered against the evidence (above) for persistence of the 'spore' form of Borrelia in human and animal hosts, and the tendency for relapses to occur after antibiotics are continued. It is possible that whereas some chronic Lyme patients retain actual populations of live spirochaetes, others have symptoms brought on only by an inflammatory or auto-immune reaction.

Researchers hope that this new developing understanding of the biomolecular basis and pathology of cell-mediated signaling events caused by B. burgdorferi infection will lead to a greater understanding of immune response and inflammation caused by Lyme disease and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.

History

The early European studies of what is now known as Lyme disease described its various skin manifestations. The first such study dates to 1883 in Wrocław, Poland (then known as Breslau, Germany) where physician Alfred Buchwald described a man who had suffered for sixteen years with a degenerative skin disorder now known as acrodermatitis chronica atrophicans. At a 1909 research conference, the Swedish dermatologist Arvid Afzelius presented a study about an expanding, ring-like lesion he had observed in an older woman following the bite of a sheep tick. He named the lesion erythema migrans. The skin condition now known as borrelial lymphocytoma was first described in 1911.

Neurological problems following tick bites were recognized starting in the 1920s. French physicians Garin and Bujadoux described a farmer with a painful sensory radiculitis accompanied by mild meningitis following a tick bite. A large ring-shaped rash was also noted, although the doctors did not relate it to the meningoradiculitis. In 1930, the Swedish dermatologist Sven Hellerstrom was the first to propose that EM and neurological symptoms following a tick bite were related. In the 1940s, German neurologist Alfred Bannwarth described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions.

Carl Lennhoff, who worked at the Karolinska Institute in Sweden, believed that many skin conditions were caused by spirochetes. In 1948, he used a special stain to microscopically observe what he believed were spirochetes in various types of skin lesions, including EM. Although his conclusions were later shown to be erroneous, interest in the study of spirochetes was sparked. In 1949, Nils Thyresson, who also worked at the Karolinska Institute, was the first to treat ACA with penicillin. In the 1950s, the relationship among tick bite, lymphocytoma, EM and Bannwarth's syndrome were recognized throughout Europe leading to the widespread use of penicillin for treatment in Europe.

In 1970 a dermatologist in Wisconsin named Rudolph Scrimenti recognized an EM lesion in a patient after recalling a paper by Hellerstrom that had been reprinted in an American science journal in 1950. This was the first documented case of EM in the United States. Based on the European literature, he treated the patient with penicillin.

The full syndrome now known as Lyme disease was not recognized until a cluster of cases originally thought to be juvenile rheumatoid arthritis was identified in three towns in southeastern Connecticut in 1975, including the towns Lyme and Old Lyme, which gave the disease its popular name. This was investigated by Dr David Snydman and Dr Allen Steere of the Epidemic Intelligence Service, and by others from Yale University. The recognition that the patients in the United States had EM led to the recognition that "Lyme arthritis" was one manifestation of the same tick-borne condition known in Europe.

Before 1976, elements of B. burgdorferi sensu lato infection were called or known as tickborne meningopolyneuritis, Garin-Bujadoux syndrome, Bannworth syndrome, Afzelius syndrome, Montauk Knee or sheep tick fever. Since 1976 the disease is most often referred to as Lyme disease, Lyme borreliosis or simply borreliosis.

In 1980 Steere, et al, began to test antibiotic regimens in adult patients with Lyme disease In 1982 a novel spirochete was cultured from the mid-gut of Ixodes ticks in Shelter Island, New York, and subsequently from patients with Lyme disease. The infecting agent was then identified by Jorge Benach at the State University of New York at Stony Brook, and soon after isolated by Willy Burgdorfer, a researcher at the National Institutes of Health, who specialized in the study of spirochete microorganisms such as Borrelia and Rickettsia. The spirochete was named Borrelia burgdorferi in his honor. Burgdorfer was the partner in the successful effort to culture the spirochete, along with Alan Barbour.

After identification B. burgdorferi as the causative agent of Lyme disease, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin and intravenous ceftriaxone. The mechanism of tick transmission was also the subject of much discussion. B. burgdorferi spirochetes were identified in tick saliva in 1987, confirming the hypothesis that transmission occurred via tick salivary glands.

External links

General

• Compilation of academic literature and electron micrographs on the existence and basis of chronic Lyme infection
• Template:Dmoz
• CDC Lyme disease page
• Columbia University - Overview of Neuropsychiatric Lyme Disease
• Eurosurveillance: Lyme disease in Europe
• Lyme Disease The Merck Manual
• US Army Factsheet on Lyme Disease (CHPPM's Entomological Sciences Program)
• National Institute for Occupational Safety and Health - Lyme Disease Page

Images

• Collection of micrographs and academic literature on the 'spore' form of Lyme
• Factsheet on Lyme Disease (Hardin MD/Univ of Iowa)
• Interactive Image of Ixodes scapularis, Deer Tick or Blacklegged Tick (CHPPM's Entomological Sciences Program)

Professional societies, foundations, advocacy

• Template:Dmoz
• National Research Fund of Tick-Borne Diseases
• Lyme Disease Research Foundation of Maryland

Other

• Lyme.startpagina.nl: Professional link-site with 100+ links to Lyme-sites
• Lyme Disease Medical Literature Summaries
• Lyme Disease Research Database
• Prehistoric Lyme - (The History of Lyme Disease) Lymenet Newsletter Volume: 1 Issue: 24 25-Oct-93