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Medical condition
Lyme disease
SpecialtyInfectious diseases, dermatology, neurology, cardiology Edit this on Wikidata

Lyme disease (Borreliosis) is a bacterial infection with a spirochete from the species complex Borrelia burgdorferi, which is most often acquired from the bite of an infected Ixodes, or black-legged, tick, also known as a deer tick. The deer tick is not the only carrier of this disease. The deer tick is frequently mistaken for a dog tick which is more common and larger in size. Borrelia burgdorferi sensu stricto is the predominant cause of Lyme disease in the U.S.; Lyme disease in Europe is more often caused by Borrelia afzelii or Borrelia garinii.

The disease varies widely in its presentation, which may include a rash and flu-like symptoms in its initial stage, followed by the possibility of musculoskeletal, arthritic, neurologic, psychiatric and cardiac manifestations. In most cases of Lyme disease, symptoms can be eliminated with antibiotics, especially if treatment is begun early in the course of illness.

A percentage of patients with Lyme disease have symptoms that last months to years after treatment with antibiotics. These symptoms can include muscle and joint pains, arthritis, stiff neck, cognitive defects, neurological complaints or fatigue. The cause of these continuing symptoms is not yet known. There is some evidence that they may result from an autoimmune type of response, in which a person’s immune system continues to respond even after the infection has been cleared, as well as evidence of ongoing infection with the spirochete.

Delayed or inadequate treatment may often lead to "late stage" Lyme disease that is disabling and difficult to treat. Amid great controversy over diagnosis, testing and treatment, two different standards of care for Lyme disease have emerged.

History

The first record of a condition associated with Lyme disease dates back to 1883 in Breslau, former Germany, where a physician named Alfred Buchwald described a degenerative skin disorder now known as Acrodermatitis Chronica Atrophicans.

In a 1909 meeting of the Swedish Society of Dermatology, Arvid Afzelius presented research about an expanding, ring like lesion he had observed. Afzelius published his work 12 years later and speculated that the rash came from the bite of an Ixodes tick, meningitic symptoms and signs in a number of cases and that both sexes were affected. This rash is now known as erythema migrans (EM), the skin rash found in early stage Lyme disease.

In the 1920s, French physicians Garin and Bujadoux described a patient with meningoencephalitis, painful sensory radiculitis, and erythema migrans following a tick bite, and they postulated the symptoms were due to a spirochetal infection. 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.

In 1948 spirochete-like structures were observed in skin specimens by Swedish dermatologist Carl Lennhoff.In the 1950s relations between tick bite, lymphocytoma, EM and Bannwarth's syndrome are seen throughout Europe leading to the use of penicillin for treatment.

Interest in tick-borne infections in the U.S. began with the first report of tick-borne relapsing fever (Borrelia hermsii) in 1915, following the recognition of five human patients in Colorado. In 1970 a physician in Wisconsin named Rudolph Scrimenti reports the first case of EM in U.S. and treats it with penicillin based on European literature.

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 Allen Steere, and 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 Borrelia 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 scientist at the National Institutes of Health, who specialized in the study of spirochete microorganisms. 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 of the Lyme disease agent, Borrelia burgdorferi, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin and intravenous ceftriaxone.

After the isolation of the spirochete from the mid-gut of Ixodes ticks, how ticks actually transmitted this new pathogen was the subject of much discussion. The hypothesis that Lyme disease spirochetes were transmitted via the salivary gland route of Ixodes ticks was confirmed when spirochetes were actually identified in tick saliva in 1987.

Microbiology

Main article: Lyme disease microbiology
File:Borrelia image.jpg
Borrelia bacteria, the causative agent of lyme disease. Magnified 400 times.

Lyme disease is caused by spirochetal bacteria from the genus Borrelia, which has at least 37 known species, 12 of which are Lyme related, and an unknown number of genomic strains. 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.

Borrelia is a gram negative bacterium.

Transmission

By ticks

Hard-bodied (Ixodes) ticks are the primary Lyme disease vectors. There have also been reports of lyme disease from cats and kittens. In Europe, Ixodes ricinus (known commonly as the sheep tick, castor bean tick, or European castor bean tick) is the transmitter. In North America, Ixodes scapularis (black-legged tick or deer tick) has been identified as the key to the disease's spread on the east coast, while on the west coast the primary vector is Ixodes pacificus (Western black-legged tick). It is important to note that the majority of infections are caused by ticks in the nymph stage, as adult ticks do not become infected through feeding.

Another possible vector is Amblyomma americanum (Lone Star tick), which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well.

It is believed that the longer the duration of tick attachment, the greater the risk of disease transmission; typically, for the spirochete to be transferred, the tick must be attached for a minimum of 24 hours, although only the first part of this statement can be said to be strictly correct. (See Removal of ticks.)

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 usually 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.

New research suggests that transmission can occur within a few hours of tick attachment, and that the rate of transmission by infected ticks may be much higher than previously assumed.

Congenital

Lyme disease can be transmitted from an infected mother to fetus through the placenta during pregnancy, possibly resulting in stillbirth. The risk of transmission is minimized if the mother receives prompt antibiotic treatment. Antibiotics that can be given to pregnant women with Lyme disease include amoxicillin, cefuroxime axetil, or penicillin (oral or intramuscular).

Other

There is at least one case report of transmission by a biting fly. Lyme spirochetes have been found in biting flies as well as mosquitos. Some researchers believe biting insects do not feed long enough to transmit the infection, while others including Borrelia burgdorferi discoverer Willy Burgdorfer believe more research is needed. Sexual transmission has been anecdotally reported; Lyme spirochetes have been found in semen and breast milk, however sexual transmission of the spirochete by these routes is not known to occur.

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.

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 Borrelia burgdorferi sensu lato couldn't be maintained in an enzootic cycle in California because it was assumed the large lizard population would dilute the prevalence of Borrelia burgdorferi in local tick populations, but this has since been proven false as lizards are now known carriers of ticks in North America, Europe and North Africa. Indeed, the DNA of Borrelia has been detected in lizards, indicating that they can be infected.

Whereas Borrelia 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 Borrelia 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 Borrelia 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.

Borrelia 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 Borrelia 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. Borrelia burgdorferi sensu stricto antigens in patients have been identified in Colombia and in Bolivia.

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

In Western and sub-Saharan Africa, tick-borne relapsing fever was first identified by the British physicians Joseph Dutton and John Todd in 1905. Borrelia in the manifestation of Lyme disease in this region is presently unknown but evidence indicates that Lyme disease may occur in humans in sub-Saharan Africa. 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.

Prevention

The best prevention involves avoiding areas in which ticks are found; this can reduce the probability of contracting Lyme disease. Other good prevention practices include wearing clothing that covers the entire body when in a wooded area; using mosquito/tick repellent; after exposure to wooded areas, checking all parts of the body (including hair) for ticks.

For clothing, you should wear long-sleeve shirts and pants that are tucked into socks or boots. One should also wear light-colored clothing so that you can see the tick on you before it attaches itself.

Vaccination

A vaccine against a North American strain of the spirochetal bacteria was available between 1998 and 2002 by GlaxoSmithKline (GSK) called Lymerix and was based on the outer surface protein A (Osp-A) of Borrelia. Osp-A causes creation of antibodies from the body's immune system to attack that protein. When taking it off the market, GSK cited poor sales, need for frequent boosters, the high price of the vaccine, and exclusion of children. Some people believe that the actual reason was that the vaccine was neither safe nor effective. A group of patients who took Lymerix developed arthritis, muscle pain and other troubling symptoms after vaccination. Class-action litigation against GSK followed. Cassidy v. SmithKline Beecham, No. 99-10423 (Ct. Common Pleas, PA state court) (common settlement case).

It was later 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 (Osp-C) and glycolipoprotein as methods of immunization.

Removal of ticks

There are many urban legends about the proper and effective method to remove a tick. One legend states that something hot (cigarette; burnt match) should be applied to the back of the tick, which causes the tick to remove its head from the victim. It further states that ticks "screw" their heads into their victims; therefore, one must "unscrew" the head. These legends are incorrect and potentially dangerous because if a tick is disturbed it may regurgitate its stomach contents into the host including the agents of tick borne disease if the tick is infected.

Proper removal of a tick: use a pair of tweezers, grab the head of the tick near the mouth, and pull it straight out, no turning or twisting. The area should then be disinfected with rubbing alcohol or hydrogen peroxide. If the head is not completely removed, local infection of the person/animal bitten may result, and a doctor should be consulted (or a veterinarian if the tick was removed from a pet). It is important not to handle the tick with bare hands or let it crawl on you because simply touching a tick that has RMSF (Rocky Mountain Spotted Fever) may transmit that infection.

An alternate method that does not risk squeezing the tick's thorax (causing regurgitation of bodily fluids into the wound) uses 18 inches of sewing thread. The thread is tied in a simple overhand knot that is tightened slowly around the tick's head. If both ends of the thread are pressed against the skin while gently pulling, the knot will tighten around the tick's head. Slowly pulling the ends of the thread will then dislodge the tick from the bite site with a reduced chance of leaving the head attached. This method also works with fine weight fishing line.

Symptoms

Acute (early) symptoms

The incubation period from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (a couple of 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 uncommon. Early symptoms of Lyme disease may be heterogeneous and nonspecific and include:

Bull's-eye-like rash caused by Lyme disease.
  • Rash

Patients may have an expanding rash, erythema migrans (EM), at the site of the tick bite. Most patients with EM do not recall a deer tick bite. The characteristic "bull's-eye" rash with central clearing is not the most common form; homogeneously red rashes are more frequent.

The rash is classically 5 to 6.8 cm in diameter appearing as an annular homogenous erythema (59%), central erythema (30%), central clearing (9%), or central purpura (2%). EM may be less than 5 cm in diameter. Multiple painless EM rashes may occur, indicating disseminated infection.

The true incidence of the rash is disputed, with estimates ranging from less than 50% to over 80% of those infected. Because of the "bull's-eye" description to describe the Lyme disease rash, the condition commonly called ringworm is sometimes confused with Lyme disease.

Late stage symptoms

Lyme disease in its tertiary form can have a multitude of symptoms. The symptoms appear heterogeneous in the infected population, which may be due to innate immunity or Borrelia sub-species bacterium. The late symptoms of Lyme disease can appear months after initial infection and often progress in cumulative fashion over time. Neuro-psychiatric symptoms often develop much later in disease sequence, much like tertiary neurosyphilis.

Physical:

Neurological (can effect central or peripheral components):

Neuropsychiatric:

Diagnosis

The most reliable method of diagnosing Lyme disease is a clinical exam by an experienced practitioner, taking into account symptoms, history, and possible exposure to ticks in an endemic area. Clinicians who diagnose strictly based on the U.S. Centers for Disease Control (CDC) Case Definition for Lyme are 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."

The EM rash, which does not occur in all cases, is considered sufficient to make a diagnosis of Lyme disease and prompt treatment without further testing. In fact because of the undisputed high rate of false negatives during the early stage of the disease (before a sufficient antibody response has been established), it is recommended that tests not be performed when a patient has an EM rash.

Serology

The serological laboratory tests most widely available and employed are the Western blot and ELISA. In the two-tiered protocol recommended by the CDC according to their case definition, the ELISA is performed first, and if it is positive or equivocal, a Western blot is then performed to support the diagnosis. The reliability of testing in diagnosis remains controversial (see Lyme disease controversy#Testing). However studies show the Western blot IgM has a specificity of 94-96% for patients with symptoms suggestive of Lyme disease with infection by Borrelia burgoferi.

False-negative test results have been widely reported in both early and late disease. False Negatives can take place for a broad spectrum of reasons, including cross reaction of other infections such as cytomegalovirus. and herpes simplex type virus 2.

Polymerase chain reaction (PCR) tests for Lyme disease may also be available to the patient. A PCR test attempts to detect the genetic material (DNA) of the Lyme disease spirochete, whereas the Western blot and ELISA tests look for antibodies to the organism. PCR tests are rarely susceptible to false-positive results but can often show false-negative results. PCR reliability is still questioned. The low number of spirochetes in tissue samples and body fluids is one of the reasons why it is difficult to demonstrate Borrelia burgdorferi active infection by PCR, especially in the late stage of the disease.

With the exception of PCR testing, currently there is no 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 cerebral spinal 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.A negative result obtained by these methods can never exclude Lyme disease. However, a positive result can confirm the diagnosis or treatment failure independently of results of antibody tests.

New tests being studied for commercial use for Borrelia infection hold more promise for unequivocal testing than the the standard commercial laboratory tests now available. These include Lymphocyte transformation tests, aka LTT-MELISA(R), and focus floating microscopy (FFM). New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.

Skin biopsy can be used to confirm infection of Borrelia but it usually reserved for research work and not used in the clinical setting.

Imaging

SPECT imaging is often used to look for cerebral hypoperfusion indicative of Lyme encephalitis in the patient. SPECT is not a diagnostic tool in and of itself, but it a useful method of determining brain function.

In Lyme patients cerebral hypoperfusion of frontal subcortical and cortical structures is usually found. 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 definite or specific for Lyme disease per se, as it can also be seen in other central nervous system (CNS) syndromes such as HIV encephalopathy, viral encephalopathy, chronic cocaine use, and vasculitides. The pattern found in Lyme patients is different from what one would see with normal controls or patients with depression or Alzheimer's.

MRI findings which are abnormal are often seen in both early and late Lyme disease. MRI scans among patients with neurologic Lyme disease may demonstrate punctated 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 hyperintensities, after antibiotic treatment, has been observed in Lyme disease.

Diagnosis of Late Stage Lyme Disease

In late stage Lyme disease it is often difficult to diagnose due to the multi-faceted appearance which can mimic symptoms of many ailments of better known 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, which leaves the infection untreated and allows it to disperse and invade various organs and tissue.

Some of these conditions may be misdiagnosed as Lyme disease, due to the wide range of symptoms found in Lyme disease, the questionable serology testing available, or due to physicians using Lyme disease as an explanation for an unknown malady.

Treatment

The mainstay of treatment for Lyme disease is antibiotics. Penicillin was first demonstrated by researchers to be useful against Borrellia in the 1950s. Today the antibiotics of choice are doxycycline, amoxicillin and ceftriaxone. Macrolide antibiotics are also used.

  • Doxycycline - bacteriostatic properties stops synthesis of bacteria replication. Inhibits bacterial protein synthesis.
  • Amoxicillin - bacteriostatic properties do not kill bacterium, but do halt bacterial growth by inhibition of cell wall synthesis.
  • Ceftriaxone - (intravenous therapy) bactericidal properties kill bacterium. Has central nervous system penetration.

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 be advised to 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 only yield positive results after an interval of one to two months.

Traditional treatment of acute Lyme disease usually consists of a minimum two-week to one-month course of antibiotics, either doxycycline 100-200mg or amoxicillin 1500-2000mg per day.

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.

Antibiotic Treatment Controversy

Further information: Lyme disease controversy

With little research conducted specifically on treatment for late/chronic Lyme disease, treatment remains controversial. 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, while the Infectious Diseases Society of America does not recognize chronic infection and recommends no treatment for persistent symptoms. Double-blind, placebo-controlled trials of long-term antibiotics for chronic Lyme have produced mixed results.

An new guidelines 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 standard therapy. The guideline is endorsed by the Infectious Diseases Society of America (IDSA). The guideline leader was John J. Halperin and was co-written by Gary Worsmer and Eugene Shapiro. Halperin, Worsmer and Shapiro were all co-authors of the IDSA Lyme guidelines released in 2006 by the Journal of Clinical Infectious Diseases.

The latest double blind, randomized, placebo-controlled multicenter clincal study, done in Finland, results 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.

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.

Experimental data is consensual on the deleterious consequences of systemic corticosteroid therapy. Corticosteroids are not indicated in Lyme disease.

Lyme arthritis which is antibiotic resistant may be treated with hydroxychloroquine or methotrexate.

Antibiotic refractory patients with neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study. The average dose leading to a clear-cut pain reduction was 700 mg.

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, Huntingtons disease, Rheumatoid Arthritis (RA) and ALS. A multi-center study is warranted.

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 Borrelia burgdorferi both in vitro and in vivo.

Alternative medicine approaches include bee venom because it contains the peptide melittin, which has been shown to exert profound inhibitory effects on lyme bacteria in vitro. The herb andrographis, though not specifically studied for Borrelia species, has been found to have both antimalarial and antibacterial properties against a wide range of organisms in vitro and in vivo, leading some herbalists to recommend it for Lyme.

Manufacturers of concentrated active garlic extract, Allicin, have recently reported results of their first clinical trial for Lyme Disease patients. The study is unpublished.

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.

Anecdotal evidence also shows a potential for intravenous ascorbic acid chelation therapy.

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 (sometimes resulting from inappropriate treatment with steroids).

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. The disease can be fatal in and of itself; deaths have been reported. The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11.

Controversy

Main article: Lyme disease controversy

There is no doubt that Lyme disease exists, and most clinicians agree on the treatment of early Lyme disease. There is, however, considerable controversy as to the prevalence of the disease, the proper procedure for diagnosis and treatment of later stages, and the likelihood of a chronic, antibiotic-resistant Lyme infection. On one side are those who believe that Lyme disease is relatively rare, easily diagnosed with available blood tests, and most often easily treated with two to four weeks of antibiotics. On the other side are those who believe that Lyme disease is under-diagnosed, that 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. While this narrower position is sometimes described as the "mainstream" view of Lyme disease, 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.

In recent years a few prominent American Lyme researchers have received funding for the study of organisms known as bioweapons that could be used in bioterrorism attacks. The funding has been granted by various U.S. Government agencies including the National Institute of Health (NIH), and the National Institute of Allergy and Infectious Diseases (NIAID).

In 2003, Lyme researcher Dr. Mark Klempner was appointed the head of a new National Bio-containment Laboratory at Boston University Medical Center called the National Emerging Infectious Diseases Laboratory. In 2004, Dr. Jorge Benach was chosen as a recipient for a $3 million NIH research grant at the State University of New York at Stony Brook,. In 2005 Dr. Alan Barbour of University of California, Irvine was awarded $40 million over four years to establish the Pacific-Southwest Center for Biodefense and Emerging Infectious Diseases Research.

These grants have become a source of controversy. Some argue that these researchers have a conflict of interest in receiving these U.S. Government funds due to the politicization of Lyme disease and their roles in the history of the controversy, others cite that the grants are warranted as the infectious agents that the researchers are studying for bioterror defense are similar to the genetic makeup and pathogenesis of Borrelia, such as Tularemia, Brucellosis and Q Fever.

In October 2006, the Lyme controversy became further entangled 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. The guidelines are published by the University of Chicago Press Journal of Clinical Infectious Diseases.

The new guidelines now require either an EM rash or positive laboratory tests for diagnosis. Seronegative Lyme disease is no longer acknowledged, except in early Lyme. 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 by the IDSA, even in late stage cases.

An opposing group of doctors making up the International Lyme and Associated Disease Society (ILADS) have purported the use of antibiotic treatment beyond four weeks for both early and late Lyme. The ILADS treatment guidelines are available through National Guideline Clearinghouse.

Advancing Immunology Research

The role of T cells concomitant to Borrelia infection was first made in 1984, and long term persistance 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 Borellia 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 Borellia 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 Lyme 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.

Researchers hope that this new developing understanding of the biomolecular basis and pathology of cell-mediated signaling events caused by Borrelia 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.

External links

Medical Resources

Government and university resources

Professional societies, disease foundations and advocacy resources

Other resources, memorials etc.

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