Lyme disease

Lyme disease, or borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi is the predominant cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii are implicated in most European cases.

Lyme disease is the most common tick-borne disease in the Northern Hemisphere. Borrelia is transmitted to humans by the bite of infected hard ticks belonging to several species of the genus Ixodes. Early manifestations of infection may include fever, headache, fatigue, depression, and a characteristic skin rash called erythema migrans. Left untreated, late manifestations involving the joints, heart, and nervous system can occur. In a majority of cases, symptoms can be eliminated with antibiotics, especially if diagnosis and treatment occur early in the course of illness. Late, delayed, or inadequate treatment can lead to late manifestations of Lyme disease which can be disabling and difficult to treat.

Some groups have argued that "chronic" Lyme disease is responsible for a range of medically unexplained symptoms beyond the objectively recognized manifestations of late Lyme disease, and that long-term antibiotic treatment is warranted in such cases. However, a series of randomized controlled trials found no significant benefit from prolonged antibiotic treatment in such patients, and most expert groups including the Infectious Diseases Society of America and the American Academy of Neurology have found that existing scientific evidence does not support a role for Borrelia nor ongoing antibiotic treatment in such cases.

Symptoms
Lyme disease can affect multiple body systems, producing a range of potential symptoms. Not all patients with Lyme disease will have all symptoms, and many of the symptoms are not specific to Lyme disease but can occur in other diseases as well. 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.

Stage 1 – Early localized infection
The classic sign of early local infection is a circular, outwardly expanding rash called erythema chronicum migrans (also erythema migrans or EM), which occurs at the site of the tick bite 3 to 32 days after being bitten. The rash is red, and may be warm, but is generally painless. Classically, the innermost portion remains dark red and becomes indurated; the outer edge remains red; and the portion in between clears – giving the appearance of a bullseye. However, the partial clearing is uncommon, and thus a true bullseye occurs in as few as 9% of cases.

Erythema migrans is thought to occur in about 80% of infected patients. Patients can also experience flu-like symptoms such as headache, muscle soreness, fever, and malaise.

Lyme disease can progress to later stages even in patients who do not develop a rash.

Stage 2 – Early disseminated infection
Within days to weeks after the onset of local infection, the borrelia bacteria may begin to spread through the bloodstream. Erythema migrans may develop at sites across the body that bear no relation to the original tick bite. Another skin condition, which is apparently absent in North American patients, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum. Other discrete symptoms include migrating pain in muscles, joint, and tendons, and heart palpitations and dizziness caused by changes in heartbeat.

Acute neurological problems, which appear in 15% of untreated patients, encompasses a spectrum of disorders.One is facial or Bell's palsy, which is the loss of muscle tone on one or both sides of the face. Another common neurologic manifestation is meningitis, characterized by severe headaches, neck stiffness, and sensitivity to light. Radiculoneuritis causes shooting pains that may interfere with sleep and abnormal skin sensations. Mild encephalitis may lead to memory loss, sleep disturbances, or changes in mood or affect. In addition, simple altered mental status as the sole presenting symptom has been reported in early neuroborreliosis.

Stage 3 – Late persistent infection
After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms affecting many organs of the body including the brain, nerves, eyes, joints and heart. Myriad disabling symptoms can occur.

Chronic neurologic symptoms occur in up to 5% of untreated patients. A polyneuropathy manifested primarily as shooting pains, numbness, and tingling in the hands or feet may develop. A neurologic syndrome called Lyme encephalopathy is associated with subtle cognitive problems such as difficulties with concentration and short term memory. Such patients may also experience profound fatigue. Other problems such as depression and fibromyalgia are no more common in people who have been infected with Lyme than in the general population. Chronic encephalomyelitis, which may be progressive, may involve cognitive impairment, weakness in the legs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. 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.

Lyme arthritis usually affects the knees. In a minority of patients arthritis can occur in other joints, including the ankles, elbows, wrist, hips, and shoulders. Pain is often mild or moderate, usually with swelling at the involved joint. Baker's cysts may form and rupture. In some cases joint erosion occurs.

Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder observed primarily in Europe. ACA begins as a reddish-blue patch of discolored skin, usually in sun-exposed regions of the upper or lower limbs. The lesion slowly atrophies, and the skin may become so thin that it resembles wrinkled cigarette paper.

Cause
Lyme disease is caused by Gram-negative spirochetal bacteria from the genus Borrelia. At least 11 Borrelia species have been described, 3 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.

Three closely-related species of spirochetes are well-established as causing Lyme disease and are probably responsible for the large majority of cases: B. burgdorferi sensu stricto (predominant in North America, but also in Europe), B. afzelii, and B. garinii (both predominant in Eurasia). Some studies have also proposed that B. bissettii and B. valaisiana may sometimes infect humans, but these species do not seem to be important causes of disease.

Transmission
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, since adult ticks are more easily detected and removed as a consequence of their relatively large size.

In Europe, the 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. Only about 20% of people who become infected with Lyme disease by the deer tick can remember having been bitten, making early detection difficult in the absence of a rash. Tick bites often go unnoticed because of 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 United States as far west as Texas, is unlikely to transmit the Lyme disease spirochete Borrelia burgdorferi, though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease.

On the West Coast, the primary vector is the western black-legged tick (Ixodes pacificus). The tendency of this tick species to feed predominantly 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.

Tick borne co-infections
Ticks that transmit B. burgorferi to humans can also carry and transmit several other parasites such as Babesia microti and Anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (HGA), respectively. Among early Lyme disease patients, depending on their location, 2-12% will also have HGA and 2-40% will have babesiosis. Cat scratch fever is another common co-infection, although there is debate among experts on this topic on tick-to-human transmission.

Co-infections complicate Lyme symptoms, especially diagnosis and treatment. It is possible for a tick to carry and transmit one of the co-infections and not Borrelia, making diagnosis difficult and often elusive. The Centers for Disease Control (CDC)'s emerging infections diseases department did a study in rural New Jersey of 100 ticks and found that 55% of the ticks were infected with at least one of the pathogens.

Diagnosis
Lyme disease is diagnosed clinically based on symptoms, objective physical findings (such as erythema migrans, facial palsy, or arthritis), a history of possible exposure to infected ticks, as well as serological tests.

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.

Because of 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 CDC Case Definition for Lyme may be in error, since the CDC explicitly states that this definition is intended for surveillance purposes only and is "not intended to be used in clinical diagnosis."

Diagnosis of late-stage Lyme disease is often difficult because of 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), lupus, or other autoimmune and neurodegenerative diseases.

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.

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 because 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.

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.

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 disease 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, since 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 CSF 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. Light-colored clothing makes the tick more easily visible before it attaches itself. People should use special care in handling and allowing outdoor pets inside homes because they can bring ticks into the 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. Reduction of the deer population may over time help break the reproductive cycle of the deer ticks and their ability to flourish in suburban and rural areas.

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 demonstrated in the communities of Monhegan, Maine and in Mumford Cove, Connecticut. The black-legged or deer tick (Ixodes scapularis) depends on the white-tailed deer for successful reproduction.

For example, in the US, it is suggested that 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 levels too low to spread Lyme and other tick-borne diseases.

Vaccination
A recombinant vaccine against Lyme disease, based on the outer surface protein A (OspA) of B. burgdorferi, was developed by GlaxoSmithKline. In clinical trials involving more than 10,000 people, the vaccine, called LYMErix, was found to confer protective immunity to Borrelia in 76% of adults and 100% of children with only mild or moderate and transient adverse effects. LYMErix was approved on the basis of these trials by the U.S. Food and Drug Administration (FDA) on December 21, 1998.

Following approval of the vaccine, its entry in clinical practice was slower than expected for a variety of reasons including its cost, which was often not reimbursed by insurance companies. Subsequently, hundreds of vaccine recipients reported that they had developed autoimmune side effects. Supported by some patient advocacy groups, a number of class-action lawsuits were filed against GlaxoSmithKline alleging that the vaccine had caused these health problems. These claims were investigated by the FDA and the U.S. Centers for Disease Control (CDC), who found no connection between the vaccine and the autoimmune complaints.

Despite the lack of evidence that the complaints were caused by the vaccine, sales plummeted and LYMErix was withdrawn from the U.S. market by GlaxoSmithKline in February 2002 in the setting of negative media coverage and fears of vaccine side effects. The fate of LYMErix was described in the medical literature as a "cautionary tale"; an editorial in Nature cited the withdrawal of LYMErix as an instance in which "unfounded public fears place pressures on vaccine developers that go beyond reasonable safety considerations,"while the original developer of the OspA vaccine at the Max Planck Institute told Nature: "This just shows how irrational the world can be... There was no scientific justification for the first OspA vaccine [LYMErix] being pulled."

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

Tick removal
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. Data have demonstrated that prompt removal of an infected tick, within approximately 36 hours, reduces the risk of transmission to nearly zero; however the small size of the tick, especially in the nymph stage, may make detection difficult.

Treatment
Antibiotics are the primary treatment for Lyme disease; the most appropriate antibiotic treatment depends upon the patient and 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. 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. It is thought that the hydroxychloroquine raises 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.

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 three 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.

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 for a minimum of four weeks. Minocycline is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier.

"Post-Lyme syndrome" and "chronic Lyme disease"
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. Some groups have attributed these symptoms to persistent infection with Borrelia and have advocated long-term antibiotic treatment in such cases. However, three randomized controlled trials showed no benefit from long-term antibiotic treatment in such patients. A fourth randomized trial, published in 2008 by a group which advocates long-term antibiotic treatment, reported a short-term and statistically insignificant improvement in cognition with the antibiotic ceftriaxone, but this improvement was not maintained in the long-term. These trials identified significant side effects and risks of prolonged antibiotic therapy, and at least one death has been reported from complications of a 27-month course of intravenous antibiotics for an unsubstantiated diagnosis of "chronic Lyme disease".

Thus, most medical authorities, including the Infectious Diseases Society of America and the American Academy of Neurology, have found that there is no convincing evidence that Borrelia is implicated in the various syndromes of "chronic Lyme disease", and recommend against long-term antibiotic treatment as ineffective and possibly harmful.

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, Parkinson's disease, 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, and simultaneous infection with other tick-borne diseases (co-infections) 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 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.&lt;ref name="fatal-cases"&gt;Fatal cases of Lyme disease reported in the medical literature include:&lt;/ref&gt;

Ecology
Urbanization and other anthropogenic factors can be implicated in the spread of Lyme disease to humans. 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. At this stage, tick infestation may be controlled using acaricides (miticides).

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 of the United States, 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 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 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 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).&lt;ref&gt;http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm&lt;/ref&gt; New 2008 CDC Lyme case definition guidelines are used to determine confirmed CDC surveillance cases.&lt;ref&gt;http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm&lt;/ref&gt; 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.&lt;ref name="pmid16995383"/&gt;

While B. burgdorferi is most associated with ticks hosted by white-tailed deer and white-footed mice, 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.&lt;ref&gt;http://www.eurosurveillance.org/ew/2006/060622.asp&lt;/ref&gt;

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 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.

Northern hemisphere temperate regions are most endemic for Lyme disease.

Controversy and politics
While there is general agreement on the optimal treatment of early Lyme disease, considerable controversy has attached to the existence, prevalence, diagnostic criteria, and treatment of "chronic" Lyme disease. The popularity of "chronic Lyme disease" as a concept despite a lack of supporting medical evidence led to a 2008 New England Journal of Medicine article calling it "the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections."&lt;ref name="nejm-feder"/&gt; Most medical authorities, including the Infectious Diseases Society of America (IDSA), the American Academy of Neurology, and the Centers for Disease Control, do not recommend long-term antibiotic treatment for "chronic" Lyme disease, since several trials have shown no benefit whatsoever and the considerable risks of long term antibiotics, especially when given intravenously.

Groups of patients, patient advocates, and physicians who support the concept of chronic Lyme disease have organized to lobby for insurance coverage of long-term antibiotic therapy, which most insurers deny given medical opinion that it is ineffective and potentially harmful. As part of this controversy, Connecticut Attorney General Richard Blumenthal opened an antitrust investigation against the IDSA, accusing the IDSA panel of undisclosed conflicts of interest and of unduly dismissing alternative therapies. This investigation was closed on May 1, 2008 without formal charges; the IDSA agreed to a review of its guidelines by a panel of independent scientists and physicians. Blumenthal's corresponding press release announcing the agreement focused on alleged wrongdoing by the IDSA, while the IDSA's press release focused on the fact that the medical validity of the IDSA guidelines was not challenged. Paul G. Auwaerter, director of infectious disease at Johns Hopkins School of Medicine, cited this political controversy as an example of the "poisonous atmosphere" surrounding Lyme disease research which has led younger researchers to avoid the field.&lt;ref name="amnews"/&gt;

In 2001, the New York Times Magazine reported that Allen Steere, chief of immunology and rheumatology at New England Medical Center and a leading expert on Lyme disease, had been harassed, stalked, and threatened by patients and patient advocacy groups angry at his refusal to substantiate their diagnoses of "chronic" Lyme disease and endorse long-term antibiotic therapy. Because of death threats, security guards were assigned to Steere.&lt;ref name="uphill"/&gt;

A significant amount of inaccurate information on Lyme disease exists on the Internet. A 2004 study found that 9 of 19 websites surveyed contained major inaccuracies. Sites found to be good sources of accurate information in this study included those of the American College of Physicians, the Centers for Disease Control, the Food and Drug Administration, and Johns Hopkins University (www.hopkins-arthritis.org).

Pathophysiology
Borrelia burgdorferi has the ability to disseminate to numerous organs during the course of disease. The spirochete has been found in many tissues, including the skin, heart, joint, peripheral nervous system, and central nervous system. Many of the signs and symptoms of Lyme disease are a consequence of the inflammatory response to the presence of the spirochete in those tissues. &lt;ref name="pmid14987414" /&gt;

B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite. This provides a protective environment where the spirochete can establish infection. The spirochetes multiply and migrate outward within the dermis. The host inflammatory response to the bacteria in the skin is associated with the appearance of the characteristic EM lesion.&lt;ref name="pmid15085185" /&gt; However neutrophils, which are necessary to eliminate the spirochetes from the skin, fail to appear in the developing EM lesion thereby permitting the bacteria to survive and eventually spread throughout the body.

Days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of clinical manifestations of disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete. The bacteria may persist at these sites for months or even years despite active production of anti-B. burgdorferi antibodies by the immune response. The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by the immune response, antigenic variation of the VlsE surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors.

In the brain B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction. The spirochetes may also induce host cells to secrete products toxic to nerve cells, including quinolinic acid and the cytokines IL-6 and TNF-alpha, which can produce fatigue and malaise. Both microglia and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete.&lt;ref name="pmid12938230"/&gt; IL-6 is also significantly indicated in cognitive impairment.

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 central nervous system (CNS) in a number of infectious diseases that affect the brain, including Lyme. Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric 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.

Immunological studies
Research has 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.

These immunological studies suggest that 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. This would be a form of pathogen-induced autoimmune disease. It is therefore possible that chronic symptoms could come from an autoimmune reaction, even after the spirochetes have been eliminated from the body. This hypothesis may explain chronic arthritis that persists after antibiotic therapy, but the wider application of this hypothesis is controversial.

History
The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in Wrocław, Poland (then known as Breslau, Germany) where physician Alfred Buchwald described a man who had suffered for 16 years with a degenerative skin disorder now known as acrodermatitis chronica atrophicans. At a 1909 research conference, 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 was 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 physicians David Snydman and 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 arthropod-borne bacteria 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.