Description

Lyme disease, or lyme borreliosis,  is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia.  Borrelia burgdorferi sensu lato is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most European cases. The disease is named after the village of Lyme, Connecticut, USA, where a number of cases were identified in 1975. Although Allen Steere realized in 1978 that Lyme disease was a tick-borne disease, the cause of the disease remained a mystery until 1982, when B. burgdorferi was identified by Willy Burgdorfer.

Lyme disease is the most common tick-borne disease in the Northern Hemisphere. Borrelia is transmitted to humans by the bite of infected ticks belonging to a few species of the genus Ixodes ("hard ticks").  Early symptoms may include fever, headache, fatigue, depression, and a characteristic circular skin rash called erythema migrans. Left untreated, later symptoms may involve the joints, heart, and central nervous system. In most cases, the infection and its symptoms are eliminated by antibiotics, especially if the illness is treated early.  Late, delayed, or inadequate treatment can lead to the more serious symptoms, which can be disabling and difficult to treat.  Occasionally, symptoms such as arthritis persist after the infection has been eliminated by antibiotics, prompting suggestions that Borrelia causes autoimmunity.

Some groups have argued that "chronic" Lyme disease is responsible for a range of medically unexplained symptoms beyond the recognized symptoms of late Lyme disease, and that additional, long-term antibiotic treatments are needed.  Of four randomized controlled trials of long-term ceftriaxone and doxycycline treatment in patients with ongoing symptoms, two found no benefit,  and two found inconsistent benefits with significant side effects and risks from the antibiotic treatment.   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.  However, the subject is controversial, with some doctors, patient advocacy groups, and politicians continuing to argue that long-term treatment is beneficial. This dispute has led to legal action over treatment guidelines, as well as harassment and death threats made against physicians who will not acknowledge "chronic" Lyme disease as a legitimate diagnosis.

Signs and symptoms

Lyme disease can affect multiple body systems and produce a range of 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 with other diseases as well. The incubation period from infection to the onset of symptoms is usually one to two 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 occurs 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 with Lyme disease 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 30 days after the tick bite.  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, partial clearing is uncommon, and the bullseye pattern more often involves central redness.

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 chronicum 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 but occurs in Europe, 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, encompass a spectrum of disorders.  These include facial or Bell's palsy, which is the loss of muscle tone on one or both sides of the face, as well as meningitis, which involves severe headaches, neck stiffness, and sensitivity to light. Radiculoneuritis causes shooting pains that may interfere with sleep as well as abnormal skin sensations. Mild encephalitis may lead to memory loss, sleep disturbances, or mood changes. In addition, some case reports have described altered mental status as the only symptom seen in a few cases of early neuroborreliosis.

Stage 3: Late persistent infection

After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms that affect many parts of the body, including the brain, nerves, eyes, joints and heart. Myriad disabling symptoms can occur, including permanent paraplegia in the most extreme cases.

Chronic neurologic symptoms occur in up to 5% of untreated patients.  A polyneuropathy that involves 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. These patients may also experience profound fatigue.  However, 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, can involve cognitive impairment, weakness in the legs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. In rare cases untreated Lyme disease may cause frank psychosis, which has been mis-diagnosed as schizophrenia or bipolar disorder. Panic attack and anxiety can occur, also delusional behavior, including somatoform delusions, sometimes accompanied by a depersonalization or derealization syndrome, where the person begins to feel detached from themselves or from reality.

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 among the elderly.  ACA begins as a reddish-blue patch of discolored skin, often on the backs of the hands or feet. The lesion slowly atrophies over several weeks or months, with the skin becoming first thin and wrinkled and then, if untreated, completely dry and hairless.

Cause

Lyme disease is caused by Gram-negative spirochetal bacteria from the genus Borrelia. At least 11 Borrelia species have been discovered, 3 of which are known to be Lyme-related.  The Borrelia species that cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity.

The group Borrelia burgdorferi sensu lato is made up of three closely-related species that are probably responsible for the large majority of cases: B. burgdorferi sensu stricto (predominant in North America, but also present 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.^[36][37]

Transmission

Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among rodents by ticks that feed on both sets of hosts.  Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease.  Most infections are caused by ticks in the nymphal stage, as they are very small and may feed for long periods of time undetected.  Larval ticks are very rarely infected.  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. However, transmission is quite rare, with only about 1% of recognized tick bites resulting in Lyme disease; this may be due to the fact that an infected tick must be attached for at least a day for transmission to occur.

In Europe the vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick.  In China Ixodes persulcatus (the taiga tick) is probably the most important vector.  In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the east coast.  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 of the United States, the main vector is the western black-legged tick (Ixodes pacificus).  The tendency of this tick species to feed predominantly on host species such as lizards that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West.

While Lyme spirochetes have been found in insects as well as ticks,  reports of actual infectious transmission appear to be rare.  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. The risk for fetal harm is much higher in the first three months of pregnancy than later. Prompt antibiotic treatment almost always prevents fetal harm. Pregnant Lyme-disease patients cannot be treated with the first-choice antibiotic, doxycycline (see below), as it is potentially harmful for the fetus. Instead, erythromycin is usually given; it is less effective against the disease but harmless for the fetus.

Tick borne co-infections

Ticks that transmit B. burgdorferi to humans can also carry and transmit several other parasites such as Theileria 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.

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 studied 100 ticks in rural New Jersey and found that 55% of the ticks were infected with at least one of the pathogens.

Pathophysiology

Borrelia burgdorferi can spread throughout the body during the course of the disease and has been found in 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 immune response to the spirochete in those tissues.

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 causes the characteristic circular EM lesion.  However neutrophils, which are necessary to eliminate the spirochetes from the skin, fail to appear in the developing EM lesion. This allows 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 symptoms of disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete.  If untreated, the bacteria may persist in the body for months or even years, despite the production of anti-B. burgdorferi antibodies by the immune system.  The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, 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.^[65][66][67] Both microglia and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete.  This cytokine response may contribute to 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.

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 blood tests. When making a diagnosis of Lyme disease, health care providers should consider other diseases that may cause similar illness. Most but not all patients with Lyme disease will develop the characteristic bulls-eye rash, but 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 serologic blood tests are negative.  Serological testing can be used to support a clinically suspected case but is not diagnostic by itself.

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, a reviewer called Lyme 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. The most widely used tests are serologies, which measure levels of specific antibodies in a patient's blood. These tests may be negative in early infection, before the body has produced significant quantites of antibody, but they are considered a reliable aid in the diagnosis of later stages of Lyme 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 sensitive ELISA test is performed first, and if it is positive or equivocal then 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.  The initial ELISA test has a sensitivity of about 70%, and in two tiered testing the overall sensitivity is only 64% although this rises to 100% in the subset of people with disseminated symptoms, such as arthritis.  However, ELISA testing is typically done against region specific epitopes and may report a false negative if the patient has been infected with Borrelia from another region than that in which they are tested.

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.  The overall rate of false positives is low, only about 1 to 3%, in comparison to a false negative rate of up to 36% using two tiered testing.

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 a highly sensitive way of detecting ospA DNA in synovial fluid.  With the exception of PCR, there is currently no practical means for detecting 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. This is because 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, PCR tests on urine, immunofluorescent staining for cell wall-deficient forms of Borrelia burgdorferi, and lymphocyte transformation tests. The CDC does not recommend these tests and a 2005 review by Aguero-Rosenfeld et al. in Clinical Microbiology Reviews stated that their use is "of great concern and is strongly discouraged".

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.^{[citation needed]} 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, brain biopsy is not commonly performed for these cases as it may be for other types of cerebral vasculitis.

Abnormal magnetic resonance imaging (MRI) findings are often seen in both early and late Lyme disease.^{[citation needed]} 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, as removal within 36 hours can reduce transmission rates to close to zero.  Protective clothing includes a hat and long-sleeved shirts and long trousers 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.

An unusual, organic approach to control of ticks and prevention of Lyme disease involves the use of domesticated guineafowl. Guineafowl are voracious consumers of insects and arachnids and have a particular fondness for ticks. Localized use of domesticated guineafowl may reduce dependence on chemical pest-control methods.

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 to 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.  However, such a drastic reduction may be impractical in many areas.

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 slow 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."  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.

Vaccines are available for dogs.

Tick removal

Folk remedies for tick removal tend to be ineffective, offer no advantages in preventing the transfer of disease, and may increase the risks of transmission or infection. Generally, the recommended method to is to simply pull the tick straight out with tweezers, without twisting.  Data suggests that the prompt removal of an infected tick, within approximately 24 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), erythromycin (for pregnant women) and ceftriaxone, with treatment lasting 14 to 28 days.  Alternative choices are cefuroxime and cefotaxime.  Treatment of pregnant women is similar, but tetracycline should not be used.

A double blind, randomized, placebo-controlled multicenter clinical study indicated that 3 weeks of treatment with intravenous ceftriaxone, followed by 100 days of treatment with oral amoxicillin did not improve symptoms any more than just 3 weeks of treatment with ceftriaxone. The researchers noted that the outcome should not be evaluated after the initial 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 disease symptoms and "chronic" Lyme disease

The term "chronic Lyme disease" is often applied to several different sets of patients. One usage refers to people with the symptoms of untreated and desseminated late-stage Lyme disease who are suffering from the symptoms of this stage of the disease: these are arthritis, peripheral neuropathy and/or encephalomyelitis. The term is also applied to people who have had the disease in the past and some symptoms remain after antibiotic treatment, which is also called post-Lyme disease syndrome. A third and controversial use of the term applies to patients with non-specific symptoms such as fatigue who show no objective evidence that they have been infected with Lyme disease in the past, since the standard diagnostic tests for infection are negative.

Up to one third of Lyme disease patients who have completed a course of antibiotic treatment continue to have symptoms such as severe fatigue, sleep disturbance, and cognitive difficulties, with these symptoms being severe in about 2% of cases.  While it is undisputed that these patients can have severe symptoms, the cause of these symptoms and appropriate treatment is controversial. The symptoms may represent "for all intents and purposes" fibromyalgia/chronic fatigue syndrome.  A few doctors attribute these symptoms to persistent infection with Borrelia, or coinfections with other tick-borne infections such as Ehrlichia and Babesia.^[126][127] Other doctors believe that the initial infection may cause an autoimmune reaction that continues to cause serious symptoms even after the bacteria have been eliminated by antibiotics.

Four randomized controlled trials have been performed in patients who have persisting complaints and a history of Borrelia infection. Some of these patients had evidence of an ongoing Borrelia infection and almost all of them were previously treated with antibiotics. The authors of all four trials concluded that their results did not support long-term antibiotic therapy. Of these four studies,

• two studies showed no benefit from 30 days of IV ceftriaxone and 60 days of oral doxycycline, concluding that "treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo".
• one study showed an improvement only in fatigue after 28 days of IV antibiotics, an effect that was significant only in a group of patients that never had antibiotics previously.  The results may have been compromised by unblinding, and detected a large placebo effect.  This trials also saw several cases of life-threatening side effects, concluding that "repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease including those related to fatigue and cognitive dysfunction, particularly in light of the frequency of serious adverse events."
• one study reported an improvement in fatigue in a subset of patients and a transient improvement in cognition after 10 weeks of IV antibiotics, but concluded that the treatment was "not an effective strategy for sustained cognitive improvement."  These patients had also been ill for many years and had taken many antibiotic courses. Also, this study performed ad hoc statistical analysis and its results were questionably significant.

A non-profit interest group called the International Lyme And Associated Diseases Society (ILADS) argues that persistence of B. burgdorferi may be responsible for manifestations of late Lyme disease symptoms.  It has questioned the generalizability and reliability of some of the above trials and the reliability of the current diagnostic tests.  Major US medical authorities, including the Infectious Diseases Society of America, the American Academy of Neurology, and the National Institutes of Health, have stated that there is no convincing evidence that Borrelia is involved in the various symptoms classed as chronic Lyme disease, and advise against long-term antibiotic treatment as ineffective and possibly harmful.^{[13][132][133][134]} There are significant side effects and risks of prolonged antibiotic therapy, and one death has been reported from complications of a 27-month course of intravenous antibiotics for an unsubstantiated diagnosis of "chronic Lyme disease".

Treatment of post-Lyme disease symptoms

Antibiotic treatment is the central pillar in the management of Lyme disease. However, in the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment.  Although it is possible that these chronic symptoms are due to either autoimmunity or residual bacteria (see immunological studies below), no Borrelia DNA can usually be detected in the joints after antibiotic treatment, which suggests that the arthritis may continue even after the bacteria have been killed.  Lyme arthritis that persists after antibiotic treatment may be treated with hydroxychloroquine or methotrexate.  Corticosteroid injections into the affected joint are not recommended for any stage of Lyme arthritis.

Patients with chronic neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study.  Some antibiotics may have a dual effect on Lyme disease, since minocycline and doxycycline have anti-inflammatory effects in addition to their antibiotic actions including anti-inflammatory effects specific to the inflammation caused by Lyme Disease.^[140][141] Indeed, 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, 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 suggested that antifungal azole medications such as diflucan could be used in the treatment of Lyme, but the use of these drugs has yet to be tested in a controlled study.

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.

 

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