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Lyme disease
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Lyme Disease
Classification and external
resources

Nymphal and adult deer ticks can

be carriers of Lyme disease.
Nymphs are about the size of a
poppy seed.

ICD-10 A69.2

ICD-9 088.81

DiseasesDB 1531

MedlinePlus 001319

eMedicine med/1346
ped/1331
neuro/521
emerg/588
 MeSH D008193

Lyme disease, or borreliosis, is an emerging infectious disease caused by at least three

species of bacteria belonging to the genus Borrelia.[1] 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.[2] 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 most cases, the infection and its symptoms are 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.[3]

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 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 additional, long-term antibiotic treatment is
warranted in such cases.[4] Of four randomized controlled trials of long-term antibiotic
courses in patients with ongoing symptoms, two found no benefit[5][6], and two found
inconsistent benefits and significant side effects and risks from further antibiotic
treatment.[7][8][9] 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.[10][11]

Contents
[hide]

• 1 Symptoms
o 1.1 Stage 1 – Early localized infection
o 1.2 Stage 2 – Early disseminated infection
o 1.3 Stage 3 – Late persistent infection
• 2 Cause
o 2.1 Transmission
• 3 Tick borne co-infections
• 4 Diagnosis
o 4.1 Laboratory testing
o 4.2 Imaging
• 5 Prevention
 o 5.1 Management of host animals
o 5.2 Vaccination
o 5.3 Tick removal
• 6 Treatment
o 6.1 Post-Lyme disease symptoms and "chronic Lyme disease"
o 6.2 Antibiotic-resistant therapies
o 6.3 Alternative therapies
• 7 Prognosis
• 8 Ecology
• 9 Epidemiology
• 10 Controversy and politics
• 11 Pathophysiology
o 11.1 Immunological studies
• 12 History
• 13 References
• 14 Bibliography
• 15 Documentary Film

• 16 External links

[edit] 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.[12]
Asymptomatic infection exists but is found in less than 7% of infected individuals in the
United States.[13] Asymptomatic infection may be much more common among those
infected in Europe.[14]

[edit] Stage 1 – Early localized infection

Common bullseye rash pattern associated with Lyme Disease.

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

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.[15] 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.[16]

Erythema migrans is thought to occur in about 80% of infected patients.[15] Patients can
also experience flu-like symptoms such as headache, muscle soreness, fever, and
malaise.[17]

Lyme disease can progress to later stages even in patients who do not develop a rash.[18]

[edit] 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.[19] 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.[20] 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.[17] 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.[21]

[edit] 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.[17] 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.[22] Other
problems such as depression and fibromyalgia are no more common in people who have
been infected with Lyme than in the general population.[23][22] 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.[24][25]

Lyme arthritis usually affects the knees.[26] 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.[20] 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.

[edit] Cause
Main article: Lyme disease microbiology

Borrelia bacteria, the causative agent of Lyme disease. Magnified 400 times.
Ixodes scapularis, the primary vector of Lyme disease in eastern North America.

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.[27][28] 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.[29]

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).[27] 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.[citation needed]

[edit] Transmission

Hard-bodied ticks of the genus Ixodes are the primary vectors of Lyme disease.[1] 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.[citation needed]
Transmission is relatively rare, with only about 1% of recognized tick bites resulting in
Lyme disease: this may be due to the fact that an infected tick has to be attached for at
least a day for transmission to occur.[30]

In Europe, the sheep tick, castor bean tick, or European castor bean tick (Ixodes ricinus)
is the transmitter.[citation needed]

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,[31] 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,[32] though it may be implicated in a related syndrome called southern tick-
associated rash illness, which resembles a mild form of Lyme disease.[33]
On the West Coast, the primary vector is the western black-legged tick (Ixodes
pacificus).[34] 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.[35][36]

While Lyme spirochetes have been found in insects other than ticks,[37] reports of actual
infectious transmission appear to be rare.[38] Sexual transmission has been anecdotally
reported; Lyme spirochetes have been found in semen[39] and breast milk,[40] however
transmission of the spirochete by these routes is not known to occur.[41]

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.[42]

[edit] Tick borne co-infections

Ticks that transmit B. burgorferi 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.[30] Among
early Lyme disease patients, depending on their location, 2-12% will also have HGA and
2-40% will have babesiosis.[43] Cat scratch fever is another common co-infection,
although there is debate among experts on this topic on tick-to-human transmission.[citation
needed]

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.[44]

[edit] 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.[1] 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.[45][46] Serological testing can be used to support a clinically suspected case but is
not diagnostic.[1] 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."[47][48]

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 been called the new "great imitator".[49] Lyme disease may be misdiagnosed as
multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome (CFS),
lupus, or other autoimmune and neurodegenerative diseases.

[edit] 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,[1] however studies show
the Western blot IgM has a specificity of 94–96% for patients with clinical symptoms of
early Lyme disease.[50][51]

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,[52] as well as
herpes simplex virus.[53]

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.[54] Even when
properly performed, PCR often shows false-negative results with blood and CSF
specimens.[55] 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.[56] 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.[57]

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.[58]

New techniques for clinical testing of Borrelia infection have been developed, such as
LTT-MELISA,[59] which is capable of identifying the active form of Borrelia infection
(Lyme disease). Others, such as focus floating microscopy, are under investigation.[60]
New research indicates chemokine CXCL13 may also be a possible marker for
neuroborreliosis.[61]

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.

[edit] Imaging

Single photon emission computed tomography (SPECT) imaging has been used to look
for cerebral hypoperfusion indicative of Lyme encephalitis in the patient.[62] 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.[63] 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.[64] 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, 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.[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.[65] Cerebral atrophy and
brainstem neoplasm has been indicated with Lyme infection as well.[66]

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.[67]

[edit] Prevention
Attached ticks should be removed promptly.[68] 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. One easy way to maintain the tick population in your area is NOT to
feed the host animals such as the ones listed above. 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.[69]

[edit] 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[70] and in Mumford Cove,
Connecticut.[71] 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.[72]
However, such a drastic reduction may be impractical in many areas.

[edit] 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.[73] 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.[74] 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.[75]

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[76] in the setting of negative media coverage and fears of vaccine side
effects.[77][75] The fate of LYMErix was described in the medical literature as a "cautionary
tale";[77] 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,"[78] 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."[75]

New vaccines are being researched using outer surface protein C (OspC) and
glycolipoprotein as methods of immunization.[79][80]

[edit] 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.[81] 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.[68]

[edit] Treatment
Antibiotics are the primary treatment for Lyme disease; the most appropriate antibiotic
treatment depends upon the patient and the stage of the disease.[1] The antibiotics of
choice are doxycycline (in adults), amoxicillin (in children), and ceftriaxone. Alternative
choices are cefuroxime and cefotaxime.[1] Macrolide antibiotics have limited efficacy
when used alone.

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.[82]

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.[83]

[edit] Post-Lyme disease symptoms and "chronic Lyme disease"

A very small minority[84] 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.[3] While it is undisputed that these patients can have severe
symptoms, the cause of these symptoms and treatment of such patients is disputed. Some
doctors attributed these symptoms to persistent infection with Borrelia, or with
coinfections of other tick-borne infections such as Ehrlichia and Babesia.[85] Additionally,
"chronic" Lyme disease has been cited by a doctor with the International Lyme And
Associated Diseases Society (ILADS) as responsible for a range of medically
unexplained symptoms beyond the objectively recognized manifestations of late Lyme
disease, with or without any evidence of past or present infection.[4] ILADS campaigns
for insurance companies to pay for expensive, long-term antibiotic treatment in such
cases.[86]

Four randomized controlled trials with have been performed with patients who have
evidence of an ongoing Lyme infection. Some of them had evidence of an ongoing
Borrelia infection and almost all of them were previously treated with antibiotics. Of
these four studies,

• two studies showed no benefit from 30 days of IV antibiotics and 60 days of oral
antibiotics.[5][6] The president of the "chronic" Lyme interest group ILADS
questioned the generalizability of the results because the studied patients had been
ill an average of 4.7 years and had an average of 3 previous courses of
antibiotics.[87]
• 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.[9] The results may have been compromised by unblinding, and a large
placebo effect was seen.[86] These trials also confirmed the significant side effects
and risks that are known to accompany long-term antibiotic therapy.
• one study reported an improvement in fatigue in a subset of patients and a
transient improvement in cognition after 10 weeks of IV antibiotics[7][8], but again
these patients had been ill for many years and had taken many antibiotic courses.
Also, this study performed ad hoc statistical analysis[88] and its results were
questionably significant.[84]
Most medical authorities, including the Infectious Diseases Society of America and the
American Academy of Neurology, have concluded 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.[89][90][10] It is well established that there are 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".[91]

[edit] 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.[92][93] Lyme arthritis which is antibiotic resistant may be treated with
hydroxychloroquine or methotrexate.[94] Experimental data are consensual on the
deleterious consequences of systemic corticosteroid therapy. Corticosteroids are not
indicated in Lyme disease.[95]

Antibiotic refractory patients with neuropathic pain responded well to gabapentin

monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study.[96]
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.[97]

[edit] 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.[98] 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.[99] 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.[100]

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;[101]
no clinical trials of this treatment have been carried out, however.

[edit] Prognosis
For early cases, prompt treatment is usually curative.[102] 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.[3] Patients with late stage Lyme disease have been shown to
experience a level of physical disability equivalent to that seen in congestive heart
failure.[103] In rare cases, Lyme disease can be fatal.[104]

[edit] 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.[105][106] Researchers are also investigating possible links between global
warming and the spread of vector-borne diseases including Lyme disease.[107]

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".[108]

[edit] 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.[109]

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).[110] New 2008 CDC Lyme
case definition guidelines are used to determine confirmed CDC surveillance cases.[111]
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.[112] Except for one study in Europe,[113]
much of the data implicating lizards is based on DNA detection of the spirochete and has
not demonstrated that lizards are able to infect ticks feeding upon them.[114][115][116][117] 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.[36]

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.[118]

B. burgdorferi sensu lato infested ticks are being found more frequently in Japan, as well
as in Northwest China and far eastern Russia.[119][120] Borrelia has been isolated in
Mongolia as well.[121]

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.[122] The
first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo.[123] 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.[124][125][126]

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.[127] In East Africa, two cases
of Lyme disease have been reported in Kenya.[128]

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.[129] 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.[130][131]

[edit] 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."[10] 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 trials have shown little or no benefit and considerable risk from 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 recognition of the disease, as well as insurance
coverage of long-term antibiotic therapy, which most insurers deny as it is at odds with
guidelines released by major medical organizations.[132] As part of this controversy,
Connecticut Attorney General Richard Blumenthal, whose decade-long ties to chronic
Lyme advocacy groups[132] had prompted the rebuke of medical experts,[133] 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 charges after the IDSA agreed to a review of its guidelines by a
panel of independent scientists and physicians.[134] Blumenthal's corresponding press
release argued that the agreement vindicated his investigation and again alleged conflicts
of interest.[135] The IDSA's press release focused on the fact that the medical validity of
the IDSA guidelines was not challenged.[136] 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.[134]
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.[137] Because of death threats, security guards were assigned to
Steere.[75]

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).[138]

[edit] 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.[139][140] 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. [17]

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. [141] 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.[139]
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.[142]

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.[143]
The bacteria may persist in the body for months or even years, despite the production of
anti-B. burgdorferi antibodies by the immune system.[30] 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.[144][145]

In the brain B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation

followed by apoptosis), which may contribute to neurodysfunction.[146] 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.[147][148][149] Both microglia and astrocytes secrete IL-6 and TNF-alpha in the
presence of the spirochete.[146][150] IL-6 is also significantly indicated in cognitive
impairment.[151]

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.[152][153] 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.[154] Researchers are investigating if this neurohormone secretion is the cause of
neuropsychiatric disorders developing in some patients with borreliosis.[155]

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.[156] Antidepressants
have also been shown to suppress Th1 upregulation.[157]

[edit] 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.[158] The signaling pathway P38
mitogen-activated protein kinases (p38 MAP kinase) has also been identified as
promoting expression of pro-inflammatory cytokines from Borrelia.[159]

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.[160] 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.[161][162]

[edit] 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.[163] The
skin condition now known as borrelial lymphocytoma was first described in 1911.[164]

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.[165] 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.[166] 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.[167] 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.[168][169]

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.[170]

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.[171] 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.[172]

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,[173][174] Lyme borreliosis or simply borreliosis.

In 1980 Steere, et al, began to test antibiotic regimens in adult patients with Lyme
disease.[175] 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.[176][177] 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.[178]

[edit] References
1. ^ a b c d e f g Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology, 4th
ed., McGraw Hill, 434–437. ISBN 0838585299.
2. ^ Johnson RC (1996). "Borrelia", Baron's Medical Microbiology (Baron S et al,
eds.), 4th ed., Univ of Texas Medical Branch. ISBN 0-9631172-1-1.
3. ^ a b c Cairns V, Godwin J (2005). "Post-Lyme borreliosis syndrome: a meta-
analysis of reported symptoms". Int J Epidemiol 34 (6): 1340–1345.
doi:10.1093/ije/dyi129. PMID 16040645.
4. ^ a b Stricker RB (July 2007). "Counterpoint: long-term antibiotic therapy
improves persistent symptoms associated with Lyme disease". Clinical infectious
diseases : an official publication of the Infectious Diseases Society of America 45
(2): 149–57. doi:10.1086/518853. PMID 17578772.
5. ^ a b Klempner MS, Hu LT, Evans J, et al (July 2001). "Two controlled trials of
antibiotic treatment in patients with persistent symptoms and a history of Lyme
disease". N. Engl. J. Med. 345 (2): 85–92. PMID 11450676.
6. ^ a b Kaplan RF, Trevino RP, Johnson GM, et al (June 2003). "Cognitive function
in post-treatment Lyme disease: do additional antibiotics help?". Neurology 60
(12): 1916–22. PMID 12821733.
7. ^ a b Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, Slavov
I, Cheng J, Dobkin J, Nelson DR, Sackeim HA (March 2008).
"["http://neurology.org/cgi/content/abstract/70/13/992" A randomized, placebo-
controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy]".
Neurology 70 (13): 992–1003. doi:10.1212/01.WNL.0000284604.61160.2d.
PMID 17928580.
8. ^ a b
http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/6946
9. ^ a b Krupp LB, Hyman LG, Grimson R, et al (June 2003). "Study and treatment
of post Lyme disease (STOP-LD): a randomized double masked clinical trial".
Neurology 60 (12): 1923–30. PMID 12821734.
10. ^ a b c Feder HM, Johnson BJ, O'Connell S, et al (October 2007). "A critical
appraisal of "chronic Lyme disease"". N. Engl. J. Med. 357 (14): 1422–30.
doi:10.1056/NEJMra072023. PMID 17914043.
11. ^ Frequently Asked Questions about Lyme Disease, from the Infectious Diseases
Society of America. Released October 2006; accessed June 24, 2008.
12. ^ Edlow JA (2007-01-25). "Lyme disease". eMedicine. Retrieved on 2007-08-21.
13. ^ Steere AC, Sikand VK, Schoen RT, Nowakowski J (2003). "Asymptomatic
infection with Borrelia burgdorferi". Clin. Infect. Dis. 37 (4): 528–532.
doi:10.1086/376914. PMID 12905137.
14. ^ Fahrer H, Sauvain MJ, Zhioua E, Van Hoecke C, Gern LE (1998). "Longterm
survey (7 years) in a population at risk for Lyme borreliosis: what happens to the
seropositive individuals?". Eur. J. Epidemiol. 14 (2): 117–123. PMID 9556169.
15. ^ a b Fauci, Anthony S. (2008). Harrison's Principles of Internal Medicine:
Editors, Anthony S. Fauci ... [Et Al.]. McGraw-Hill Medical Publishing, Chapter
166. ISBN 0-07-159991-6.
16. ^ Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL,
Holman MS, Persing DH, Steere AC (March 2002). "Clinical characteristics and
treatment outcome of early Lyme disease in patients with microbiologically
confirmed erythema migrans". Ann. Intern. Med. 136 (6): 421–428. PMID
11900494.
17. ^ a b c d Auwaerter PG, Aucott J, Dumler JS (January 2004). "Lyme borreliosis
(Lyme disease): molecular and cellular pathobiology and prospects for prevention,
diagnosis and treatment". Expert Rev Mol Med 6 (2): 1–22.
doi:10.1017/S1462399404007276. PMID 14987414.
18. ^ Steere AC, Dhar A, Hernandez J, et al (January 2003). "Systemic symptoms
without erythema migrans as the presenting picture of early Lyme disease". Am.
J. Med. 114 (1): 58–62. PMID 12543291.
19. ^ Dandache P, Nadelman RB (June 2008). "Erythema migrans". Infect. Dis. Clin.
North Am. 22 (2): 235–60, vi. doi:10.1016/j.idc.2007.12.012. PMID 18452799.
20. ^ a b Stanek G, Strle F (June 2008). "Lyme disease: European perspective". Infect.
Dis. Clin. North Am. 22 (2): 327–39, vii. doi:10.1016/j.idc.2008.01.001. PMID
18452805.
21. ^ Chabria SB, Lawrason J (2007). "Altered mental status, an unusual
manifestation of early disseminated Lyme disease: A case report". Journal of
Medical Case Reports 1 (1): 62. doi:10.1186/1752-1947-1-62. PMID 17688693.
22. ^ a b Shadick NA, Phillips CB, Sangha O, et al (December 1999).
"Musculoskeletal and neurologic outcomes in patients with previously treated
Lyme disease". Ann. Intern. Med. 131 (12): 919–26. PMID 10610642.
23. ^ Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED (February
2000). "Long-term outcomes of persons with Lyme disease". JAMA 283 (5): 609–
16. PMID 10665700.
24. ^ Fallon BA, Nields JA (1994). "Lyme disease: a neuropsychiatric illness". The
American journal of psychiatry 151 (11): 1571–1583. PMID 7943444.
25. ^ Hess A, Buchmann J, Zettl UK, et al (1999). "Borrelia burgdorferi central
nervous system infection presenting as an organic schizophrenia-like disorder".
Biol. Psychiatry 45 (6): 795. doi:10.1016/S0006-3223(98)00277-7. PMID
10188012.)
26. ^ Puius YA, Kalish RA (June 2008). "Lyme arthritis: pathogenesis, clinical
presentation, and management". Infect. Dis. Clin. North Am. 22 (2): 289–300, vi–
vii. doi:10.1016/j.idc.2007.12.014. PMID 18452802.
27. ^ a b Wang G, van Dam AP, Schwartz I, Dankert J (October 1999). "Molecular
typing of Borrelia burgdorferi sensu lato: taxonomic, epidemiological, and clinical
implications". Clin. Microbiol. Rev. 12 (4): 633–53. PMID 10515907.
PMC:88929.
28. ^ Derdáková M, Lencáková D (2005). "Association of genetic variability within
the Borrelia burgdorferi sensu lato with the ecology, epidemiology of Lyme
borreliosis in Europe". Ann Agric Environ Med 12 (2): 165–72. PMID 16457468.
29. ^ Bunikis J, Garpmo U, Tsao J, Berglund J, Fish D, Barbour AG (2004).
"Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents
Borrelia burgdorferi in North America and Borrelia afzelii in Europe" (PDF).
Microbiology 150 (Pt 6): 1741–1755. doi:10.1099/mic.0.26944-0. PMID
15184561.
30. ^ a b c Steere AC (July 2001). "Lyme disease". N. Engl. J. Med. 345 (2): 115–25.
PMID 11450660.
31. ^ Wormser G, Masters E, Nowakowski J, et al (2005). "Prospective clinical
evaluation of patients from missouri and New York with erythema migrans-like
skin lesions". Clin Infect Dis 41 (7): 958–965. doi:10.1086/432935. PMID
16142659.
32. ^ Ledin KE, et al (2005). "Borreliacidal activity of saliva of the tick Amblyomma
americanum". Med Vet Entomol 19 (1): 90–95. doi:10.1111/j.0269-
283X.2005.00546.x. PMID 15752182.
33. ^ Masters EJ, Grigery CN, Masters RW (June 2008). "STARI, or Masters disease:
Lone Star tick-vectored Lyme-like illness". Infect. Dis. Clin. North Am. 22 (2):
361–76, viii. doi:10.1016/j.idc.2007.12.010. PMID 18452807.
34. ^ Clark K (2004). "Borrelia species in host-seeking ticks and small mammals in
northern Florida" (PDF). J Clin Microbiol 42 (11): 5076–5086.
doi:10.1128/JCM.42.11.5076-5086.2004. PMID 15528699.
35. ^ Eisen L, Eisen RJ, Lane RS (2004). "The roles of birds, lizards, and rodents as
hosts for the western black-legged tick Ixodes pacificus". J. Vector Ecol. 29 (2):
295–308. PMID 15709249.
36. ^ a b Lane RS, Mun J, Eisen L, Eisen RJ (2006). "Refractoriness of the western
fence lizard (Sceloporus occidentalis) to the Lyme disease group spirochete
Borrelia bissettii". J. Parasitol. 92 (4): 691–696. PMID 16995383.
37. ^ Magnarelli L, Anderson J (1988). "Ticks and biting insects infected with the
etiologic agent of Lyme disease, Borrelia burgdorferi" (PDF). J Clin Microbiol 26
(8): 1482–1486. PMID 3170711.
38. ^ Luger S (1990). "Lyme disease transmitted by a biting fly". N Engl J Med 322
(24): 1752. PMID 2342543.
39. ^ Bach G (2001). "Recovery of Lyme spirochetes by PCR in semen samples of
previously diagnosed Lyme disease patients.". 14th International Scientific
Conference on Lyme Disease.
40. ^ Schmidt B, Aberer E, Stockenhuber C, et al (1995). "Detection of Borrelia
burgdorferi DNA by polymerase chain reaction in the urine and breast milk of
 patients with Lyme borreliosis". Diagn Microbiol Infect Dis 21 (3): 121–128.
doi:10.1016/0732-8893(95)00027-8. PMID 7648832.
41. ^ Steere AC (2003-02-01). "Lyme Disease: Questions and Answers" (PDF).
Massachusetts General Hospital / Harvard Medical School. Retrieved on 2007-03-
22.
42. ^ Walsh CA, Mayer EW, Baxi LV (2007). "Lyme disease in pregnancy: case
report and review of the literature". Obstetrical & gynecological survey 62 (1):
41–50. doi:10.1097/01.ogx.0000251024.43400.9a. PMID 17176487.
43. ^ Wormser GP (June 2006). "Clinical practice. Early Lyme disease". N. Engl. J.
Med. 354 (26): 2794–801. doi:10.1056/NEJMcp061181. PMID 16807416.
44. ^ Varde S, Beckley J, Schwartz I (1998). "Prevalence of tick-borne pathogens in
Ixodes scapularis in a rural New Jersey County". Emerging Infect. Dis. 4 (1): 97–
9. PMID 9452402.
45. ^ Brown SL, Hansen SL, Langone JJ (1999). "Role of serology in the diagnosis
of Lyme disease". JAMA 282 (1): 62–66. doi:10.1001/jama.282.1.62. PMID
10404913.
46. ^ Hofmann H (1996). "Lyme borreliosis—problems of serological diagnosis".
Infection 24 (6): 470–472. doi:10.1007/BF01713052. PMID 9007597.
47. ^ "Lyme Disease (Borrelia burgdorferi): 1996 Case Definition". CDC Case
Definitions for Infectious Conditions under Public Health Surveillance (1996).
Retrieved on 2007-08-23.
48. ^ "CDC Testimony before the Connecticut Department of Health and Attorney
General's Office". CDC's Lyme Prevention and Control Activities (2004-01-24).
Retrieved on 2007-08-23.
49. ^ Pachner AR (1989). "Neurologic manifestations of Lyme disease, the new
"great imitator"". Rev. Infect. Dis. 11 Suppl 6: S1482–1486. PMID 2682960.
50. ^ Engstrom SM, Shoop E, Johnson RC (1995). "Immunoblot interpretation
criteria for serodiagnosis of early Lyme disease" (PDF). J Clin Microbiol 33 (2):
419–427. PMID 7714202.
51. ^ Sivak SL, Aguero-Rosenfeld ME, Nowakowski J, Nadelman RB, Wormser GP
(1996). "Accuracy of IgM immunoblotting to confirm the clinical diagnosis of
early Lyme disease". Arch Intern Med 156 (18): 2105–2109.
doi:10.1001/archinte.156.18.2105. PMID 8862103.
52. ^ Goossens HA, Nohlmans MK, van den Bogaard AE (1999). "Epstein-Barr virus
and cytomegalovirus infections cause false-positive results in IgM two-test
protocol for early Lyme borreliosis". Infection 27 (3): 231.
doi:10.1007/BF02561539. PMID 10378140.
53. ^ Strasfeld L, Romanzi L, Seder RH, Berardi VP (2005). "False-positive
serological test results for Lyme disease in a patient with acute herpes simplex
virus type 2 infection". Clin Infect Dis 41 (12): 1826–1827. doi:10.1086/498319.
PMID 16288417.
54. ^ Molloy PJ, Persing DH, Berardi VP (2001). "False-positive results of PCR
testing for Lyme disease". Clin. Infect. Dis. 33 (3): 412–413. PMID 11438915.
55. ^ Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP (2005). "Diagnosis
of Lyme borreliosis". Clin. Microbiol. Rev. 18 (3): 484–509.
doi:10.1128/CMR.18.3.484-509.2005. PMID 16020686.
56. ^ Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC (1994).
"Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial
fluid from patients with Lyme arthritis". N. Engl. J. Med. 330 (4): 229–234. PMID
8272083.
57. ^ Burdash N, Fernandes J (1991). "Lyme borreliosis: detecting the great imitator".
The Journal of the American Osteopathic Association 91 (6): 573–574, 577–578.
PMID 1874654.
58. ^ Coyle PK, Schutzer SE, Deng Z, et al (1995). "Detection of Borrelia
burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in
neurologic Lyme disease". Neurology 45 (11): 2010–2015. PMID 7501150.
59. ^ Valentine-Thon E, Ilsemann K, Sandkamp M (2007). "A novel lymphocyte
transformation test (LTT-MELISA) for Lyme borreliosis". Diagn. Microbiol.
Infect. Dis. 57 (1): 27–34. doi:10.1016/j.diagmicrobio.2006.06.008. PMID
16876371.
60. ^ Eisendle K, Grabner T, Zelger B (2007). "Focus floating microscopy: "gold
standard" for cutaneous borreliosis?". Am. J. Clin. Pathol. 127 (2): 213–222.
doi:10.1309/3369XXFPEQUNEP5C. PMID 17210530.
61. ^ Cadavid D (2006). "The mammalian host response to borrelia infection". Wien.
Klin. Wochenschr. 118 (21–22): 653–658. doi:10.1007/s00508-006-0692-0. PMID
17160603.
62. ^ Sumiya H, Kobayashi K, Mizukoshi C, et al (1997). "Brain perfusion SPECT in
Lyme neuroborreliosis". J. Nucl. Med. 38 (7): 1120–1122. PMID 9225802.
63. ^ Logigian EL, Johnson KA, Kijewski MF, et al (1997). "Reversible cerebral
hypoperfusion in Lyme encephalopathy". Neurology 49 (6): 1661–1670. PMID
9409364.
64. ^ Fallon BA, Das S, Plutchok JJ, Tager F, Liegner K, Van Heertum R (1997).
"Functional brain imaging and neuropsychological testing in Lyme disease". Clin.
Infect. Dis. 25 Suppl 1: S57–63. PMID 9233666.
65. ^ Fallon, BA (2000). "Review of Lyme Neuroborreliosis" in 3th International
Scientific Conference on Lyme Disease and other Tick-borne Disorders..
66. ^ Kalina P, Decker A, Kornel E, Halperin JJ (2005). "Lyme disease of the
brainstem". Neuroradiology 47 (12): 903–907. doi:10.1007/s00234-005-1440-2.
PMID 16158278.
67. ^ Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ (2003). "Regional
cerebral blood flow and cognitive deficits in chronic Lyme disease". The Journal
of neuropsychiatry and clinical neurosciences 15 (3): 326–332. PMID 12928508.
68. ^ a b Piesman J, Dolan MC (2002). "Protection against Lyme disease spirochete
transmission provided by prompt removal of nymphal Ixodes scapularis (Acari:
Ixodidae)". J Med Entomol 39 (3): 509–512. PMID 12061448.
69. ^ http://www.ct.gov/caes/lib/caes/documents/publications/bulletins/b1010.pdf
70. ^ Rand PW, Lubelczyk C, Holman MS, Lacombe EH, Smith RP (2004).
"Abundance of Ixodes scapularis (Acari: Ixodidae) after the complete removal of
deer from an isolated offshore island, endemic for Lyme Disease". J. Med.
Entomol. 41 (4): 779–784. PMID 15311475.
71. ^ "Managing Urban Deer in Connecticut, Figure 2, p.4." (PDF). 2nd edition.
Connecticut Department of Environmental Protection - Wildlife Division (June
2007). Retrieved on 2008-05-02.
72. ^ Stafford KC (2004). "Tick Management Handbook" (PDF) 46. Connecticut
Agricultural Experiment Station and Connecticut Department of Public Health.
Retrieved on 2007-08-21.
73. ^ Poland GA, Jacobson RM (March 2001). "The prevention of Lyme disease with
vaccine". Vaccine 19 (17-19): 2303–8. PMID 11257352.
74. ^ Lukewarm Response To New Lyme Vaccine, by Claudia Rowe. Published in the
New York Times on June 13, 1999; accessed July 11, 2008.
75. ^ a b c d Abbott A (February 2006). "Lyme disease: uphill struggle". Nature 439
(7076): 524–5. doi:10.1038/439524a. PMID 16452949.
76. ^ Sole Lyme Vaccine Is Pulled Off Market, published in the New York Times on
February 28, 2002; accessed July 11, 2008.
77. ^ a b Nigrovic LE, Thompson KM (January 2007). "The Lyme vaccine: a
cautionary tale". Epidemiol. Infect. 135 (1): 1–8.
doi:10.1017/S0950268806007096. PMID 16893489.
78. ^ "When a vaccine is safe" (February 2006). Nature 439 (7076): 509.
doi:10.1038/439509a. PMID 16452935.
79. ^ Earnhart CG, Marconi RT (2007). "OspC phylogenetic analyses support the
feasibility of a broadly protective polyvalent chimeric Lyme disease vaccine".
Clin. Vaccine Immunol. 14 (5): 628–634. doi:10.1128/CVI.00409-06. PMID
17360854.
80. ^ Pozsgay V, Kubler-Kielb J (2007). "Synthesis of an experimental
glycolipoprotein vaccine against Lyme disease". Carbohydr. Res. 342 (3–4): 621–
626. doi:10.1016/j.carres.2006.11.014. PMID 17182019.
81. ^ Zeller JL, Burke AE, Glass RM (2007). "JAMA patient page. Lyme disease".
JAMA 297 (23): 2664. doi:10.1001/jama.297.23.2664. PMID 17579234.
82. ^ Oksi J, Nikoskelainen J, Hiekkanen H, et al (2007). "Duration of antibiotic
treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-
controlled, multicenter clinical study". Eur. J. Clin. Microbiol. Infect. Dis. 26 (8):
571–581. doi:10.1007/s10096-007-0340-2. PMID 17587070.
83. ^ Elewa HF, Hilali H, Hess DC, Machado LS, Fagan SC (April 2006).
"Minocycline for short-term neuroprotection". Pharmacotherapy 26 (4): 515–21.
doi:10.1592/phco.26.4.515. PMID 16553511.
84. ^ a b {{cite journal |author=Halperin JJ |title=Prolonged Lyme disease treatment:
Enough is enough |journal=Neurology |volume=70 |issue=13 |pages=986-7 |
year=2008
85. ^ Cameron D, Gaito A, Harris N, et al (2004
url="http://www.guideline.gov/summary/summary.aspx?doc_id=4836&nbr=3481
&string=lyme"). "Evidence-based guidelines for the management of Lyme
disease". Expert Rev Anti Infect Ther 2 (1 Suppl): S1–13. PMID 15581390.
86. ^ a b Baker PJ (2008). "Perspectives on “Chronic Lyme Disease”". American
Journal of Medicine 121 (7): 562-4.
87. ^ http://www.epi-perspectives.com/content/3/1/12
88. ^ Marques A et al Neurology, 2008.
89. ^ Wormser GP, Dattwyler RJ, Shapiro ED, et al (November 2006). "The clinical
assessment, treatment, and prevention of lyme disease, human granulocytic
anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious
Diseases Society of America". Clin. Infect. Dis. 43 (9): 1089–134.
doi:10.1086/508667. PMID 17029130.
90. ^ Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP,
Krupp L, Gronseth G, Bever CT (2007). "Practice parameter: treatment of
nervous system Lyme disease (an evidence-based review): report of the Quality
Standards Subcommittee of the American Academy of Neurology". Neurology 69
(1): 91–102. doi:10.1212/01.wnl.0000265517.66976.28. PMID 17522387.
91. ^ Patel R, Grogg KL, Edwards WD, Wright AJ, Schwenk NM (October 2000).
"Death from inappropriate therapy for Lyme disease". Clin. Infect. Dis. 31 (4):
1107–9. PMID 11049799.
92. ^ Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK (1999). "Borrelia
burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme
borreliosis". Ann. Med. 31 (3): 225–232. doi:10.3109/07853899909115982.
PMID 10442678.
93. ^ Hartiala P, Hytönen J, Pelkonen J, et al (2007). "Transcriptional response of
human dendritic cells to Borrelia garinii—defective CD38 and CCR7 expression
detected". J. Leukoc. Biol. 82 (1): 33–43. doi:10.1189/jlb.1106709. PMID
17440035.
94. ^ Massarotti EM (2002). "Lyme arthritis". Med. Clin. North Am. 86 (2): 297–309.
doi:10.1016/S0025-7125(03)00088-9. PMID 11982303.
95. ^ Puéchal X (2007). "[Non antibiotic treatments of Lyme borreliosis]" (in
French). Med Mal Infect 37 (7–8): 473–8. doi:10.1016/j.medmal.2006.01.021.
PMID 17376627.
96. ^ Weissenbacher S, Ring J, Hofmann H (2005). "Gabapentin for the symptomatic
treatment of chronic neuropathic pain in patients with late-stage lyme borreliosis:
a pilot study". Dermatology (Basel) 211 (2): 123–127. doi:10.1159/000086441.
PMID 16088158.
97. ^ Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M (2004). "Clinical
potential of minocycline for neurodegenerative disorders". Neurobiol. Dis. 17 (3):
359–366. doi:10.1016/j.nbd.2004.07.012. PMID 15571972.
98. ^ Taylor R, Simpson I (2005). "Review of treatment options for Lyme
borreliosis". J Chemother 17 Suppl 2: 3–16. PMID 16315580.
99. ^ Pavia C (2003). "Current and novel therapies for Lyme disease". Expert Opin
Investig Drugs 12 (6): 1003–1016. doi:10.1517/13543784.12.6.1003. PMID
12783604.
100.^ Schardt FW (2004). "Clinical effects of fluconazole in patients with
neuroborreliosis". Eur. J. Med. Res. 9 (7): 334–336. PMID 15337633.
101.^ Lubke LL, Garon CF (1997). "The antimicrobial agent melittin exhibits
powerful in vitro inhibitory effects on the Lyme disease spirochete". Clin. Infect.
Dis. 25 Suppl 1: S48–51. PMID 9233664.
102.^ Krause PJ, Foley DT, Burke GS, Christianson D, Closter L, Spielman A (2006).
"Reinfection and relapse in early Lyme disease". Am. J. Trop. Med. Hyg. 75 (6):
1090–1094. PMID 17172372.
103.^ Klempner MS, Hu LT, Evans J, et al (2001). "Two controlled trials of antibiotic
treatment in patients with persistent symptoms and a history of Lyme disease". N
Engl J Med 345 (2): 85–92. doi:10.1056/NEJM200107123450202. PMID
11450676.
104.^ Fatal cases of Lyme disease reported in the medical literature include:
o Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A
(1988). "Fatal adult respiratory distress syndrome in a patient with Lyme
disease". JAMA 259 (18): 2737–2739. doi:10.1001/jama.259.18.2737.
PMID 3357244.
o Oksi J, Kalimo H, Marttila RJ, et al (1996). "Inflammatory brain changes
in Lyme borreliosis. A report on three patients and review of literature".
Brain 119 (Pt 6): 2143–2154. doi:10.1093/brain/119.6.2143. PMID
9010017.
o Waniek C, Prohovnik I, Kaufman MA, Dwork AJ (1995). "Rapidly
progressive frontal-type dementia associated with Lyme disease". J
Neuropsychiatry Clin Neurosci 7 (3): 345–347. PMID 7580195.
o Cary NR, Fox B, Wright DJ, Cutler SJ, Shapiro LM, Grace AA (1990).
"Fatal Lyme carditis and endodermal heterotopia of the atrioventricular
node". Postgrad Med J 66 (772): 134–136. PMID 2349186.
105.^ LoGiudice K, Ostfeld R, Schmidt K, Keesing F (2003). "The ecology of
infectious disease: effects of host diversity and community composition on Lyme
disease risk". Proc Natl Acad Sci U S A 100 (2): 567–571.
doi:10.1073/pnas.0233733100. PMID 12525705.
106.^ Patz J, Daszak P, Tabor G, et al (2004). "Unhealthy landscapes: Policy
recommendations on land use change and infectious disease emergence". Environ
Health Perspect 112 (10): 1092–1098. PMID 15238283.
107.^ Khasnis AA, Nettleman MD (2005). "Global warming and infectious disease".
Arch. Med. Res. 36 (6): 689–696. doi:10.1016/j.arcmed.2005.03.041. PMID
16216650.
108.^ Perkins SE, Cattadori IM, Tagliapietra V, Rizzoli AP, Hudson PJ (2006).
"Localized deer absence leads to tick amplification". Ecology 87 (8): 1981–1986.
doi:10.1890/0012-9658(2006)87[1981:LDALTT]2.0.CO;2. PMID 16937637.
109.^ CDC (2006-10-02). "Reported Cases of Lyme Disease by Year, United States,
1991–2005". Retrieved on 2007-08-20.
110.^ http://www.cdc.gov/ncidod/dvbid/lyme/ld_statistics.htm
111.^ http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm
112.^ Swanson KI, Norris DE (2007). "Detection of Borrelia burgdorferi DNA in
lizards from Southern Maryland". Vector Borne Zoonotic Dis. 7 (1): 42–49.
doi:10.1089/vbz.2006.0548. PMID 17417956.
113.^ Richter D, Matuschka FR (July 2006). "Perpetuation of the Lyme disease
spirochete Borrelia lusitaniae by lizards". Appl. Environ. Microbiol. 72 (7): 4627–
4632. doi:10.1128/AEM.00285-06. PMID 16820453.
114.^ Giery ST, Ostfeld RS (June 2007). "The role of lizards in the ecology of Lyme
disease in two endemic zones of the northeastern United States". J. Parasitol. 93
(3): 511–517. PMID 17626342.
115.^ Amore G, Tomassone L, Grego E, et al (March 2007). "Borrelia lusitaniae in
immature Ixodes ricinus (Acari: Ixodidae) feeding on common wall lizards in
Tuscany, central Italy". J. Med. Entomol. 44 (2): 303–307. PMID 17427701.
116.^ Swanson KI, Norris DE (2007). "Detection of Borrelia burgdorferi DNA in
lizards from Southern Maryland". Vector Borne Zoonotic Dis. 7 (1): 42–49.
doi:10.1089/vbz.2006.0548. PMID 17417956.
117.^ Majláthová V, Majláth I, Derdáková M, Víchová B, Pet'ko B (December 2006).
"Borrelia lusitaniae and green lizards (Lacerta viridis), Karst Region, Slovakia".
Emerging Infect. Dis. 12 (12): 1895–1901. PMID 17326941.
118.^ http://www.eurosurveillance.org/ew/2006/060622.asp
119.^ Li M, Masuzawa T, Takada N, et al (1998). "Lyme disease Borrelia species in
northeastern China resemble those isolated from far eastern Russia and Japan".
Appl. Environ. Microbiol. 64 (7): 2705–2709. PMID 9647853.
120.^ Masuzawa T (2004). "Terrestrial distribution of the Lyme borreliosis agent
Borrelia burgdorferi sensu lato in East Asia". Jpn. J. Infect. Dis. 57 (6): 229–235.
PMID 15623946.
121.^ Walder G, Lkhamsuren E, Shagdar A, et al (2006). "Serological evidence for
tick-borne encephalitis, borreliosis, and human granulocytic anaplasmosis in
Mongolia". Int. J. Med. Microbiol. 296 Suppl 40: 69–75.
doi:10.1016/j.ijmm.2006.01.031. PMID 16524782.
122.^ Mantovani E, Costa IP, Gauditano G, Bonoldi VL, Higuchi ML, Yoshinari NH
(2007). "Description of Lyme disease-like syndrome in Brazil. Is it a new tick
borne disease or Lyme disease variation?". Braz. J. Med. Biol. Res. 40 (4): 443–
456. PMID 17401487.
123.^ Yoshinari NH, Oyafuso LK, Monteiro FG, et al (1993). "Lyme disease. Report
of a case observed in Brazil" (in Portuguese). Revista do Hospital das Clínicas 48
(4): 170–174. PMID 8284588.
124.^ Bouattour A, Ghorbel A, Chabchoub A, Postic D (2004). "Lyme borreliosis
situation in North Africa" (in French). Archives de l'Institut Pasteur de Tunis 81
(1–4): 13–20. PMID 16929760.
125.^ Dsouli N, Younsi-Kabachii H, Postic D, et al (2006). "Reservoir role of lizard
Psammodromus algirus in transmission cycle of Borrelia burgdorferi sensu lato
(Spirochaetaceae) in Tunisia". J. Med. Entomol. 43 (4): 737–742.
doi:10.1603/0022-2585(2006)43[737:RROLPA]2.0.CO;2. PMID 16892633.
126.^ Helmy N (2000). "Seasonal abundance of Ornithodoros (O.) savignyi and
prevalence of infection with Borrelia spirochetes in Egypt". Journal of the
Egyptian Society of Parasitology 30 (2): 607–619. PMID 10946521.
127.^ Fivaz BH, Petney TN (1989). "Lyme disease—a new disease in southern
Africa?". Journal of the South African Veterinary Association 60 (3): 155–158.
PMID 2699499.
128.^ Jowi JO, Gathua SN (2005). "Lyme disease: report of two cases". East African
medical journal 82 (5): 267–269. PMID 16119758.
129.^ Piesman J, Stone BF (1991). "Vector competence of the Australian paralysis
tick, Ixodes holocyclus, for the Lyme disease spirochete Borrelia burgdorferi".
Int. J. Parasitol. 21 (1): 109–111. doi:10.1016/0020-7519(91)90127-S. PMID
2040556.
130.^ Grubhoffer L, Golovchenko M, Vancová M, Zacharovová-Slavícková K,
Rudenko N, Oliver JH (2005). "Lyme borreliosis: insights into tick-/host-borrelia
relations". Folia Parasitol. 52 (4): 279–294. PMID 16405291.
131.^ Higgins R (2004). "Emerging or re-emerging bacterial zoonotic diseases:
bartonellosis, leptospirosis, Lyme borreliosis, plague". Rev. - Off. Int. Epizoot. 23
(2): 569–581. PMID 15702720.
132.^ a b Whelan, David (2007-03-12). "Lyme Inc", Forbes. Retrieved on 2008-06-24.
133.^ William Hathaway and Hilary Waldman (2007-03-27). "Lyme Disease Experts:
Butt Out, Blumenthal", The Hartford Courant. Retrieved on 2008-10-18.
134.^ a b Landers, Susan J (2008-06-09). "Lyme treatment accord ends antitrust
probe". American Medical News. Retrieved on 2008-06-24.
135.^ State of Connecticut Attorney General's Office (2008-05-01). "Attorney
General's Investigation Reveals Flawed Lyme Disease Guideline Process, IDSA
Agrees To Reassess Guidelines, Install Independent Arbiter". Press release.
Retrieved on 2008-06-24.
136.^ Infectious Diseases Society of America (2008-05-01). "Agreement Ends Lyme
Disease Investigation By Connecticut Attorney General: Medical Validity of
IDSA Guidelines Not Challenged". Press release. Retrieved on 2008-06-24.
137.^ Grann, David (2001-06-17). "Stalking Dr. Steere Over Lyme Disease", New
York Times Magazine. Retrieved on 2008-06-25.
138.^ Cooper JD, Feder HM (December 2004). "Inaccurate information about lyme
disease on the internet". Pediatr. Infect. Dis. J. 23 (12): 1105–8. PMID 15626946.
139.^ a b Steere AC, Coburn J, Glickstein L (April 2004). "The emergence of Lyme
disease". J. Clin. Invest. 113 (8): 1093–101. doi:10.1172/JCI21681. PMID
15085185.
140.^ Pachner AR, Steiner I (June 2007). "Lyme neuroborreliosis: infection,
immunity, and inflammation". Lancet Neurol 6 (6): 544–52. doi:10.1016/S1474-
4422(07)70128-X. PMID 17509489.
141.^ Fikrig E, Narasimhan S (April 2006). "Borrelia burgdorferi--traveling
incognito?". Microbes Infect. 8 (5): 1390–9. doi:10.1016/j.micinf.2005.12.022.
PMID 16698304.
142.^ Xu Q, Seemanapalli SV, Reif KE, Brown CR, Liang FT (April 2007).
"Increasing the recruitment of neutrophils to the site of infection dramatically
attenuates Borrelia burgdorferi infectivity". J. Immunol. 178 (8): 5109–15. PMID
17404293.
143.^ Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL (June
1997). "Plasminogen is required for efficient dissemination of B. burgdorferi in
ticks and for enhancement of spirochetemia in mice". Cell 89 (7): 1111–9. PMID
9215633.
144.^ Rupprecht TA, Koedel U, Fingerle V, Pfister HW (2008). "The pathogenesis of
Lyme neuroborreliosis: from infection to inflammation". Mol. Med. 14 (3-4):
205–12. doi:10.2119/2007-00091.Rupprecht. PMID 18097481.
145.^ Cabello FC, Godfrey HP, Newman SA (August 2007). "Hidden in plain sight:
Borrelia burgdorferi and the extracellular matrix". Trends Microbiol. 15 (8): 350–
4. doi:10.1016/j.tim.2007.06.003. PMID 17600717.
146.^ a b Ramesh G, Alvarez AL, Roberts ED, et al (September 2003). "Pathogenesis
of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both
proliferation and apoptosis in rhesus monkey astrocytes". Eur. J. Immunol. 33 (9):
2539–50. doi:10.1002/eji.200323872. PMID 12938230.
147.^ Halperin JJ, Heyes MP (January 1992). "Neuroactive kynurenines in Lyme
borreliosis". Neurology 42 (1): 43–50. PMID 1531156.
148.^ "Treatment of Lyme Disease". Columbia University. Retrieved on 2007-08-23.
149.^ Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP (1998). "The
pathophysiologic roles of interleukin-6 in human disease". Ann. Intern. Med. 128
(2): 127–137. PMID 9441573.
150.^ Rasley A, Anguita J, Marriott I (2002). "Borrelia burgdorferi induces
inflammatory mediator production by murine microglia". J. Neuroimmunol. 130
(1–2): 22–31. doi:10.1016/S0165-5728(02)00187-X. PMID 12225885.
151.^ Wright CB, Sacco RL, Rundek TR, et al (2006). "Interleukin-6 is associated
with cognitive function: the Northern Manhattan Study". Journal of Stroke and
Cerebrovascular Diseases 15 (1): 34–38.
doi:10.1016/j.jstrokecerebrovasdis.2005.08.009. PMID 16501663.
152.^ Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP (2005). "Cytokine
dysregulation, inflammation and well-being". Neuroimmunomodulation 12 (5):
255–269. doi:10.1159/000087104. PMID 16166805.
153.^ Calcagni E, Elenkov I (2006). "Stress system activity, innate and T helper
cytokines, and susceptibility to immune-related diseases". Ann. N. Y. Acad. Sci.
1069: 62–76. doi:10.1196/annals.1351.006. PMID 16855135.
154.^ Gasse T, Murr C, Meyersbach P, et al (1994). "Neopterin production and
tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme
encephalopathy". European journal of clinical chemistry and clinical
biochemistry : journal of the Forum of European Clinical Chemistry Societies 32
(9): 685–689. PMID 7865624.
155.^ Zajkowska J, Grygorczuk S, Kondrusik M, Pancewicz S, Hermanowska-
Szpakowicz T (2006). "New aspects of pathogenesis of Lyme borreliosis" (in
Polish). Przegla̧d epidemiologiczny 60 Suppl 1: 167–170. PMID 16909797.
156.^ Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M (2001).
"Anti-Inflammatory effects of antidepressants through suppression of the
interferon-gamma/interleukin-10 production ratio". Journal of clinical
psychopharmacology 21 (2): 199–206. doi:10.1097/00004714-200104000-00012.
PMID 11270917.
157.^ Diamond M, Kelly JP, Connor TJ (2006). "Antidepressants suppress production
of the Th1 cytokine interferon-gamma, independent of monoamine transporter
blockade". European neuropsychopharmacology : the journal of the European
College of Neuropsychopharmacology 16 (7): 481–490.
doi:10.1016/j.euroneuro.2005.11.011. PMID 16388933.
158.^ Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C (2007).
"Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-
gamma secretion and increased number of forkhead box P3-expressing cells in
patients with a history of chronic Lyme borreliosis compared with asymptomatic
 Borrelia-exposed individuals". Clin. Exp. Immunol. 147 (1): 18–27.
doi:10.1111/j.1365-2249.2006.03245.x. PMID 17177959.
159.^ Ramesh G, Philipp MT (2005). "Pathogenesis of Lyme neuroborreliosis:
mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of
astrocytes to Borrelia burgdorferi lipoproteins". Neurosci. Lett. 384 (1–2): 112–
116. doi:10.1016/j.neulet.2005.04.069. PMID 15893422.
160.^ Singh SK, Girschick HJ (2006). "Toll-like receptors in Borrelia burgdorferi-
induced inflammation". Clin. Microbiol. Infect. 12 (8): 705–717.
doi:10.1111/j.1469-0691.2006.01440.x. PMID 16842565.
161.^ Weinstein A, Britchkov M (July 2002). "Lyme arthritis and post-Lyme disease
syndrome". Curr Opin Rheumatol 14 (4): 383–7. PMID 12118171.
162.^ Bolz DD, Weis JJ (August 2004). "Molecular mimicry to Borrelia burgdorferi:
pathway to autoimmunity?". Autoimmunity 37 (5): 387–92.
doi:10.1080/08916930410001713098. PMID 15621562.
163.^ Afzelius A (1910). "Verhandlungen der Dermatologischen Gesellshaft zu
Stockholm" (in German). Archives of Dermatology and Syphilis 101: 100–102.
164.^ Burckhardt JL (1911). "Zur Frage der Follikel- und Keimzentrenbildung in der
Haut" (in German). Frankfurter Zeitschrift fur Pathologie 6: 352–359.
165.^ Hellerstrom S (1930). "Erythema chronicum migrans Afzelii" (in German).
Archiv Dermatologie and Venereologie (Stockholm) 11: 315–321.
166.^ Lenhoff C (1948). "Spirochetes in aetiologically obscure diseases". Acta
Dermato-Venreol 28: 295–324.
167.^ Thyresson N (1949). "The penicillin treatment of acrodermatitis atrophicans
chronica (Herxheimer)". Acta Derm. Venereol. 29 (6): 572–621. PMID 18140373.
168.^ Bianchi GE (1950). "Penicillin therapy of lymphocytoma". Dermatologica 100
(4–6): 270–273. PMID 15421023.
169.^ Paschoud JM (1954). "Lymphocytoma after tick bite" (in German).
Dermatologica 108 (4–6): 435–437. PMID 13190934.
170.^ Scrimenti RJ (1970). "Erythema chronicum migrans". Archives of dermatology
102 (1): 104–105. doi:10.1001/archderm.102.1.104. PMID 5497158.
171.^ Steere AC (2006). "Lyme borreliosis in 2005, 30 years after initial observations
in Lyme, Connecticut". Wien. Klin. Wochenschr. 118 (21–22): 625–633.
doi:10.1007/s00508-006-0687-x. PMID 17160599.
172.^ Sternbach G, Dibble C (1996). "Willy Burgdorfer: Lyme disease". J Emerg
Med 14 (5): 631–634. doi:10.1016/S0736-4679(96)00143-6. PMID 8933327.
173.^ Mast WE, Burrows WM (1976). "Erythema chronicum migrans and "Lyme
arthritis"". JAMA 236 (21): 2392. doi:10.1001/jama.236.21.2392d. PMID 989847.
174.^ Steere AC, Malawista SE, Snydman DR, et al (1977). "Lyme arthritis: an
epidemic of oligoarticular arthritis in children and adults in three connecticut
communities". Arthritis Rheum. 20 (1): 7–17. doi:10.1002/art.1780200102. PMID
836338.
175.^ Steere AC, Hutchinson GJ, Rahn DW, et al (1983). "Treatment of the early
manifestations of Lyme disease". Ann. Intern. Med. 99 (1): 22–26. PMID
6407378.
176.^ Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ (1988). "New
chemotherapeutic approaches in the treatment of Lyme borreliosis". Ann. N. Y.
 Acad. Sci. 539: 352–361. doi:10.1111/j.1749-6632.1988.tb31869.x. PMID
3056203.
177.^ Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ (1990).
"Amoxycillin plus probenecid versus doxycycline for treatment of erythema
migrans borreliosis". Lancet 336 (8728): 1404–1406. doi:10.1016/0140-
6736(90)93103-V. PMID 1978873.
178.^ Ribeiro JM, Mather TN, Piesman J, Spielman A (1987). "Dissemination and
salivary delivery of Lyme disease spirochetes in vector ticks (Acari: Ixodidae)". J.
Med. Entomol. 24 (2): 201–205. PMID 3585913.

[edit] Bibliography
• Jonathan A. Edlow MD, Bull's Eye: Unraveling the Medical Mystery of Lyme
Disease, Yale University Press, 2003

[edit] Documentary Film

• Under Our Skin: The Untold Story of Lyme Disease (2008)

[edit] External links

General

• Lyme disease at the Open Directory Project

• Lyme disease organizations at the Open Directory Project
• CDC Lyme disease page
o National Institute for Occupational Safety and Health - Lyme Disease
Page
• Columbia University - Overview of Neuropsychiatric Lyme Disease
• Lyme Disease The Merck Manual
• US Army Factsheet on Lyme Disease (CHPPM's Entomological Sciences
Program)
• Interactive Image of Ixodes scapularis, Deer Tick or Blacklegged Tick (CHPPM's
Entomological Sciences Program)
 [show]
v•d•e
Infectious diseases - Bacterial diseases (primarily A00-A79, 001-041,080-
109)

Pseudomembranous colitis - Botulism - Tetanus - Gas

Clostridium
gangrene

Strep-: Alpha (pneumoniae, mutans,

viridans) - Beta A pyogenes (Scarlet
fever, Erysipelas, Rheumatic fever,
Firmicutes Coccus
Streptococcal pharyngitis), B
Bacilli
agalactiae - D Entero-
(class)
Staphylo- - Toxic shock syndrome

Bacillus (Anthrax) - Listeria

Bacillus (shape)
(Listeriosis)

Actinomycosis/Actinomycetoma (Whipple's
disease) - Corynebacterium (Diphtheria,
Actinomycetales
Erythrasma) - Nocardia (Nocardiosis,
Maduromycosis)

M. tuberculosis (Tuberculosis): Ghon

focus/Ghon's complex - Pott disease - brain
(Meningitis, Rich focus) - cutaneous (Scrofula,
Actinobacteria
Bazin disease, Lupus vulgaris, Prosector's wart) -
Miliary
Mycobacterium
M. leprae (Leprosy)

Nontuberculous: Mycobacterium avium (Lady

Windermere syndrome) - Mycobacterium
ulcerans (Buruli ulcer)

Treponema: Syphilis (Bejel) - Yaws - Pinta

Borrelia: Relapsing fever - Lyme disease (Erythema chronicum

Spirochetalmigrans, Neuroborreliosis)

other/multiple/unknown: Noma - Trench mouth - Rat-bite fever

(Sodoku) - Leptospirosis

MycoplasmatalesMycoplasma pneumonia - Ureaplasma infection

 [show]
v•d•e
Tick-borne diseases

Retrieved from "http://en.wikipedia.org/wiki/Lyme_disease"

Categories: Lyme disease | Bacterial diseases | Insect-borne diseases | Zoonoses |
Spirochaetes
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