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1.  Diagnostic challenges of early Lyme disease: Lessons from a community case series 
Background
Lyme disease, the most common vector-borne infection in North America, is increasingly reported. When the characteristic rash, erythema migrans, is not recognized and treated, delayed manifestations of disseminated infection may occur. The accuracy of diagnosis and treatment of early Lyme disease in the community is unknown.
Methods
A retrospective, consecutive case series of 165 patients presenting for possible early Lyme disease between August 1, 2002 and August 1, 2007 to a community-based Lyme referral practice in Maryland. All patients had acute symptoms of less than or equal to 12 weeks duration. Patients were categorized according to the Centers for Disease Control and Prevention criteria and data were collected on presenting history, physical findings, laboratory serology, prior diagnoses and prior treatments.
Results
The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease.
Conclusion
For community physicians practicing in high-risk geographic areas, the diagnosis of Lyme disease remains a challenge. Failure to recognize erythema migrans or alternatively, viral-like presentations without a rash, can lead to missed or delayed diagnosis of Lyme disease, ineffective antibiotic treatment, and the potential for late manifestations.
doi:10.1186/1471-2334-9-79
PMCID: PMC2698836  PMID: 19486523
2.  Lyme disease 
Clinical Evidence  2004;2004:0910.
Introduction
Lyme disease is caused by infection with Borrelia burgdorferi transmitted by ticks in temperate areas, typically causing an expanding circular rash around the infectious tick attachment site. Early disseminated infection can cause neuropathies, meningitis, arthralgia and cardiac disease, although spontaneous resolution usually occurs over time. Untreated or inadequately treated Lyme disease can cause late disseminated infection, with arthritis, polyneuropathy and encephalopathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: what are the effects of measures to prevent Lyme disease? What are the effects of antibiotic treatment for Lyme disease arthritis? What are the effects of antibiotic treatments for late neurological Lyme disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2003 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 11 systematic reviews, RCTs or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: prophylactic antibiotic treatment of tick bite, treatment of Lyme disease arthritis with antibiotics, and treatment of late neurological Lyme disease with antibiotics.
Key Points
Lyme disease is caused by infection with Borrelia burgdorferi transmitted by ticks in temperate areas, typically causing an expanding circular rash around the infectious tick attachment site. Early disseminated infection can cause neuropathies, meningitis, arthralgia and cardiac disease, although spontaneous resolution usually occurs over time.Untreated or inadequately treated Lyme disease can cause late disseminated infection, with arthritis, polyneuropathy and encephalopathy.
Prophylactic antibiotics such as single dose doxycycline reduce the risk of developing early Lyme disease in people exposed to tick bites but increase the risk of adverse effects. Limiting prophylactic treatment to people with engorged nymphal ticks may be the best strategy to maximise benefit and minimise harm from adverse effects.
In people with Lyme arthritis, penicillin increases resolution of symptoms compared with placebo. Cefotaxime and ceftriaxone may improve symptoms compared with penicillin, but few good quality studies have been found.Doxycycline may be as effective as amoxicillin plus probenecid at improving symptoms of Lyme arthritis.
In people with late neurological Lyme disease, cefotaxime may be more effective than penicillin at improving symptoms, but we don't know whether ceftriaxone is also beneficial. Ceftriaxone may be no more effective than placebo at improving cognitive functioning in people with late neurological Lyme disease who had received prior treatment.Ceftriaxone plus doxycycline has not been shown to improve health related quality of life in people with late neurological Lyme disease who have previously received treatment.
PMCID: PMC2907555
3.  Clinical characteristics and cerebrospinal fluid parameters in patients with peripheral facial palsy caused by Lyme neuroborreliosis compared with facial palsy of unknown origin (Bell's palsy) 
BMC Infectious Diseases  2011;11:215.
Background
Bell's palsy and Lyme neuroborreliosis are the two most common diagnoses in patients with peripheral facial palsy in areas endemic for Borrelia burgdorferi. Bell's palsy is treated with corticosteroids, while Lyme neuroborreliosis is treated with antibiotics. The diagnosis of Lyme neuroborreliosis relies on the detection of Borrelia antibodies in blood and/or cerebrospinal fluid, which is time consuming. In this study, we retrospectively analysed clinical and cerebrospinal fluid parameters in well-characterised patient material with peripheral facial palsy caused by Lyme neuroborreliosis or Bell's palsy, in order to obtain a working diagnosis and basis for treatment decisions in the acute stage.
Methods
Hospital records from the Department of Infectious Diseases, Sahlgrenska University Hospital, for patients with peripheral facial palsy that had undergone lumbar puncture, were reviewed. Patients were classified as Bell's palsy, definite Lyme neuroborreliosis, or possible Lyme neuroborreliosis, on the basis of the presence of Borrelia antibodies in serum and cerebrospinal fluid and preceding erythema migrans.
Results
One hundred and two patients were analysed; 51 were classified as Bell's palsy, 34 as definite Lyme neuroborreliosis and 17 as possible Lyme neuroborreliosis. Patients with definite Lyme neuroborreliosis fell ill during the second half of the year, with a peak in August, whereas patients with Bell's palsy fell ill in a more evenly distributed manner over the year. Patients with definite Lyme neuroborreliosis had significantly more neurological symptoms outside the paretic area of the face and significantly higher levels of mononuclear cells and albumin in their cerebrospinal fluid. A reported history of tick bite was uncommon in both groups.
Conclusions
We found that the time of the year, associated neurological symptoms and mononuclear pleocytosis were strong predictive factors for Lyme neuroborreliosis as a cause of peripheral facial palsy in an area endemic for Borrelia. For these patients, we suggest that ex juvantibus treatment with oral doxycycline should be preferred to early corticosteroid treatment.
doi:10.1186/1471-2334-11-215
PMCID: PMC3176206  PMID: 21831262
4.  Implications of Gender in Chronic Lyme Disease 
Journal of Women's Health  2009;18(6):831-834.
Abstract
Background
“Post-Lyme disease syndrome” refers to prolonged subjective symptoms after antibiotic treatment and resolution of an objective manifestation of Borrelia burgdorferi infection (Lyme disease). “Chronic Lyme disease” is a vaguely defined term that has been applied to patients with unexplained prolonged subjective symptoms, whether or not there was or is evidence of B. burgdorferi infection.
Objective
To determine if the population of patients with chronic Lyme disease differs from the populations of patients with either Lyme disease or post-Lyme disease syndrome by examining the gender of patients with these diagnoses.
Methods
Data on gender were compiled in this cross-sectional study based on a systematic review of published studies of antibiotic treatment in United States patients with post-Lyme disease syndrome (n = 184) or chronic Lyme disease (n = 490), and on cases of adults with Lyme disease reported to the Centers for Disease Control and Prevention from 2003 to 2005 (n = 43,282).
Results
Patients with chronic Lyme disease were significantly more likely to be female than were patients diagnosed with either Lyme disease (odds ratio [OR] 2.42, 95% confidence interval [CI] 1.98–2.94, p < 0.0001) or with post-Lyme disease syndrome (OR 2.32, 95% CI 1.62–3.34, p < 0.0001).
Conclusions
Patients with chronic Lyme disease differ with regard to gender from those with either B. burgdorferi infection or post-Lyme disease syndrome. This finding suggests that illnesses with a female preponderance, such as fibromyalgia, chronic fatigue syndrome, or depression, may be misdiagnosed as chronic Lyme disease.
doi:10.1089/jwh.2008.1193
PMCID: PMC2913779  PMID: 19514824
5.  Lyme disease in northwestern coastal California. 
Western Journal of Medicine  1994;160(6):534-539.
To determine the incidence of physician-diagnosed Lyme disease in an endemic area of California, an active surveillance program was implemented in Lake, Mendocino, Sonoma, and southern Humboldt counties. More than 200 medical care providers were called monthly for their list of suspected cases of Lyme disease. Pertinent information was abstracted from the medical record of each patient. Of 153 cases of possible early Lyme disease ascertained from July 1991 to December 1992, 37% consisted of physician-diagnosed erythema migrans. Only 58% of erythema migrans rashes were at least 5 cm in diameter. An additional 43 patients had suspicious rashes not classified as erythema migrans. Of 166 patients with possible late-stage Lyme disease, 31% had specific clinical symptoms and 75% had a positive serologic test. With an incident case defined as physician-diagnosed erythema migrans of at least 5 cm in diameter, the annual incidence of Lyme disease in northwestern coastal California according to active surveillance only was 5.5 per 100,000. The rate of Lyme disease in California is substantially lower than that in the Atlantic northeastern United States. Many suspected cases of Lyme disease in this endemic area do not meet surveillance criteria, which are intentionally restrictive. Although some of the illnesses not meeting surveillance criteria may be due to infection with Borrelia burgdorferi, it appears that Lyme disease is being overdiagnosed in this area.
Images
PMCID: PMC1022555  PMID: 8053175
6.  Issues in the Diagnosis and Treatment of Lyme Disease 
The Open Neurology Journal  2012;6:140-145.
Since the identification of the causative organism more than 30 years ago, there remain questions about the di-agnosis and treatment of Lyme Disease. In this article, what is known about the disease will be reviewed, and approaches to the successful diagnosis and treatment of Lyme disease described.
In considering the diagnosis of Lyme disease, a major problem is the inability of documenting the existence and location of the bacteria. After the initial transfer of the bacteria from the Ixodes tick into the person, the spirochetes spread locally, but after an initial bacteremic phase, the organisms can no longer be reliably found in body fluids. The bacteria are proba-bly present in subcutaneous sites and intracellular loci. Currently, the use of circulating antibodies directed against spe-cific antigens of the Lyme borrelia are the standard means to diagnose the disease, but specific antibodies are not an ade-quate means to assess the presence or absence of the organism. What is needed is a more Lyme-specific antigen as a more definitive adjunct to the clinical diagnosis.
As for the treatment of Lyme disease, the earliest phase is generally easily treated. But it is the more chronic form of the disease that is plagued with lack of information, frequently leading to erroneous recommendations about the type and du-ration of treatments. Hence, often cited recommendations about the duration of treatment, eg four weeks is adequate treatment, have no factual basis to support that recommendation, often leading to the conclusion that there is another, per-haps psychosomatic reason, for the continuing symptoms. B. burgdorferi is sensitive to various antibiotics, including pe-nicillins, tetracyclines, and macrolides, but there are a number of mitigating factors that affect the clinical efficacy of these antibiotics, and these factors are addressed. The successful treatment of Lyme disease appears to be dependent on the use of specific antibiotics over a sufficient period of time. Further treatment trials would be helpful in finding the best regimens and duration periods.
At present, the diagnosis of Lyme disease is based primarily on the clinical picture. The pathophysiology of the disease remains to be determined, and the basis for the chronic illness in need of additional research. Whether there is continuing infection, auto-immunity to residual or persisting antigens, and whether a toxin or other bacterial-associated product(s) are responsible for the symptoms and signs remains to be delineated.
doi:10.2174/1874205X01206010140
PMCID: PMC3520031  PMID: 23248715
Lyme disease; chronic; brain SPECT.
7.  Early Lyme disease with spirochetemia - diagnosed by DNA sequencing 
BMC Research Notes  2010;3:273.
Background
A sensitive and analytically specific nucleic acid amplification test (NAAT) is valuable in confirming the diagnosis of early Lyme disease at the stage of spirochetemia.
Findings
Venous blood drawn from patients with clinical presentations of Lyme disease was tested for the standard 2-tier screen and Western Blot serology assay for Lyme disease, and also by a nested polymerase chain reaction (PCR) for B. burgdorferi sensu lato 16S ribosomal DNA. The PCR amplicon was sequenced for B. burgdorferi genomic DNA validation. A total of 130 patients visiting emergency room (ER) or Walk-in clinic (WALKIN), and 333 patients referred through the private physicians' offices were studied. While 5.4% of the ER/WALKIN patients showed DNA evidence of spirochetemia, none (0%) of the patients referred from private physicians' offices were DNA-positive. In contrast, while 8.4% of the patients referred from private physicians' offices were positive for the 2-tier Lyme serology assay, only 1.5% of the ER/WALKIN patients were positive for this antibody test. The 2-tier serology assay missed 85.7% of the cases of early Lyme disease with spirochetemia. The latter diagnosis was confirmed by DNA sequencing.
Conclusion
Nested PCR followed by automated DNA sequencing is a valuable supplement to the standard 2-tier antibody assay in the diagnosis of early Lyme disease with spirochetemia. The best time to test for Lyme spirochetemia is when the patients living in the Lyme disease endemic areas develop unexplained symptoms or clinical manifestations that are consistent with Lyme disease early in the course of their illness.
doi:10.1186/1756-0500-3-273
PMCID: PMC2984391  PMID: 21040573
8.  Case report: papillitis as the sole ocular sign in Lyme disease 
Background
Lyme disease is a spirochetal disease responsible for a multitude of ocular and systemic manifestations, and patients may present to ophthalmologists and general clinicians with a wide variety of generalized and ocular signs which can result in chronic and disabling sequelae. Here we report two cases of patients suffering with Lyme disease who developed a rare associated papillitis.
Methods
A 48-year-old Scottish man presented with diminished visual acuity, painful ocular eye movements, photophobia, and mild ataxia. Fundus examination revealed bilateral disc swelling with associated hemorrhages in the right eye. Following exclusion of raised intracranial pressure as the cause of the findings, enzyme-linked immunosorbent assay and Western blot serology confirmed a positive result for Borrelia burgdorferi which, along with ophthalmic signs and exposure to an endemic area, confirmed the diagnosis of Lyme disease. A 79-year-old gentleman presented with intermittent short-duration “gray film” in his left eye. Fundus examination revealed left optic disc swelling. He was positive for Lyme’s serology and his condition was treated with 2 weeks of intravenous ceftriaxone.
Results
The first patient’s inflammation resolved and visual acuity returned to normal following a course of high-dose steroids and intravenous ceftriaxone, followed by oral doxycycline. The second patient’s condition improved with high-dose intravenous ceftriaxone.
Conclusion
These patients highlight the fact that Lyme disease should be considered as a differential diagnosis for patients presenting with papillitis. With the incidence of this disease rising and more cases being reported, practitioners in Lyme-endemic areas need to be aware of the various manifestations so that appropriate referrals for treatment can be made.
doi:10.2147/OPTH.S32601
PMCID: PMC3413342  PMID: 22888207
Lyme disease; ocular papillitis; Borrelia burgdorferi
9.  Misdiagnosis of Late-Onset Lyme Arthritis by Inappropriate Use of Borrelia burgdorferi Immunoblot Testing with Synovial Fluid 
Clinical and Vaccine Immunology : CVI  2012;19(11):1806-1809.
The primary objective of this study was to determine whether patients with putative late-onset Lyme arthritis based upon synovial fluid Borrelia burgdorferi IgM and IgG immunoblot testing offered by commercial laboratories satisfied conventional criteria for the diagnosis of Lyme arthritis. Secondary objectives included assessing the prior duration and responsiveness of associated antibiotic therapy. We conducted a retrospective analysis of 11 patients referred to an academic medical center infectious disease clinic during the years 2007 to 2009 with a diagnosis of Lyme disease based upon previously obtained synovial fluid B. burgdorferi immunoblot testing. Ten of the 11 (91%) patients with a diagnosis of late-onset Lyme arthritis based upon interpretation of synovial fluid B. burgdorferi immunoblot testing were seronegative and did not satisfy published criteria for the diagnosis of late-onset Lyme arthritis. None of the 10 patients had a clinical response to previously received antibiotics despite an average course of 72 days. Diagnosis of Lyme arthritis should not be based on synovial fluid B. burgdorferi immunoblot testing. This unvalidated test does not appear useful for the diagnosis of Lyme disease, and this study reinforces the longstanding recommendation to use B. burgdorferi immunoblot testing only on serum samples and not other body fluids. Erroneous interpretations of “positive” synovial fluid immunoblots may lead to inappropriate antibiotic courses and delays in diagnosis of other joint diseases.
doi:10.1128/CVI.00383-12
PMCID: PMC3491552  PMID: 22971779
10.  Human Lyme Arthritis and the Immunoglobulin G Antibody Response to the 37-Kilodalton Arthritis-Related Protein of Borrelia burgdorferi  
Infection and Immunity  2005;73(5):2951-2957.
In Borrelia burgdorferi-infected C3H-scid mice, antiserum to a differentially expressed, 37-kDa spirochetal outer-surface protein, termed arthritis-related protein (Arp), has been shown to prevent or reduce the severity of arthritis. In this study, we determined the immunoglobulin G (IgG) antibody responses to this spirochetal protein in single serum samples from 124 antibiotic-treated human patients with early or late manifestations of Lyme disease and in serial serum samples from 20 historic, untreated patients who were followed longitudinally from early infection through the period of arthritis. These 20 patients were representative of the spectrum of the severity and duration of Lyme arthritis. Among the 124 antibiotic-treated patients, 53% with culture-proven erythema migrans (EM) had IgG responses to recombinant glutathione S-transferase (GST)-Arp, as did 59% of the patients with facial palsy and 68% of those with Lyme arthritis. In addition, 75 to 80% of the 20 past, untreated patients had reactivity with this protein when EM was present, during initial episodes of joint pain, or during the maximal period of arthritis. There was no association at any of these three time points between GST-Arp antibody levels and the severity of the maximal attack of arthritis or the total duration of arthritis. Thus, after the first several weeks of infection, 60 to 80% of patients had IgG antibody responses to GST-Arp, but this response did not correlate with the severity or duration of Lyme arthritis.
doi:10.1128/IAI.73.5.2951-2957.2005
PMCID: PMC1087337  PMID: 15845501
11.  Brief, recurrent, and spontaneous episodes of loss of consciousness in a healthy young male 
Introduction
Lyme disease is caused by bacterial spirochete Borrelia burgdorferi and is transmitted by Ixodes scapularis and Ixodes pacificus ticks, which get infected while feeding on the reservoir host of the bacteria.1 About 248,074 cases of Lyme disease were reported by the US Centers for Disease Control and Prevention from 1992–2006.2 Over 95% of these cases are reported from the Northeastern and upper Midwestern United States.3 Carditis is usually a clinical manifestation/complication of Lyme disease and is seen in approximately 5% of untreated cases.4
Case presentation
A 32-year-old male Hispanic from Chile presented with brief episodes of loss of consciousness and awareness of irregular heart beat, and denied any history of tick bite. The patient was found to have a heart rate of 40 beats per minute and fluctuating variable atrioventricular blocks. A transvenous pacemaker was placed with good capture. The diagnosis was made with serological testing and gallium scanning. Treatment with antibiotics and continuous cardiac monitoring resulted in remarkable symptomatic improvement of the patient.
Conclusion
Absence of history or evidence of tick bite must not rule out the possibility of Lyme carditis in a patient with a transient heart block. Prompt recognition of this reversible cause of heart block is essential for avoiding implantation of an unnecessary, permanent pacemaker.
PMCID: PMC3658225  PMID: 23754893
Lyme carditis; transient heart block
12.  Neurogenic Bladder in Lyme Disease 
Lyme disease is a multi-systemic, tick-borne infectious disease caused by a spirochete, Borrelia burgdorferi. Various urologic symptoms are associated with Lyme disease, which can be primary or late manifestations of the disease. Although voiding dysfunction is a rarely reported symptom in patients with Lyme disease, it is one of the most disabling complications of Lyme disease. Korea is not an endemic area of Lyme disease, thus, fewer cases have been reported. Herein, we report a case of a 32-year-old man with rapidly progressive bilateral ptosis, dysphagia, spastic paraparesis, and voiding difficulty in whom Lyme disease was diagnosed through serologic tests for antibodies and Western blot testing. A urodynamic study demonstrated detrusor areflexia and bulbocavernosus reflex tests showed delayed latency, indicating demyelination at S2-S4 levels. He received a 4-week course of intravenous ceftriaxone (2 g/day). The patient has recovered from the bilateral ptosis and spastic paraparesis but still suffers from neurogenic bladder.
doi:10.5213/inj.2012.16.4.201
PMCID: PMC3547183  PMID: 23346488
Lyme disease; Neurogenic urinary bladder; Urodynamics
13.  Anti-Borrelia burgdorferi Antibody Profile in Post-Lyme Disease Syndrome ▿ 
Patients with post-Lyme disease syndrome (PLDS) report persistent symptoms of pain, fatigue, and/or concentration and memory disturbances despite antibiotic treatment for Lyme borreliosis. The etiopathogenesis of these symptoms remains unknown and no effective therapies have been identified. We sought to examine the antiborrelia antibody profile in affected patients with the aim of finding clues to the mechanism of the syndrome and its relationship to the original spirochetal infection. Serum specimens from 54 borrelia-seropositive PLDS patients were examined for antibodies to Borrelia burgdorferi proteins p18, p25, p28, p30, p31, p34, p39, p41, p45, p58, p66, p93, and VlsE by automated immunoblotting and software-assisted band analysis. The presence of serum antibodies to the 31-kDa band was further investigated by examination of reactivity against purified recombinant OspA protein. Control specimens included sera from 14 borrelia-seropositive individuals with a history of early localized or disseminated Lyme disease who were symptom free (post-Lyme healthy group), as well as 20 healthy individuals without serologic evidence or history of Lyme disease. In comparison to the post-Lyme healthy group, higher frequencies of antibodies to p28 (P < 0.05), p30 (P < 0.05), p31 (P < 0.0001), and p34 (P < 0.05) proteins were found in the PLDS group. Assessment of antibody reactivity to recombinant OspA confirmed the presence of elevated levels in PLDS patients (P < 0.005). The described antiborrelia antibody profile in PLDS offers clues about the course of the antecedent infection in affected patients, which may be useful for understanding the pathogenic mechanism of the disease.
doi:10.1128/CVI.00002-11
PMCID: PMC3122515  PMID: 21411605
14.  Microglia Are Mediators of Borrelia burgdorferi–Induced Apoptosis in SH-SY5Y Neuronal Cells 
PLoS Pathogens  2009;5(11):e1000659.
Inflammation has long been implicated as a contributor to pathogenesis in many CNS illnesses, including Lyme neuroborreliosis. Borrelia burgdorferi is the spirochete that causes Lyme disease and it is known to potently induce the production of inflammatory mediators in a variety of cells. In experiments where B. burgdorferi was co-cultured in vitro with primary microglia, we observed robust expression and release of IL-6 and IL-8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES), but we detected no induction of microglial apoptosis. In contrast, SH-SY5Y (SY) neuroblastoma cells co-cultured with B. burgdorferi expressed negligible amounts of inflammatory mediators and also remained resistant to apoptosis. When SY cells were co-cultured with microglia and B. burgdorferi, significant neuronal apoptosis consistently occurred. Confocal microscopy imaging of these cell cultures stained for apoptosis and with cell type-specific markers confirmed that it was predominantly the SY cells that were dying. Microarray analysis demonstrated an intense microglia-mediated inflammatory response to B. burgdorferi including up-regulation in gene transcripts for TLR-2 and NFκβ. Surprisingly, a pathway that exhibited profound changes in regard to inflammatory signaling was triggering receptor expressed on myeloid cells-1 (TREM1). Significant transcript alterations in essential p53 pathway genes also occurred in SY cells cultured in the presence of microglia and B. burgdorferi, which indicated a shift from cell survival to preparation for apoptosis when compared to SY cells cultured in the presence of B. burgdorferi alone. Taken together, these findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect. If, as we hypothesized, neuronal apoptosis is the key pathogenic event in Lyme neuroborreliosis, then targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease.
Author Summary
Lyme disease, which is transmitted to humans through the bite of a tick, is currently the most frequently reported vector-borne illness in the northern hemisphere. Borrelia burgdorferi is the bacterium that causes Lyme disease and it is known to readily induce inflammation within a variety of infected tissues. Many of the neurological signs and symptoms that may affect patients with Lyme disease have been associated with B. burgdorferi-induced inflammation in the central nervous system (CNS). In this report we investigated which of the primary cell types residing in the CNS might be functioning to create the inflammatory environment that, in addition to helping clear the pathogen, could simultaneously be harming nearby neurons. We report findings that implicate microglia, a macrophage cell type in the CNS, as the key responders to infection with B. burgdorferi. We also present evidence indicating that this organism is not directly toxic to neurons; rather, a bystander effect is generated whereby the inflammatory surroundings created by microglia in response to B. burgdorferi may themselves be toxic to neuronal cells.
doi:10.1371/journal.ppat.1000659
PMCID: PMC2771360  PMID: 19911057
15.  C6 Test as an Indicator of Therapy Outcome for Patients with Localized or Disseminated Lyme Borreliosis 
Journal of Clinical Microbiology  2003;41(11):4955-4960.
Management of Lyme disease would benefit from a test to assess therapy outcome. Such a test could be employed to ascertain if treatment of early Lyme disease was successful and would be helpful to clinicians assessing patients with lingering posttreatment symptoms. We reported recently that levels of the antibody to C6, a Borrelia burgdorferi-derived peptide that is used as an antigen in the C6-Lyme diagnostic test, declined after successful antibiotic treatment of Lyme borreliosis patients. We assessed retrospectively the change in anti-C6 antibody titers in 131 patients with either early localized disease (erythema migrans) or disseminated disease. All of these patients were treated with antibiotics and were free of the clinical signs shown at presentation within 12 weeks after the initiation of treatment. Decreases in reciprocal geometric mean titers (rGMT) of the anti-C6 antibody were quantified for the subpopulation of 45 patients whose baseline rGMT were ≥80 and whose second serum specimens were obtained at least 6 months after the baseline specimen. Eighty percent of this patient group (36 of 45) experienced a ≥4-fold decrease in their rGMT (P < 0.0003). These results suggest that a change in the anti-C6 antibody titer may serve as an indicator of therapy outcome for patients with localized or disseminated Lyme borreliosis.
doi:10.1128/JCM.41.11.4955-4960.2003
PMCID: PMC262468  PMID: 14605123
16.  Lyme Borreliosis in Human Patients in Florida and Georgia, USA 
The aim of this study was to determine the cause of illness in several human patients residing in Florida and Georgia, USA, with suspected Lyme disease based upon EM-like skin lesions and/or symptoms consistent with early localized or late disseminated Lyme borreliosis. Using polymerase chain reaction (PCR) assays developed specifically for Lyme group Borrelia spp., followed by DNA sequencing for confirmation, we identified Borrelia burgdorferi sensu lato DNA in samples of blood and skin and also in lone star ticks (Amblyomma americanum) removed from several patients who either live in or were exposed to ticks in Florida or Georgia. This is the first report to present combined PCR and DNA sequence evidence of infection with Lyme Borrelia spp. in human patients in the southern U.S., and to demonstrate that several B. burgdorferi sensu lato species may be associated with Lyme disease-like signs and symptoms in southern states. Based on the findings of this study, we suggest that human Lyme borreliosis occurs in Florida and Georgia, and that some cases of Lyme-like illness referred to as southern tick associated rash illness (STARI) in the southern U.S. may be attributable to previously undetected B. burgdorferi sensu lato infections.
doi:10.7150/ijms.6273
PMCID: PMC3675506  PMID: 23781138
Lyme borreliosis; Florida; Georgia
17.  Lyme Disease and the Orthopaedic Implications of Lyme Arthritis 
Lyme disease is the most common tick-borne disease in the United States and Europe. Increased awareness of the clinical manifestations of the disease is needed to improve detection and treatment. In the acute and late stages, Lyme disease may be difficult to distinguish from other disease processes. The epidemiology and pathophysiology of Lyme disease are directly related to the Borrelia burgdorferi spirochete and its effects on the integumentary, neurologic, cardiac, and musculoskeletal systems. Lyme arthritis is a common clinical manifestation of Lyme disease and should be considered in the evaluation of patients with monoarticular or pauciarticular joint complaints in a geographic area in which Lyme disease is endemic. Management of Lyme arthritis involves eradication of the spirochete with antibiotics. Generally, the prognosis is excellent. Arthroscopic synovectomy is reserved for refractory cases that do not respond to antibiotics.
PMCID: PMC3656475  PMID: 21292932
18.  Lyme Disease in Maine: a Comparison of NEDSS Surveillance Data and Maine Health Data Organization Hospital Discharge data 
Background
Lyme disease is the most commonly reported vector borne disease in the United States and is a major public health concern in Maine. Maine Center for Disease Control and Prevention (Maine CDC) monitors Lyme disease through a passive surveillance system. In order to validate the Lyme disease surveillance system, Maine CDC was interested in comparing trends with a secondary data source. Specifically, Maine CDC was interested in comparing trends by age group, gender, geography, and timelines. Also, because hospitalization due to Lyme disease is rare, this analysis provided an opportunity to look at the diagnosis codes used for Lyme disease visits. The purpose of this paper is to compare the data acquired through surveillance to a secondary data source in order to evaluate the completeness of the data and verify trends.
Methods
Surveillance data was extracted from Maine’s NEDSS Base System for the years 2008 – 2011. Only confirmed and probable cases were included in data analysis. The Maine Health Data Organization (MHDO) collects information on all hospital inpatient and outpatient data visits and was used for this comparison. MHDO inpatient and outpatient hospital encounters with a diagnosis of 08881 in any diagnosis field were extracted from the full dataset from 2008 – 2011.
Results
Surveillance data showed the 5-14 year old age group had the highest rates of Lyme disease while outpatient data showed adults over the age of 45 to have the highest rates. Outpatient data showed a higher percentage of females with Lyme disease visits. Geographic trends did not match well between surveillance data and MHDO data which may be due to the hospital being used as proxy for the patient address. Timeliness trends were consistent between all sources, with the majority of Lyme disease occurring in the summer months of June, July and August. The majority of outpatient visits had Lyme disease listed as their primary diagnosis while the majority of inpatient visits had Lyme disease as a secondary or lower diagnosis.
Conclusions
There were several limitations to this study including incomplete data, and the inability to differentiate between new and old Lyme diagnoses. There is reasonably good similarity in the trends of these two systems helping validate the usefulness of Maine’s Lyme disease surveillance system. Many of the discrepancies warrant further investigation, and may lead to future opportunities for education or improvement in Lyme disease surveillance.
doi:10.5210/ojphi.v5i3.4990
PMCID: PMC3959910  PMID: 24678383
19.  Antibiotic Treatment of Animals Infected with Borrelia burgdorferi 
Clinical Microbiology Reviews  2009;22(3):387-395.
Summary: Despite resolution of the objective manifestations of Lyme disease after antibiotic treatment, a minority of patients have fatigue, musculoskeletal pain, and/or difficulties with concentration or short-term memory of uncertain etiology; these are called post-Lyme disease symptoms or, in more severe cases, post-Lyme disease syndrome or “chronic Lyme disease.” Several recent studies in which Borrelia burgdorferi-infected animals were treated with antibiotic therapy have demonstrated the presence of PCR positivity for B. burgdorferi DNA in the absence of culture positivity. In mice that were treated with antibiotic therapy, residual spirochetes could be taken up by ticks during a blood meal and could be transmitted to SCID mice. These spirochetes are attenuated; their presence is not associated with either inflammation or disease. In this review the methodology and findings of these studies are critically analyzed, and the significance of the results with regard to human Lyme disease is evaluated, with special emphasis on whether these studies provide useful insights into post-Lyme disease syndrome. A serious methodological concern is the failure to consider the pharmacokinetic-pharmacodynamic properties of the antibiotic in choosing the dosage regimen used. We conclude that there is no scientific evidence to support the hypothesis that such spirochetes, should they exist in humans, are the cause of post-Lyme disease syndrome.
doi:10.1128/CMR.00004-09
PMCID: PMC2708393  PMID: 19597005
20.  Detection of Borreliae in Archived Sera from Patients with Clinically Suspect Lyme Disease 
The diagnoses of Lyme disease based on clinical manifestations, serological findings and detection of infectious agents often contradict each other. We tested 52 blind-coded serum samples, including 20 pre-treatment and 12 post-treatment sera from clinically suspect Lyme disease patients, for the presence of residual Lyme disease infectious agents, using nested PCR amplification of a signature segment of the borrelial 16S ribosomal RNA gene for detection and direct DNA sequencing of the PCR amplicon for molecular validation. These archived sera were split from the samples drawn for the 2-tier serology tests performed by a CDC-approved laboratory, and are used as reference materials for evaluating new diagnostic reagents. Of the 12 post-treatment serum samples, we found DNA evidence of a novel borrelia of uncertain significance in one, which was also positive for the 2-tier serology test. The rest of the post-treatment sera and all 20 control sera were PCR-negative. Of the 20 pre-treatment sera from clinically suspect early Lyme disease patients, we found Borrelia miyamotoi in one which was 2-tier serology-negative, and a Borrelia burgdorferi in two—one negative and one positive for 2-tier serology. We conclude that a sensitive and reliable DNA-based test is needed to support the diagnosis of Lyme disease and Lyme disease-like borreliosis.
doi:10.3390/ijms15034284
PMCID: PMC3975398  PMID: 24619223
DNA sequencing; same-nested PCR; 16S rDNA; Lyme borreliosis; novel borrelia; Lyme disease; Borrelia burgdorferi; Borrelia miyamotoi; 2-tier serology
21.  Clinical features of double infection with tick‐borne encephalitis and Lyme borreliosis transmitted by tick bite 
Background
In Latvia and other endemic regions, a single tick bite has the potential to transmit both tick‐borne encephalitis (TBE) and Lyme borreliosis.
Objective
To analyse both the clinical features and differential diagnosis of combined tick‐borne infection with TBE and Lyme borreliosis, in 51 patients with serological evidence, of whom 69% had tick bites.
Results
Biphasic fever suggestive of TBE occurred in 55% of the patients. Meningitis occurred in 92%, with painful radicular symptoms in 39%. Muscle weakness occurred in 41%; in 29% the flaccid paralysis was compatible with TBE. Only two patients presented with the bulbar palsy typical of TBE. Typical Lyme borreliosis facial palsy occurred in three patients. Typical TBE oculomotor disturbances occurred in two. Other features typical of Lyme borreliosis detected in our patients were distal peripheral neuropathy (n = 4), arthralgia (n = 9), local erythema 1–12 days after tick bite (n = 7) and erythema chronicum migrans (n = 1). Echocardiogram abnormalities occurred in 15.
Conclusions
Patients with double infection with TBE and Lyme borreliosis fell into three main clinical groups: febrile illness, 3 (6%); meningitis, 15 (30%); central or peripheral neurological deficit (meningoencephalitis, meningomyelitis, meningoradiculitis and polyradiculoneuritis), 33 (65%). Systemic features pointing to Lyme borreliosis were found in 25 patients (49%); immunoglobulin (Ig)M antibodies to borreliosis were present in 18 of them. The clinical occurrence of both Lyme borreliosis and TBE vary after exposure to tick bite, and the neurological manifestations of each disorder vary widely, with considerable overlap. This observational study provides no evidence that co‐infection produces unusual manifestations due to unpredicted interaction between the two diseases. Patients with tick exposure presenting with acute neurological symptoms in areas endemic for both Lyme borreliosis and TBE should be investigated for both conditions. The threshold for simultaneous treatment of both conditions should be low, given the possibility of co‐occurrence and the difficulty in ascribing individual neurological manifestations to one condition or the other.
doi:10.1136/jnnp.2004.060731
PMCID: PMC2077418  PMID: 16754695
22.  MicroRNA-146a Provides Feedback Regulation of Lyme Arthritis but Not Carditis during Infection with Borrelia burgdorferi 
PLoS Pathogens  2014;10(6):e1004212.
MicroRNAs have been shown to be important regulators of inflammatory and immune responses and are implicated in several immune disorders including systemic lupus erythematosus and rheumatoid arthritis, but their role in Lyme borreliosis remains unknown. We performed a microarray screen for expression of miRNAs in joint tissue from three mouse strains infected with Borrelia burgdorferi. This screen identified upregulation of miR-146a, a key negative regulator of NF-κB signaling, in all three strains, suggesting it plays an important role in the in vivo response to B. burgdorferi. Infection of B6 miR-146a−/− mice with B. burgdorferi revealed a critical nonredundant role of miR-146a in modulating Lyme arthritis without compromising host immune response or heart inflammation. The impact of miR-146a was specifically localized to the joint, and did not impact lesion development or inflammation in the heart. Furthermore, B6 miR-146a−/− mice had elevated levels of NF-κB-regulated products in joint tissue and serum late in infection. Flow cytometry analysis of various lineages isolated from infected joint tissue of mice showed that myeloid cell infiltration was significantly greater in B6 miR-146a−/− mice, compared to B6, during B. burgdorferi infection. Using bone marrow-derived macrophages, we found that TRAF6, a known target of miR-146a involved in NF-κB activation, was dysregulated in resting and B. burgdorferi-stimulated B6 miR-146a−/− macrophages, and corresponded to elevated IL-1β, IL-6 and CXCL1 production. This dysregulated protein production was also observed in macrophages treated with IL-10 prior to B. burgdorferi stimulation. Peritoneal macrophages from B6 miR-146a−/− mice also showed enhanced phagocytosis of B. burgdorferi. Together, these data show that miR-146a-mediated regulation of TRAF6 and NF-κB, and downstream targets such as IL-1β, IL-6 and CXCL1, are critical for modulation of Lyme arthritis during chronic infection with B. burgdorferi.
Author Summary
Lyme Disease is caused by infection with the bacteria Borrelia burgdorferi, is transmitted through infected deer ticks (Ixodes scapularis), and often leads to arthritis that can persist, even after antibiotic treatment. Here, we have identified a microRNA that is critical in modulating Lyme arthritis, but not carditis. This microRNA, miR-146a, is a negative regulator of NF-κB signaling, known to be important in host defense against pathogens, and long suspected to play a role in Lyme arthritis development. Mice lacking miR-146a develop more severe arthritis and show signs of hyperactive NF-κB activation during the persistent phase of infection. Heart manifestations of disease were not altered. Furthermore, this severe arthritis is independent of host defense, since these mice are better able to clear invading bacteria in joints, and bacterial numbers are similar in heart and ear tissue. We identified TRAF6 as an important target of miR-146a-mediated NF-κB regulation of pro-inflammatory cytokines IL-6 and IL-1β, as well as chemokines CXCL1 and CXCL2. Our data demonstrate the importance of maintaining appropriate regulation of amplitude and resolution of NF-κB activation during Borrelia burgdorferi infection, and provide a novel model for elucidating the role of NF-κB in Lyme arthritis development, independent of effect on host defense.
doi:10.1371/journal.ppat.1004212
PMCID: PMC4072785  PMID: 24967703
23.  Chronic Lyme Disease and Co-infections: Differential Diagnosis 
The Open Neurology Journal  2012;6:158-178.
In Lyme disease concurrent infections frequently occur. The clinical and pathological impact of co-infections was first recognized in the 1990th, i.e. approximately ten years after the discovery of Lyme disease. Their pathological synergism can exacerbate Lyme disease or induce similar disease manifestations. Co-infecting agents can be transmitted together with Borrelia burgdorferi by tick bite resulting in multiple infections but a fraction of co-infections occur independently of tick bite. Clinically relevant co-infections are caused by Bartonella species, Yersinia enterocolitica, Chlamydophila pneumoniae, Chlamydia trachomatis, and Mycoplasma pneumoniae. In contrast to the USA, human granulocytic anaplasmosis (HGA) and babesiosis are not of major importance in Europe. Infections caused by these pathogens in patients not infected by Borrelia burgdorferi can result in clinical symptoms similar to those occurring in Lyme disease. This applies particularly to infections caused by Bartonella henselae, Yersinia enterocolitica, and Mycoplasma pneumoniae. Chlamydia trachomatis primarily causes polyarthritis. Chlamydophila pneumoniae not only causes arthritis but also affects the nervous system and the heart, which renders the differential diagnosis difficult. The diagnosis is even more complex when co-infections occur in association with Lyme disease. Treatment recommendations are based on individual expert opinions. In antibiotic therapy, the use of third generation cephalosporins should only be considered in cases of Lyme disease. The same applies to carbapenems, which however are used occasionally in infections caused by Yersinia enterocolitica. For the remaining infections predominantly tetracyclines and macrolides are used. Quinolones are for alternative treatment, particularly gemifloxacin. For Bartonella henselae, Chlamydia trachomatis, and Chlamydophila pneumoniae the combination with rifampicin is recommended. Erythromycin is the drug of choice for Campylobacter jejuni.
doi:10.2174/1874205X01206010158
PMCID: PMC3565243  PMID: 23400696
Bartonellosis; Borellia burgdorferi; Chlamydophila pneumoniae; Chlamydia trachomatis; co-infection; Lyme disease; Mycoplasma pneumoniae; treatment; Yersinia enterocolitica.
24.  Chronic or Late Lyme Neuroborreliosis: Analysis of Evidence Compared to Chronic or Late Neurosyphilis 
The Open Neurology Journal  2012;6:146-157.
Whether spirochetes persist in affected host tissues and cause the late/chronic manifestations of neurosyphilis was the subject of long-lasting debate. Detection of Treponema pallidum in the brains of patients with general paresis established a direct link between persisting infection and tertiary manifestations of neurosyphilis.
Today, the same question is in the center of debate with respect to Lyme disease. The goal of this review was to compare the established pathological features of neurosyphilis with those available for Lyme neuroborreliosis. If the main tertiary forms of neurosyphilis also occur in Lyme neuroborreliosis and Borrelia burgdorferi can be detected in brain lesions would indicate that the spirochete is responsible for the neuropsychiatric manifestations of late/chronic Lyme neuroborreliosis.
The substantial amounts of data available in the literature show that the major forms of late/chronic Lyme neuroborreliosis (meningovascular and meningoencephalitis) are clinically and pathologically confirmed. Borrelia burgdorferi was detected in association with tertiary brain lesions and cultivated from the affected brain or cerebrospinal fluid. The accumulated data also indicate that Borrelia burgdorferi is able to evade from destruction by the host immune reactions, persist in host tissues and sustain chronic infection and inflammation. These observations represent evidences that Borrelia burgdorferi in an analogous way to Treponema pallidum is responsible for the chronic/late manifestations of Lyme neuroborreliosis.
Late Lyme neuroborreliosis is accepted by all existing guidelines in Europe, US and Canada. The terms chronic and late are synonymous and both define tertiary neurosyphilis or tertiary Lyme neuroborreliosis. The use of chronic and late Lyme neuroborreliosis as different entities is inaccurate and can be confusing. Further pathological investigations and the detection of spirochetes in infected tissues and body fluids are strongly needed.
doi:10.2174/1874205X01206010146
PMCID: PMC3551238  PMID: 23346260
Borrelia burgdorferi; Chronic Lyme disease; Late Lyme disease; Lyme neuroborrelisosis; Chronic infection; Neurosyphilis; Syphilis; Treponema pallidum.
25.  Ability of the Borreliacidal Antibody Test To Confirm Lyme Disease in Clinical Practice 
Highly specific borreliacidal antibodies are induced by infection with Borrelia burgdorferi, and a borreliacidal antibody test (BAT) may be an accurate laboratory procedure for confirming Lyme disease in clinical practice. To investigate this, 34 Lyme disease sera and 34 sera from patients with other illnesses who had presented to a primary-care facility located in an area of borreliosis endemicity were tested by the BAT and Western blotting (WB). The BAT was more sensitive (79% versus 65%; P = 0.090), especially in cases in which patients had a single erythema migrans lesion (P = 0.021). In addition, the potentially cross-reactive sera were negative by the BAT but WB yielded three (9%) false-positive results. The results from 104 sera from possible Lyme disease patients demonstrated the clinical usefulness of the more sensitive and specific BAT. The BAT was positive for 40 (38%) sera from patients with Lyme disease-related symptoms and appropriate clinical and epidemiological findings. WB confirmed Lyme disease in 30 (75%) of the 40 BAT-positive patients but failed to detect B. burgdorferi infection in 10 BAT-positive patients. WB was also positive for 11 BAT-negative sera, but six (55%) patients had case histories which suggested that the results were false positives. Collectively, the results confirm that the BAT is a sensitive and highly specific test and suggest that widespread use would increase the accuracy of serodiagnostic confirmation of Lyme disease.
doi:10.1128/CDLI.9.4.908-912.2002
PMCID: PMC120016  PMID: 12093694

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