Original Article
Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a History of Lyme Disease
N Engl J Med 2001; 345:85-92July 12, 2001
- Abstract
Background
It is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease.
Methods
We conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health–component summary scales of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) — a scale measuring the health-related quality of life — on day 180 of the study.
Results
After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients' health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo among either the seropositive or the seronegative patients.
Conclusions
There is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.
Media in This Article
Figure 1
Change or Lack of Change from Base Line in the Health-Related Quality of Life as Measured by the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36).Table 1
Base-Line Characteristics of the Patients.Article Activity
- Article
Antibiotic treatment is highly effective for the acute and late septic manifestations of Lyme disease, which is caused by the tick-borne bacterium Borrelia burgdorferi.1 However, some patients have persistent fatigue, myalgias, arthralgias without arthritis, dysesthesias or paresthesias, or mood and memory disturbances after the standard courses of antibiotics.2,3 Persistent symptoms have been reported both in patients who are seropositive for antibodies against B. burgdorferi and in patients who are seronegative. Although the cause of persistent symptoms has not been determined, their temporal association with B. burgdorferi infection has led some physicians to treat patients with prolonged courses of antibiotics. Case reports and uncontrolled trials describe success with prolonged antibiotic therapy, often with a recurrence of the symptoms after the discontinuation of therapy.4 In view of the substantial morbidity and even death5 associated with prolonged parenteral antibiotic treatment of Lyme disease, it is important to determine the efficacy of such therapy. We report results from randomized, placebo-controlled, double-blind trials of antibiotic therapy in seropositive and seronegative patients who had chronic symptoms after treatment for Lyme disease.
Methods
Patients
Patients were recruited by means of advertisements and referrals from physicians. Between July 24, 1997, and November 14, 2000, eligible patients were enrolled in two double-blind, placebo-controlled trials, each conducted at three sites. Patients with a positive Western blot for IgG antibodies against B. burgdorferi antigens6 were enrolled in a study of seropositive patients, and patients who were seronegative were enrolled in a separate study. Seronegative patients were required to have documentation of an erythema migrans skin lesion provided by an experienced physician. We initially planned to enroll 260 patients in the studies (194 seropositive and 66 seronegative patients). Patients were eligible if they were at least 18 years old, had a history of acute Lyme disease acquired in the United States, and had at least one of the following: a history of single or multiple erythema migrans skin lesions, early neurologic or cardiac symptoms attributed to Lyme disease, radiculoneuropathy, or Lyme arthritis. Documentation by a physician of previous treatment of acute Lyme disease with a recommended antibiotic regimen was also required. At the time of enrollment, all patients had one or more of the following symptoms that interfered with their functioning: widespread musculoskeletal pain, cognitive impairment, radicular pain, paresthesias, or dysesthesias. Profound fatigue often accompanied one or more of these symptoms. The chronic symptoms had to have begun within 6 months after the initial infection with B. burgdorferi and had to have persisted for at least 6 months but less than 12 years.
Patients were excluded if they had hypersensitivity to the study medications, had previously received parenteral antibiotic therapy for 60 days or more for their current symptoms, had active inflammatory synovitis, had a coexisting condition that could have accounted for their symptoms, or were unable to discontinue medications that could interfere with the evaluation of their response to the treatment regimen (e.g., narcotic analgesics or prednisone in a dose of 10 mg per day or more). Patients with a positive polymerase-chain-reaction (PCR) test for B. burgdorferi DNA in plasma or cerebrospinal fluid at base line were also excluded.
Study Protocols
The study protocols were approved by the institutional review boards for human investigations at the participating centers, and each patient gave written informed consent. A data and safety monitoring board planned an interim analysis after at least 110 subjects had been enrolled. Patients were randomly assigned in a 1:1 ratio to receive either antibiotics or placebo. The antibiotic treatment regimen consisted of intravenous ceftriaxone for 30 consecutive days (2 g per day), followed by oral doxycycline for 60 consecutive days (100 mg twice daily). The patients in the placebo group received an intravenous dextrose solution that was the same color as the ceftriaxone solution and oral placebo capsules identical in appearance to the doxycycline, both for the same lengths of time as the antibiotics were administered. Compliance and safety were monitored by home visits by study nurses every other day during the intravenous-treatment phase and twice (on days 45 and 75) during the oral-treatment phase.
Clinical and laboratory evaluations were performed at screening, at base line, and on days 3, 5, 13, 21, 30, 45, 75, 90, and 180. The base-line evaluation included a complete medical history taking, a detailed physical examination, neuropsychological testing, a lumbar puncture, and sampling of peripheral blood.
Clinical Response
The primary outcome was an improvement in the patients' health-related quality of life, which was measured by means of the Medical Outcomes Study (MOS) 36-item Short-Form General Health Survey (SF-36).7,8 Additional measures of the health-related quality of life included the MOS scales for pain, cognition, and role functioning (the ability to participate in usual daily activities)9-11 and a modified version of the Fibromyalgia Impact Questionnaire (FIQ).12,13 Each of the instruments used to measure the health-related quality of life was administered to study participants at base line and at 30, 90, and 180 days. The SF-36 includes eight multiple-item scales that measure physical functioning, physical limitations on usual role-related activities, bodily pain, general health perceptions, vitality, social functioning, emotional limitations on usual role-related activities, and mental health. These scales provide the basis for calculating the summary scores on the physical component and the mental component of the SF-36.7,8 The scores range from 0 (worst) to 100 (best). For each of the scales, the mean (±SD) score for members of the general population of the United States without chronic conditions was considered to be 50±10.
To assess changes in the health-related quality of life over time, a change score for each SF-36 summary scale was calculated by subtracting the base-line score from the scores at 30, 90, and 180 days. With the use of 2 SE as the criterion,8,14 individual patients were classified into three categories of change: those whose follow-up scores did not change more than would be expected by chance (unchanged group); those whose follow-up scores improved by more than 2 SE (improved group); and those whose follow-up scores declined by more than 2 SE (worse group). According to previous studies, a change of 2 SE is 6.5 points on the SF-36 physical-health summary scale and 7.9 points on the SF-36 mental-health summary scale.8,14 The overall change in health status was calculated for each patient. Patients were categorized as having improved health status if they had better scores on both scales or had a better score on one scale and a score on the other scale that was not worse. Patients were categorized as having worsened health status if they had worse scores on one or both of the scales and as having the same health status if their scores on both the physical- and mental-component scales were unchanged.
Three additional multiple-item scales from the MOS were used as secondary measures of cognitive functioning, pain, and functioning in role-related activities.9-11,15 Clinical response was also measured with the use of the modified version of the FIQ, for which the scores range from 0 (best) to 110 (worst). This version of the FIQ has been validated for patients who have persistent symptoms after treatment for Lyme disease.13 In a control population without chronic illness, the mean total score on the modified FIQ was 14.0, whereas the mean for patients with chronic Lyme disease after treatment was 50.2.13 Previous studies have indicated that a change of 16.0 points is clinically meaningful.16-19
Laboratory Studies
Western blotting for IgG antibodies against B. burgdorferi antigens was performed with the IgG MarBlot (MarDx Diagnostics, Carlsbad, Calif.) according to the manufacturer's instructions.6 The intrathecal production of antibodies against B. burgdorferi was measured as previously described.20 Base-line specimens of cerebrospinal fluid and plasma specimens obtained at base line and on days 3, 5, 21, and 45 were tested by PCR for the presence of B. burgdorferi DNA, as previously described.21 All samples of cerebrospinal fluid were cultured in Barbour–Stoenner–Kelly II medium to detect B. burgdorferi and were monitored by dark-field microscopy for six weeks.22 Some blood samples were cultured for B. burgdorferi in hypertonic medium.23
Adverse Events
Adverse events and changes in laboratory values were evaluated and graded with the use of scales derived from the Common Toxicity Criteria of the National Cancer Institute.
Compliance
Compliance with the regimen of medications was assessed by counts of both the number of doses of the intravenous medication the patients received and the pills they had remaining. The actual pill counts were compared with the number of pills that the patient should have had remaining at the time of the home visit by a nurse on day 75.
Statistical Analysis
The primary analysis was an intention-to-treat analysis of all the patients enrolled in the studies. The primary clinical end point was the proportion of patients whose condition was categorized as improved, unchanged, and worse on the basis of the summary scores for the mental and physical components of the SF-36 at 180 days. Patients who withdrew from the study were categorized as having worsened health status on both of these scales.
The study of seropositive patients was designed to have a power of 90 percent, with a 5 percent level of significance in a two-sided test and a sample size of 194, to detect a difference of 25 percent between the antibiotic group and the placebo group in the proportion of patients with improved health status.24 With the enrollment of 66 patients, the study of seronegative patients would have 80 percent power, with a 5 percent level of significance in a two-sided test, to detect a 35 percent difference between the antibiotic group and the placebo group.24
In the interim analysis of the primary outcome, the O'Brien–Fleming adjustment for multiple testing and the B-value stochastic curtailment method were used.25 The primary outcome for each trial was analyzed by the chi-square test with individual type I error rates of 0.05. The efficacy of the treatment in each trial was estimated as the difference in risk (with 95 percent confidence interval). Secondary outcomes included improvement or worsening as measured by the SF-36 at 30 and 90 days, the total FIQ score, and the MOS pain, cognition, and role-functioning scores at 30, 90, and 180 days.
Results
Characteristics of the Patients
A total of 129 patients were enrolled in the studies (78 seropositive and 51 seronegative). The base-line characteristics of the patients are shown in Table 1Table 1
Base-Line Characteristics of the Patients.. A total of 42 (33 percent) of the patients had previously received intravenous antibiotic treatment for a mean (±SD) of 30±12 days. All other previous treatment consisted of oral antibiotics. There were no significant differences between the seropositive patients and the seronegative patients other than the presence or absence of serum antibodies to B. burgdorferi. All cultures of cerebrospinal fluid in standard Barbour–Stoenner–Kelly II medium and of blood in hypertonic medium were negative for B. burgdorferi. B. burgdorferi DNA was not detected in any base-line sample of cerebrospinal fluid or blood, nor was it detected in any of the blood samples obtained during the treatment phase (on days 3, 5, 21, and 45). Given a cutoff of 1.2 for the ratio of antibody against B. burgdorferi in cerebrospinal fluid to antibody in serum, the intrathecal production of antibody was detected in eight patients (five in the combined antibiotic groups and three in the combined placebo groups).Treatment was discontinued in 14 patients (8 seropositive and 6 seronegative). The reasons for the discontinuation of treatment were similar across the groups of patients. An adverse event was the reason for the discontinuation of treatment in three of the patients in the combined antibiotic groups (5 percent) and three of those in the combined placebo groups (5 percent). Treatment was discontinued in the other eight patients for reasons other than an adverse event.
In the combined population of both studies, the mean base-line summary score for the physical component of the SF-36 was approximately 1.5 SD below that of age-matched members of the general population of the United States who did not have a chronic illness, and the mean base-line summary score for the mental component was approximately 0.5 SD below that of such a control group. Similarly, the base-line FIQ scores were markedly abnormal.
Compliance
All patients who completed 180 days in one of the trials took at least 75 percent of the prescribed medications. There were no differences between the treatment groups in either the seropositive or the seronegative study in patients' compliance with medication.
Efficacy
The interim analysis was performed with the use of data on 107 patients who had completed 180 days in one of the trials. This analysis indicated that there was a 1.4 percent chance in the seropositive study and a 4.0 percent chance in the seronegative study that a significant difference in the efficacy of treatment between the antibiotic group and the placebo group would be observed when the full projected enrollment was reached. An analysis that included the patients in both studies indicated that there was a 3.9 percent chance of observing a significant difference at full enrollment. Because of the lack of efficacy of the antibiotic treatment at the time of the interim analysis, the data and safety monitoring board recommended discontinuation of the active treatment of enrolled patients and of further enrollment in the treatment phase of the studies.
The responses of the 115 patients who were enrolled in the studies at least 180 days before enrollment was stopped are shown in Table 2Table 2
Clinical Responses at 180 Days. and Figure 1Figure 1Change or Lack of Change from Base Line in the Health-Related Quality of Life as Measured by the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36).. Intention-to-treat analyses at 30, 90, and 180 days showed no significant differences in the measures of the health-related quality of life between the patients in the antibiotic groups and those in the placebo groups in the seropositive study, the seronegative study, or both studies combined.In the combined study populations, changes in the score on the modified FIQ at 180 days also revealed no significant differences between the antibiotic groups and the placebo groups. We defined a decrease of 25 percent from the base-line score on the modified FIQ as indicative of clinical improvement and an increase of 25 percent as indicative of clinical worsening. Given these definitions, 28 of the 51 patients in the combined antibiotic groups (55 percent) had improved health status as measured by the FIQ at 180 days, as compared with 22 of the 53 patients in the combined placebo groups (42 percent) (P=0.17). Conversely, 14 percent of the patients in the antibiotic groups (7 of 51) had worsened health status as measured by the FIQ at 180 days, as compared with 19 percent (10 of 53) in the placebo groups (P=0.48). Separate comparisons of the FIQ scores in the antibiotic group and the placebo group of the seropositive study and of those in the two treatment groups in the seronegative study found no statistically significant differences according to treatment.
Adverse Events
At least one study-related adverse event occurred in 16 of the 64 patients in the combined antibiotic groups (25 percent) and 11 of the 65 patients in the combined placebo groups (17 percent). Most of the adverse events were minor and resolved without intervention or sequelae. However, the two patients in whom a study-related serious adverse event occurred were both in the antibiotic group. During intravenous treatment, one had a life-threatening pulmonary embolism and the other had fever, anemia, and gastrointestinal bleeding. Although the overall rate of adverse events was not significantly different in the two treatment groups, rash, diarrhea, and vaginal pruritus occurred more frequently among the patients in the antibiotic groups (9 of 64 patients) than among those in the placebo groups (2 of 65 patients). There were no infections associated with the intravenous catheter, and there were no deaths.
Discussion
The primary goals of these studies in patients with symptoms that persist after recommended antibiotic treatment for Lyme disease were to characterize the impairment in health-related quality of life among such patients and to determine the efficacy of prolonged treatment with antibiotics. The effect of chronic Lyme disease on the health-related quality of life was substantial in both seropositive and seronegative patients. The deficits in physical health status as measured by the SF-36 were equivalent to those observed in patients with congestive heart failure or osteoarthritis and were more than 0.5 SD greater than the impairment observed in patients with type 2 diabetes or a recent myocardial infarction.7,8 Chronic pain was an important contributor to the impairment of physical health and was similar to that reported by patients with osteoarthritis.7,8 The impairment of mental health status was similar to that observed in patients with subthreshold lifetime depression (a depressive disorder that does not meet all of the criteria for major depression of the Diagnostic and Statistical Manual of Mental Disorders, third edition).7,8,26 The study patients also had some impairment in cognitive functioning. Their base-line FIQ scores reflected the impairments in health status that were evident in the SF-36 scores and were similar to those in previous studies of patients with fibromyalgia or those with chronic Lyme disease after treatment.8-13
The administration of placebo and treatment with a regimen of parenteral ceftriaxone for 30 days, followed by oral doxycycline for 60 days, had similar effects on the patients' health-related quality of life. This antibiotic-treatment regimen was selected because of the in vitro and in vivo activity of both of these antibiotics against B. burgdorferi and because they are effective for the treatment of neuroborreliosis.1 Experience with other chronic infectious diseases caused by persistent bacteria (e.g., syphilis, tuberculosis, and helicobacter infection) suggests that it is unlikely that more prolonged antibiotic therapy or a different combination of antibiotics would result in greater improvement than was observed in this study.
Although we used both conventional and hypertonic culture mediums to isolate B. burgdorferi in base-line samples of cerebrospinal fluid and blood and used PCR to detect B. burgdorferi DNA in base-line samples of blood and cerebrospinal fluid as well as samples of blood collected during treatment, we did not find evidence of persistent infection with B. burgdorferi in these patients. There was no evidence of B. burgdorferi in a total of more than 700 different blood and cerebrospinal fluid samples from the 129 patients in these studies.
The placebo groups in these studies provide a view of the natural history of symptoms among patients with chronic Lyme disease after treatment. During the six-month evaluation period, we observed improvement in health status in 36 percent of patients, worsening health status in 39 percent, and no significant change in 25 percent. A similar relation between the administration of placebo and health-related quality of life has been reported previously among patients with other rheumatologic diseases that do not appear to be related to persistent infection. For example, a randomized, placebo-controlled trial in patients with mild-to-moderate rheumatoid arthritis found an improved clinical response after 48 weeks of placebo treatment in 39 to 41 percent of patients, as compared with 54 to 56 percent of patients treated with minocycline.27
In summary, patients with chronic musculoskeletal pain, neurocognitive symptoms, or both that persist after antibiotic treatment for well-documented Lyme disease have considerable impairment in their health-related quality of life. The patients enrolled in these studies did not have evidence of persistent infection by B. burgdorferi, as judged on the basis of the available microbiologic and molecular methods of detection. There were no significant differences between clinical responses of patients who received intravenous and oral antibiotics for 90 days and those of patients who received placebo.
Supported by grants (N01-AI-65308 and M01 RR000054) from the National Institutes of Health. Roche provided the ceftriaxone for the study, and Pfizer provided the doxycycline.
Because of its potential importance in the treatment of Lyme disease, this article was published at www.nejm.org on June 12, 2001.
We are indebted to Philip J. Baker, Ph.D., Steven P. Heyse, M.D., Marilyn Tuttleman, M.S., Dennis Dixon, Ph.D., and Mark Van Raden, Ph.D., of the National Institute of Allergy and Infectious Diseases Lyme Disease Program; to Barbara E. Murray, M.D., Robert Edelman, M.D., Frank G. Miller, Ph.D., Donald Rosenstein, M.D., and Barbara Tilley, Ph.D., of the data and safety monitoring board; to John E. Edwards, Jr., M.D., Carl Brenner, J. Stephen Dumler, M.D., Fred A. Gill, M.D., Phyllis Mervine, Justin Radolf, M.D., and Gregory Owens, Ph.D., of the Scientific Advisory Committee; and to the following persons who provided helpful services: Rich Noring, Bilaal McCloud, Bo Lin, Ph.D., Richard Kaplan, Ph.D., David Weld, Roger D'Entremont, Kitty Mullen, Chris Covington, Vincent DiPaola, Paul Drouilhet, David Fletcher, Jerrold Gold, Thomas Hirsch, Clyde Kessel, Keith Krewson, Laura Lattanzio, Rebecca Leland, Shawn Lyden, William Macleod, Roy Matthews, Peter Morton, Dave Murray, Jim Platz, John Sample, Elliott Schiffman, Michael Shabazian, Jason Stone, John Taylor, Bradford Von Weise, Frank Weldon, Larry Camerlin, Raymond Partridge, M.D., Marianna Wilson, M.S., John Consoletti, Pharm.D., Cindy Mason, R.N., David Thorpe, Pharm.D., Cindy Moore, R.N., June Novio, R.N., Eileen Regan, R.N., Andy Dousa, Pharm.D., Don Morrison, Pharm.D., Laura Cavagna, Pharm.D., Linda Griffith, Pharm.D., Sean Corbett, Pharm.D., Scott Reid, Pharm.D., Fran Bickert, R.N., John Opolski, R.N., Karen Tooker, R.N., Mark Wolff, Ph.D., Phyllis Barr, Ph.D., Anna Lornell, M.D., Phil Molloy, M.D., Karen Forschner, Dennis Hoak, M.D., David N. Mesches, M.D., Tim Lepore, M.D., Robina Folland, Robert Lopez, Bai Margolin, Crystal Sylvester, George Perides, Ph.D., Allen Steere, M.D., Ellen Jamieson, Jim Grayson, Timothy Brauns, Lilla Rogers, Jenn Finn, R.N., Pamela Norton, R.N., Karen Mazzotta, Anh Nguyen, M.D., Eric Logigian, M.D., William Brown, M.D., Anne Donohoe, Sandy Doveikis, Karen Fenicchia, R.N., Hua Wang, R.N., Nancy Zajac, R.N., Jamie Evanowski, David Carlson, Jason Hoitt, Carol Bauscher, L.P.N., Teryi Deshefy-Longhi, R.N., M.S., Carl Henn, Dee Dee Moss, Glynnis Fisher, Janet Mattson, Rosemary Hammil, Beth Horrigan, William Blackwelder, M.D., Frank Cavileri, M.D., John Nowakowski, M.D., Morris Dannon, M.D., Brij Mohan Singh Ahluwalia, M.D., Gary Wormser, M.D., Rhea Dornbush, Ph.D., Catherine Crea, Maria Aguero-Rosenfeld, M.D., Alan Gerber, M.D., Michael Tenner, M.D., Maureen Grix, Ph.D., Lois Zentmaier, Denise Cooper, Susan Bittker, Sheila Hughes, R.N., Junius Edlow, Tim McGarty, Jeffrey Bandola, M.D., Andrew Artenstein, M.D., Nancy Clark, R.N., Jerry Fingerut, M.D., Robert Schoen, M.D., Donna D'Euginio, R.N., Linda Bockenstedt, M.D., Alexia Bellperron, Brad Herskowitz, M.D., George Rickerson, M.D., LeBraun Paige, M.D., Volker Knappertz, M.D., Kimberly Stoddard, Ph.D., Ann Sweeney, R.N., Michael Westerveldt, Ph.D., Maureen Tacey, Thomas Rush, M.D., Jill Auerbach, Betty Gross, Manuel DaSilva, M.D., Arthur Rabson, M.D., Brian Fallon, M.D., Linda Tanner, Richard Horowitz, M.D., Edmond Yunis, M.D., Paul Alexander, R.N., and Ann Marie McClean, R.N.
Source Information
From New England Medical Center and Tufts University School of Medicine, Boston (M.S.K., L.T.H., C.H.S., G.M.J., R.P. T., J.M.); Yale–New Haven Hospital, New Haven, Conn. (J.E., D.W.), New York Medical College, Valhalla (D.N., L.L., A.W.); and Quality Metric, Lincoln, R.I. (M.K.).
Address reprint requests to Dr. Klempner at the Department of Medicine, Boston University School of Medicine, 715 Albany St., Boston, MA 02118, or at klempner@bu.edu.
- References
References
1
Wormser GP ,Nadelman RB ,Dattwyler RJ , et al. Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 2000;31:Suppl 1:1-14
CrossRef | Web of Science | Medline2
Asch ES ,Bujak DI ,Weiss M ,Peterson MGE ,Weinstein A . Lyme disease: an infectious and post infectious syndrome. J Rheumatol 1994;21:454-461
Web of Science | Medline3
Bujak DI ,Weinstein A ,Dornbush RL . Clinical and neurocognitive features of the post Lyme syndrome. J Rheumatol 1996;23:1392-1397
Web of Science | Medline4
Donta ST . Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997;25:Suppl 1:S52-S56
CrossRef | Web of Science | Medline5
Patel R ,Grogg KL ,Edwards WD ,Wright AJ ,Schwenk NM . Death from inappropriate therapy for Lyme disease. Clin Infect Dis 2000;31:1107-1109
CrossRef | Web of Science | Medline6
Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995;44:590-591
Medline7
Ware JE Jr. SF-36 Health Survey: manual and interpretation guide. Boston: Health Institute, New England Medical Center, 1993.
8
Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: a user's manual. Boston: Health Assessment Lab, 1994.
9
Stewart AL, Ware JE Jr, Sherbourne CD, Wells KB. Psychological distress/well-being and cognitive functioning measures. In: Stewart AL, Ware JE Jr, eds. Measuring functioning and well-being: the Medical Outcomes Study approach. Durham, N.C.: Duke University Press, 1992:102-42.
10
Sherbourne CD, Stewart AL, Wells KB. Role functioning measures. In: Stewart AL, Ware JE Jr, eds. Measuring functioning and well-being: the Medical Outcomes Study approach. Durham, N.C.: Duke University Press, 1992:205-19.
11
Sherbourne CD. Pain measures. In: Stewart AL, Ware JE Jr, eds. Measuring functioning and well-being: the Medical Outcomes Study approach. Durham, N.C.: Duke University Press, 1992:220-34.
12
Burckhardt CS ,Clark SR ,Bennett RM . The Fibromyalgia Impact Questionnaire: development and validation. J Rheumatol 1991;18:728-733
Web of Science | Medline13
Fallon J ,Bujak DI ,Guardino S ,Weinstein A . The Fibromyalgia Impact Questionnaire: a useful tool in evaluating patients with post-Lyme disease syndrome. Arthritis Care Res 1999;12:42-47
CrossRef | Medline14
Ware JE Jr ,Bayliss MS ,Rogers WH ,Kosinski M ,Tarlov AR . Differences in 4-year health outcomes for elderly and poor, chronically ill patients treated in HMO and fee-for-service systems: results from the Medical Outcomes Study. JAMA 1996;276:1039-1047
CrossRef | Web of Science | Medline15
Bergner M ,Bobbitt RA ,Carter WB ,Gilson BS . The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981;19:787-805
CrossRef | Web of Science | Medline16
Goldenberg D ,Mayskiy M ,Mossey C ,Ruthazer R ,Schmid C . A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum 1996;39:1852-1859
CrossRef | Web of Science | Medline17
Bennett RM ,Clark SC ,Walczyk J . A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med 1998;104:227-231
CrossRef | Web of Science | Medline18
Bennett RM ,Burckhardt CS ,Clark SR ,O'Reilly CA ,Wiens AN ,Campbell SM . Group treatment of fibromyalgia: a 6 month outpatient program. J Rheumatol 1996;23:521-528
Web of Science | Medline19
Dunkl PR ,Taylor AG ,McConnell GG ,Alfano AP ,Conaway MR . Responsiveness of fibromyalgia clinical trial outcome measures. J Rheumatol 2000;27:2683-2691
Web of Science | Medline20
Steere AC ,Berardi VP ,Weeks KE ,Logigian EL ,Ackermann R . Evaluation of the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for Lyme neuroborreliosis. J Infect Dis 1990;161:1203-1209
CrossRef | Web of Science | Medline21
Nocton JJ ,Bloom BJ ,Rutledge BJ , et al. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in cerebrospinal fluid in Lyme neuroborreliosis. J Infect Dis 1996;174:623-627
CrossRef | Web of Science | Medline22
Klempner MS ,Noring R ,Rogers RA . Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi. J Infect Dis 1993;167:1074-1081
CrossRef | Web of Science | Medline23
Phillips SE ,Mattman LH ,Hulinska D ,Moayad H . A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364-367
CrossRef | Web of Science | Medline24
Farrington CP ,Manning G . Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non zero risk difference or non-unity relative risk. Stat Med 1990;9:1447-1454
CrossRef | Web of Science | Medline25
Lan KKG ,Wittes J . The B-value: a tool for monitoring data. Biometrics 1988;44:579-585
CrossRef | Web of Science | Medline26
Wells KB ,Burnam MA ,Rogers WH ,Hays R ,Camp P . The course of depression in adult outpatients: results from the Medical Outcomes Study. Arch Gen Psychiatry 1992;49:788-794
Web of Science | Medline27
Tilley BC ,Alarcon GS ,Heyse SP , et al. Minocycline in rheumatoid arthritis: a 48-week, double blind, placebo-controlled trial. Ann Intern Med 1995;122:81-89
Web of Science | Medline
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John N. Aucott, Alison W. Rebman, Lauren A. Crowder, Kathleen B. Kortte. (2012) Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here?. Quality of Life Research
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R. Eikeland, Å. Mygland, K. Herlofson, U. Ljøstad. (2011) European neuroborreliosis: quality of life 30 months after treatment. Acta Neurologica Scandinavica 124:5, 349-354
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Abhishek Chandra, Norman Latov, Gary P. Wormser, Adriana R. Marques, Armin Alaedini. (2011) Epitope mapping of antibodies to VlsE protein of Borrelia burgdorferi in post-Lyme disease syndrome. Clinical Immunology 141:1, 103-110
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Åse Mygland, Unn Ljøstad, Volker Fingerle, Tobias Rupprecht, Erich Schmutzhard, Israel Steiner. 2011. Diagnosis and Management of European Lyme Neuroborreliosis. , 159-173.
CrossRef7
Lorraine Johnson, Alexandra Aylward, Raphael B. Stricker. (2011) Healthcare access and burden of care for patients with Lyme disease: A large United States survey. Health Policy 102:1, 64-71
CrossRef8
Paul G Auwaerter, Johan S Bakken, Raymond J Dattwyler, J Stephen Dumler, John J Halperin, Edward McSweegan, Robert B Nadelman, Susan O'Connell, Eugene D Shapiro, Sunil K Sood, Allen C Steere, Arthur Weinstein, Gary P Wormser. (2011) Antiscience and ethical concerns associated with advocacy of Lyme disease. The Lancet Infectious Diseases 11:9, 713-719
CrossRef9
Gerold Stanek, Gary P Wormser, Jeremy Gray, Franc Strle. (2011) Lyme borreliosis. The Lancet
CrossRef10
John J. Halperin. (2011) Neurologic Manifestations of Lyme Disease. Current Infectious Disease Reports 13:4, 360-366
CrossRef11
Paul M Lantos. (2011) Chronic Lyme disease: the controversies and the science. Expert Review of Anti-infective Therapy 9:7, 787-797
CrossRef12
Mark M. Macauda, Pamela Erickson, Janice Miller, Paul Mann, Linda Closter, Peter J. Krause. (2011) Long-Term Lyme Disease Antibiotic Therapy Beliefs Among New England Residents. Vector-Borne and Zoonotic Diseases 11:7, 857-862
CrossRef13
Barbara J. B. Johnson, Maria E. Aguero-Rosenfeld, Bettina Wilske. 2011. Serodiagnosis of Lyme Borreliosis. , 185-212.
CrossRef14
John J. Halperin, Leif Dotevall. 2011. Nervous System Lyme Borreliosis. , 93-113.
CrossRef15
Eugene D. Shapiro, Sunil K. Sood. 2011. Prognosis of Persons with Lyme Borreliosis. , 213-223.
CrossRef16
Gary P. Wormser, Guiqing Wang. 2011. The Role of Culture and Nucleic Acid Amplification in Diagnosis of Lyme Borreliosis. , 159-183.
CrossRef17
British Infection Association. (2011) The epidemiology, prevention, investigation and treatment of Lyme borreliosis in United Kingdom patients: A position statement by the British Infection Association. Journal of Infection 62:5, 329-338
CrossRef18
Chinmoy Bhate, Robert A. Schwartz. (2011) Lyme disease. Journal of the American Academy of Dermatology 64:4, 639-653
CrossRef19
M. Djukic, C. Schmidt-Samoa, R. Nau, N. von Steinbüchel, H. Eiffert, H. Schmidt. (2011) The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis - the experience from one year of a university hospital’s Lyme neuroborreliosis outpatients clinic. European Journal of Neurology 18:4, 547-555
CrossRef20
Tobias A Rupprecht, Volker Fingerle. (2011) Neuroborreliosis: pathogenesis, symptoms, diagnosis and treatment. Future Neurology 6:2, 273-289
CrossRef21
Alje P van Dam. (2011) Molecular diagnosis of Borrelia bacteria for the diagnosis of Lyme disease. Expert Opinion on Medical Diagnostics 5:2, 135-149
CrossRef22
Jennifer Graham, Katrina Stockley, Ran D. Goldman. (2011) Tick-Borne Illnesses. Pediatric Emergency Care 27:2, 141-147
CrossRef23
Gary P Wormser, Susan O’Connell. (2011) Treatment of infection caused by Borrelia burgdorferi sensu lato. Expert Review of Anti-infective Therapy 9:2, 245-260
CrossRef24
Eugene D. Shapiro, Michael A. Gerber. 2011. Borrelia Infections. , 564-576.
CrossRef25
G. Stanek, V. Fingerle, K.-P. Hunfeld, B. Jaulhac, R. Kaiser, A. Krause, W. Kristoferitsch, S. O’Connell, K. Ornstein, F. Strle, J. Gray. (2011) Lyme borreliosis: Clinical case definitions for diagnosis and management in Europe. Clinical Microbiology and Infection 17:1, 69-79
CrossRef26
Jeffrey T. Guptill, Wayne Massey. 2010. Psychiatric Manifestations of Nervous System Infections. , 426-432.
CrossRef27
Raphael B. Stricker, Lorraine Johnson. (2010) Letter to the Editor re “Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms” by Chandra et al.. Brain, Behavior, and Immunity 24:6, 1025
CrossRef28
Abhishek Chandra, Gary P. Wormser, Mark S. Klempner, Richard P. Trevino, Mary K. Crow, Norman Latov, Armin Alaedini. (2010) Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. Brain, Behavior, and Immunity 24:6, 1018-1024
CrossRef29
Daša Cerar, Tjaša Cerar, Eva Ružić-Sabljić, Gary P. Wormser, Franc Strle. (2010) The Reply. The American Journal of Medicine 123:8, e27-e28
CrossRef30
Armin Alaedini. (2010) Reply to Letter to the Editor by R. Stricker and L. Johnson re “Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms” by Chandra et al.. Brain, Behavior, and Immunity 24:6, 1026
CrossRef31
Thomas S. Murray, Eugene D. Shapiro. (2010) Lyme Disease. Clinics in Laboratory Medicine 30:1, 311-328
CrossRef32
John J. Halperin. (2010) A Tale of Two Spirochetes: Lyme Disease and Syphilis. Neurologic Clinics 28:1, 277-291
CrossRef33
U. Ljøstad, Ã. Mygland. (2010) Remaining complaints 1âyear after treatment for acute Lyme neuroborreliosis; frequency, pattern and risk factors. European Journal of Neurology 17:1, 118-123
CrossRef34
Ã. Mygland, U. Ljøstad, V. Fingerle, T. Rupprecht, E. Schmutzhard, I. Steiner. (2010) EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. European Journal of Neurology 17:1, 8-e4
CrossRef35
Daniel J. Cameron. (2010) Proof That Chronic Lyme Disease Exists. Interdisciplinary Perspectives on Infectious Diseases 2010, 1-4
CrossRef36
Daša Cerar, Tjaša Cerar, Eva Ružić-Sabljić, Gary P. Wormser, Franc Strle. (2010) Subjective Symptoms after Treatment of Early Lyme Disease. The American Journal of Medicine 123:1, 79-86
CrossRef37
Robert T. Schoen. 2010. Management of Lyme Disease. , 276-292.
CrossRef38
Gary P. Wormser, Eugene D. Shapiro. (2009) Authors' Reply. Journal of Women's Health 18:10, 1719-1720
CrossRef39
R. Kaiser, V. Fingerle. (2009) Neuroborreliose. Der Nervenarzt 80:10, 1239-1251
CrossRef40
Afton L. Hassett, Diane C. Radvanski, Steven Buyske, Shantal V. Savage, Leonard H. Sigal. (2009) Psychiatric Comorbidity and Other Psychological Factors in Patients with “Chronic Lyme Disease”. The American Journal of Medicine 122:9, 843-850
CrossRef41
&NA;. (2009) Treatment with antibacterials gets the ‘tick’ when treating skin manifestations of Lyme disease. Drugs & Therapy Perspectives 25:7, 17-19
CrossRef42
Gary P. Wormser, Eugene D. Shapiro. (2009) Implications of Gender in Chronic Lyme Disease. Journal of Women's Health 18:6, 831-834
CrossRef43
A. Krause, V. Fingerle. (2009) Lyme-Borreliose. Zeitschrift für Rheumatologie 68:3, 239-254
CrossRef44
Chris D. Meletis, Nieske Zabriskie, Robert Rountree. (2009) Identifying and Treating Lyme Disease. Alternative and Complementary Therapies 15:1, 17-23
CrossRef45
Afton L. Hassett, Diane C. Radvanski, Steven Buyske, Shantal V. Savage, Michael Gara, Javier I. Escobar, Leonard H. Sigal. (2008) Role of psychiatric comorbidity in chronic Lyme disease. Arthritis & Rheumatism 59:12, 1742-1749
CrossRef46
J. K. LOVETT, P. H. EVANS, S. O'CONNELL, N. J. GUTOWSKI. (2008) Neuroborreliosis in the South West of England. Epidemiology and Infection 136:12, 1707
CrossRef47
Phillip J. Baker. (2008) Beating Lyme. Journal of Clinical Investigation 118:9, 2990-2990
CrossRef48
Nataliya V. Fomenko, Natalya N. Livanova, Nailya Ya. Chernousova. (2008) Diversity of Borrelia burgdorferi sensu lato in natural foci of Novosibirsk region. International Journal of Medical Microbiology 298, 139-148
CrossRef49
Unn Ljøstad, Eirik Skogvoll, Randi Eikeland, Rune Midgard, Tone Skarpaas, Åse Berg, Åse Mygland. (2008) Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial. The Lancet Neurology 7:8, 690-695
CrossRef50
Allen C. Steere, Gail McHugh, Nitin Damle, Vijay K. Sikand. (2008) Prospective Study of Serologic Tests for Lyme Disease. Clinical Infectious Diseases 47:2, 188-195
CrossRef51
Phillip J. Baker. (2008) Perspectives on “Chronic Lyme Disease”. The American Journal of Medicine 121:7, 562-564
CrossRef52
David J. Volkman. (2008) Seronegative disease after inadequate therapy in lyme arthritis: Comment on the article by Kannian et al. Arthritis & Rheumatism 58:7, 2212-2213
CrossRef53
Adriana Marques. (2008) Chronic Lyme Disease: A Review. Infectious Disease Clinics of North America 22:2, 341-360
CrossRef54
Patricia Dandache, Robert B. Nadelman. (2008) Erythema Migrans. Infectious Disease Clinics of North America 22:2, 235-260
CrossRef55
U. Ljøstad, T.-H. Henriksen. (2008) Management of neuroborreliosis in European adult patients. Acta Neurologica Scandinavica 117:s188, 22-28
CrossRef56
Kristin M Corapi, Samardeep Gupta, Matthew H Liang. (2008) Management of Lyme disease. Expert Review of Anti-infective Therapy 6:2, 241-250
CrossRef57
(2008) An Appraisal of “Chronic Lyme Disease”. New England Journal of Medicine 358:4, 428-431
Full Text58
Diego Cadavid, Paul Auwaerter, John Aucott, Jeffrey Rumbaugh, Jeffrey Rumbaugh. 2008. Treatment for the neurological complications of Lyme disease. .
CrossRef59
Robert R Müllegger, Martin Glatz. (2008) Skin Manifestations of Lyme Borreliosis. American Journal of Clinical Dermatology 9:6, 355-368
CrossRef60
Feder, Henry M. Jr., Johnson, Barbara J.B., O'Connell, Susan, Shapiro, Eugene D., Steere, Allen C., Wormser, Gary P., the Ad Hoc International Lyme Disease Group. (2007) A Critical Appraisal of “Chronic Lyme Disease”. New England Journal of Medicine 357:14, 1422-1430
Full Text61
Lisa Phillips. (2007) Guidelines on Trial. Neurology Today 7:20, 1,12-13
CrossRef62
Raphael B Stricker, Lorraine Johnson. (2007) Lyme disease: a turning point. Expert Review of Anti-infective Therapy 5:5, 759-762
CrossRef63
M. F. Seidel, A. Belda Domene, H. Vetter. (2007) Differential diagnoses of suspected Lyme borreliosis or post-Lyme-disease syndrome. European Journal of Clinical Microbiology & Infectious Diseases 26:9, 611-617
CrossRef64
J. Oksi, J. Nikoskelainen, H. Hiekkanen, A. Lauhio, M. Peltomaa, A. Pitkäranta, D. Nyman, H. Granlund, S.-A. Carlsson, I. Seppälä, V. Valtonen, M. Viljanen. (2007) Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. European Journal of Clinical Microbiology & Infectious Diseases 26:8, 571-581
CrossRef65
R. B. Stricker. (2007) Counterpoint: Long-Term Antibiotic Therapy Improves Persistent Symptoms Associated with Lyme Disease. Clinical Infectious Diseases 45:2, 149-157
CrossRef66
P. G. Auwaerter. (2007) Point: Antibiotic Therapy Is Not the Answer for Patients with Persisting Symptoms Attributable to Lyme Disease. Clinical Infectious Diseases 45:2, 143-148
CrossRef67
Andrew R Pachner, Israel Steiner. (2007) Lyme neuroborreliosis: infection, immunity, and inflammation. The Lancet Neurology 6:6, 544-552
CrossRef68
Eric Hoppa, Richard Bachur. (2007) Lyme disease update. Current Opinion in Pediatrics 19:3, 275-280
CrossRef69
Daniel J. Cameron. (2007) Consequences of treatment delay in Lyme disease. Journal of Evaluation in Clinical Practice 13:3, 470-472
CrossRef70
S. T. Donta. (2007) Lyme Disease Guidelines--It's Time to Move Forward. Clinical Infectious Diseases 44:8, 1134-1135
CrossRef71
A. A. Pollock. (2007) Accuracy of Recommendations in the Infectious Diseases Society of America Clinical Practice Guidelines for Lyme Disease. Clinical Infectious Diseases 44:8, 1135-1135
CrossRef72
G. P. Wormser, R. J. Dattwyler, E. D. Shapiro, J. J. Halperin, A. C. Steere, M. S. Klempner, P. J. Krause, J. S. Bakken, F. Strle, G. Stanek, L. K. Bockenstedt, D. Fish, J. S. Dumler, R. B. Nadelman. (2007) Reply to Pollock, Donta, Wilson, and Arne. Clinical Infectious Diseases 44:8, 1137-1139
CrossRef73
John J. Halperin. (2007) Diagnosis and treatment of the neuromuscular manifestations of Lyme disease. Current Treatment Options in Neurology 9:2, 93-100
CrossRef74
J. Pourel, I. Chary-Valckenaere. (2007) Borreliosis de Lyme. EMC - Aparato Locomotor 40:2, 1-14
CrossRef75
J. Salomon, J. Clarissou, F. Ader, C. Perronne. (2007) Malattia di Lyme. EMC - AKOS - Trattato di Medicina 9:4, 1-5
CrossRef76
Sebastian Schnarr, Juliane K. Franz, Andreas Krause, Henning Zeidler. (2006) Lyme borreliosis. Best Practice & Research Clinical Rheumatology 20:6, 1099-1118
CrossRef77
S. Jarefors, C. K. Janefjord, P. Forsberg, M. C. Jenmalm, C. Ekerfelt. (2006) Decreased up-regulation of the interleukin-12R?2-chain and interferon-? 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. Clinical and Experimental Immunology 0:0, 061120065600011-???
CrossRef78
Allen C. Steere. (2006) Lyme borreliosis in 2005, 30 years after initial observations in Lyme Connecticut. Wiener klinische Wochenschrift 118:21-22, 625-633
CrossRef79
Henry M. Feder, Micha Abeles, Megan Bernstein, Diane Whitaker-Worth, Jane M. Grant-Kels. (2006) Diagnosis, treatment, and prognosis of erythema migrans and Lyme arthritis. Clinics in Dermatology 24:6, 509-520
CrossRef80
Gary P. Wormser, Raymond J. Dattwyler, Eugene D. Shapiro, John J. Halperin, Allen C. Steere, Mark S. Klempner, Peter J. Krause, Johan S. Bakken, Franc Strle, Gerold Stanek, Linda Bockenstedt, Durland Fish, J. Stephen Dumler, Robert B. Nadelman. (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. Clinical Infectious Diseases 43:9, 1089-1134
CrossRef81
Wormser, Gary P., . (2006) Early Lyme Disease. New England Journal of Medicine 354:26, 2794-2801
Full Text82
Klaus-Peter Hunfeld, Eva Ružić-Sabljić, Douglas E. Norris, Peter Kraiczy, Franc Strle. (2006) Risk of culture-confirmed borrelial persistence in patients treated for erythema migrans and possible mechanisms of resistance. International Journal of Medical Microbiology 296, 233-241
CrossRef83
Hans-Walter Pfister, Tobias A. Rupprecht. (2006) Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients. International Journal of Medical Microbiology 296, 11-16
CrossRef84
Meryl P. Littman, Richard E. Goldstein, Mary A. Labato, Michael R. Lappin, George E. Moore. (2006) ACVIM Small Animal Consensus Statement on Lyme Disease in Dogs: Diagnosis, Treatment, and Prevention. Journal of Veterinary Internal Medicine 20:2, 422-434
CrossRef85
D. T. Dennis. (2006) Reply to Phillips et al. Clinical Infectious Diseases 42:2, 307-308
CrossRef86
Eugene D. Shapiro, Michael A. Gerber. 2006. Lyme Disease. , 485-497.
CrossRef87
Raphael B. Stricker, Andrew Lautin, Joseph J. Burrascano. (2006) Lyme Disease: The Quest for Magic Bullets. Chemotherapy 52:2, 53-59
CrossRef88
John J. Halperin. (2005) Central nervous system Lyme disease. Current Neurology and Neuroscience Reports 5:6, 446-452
CrossRef89
&NA;. (2005) Treatment of Lyme Disease. Obstetrics & Gynecology 106:5, Part 1, 1099-1100
CrossRef90
H. Hofmann. (2005) Lyme-Borreliose. Der Hautarzt 56:8, 783-796
CrossRef91
Henry M. Feder. (2005) Inaccurate Information About Lyme Disease on the Internet. The Pediatric Infectious Disease Journal 24:6, 578-579
CrossRef92
Raphael B Stricker, Andrew Lautin, Joseph J Burrascano. (2005) Lyme disease: point/counterpoint. Expert Review of Anti-infective Therapy 3:2, 155-165
CrossRef93
Mireia Guerau-de-Arellano, Brigitte T. Huber. (2005) Chemokines and Toll-like receptors in Lyme disease pathogenesis. Trends in Molecular Medicine 11:3, 114-120
CrossRef94
G??ran G??nther, Mats Haglund. (2005) Tick-Borne Encephalopathies. CNS Drugs 19:12, 1009-1032
CrossRef95
Steven C Buckingham. (2005) Tick-Borne Infections in Children. Pediatric Drugs 7:3, 163-176
CrossRef96
S. Weissenbacher, J. Ring, H. Hofmann. (2005) Gabapentin for the Symptomatic Treatment of Chronic Neuropathic Pain in Patients with Late-Stage Lyme Borreliosis: A Pilot Study. Dermatology 211:2, 123-127
CrossRef97
Harald Gelderblom, Roland Martin, Adriana R. Marques. (2004) Research Opportunities on Human Neuroborreliosis. Vector-Borne and Zoonotic Diseases 4:3, 261-272
CrossRef98
Lorraine Johnson, Raphael B Stricker. (2004) Treatment of Lyme disease: a medicolegal assessment. Expert Review of Anti-infective Therapy 2:4, 533-557
CrossRef99
John J. Halperin. (2004) Central nervous system lyme disease. Current Infectious Disease Reports 6:4, 298-304
CrossRef100
Allen C. Steere, Jenifer Coburn, Lisa Glickstein. (2004) The emergence of Lyme disease. Journal of Clinical Investigation 113:8, 1093-1101
CrossRef101
Monica E. Embers, Ramesh Ramamoorthy, Mario T. Philipp. (2004) Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease. Microbes and Infection 6:3, 312-318
CrossRef102
(2004) Evidence-based guidelines for the management of Lyme disease. Expert Review of Anti-infective Therapy 2:1s1, S1-S13
CrossRef103
Brandt P. Groh. (2003) Current concepts in pediatric rheumatology. Current Opinion in Orthopaedics 14:6, 385-391
CrossRef104
Gerold Stanek. (2003) Reflections on the Clinical and Epidemiological Studies Presented at the IX International Conference on Lyme Borreliosis and Other Tick-Borne Diseases and Future Directions. Vector-Borne and Zoonotic Diseases 3:4, 229-247
CrossRef105
Gerald Stanek, Franc Strle. (2003) Lyme borreliosis. The Lancet 362:9396, 1639-1647
CrossRef106
Mark S Hanson, Robert Edelman. (2003) Progress and controversy surrounding vaccines against Lyme disease. Expert Review of Vaccines 2:5, 683-703
CrossRef107
Raphael B Stricker, Andrew Lautin. (2003) The Lyme Wars: time to listen. Expert Opinion on Investigational Drugs 12:10, 1609-1614
CrossRef108
Charles S Pavia. (2003) The Lyme disease controversies continue. Expert Opinion on Investigational Drugs 12:10, 1615-1620
CrossRef109
John J. Halperin. (2003) Lyme disease and the peripheral nervous system. Muscle & Nerve 28:2, 133-143
CrossRef110
Hayes, Edward B., Piesman, Joseph, . (2003) How Can We Prevent Lyme Disease?. New England Journal of Medicine 348:24, 2424-2430
Full Text111
Charles S Pavia. (2003) Current and novel therapies for Lyme disease. Expert Opinion on Investigational Drugs 12:6, 1003-1016
CrossRef112
Stephen C Eppes. (2003) Diagnosis, Treatment, and Prevention of Lyme Disease in Children. Pediatric Drugs 5:6, 363-372
CrossRef113
Thomas D. Sabin. (2003) AN APPROACH TO CHRONIC FATIGUE SYNDROME IN ADULTS. The Neurologist 9:1, 28-34
CrossRef114
Lauren B. Krupp. 2003. Lyme Disease. , 447-451.
CrossRef115
Gary P. Wormser. (2002) Impressions of the IX Conference on Lyme Borreliosis and Other Tick-Borne Diseases, August 18–22, 2002. Vector-Borne and Zoonotic Diseases 2:4, 201-207
CrossRef116
Mark S. Klempner. (2002) Controlled Trials of Antibiotic Treatment in Patients with Post-Treatment Chronic Lyme Disease. Vector-Borne and Zoonotic Diseases 2:4, 255-263
CrossRef117
John J. Halperin. (2002) Nervous System Lyme Disease. Vector-Borne and Zoonotic Diseases 2:4, 241-247
CrossRef118
Arthur Weinstein, Michael Britchkov. (2002) Lyme arthritis and post-Lyme disease syndrome. Current Opinion in Rheumatology 14:4, 383-387
CrossRef119
Pariwat Thaisetthawatkul, Eric L. Logigian. (2002) Peripheral Nervous System Manifestations of Lyme Borreliosis. Journal of Clinical Neuromuscular Disease 3:4, 165-171
CrossRef120
J. Sibilia, B. Jaulhac, F.X. Limbach. (2002) Les manifestations rhumatologiques de la borréliose de Lyme. La Revue de Médecine Interne 23:4, 378-385
CrossRef121
Sam T Donta. (2002) Late and chronic lyme disease. Medical Clinics of North America 86:2, 341-349
CrossRef122
P.K Coyle, S.E Schutzer. (2002) Neurologic aspects of lyme disease. Medical Clinics of North America 86:2, 261-284
CrossRef123
Cynthia J. Mollen, Louis M. Bell. (2002) Tick-Borne Illnesses in the United States. Pediatric Case Reviews 2:1, 14-25
CrossRef124
(2001) Treatment of Patients with Persistent Symptoms and a History of Lyme Disease. New England Journal of Medicine 345:19, 1424-1425
Full Text125
(2001) Single-Dose Doxycycline for the Prevention of Lyme Disease. New England Journal of Medicine 345:18, 1348-1350
Full Text126
Steere, Allen C., . (2001) Lyme Disease. New England Journal of Medicine 345:2, 115-125
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