Lyme neuroborreliosis - Epidemiology, diagnosis and management

Nature Reviews Neurology

Volumn 11, Issue 8, 2015, Pages 446-456

  Koedel, Uwe ^a   Fingerle, Volker ^b   Pfister, Hans Walter ^a  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^b Bavarian Health and Food Safety Authority   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; CEFTRIAXONE; DOXYCYCLINE; BACTERIUM ANTIBODY; BIOLOGICAL MARKER; CXCL13 CHEMOKINE; CXCL13 PROTEIN, HUMAN;

ANTIBIOTIC THERAPY; BORRELIA BURGDORFERI; CLINICAL FEATURE; DISEASE CARRIER; HUMAN; INCIDENCE; LYME DISEASE; NORTHERN HEMISPHERE; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; ALGORITHM; BLOOD; CHRONIC DISEASE; EUROPE; IMMUNOLOGY; LYME NEUROBORRELIOSIS; METABOLISM; NORTH AMERICA; NUCLEAR MAGNETIC RESONANCE IMAGING; SCANNING ELECTRON MICROSCOPY; TIME;

ALGORITHMS; ANTI-INFECTIVE AGENTS; ANTIBODIES, BACTERIAL; BIOMARKERS; BORRELIA BURGDORFERI; CHEMOKINE CXCL13; CHRONIC DISEASE; EUROPE; HUMANS; LYME NEUROBORRELIOSIS; MAGNETIC RESONANCE IMAGING; MICROSCOPY, ELECTRON, SCANNING; NORTH AMERICA; TIME FACTORS;

EID: 84938985622     PISSN: 17594758     EISSN: 17594766     Source Type: Journal    
DOI: 10.1038/nrneurol.2015.121     Document Type: Review

References (157)

1. Bannwarth, A. Chronische lymphozytäre Meningitis, entzündliche Polyneuritis und "Rheumatismus" [German]. Arch. Psychiatr. Nervenkr. 113, 284-376 (1941).
2. Reik, L., Steere, A. C., Bartenhagen, N. H., Shope, R. E. & Malawista, S. E. Neurologic abnormalities of Lyme disease. Medicine (Baltimore) 58, 281-294 (1979).
3. Pfister, H. W. et al. Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. J. Infect. Dis. 163, 311-318 (1991).
4. Preac-Mursic, V. et al. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 17, 355-359 (1989).
5. Shadick, N. A. et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann. Intern. Med. 131, 919-926 (1999).
6. Ackermann, R., Gollmer, E. & Rehse-Kupper, B. Progressive Borrelia encephalomyelitis. Chronic manifestation of erythema chronicum migrans disease of the nervous system [German]. Dtsch. Med. Wochenschr. 110, 1039-1042 (1985).
7. Logigian, E. L., Kaplan, R. F. & Steere, A. C. Chronic neurologic manifestations of Lyme disease. N. Engl. J. Med. 323, 1438-1444 (1990).
8. France, D. A war over Lyme disease. Newsweek 136, 72 (2000).
9. Lyme disease: data and statistics. Centers for Disease Control and Prevention [online], http://www.cdc.gov/lyme/stats/index.html (2015).
10. Naleway, A. L., Belongia, E. A., Kazmierczak, J. J., Greenlee, R. T. & Davis, J. P. Lyme disease incidence in Wisconsin: a comparison of state-reported rates and rates from a population-based cohort. Am. J. Epidemiol. 155, 1120-1127 (2002).
11. Henry, B. et al. How big is the Lyme problem? Using novel methods to estimate the true number of Lyme disease cases in British Columbia residents from 1997 to 2008. Vector Borne Zoonotic Dis. 11, 863-868 (2011).
12. Kuehn, B. M. CDC estimates 300,000 US cases of Lyme disease annually. JAMA 310, 1110 (2013).
13. Hinckley, A. F. et al. Lyme disease testing by large commercial laboratories in the United States. Clin. Infect. Dis. 59, 676-681 (2014).
14. Wilking, H. & Stark, K. Trends in surveillance data of human Lyme borreliosis from six federal states in eastern Germany, 2009-2012. Ticks Tick Borne Dis. 5, 219-224 (2014).
15. Muller, I. et al. Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany: a retrospective model analysis. Clin. Dev. Immunol. 2012, 595427 (2012).
16. Bacon, R. M. et al. Surveillance for Lyme disease-United States, 1992-2006. MMWR Surveill. Summ. 57, 1-9 (2008).
17. Clark, K. L., Leydet, B. F. & Threlkeld, C. Geographical and genospecies distribution of Borrelia burgdorferi sensu lato DNA detected in humans in the USA. J. Med. Microbiol. 63, 674-684 (2014).
18. Margos, G. et al. Borrelia bavariensis sp. nov. is widely distributed in Europe and Asia. Int. J. Syst. Evol. Microbiol. 63, 4284-4288 (2013).
19. Fingerle, V. et al. Epidemiological aspects and molecular characterization of Borrelia burgdorferi s.l. from southern Germany with special respect to the new species Borrelia spielmanii sp. nov. Int. J. Med. Microbiol. 298, 279-290 (2008).
20. Wilhelmsson, P. et al. Prevalence, diversity, and load of Borrelia species in ticks that have fed on humans in regions of Sweden and Aland Islands, Finland with different Lyme borreliosis incidences. PLoS ONE 8, e81433 (2013).
21. van Dam, A. P. et al. Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis. Clin. Infect. Dis. 17, 708-717 (1993).
22. Lin, Y. P. et al. Strain-specific variation of the decorin-binding adhesin DbpA influences the tissue tropism of the Lyme disease spirochete. PLoS Pathog. 10, e1004238 (2014).
23. Tijsse-Klasen, E. et al. Ability to cause erythema migrans differs between Borrelia burgdorferi sensu lato isolates. Parasit. Vectors 6, 23 (2013).
24. Wilske, B. et al. Diversity of OspA and OspC among cerebrospinal fluid isolates of Borrelia burgdorferi sensu lato from patients with neuroborreliosis in Germany. Med. Microbiol. Immunol. 184, 195-201 (1996).
25. Ornstein, K., Berglund, J., Bergstrom, S., Norrby, R. & Barbour, A. G. Three major Lyme Borrelia genospecies (Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii) identified by PCR in cerebrospinal fluid from patients with neuroborreliosis in Sweden. Scand. J. Infect. Dis. 34, 341-346 (2002).
26. Ogrinc, K. et al. Suspected early Lyme neuroborreliosis in patients with erythema migrans. Clin. Infect. Dis. 57, 501-509 (2013).
27. Bazovska, S. et al. The genospecies B. burgdorferi s.l., isolated from ticks and from neurological patients with suspected Lyme borreliosis. Neuro Endocrinol. Lett. 32, 491-495 (2011).
28. Brisson, D., Baxamusa, N., Schwartz, I. & Wormser, G. P. Biodiversity of Borrelia burgdorferi strains in tissues of Lyme disease patients. PLoS ONE 6, e22926 (2011).
29. Wormser, G. P. & Halperin, J. J. Toward a better understanding of European lyme neuroborreliosis. Clin. Infect. Dis. 57, 510-512 (2013).
30. Hansen, K. & Lebech, A. M. The clinical and epidemiological profile of Lyme neuroborreliosis in Denmark 1985-1990. A prospective study of 187 patients with Borrelia burgdorferi specific intrathecal antibody production. Brain 115, 399-423 (1992).
31. Henningsson, A. J., Malmvall, B. E., Ernerudh, J., Matussek, A. & Forsberg, P. Neuroborreliosis-An epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden. Clin. Microbiol. Infect. 16, 1245-1251 (2010).
32. Kruger, H. et al. Meningoradiculitis and encephalomyelitis due to Borrelia burgdorferi: a follow-up study of 72 patients over 27 years. J. Neurol. 236, 322-328 (1989).
33. Kaiser, R. Variable CSF findings in early and late Lyme neuroborreliosis: a follow-up study in 47 patients. J. Neurol. 242, 26-36 (1994).
34. Oschmann, P. et al. Stages and syndromes of neuroborreliosis. J. Neurol. 245, 262-272 (1998).
35. Kristoferitsch, W. Neurologic manifestations in Lyme borreliosis. Clin. Dermatol. 11, 393-400 (1993).
36. Pfister, H. W., Einhaupl, K., Preac-Mursic, V., Wilske, B. & Schierz, G. The spirochetal etiology of lymphocytic meningoradiculitis of Bannwarth (Bannwarth's syndrome). J. Neurol. 231, 141-144 (1984).
37. Mygland, A. et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur. J. Neurol. 17, 8-4 (2010).
38. Skogman, B. H. et al. Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome. Pediatr. Infect. Dis. J. 27, 1089-1094 (2008).
39. Tveitnes, D., Oymar, K. & Natas, O. Laboratory data in children with Lyme neuroborreliosis, relation to clinical presentation and duration of symptoms. Scand. J. Infect. Dis. 41, 355-362 (2009).
40. Pfister, H. W. et al. Catatonic syndrome in acute severe encephalitis due to Borrelia burgdorferi infection. Neurology 43, 433-435 (1993).
41. Rousseau, J. J., Lust, C., Zangerle, P. F. & Bigaignon, G. Acute transverse myelitis as presenting neurological feature of Lyme disease. Lancet 2, 1222-1223 (1986).
42. Pachner, A. R. & Steere, A. C. The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology 35, 47-53 (1985).
43. Steere, A. C., Pachner, A. R. & Malawista, S. E. Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin. Ann. Intern. Med. 99, 767-772 (1983).
44. Huppertz, H. I., Bohme, M., Standaert, S. M., Karch, H. & Plotkin, S. A. Incidence of Lyme borreliosis in the Wurzburg region of Germany. Eur. J. Clin. Microbiol. Infect. Dis. 18, 697-703 (1999).
45. Kohler, J., Kasper, J., Kern, U., Thoden, U. & Rehse-Kupper, B. Borrelia encephalomyelitis. Lancet 2, 35 (1986).
46. Lebas, A., Toulgoat, F., Saliou, G., Husson, B. & Tardieu, M. Stroke due to Lyme neuroborreliosis: changes in vessel wall contrast enhancement. J. Neuroimaging 22, 210-212 (2012).
47. Zajkowska, J. et al. Vasculitis and stroke due to Lyme neuroborreliosis-A review. Infect. Dis. (Lond.) 47, 1-6 (2014).
48. Back, T. et al. Neuroborreliosis-Associated cerebral vasculitis: long-Term outcome and health-related quality of life. J. Neurol. 260, 1569-1575 (2013).
49. Hopf, H. C. Peripheral neuropathy in acrodermatitis chronica atrophicans (Herxheimer). J. Neurol. Neurosurg. Psychiatry 38, 452-458 (1975).
50. Kristoferitsch, W. et al. Neuropathy associated with acrodermatitis chronica atrophicans. Clinical and morphological features. Ann. N. Y. Acad. Sci. 539, 35-45 (1988).
51. Kindstrand, E. et al. Polyneuropathy in late Lyme borreliosis-A clinical, neurophysiological and morphological description. Acta Neurol. Scand. 101, 47-52 (2000).
52. Mygland, A., Skarpaas, T. & Ljøstad, U. Chronic polyneuropathy and Lyme disease. Eur. J. Neurol. 13, 1213-1215 (2006).
53. Meier, C., Grahmann, F., Engelhardt, A. & Dumas, M. Peripheral nerve disorders in Lyme-Borreliosis. Nerve biopsy studies from eight cases. Acta Neuropathol. 79, 271-278 (1989).
54. Kindstrand, E., Nilsson, B. Y., Hovmark, A., Pirskanen, R. & Asbrink, E. Peripheral neuropathy in acrodermatitis chronica atrophicans-effect of treatment. Acta Neurol. Scand. 106, 253-257 (2002).
55. Halperin, J., Luft, B. J., Volkman, D. J. & Dattwyler, R. J. Lyme neuroborreliosis. Peripheral nervous system manifestations. Brain 113, 1207-1221 (1990).
56. Wilking, H., Fingerle, V., Klier, C., Thamm, M. & Stark, K. Antibodies against Borrelia burgdorferi sensu lato among Adults, Germany, 2008-2011. Emerg. Infect. Dis. 21, 107-110 (2015).
57. Kruger, H., Heim, E., Schuknecht, B. & Scholz, S. Acute and chronic neuroborreliosis with and without CNS involvement: a clinical, MRI, and HLA study of 27 cases. J. Neurol. 238, 271-280 (1991).
58. Dotevall, L. & Hagberg, L. Successful oral doxycycline treatment of Lyme disease-Associated facial palsy and meningitis. Clin. Infect. Dis. 28, 569-574 (1999).
59. Vrethem, M. et al. Chronic symptoms are common in patients with neuroborreliosis-A questionnaire follow-up study. Acta Neurol. Scand. 106, 205-208 (2002).
60. Ljøstad, U. et al. Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial. Lancet Neurol. 7, 690-695 (2008).
61. Kowalski, T. J., Berth, W. L., Mathiason, M. A. & Agger, W. A. Oral antibiotic treatment and long-Term outcomes of Lyme facial nerve palsy. Infection 39, 239-245 (2011).
62. Wormser, G. P. et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin. Infect. Dis. 43, 1089-1134 (2006).
63. Dattwyler, R. J., Volkman, D. J., Conaty, S. M., Platkin, S. P. & Luft, B. J. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet 336, 1404-1406 (1990).
64. Nadelman, R. B. et al. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann. Intern. Med. 117, 273-280 (1992).
65. Hammers-Berggren, S. et al. Serological follow-up after treatment of patients with erythema migrans and neuroborreliosis. J. Clin. Microbiol. 32, 1519-1525 (1994).
66. Luger, S. W. et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob. Agents Chemother. 39, 661-667 (1995).
67. Luft, B. J. et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans. A double-blind, randomized, controlled trial. Ann. Intern. Med. 124, 785-791 (1996).
68. Dattwyler, R. J. et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N. Engl. J. Med. 337, 289-294 (1997).
69. Smith, R. P. et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann. Intern. Med. 136, 421-428 (2002).
70. Nowakowski, J. et al. Long-Term follow-up of patients with culture-confirmed Lyme disease. Am. J. Med. 115, 91-96 (2003).
71. Wormser, G. P. et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 138, 697-704 (2003).
72. Stupica, D., Lusa, L., Cerar, T., Ruzic-Sabljic, E. & Strle, F. Comparison of post-Lyme Borreliosis symptoms in erythema migrans patients with positive and negative Borrelia burgdorferi sensu lato skin culture. Vector Borne Zoonotic Dis. 11, 883-889 (2011).
73. Wormser, G. P. et al. Long-Term assessment of fatigue in patients with culture-confirmed Lyme disease. Am. J. Med. 128, 181-184 (2015).
74. Treib, J. et al. Clinical and serologic follow-up in patients with neuroborreliosis. Neurology 51, 1489-1491 (1998).
75. Karkkonen, K., Stiernstedt, S. H. & Karlsson, M. Follow-up of patients treated with oral doxycycline for Lyme neuroborreliosis. Scand. J. Infect. Dis. 33, 259-262 (2001).
76. Berglund, J., Stjernberg, L., Ornstein, K., Tykesson-Joelsson, K. & Walter, H. 5-y follow-up study of patients with neuroborreliosis. Scand. J. Infect. Dis. 34, 421-425 (2002).
77. Borg, R. et al. Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scand. J. Infect. Dis. 37, 449-454 (2005).
78. Picha, D., Moravcova, L., Lasikova, S., Holeckova, D. & Maresova, V. Symptoms of post-Lyme syndrome in long-Term outcome of patients with neuroborreliosis. Scand. J. Infect. Dis. 38, 747-748 (2006).
79. Oksi, J. et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur. J. Clin. Microbiol. Infect. Dis. 26, 571-581 (2007).
80. Ljøstad, U. & Mygland, A. Remaining complaints 1 year after treatment for acute Lyme neuroborreliosis; frequency, pattern and risk factors. Eur. J. Neurol. 17, 118-123 (2010).
81. Eikeland, R., Mygland, A., Herlofson, K. & Ljøstad, U. European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol. Scand. 124, 349-354 (2011).
82. Bremell, D. & Dotevall, L. Oral doxycycline for Lyme neuroborreliosis with symptoms of encephalitis, myelitis, vasculitis or intracranial hypertension. Eur. J. Neurol. 21, 1162-1167 (2014).
83. Eikeland, R., Mygland, A., Herlofson, K. & Ljøstad, U. Risk factors for a non-favorable outcome after treated European neuroborreliosis. Acta Neurol. Scand. 127, 154-160 (2013).
84. Cairns, V. & Godwin, J. Post-Lyme borreliosis syndrome: a meta-Analysis of reported symptoms. Int. J. Epidemiol. 34, 1340-1345 (2005).
85. Wang, T. J. et al. Outcomes of children treated for Lyme disease. J. Rheumatol. 25, 2249-2253 (1998).
86. Vazquez, M., Sparrow, S. S. & Shapiro, E. D. Long-Term neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Pediatrics 112, e93-e97 (2003).
87. Seltzer, E. G., Gerber, M. A., Cartter, M. L., Freudigman, K. & Shapiro, E. D. Long-Term outcomes of persons with Lyme disease. JAMA 283, 609-616 (2000).
88. Cerar, D., Cerar, T., Ruzic-Sabljic, E., Wormser, G. P. & Strle, F. Subjective symptoms after treatment of early Lyme disease. Am. J. Med. 123, 79-86 (2010).
89. Lantos, P. M. Chronic Lyme disease: the controversies and the science. Expert Rev. Anti. Infect. Ther. 9, 787-797 (2011).
90. Stricker, R. B. & Johnson, L. Persistent symptoms following treatment of early Lyme disease: false hope? Am. J. Med. 123, e25-e28 (2010).
91. Stricker, R. B. et al. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int. J. Gen. Med. 4, 639-646 (2011).
92. Krupp, L. B. et al. Study and treatment of post Lyme disease (STOP-Lyme disease): a randomized double masked clinical trial. Neurology 60, 1923-1930 (2003).
93. Fallon, B. A. et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 70, 992-1003 (2008).
94. Klempner, M. S. et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N. Engl. J. Med. 345, 85-92 (2001).
95. Sjowall, J., Ledel, A., Ernerudh, J., Ekerfelt, C. & Forsberg, P. Doxycycline-mediated effects on persistent symptoms and systemic cytokine responses post-neuroborreliosis: a randomized, prospective, cross-over study. BMC Infect. Dis. 12, 186 (2012).
96. Halperin, J. J. Lyme disease: neurology, neurobiology, and behavior. Clin. Infect. Dis. 58, 1267-1272 (2014).
97. Feder, H. M. Jr et al. A critical appraisal of "chronic Lyme disease". N. Engl. J. Med. 357, 1422-1430 (2007).
98. Katz, B. Z. & Jason, L. A. Chronic fatigue syndrome following infections in adolescents. Curr. Opin. Pediatr. 25, 95-102 (2013).
99. Cameron, D. J. Proof that chronic Lyme disease exists. Interdiscip. Perspect. Infect. Dis. 2010, 876450 (2010).
100. Cameron, D. J., Johnson, L. B. & Maloney, E. L. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev. Anti Infect. Ther. 12, 1103-1135 (2014).
101. Hodzic, E., Feng, S., Holden, K., Freet, K. J. & Barthold, S. W. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob. Agents Chemother. 52, 1728-1736 (2008).
102. Embers, M. E. et al. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS ONE 7, e29914 (2012).
103. Marques, A. et al. Xenodiagnosis to detect Borrelia burgdorferi infection: a first-in-human study. Clin. Infect. Dis. 58, 937-945 (2014).
104. Miklossy, J. et al. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J. Neuroinflammation 5, 40 (2008).
105. Stricker, R. B., Green, C. L., Savely, V. R., Chamallas, S. N. & Johnson, L. Safety of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Minerva Med. 101, 1-7 (2010).
106. Berghoff, W. Chronic Lyme disease and co-infections: differential diagnosis. Open Neurol. J. 6, 158-178 (2012).
107. Oliveira, C. R. & Shapiro, E. D. Update on persistent symptoms associated with Lyme disease. Curr. Opin. Pediatr. 27, 100-104 (2015).
108. Lantos, P. M., Auwaerter, P. G. & Wormser, G. P. A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease. Clin. Infect. Dis. 58, 663-671 (2014).
109. Lantos, P. M. & Wormser, G. P. Chronic coinfections in patients diagnosed with chronic Lyme disease: a systematic review. Am. J. Med. 127, 1105-1110 (2014).
110. Hassett, A. L., Radvanski, D. C., Buyske, S., Savage, S. V. & Sigal, L. H. Psychiatric comorbidity and other psychological factors in patients with "chronic Lyme disease". Am. J. Med. 122, 843-850 (2009).
111. Ljøstad, U. & Mygland, A. The phenomenon of 'chronic Lyme'; an observational study. Eur. J. Neurol. 19, 1128-1135 (2012).
112. Djukic, M. et al. The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis-The experience from one year of a university hospital's Lyme neuroborreliosis outpatients clinic. Eur. J. Neurol. 18, 547-555 (2011).
113. Coumou, J. et al. Ticking the right boxes: classification of patients suspected of Lyme borreliosis at an academic referral center in the Netherlands. Clin. Microbiol. Infect. 21, 368.e11-368.e20 (2014).
114. Luo, N., Johnson, J. A., Shaw, J. W., Feeny, D. & Coons, S. J. Self-reported health status of the general adult U.S. population as assessed by the EQ-5D and Health Utilities Index. Med. Care 43, 1078-1086 (2005).
115. Baker, P. J. The pain of "chronic Lyme disease": moving the discourse in a different direction. FASEB J. 26, 11-12 (2012).
116. Benedetti, F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84, 623-637 (2014).
117. Cockshell, S. J. & Mathias, J. L. Cognitive functioning in people with chronic fatigue syndrome: a comparison between subjective and objective measures. Neuropsychology. 28, 394-405 (2014).
118. Tikka, T., Usenius, T., Tenhunen, M., Keinanen, R. & Koistinaho, J. Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation. J. Neurochem. 78, 1409-1414 (2001).
119. Leite, L. M. et al. Anti-inflammatory properties of doxycycline and minocycline in experimental models: an in vivo and in vitro comparative study. Inflammopharmacology 19, 99-110 (2011).
120. Hickie, I. et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 333, 575 (2006).
121. Karlsson, M., Hovind-Hougen, K., Svenungsson, B. & Stiernstedt, G. Cultivation and characterization of spirochetes from cerebrospinal fluid of patients with Lyme borreliosis. J. Clin. Microbiol. 28, 473-479 (1990).
122. Nowakowski, J. et al. Blood cultures for patients with extracutaneous manifestations of Lyme disease in the United States. Clin. Infect. Dis. 49, 1733-1735 (2009).
123. Dumler, J. S. Molecular diagnosis of Lyme disease: review and meta-Analysis. Mol. Diagn. 6, 1-11 (2001).
124. Cerar, T. et al. Validation of cultivation and PCR methods for diagnosis of Lyme neuroborreliosis. J. Clin. Microbiol. 46, 3375-3379 (2008).
125. Tugwell, P. et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann. Intern. Med. 127, 1109-1123 (1997).
126. Wilske, B., Fingerle, V. & Schulte-Spechtel, U. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol. Med. Microbiol. 49, 13-21 (2007).
127. Aguero-Rosenfeld, M. E. & Wormser, G. P. Lyme disease: diagnostic issues and controversies. Expert Rev. Mol. Diagn. 15, 1-4 (2015).
128. Wormser, G. P. et al. Utility of serodiagnostics designed for use in the United States for detection of Lyme borreliosis acquired in Europe and vice versa. Med. Microbiol. Immunol. 203, 65-71 (2014).
129. Fallon, B. A., Pavlicova, M., Coffino, S. W. & Brenner, C. A comparison of Lyme disease serologic test results from 4 laboratories in patients with persistent symptoms after antibiotic treatment. Clin. Infect. Dis. 59, 1705-1710 (2014).
130. Tumani, H., Nolker, G. & Reiber, H. Relevance of cerebrospinal fluid variables for early diagnosis of neuroborreliosis. Neurology 45, 1663-1670 (1995).
131. Blanc, F. et al. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology 69, 953-958 (2007).
132. Ljøstad, U., Skarpaas, T. & Mygland, A. Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur. J. Neurol. 14, 873-876 (2007).
133. Hansen, K. & Lebech, A. M. Lyme neuroborreliosis: a new sensitive diagnostic assay for intrathecal synthesis of Borrelia burgdorferi-specific immunoglobulin G, A and M. Ann. Neurol. 30, 197-205 (1991).
134. Kaiser, R. & Rauer, S. Analysis of the intrathecal immune response in neuroborreliosis to a sonicate antigen and three recombinant antigens of Borrelia burgdorferi sensu stricto. Eur. J. Clin. Microbiol. Infect. Dis. 17, 159-166 (1998).
135. Reiber, H. & Peter, J. B. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J. Neurol. Sci. 184, 101-122 (2001).
136. Pfister, H. W. & Rupprecht, T. A. Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients. Int. J. Med. Microbiol. 296 (Suppl. 40), 11-16 (2006).
137. Dattwyler, R. J. et al. Seronegative Lyme disease. Dissociation of specific T-And B-lymphocyte responses to Borrelia burgdorferi. N. Engl. J. Med. 319, 1441-1446 (1988).
138. Valentine-Thon, E. et al. LTT-MELISA is clinically relevant for detecting and monitoring metal sensitivity. Neuro. Endocrinol. Lett. 27 (Suppl. 1), 17-24 (2006).
139. von Baehr, V., Doebis, C., Volk, H. D. & von Baehr, R. The lymphocyte transformation test for Borrelia detects active Lyme borreliosis and verifies effective antibiotic treatment. Open. Neurol. J. 6, 104-112 (2012).
140. Dessau, R. B. et al. The lymphocyte transformation test for the diagnosis of Lyme borreliosis has currently not been shown to be clinically useful. Clin. Microbiol. Infect. 20, O786-O787 (2014).
141. Nordberg, M. et al. Can ELISPOT be applied to a clinical setting as a diagnostic utility for neuroborreliosis? Cells 1, 153-167 2012).
142. Stricker, R. B. & Winger, E. E. Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Immunol. Lett. 76, 43-48 (2001).
143. Bockenstedt, L. K. & Radolf, J. D. Xenodiagnosis for posttreatment Lyme disease syndrome: resolving the conundrum or adding to it? Clin. Infect. Dis. 58, 946-948 (2014).
144. Smit, P. W., Kurkela, S., Kuusi, M. & Vapalahti, O. Evaluation of two commercially available rapid diagnostic tests for Lyme borreliosis. Eur. J. Clin. Microbiol. Infect. Dis. 34, 109-113 (2015).
145. Rupprecht, T. A. et al. The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis. Neurology 65, 448-450 (2005).
146. Ljøstad, U. & Mygland, A. CSF B-lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis. J. Neurol. 255, 732-737 (2008).
147. Schmidt, C. et al. A prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology 76, 1051-1058 (2011).
148. Tjernberg, I., Henningsson, A. J., Eliasson, I., Forsberg, P. & Ernerudh, J. Diagnostic performance of cerebrospinal fluid chemokine CXCL13 and antibodies to the C6-peptide in Lyme neuroborreliosis. J. Infect. 62, 149-158 (2011).
149. Hytonen, J. et al. CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation. J. Neuroinflammation. 11, 103 (2014).
150. Rupprecht, T. A., Lechner, C., Tumani, H. & Fingerle, V. CXCL13: a biomarker for acute Lyme neuroborreliosis: investigation of the predictive value in the clinical routine [German]. Nervenarzt 85, 459-464 (2014).
151. Rubenstein, J. L. et al. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 121, 4740-4748 (2013).
152. Rupprecht, T. A. et al. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J. Neuroinflammation 6, 42 (2009).
153. Kruger, H., Kohlhepp, W. & Konig, S. Follow-up of antibiotically treated and untreated neuroborreliosis. Acta Neurol. Scand. 82, 59-67 (1990).
154. Karlsson, M., Hammers-Berggren, S., Lindquist, L., Stiernstedt, G. & Svenungsson, B. Comparison of intravenous penicillin G. and oral doxycycline for treatment of Lyme neuroborreliosis. Neurology 44, 1203-1207 (1994).
155. Ogrinc, K. et al. Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wien Klin. Wochenschr. 118, 696-701 (2006).
156. Kaiser, R. Clinical courses of acute and chronic neuroborreliosis following treatment with ceftriaxone [German]. Nervenarzt 75, 553-557 (2004).
157. Johnson, M. & Feder, H. M. Jr. Chronic Lyme disease: a survey of Connecticut primary care physicians. J. Pediatr. 157, 1025-1029 (2010).