Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lyme neuroborreliosis—epidemiology, diagnosis and management

Nature Reviews Neurology volume 11, pages 446–456 (2015)Cite this article

Subjects

Key Points

  • Diagnosis of Lyme neuroborreliosis is made by history taking, clinical examination, cerebrospinal fluid (CSF) analysis, and Borrelia burgdorferi antibody testing

  • B. burgdorferi antibody testing should be performed only in patients presenting with clinical signs suggestive of infection

  • CSF levels of the chemokine CXCL13 might be useful as a complementary diagnostic tool for early Lyme neuroborreliosis

  • Patients with post-treatment Lyme disease syndrome do not have ongoing B. burgdorferi infection and, thus, do not benefit from additional (for example, long-term) antibiotic therapy

  • Alternative treatment options must be established for patients with post-treatment Lyme disease syndrome

  • Chronic Lyme disease is a poorly defined term, used by some practitioners for patients with a wide variety of subjective complaints that can often be attributed to other illnesses

Abstract

Lyme disease, caused by the Borrelia burgdorferi bacterium, is the most common vector-borne disease in the northern hemisphere. The clinical presentation varies with disease stage, and neurological manifestations (often referred to as Lyme neuroborreliosis) are reported in up to 12% of patients with Lyme disease. Most aspects of the epidemiology, clinical manifestation and treatment of Lyme neuroborreliosis are well known and accepted; only the management of so-called chronic Lyme disease is surrounded by considerable controversy. This term is used for disparate patient groups, including those who have untreated late-stage infection (for example, late neuroborreliosis), those with subjective symptoms that persist after treatment (termed 'post-treatment Lyme disease syndrome' [PTLDS]), and those with unexplained subjective complaints that may or may not be accompanied by positive test results for B. burgdorferi infection in serum (here called 'chronic Lyme disease'). The incidence of PTLDS is still a matter of debate, and its pathogenesis is unclear, but there is evidence that these patients do not have ongoing B. burgdorferi infection and, thus, do not benefit from additional antibiotic therapy. Chronic Lyme disease lacks an accepted clinical definition, and most patients who receive this diagnosis have other illnesses. Thus, a careful diagnostic work-up is needed to ensure proper treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ticks and Borrelia under the microscope.
Figure 2: Proposed diagnostic work-up for adult patients with early Lyme neuroborreliosis.
Figure 3: Proposed diagnostic algorithm for adult patients with late Lyme neuroborreliosis.
Figure 4: Follow-up MRI and CSF findings in two patients with late Lyme neuroborreliosis.

Similar content being viewed by others

References

  1. Bannwarth, A. Chronische lymphozytäre Meningitis, entzündliche Polyneuritis und “Rheumatismus” [German]. Arch. Psychiatr. Nervenkr. 113, 284–376 (1941).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  3. Pfister, H. W. et al. Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. J. Infect. Dis. 163, 311–318 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Preac-Mursic, V. et al. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 17, 355–359 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Shadick, N. A. et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann. Intern. Med. 131, 919–926 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  7. Logigian, E. L., Kaplan, R. F. & Steere, A. C. Chronic neurologic manifestations of Lyme disease. N. Engl. J. Med. 323, 1438–1444 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. France, D. A war over Lyme disease. Newsweek 136, 72 (2000).

    CAS  PubMed  Google Scholar 

  9. Lyme disease: data and statistics. Centers for Disease Control and Prevention [online], (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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  12. Kuehn, B. M. CDC estimates 300,000 US cases of Lyme disease annually. JAMA 310, 1110 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Hinckley, A. F. et al. Lyme disease testing by large commercial laboratories in the United States. Clin. Infect. Dis. 59, 676–681 (2014).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  16. Bacon, R. M. et al. Surveillance for Lyme disease—United States, 1992–2006. MMWR Surveill. Summ. 57, 1–9 (2008).

    PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Tijsse-Klasen, E. et al. Ability to cause erythema migrans differs between Borrelia burgdorferi sensu lato isolates. Parasit. Vectors 6, 23 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  26. Ogrinc, K. et al. Suspected early Lyme neuroborreliosis in patients with erythema migrans. Clin. Infect. Dis. 57, 501–509 (2013).

    Article  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wormser, G. P. & Halperin, J. J. Toward a better understanding of European lyme neuroborreliosis. Clin. Infect. Dis. 57, 510–512 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  34. Oschmann, P. et al. Stages and syndromes of neuroborreliosis. J. Neurol. 245, 262–272 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Kristoferitsch, W. Neurologic manifestations in Lyme borreliosis. Clin. Dermatol. 11, 393–400 (1993).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  37. Mygland, A. et al. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur. J. Neurol. 17, 8–4 (2010).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  40. Pfister, H. W. et al. Catatonic syndrome in acute severe encephalitis due to Borrelia burgdorferi infection. Neurology 43, 433–435 (1993).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  45. Kohler, J., Kasper, J., Kern, U., Thoden, U. & Rehse-Kupper, B. Borrelia encephalomyelitis. Lancet 2, 35 (1986).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  47. Zajkowska, J. et al. Vasculitis and stroke due to Lyme neuroborreliosis—a review. Infect. Dis. (Lond.) 47, 1–6 (2014).

    Google Scholar 

  48. Back, T. et al. Neuroborreliosis-associated cerebral vasculitis: long-term outcome and health-related quality of life. J. Neurol. 260, 1569–1575 (2013).

    Article  PubMed  Google Scholar 

  49. Hopf, H. C. Peripheral neuropathy in acrodermatitis chronica atrophicans (Herxheimer). J. Neurol. Neurosurg. Psychiatry 38, 452–458 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kristoferitsch, W. et al. Neuropathy associated with acrodermatitis chronica atrophicans. Clinical and morphological features. Ann. N. Y. Acad. Sci. 539, 35–45 (1988).

    Article  CAS  PubMed  Google Scholar 

  51. Kindstrand, E. et al. Polyneuropathy in late Lyme borreliosis—a clinical, neurophysiological and morphological description. Acta Neurol. Scand. 101, 47–52 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Mygland, A., Skarpaas, T. & Ljøstad, U. Chronic polyneuropathy and Lyme disease. Eur. J. Neurol. 13, 1213–1215 (2006).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  55. Halperin, J., Luft, B. J., Volkman, D. J. & Dattwyler, R. J. Lyme neuroborreliosis. Peripheral nervous system manifestations. Brain 113, 1207–1221 (1990).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  58. Dotevall, L. & Hagberg, L. Successful oral doxycycline treatment of Lyme disease-associated facial palsy and meningitis. Clin. Infect. Dis. 28, 569–574 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  70. Nowakowski, J. et al. Long-term follow-up of patients with culture-confirmed Lyme disease. Am. J. Med. 115, 91–96 (2003).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  74. Treib, J. et al. Clinical and serologic follow-up in patients with neuroborreliosis. Neurology 51, 1489–1491 (1998).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  83. Eikeland, R., Mygland, Å., Herlofson, K. & Ljøstad, U. Risk factors for a non-favorable outcome after treated European neuroborreliosis. Acta Neurol. Scand. 127, 154–160 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Cairns, V. & Godwin, J. Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int. J. Epidemiol. 34, 1340–1345 (2005).

    Article  PubMed  Google Scholar 

  85. Wang, T. J. et al. Outcomes of children treated for Lyme disease. J. Rheumatol. 25, 2249–2253 (1998).

    CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  89. Lantos, P. M. Chronic Lyme disease: the controversies and the science. Expert Rev. Anti. Infect. Ther. 9, 787–797 (2011).

    Article  PubMed  Google Scholar 

  90. Stricker, R. B. & Johnson, L. Persistent symptoms following treatment of early Lyme disease: false hope? Am. J. Med. 123, e25–e28 (2010).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  93. Fallon, B. A. et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 70, 992–1003 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Halperin, J. J. Lyme disease: neurology, neurobiology, and behavior. Clin. Infect. Dis. 58, 1267–1272 (2014).

    Article  PubMed  Google Scholar 

  97. Feder, H. M. Jr et al. A critical appraisal of “chronic Lyme disease”. N. Engl. J. Med. 357, 1422–1430 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Katz, B. Z. & Jason, L. A. Chronic fatigue syndrome following infections in adolescents. Curr. Opin. Pediatr. 25, 95–102 (2013).

    Article  PubMed  Google Scholar 

  99. Cameron, D. J. Proof that chronic Lyme disease exists. Interdiscip. Perspect. Infect. Dis. 2010, 876450 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Embers, M. E. et al. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS ONE 7, e29914 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Marques, A. et al. Xenodiagnosis to detect Borrelia burgdorferi infection: a first-in-human study. Clin. Infect. Dis. 58, 937–945 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Miklossy, J. et al. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J. Neuroinflammation 5, 40 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  106. Berghoff, W. Chronic Lyme disease and co-infections: differential diagnosis. Open Neurol. J. 6, 158–178 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Oliveira, C. R. & Shapiro, E. D. Update on persistent symptoms associated with Lyme disease. Curr. Opin. Pediatr. 27, 100–104 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Ljøstad, U. & Mygland, Å. The phenomenon of 'chronic Lyme'; an observational study. Eur. J. Neurol. 19, 1128–1135 (2012).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  115. Baker, P. J. The pain of “chronic Lyme disease”: moving the discourse in a different direction. FASEB J. 26, 11–12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Benedetti, F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84, 623–637 (2014).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  123. Dumler, J. S. Molecular diagnosis of Lyme disease: review and meta-analysis. Mol. Diagn. 6, 1–11 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Cerar, T. et al. Validation of cultivation and PCR methods for diagnosis of Lyme neuroborreliosis. J. Clin. Microbiol. 46, 3375–3379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Tugwell, P. et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann. Intern. Med. 127, 1109–1123 (1997).

    Article  CAS  PubMed  Google Scholar 

  126. Wilske, B., Fingerle, V. & Schulte-Spechtel, U. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol. Med. Microbiol. 49, 13–21 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Aguero-Rosenfeld, M. E. & Wormser, G. P. Lyme disease: diagnostic issues and controversies. Expert Rev. Mol. Diagn. 15, 1–4 (2015).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  130. Tumani, H., Nolker, G. & Reiber, H. Relevance of cerebrospinal fluid variables for early diagnosis of neuroborreliosis. Neurology 45, 1663–1670 (1995).

    Article  CAS  PubMed  Google Scholar 

  131. Blanc, F. et al. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology 69, 953–958 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Ljøstad, U., Skarpaas, T. & Mygland, A. Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur. J. Neurol. 14, 873–876 (2007).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  135. Reiber, H. & Peter, J. B. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J. Neurol. Sci. 184, 101–122 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  141. Nordberg, M. et al. Can ELISPOT be applied to a clinical setting as a diagnostic utility for neuroborreliosis? Cells 1, 153–167 2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Stricker, R. B. & Winger, E. E. Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Immunol. Lett. 76, 43–48 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  145. Rupprecht, T. A. et al. The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis. Neurology 65, 448–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Ljøstad, U. & Mygland, A. CSF B-lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis. J. Neurol. 255, 732–737 (2008).

    Article  PubMed  CAS  Google Scholar 

  147. Schmidt, C. et al. A prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology 76, 1051–1058 (2011).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  151. Rubenstein, J. L. et al. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 121, 4740–4748 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Kruger, H., Kohlhepp, W. & Konig, S. Follow-up of antibiotically treated and untreated neuroborreliosis. Acta Neurol. Scand. 82, 59–67 (1990).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  155. Ogrinc, K. et al. Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wien Klin. Wochenschr. 118, 696–701 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Kaiser, R. Clinical courses of acute and chronic neuroborreliosis following treatment with ceftriaxone [German]. Nervenarzt 75, 553–557 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Johnson, M. & Feder, H. M. Jr. Chronic Lyme disease: a survey of Connecticut primary care physicians. J. Pediatr. 157, 1025–1029 (2010).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are very grateful for the clinical cooperation of K. Seelos and M. Wick from the University of Munich. The authors would also like to thank G. Wanner from Ludwig-Maximilians University Munich for his support in generating the electron microscopic images of Borrelia afzelii. The authors' work has been funded by the German Research Foundation, the Else Kröner Fresenius Stiftung, and the University of Munich (FöFoLe programme). V.F. receives research funding from the Robert Koch Institute (ZV2-1369-338 and ZV2-1369-488), the Bavarian State Ministry of Public Health and Care (Z3 12-04 and Z3 13-28) and INSTAND (Z3 13-28).

Author information

Authors and Affiliations

  1. Department of Neurology, Clinic Grosshadern of the Ludwig-Maximilians University of Munich, Marchioninistrasse 15, D-81377, Munich, Germany

    Uwe Koedel & Hans-Walter Pfister

  2. Bavarian Health and Food Safety Authority & German National Reference Centre for Borrelia, Veterinärstrasse 2, Oberschleissheim, 85764, Germany

    Volker Fingerle

Authors
  1. Uwe Koedel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Volker Fingerle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans-Walter Pfister
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

U.K. and V.F. researched data for the article, and U.K. and H.-W.P. wrote the article. All authors made substantial contributions to the discussion of content, and V.F. and H.-W.P. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Hans-Walter Pfister.

Ethics declarations

Competing interests

V.F. has acted as a consultant for the European Centre for Disease Control and for QCMD (Quality Control for Molecular Diagnostics), and he has received honoraria from DiaSorin, Mikrogen, Siemens and Virotech. The other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koedel, U., Fingerle, V. & Pfister, HW. Lyme neuroborreliosis—epidemiology, diagnosis and management. Nat Rev Neurol 11, 446–456 (2015). https://doi.org/10.1038/nrneurol.2015.121

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2015.121

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing