CNS Infections pp 211-226 | Cite as

The Human Borreliosis: Lyme Neuroborreliosis and Relapsing Fever

  • John J. Halperin
  • Juan Carlos García-MoncóEmail author


Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, infects the nervous system in up to 15 % of patients. Involvement can include the peripheral nervous system, with a mononeuropathy multiplex manifest as a radiculopathy, cranial neuropathy, plexopathy, or confluent mononeuropathy multiplex. In most instances, central nervous system involvement is limited to meningitis; rarely the spinal cord or brain parenchyma can be involved. Recent work has shed light on the pathophysiologic sequence that results in neuroborreliosis, including early CNS invasion, CXCL13-stimulated B cell entry into and proliferation within the CNS, and then a prominent immune response that requires ongoing presence of organisms. Pathophysiology of peripheral nerve involvement is not well established although it similarly requires the presence of viable organisms. Future work should focus on the mechanisms of tissue injury. Regardless of the presentation, infection is highly responsive to antimicrobial therapy.

Relapsing fever is another human borreliosis caused by a variety of Borrelia species and transmitted by lice (epidemic form) or ticks (endemic form). Both are characterized by recurrent spirochetemia and can cause neurological complications similar to Lyme neuroborreliosis. Diagnosis is made by the direct observation of the spirochetes in peripheral blood during febrile episodes and by PCR. Tetracycline therapy is used.


Lyme disease Neuroborreliosis Diagnosis Treatment Pathophysiology Garin-Bujadoux-Bannwarth syndrome Erythema migrans Relapsing fever Louse-borne relapsing fever Tick-borne relapsing fever Borrelia recurrentis 


  1. 1.
    Steere AC, Malawista SE, Hardin JA, Ruddy S, Askenase W, Andiman WA. Erythema chronicum migrans and Lyme arthritis. The enlarging clinical spectrum. Ann Intern Med. 1977;86:685–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Reik L, Steere AC, Bartenhagen NH, Shope RE, Malawista SE. Neurologic abnormalities of Lyme disease. Medicine. 1979;58:281–94.PubMedCrossRefGoogle Scholar
  3. 3.
    Benach JL, Bosler EM, Hanrahan JP, et al. Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med. 1983;308:740–2.PubMedCrossRefGoogle Scholar
  4. 4.
    Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Lyme disease-a tick-borne spirochetosis? Science. 1982;216:1317–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Steere AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med. 1983;308:733–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Scrimenti RJ. Erythema chronicum migrans. Arch Dermatol. 1970;102:104–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Hollstrom E. Successful treatment of erythema migrans Afzelius. Acta Derm Venereol. 1951;31:235–43.PubMedGoogle Scholar
  8. 8.
    Azfellius A. Erythema chronicum migrans. Arch Dermatol Venereol (Stockh). 1921;2:120–5.Google Scholar
  9. 9.
    Garin C, Bujadoux A. Paralysie par les tiques. J Med Lyon. 1922;71:765–7.Google Scholar
  10. 10.
    Asbrink E, Hovmark A, Hederstedt B. The spirochetal etiology of acrodermatitis chronica atrophicans Herxheimer. Acta Derm Venereol. 1984;64:506–12.PubMedGoogle Scholar
  11. 11.
    Nowakowski J, Schwartz I, Liveris D, et al. Laboratory diagnostic techniques for patients with early Lyme disease associated with erythema migrans: a comparison of different techniques. Clin Infect Dis. 2001;33:2023–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Anonymous. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR. 1995;44:590–1.Google Scholar
  14. 14.
    Wormser GP, Schriefer M, Aguero-Rosenfeld ME, et al. Single-tier testing with the C6 peptide ELISA kit compared with two-tier testing for Lyme disease. Diagn Microbiol Infect Dis. 2013;75:9–15.PubMedCrossRefGoogle Scholar
  15. 15.
    Branda JA, Strle F, Strle K, Sikand N, Ferraro MJ, Steere AC. Performance of United States serologic assays in the diagnosis of lyme borreliosis acquired in Europe. Clin Infect Dis. 2013;57:333–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Halperin JJ, Luft BJ, Anand AK, et al. Lyme neuroborreliosis: central nervous system manifestations. Neurology. 1989;39:753–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Hansen K, Cruz M, Link H. Oligoclonal Borrelia burgdorferi-specific IgG antibodies in cerebrospinal fluid in Lyme neuroborreliosis. J Infect Dis. 1990;161:1194–202.PubMedCrossRefGoogle Scholar
  18. 18.
    Stiernstedt GT, Granstrom M, Hederstedt B, Skoldenberg B. Diagnosis of spirochetal meningitis by enzyme-linked immunosorbent assay and indirect immunofluorescence assay in serum and cerebrospinal fluid. J Clin Microbiol. 1985;21:819–25.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Hammers-Berggren S, Hansen K, Lebech AM, Karlsson M. Borrelia burgdorferi-specific intrathecal antibody production in neuroborreliosis: a follow-up study. Neurology. 1993;43:169–75.PubMedCrossRefGoogle Scholar
  20. 20.
    Halperin JJ, Volkman DJ, Wu P. Central nervous system abnormalities in Lyme neuroborreliosis. Neurology. 1991;41:1571–82.PubMedCrossRefGoogle Scholar
  21. 21.
    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;161:1203–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Gerber MA, Shapiro ED, Burke GS, Parcells VJ, Bell GL. Lyme disease in children in southeastern Connecticut. Pediatric Lyme Disease Study Group. N Engl J Med. 1996;335:1270–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Bannwarth A. Chronische lymphocytare meningitis, entzundliche polyneuritis und “rheumatismus”. Arch Psychiatr Nervenkr. 1941;113:284–376.CrossRefGoogle Scholar
  24. 24.
    Bacon RM, Kugeler KJ, Mead PS, Centers for Disease Control, and Prevention. Surveillance for Lyme diseas--nited States, 1992–2006. MMWR Surveill Summ. 2008;57:1–9.Google Scholar
  25. 25.
    Garcia-Monco JC, Benach JL. Lyme neuroborreliosis. Ann Neurol. 1995;37:691–702.PubMedCrossRefGoogle Scholar
  26. 26.
    Cohn KA, Thompson AD, Shah SS, et al. Validation of a clinical prediction rule to distinguish Lyme meningitis from aseptic meningitis. Pediatrics. 2012;129:e46–53.PubMedCrossRefGoogle Scholar
  27. 27.
    Garro AC, Rutman M, Simonsen K, Jaeger JL, Chapin K, Lockhart G. Prospective validation of a clinical prediction model for Lyme meningitis in children. Pediatrics. 2009;123:e829–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Tuerlinckx D, Bodart E, Jamart J, Glupczynski Y. Prediction of Lyme meningitis based on a logistic regression model using clinical and cerebrospinal fluid analysis: a European study. Pediatr Infect Dis J. 2009;28:394–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Halperin JJ, Golightly M. Lyme borreliosis in Bell’s palsy. Long Island Neuroborreliosis Collaborative Study Group. Neurology. 1992;42:1268–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Bremell D, Hagberg L. Clinical characteristics and cerebrospinal fluid parameters in patients with peripheral facial palsy caused by Lyme neuroborreliosis compared with facial palsy of unknown origin (Bell’s palsy). BMC Infect Dis. 2011;11:215.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Sibony P, Halperin J, Coyle PK, Patel K. Reactive Lyme serology in optic neuritis. J Neuroophthalmol. 2005;25:71–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Halperin J, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme neuroborreliosis. Peripheral nervous system manifestations. Brain. 1990;113(Pt 4):1207–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Logigian EL, Steere AC. Clinical and electrophysiologic findings in chronic neuropathy of Lyme disease. Neurology. 1992;42:303–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Camponovo F, Meier C. Neuropathy of vasculitic origin in a case of Garin-Bujadoux-Bannwarth syndrome with positive borrelia antibody response. J Neurol. 1986;233:69–72.PubMedCrossRefGoogle Scholar
  35. 35.
    Elamin M, Alderazi Y, Mullins G, Farrell MA, O’Connell S, Counihan TJ. Perineuritis in acute lyme neuroborreliosis. Muscle Nerve. 2009;39:851–4.PubMedCrossRefGoogle Scholar
  36. 36.
    England JD, Bohm Jr RP, Roberts ED, Philipp MT. Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease. Ann Neurol. 1997;41:375–84.PubMedCrossRefGoogle Scholar
  37. 37.
    Halperin JJ, Little BW, Coyle PK, Dattwyler RJ. Lyme disease: cause of a treatable peripheral neuropathy. Neurology. 1987;37:1700–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Vallat JM, Hugon J, Lubeau M, Leboutet MJ, Dumas M, Desproges-Gotteron R. Tick-bite meningoradiculoneuritis: clinical, electrophysiologic, and histologic findings in 10 cases. Neurology. 1987;37:749–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Ackermann R, Rehse-Kupper B, Gollmer E, Schmidt R. Chronic neurologic manifestations of erythema migrans borreliosis. Ann N Y Acad Sci. 1988;539:16–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Kalina P, Decker A, Kornel E, Halperin JJ. Lyme disease of the brainstem. Neuroradiology. 2005;47:903–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Halperin JJ, Krupp LB, Golightly MG, Volkman DJ. Lyme borreliosis-associated encephalopathy. Neurology. 1990;40:1340–3.PubMedCrossRefGoogle Scholar
  42. 42.
    Krupp LB, Masur D, Schwartz J, et al. Cognitive functioning in late Lyme borreliosis. Arch Neurol. 1991;48:1125–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323:1438–44.PubMedCrossRefGoogle Scholar
  44. 44.
    Eikeland R, Mygland A, Herlofson K, Ljostad U. Risk factors for a non-favorable outcome after treated European neuroborreliosis. Acta Neurol Scand. 2013;127:154–60.PubMedCrossRefGoogle Scholar
  45. 45.
    Ljostad U, Mygland A. Remaining complaints 1 year after treatment for acute Lyme neuroborreliosis; frequency, pattern and risk factors. Eur J Neurol. 2010;17:118–23.PubMedCrossRefGoogle Scholar
  46. 46.
    Skogman BH, Glimaker K, Nordwall M, Vrethem M, Odkvist L, Forsberg P. Long-term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics. 2012;130:262–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED. Long-term outcomes of persons with Lyme disease. JAMA. 2000;283:609–16.PubMedCrossRefGoogle Scholar
  48. 48.
    Shadick NA, Phillips CB, Sangha O, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999;131:919–26.PubMedCrossRefGoogle Scholar
  49. 49.
    Cerar D, Cerar T, Ruzic-Sabljic E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med. 2010;123:79–86.PubMedCrossRefGoogle Scholar
  50. 50.
    Luo N, Johnson JA, Shaw JW, Feeny D, Coons SJ. Self-reported health status of the general adult U.S. population as assessed by the EQ-5D and Health Utilities Index. Med care. 2005;43:1078–86.PubMedCrossRefGoogle Scholar
  51. 51.
    Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology. 1992;42:32–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Luft BJ, Steinman CR, Neimark HC, et al. Invasion of the central nervous system by Borrelia burgdorferi in acute disseminated infection. JAMA. 1992;267:1364–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Garcia-Monco JC, Villar BF, Alen JC, Benach JL. Borrelia burgdorferi in the central nervous system: experimental and clinical evidence for early invasion. J Infect Dis. 1990;161:1187–93.PubMedCrossRefGoogle Scholar
  54. 54.
    Grab DJ, Perides G, Dumler JS, et al. Borrelia burgdorferi, host-derived proteases, and the blood–brain barrier. Infect Immun. 2005;73:1014–22.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Grab DJ, Nyarko E, Nikolskaia OV, Kim YV, Dumler JS. Human brain microvascular endothelial cell traversal by Borrelia burgdorferi requires calcium signaling. Clin Microbiol Infect. 2009;15:422–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Rupprecht TA, Plate A, Adam M, et al. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J Neuroinflammation. 2009;6:42.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Lebech AM, Hansen K, Brandrup F, Clemmensen O, Halkier-Sorensen L. Diagnostic value of PCR for detection of Borrelia burgdorferi DNA in clinical specimens from patients with erythema migrans and Lyme neuroborreliosis. Mol Diagn. 2000;5:139–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Sigal LH. Molecular mimicry and Lyme borreliosis. Ann Neurol. 1990;28:195–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Sigal LH, Tatum AH. Lyme disease patients’ serum contains IgM antibodies to Borrelia burgdorferi that cross-react with neuronal antigens. Neurology. 1988;38:1439–42.PubMedCrossRefGoogle Scholar
  60. 60.
    Pachner AR, Zhang WF, Schaefer H, Schaefer S, O’Neill T. Detection of active infection in nonhuman primates with Lyme neuroborreliosis: comparison of PCR, culture, and a bioassay. J Clin Microbiol. 1998;36:3243–7.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Ramesh G, Borda JT, Gill A, et al. Possible role of glial cells in the onset and progression of Lyme neuroborreliosis. J Neuroinflammation. 2009;6:23.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Ramesh G, Benge S, Pahar B, Philipp MT. A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflammation. 2012;9:72.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007;69:91–102.PubMedCrossRefGoogle Scholar
  64. 64.
    Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008;70:992–1003.PubMedCrossRefGoogle Scholar
  65. 65.
    Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345:85–92.PubMedCrossRefGoogle Scholar
  66. 66.
    Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60:1923–30.PubMedCrossRefGoogle Scholar
  67. 67.
    Barbour AG. Antigenic variation of a relapsing fever Borrelia species. Annu Rev Microbiol. 1990;44:155–71.PubMedCrossRefGoogle Scholar
  68. 68.
    Cadavid D, Barbour AG. Neuroborreliosis during relapsing fever: review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis. 1998;26:151–64.PubMedCrossRefGoogle Scholar
  69. 69.
    Bergeret C, Raoult A. Notes sur les formes nerveuses de la fievre recurrente & tiques en Afrique Occidentale Franchise. Bulletin Medicale de l’Afrique Occidentale Francaise 1948;5:271–9.Google Scholar
  70. 70.
    Salih SY, Mustafa D, Abdel Wahab SM, Ahmed MA, Omer A. Louse-borne relapsing fever: I. A clinical and laboratory study of 363 cases in the Sudan. Trans R Soc Trop Med Hyg. 1977;71:43–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Hamilton J. Ocular complications in relapsing fever. Br J Ophthalmol. 1943;27:68–80.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Southern P, Sanford JP. Relapsing fever: a clinical and microbiological review. Medicine. 1969;48:129–50.CrossRefGoogle Scholar
  73. 73.
    Brahim H, Perrier-Gros-Claude JD, Postic D, Baranton G, Jambou R. Identifying relapsing fever Borrelia, Senegal. Emerg Infect Dis. 2005;11:474–5.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Garcia-Monco JC, Miller NS, Backenson PB, Anda P, Benach JL. A mouse model of Borrelia meningitis after intradermal injection. J Infect Dis. 1997;175:1243–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Cadavid D, Sondey M, Garcia E, Lawson CL. Residual brain infection in relapsing-fever borreliosis. J Infect Dis. 2006;193:1451–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Gugliotta JL, Goethert HK, Berardi VP, Telford 3rd SR. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 2013;368:240–5.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Arteaga F, Golightly MG, Garcia Perez A, Barral M, Anda P, Garcia-Monco JC. Disparity between serological reactivity to Borrelia burgdorferi and evidence of past disease in a high-risk group. Clin Infect Dis. 1998;27:1210–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • John J. Halperin
    • 1
  • Juan Carlos García-Moncó
    • 2
    Email author
  1. 1.Department of NeurosciencesOverlook Medical CenterSummitUSA
  2. 2.Department of NeurologyHospital de Galdakao-UsansoloGaldakao, VizcayaSpain

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