Journal of Neurology

, Volume 263, Issue 1, pp 17–24 | Cite as

Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review

  • R. DerschEmail author
  • H. Sommer
  • S. Rauer
  • J. J. Meerpohl
Original Communication


Controversy exists about residual symptoms after pharmacological treatment of Lyme neuroborreliosis. Reports of disabling long-term sequels lead to concerns in patients and health care providers. We systematically reviewed the available evidence from studies reporting treatment of Lyme neuroborreliosis to assess the prevalence and spectrum of residual symptoms after treatment. A literature search was performed in three databases and three clinical trial registers to find eligible studies reporting on residual symptoms in patients after pharmacological treatment of LNB. Diagnosis must have been performed according to consensus-derived case definitions. No restrictions regarding study design or language were set. Symptom prevalence was pooled using a random-effects model. Forty-four eligible clinical trials and studies were found: 8 RCTs, 17 cohort studies, 2 case–control studies, and 17 case series. The follow-up period in the eligible studies ranged from 7 days to 20 years. The weighted mean proportion of residual symptoms was 28 % (95 % CI 23–34 %, n = 34 studies) for the latest reported time point. Prevalence of residual symptoms was statistically significantly higher in studies using the “possible” case definition (p = 0.0048). Cranial neuropathy, pain, paresis, cognitive disturbances, headache, and fatigue were statistically significantly lower in studies using the “probable/definite” case definition. LNB patients may experience residual symptoms after treatment with a prevalence of approximately 28 %. The prevalence and spectrum of residual symptoms differ according to the applied case definition. Symptoms like fatigue are not reported in studies using the “probable/definite” case definition. As the “possible” case definition is more unspecific, patients with other conditions may be included. Reports of debilitating fatigue and cognitive impairment after LNB, a “post-Lyme syndrome”, could therefore be an artifact of unspecific case definitions in single studies.


Lyme disease Lyme neuroborreliosis Systematic review Prevalence review Residual symptoms Fatigue 


Compliance with ethical standards

Ethical standards

The manuscript does not contain a primary clinical study or patient data.

Conflicts of interest

SR reports receiving consulting and lecture fees, grant and research support from Bayer Vital GmbH, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Baxter, RG, and Teva. Furthermore, SR indicates that he is a founding executive board member of ravo Diagnostika GmbH. All other authors (RD, HS and JJM) declare that they have no competing interests.

Supplementary material

415_2015_7923_MOESM1_ESM.docx (21 kb)
Supplementary material 1 Appendix 1: References to included studies (DOCX 21 kb)
415_2015_7923_MOESM2_ESM.pdf (9 kb)
Supplementary material Appendix 2: Characteristics of included studies2 (PDF 8 kb)
415_2015_7923_MOESM3_ESM.docx (18 kb)
Supplementary material 3 Appendix 3: Funnel plot of prevalence of residual symptoms in included studies. Prevalence is plotted against the reciprocal value of the sample size (larger studies are higher on the y-axis). (DOCX 18 kb)


  1. 1.
    Huppertz HI, Bohme M, Standaert SM, Karch H, Plotkin SA (1999) Incidence of Lyme borreliosis in the Wurzburg region of Germany. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol 18:697–703CrossRefGoogle Scholar
  2. 2.
    Halperin JJ (2012) Lyme disease: a multisystem infection that affects the nervous system. Continuum 18:1338–1350PubMedGoogle Scholar
  3. 3.
    Nadelman RB, Wormser GP (1998) Lyme borreliosis. Lancet 352:557–565CrossRefPubMedGoogle Scholar
  4. 4.
    Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I, European Federation of Neurological S (2010) EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol Off J Eur Fed Neurol Soc 17(8–16):e11–e14Google Scholar
  5. 5.
    Halperin JJ, Logigian EL, Finkel MF, Pearl RA (1996) Practice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease). Quality Standards Subcommittee of the American Academy of Neurology. Neurology 46:619–627CrossRefGoogle Scholar
  6. 6.
    Kaiser R (1998) Neuroborreliosis. J Neurol 245:247–255CrossRefPubMedGoogle Scholar
  7. 7.
    Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G et al (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. Clin Infect Dis Off Publ Infect Dis Soc Am 43:1089–1134CrossRefGoogle Scholar
  8. 8.
    Eikeland R, Mygland A, Herlofson K, Ljostad U (2013) Risk factors for a non-favorable outcome after treated European neuroborreliosis. Acta Neurol Scand 127:154–160CrossRefPubMedGoogle Scholar
  9. 9.
    Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A (1994) Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 21:454–461PubMedGoogle Scholar
  10. 10.
    Cameron D, Gaito A, Harris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R et al (2004) Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther 2:S1–13CrossRefPubMedGoogle Scholar
  11. 11.
    Edelsberg JS, Lord C, Oster G (2011) Systematic review and meta-analysis of efficacy, safety, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia. Ann Pharmacother 45:1483–1490CrossRefPubMedGoogle Scholar
  12. 12.
    Sili U, Kaya A, Mert A, Group HSVES (2014) Herpes simplex virus encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. J Clin Virol Off Publ Pan Am Soc Clin Virol 60:112–118CrossRefGoogle Scholar
  13. 13.
    Fowler A, Forsman L, Eriksson M, Wickstrom R (2013) Tick-borne encephalitis carries a high risk of incomplete recovery in children. J Pediatr 163:555–560CrossRefPubMedGoogle Scholar
  14. 14.
    Cerar D, Cerar T, Ruzic-Sabljic E, Wormser GP, Strle F (2010) Subjective symptoms after treatment of early Lyme disease. Am J Med 123:79–86CrossRefPubMedGoogle Scholar
  15. 15.
    Baker PJ (2008) Perspectives on “chronic Lyme disease”. Am J Med 121:562–564CrossRefPubMedGoogle Scholar
  16. 16.
    Dersch R, Freitag MH, Schmidt S, Sommer H, Rucker G, Rauer S, Meerpohl JJ (2014) Efficacy and safety of pharmacological treatments for neuroborreliosis—protocol for a systematic review. Syst Rev 3:117PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Stanek G, Fingerle V, Hunfeld KP, Jaulhac B, Kaiser R, Krause A, Kristoferitsch W, O’Connell S, Ornstein K, Strle F, Gray J (2011) Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 17:69–79Google Scholar
  18. 18.
    Yates F (1934) Contingency table involving small numbers and the χ 2 test. J R Stat Soc 1:217–235Google Scholar
  19. 19.
    Dunn OJ (1961) Multiple comparisons among Means. J Am Stat Assoc 56:52–64CrossRefGoogle Scholar
  20. 20.
    The R Project for Statistical Computing. (
  21. 21.
    GraphPad Prism. (
  22. 22.
    Kalish RA, Kaplan RF, Taylor E, Jones-Woodward L, Workman K, Steere AC (2001) Evaluation of study patients with Lyme disease, 10–20-year follow-up. J Infect Dis 183:453–460CrossRefPubMedGoogle Scholar
  23. 23.
    Eikeland R, Mygland A, Herlofson K, Ljostad U (2011) European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol Scand 124:349–354CrossRefPubMedGoogle Scholar
  24. 24.
    Benke T, Gasse T, Hittmair-Delazer M, Schmutzhard E (1995) Lyme encephalopathy: long-term neuropsychological deficits years after acute neuroborreliosis. Acta Neurol Scand 91:353–357CrossRefPubMedGoogle Scholar
  25. 25.
    Stanek G, Wormser GP, Gray J, Strle F (2012) Lyme borreliosis. Lancet 379:461–473CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • R. Dersch
    • 1
    • 2
    Email author
  • H. Sommer
    • 3
  • S. Rauer
    • 1
  • J. J. Meerpohl
    • 2
  1. 1.Department of NeurologyMedical Center-University of FreiburgFreiburgGermany
  2. 2.German Cochrane CentreMedical Center-University of FreiburgFreiburgGermany
  3. 3.Institute of Medical Biometry and StatisticsMedical Center-University of FreiburgFreiburgGermany

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