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Neuroborreliosis: Pathogenesis, Symptoms, Diagnosis, and Treatment

  • Authors: Tobias A. Rupprecht, MD; Volker Fingerle, MD
  • CME Released: 3/7/2011
  • Valid for credit through: 3/7/2012
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Target Audience and Goal Statement

This activity is intended for primary care clinicians, infectious disease physicians, neurologists, and other health professionals caring for patients with Lyme disease.

The goal of this activity is to describe the pathogenesis, symptoms, diagnosis, and management of neuroborreliosis, based on a review.

Upon completion of this activity, participants will be able to:

  1. Describe the epidemiology and pathogenesis of Lyme neuroborelliosis (LNB)
  2. Describe the characteristic symptoms and diagnosis of LNB
  3. Describe the treatment and management of LNB


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  • Tobias A. Rupprecht, MD

    Abteilung für Neurologie, AmperKliniken AG Dachau, Dachau, Germany


    Disclosure: Tobias A. Rupprecht, MD, disclosed the following relevant financial relationships:
    Served as a consultant for: Genzyme Corporation; Mikrogen; Virotech

  • Volker Fingerle, MD

    National Reference Centre for Borrelia, LGL Oberschleißheim, Germany


    Disclosure: Volker Fingerle, MD, has disclosed no relevant financial relationships.


  • Elisa Manzotti

    Editorial Director, Future Science Group, London, United Kingdom


    Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC


    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Neuroborreliosis: Pathogenesis, Symptoms, Diagnosis, and Treatment: Diagnosis



The definite diagnosis of LNB is essentially based on three aspects: an appropriate clinical picture, a lymphocytic pleocytosis and the detection of intrathecally produced, B. burgdorferi-specific antibodies (as expressed by a positive antibody index AI).[123,139] Nevertheless, it has to be kept in mind that the intrathecal production of antibodies can take several weeks and, therefore, the AI is positive in only 79–94% of LNB patients in the first 2–3 weeks.[122,139–141] Furthermore, in rare cases, the CSF cell count might even be in the normal range.[142] A study from Slovenia suggested that this is a common phenomenon of B. afzelii infection,[71] but this has not yet been confirmed by further studies. In such suspected cases without a CSF pleocytosis, a PCR might be of help to confirm the diagnosis, but the sensitivity of this technique for LNB is rather low (10–30%).[139] The same applies for a CSF culture of B. burgdorferi, with a sensitivity of between 10 and 30%.[143]

If the intrathecal production of antibodies has not been determined but the CSF cell count is elevated and other diagnoses are virtually excluded, the diagnosis of LNB is not definite, but probable. If no CSF analysis has been performed at all, only a possible LNB can be assumed (Figure 3). Therefore, analysis of the CSF is necessary to confirm a clinically suspected diagnosis.[144] In cases with a very typical clinical picture (e.g., Bannwarth’s syndrome with intense, lancinating pain, exacerbating during the night and a recent history of an erythema migrans), the diagnosis is sufficiently definite even without laboratory aid. However, CSF analysis allows the opportunity to perform a follow-up if, for example, a treatment failure is suspected.[144]

Figure 3.


Diagnostic Pathway for Acute Lyme Neuroborreliosis.CSF: Cerebrospinal fluid.
Reproduced with permission from 121.

A novel biomarker with a high potential is the B-cell-attracting chemokine CXCL13. It is produced upon detection of intrathecal spirochetes by monocytes,[85] dendritic cells[93] and several other cell types (as depicted previously)[94] and is a key factor for B-cell immigration into the CSF in LNB.[91] Therefore, the presence of this chemokine precedes the production of antibodies, and the sensitivity in early LNB appears to be higher than the AI.[97,98,145] In the studies published to date, CXCL13 has been found in high levels in the CSF in acute, untreated LNB.[92,98,145–147] In addition, it rapidly decreases under antibiotic therapy, therefore qualifying as an activity or therapy response marker.[92,119,146,147] There are several further studies regarding the diagnostic potency of this chemokine for LNB, which have been presented at the International Conference of Lyme Borreliosis (ICLB) 2010 in Ljubljana, Slovenia, and will presumably be published shortly.[148–151] Taking the results of these published and as yet unpublished studies together, CXCL13 shows a high sensitivity. However, it must be remembered that there are other disease entities, in which highly elevated CXCL13 levels can also be found in the CSF (e.g., neurosyphilis, cryptococcal meningitis, cerebral lymphoma, tuberculous meningitis and HIV meningitis[85,147,148,152]). Due to the low incidence of the aforementioned diseases, the positive and, in particular, the negative predictive value of CXCL13 for acute LNB still appears to be high. A recently published prospective study from Munich found a higher sensitivity of this novel biomarker compared with the AI (94.1 vs 88.8%), with an equal specificity (96.1%). As a conclusion, CXCL13 was proposed to be an additional marker in early cases with a negative AI, in patients with atypical clinical presentation to strengthen the diagnosis and finally as a therapy response marker.[147]

In 2007, two studies suggested the lymphocyte transformation test (LTT) to be a potential tool for the diagnosis of LNB in seronegative patients.[153,154] Due to their results, the LTT indicates an active borrelial infection even if the pathogens are not discovered by the humoral immune system and therefore no B. burgdorferi-specific antibodies are detectable. Testing the T-cell response is, in general, a very attractive method for the diagnosis of possibly camouflaged infectious diseases. However, both studies lack an adequate control group and reliable case definitions and, therefore, the specificity of the findings remains unclear. The LTT might only reflect a general activation of the immune system, and testing other inflammatory and infectious neurological diseases would be important to confirm these findings. In conclusion, the LTT can not be recommended as a diagnostic tool for the diagnosis of LNB.[139]

Stricker and Winger advocated the CD57+ lymphocytes count to be an important marker to diagnose chronic Lyme disease.[155] They found a decreased number of CD57+ cells in patients with chronic Lyme disease, which increased during a month-long antibiotic therapeutic regimen. In this study, no adequate control group was examined, the clinical picture of the patients was not described and their form of chronic Lyme disease is not well defined, thus their results could not be confirmed by other study groups. A recent study even found no alterations of the CD57+ cell count in patients with persisting symptoms after Lyme disease.[156] Taken together, due to the lack of reliable studies, the CD57+ cell count is not recommendable for the diagnosis of chronic Lyme disease.[139]