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^• These guidelines are very helpful in the diagnostic approach to a patient with suspected Lyme neuroborreliosis.
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Ljostad U, Skarpaas T, Mygland A: Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur. J. Neurol. 14, 873—876 (2007).
Blanc F, Jaulhac B, Fleury M et al.: Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology 69, 953—958 (2007).
Zore A, Ruzic-Sabljic E, Maraspin V et al.: Sensitivity of culture and polymerase chain reaction for the etiologic diagnosis of erythema migrans. Wien. Klin. Wochenschr. 114, 606—609 (2002).
Rupprecht TA, Pfister HW: What are the indications for lumbar puncture in patients with Lyme disease? Curr. Probl. Dermatol. 37, 200—206 (2009).
Tjernberg I, Henningsson AJ, 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(2), 149—158 (2011).
Senel M, Rupprecht TA, Tumani H, Pfister HW, Ludolph AC, Brettschneider J: The chemokine CXCL13 in acute neuroborreliosis. J. Neurol. Neurosurg. Psychiatry 81, 929—933 (2010).
Schmidt C, Plate A, Angele B et al.: ProCL—a prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology (2011) (In press).
van Burgel ND, Kroes ACM, van Dam A: CXCL13 in CSF as a biomarker for diagnosing Lyme neuroborreliosis. Presented at: International Conference on Lyme Borreliosis (ICLB) 2010. Ljubljana, Slovenia, 26—29 September 2010.
Wutte N, Berghold A, Löffler S et al.: The chemokine CXCL13 in Lyme borreliosis. Presented at: International Conference on Lyme Borreliosis (ICLB) 2010. Ljubljana, Slovenia, 26—29 September 2010.
Nordberg M, Forsberg P, Johansson A et al.: Cytokines IL-10, IL-17 and CXCL13 in CSF during neuroborreliosis. Presented at: International Conference on Lyme Borreliosis (ICLB) 2010. Ljubljana, Slovenia, 26—29 September 2010.
Owlasiuk P, Zajkowska J, Pancewicz S et al.: Concentrations of five CXC chemokines and fractalkine in serum and cerebrospinal fluid of patients with Lyme neuroborreliosis. Presented at: International Conference on Lyme Borreliosis (ICLB) 2010. Ljubljana, Slovenia, 26—29 September 2010.
Fischer L, Korfel A, Pfeiffer S et al.: CXCL13 and CXCL12 in central nervous system lymphoma patients. Clin. Cancer Res. 15, 5968—5973 (2009).
von Baehr V, Liebenthal C, Gaida B, Schmidt F-P, von Baehr R, Volk H-D: Evaluation of the diagnostic significance of the lymphocyte proliferation test in patients with Lyme borreliosis. J. Lab. Med. 149—158 (2007).
Valentine-Thon E, Ilsemann K, Sandkamp M: A novel lymphocyte transformation test (LTT-MELISA) for Lyme borreliosis. Diagn. Microbiol. Infect. Dis. 57, 27—34 (2007).
Stricker RB, Winger EE: Decreased CD57 lymphocyte subset in patients with chronic Lyme disease. Immunol. Lett. 76, 43—48 (2001).
Marques A, Brown MR, Fleisher TA: Natural killer cell counts are not different between patients with post-Lyme disease syndrome and controls. Clin. Vaccine Immunol. 16, 1249—1250 (2009).
Ljostad U, Skogvoll E, Eikeland R 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).
•• Demonstrates the equal efficacy of oral doxycycline and intravenous ceftriaxone and therefore advocates treatment via the oral route for patients with Lyme neuroborreliosis.
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 69, 91—102 (2007).
Oksi J, Nikoskelainen J, Hiekkanen H 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).
Pfister HW, Preac-Mursic V, Wilske B, Einhaupl KM: Cefotaxime vs penicillin G for acute neurologic manifestations in Lyme borreliosis. A prospective randomized study. Arch. Neurol. 46, 1190—1194 (1989).
Horstrup P, Ackermann R: Tick-borne meningopolyneuritis (Garin-Bujadoux, Bannwarth). Fortschr. Neurol. Psychiatr. Grenzgeb. 41, 583—606 (1973).
Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP: Lyme disease — a tick-borne spirochetosis? Science 216, 1317—1319 (1982).
•• First description of Borrelia burgdorferi and therefore probably the most important publication on this topic.

Papers of special note have been highlighted as:
• of interest
•• of considerable interest

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Author(s)

Tobias A. Rupprecht, MD

Abteilung für Neurologie, AmperKliniken AG Dachau, Dachau, Germany

Disclosures

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

Disclosures

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

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom

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Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

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

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

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

Sarah Fleischman

CME Program Manager, Medscape, LLC

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Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

CME

Neuroborreliosis: Pathogenesis, Symptoms, Diagnosis, and Treatment

Authors: Tobias A. Rupprecht, MD; Volker Fingerle, MD
CME Released: 3/7/2011
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 3/7/2012

Start Activity

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:

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

Disclosures

Author(s)

Tobias A. Rupprecht, MD

Abteilung für Neurologie, AmperKliniken AG Dachau, Dachau, Germany

Disclosures

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

Disclosures

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

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom

Disclosures

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosures

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

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosures

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

Sarah Fleischman

CME Program Manager, Medscape, LLC

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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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.

Enlarge

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]

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Treatment

CME Information

References

CME

Neuroborreliosis: Pathogenesis, Symptoms, Diagnosis, and Treatment

Target Audience and Goal Statement

Disclosures

Author(s)

Tobias A. Rupprecht, MD

Volker Fingerle, MD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman