Baranton G, de Martino SJ: Borrelia burgdorferi sensu lato diversity and its influence on pathogenicity in humans. Curr. Probl. Dermatol. 37, 1—17 (2009).
Margos G, Vollmer SA, Cornet M et al.: A new Borrelia species defined by multilocus sequence analysis of housekeeping genes. Appl. Environ. Microbiol. 75, 5410—5416 (2009).
Fingerle V, Schulte-Spechtel UC, Ruzic-Sabljic E 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).
Diza E, Papa A, Vezyri E, Tsounis S, Milonas I, Antoniadis A: Borrelia valaisiana in cerebrospinal fluid. Emerg. Infect. Dis. 10, 1692—1693 (2004).
Picken RN, Cheng Y, Strle F et al.: Molecular characterization of Borrelia burgdorferi sensu lato from Slovenia revealing significant differences between tick and human isolates. Eur. J. Clin. Microbiol. Infect. Dis. 15, 313—323 (1996).
Collares-Pereira M, Couceiro S, Franca I et al.: First isolation of Borrelia lusitaniae from a human patient. J. Clin. Microbiol. 42, 1316—1318 (2004).
Hubalek Z: Epidemiology of Lyme borreliosis. Curr. Probl. Dermatol. 37, 31—50 (2009) .
Adlhoch C, Poggensee G: Lyme-Borreliose: Analyse der gemeldeten Erkrankungsfalle der Jahre 2007 bis 2009 aus den sechs ostlichen Bundeslandern. Epidem. Bull. 101—107 (2010) .
Huppertz HI, Bohme M, Standaert SM, Karch H, Plotkin SA: Incidence of Lyme borreliosis in the Wurzburg region of Germany. Eur. J. Clin. Microbiol. Infect. Dis. 18, 697—703 (1999).
• Well-designed, prospective, population-based study that covers the true regional incidence of the different manifestations of Lyme disease.
Rauter C, Hartung T: Prevalence of Borrelia burgdorferi sensu lato genospecies in Ixodes ricinus ticks in Europe: a metaanalysis. Appl. Environ. Microbiol. 71, 7203—7216 (2005).
Piesman J, Mather TN, Sinsky RJ, Spielman A: Duration of tick attachment and Borrelia burgdorferi transmission. J. Clin. Microbiol. 25, 557—558 (1987).
Piesman J, Dolan MC: Protection against Lyme disease spirochete transmission provided by prompt removal of nymphal Ixodes scapularis (Acari: Ixodidae). J. Med. Entomol. 39, 509—512 (2002).
Kahl O, Janetzki-Mittmann C, Gray JS, Jonas R, Stein J, de Boer R: Risk of infection with Borrelia burgdorferi sensu lato for a host in relation to the duration of nymphal Ixodes ricinus feeding and the method of tick removal. Zentralbl. Bakteriol. 287, 41—52 (1998).
Gern L: Life cycle of Borrelia burgdorferi sensu lato and transmission to humans. Curr. Probl. Dermatol. 37, 18—30 (2009).
Ruzic-Sabljic E, Strle F, Cimperman J, Maraspin V, Lotric-Furlan S, Pleterski-Rigler D: Characterisation of Borrelia burgdorferi sensu lato strains isolated from patients with skin manifestations of Lyme borreliosis residing in Slovenia. J. Med. Microbiol. 49, 47—53 (2000).
Maiwald M, Oehme R, March O et al.: Transmission risk of Borrelia burgdorferi sensu lato from Ixodes ricinus ticks to humans in southwest Germany. Epidemiol. Infect. 121, 103—108 (1998).
Berglund J, Eitrem R, Ornstein K et al.: An epidemiologic study of Lyme disease in southern Sweden. V. Engl. J. Med. 333, 1319—1327 (1995).
Pal U, de Silva AM, Montgomery RR et al.: Attachment of Borrelia burgdorferi within Ixodes scapularis mediated by outer surface protein A. J. Clin. Invest. 106, 561—569 (2000).
Pal U, Li X, Wang T et al.: TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi. Cell 119, 457—468 (2004).
Morrison TB, Weis JH, Weis JJ: Borrelia burgdorferi outer surface protein A (OspA) activates and primes human neutrophils. J. Immunol. 158, 4838—4845 (1997).
Häupl T, Landgraf S, Netusil P et al.: Activation of monocytes by three OspA vaccine candidates: lipoprotein OspA is a potent stimulator of monokines. FEMSImmunol. Med. Microbiol. 19, 15—23 (1997).
Wilske B, Pfister HW: Lyme borreliosis research. Curr. Opin. Infect. Dis. 8, 137—144 (1995).
Schwan TG, Piesman J: Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice. J. Clin. Microbiol. 38, 382—388 (2000).
Pal U, Yang X, Chen M et al.: OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands. J. Clin. Invest. 113, 220—230 (2004).
Fingerle V, Goettner G, Gern L, Wilske B, Schulte-Spechtel U: Complementation of a Borrelia afzelii OspC mutant highlights the crucial role of OspC for dissemination of Borrelia afzelii in Ixodes ricinus. Int. J. Med. Microbiol. 297, 97—107 (2007).
Anguita J, Ramamoorthi N, Hovius JW et al.: Salp15, an Ixodes scapularis salivary protein, inhibits CD4+ T cell activation. Immunity 16, 849—859 (2002).
Ramamoorthi N, Narasimhan S, Pal U et al.: The Lyme disease agent exploits a tick protein to infect the mammalian host. Vature 436, 573—577 (2005).
Schuijt TJ, Hovius JW, van Burgel ND, Ramamoorthi N, Fikrig E, van Dam AP: The tick salivary protein Salp15 inhibits the killing of serum-sensitive Borrelia burgdorferi sensu lato isolates. Infect. Immun. 76, 2888—2894 (2008).
Tilly K, Bestor A, Jewett MW, Rosa P: Rapid clearance of Lyme disease spirochetes lacking OspC from skin. Infect. Immun. 75, 1517—1519 (2007).
Zhang JR, Hardham JM, Barbour AG, Norris SJ: Antigenic variation in Lyme disease Borreliae by promiscuous recombination of VMP-like sequence cassettes. Cell 89, 275—285 (1997).
Valenzuela JG, Charlab R, Mather TN, Ribeiro JM: Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis. J. Biol. Chem. 275, 18717—18723 (2000).
Daix V, Schroeder H, Praet N et al.: Ixodes ticks belonging to the Ixodes ricinus complex encode a family of anticomplement proteins. Insect Mol. Biol. 16, 155—166 (2007).
Tyson K, Elkins C, Patterson H, Fikrig E, de Silva A: Biochemical and functional characterization of Salp20, an Ixodes scapularis tick salivary protein that inhibits the complement pathway. Insect Mol. Biol. 16, 469—479 (2007).
Alitalo A, Meri T, Lankinen H et al.: Complement inhibitor factor H binding to Lyme disease spirochetes is mediated by inducible expression of multiple plasmid-encoded outer surface protein E paralogs. J. Immunol. 169, 3847—3853 (2002).
Kraiczy P, Skerka C, Kirschfink M, Zipfel PF, Brade V: Immune evasion of Borrelia burgdorferi: insufficient killing of the pathogens by complement and antibody. Int. J. Med. Microbiol. 291(Suppl. 33), 141—146 (2002).
Pausa M, Pellis V, Cinco M et al.: Serum-resistant strains of Borrelia burgdorferi evade complement-mediated killing by expressing a CD59-like complement inhibitory molecule. J. Immunol. 170, 3214—3222 (2003).
Singh SK, Girschick HJ: Molecular survival strategies of the Lyme disease spirochete Borrelia burgdorferi. Lancet Infect. Dis. 4, 575—583 (2004).
Bhide MR, Travnicek M, Levkutova M, Curlik J, Revajova V, Levkut M: Sensitivity of Borrelia genospecies to serum complement from different animals and human: a host-pathogen relationship. FEMS Immunol. Med. Microbiol. 43, 165—172 (2005).
Giambartolomei GH, Dennis VA, Philipp MT: Borrelia burgdorferi stimulates the production of interleukin-10 in peripheral blood mononuclear cells from uninfected humans and rhesus monkeys. Infect. Immun. 66, 2691—2697 (1998).
Lazarus JJ, Meadows MJ, Lintner RE, Wooten RM: IL-10 deficiency promotes increased Borrelia burgdorferi clearance predominantly through enhanced innate immune responses. J. Immunol. 177, 7076—7085 (2006).
Coyle PK, Schutzer SE, Belman AL, Krupp LB, Golightly MG: Cerebrospinal fluid immune complexes in patients exposed to Borrelia burgdorferi: detection of Borrelia-specific and -nonspecific complexes. Ann. Veurol. 28, 739—744 (1990).
Schutzer SE, Coyle PK, Reid P, Holland B: Borrelia burgdorferi-specific immune complexes in acute Lyme disease. JAMA 282, 1942—1946 (1999).
Embers ME, Ramamoorthy R, Philipp MT: Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease. Microbes Infect. 6, 312—318 (2004).
Liang FT, Brown EL, Wang T, Iozzo RV, Fikrig E: Protective niche for Borrelia burgdorferi to evade humoral immunity. Am. J. Pathol. 165, 977—985 (2004).
Cabello FC, Godfrey HP, Newman SA: Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix. Trends Microbiol. 15, 350—354. (2007).
Fuchs H, Wallich R, Simon MM, Kramer MD: The outer surface protein A of the spirochete Borrelia burgdorferi is a plasmin(ogen) receptor. Proc. Vatl Acad. Sci. USA 91, 12594—12598 (1994).
Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL: Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice. Cell 89, 1111—1119 (1997).
Coleman JL, Roemer EJ, Benach JL: Plasmin-coated Borrelia burgdorferi degrades soluble and insoluble components of the mammalian extracellular matrix. Infect. Immun. 67, 3929—3936 (1999).
Coleman JL, Benach JL: The generation of enzymatically active plasmin on the surface of spirochetes. Methods 21, 133—141 (2000).
Cassatt DR, Patel NK, Ulbrandt ND, Hanson MS: DbpA, but not OspA, is expressed by Borrelia burgdorferi during spirochetemia and is a target for protective antibodies. Infect. Immun. 66, 5379—5387 (1998).
Onishi H, Morisaki T, Baba E et al. : Dysfunctional and short-lived subsets in monocyte-derived dendritic cells from patients with advanced cancer. Clin. Immunol. 105, 286—295 (2002).
Zhao Z, Chang H, Trevino RP, Whren K, Bhawan J, Klempner MS : Selective up-regulation of matrix metalloproteinase-9 expression in human erythema migrans skin lesions of acute lyme disease. J. Infect. Dis. 188, 1098—1104 (2003).
Kirchner A, Koedel U, Fingerle V, Paul R, Wilske B, Pfister H: Upregulation of matrix metalloproteinase-9 in the cerebrospinal fluid of patients with acute Lyme neuroborreliosis. J. Veurol. Veurosurg. Psychiatry 68, 368—371 (2000).
Heilpern AJ, Wertheim W, He J, Perides G, Bronson RT, Hu LT: Matrix metalloproteinase 9 plays a key role in Lyme arthritis but not in dissemination of Borrelia burgdorferi. Infect. Immun. 77, 2643—2649 (2009).
Guo BP, Norris SJ, Rosenberg LC, Hook M: Adherence of Borrelia burgdorferi to the proteoglycan decorin. Infect. Immun. 63, 3467—3472 (1995).
Fischer JR, Parveen N, Magoun L, Leong JM: Decorin-binding proteins A and B confer distinct mammalian cell type-specific attachment by Borrelia burgdorferi, the Lyme disease spirochete. Proc. Vatl Acad. Sci. USA 100, 7307—7312 (2003).
Coburn J, Fischer JR, Leong JM: Solving a sticky problem: new genetic approaches to host cell adhesion by the Lyme disease spirochete. Mol. Microbiol. 57, 1182—1195 (2005).
Ma Y, Sturrock A, Weis JJ: Intracellular localization of Borrelia burgdorferi within human endothelial cells. Infect. Immun. 59, 671—678 (1991).
Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H: Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol. Int. 16, 125—132 (1996).
Livengood JA, Gilmore RD Jr: Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes Infect. 8, 2832—2840 (2006).
Mullegger RR: Dermatological manifestations of Lyme borreliosis. Eur. J. Dermatol. 14, 296—309 (2004).
Rupprecht TA, Koedel U, Fingerle V, Pfister HW: The pathogenesis of Lyme neuroborreliosis: from infection to inflammation. Mol. Med. 14, 205—212 (2008).
Coulter P, Lema C, Flayhart D: Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J. Clin. Microbiol. 43, 5080—5084 (2005).
Wormser GP, McKenna D, Carlin J et al.: Brief communication: hematogenous dissemination in early Lyme disease. Ann. Intern. Med. 142, 751—755 (2005).
Maraspin V, Ruzic-Sabljic E, Cimperman J et al.: Isolation of Borrelia burgdorferi sensu lato from blood of patients with erythema migrans. Infection 29, 65 —70 (2001).
Steere AC, Bartenhagen NH, Craft JE et al.: The early clinical manifestations of Lyme disease. Ann. Intern. Med. 99, 76—82 (1983).
Asbrink E, Olsson I, Hovmark A: Erythema chronicum migrans Afzelius in Sweden. A study on 231 patients. Zentralbl. Bakteriol. Mikrobiol. Hyg. A 263, 229—236 (1986).
Strle F, Videcnik J, Zorman P, Cimperman J, Lotric-Furlan S, Maraspin V: Clinical and epidemiological findings for patients with erythema migrans. Comparison of cohorts from the years 1993 and 2000. Wien. Klin. Wochenschr. 114, 493—497 (2002).
Hengge UR, Tannapfel A, Tyring SK, Erbel R, Arendt G, Ruzicka T: Lyme borreliosis. Lancet Infect. Dis. 3, 489—500 (2003).
Steere AC: Lyme disease. V. Engl. J. Med. 345, 115—125 (2001).
Strle F, Ruzic-Sabljic E, Cimperman J, Lotric-Furlan S, Maraspin V: Comparison of findings for patients with Borrelia garinii and Borrelia afzelii isolated from cerebrospinal fluid. Clin. Infect. Dis. 43, 704—710 (2006).
• Demonstrates for the first time that the underlying borrelial species may have a high impact on the neurological symptomatology.
Schutzer SE, Fraser-Liggett CM, Casjens SR et al. : Whole genome sequences of thirteen isolates of Borrelia burgdorferi. J. Bacteriol. 193(4), 1018—1020 (2011) .
Barker CF, Billingham RE: Immunologically privileged sites. Adv. Immunol. 25, 1—54 (1977).
Koedel U, Scheld WM, Pfister HW: Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect. Dis. 2, 721—736 (2002).
Hatterer E, Davoust N, Didier-Bazes M et al.: How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 107, 806—812 (2006).
van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M: Clinical features and prognostic factors in adults with bacterial meningitis. N. Engl. J. Med. 351, 1849—1859 (2004).
Takayama K, Rothenberg RJ, Barbour AG: Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect. Immun. 55, 2311—2313 (1987).
Frei K, Siepl C, Groscurth P, Bodmer S, Schwerdel C, Fontana A: Antigen presentation and tumor cytotoxicity by interferon-g-treated microglial cells. Eur. J. Immunol. 17, 1271—1278 (1987).
Hickey WF, Kimura H: Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239, 290—292 (1988).
Graeber MB, Streit WJ, Buringer D, Sparks DL, Kreutzberg GW: Ultrastructural location of major histocompatibility complex (MHC) class II positive perivascular cells in histologically normal human brain. J. Neuropathol. Exp. Neurol. 51, 303—311 (1992).
Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392, 245—252 (1998).
Fierz W, Endler B, Reske K, Wekerle H, Fontana A: Astrocytes as antigen-presenting cells. I. Induction of Ia antigen expression on astrocytes by T cells via immune interferon and its effect on antigen presentation. J. Immunol. 134, 3785—3793 (1985).
Hirschfeld M, Kirschning CJ, Schwandner R et al.: Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by Toll-like receptor 2. J. Immunol. 163, 2382—2386 (1999).
• Identifies Toll-like receptor 2 as an important receptor of the innate immune system for the recognition of Borrelia burgdorferi.
Cabral ES, Gelderblom H, Hornung RL, Munson PJ, Martin R, Marques AR: Borrelia burgdorferi lipoprotein-mediated TLR2 stimulation causes the down-regulation of TLR5 in human monocytes. J. Infect. Dis. 193, 849—859 (2006).
Rupprecht TA, Kirschning CJ, Popp B et al.: Borrelia garinii induces CXCL13 production in human monocytes through Toll-like receptor 2. Infect. Immun. 75, 4351—4356 (2007).
Petzke MM, Brooks A, Krupna MA, Mordue D, Schwartz I: Recognition of Borrelia burgdorferi, the Lyme disease spirochete, by TLR7 and TLR9 induces a type I IFN response by human immune cells. J. Immunol. 183, 5279—5292 (2009).
Bernardino AL, Myers TA, Alvarez X, Hasegawa A, Philipp MT: Toll-like receptors: insights into their possible role in the pathogenesis of Lyme neuroborreliosis. Infect. Immun. 76, 4385—4395 (2008).
Bolz DD, Sundsbak RS, Ma Y et al.: MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J. Immunol. 173, 2003—2010 (2004) .
Liu N, Montgomery RR, Barthold SW, Bockenstedt LK: Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect. Immun. 72, 3195—3203 (2004).
Guerau-de-Arellano M, Huber BT: Chemokines and Toll-like receptors in Lyme disease pathogenesis. Trends Mol. Med. 11, 114—120 (2005).
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 6, 42 (2009).
Rupprecht TA, Pfister HW, Angele B, Kastenbauer S, Wilske B, Koedel U: The chemokine CXCL13 (BLC): a putative diagnostic marker for neuroborreliosis. Neurology 65, 448—450 (2005).
• First description of CXCL13 as a promising biomarker for acute Lyme neuroborreliosis, offering a new diagnostic approach to this disease.
Narayan K, Dail D, Li L et al.: The nervous system as ectopic germinal center: CXCL13 and IgG in Lyme neuroborreliosis. Ann. Neurol. 57, 813—823 (2005) .
Ramesh G, Borda JT, Gill A et al.: Possible role of glial cells in the onset and progression of Lyme neuroborreliosis. J. Neuroinflammation 6, 23 (2009).
Cepok S, Zhou D, Vogel F et al.: The immune response at onset and during recovery from Borrelia burgdorferi meningoradiculitis. Arch. Neurol. 60, 849—855 (2003).
Cepok S, Rosche B, Grummel V et al.: Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128, 1667—1676 (2005).
Rupprecht TA, Koedel U, Angele B, Fingerle V, Pfister HW: Cytokine CXCL13 — a possible early CSF marker for neuroborreliosis. Nervenarzt 77, 470—473 (2006).
Ljostad U, Mygland A: CSF B-lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis. J. Neurol. 255, 732—737. (2008).
Jacobsen M, Zhou D, Cepok S et al.: Clonal accumulation of activated CD8⁺ T cells in the central nervous system during the early phase of neuroborreliosis. J. Infect. Dis. 187, 963—973 (2003).
Baggiolini M: Chemokines and leukocyte traffic. Nature 392, 565—568 (1998).
Pashenkov M, Teleshova N, Kouwenhoven M et al. : Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J. Neuroimmunol. 122, 106—116 (2002).
Lepej SZ, Rode OD, Jeren T, Vince A, Remenar A, Barsic B: Increased expression of CXCR3 and CCR5 on memory CD4⁺ T-cells migrating into the cerebrospinal fluid of patients with neuroborreliosis: the role of CXCL10 and CXCL11. J. Neuroimmunol. 163, 128—134 (2005).
Rupprecht TA, Koedel U, Muhlberger B, Wilske B, Fontana A, Pfister HW: CXCL11 is involved in leucocyte recruitment to the central nervous system in neuroborreliosis. J. Neurol. 252, 820—823 (2005).
Garcia-Monco JC, Fernandez-Villar B, Rogers RC, Szczepanski A, Wheeler CM, Benach JL: Borrelia burgdorferi and other related spirochetes bind to galactocerebroside. Neurology 42, 1341—1348 (1992).
Peters DJ, Benach JL: Borrelia burgdorferi adherence and injury to undifferentiated and differentiated neural cells in vitro. J. Infect. Dis. 176, 470—477 (1997).
Rupprecht TA, Koedel U, Heimerl C et al.: Adhesion of Borrelia garinii to neuronal cells is mediated by the interaction of OspA with proteoglycans. J. Neuroimmunol. 175, 5—11 (2006).
Ramesh G, Alvarez AL, Roberts ED et al.: Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes. Eur. J. Immunol. 33, 2539—2550 (2003).
Norgard M, Arndt L, Akins D, Curetty L, Harrich D, Radolf J: Activation of human monocytic cells by Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides proceeds via a pathway distinct from that of lipopolysaccharide but involves the transcriptional activator NF-kB. Infect. Immun. 64, 3845—3852 (1996).
Beck G, Habicht GS, Benach JL, Coleman JL: Chemical and biologic characterization of a lipopolysaccharide extracted from the Lyme disease spirochete (Borrelia burgdorferi). J. Infect. Dis. 152, 108—117 (1985).
Roberts ED, Bohm RP, Lowrie RC et al.: Pathogenesis of Lyme neuroborreliosis in the Rhesus monkey: the early disseminated and chronic phases of disease in the peripheral nervous system. J. Infect. Dis. 178, 722—732 (1998).
Tatro J, Romero L, Beasley D, Steere A, Reichlin S : Borrelia burgdorferi and Escherichia coli lipopolysaccharides induce nitric oxide and interleukin-6 production in cultured rat brain cells. J. Infect. Dis. 169, 1014—1022 (1994).
Halperin JJ, Heyes MP: Neuroactive kynurenines in Lyme borreliosis. Neurology 42, 43—50 (1992).
Myers TA, Kaushal D, Philipp MT: Microglia are mediators of Borrelia burgdorferi-induced apoptosis in SH-SY5Y neuronal cells. PLoS Pathog. 5, E1000659 (2009).
Alaedini A, Latov N: Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J. Neuroimmunol. 159, 192—195 (2005).
Garcia-Monco JC, Seidman RJ, Benach JL: Experimental immunization with Borrelia burgdorferi induces development of antibodies to gangliosides. Infect. Immun. 63, 4130—4137 (1995).
Sigal LH: Cross-reactivity between Borrelia burgdorferi flagellin and a human axonal 64.000 molecular weight protein. J. Infect. Dis. 167, 1372—1378 (1993).
Sigal LH, Tatum AH: Lyme disease patients' serum contains IgM antibodies to Borrelia burgdorferi that cross-react with neuronal antigens. Neurology 38, 1439—1442 (1988).
Kuenzle S, von Budingen HC, Meier M et al.: Pathogen specificity and autoimmunity are distinct features of antigen-driven immune responses in neuroborreliosis. Infect. Immun. 75, 3842—3847 (2007).
Rupprecht TA, Elstner M, Weil S, Pfister HW: Autoimmune-mediated polyneuropathy triggered by borrelial infection? Muscle Nerve 37, 781—785 (2008).
Chandra A, Wormser GP, Klempner MS et al. : Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. Brain Behav. Immun. 24, 1018—1024 (2010).
Rupprecht TA, Birnbaum T, Pfister HW: Pain and neuroborreliosis: significance, diagnosis and treatment. Schmerz 22, 615—623 (2008).
Hansen K, Lebech AM: 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).
^•• By far the most important epidemiological study on Lyme neuroborreliosis, covering all aspects of this disease.
Pfister HW, Rupprecht TA: Clinical aspects of neuroborreliosis and post-Lyme d isease synd rome in adult patients. Int. J. Med. Microbiol. 296(Suppl. 1), 11—16 (2006).
Kindstrand E, Nilsson BY, Hovmark A, Pirskanen R, Asbrink E: Peripheral neuropathy in acrodermatitis chronica atrophicans — a late Borrelia manifestation. Acta Neurol. Scand. 95, 338—345 (1997).
Mario-Ubaldo M: Cerebellitis associated with Lyme disease. Lancet 345, 1060 (1995).
Halperin JJ, Volkman DJ, Luft BJ, Dattwyler RJ: Carpal tunnel syndrome in Lyme borreliosis. Muscle Nerve 12, 397—400 (1989).
Auwaerter PG: Point: antibiotic therapy is not the answer for patients with persisting symptoms attributable to Lyme disease. Clin. Infect. Dis. 45, 143—148 (2007).
Feder HM Jr, Johnson BJ, O'Connell S et al.: A critical appraisal of "chronic Lyme disease". N. Engl. J. Med. 357, 1422—1430 (2007).
Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED: Long-term outcomes of persons with Lyme disease. JAMA 283, 609—616 (2000).
Cairns V, Godwin J: Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int. J. Epidemiol. 34, 1340—1345 (2005).
Treib J, Grauer MT, Haass A, Langenbach J, Holzer G, Woessner R: Chronic fatigue syndrome in patients with Lyme borreliosis. Eur. Neurol. 43, 107—109 (2000).
Eikeland R, Mygland A, Herlofson K, Ljostad U: European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol. Scand. DOI: 10.1111/j.1600-0404.2010.01482.x (2010). (Epub ahead of print).
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. 345, 85—92 (2001).
•• Well-designed study that clearly shows that extending the duration of antibiotic treatment in 'post-Lyme disease' has no beneficial effect.
Kowalski TJ, Tata S, Berth W, Mathiason MA, Agger WA: Antibiotic treatment duration and long-term outcomes of patients with early Lyme disease from a Lyme disease-hyperendemic area. Clin. Infect. Dis. 50, 512—520 (2010).
Kuenzle S, von Budingen HC, Meier M et al.: Pathogen specificity and autoimmunity are distinct features of antigen-driven immune responses in neuroborreliosis. Infect. Immun. 75, 3842—3847 (2007).
Tjernberg I, Carlsson M, Ernerudh J, Eliasson I, Forsberg P: Mapping of hormones and cortisol responses in patients after Lyme neuroborreliosis. BMC Infect. Dis. 10, 20 (2010).
Lj0stad U, Mygland A: Remaining complaints 1 year after treatment for acute Lyme neuroborreliosis; frequency, pattern and risk factors. Eur J. Neurol. 17(1), 118—123 (2010).
Seidel MF, Domene AB, Vetter H: Differential diagnoses of suspected Lyme borreliosis or post-Lyme-disease syndrome. Eur. J. Clin. Microbiol. Infect. Dis. 26, 611—617 (2007).
Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I: EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur. J. Neurol. 17, 8—16 (2010).
^• These guidelines are very helpful in the diagnostic approach to a patient with suspected Lyme neuroborreliosis.
Kaiser R: Variable CSF findings in early and late Lyme neuroborreliosis: a follow-up study in 47 patients. J. Neurol. 242, 26—36 (1994).
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

Disclosures

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
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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Epidemiology

The incidence of Lyme borreliosis varies considerably from region to region (an overview is given by Hubalek^[7]). In Germany, Lyme borreliosis must legally be notified to local health services in the six eastern states only. Between 2002 and 2009, the reported incidence in these six territories varied between 17.8 and 37.5 per 100,000 inhabitants.^[8] In a prospective, population-based study covering the region of Würzburg, the incidence was 111/100,000 per year.^[9] The individual probability of becoming infected with B. burgdorferi by a tick bite depends on several factors:

The proportion of infected ticks – a European meta-analysis found 18.6% of the adult and 10.1% of the nymphal ticks to be infected, but the rate varied, depending on the region and the tick stage, from 1.5 to 75%.^[10] Of note, there was no differentiation between human-pathogenic and -nonpathogenic B. burgdorferi species.
The duration of the tick’s feeding – while the North American tick Ixodes scapularis needs at least 24–48 h of feeding until Borrelia are transmitted, experiments with gerbils and Ixodes ricinus (endemic to Europe) have shown that after only 16.7 h of feeding, 50% of the animals were infected with B. burgdorferi.^[11–13] The reason for this discrepancy can be found at the location of B. burgdorferi inside of the ticks: while Ixodes scapularis harbors the bacteria only in the mid-gut (where they have to detach and migrate to the salivary gland before being injected into the host), a part of the Borrelia in I. ricinus can already be found directly in the salivary glands.^[14]
The borrelial species – skin biopsies from patients with erythema migrans reveal mostly B. afzelii (in 70–90% of the cases) and significantly less B. garinii (10–20%), while both species can be equally found in the ticks.^[3,7,10,15] This suggests that borrelial species vary in their infectivity.

Considering the necessary duration of feeding and the proportion of infected ticks, spirochetal inoculation after a tick bite is the exception and not the rule. A study from south-west Germany has shown that only approximately 2.6% of all tick bites lead to a clinically apparent infection.^[16]

The most frequent manifestation of Lyme borreliosis – accounting for approximately 90% of cases – is erythema migrans, while the CNS is the most frequent destination of dissemination. According to population-based prospective studies performed both in Germany and Sweden, the incidence of Lyme neuroborreliosis (LNB) is approximately 3–11/100,000 per year.^[9,17]

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Page 2 of 8

Pathogenesis

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

Accreditation Statements

For Physicians

Instructions for Participation and Credit

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

Epidemiology

Table of Contents

References

Faculty and 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

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

Accreditation Statements

For Physicians

Instructions for Participation and Credit

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

Epidemiology

Table of Contents