Lyme Neuroborreliosis - The Mystifying Pitfall: “Neuropathology and Current Therapeutics”

Author(s): Vishal Chavda, Snehal Patel*.

Journal Name: Recent Patents on Anti-Infective Drug Discovery

Volume 14 , Issue 1 , 2019

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Graphical Abstract:


Lyme’s Disease (LD) is a severe, rapidly growing, broad spectrum chronic infection caused by the bacterium ‘Borrelia (B.) burgdorferi', which can be easily transmitted through the bite of certain species of ticks. The prevalence of LD is swiftly mounting in the present scenario in many countries from species to species. Although Lyme’s infection is now detectable via serologic examination of early and late Lyme neuroborreliosis (LNB), the management of persistent symptoms is still fraught with quora of doubt and debate. LD is a multisystem spirochete which results after the dissemination of B. burgdorferi from a dermal inoculation site after a tick bite. Lyme's infection can easily get transmitted to the central nervous system and develop various neurological symptoms due to inflammation and an autoimmune response from body may lead to life-threatening “Lyme Borreliosis”. The neurological symptoms are well mixed in presentation, late and confusing to get differentiated easily from other diseases. The use of antibiotics in post Lyme infection with neurological complications is still a topic of debate. Babesiosisstates, and human ehrlichiosis' the two other diseases, are associated with the same ticks that spread the LD. However, the prevalence of diagnosed human cases is usually much lower than that of actual cases of LD due to misdiagnosis, late diagnosis or undiagnosis at y such lateral neuroinfection stage after the tick bite. The current review focuses on the molecular neuropathology and current advancements in LD. There are very few patents or discoveries made on borrelia infection, drawing attention towards more focused and targeted research for the cure.

Keywords: Lyme neuroborreliosis (LNB), B. burgdorferi, neuro-inflammation, tick-borne disease, lyme disease vaccine, current therapeutics, mystifying disease.

Gulia-Nuss M, Nuss AB, Meyer JM, Sonenshine DE, Roe RM, Waterhouse RM. e t al. Genomic insights into the Ixodes scapularis tick vector of Lyme disease Nat Commun 2016; 7: 10507.
Nayak S, Sridhara A, Melo R, Richer L, Chee NH, Kim J. et al. Microfluidics-based point-of-care test for serodiagnosis of Lyme disease. Sci Rep 2016; 6: 35069.
Radolf JD, Caimano MJ, Stevenson B, Hu LT. Of ticks, mice and men: Understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol 2012; 10(2): 87-99.
Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of lyme borreliosis. Clin Microbiol Rev 2005; 18(3): 484-509.
Masters EJ, Grigery CN, Masters RW. STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness. Infect Dis Clin North Am 2008; 22(2): 361-76. [viii.].
Sharma A, Guleria S, Sharma R, Sharma A. Lyme disease: A case report with typical and atypical lesions. Indian Dermatol Online J 2017; 8(2): 124-7.
Guliani BP, Kumar S, Chawla N, Mehta A. Neuroretinitis as presenting and the only presentation of Lyme disease: Diagnosis and management. Indian J Ophthalmol 2017; 65(3): 250-2.
Patel K, Shah S, Subedi D. Clinical association: Lyme disease and Guillain-Barre syndrome. Am J Emerg Med 2017; 35(10): 1583.e1-2.
Tomassone L, Ceballos LA, Ragagli C, Martello E, De Sousa R, Stella MC, et al. Importance of common wall lizards in the transmission dynamics of tick-borne pathogens in the Northern Apennine Mountains, Italy. Microb Ecol 2017; 74(4): 961-8.
Sajanti E, Virtanen M, Helve O, Kuusi M, Lyytikäinen O, Hytönen J, et al. Lyme Borreliosis in Finland, 1995-2014. Emerg Infect Dis 2017; 23(8): 1282-8.
Szekeres S, Lügner J, Fingerle V, Margos G, Földvári G. Prevalence of Borrelia miyamotoi and Borrelia burgdorferi sensu lato in questing ticks from a recreational coniferous forest of East Saxony, Germany. Ticks Tick Borne Dis 2017; 8(6): 922-7.
Stone BL, Tourand Y, Brissette CA. Brave new worlds: The expanding universe of Lyme disease. Vector Borne Zoonotic Dis 2017; 17(9): 619-29.
Ruzek D, Avšič Županc T, Borde J, Chrdle A, Eyer L, Karganova G, et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res 2019; 164: 23-51.
Łuczaj W, Moniuszko-Malinowska A, Domingues P, Domingues MR, Gindzienska-Sieskiewicz E, Skrzydlewska E. Plasma lipidomic profile signature of rheumatoid arthritis versus Lyme arthritis patients. Arch Biochem Biophys 2018; 654: 105-14.
Bransfield RC. Suicide and Lyme and associated diseases. Neuropsychiatr Dis Treat 2017; 13: 1575-87.
Donta ST. Late and chronic Lyme disease. Med Clin North Am 2002; 86(2): 341-9. [vii.].
Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012; 379(9814): 461-73.
Stanek G, O’Connell S, Cimmino M, Aberer E, Kristoferitsch W, Granström M, et al. European Union concerted action on risk assessment in lyme borreliosis: Clinical case definitions for lyme borreliosis. Wien Klin Wochenschr 1996; 108(23): 741-7.
Meier C, Grahmann F, Engelhardt A, Dumas M. Peripheral nerve disorders in Lyme-Borreliosis. Nerve biopsy studies from eight cases. Acta Neuropathol 1989; 79(3): 271-8.
Veenendaal-Hilbers JA, Perquin WV, Hoogland PH, Doornbos L. Basal meningovasculitis and occlusion of the basilar artery in two cases of Borrelia burgdorferi infection. Neurology 1988; 38(8): 1317-9.
Fallon BA, Nields JA. Lyme disease: A neuropsychiatric illness. Am J Psychiatry 1994; 151(11): 1571-83.
Wilke M, Eiffert H, Christen HJ, Hanefeld F. Primarily chronic and cerebrovascular course of Lyme neuroborreliosis: Case reports and literature review. Arch Dis Child 2000; 83(1): 67-71.
Pachner AR. A Introduction to Neurological Infections: Neuro-infectious Disease as Part of Neuroimmunology.In A Primer of Neuroimmunological Disease. New York: Springer-Verlag 2012; pp. 115-39.
Feder HM Jr, Johnson BJ, O’Connell S, Shapiro ED, Steere AC, Wormser GP, et al. A critical appraisal of “chronic Lyme disease”. N Engl J Med 2007; 357(14): 1422-30.
Schmutzhard E, Pfausler B, Gasse T, Hittmair-Delazer M, Benke T. Follow-up and sequelae in chronic neuroborreliosis Wiener medizinische Wochenschrift (1946). 1995;145(7-8): 183-6.
Wilske B, Busch U, Fingerle V, et al. Immunological and molecular variability of OspA and OspC. Implications for Borrelia vaccine development. Infection 1996; 24(2): 208-12.
Halperin JJ, Volkman DJ, Wu P. Central nervous system abnormalities in Lyme neuroborreliosis. Neurology 1991; 41(10): 1571-82.
Kontodimopoulos N, Nanos P, Niakas D. Balancing efficiency of health services and equity of access in remote areas in Greece. Health Policy 2006; 76(1): 49-57.
Sigal LH. Lyme disease: A review of aspects of its immunology and immunopathogenesis. Annu Rev Immunol 1997; 15(1): 63-92.
Sigal LH. Persisting complaints attributed to chronic Lyme disease: Possible mechanisms and implications for management. Am J Med 1994; 96(4): 365-74.
Garcia-Monco JC, Benach JL. Lyme neuroborreliosis. Ann Neurol 1995; 37(6): 691-702.
Garcia-Monco JC, Benach JL. Mechanisms of injury in Lyme neuroborreliosis.In Seminars in neurology. Vol. 17 Stuttgart, Germany: Thieme Medical Publishers, Inc. 1997; pp. 57-62.
Miklossya J, Khalilib K, Gernc L, Ericson RL, Darekar P, Bolle L, et al. Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer. J Alzheimers Dis 2004; Dec 6(6): 639-649 discussion 673-81.
Miklossy J. Chronic or late lyme neuroborreliosis: Analysis of evidence compared to chronic or late neurosyphilis. Open Neurol J 2012; 6: 146-57.
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 1992; 115(Pt 2): 399-423.
Meurers B, Kohlhepp W, Gold R, Rohrbach E, Mertens HG. Histopathological findings in the central and peripheral nervous systems in neuroborreliosis. A report of three cases. J Neurol 1990; 237(2): 113-6.
Krüger H, Heim E, Schuknecht B, Scholz S. Acute and chronic neuroborreliosis with and without CNS involvement: A clinical, MRI, and HLA study of 27 cases. J Neurol 1991; 238(5): 271-80.
Donta ST. Tetracycline therapy for chronic Lyme disease. Clinical infectious diseases 1997; 25(Suppl. 1): S52-6.
Pennekamp A, Jaques M. Chronic neuroborreliosis with gait ataxia and cognitive disorders Praxis (Bern 1994) 1997; 86(20): 867-9.
Ackermann R, Gollmer E, Rehse-Küpper B. Progressive borrelien-enzephalomyelitis. Chronische manifestation der erythema-chronicum-migrans-krankheit am nervensystem. Dtsch Med Wochenschr 1985; 110(26): 1039-42.
Brower MC, Rollins N, Roach ES. Basal ganglia and thalamic infarction in children. Cause and clinical features. Arch Neurol 1996; 53(12): 1252-6.
van den Bergen HA, Smith JP, van der Zwan A. Lyme psychosis. Ned Tijdschr Geneeskd 1993; 137(41): 2098-100.
Roelcke U, Barnett W, Wilder-Smith E, Sigmund D, Hacke W. Untreated neuroborreliosis: Bannwarth’s syndrome evolving into acute schizophrenia-like psychosis. A case report. J Neurol 1992; 239(3): 129-31.
Bransfield RC. Neuropsychiatric Borreliosis/Tick-Borne Disease. An Overview [Preprint]
Almeida OP, Lautenschlager NT. Dementia associated with infectious diseases. Int Psychogeriatr 2005; 17(Suppl. 1): S65-77.
Roelcke U, Barnett W, Wilder-Smith E, Sigmund D, Hacke W. Untreated neuroborreliosis: Bannwarth’s syndrome evolving into acute schizophrenia-like psychosis. A case report. J Neurol 1992; 239(3): 129-31.
Lebas A, Toulgoat F, Saliou G, Husson B, Tardieu M. Stroke due to lyme neuroborreliosis: Changes in vessel wall contrast enhancement. J Neuroimaging 2012; 22(2): 210-2.
Schmiedel J, Gahn G, von Kummer R, Reichmann H. Cerebral vasculitis with multiple infarcts caused by lyme disease. Cerebrovasc Dis 2004; 17(1): 79-81.
Kuntzer T, Bogousslavsky J, Miklossy J, Steck AJ, Janzer R, Regli F. Borrelia rhombencephalomyelopathy. Arch Neurol 1991; 48(8): 832-6.
Miklossy J. Biology and neuropathology of dementia in syphilis and Lyme disease. Handb Clin Neurol 2008; 89: 825-44.
Ackermann R, Gollmer E, Rehse-Küpper B. Progressive Borrelien-Enzephalomyelitis. Chronische Manifestation der Erythema-chronicum-migrans-Krankheit am Nervensystem. Dtsch Med Wochenschr 1985; 110(26): 1039-42.
Oksi J, Viljanen MK, Kalimo H, et al. Fatal encephalitis caused by concomitant infection with tick-borne encephalitis virus and Borrelia burgdorferi. Clin Infect Dis 1993; 16(3): 392-6.
Bensch J, Olcén P, Hagberg L. Destructive chronic borrelia meningoencephalitis in a child untreated for 15 years. Scand J Infect Dis 1987; 19(6): 697-700.
Bertrand E, Szpak GM, Piłkowska E, et al. Central nervous system infection caused by Borrelia burgdorferi. Clinico-pathological correlation of three post-mortem cases. Folia Neuropathol 1999; 37(1): 43-51.
Oksi J, Kalimo H, Marttila RJ, et al. Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature. Brain 1996; 119(Pt 6): 2143-54.
Liegner KB, Duray P, Agricola M, et al. Lyme disease and the clinical spectrum of antibiotic responsive chronic meningoencephalomyelitidis. J Spirochetal Tick-borne Dis 1997; 4: 61-73.
Miklossy J, Kasas S, Janzer RC, Ardizzoni F, Van der Loos H. Further ultrastructural evidence that spirochaetes may play a role in the aetiology of Alzheimer’s disease. Neuroreport 1994; 5(10): 1201-4.
Tarasów E, Ustymowicz A, Zajkowska J, Hermanowska-Szpakowicz T. Neuroborreliosis: CT and MRI findings in 14 cases. Preliminary communication. Neurol Neurochir Pol 2001; 35(5): 803-13.
MacDonald AB. Plaques of Alzheimer’s disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete. Med Hypotheses 2006; 67(3): 592-600.
Miklossy J, Khalili K, Gern L, et al. Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis 2004; 6(6): 639-49.
Topakian R, Stieglbauer K, Nussbaumer K, Aichner FT. Cerebral vasculitis and stroke in Lyme neuroborreliosis. Two case reports and review of current knowledge. Cerebrovasc Dis 2008; 26(5): 455-61.
Sellati TJ, Bouis DA, Kitchens RL, Darveau RP, Pugin J, Ulevitch RJ, et al. Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytic cells via a CD14-dependent pathway distinct from that used by lipopolysaccharide. J Immunol 1998; 160(11): 5455-64.
Marangoni A, Aldini R, Sambri V, Giacani L, Di Leo K, Cevenini R. Production of tumor necrosis factor α by Treponema pallidum, Borrelia burgdorferi s.l., and Leptospira interrogans in isolated rat Kupffer cells. FEMS Immunol Med Microbiol 2004; 40(3): 187-91.
Kraiczy P, Würzner R. Complement escape of human pathogenic bacteria by acquisition of complement regulators. Mol Immunol 2006; 43(1-2): 31-44.
Pausa M, Pellis V, Cinco M, Giulianini PG, Presani G, Perticarari S, et al. Serum-resistant strains of Borrelia burgdorferi evade complement-mediated killing by expressing a CD59-like complement inhibitory molecule. J Immunol 2003; 170(6): 3214-22.
Ramesh G, Alvarez AL, Roberts ED, Dennis VA, Lasater BL, Alvarez X, et al. Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes. Eur J Immunol 2003; 33(9): 2539-50.
Riviere GR, Riviere KH, Smith KS. Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol 2002; 17(2): 113-8.
Duray PH, Yin SR, Ito Y, Bezrukov L, Cox C, Cho MS, et al. Invasion of human tissue ex vivo by Borrelia burgdorferi. J Infect Dis 2005; 191(10): 1747-54.
Shaw MA, Donaldson IJ, Collins A, Peacock CS, Lins-Lainson Z, Shaw JJ, et al. Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes Immun 2001; 2(4): 196-204.
Rasley A, Anguita J, Marriott I. Borrelia burgdorferi induces inflammatory mediator production by murine microglia. J Neuroimmunol 2002; 130(1-2): 22-31.
Rizzo C. Ricerche sulle spirochete nel cervello dei paralitici. Riv Pathol Nerv 1931; 37: 797-814.
Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, et al. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 1994; 121(8): 560-7.
Chang YF, Novosel V, Chang CF, Summers BA, Ma DP, Chiang YW, et al. Experimental induction of chronic borreliosis in adult dogs exposed to Borrelia burgdorferi-infected ticks and treated with dexamethasone. Am J Vet Res 2001; 62(7): 1104-12.
Pachner AR, Delaney E, O’Neill T, Major E. Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease. Neurology 1995; 45(1): 165-72.
Pal U, Li X, Wang T, Montgomery RR, Ramamoorthi N, Desilva AM, et al. TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi. Cell 2004; 119(4): 457-68.
Rupprecht TA, Koedel U, Fingerle V, Pfister HW. The pathogenesis of lyme neuroborreliosis: From infection to inflammation. Mol Med 2008; 14(3-4): 205-12.
Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, Wooten RM, et al. Cutting edge: Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J Immunol 1999; 163(5): 2382-6.
Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012; 379(9814): 461-73.
Norman MU, Moriarty TJ, Dresser AR, Millen B, Kubes P, Chaconas G. Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. PLoS Pathog 2008; 4(10)e1000169
Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Inflammation and central nervous system Lyme disease. Neurobiol Dis 2010; 37(3): 534-41.
Giambartolomei GH, Dennis VA, Lasater BL, Philipp MT. Induction of pro- and anti-inflammatory cytokines by Borrelia burgdorferi lipoproteins in monocytes is mediated by CD14. Infect Immun 1999; 67(1): 140-7.
Halperin JJ. Nervous system Lyme disease. Vector Borne Zoonotic Dis 2002; 2(4): 241-7.
Ebnet K, Brown KD, Siebenlist UK, Simon MM, Shaw S. Borrelia burgdorferi activates nuclear factor-kappa B and is a potent inducer of chemokine and adhesion molecule gene expression in endothelial cells and fibroblasts. J Immunol 1997; 158(7): 3285-92.
Fallahi P, Elia G, Bonatti A. Interferon-γ-induced protein 10 in Lyme disease. Clin Ter 2017; 168(2): e146-50.
Pashenkov M, Teleshova N, Kouwenhoven M, Smirnova T, Jin YP, Kostulas V, et al. Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol 2002; 122(1-2): 106-16.
Ramesh G, Alvarez AL, Roberts ED, Dennis VA, Lasater BL, Alvarez X, et al. Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes. Eur J Immunol 2003; 33(9): 2539-50.
Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED. Long-term outcomes of persons with Lyme disease. JAMA 2000; 283(5): 609-16.
Skar GL, Simonsen KA. Lyme Disease. Treasure Island, FL: StatPearls Publishing 2019.
Koedel U, Pfister HW. Lyme neuroborreliosis. Curr Opin Infect Dis 2017; 30(1): 101-7.
Ružić-Sabljić E, Cerar T. Progress in the molecular diagnosis of Lyme. Expert Rev Mol Diagn 2017; 17(1): 19-30.
Patel K, Shah S, Subedi D. Clinical association: Lyme disease and Guillain-Barre syndrome. Am J Emerg Med 2017; 35(10): 1583.e1-2.
Rupprecht TA, Koedel U, Fingerle V, Pfister HW. The pathogenesis of lyme neuroborreliosis: From infection to inflammation. Mol Med 2008; 14(3-4): 205-12.
Tatro JB, Romero LI, Beasley D, Steere AC, Reichlin S. Borrelia burgdorferi and Escherichia coli lipopolysaccharides induce nitric oxide and interleukin-6 production in cultured rat brain cells. J Infect Dis 1994; 169(5): 1014-22.
Melchers W, Meis J, Rosa P, Claas E, Nohlmans L, Koopman R, et al. Amplification of Borrelia burgdorferi DNA in skin biopsies from patients with Lyme disease. J Clin Microbiol 1991; 29(11): 2401-6.
Schwartz JJ, Gazumyan A, Schwartz I. rRNA gene organization in the Lyme disease spirochete, Borrelia burgdorferi. J Bacteriol 1992; 174(11): 3757-65.
Brettschneider S, Bruckbauer H, Klugbauer N, Hofmann H. Diagnostic value of PCR for detection of Borrelia burgdorferi in skin biopsy and urine samples from patients with skin borreliosis. J Clin Microbiol 1998; 36(9): 2658-65.
Halperin JJ. Nervous system Lyme disease. Handbook of clinical neurology 2014; Vol 121: 1473-83.
Kohlhepp W, Kuhn W, Krüger H. Extrapyramidal features in central Lyme borreliosis. Eur Neurol 1989; 29(3): 150-5.
Kohler J, Kern U, Kasper J, Rhese-Küpper B, Thoden U. Chronic central nervous system involvement in Lyme borreliosis. Neurology 1988; 38(6): 863-7.
Lebas A, Toulgoat F, Saliou G, Husson B, Tardieu M. Stroke due to lyme neuroborreliosis: Changes in vessel wall contrast enhancement. J Neuroimaging 2012; 22(2): 210-2.
Zajkowska J, Garkowski A, Moniuszko A, Czupryna P, Ptaszyńska-Sarosiek I, Tarasów E, et al. Vasculitis and stroke due to Lyme neuroborreliosis - a review. Infect Dis (Lond) 2015; 47(1): 1-6.
Cutler SJ, Rudenko N, Golovchenko M, Cramaro WJ, Kirpach J, Savic S, et al. Diagnosing borreliosis. Vector Borne Zoonotic Dis 2017; 17(1): 2-11.
Koedel U, Fingerle V, Pfister HW. Lyme neuroborreliosis-epidemiology, diagnosis and management. Nat Rev Neurol 2015; 11(8): 446-56.
Dillon R, O’Connell S, Wright S. Lyme disease in the U.K.: Clinical and laboratory features and response to treatment. Clin Med (Lond) 2010; 10(5): 454-7.
Biesiada G, Czepiel J, Leśniak MR, Garlicki A, Mach T. Lyme disease. Arch Med Sci 2012; 8(6): 978.
Arvikar SL, Steere AC. Diagnosis and treatment of Lyme arthritis. Infect Dis Clin North Am 2015; 29(2): 269-80.
Cairns V, Godwin J. Post-Lyme borreliosis syndrome: A meta-analysis of reported symptoms. Int J Epidemiol 2005; 34(6): 1340-5.
Phillips SE, Burrascano JJ, Harris NS, Johnson L, Smith PV, Stricker RB. Chronic infection in ‘post-Lyme borreliosis syndrome’. Int J Epidemiol 2005; 34(6): 1439-40.
Stanek G, Strle F. Lyme borreliosis: A European perspective on diagnosis and clinical management. Curr Opin Infect Dis 2009; 22(5): 450-4.
Freedman JC, Rogers EA, Kostick JL, Zhang H, Iyer R, Schwartz I, et al. Identification and molecular characterization of a cyclic-di-GMP effector protein, PlzA (BB0733): Additional evidence for the existence of a functional cyclic-di-GMP regulatory network in the Lyme disease spirochete, Borrelia burgdorferi. FEMS Immunol Med Microbiol 2010; 58(2): 285-94.
Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK. Diagnostic challenges of early Lyme disease: Lessons from a community case series. BMC Infect Dis 2009; 9(1): 79.
Barthold SW, Beck DS, Hansen GM, Terwilliger GA, Moody KD. Lyme borreliosis in selected strains and ages of laboratory mice. J Infect Dis 1990; 162(1): 133-8.
Cadavid D, O’Neill T, Schaefer H, Pachner AR. Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of lyme disease. Lab Invest 2000; 80(7): 1043-54.
Philipp MT, Johnson BJ. Animal models of Lyme disease: Pathogenesis and immunoprophylaxis. Trends Microbiol 1994; 2(11): 431-7.
Johnson PT, Thieltges DW. Diversity, decoys and the dilution effect: How ecological communities affect disease risk. J Exp Biol 2010; 213(6): 961-70.
Hildenbrand P, Craven DE, Jones R, Nemeskal P. Lyme neuroborreliosis: Manifestations of a rapidly emerging zoonosis. Am J Neuroradiol 2009; 30(6): 1079-87.
Sangha O, Phillips CB, Fleischmann KE, Wang TJ, Fossel AH, Lew R, et al. Lack of cardiac manifestations among patients with previously treated Lyme disease. Ann Intern Med 1998; 128(5): 346-53.
Kobayashi K, Mizukoshi C, Aoki T, Muramori F, Hayashi M, Miyazu K, et al. Borrelia burgdorferi-seropositive chronic encephalomyelopathy: Lyme neuroborreliosis? An autopsied report. Dement Geriatr Cogn Disord 1997; 8(6): 384-90.
Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138(9): 697-704.
Nadelman RB, Wormser GP. Reinfection in patients with Lyme disease. Clin Infect Dis 2007; 45(8): 1032-8.
Schwameis M, Kündig T, Huber G, von Bidder L, Meinel L, Weisser R, et al. Topical azithromycin for the prevention of Lyme borreliosis: A randomised, placebo-controlled, phase 3 efficacy trial. Lancet Infect Dis 2017; 17(3): 322-9.
Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, et al. Lyme borreliosis. Nat Rev Dis Primers 2016; 2: 16090.
Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, 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(1): 91-102.
Lantos PM, Shapiro ED, Auwaerter PG, Baker PJ, Halperin JJ, McSweegan E, et al. Unorthodox alternative therapies marketed to treat Lyme disease. Clin Infect Dis 2015; 60(12): 1776-82.
Paul B. Vaccines for Lyme disease. US2004O197339A1 (2004).
Alliger H, Frey A. Production of Borrella burgdorferi vaccine, product produced thereby and method of use. USOO6303129B1 (2001).

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Year: 2019
Page: [49 - 68]
Pages: 20
DOI: 10.2174/1574891X14666190327114641

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