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  • Epidemiology of LymeNeuroborreliosis

    David S. Younger, MD, MPH, MSa,b,*


    Lyme disease Borrelia burgdorferi Neurology Public health Epidemiology


    According to the Centers for Disease Control and Prevention, Lyme disease is the mostcommonly reported vector-borne illness and the fifth most common disease in the Na-tional Notifiable Diseases Surveillance System, making it an important public healthconcern.

    Lyme disease is caused by the bacterium Borrelia burgdorferi and is transmitted to hu-mans through the bite of infected blacklegged Ixodes ticks.

    Typical symptoms include fever, headache, fatigue, and a characteristic skin rash callederythema migrans.

    Undiagnosed and therefore untreated, infection disseminates to the nervous system. The nonhuman primate model of Lyme neuroborreliosis accurately mimicked the microbi-ological, clinical, immunologic, and neuropathologic aspects of human Lymeneuroborreliosis.


    Lyme disease in humans is caused by the transmission ofBorrelia (B) burgdorferi in thebite of infected blacklegged Ixodes ticks. Typical symptoms include fever, headache,fatigue, and a characteristic skin rash called erythema migrans (EM). If left undiag-nosed and therefore untreated, infection disseminates to the nervous system causingLyme neuroborreliosis (LNB). The clinical diagnosis is based on symptoms, physicalfindings, and the probability of exposure to infected ticks in endemic geographic areasand confirmed by serologic and cerebrospinal fluid (CSF) testing with the demonstra-tion of intrathecal production of Borrelia-specific antibodies. There is general recogni-tion for the potential of infectious-related autoimmune processes contributing tonervous system disease progression.

    The author has nothing to disclose.a Division of Neuroepidemiology, Department of Neurology, New York University School ofMedicine, New York, NY, USA; b College of Global Public Health, New York University, NewYork, NY, USA* Corresponding author. 333 East 34th Street, 1J, New York, NY 10016.E-mail address: david.younger@nyumc.org

    Neurol Clin 34 (2016) 875886http://dx.doi.org/10.1016/j.ncl.2016.05.005 neurologic.theclinics.com0733-8619/16/ 2016 Elsevier Inc. All rights reserved.

    Downloaded from ClinicalKey.com at New York University October 23, 2016.For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.


  • Younger876


    Originally named for Lyme and Old Lyme, Connecticut, wherein a tight clustering ofrecurrent attacks of childhood and adult asymmetric oligoarticular arthralgia occurredbeginning in 1972, Lyme disease showed a peak incidence of new cases in the sum-mer and early fall.1,2 Epidemiologic analysis of the clustering suggested transmissionof a causative agent by an arthropod vector to humans, in whom 25% describe anexpanding annular EM rash before onset of the arthritis. Cultures of the synoviumand synovial fluid did not suggest infection with agents known to cause other formsof arthritis. Those in whom arthritis developed seemed to have significantly elevatedESR, lower third and fourth components of complement (C3, C4), higher serum IgMlevels, and serum cryoprecipitates at the time of the skin lesions, suggesting an activeimmunologic response. Five years later, Burgdorfer and colleagues3 isolated a spiro-chete from the tick Ixodes (I) dammini that bound immunoglobulins of patients conva-lescing from Lyme disease and recorded the development of lesions resembling EM inNew Zealand white rabbits 10 to 12 weeks after being bitten by the ticks. One yearlater in the same volume of The New England Journal of Medicine, Steere and co-workers4 and Benach and colleagues5 described the spirochetal etiology of Lyme dis-ease. Benach and colleagues4 isolated spirochetes from the blood of 2 of 36 patientsin Long Island and Westchester County, New York with signs and symptoms sugges-tive of Lyme disease that were morphologically similar and serologically identical toorganisms known to infect I dammini ticks, endemic to the area and epidemiologicallyimplicated as vectors of Lyme disease.


    By 1989 Steere6 summarized the causation, vector and animal hosts, clinical manifes-tations, pathogenesis, and treatment of human Lyme disease. Three stages of infec-tion were recognized, each with different clinical manifestations. Stage 1 followed thebite by the tick with spread of bacteria locally in the skin in 60% to 80% of patients,resulting in EM rash that faded in 3 to 4 weeks but often accompanied by fever, minorconstitutional symptoms, or regional adenopathy. At this time, the patients mononu-clear cells responded minimally to spirochete antigens, and even specific antibodymight be lacking. Stage 2 of early infection followed days or weeks after the bitewith bloodstream or lymphatic spread to many organ sites. More common in theUnited States than in Europe, widespread dissemination resulted in recovery of spiro-chete from tissue specimens of meninges, brain, myocardium, retina, muscle, bone,synovium, spleen, and liver.7


    Between 1998 and 1993 two animal models, a murine8 and nonhuman primate(NHP)9,10 accurately mimicked the microbiological, clinical, immunologic, and neuro-pathologic aspects of LNB. Two methods of spirochete inoculation, by needle injec-tion of 1 million N40Br strain spirochetes and feeding of infected ticks were foundto be comparable in establishing infection. Transient immunosuppression maximizedthe yield of infection in some of the NHPs. The central nervous system (CNS) was amajor reservoir of spirochetal infection and showed that a strong, well-developedanti-Borrelia humoral immune response did not clear spirochetes from NHP duringthe months of infection. Accordingly, spirochetal presence was a necessary but notsufficient condition for inflammation.

    Downloaded from ClinicalKey.com at New York University October 23, 2016.For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.

  • Epidemiology of Lyme Neuroborreliosis 877


    The public health surveillance of Lyme disease is reviewed elsewhere.11 Lyme diseaseis the most commonly reported vector-borne illness and the fifth most common dis-ease in the National Notifiable Diseases Surveillance System. The Centers for DiseaseControl and Prevention (CDC) reported 22,014 confirmed and 8817 probable incidentUS cases of Lyme disease reported during 2012. These data were similar to those of2010 and 2011 but substantially lower than the number reported in 2008 and 2009.One important development, however, was an increase in the geographic distribution.In 2012, a total of 356 counties had a reported incidence of 10 confirmed cases per100,000 persons compared with 324 counties in 2008. In 2013, 95% of confirmed inci-dent cases were reported from 14 northeast and midwestern states including Con-necticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire,New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, and Wiscon-sin. The seasonal occurrence of Lyme disease follows the life cycle of Ixodes ticks.Children age 5 to 14 years and adults age greater than 65 years are most susceptiblewhen they engage in activities that heighten exposure to tick bites infected with Bburgdorferi. Most cases occur from late spring to early fall when larval ticks matureinto nymphs. Nymphs are infected by primary mammalian hosts transmitting the dis-ease to secondary human hosts. Biodiverse habitats have reduced risk of Lyme dis-ease. Forest clearings favor more efficient mammalian hosts such as micespreading infection to people.Surveillance methods to ascertain cases of Lyme disease use rigorous clinical and

    laboratory criteria to verify the diagnosis for reporting purposes, the results of whichare verified and tabulated in final numbers in the Morbidity and Mortality WeeklyReport in early August of the following year and summarized in the annual Morbidityand Mortality Weekly Report Summary of Notifiable Diseases (www.cdc/gov/mmwr/mmwr_nd/). A CDC public use dataset provides the number of confirmed cases bycounty in 5-year intervals, enabling investigators to access and download the informa-tion into compatible research-driven computer software for epidemiologic analysis. Itshould be emphasized that the methodology and specific criteria used in case ascer-tainment for epidemiologic and public health activities are not intended to be appli-cable to routine clinical diagnosis or the selection of antibiotic regimens, as asizable population would be excluded from consideration of the diagnosis and treat-ment, specifically those with less-compelling, incomplete, or atypical presentations.For surveillance purposes, the clinical description of Lyme disease is a systemic

    tick-borne disease with protean manifestations including dermatologic, rheumato-logic, neurologic, and cardiac manifestations. The most common clinical marker forthe disease is the EM rash, the initial skin lesion so noted in up to three-quarters ofconfirmed cases. Late manifestations include musculoskeletal (joint swelling, monoar-thritis and oligoarthritis), nervous system (lymphocytic meningitis, cranial neuritis, rad-iculoneuropathy, and encephalomyelitis), and cardiovascular (high-grade heart blockand atrioventricular conduction defects). Arthralgia, myalgia, and fibromyalgia; head-ache, fatigue, paresthesia, stiff neck; and palpitation, bradycardia, bundle branchheart block, and myocarditis, which may be highly suggestive of an index cas


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