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  • DOI 10.1212/01.wnl.0000265517.66976.28; Prepublished online May 23, 2007;Neurology

    J. J. Halperin, E. D. Shapiro, E. Logigian, et al.Subcommittee of the American Academy of Neurology

    (an evidence-based review). Report of the Quality Standards Practice Parameter: Treatment of nervous system Lyme disease

    August 14, 2011This information is current as of

    on on the World Wide Web at:

    The online version of this article, along with updated information and services, is

    rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.Allsince 1951, it is now a weekly with 48 issues per year. Copyright 2007 by AAN Enterprises, Inc.

    is the official journal of the American Academy of Neurology. Published continuouslyNeurology

    by guest on August 14, 2011www.neurology.orgDownloaded from

  • Practice Parameter: Treatment of nervoussystemLymedisease (an evidence-based review)Report of theQuality Standards Subcommittee of theAmericanAcademyofNeurology

    J.J. Halperin, MDE.D. Shapiro, MDE. Logigian, MDA.L. Belman, MDL. Dotevall, MDG.P. Wormser, MDL. Krupp, MDG. Gronseth, MDC.T. Bever Jr., MD

    ABSTRACT Objective: To provide evidence-based recommendations on the treatment of nervous sys-tem Lyme disease and postLyme syndrome. Three questions were addressed: 1) Which antimicrobialagents are effective? 2) Are different regimens preferred for different manifestations of nervous sys-tem Lyme disease? 3) What duration of therapy is needed? Methods: The authors analyzed publishedstudies (19832003) using a structured review process to classify the evidence related to the ques-tions posed. Results: The panel reviewed 353 abstracts which yielded 112 potentially relevant arti-cles that were reviewed, from which 37 articles were identified that were included in the analysis.Conclusions: There are sufficient data to conclude that, in both adults and children, this nervous sys-tem infection responds well to penicillin, ceftriaxone, cefotaxime, and doxycycline (Level B recommen-dation). Although most studies have used parenteral regimens for neuroborreliosis, several Europeanstudies support use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis (LevelB), reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neu-rologic symptomatology, or failure to respond to oral regimens. The number of children (8 years ofage) enrolled in rigorous studies of oral vs parenteral regimens has been smaller, making conclusionsless statistically compelling. However, all available data indicate results are comparable to those ob-served in adults. In contrast, there is no compelling evidence that prolonged treatment with antibioticshas any beneficial effect in postLyme syndrome (Level A). NEUROLOGY 2007;69:11

    STATEMENT OF PURPOSE The Quality Stan-dards Subcommittee (QSS) develops scientificallysound, clinically relevant practice parameters to aidin the practice of neurology. This article addressesthe use of antibiotic treatments in patients with ner-vous system Lyme disease and post-Lyme syn-drome. These recommendations address the needsof medical providers caring for patients with theseconditions.

    Lyme disease is a multisystem infectious diseasecaused by the tick-borne spirochete Borrelia burg-dorferi, which frequently affects the nervous sys-tem. Published guidelines are available to assist inthe diagnosis of nervous system Lyme disease,1 andfor treatment of Lyme disease in general.2 However,there continues to be considerable controversy anduncertainty about the best approach to treatment ofneuroborreliosis. In the United States, Lyme diseaseaffecting the nervous system is generally treated

    with parenteral antibiotics, although several Euro-pean studies have demonstrated comparable effi-cacy with oral doxycycline, a drug that achievesadequate levels in the nervous system. Duration oftreatment varies widely, with published recommenda-tions ranging up to 4 weeks, despite a lack of compel-ling data supporting courses longer than 2 weeks.Some practitioners treat with combinations of antimi-crobials for many months, despite an absence of datato indicate this is rational or effective. Finally, there is alack of clarity as to which syndromes associated withLyme disease reflect nervous system infection, whichare consequences of infection outside the nervous sys-tem, and which are postinfectious.

    The relevant literature was reviewed in detail todetermine the following:

    1. Which antimicrobial agents have been shownto be effective or ineffective in the treatment of ner-vous system Lyme disease

    This article was previously published in electronic format as an Expedited EPub at

    From the Department of Neurosciences (J.J.H.), Overlook Hospital, NYU School of Medicine, Summit, NJ; Departments of Pediatrics andEpidemiology and Public Health (E.D.S.), Yale University School of Medicine, New Haven, CT; Department of Neurology (E.L.), University ofRochester School of Medicine and Dentistry, NY; Department of Neurology (A.L.B., L.K.), SUNY, Stony Brook, NY; Department of InfectiousDiseases (L.D.), Sahlgrenska University Hospital, Gothenburg, Sweden; Division of Infectious Diseases (G.P.W.), Department of Medicine, NewYork Medical College, Valhalla; Department of Neurology (G.G.), University of Kansas Medical Center; and Research Service, VAMHCS, and theDepartment of Neurology (C.T.B.), University of Maryland School of Medicine.

    Approved by the Quality Standards Subcommittee on July 29, 2006; by the Practice Committee on March 15, 2007; and by the AAN Board ofDirectors on April 5, 2007.

    Disclosure: The authors report no conflicts of interest. Received December 26, 2006. Accepted in final form March 7, 2007.

    Supplemental data

    Address correspondence andreprint requests to the AmericanAcademy of Neurology, 1080Montreal Ave., St. Paul,


    Copyright 2007 by AAN Enterprises, Inc. 1

    Published Ahead of Print on May 23, 2007 as 10.1212/01.wnl.0000265517.66976.28

    by guest on August 14, 2011www.neurology.orgDownloaded from

  • 2. If different regimens are preferred for differentmanifestations of neuroborreliosis

    3. What duration of therapy is needed

    DESCRIPTION OF THE ANALYTIC PROCESS Inthe spring of 2004 the Quality Standards Subcom-mittee (QSS) of the American Academy of Neurol-ogy (AAN) convened an expert panel ofinvestigators from the United States and Europewho have published extensively in the field. Thepanel was selected to represent a broad range of rel-evant expertise and opinion.

    In May 2004, a literature search was performed(all languages) using OvidMEDLINE, Pubmed, andEMBASE, using search terms Lyme Disease/[DrugTherapy, Therapy], Borrelia Infections/[DrugTherapy, Therapy], Borrelia burgdorferi group/and (borreliosis or Borrelia or neuroborreliosis),and Anti-Infective Agents/[Therapeutic Use] and(antibiotic$ or antimicrob$ or anti-microb$). Thisresulted in 353 citations. After elimination of dupli-cate citations, each abstract was reviewed by at leasttwo members of the panel for relevance for furtherreview. Any disagreements were arbitrated by athird reviewer. This resulted in a list of 112 articles,each of which was then reviewed by at least twomembers of the panel. Members of the panel recom-mended adding 10 additional references. After de-tailed review of all 122, the panel decided 37 articlescontributed relevant, assessable data. Articles wereexcluded if they did not address treatment of neu-roborreliosis, were not peer reviewed, or were solelyreview articles. The selected articles were then re-viewed in detail by all panel members to assess thequality of the evidence contained.

    Studies were divided into three groups: adultLyme disease, pediatric Lyme disease, and post-Lyme syndrome. Each article was reviewed to deter-mine if it specifically addressed treatment of neu-roborreliosis, and if it contained original data.Those that were relevant were then graded as ClassI through IV, using standard criteria, as listed inAppendix 2. An evidence table was constructed list-ing each study, its class, the treatment regimens as-sessed, whether it was prospective or retrospective,whether it was blinded or open, whether it was con-trolled or not, whether it used explicit or objectiveresponse criteria, the number of subjects, the dura-tion of observation, the completeness of follow-up,and the outcomes.

    Overall, four studies5-7,47 were Class I (three inpost-Lyme syndrome). One,47 performed in chil-dren, was considered Class I with regard to its pre-determined outcome measure, CSF antibiotic levels,but this study did not discuss clinical outcomes.

    Four studies were Class II (three in adults with neu-roborreliosis,15,18,19 one in children48). All were ratedClass II with regard to at least one of their predeter-mined objective measures of disease activity: ELISA,CSF cell count or culture, all of which were appar-ently measured in masked fashion. All four of thesestudies would be considered Class III with regard toclinical outcomes, for which assessments were notmasked. All other studies were Class III or IV.

    ANALYSIS OF THE EVIDENCE When Lyme borre-liosis affects the nervous system, it typically presentswith (a) all or part of a triadmeningitis, cranialneuritis, and radiculoneuritis (known in Europe asGarin-Bujadoux-Bannwarth syndrome); (b) paren-chymal inflammation of the brain or spinal cord; (c)mild radiculoneuropathy presenting as a more dif-fuse, predominantly sensory peripheral


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