1338 Lyme Disease

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Text of 1338 Lyme Disease

  • Lyme Disease: AMultisystem InfectionThat Affects theNervous System

    John J. Halperin, MD, FAAN, FACP

    ABSTRACTPurpose of Review: This article will enable the reader to diagnose and treatnervous system Lyme disease appropriately.Recent Findings: Appropriately applied serologic testing has high positive and neg-ative predictive values in nervous system Lyme disease. Oral antibiotics can be curativein most cases.Summary: Infection with the tick-transmitted spirochete Borrelia burgdorferi causesLyme disease, a disorder that involves the nervous system in about 15% of patients.Common manifestations include lymphocytic meningitis, cranial neuritis (particularlycranial nerve VII), painful radiculitis, other forms of mononeuropathy multiplex, andrarely CNS parenchymal involvement. Diagnosis is supported primarily by demon-stration of antiYB. burgdorferi antibodies in serum. CSF examination can be informativein problematic cases with parenchymal CNS infection or to identify meningitis. How-ever, oral antibiotics are probably effective in patients with meningitis and other formsof involvement, with the likely exception of parenchymal CNS infection.

    Continuum Lifelong Learning Neurol 2012;18(6):13381350.

    INTRODUCTIONBacterial infections of the CNS are notusually subtle. Depending on the organ-ism, illness can be fulminant and rapidlylethal (Neisseria meningitidis) or sub-acutely progressive, debilitating, andlethal (Mycobacterium tuberculosis).More indolent CNS infections, such aswith Treponema pallidum, tend to haveeffects less deadly but no less substan-tial. The neurobehavioral effects ofneurosyphilis are thought to have hadsignificant effects on world history asnumerous famous figures succumbedto general paresis of the insane. In thiscontext it should not be surprising thatthe observation thatBorrelia burgdorferi,the organism responsible for Lyme

    disease, can infect the CNS has led tosubstantial patient fear, physician anxi-ety, and Internet misinformation.

    While neuroborreliosis has fre-quently been likened to neurosyphilis,perhaps themost significant similarity isthat limitations ofmedical knowledge atthe time of both diseases initial recog-nition resulted in misattribution of allmanner of unrelated clinical syndromesto these infections. Although the tech-nology to diagnose Lyme disease has im-proved rapidly, many of the initialconcerns and misunderstandings havepersisted long after diagnostic issueswere largely resolved, leading to a per-sistent mythology that has proven verydifficult to debunk.

    Address correspondence toDr John J. Halperin, OverlookMedical Center, Department ofNeurosciences, 99 BeauvoirAve, Summit, NJ 07902,[email protected] Disclosure:Dr Halperin serves on theeditorial board of TheNeurologist, holds stock orstock options greater than5% of the company or greaterthan $10,000 in value inAbbott Laboratories,Bristol-Myers Squibb, Johnson& Johnson, Inc, and Merck &Co, Inc. Dr Halperin has servedas an expert witness defendingphysicians in medicalmalpractice cases.

    Unlabeled Use of Products/Investigational UseDisclosure: Dr Halperinreports no disclosure.

    * 2012, American Academyof Neurology.

    1338 www.aan.com/continuum December 2012

    Review Article

    Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

  • In fact, much is currently knownabout this infection. Its neurologic man-ifestations are quite well defined andgenerally easily treated; the infection isusually straightforward to diagnose andcure. The goal of this article is to providea framework for understanding whatdoes and does not constitute nervoussystem Lyme disease; how most appro-priately to diagnose it; and, most impor-tantly, how to treat it effectively.

    BACKGROUNDThe disease we refer to as Lyme diseaseis a multisystem infection caused by thetick-transmitted spirochete, B. burg-dorferi. The most common manifesta-tion of this infection is the almost uniquerash known as erythema migrans, firstdescribed more than a century ago,1 70years before the responsible micro-organism was identified. Over those 7decades the disease was described syn-dromically, a historical precedent thatnow needs to be discarded.

    As with many infections, the dissem-inating microorganism has specificorganotropisms. In Europe, the first formof extracutaneous involvement de-scribed was neurologic. In 1922, Garinand Bujadoux2 reported a patient withmeningitis and painful polyradiculitis fol-lowing a tick bite. In the United States,the earliest observations focused on rheu-matologic involvement.3 Characteriza-tion of Lyme arthritis led to a series oflandmark studies culminating in the iso-lation of B. burgdorferi in 1982,4 followedshortly thereafter by the demonstra-tion that this organism was indeed thecause of this disease.5,6 At the sametime, it became clear that Lyme arthritiswas actually part of a multisystem dis-order, usually associated with a priorerythema migrans, with occasionalpatients developing cardiac conductionabnormalities and a larger percentagedeveloping the syndrome describedyears earlier by Garin and Bujadoux.7 To

    complete the picture, in 1984, Europeaninvestigators were able to identify theclosely related microorganisms,8 ulti-mately characterized as Borrelia gariniiand Borrelia afzelii (and occasionallyB. burgdorferi), responsible for the re-lated disorders they had been treatingwith antibiotics for decades.

    DIAGNOSISNormally the identification of a micro-organism as the cause of an illness wouldbe expected to simplify its diagnosis,allowing for greater clarity regarding thetrue spectrum of the disease and forbetter-informed treatment. However,this step was not as simple as one mighthave hoped. First, direct isolation ofspirochetes from infected patientsproved challenging, as it is difficult togrow B. burgdorferi in cultureVnotimpossible, as in syphilis, but problem-atic. Culture requires special media,with incubation at lower temperaturesand for a substantially longer period oftime than for other organisms, condi-tions not easily provided in most diag-nostic microbiology laboratories. EvenPCR-based technologies have proven tobe of low diagnostic sensitivity, probablybecause the organism is present primar-ily in tissue, with very few spirochetes inaccessible fluids such as blood or CSF.As a result, diagnosis remains dependentprimarily on demonstration of the sero-logic response to the organism.

    Serologic testing for diagnosing anyinfection has at least three inherent lim-itations. (1) When the host immunesystem is first exposed to a microorgan-ism, it takes time before the antibodyresponse develops to the point whereantibody concentrations are discernibleabove background nonspecific reactiv-ity. Thus, in patients in the first 4 weeksor so of Lyme disease, such as in manypatients with erythema migrans andeven some with cranial neuropathies,serologic test results are often negative.


    h The neurologicmanifestations of Lymedisease are quite welldefined and generallyeasily treated; theinfection is usuallystraightforward todiagnose and cure.

    h Lyme disease is amultisystem infectioncaused by thetick-transmittedspirocheteBorrelia burgdorferi.

    h In 1922, Garin andBujadoux reported apatient with meningitis,painful polyradiculitis,and cranial neuritisfollowing a tick bite.

    h Diagnosis of Lymedisease remainsdependent primarilyon demonstration ofthe serologic responseto the organism.

    h When the host immunesystem is first exposedto a microorganism, ittakes time before theantibody responsedevelops to the pointwhere antibodyconcentrations arediscernible abovebackground nonspecificreactivity.

    1339Continuum Lifelong Learning Neurol 2012;18(6):13381350 www.aan.com/continuumCopyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

  • While this is a false negative in thestrictest sense, it is also a normal bio-logic phenomenon seen in all infectionsand does not invalidate the use ofserologic tests in other, more appropri-ate contexts. In patients who have beenill for 4 weeks or longer, serologiesshould be positive in most instances(Table 5-1 and Figure 5-1).

    (2) By design (teleologically speak-ing), once the hosts immune responsehas started to produce antibodies, it willtypically continue to do so for an ex-

    tended period of time. This poses twochallenges. Since antibodies do not dis-appear the instant an infection is cured,serologic testing cannot be used as anindication of treatment efficacy or as arationale for continued treatment.Equally importantly, since antibodiescan be present years or decades9 aftersuccessful elimination of an infection, itis always important to consider whethera positive serology relates to a currentactive infection or an irrelevant expo-sure in the remote past.


    h In patients who havebeen ill for more than4 weeks, serologiesshould be positive inmost instances.

    h Serologic testing cannotbe used as an indicationof treatment efficacyor as a rationale forcontinued treatment.

    h Since antibodies canbe present years ordecades after successfulelimination of aninfection, it is alwaysimportant to considerwhether a positiveserology relatesto a current activeinfection or an irrelevantexposure in theremote past.

    TABLE 5-1 Interpretation of Western Blots in Lyme DiseaseTwo-Tier Testinga

    IgM IgG

    Bands 23, 39, 41 kD 18, 23, 28, 31, 39, 41, 45, 58, 66, 93 kD

    Positive if 2 of 3 5 of 10

    Role Early disease only Disease 94 to 6 weeks durationa Applicable if ELISA (usual first-tier test, although immunofluorescence can be used) result ispositive or borderline, but undefined if first-tier test result is negative.

    FIGURE 5-1 Diagnostic stratagem: If ELISA is positive or borderline then