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.

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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.

KEY POINTS

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.

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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.

KEY POINTS

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 assess IgM and IgGWestern blots.


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(3) Antibodies react to molecularshapes, not specific organisms. Cross-reactivity can be specific for closely re-lated organisms, such as Treponemapallidum or relapsing fever Borreliaesp, or nonspecific, such as occurs inpolyclonal gammopathies in endocar-ditis, lupus, or even multiple sclerosis.The latter can be addressed satisfacto-rily with Western blots. The former canbe technically challenging but usuallycan be resolved by combining epide-miologic insights (fortunately, relapsingfevers and Lyme disease do not overlapgeographically) and the use of nonspe-cific reaginic tests such as the VenerealDisease Research Laboratory test, forwhich results are positive in syphilis butnot Lyme disease.

Persistent and inappropriate con-cerns about the validity of serologic test-ing have led some to continue toemphasize a syndromic definition ofLyme disease. Defining the disease clin-ically rather than microbiologically hasbeen taken as license to include anyconceivable clinical phenomenon withinthe spectrum of Lyme disease, based onanecdotal observations or preconceivednotions. Not surprisingly, if cases arediagnosed in the absence of compellingevidence of the causative infection,treatment response, particularly foratypical cases, will be inconsistent, lead-ing to inappropriate doubts about rec-ommended treatment strategies.

Excluding patients in the first 4weeks or so of infection, currently recom-mended two-tier serologic testing hashigh sensitivity, specificity, and predic-tive value (Table 5-1). The recommen-ded procedure10 begins with a sensitivebut less specific screening test, typicallyan ELISA for antiYB. burgdorferi anti-bodies. Sera that are positive or border-line are then tested by Western blot toidentify the specific antigens to whichantibodies react. Criteria for interpret-ing IgM and IgG blots were developed

based on a statistical analysis of patternsin large numbers of patients with andwithout B. burgdorferi infection.11

Some bands that are known to be highlyspecific for B. burgdorferi were not in-cluded, because these antibodies occurso infrequently as to have little predic-tive value. None of the bands used wereselected for their uniqueness, butrather because in various combinations,they provide excellent diagnostic spe-cificity and positive and negative pre-dictive values. IgG blots are interpretedas positive when five of 10 selectedbands are present (Table 5-1). IgM blotsare interpreted as positive when two ofthree selected bands are present. Be-cause only two IgM bands are required,and because IgM has far more non-specific binding than IgG, great cautionis required in interpreting IgM blots.They should only be used in patientsin whom symptoms are of a monthsduration or less. Beyond this timepatients should have developed anIgG response, and IgG blots will befar more specific. In patients with onlyIgM positivity but symptoms lasting1 month or longer, or with a negativeELISA result but positive blot, theWestern blot findings are almost alwaysspurious.12

Serologies do not become tempo-rarily negative while a patient receivesantibiotics. Early concerns that partialincomplete treatment might render apatient seronegative13 despite on-going infection have not been sup-ported by subsequent studies. In brief,while false negatives are common inthe first month or so of infection, theyare not established to occur in patientswith infection of longer duration.

Analogous techniques can be usedto diagnose CNS infection. The CNS be-haves as an independent immune com-partment. Infection leads to in-migrationand proliferation of B cells specificto the invading organism and, hence,

KEY POINTS

h Currently recommendedtwo-tier serologictesting has highsensitivity, specificity,and predictive value.

h Criteria for interpretingIgM and IgG blots weredeveloped based on astatistical analysis ofpatterns in largenumbers of patientswith and without B.burgdorferi infection.

h In patients with onlyIgM positivity butsymptoms of a durationof 1 month or longer,or patients with anegative ELISA resultbut positive blot, theWestern blot findingsare almost alwaysspurious.

h While false negativesare common in thefirst month or so ofinfection, they are notestablished to occur inpatients with infectionof longer duration.


intrathecal production of the antibodytargeted against B. burgdorferi. Thisin-migration appears to be driven byearly elevations in the CSF concentra-tion of CXCL13,14 a B-cellYattractingchemokine; some have suggested thatmeasurement of this can be diagnosti-cally useful.15

A small amount of peripheral bloodimmunoglobulin (approximately 0.5%to 1.0%) normally filters into CSF. As aresult, if a patient has circulating antiYB.burgdorferi antibodies in serum, theywill be detectable in CSF. Similarly, ifthere is blood-brain barrier breakdownwith a higher concentration of CSF im-munoglobulin than normally expected,this too will lead to the detection ofmore B. burgdorferiYadhering anti-body in the CSF than expected (reflect-ing higher nonspecific cross-reactivity).Consequently, assessment of intrathe-cal antibody production requires com-parison of CSF and serum concentrationsof specific antibodies, correcting fortotal immunoglobulin concentration inboth compartments.16 This can bedone by a capture assay, by immuno-globulin measurement in serum andCSF with appropriate dilution of both,or by mathematic correction. Simulta-neous measurement of serum and CSFconcentrations is essential, however.Only when the relative concentrationof specific antibody in the CSF exceedsthat in serum (CSF to serum indexgreater than 1.0) can this be consideredevidence of CNS infection.

Measurement of the amount of intra-thecally produced antibody that is spe-cific to B. burgdorferi can be useful inthe diagnosis of CNS infection. In pa-tients with only peripheral nervoussystem involvement, or with no neuro-logic involvement at all, there is noreason to expect CSF antibody to bepresent. Importantly, just as in periph-eral blood, apparent CSF antibody ex-cess can persist years after cure of a

CNS infection.9 Fortunately (from a diag-nostic perspective), active CNS infectionis usually marked by a CSF pleocytosisor increased protein concentration,changes that should improve followingsuccessful antimicrobial therapy.

The other principal shortcoming ofthis measurement as a diagnostic tech-nique is that its sensitivity is undefined,ranging from 50% to 95% in variousstudies of differing populations.17Y19

The potential for cross-reactions in otherinfections also exists, but only neuro-syphilis results in significant CSF antibodycross-reactivity (relapsing fevers do nottypically infect the CNS), and this canusually be differentiated with a non-specific reaginic test such as the CSFrapid plasma reagin; results of these arerarely, if ever, positive in neuroborreliosis.

CLINICAL MANIFESTATIONSHistorically, the first described manifes-tations of the infection we now know asLyme disease were dermatologic. In par-ticular, erythema migrans, also knownas erythema chronicum migrans, wasfirst described in Europe in 1910 and inthe United States in 1970.20 A virtuallypathognomonic rash beginning at thesite of a hard-shelled Ixodes tick bite,erythema migrans consists of a slowlyexpanding erythroderma that enlargesover days to weeks, often reachingmany inches in diameter. Spirochetesinitially proliferate at the site of the tickbite. When sufficiently numerous, theyslowly migrate centrifugally from thesite of inoculation, typically for up to30 days after the bite. Depending onthe location on the body, the rash maybe round or elliptical. Central pallormay be present, often but not in-variably giving rise to a targetoidappearance. Hallmarks include its slow,steady enlargement and relativelyasymptomatic nature. It usually is easilydifferentiated from an acute allergicreaction to the tick bite, which also is

KEY POINTS

h Assessment ofintrathecal antibodyproduction requirescomparison of CSF andserum concentrationsof specific antibodies,correcting for totalimmunoglobulinconcentration in bothcompartments.

h In patients with onlyperipheral nervoussystem involvement,or with no neurologicinvolvement at all,there is no reason toexpect CSF antibodyto be present.

h Active CNS infection isusually marked by aCSF pleocytosis orincreased proteinconcentration, changesthat should improvefollowing successfulantimicrobial therapy.

h Hallmarks of theerythroderma of Lymedisease include its slow,steady enlargement andrelatively asymptomaticnature.


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red and expands, but which typicallyoccurs within hours of the bite, is in-tensely pruritic, and subsides spontane-ously within a few days.

In some patients the rash becomesmultifocal, with each new focus repre-senting a nidus of spirochetes thatspread hematogenously from the initialsite, and the spirochetes thenmigratingcentrifugally from this new focus. Notsurprisingly, this bacterial dissemina-tion is accompanied by the usual hostinflammatory reaction to a bacteremia:fever, diffuse aches and pains, head-aches, malaise, fatigue, etc. While this isoften referred to as flulike, it is impor-tant to note that Lyme disease does notcause upper respiratory or gastrointes-tinal symptoms.

The differential diagnosis is limited.Fixed drug eruptions can appear sim-ilarly targetoid but do not evolve.Southern tickYassociated rash illnesshas been described in recent years inMissouri and surrounding states.21 Theetiology remains undetermined, but itclearly is not associated with a borrelialor other identified infection and hasnot been associated with extracutane-ous manifestations.

In addition to erythema migrans,European dermatologists recognizetwo manifestations reported rarely inthe United States. Borrelia lymphocy-toma consists of an erythematous swell-ing, typically affecting the earlobe orthe areola of the breast, and occursrelatively early in disseminated infec-tion. Acrodermatitis atrophicans, a latemanifestation, consists of tissue paperYlike thinning and discoloration of theskin of one or more limbs.

When Garin and Bujadoux describedthe first form of extracutaneous involve-ment, consisting of lymphocytic menin-gitis and painful polyradiculitis, theyconjectured that it was caused by atick-transmitted spirochetal infection,because of faintly positive Wasserman

test results in their patients.2 By the1950s, it was widely recognized thatthe syndrome improved following pen-icillin treatment.22 This disorder, knownas Garin-Bujadoux-Bannwarth syndrome,is now considered to include all or partof a classic triad: lymphocytic meningitis,cranial neuritis, and polyradiculitis.

In the United States, the first extrac-utaneous manifestations described wererheumatologic.3 It was the identificationof a surprising number of children inLyme and Old Lyme, Connecticut, diag-nosed with juvenile rheumatoid arthritisthat led directly to the identification of B.burgdorferi. As the affected populationwas studied further, additional extracu-taneous disorders became apparent. Upto 5% of infected individuals developedotherwise unexplained heart block, onoccasion requiring a temporary pace-maker. Ultimately a pattern of neuro-logic manifestations very similar to thatdescribed in Europe decades earlierbecame apparent.

NEUROLOGIC MANIFESTATIONSOne of themany oddities in themedicalliterature about this infection is the re-peated emphasis on the differences be-tween European and North AmericanLyme disease, which are attributed todifferent organotropisms or immuno-genic features of the organisms pre-valent in the two regions. Yet fromneurologists perspectives, the similar-ities are striking. In both regions, thenervous system is affected in 10% to15% of patients, primarily in the first fewmonths after the initial infection, duringwhat is often termed acute dissemi-nated infection (analogous to the sec-ond stage of syphilis). Approximatelytwo-thirds of these individuals havelymphocytic meningitis, slightly fewerhave a cranial neuropathy, and abouthalf as many have painful radiculitis.

Lymphocytic meningitis presentswith the same range of symptoms as

KEY POINTS

h While often referred toas flulike, Lymedisease does not causeupper respiratory orgastrointestinalsymptoms.

h Garin-Bujadoux-Bannwarthsyndrome is nowconsidered to includeall or part of a classictriad: lymphocyticmeningitis, cranialneuritis, andpolyradiculitis.

h In both the UnitedStates and Europe, thenervous system isaffected in 10% to15% of patients withLyme disease, primarilyin the first few monthsafter the initial infection.

h Approximatelytwo-thirds of individualswith Lyme disease havelymphocytic meningitis;slightly fewer have acranial neuropathy;and about half asmany have painfulradiculitis.


aseptic meningitis and is similarly be-nign in nature. Algorithms have beenproposed to differentiate it from enter-oviral and other viral causes of menin-gitis.23 Viral meningitis tends to have amore abrupt onset; Lyme meningitis ismuch more likely if a concomitant cra-nial neuropathy is present. CSF findingsare similar, with a modest elevation ofprotein concentration (typically lessthan 150 mg/dL) and lymphocytic pleo-cytosis (typically less than 200 cells/2L)and normal glucose concentration.Lymphocytes often have a strong B-cellpredominance. In patients with CNSinflammation of longer duration, partic-ularly those infected with Europeanstrains, this persistent B-cell stimulationis reflected in the presence of oligoclo-nal bands and increased overall immu-noglobulin production, as reflected inelevated IgG index or IgG synthesisrates.19

Although lymphocytic meningitisoften occurs in patients with Lymeradiculitis or cranial neuritis, it appearsthis association is neither necessary norsufficient. Cranial and peripheral nerveinvolvement can occur anywhere alongthe course of affected nerves, not pref-erentially in the subarachnoid space.24

Approximately three-fourths of patientswith Lyme-associated cranial neuropa-thies present with a facial nerve palsy.Early studies suggested this could bebilateral in up to one-fourth of cases.25

More recent data are lacking. In en-demic areas in warm months, as manyas one-fourth of facial nerve palsies maybe associated with Lyme disease.26 Sinceobviously this means three-fourths arenot, a diagnosis of Lyme disease cannotbe assumed in patients with facial nervepalsies. Outcomes are generally excel-lent. Antimicrobial treatment is recom-mended, primarily to prevent continuedinfection. Concomitant corticosteroidtreatment does not appear to have anadverse effect on outcomes.

Other cranial nerves can be involved,withmore rostral nerves appearing to beinvolved more frequently. Extraocularmuscle palsies, trigeminal nerve symp-toms, and hearing and balance issuesoccur infrequently compared to theseventh nerve. Only isolated case re-ports describe involvement of the vagus,glossopharyngeal, accessory, and hypo-glossal nerves.

Probably the most frequently mis-diagnosed entity is radiculoneuropathy.Patients present with acute dermatomalpain, largely indistinguishable from thatof a mechanical radiculopathy, withsimilar weakness and reflex changes(Case 5-1 and Case 5-2). Hints in thehistory include the lack of a clearprecipitant, but this is hardly unique.Findings often involve more than onedermatome, suggesting a less focalprocess. Ultimately the diagnosis re-quires thinking of it, eliminating amechanical cause by imaging, and con-firming the presence of B. burgdorferiinfection serologically.

Neurophysiologic studies suggestthat both cranial neuropathies andradiculoneuropathies are actuallymanifestations of a mononeuropathymultiplex.24 In fact, this probablyrepresents the underlying pathophysi-ology for virtually all peripheral nervoussystem Lyme disease, with describedassociated syndromes including typicalmononeuropathies, brachial and lum-bosacral plexopathies, and what ap-pears to be a diffuse neuropathy but isactually a confluent mononeuropathymultiplex. Rare patients have beendescribed with a Guillain-BarreYlikepicture.27 In at least one case series, neu-rophysiologic findings were convincingfor demyelination. This has been soinfrequent, however, that it is notobvious whether this is more than achance co-occurrence.

Rare patients develop inflammationwithin the substance of the CNS. This

KEY POINTS

h Approximatelythree-fourths of patientswith Lyme-associatedcranial neuropathiespresent with a facialnerve palsy.

h As many as one-fourthof facial nerve palsies inLyme-endemic areasmay be associated withLyme disease.

h Patients with Lymedisease present withacute dermatomalpain, largelyindistinguishablefrom that of amechanicalradiculopathy, withsimilar weakness andreflex changes.

h In Lyme disease,findings may involvemore than onedermatome.

h Cranialneuropathies andradiculoneuropathiesare actuallymanifestations of amononeuropathymultiplex.


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encephalomyelitis most commonlyinvolves the spinal cord at the level ofa radiculopathy; very rarely it involvesinflammation in the substance of the

brain. Such involvement is usually appa-rent on MRI scans and accompanied byinflammatory CSF; involved areas arehypermetabolic on PET scans.28

KEY POINT

h Rare patients withLyme disease developinflammation withinthe substance ofthe CNS.

Case 5-1A 45-year-old man from a Lyme-endemic area presented with 5 months ofintractable right upper-extremity pain described as burning in characterand radiating down the neck and over the shoulder. Previous evaluationincluded MRI of the cervical spine demonstrating multilevel disc bulgingwithout foraminal or central canal impingement. Extensive shoulder andchest imaging had been unrevealing. EMG showed primarily a C5radiculopathy including paraspinous denervation, with additional changesin C6 innervated muscles. Three months of symptomatic management,including physical therapy, acupuncture, nonsteroidal anti-inflammatories,a trial of a methylprednisolone dose pack, and three cervical epiduralsteroid injections, provided no relief. On referral, his examinationdemonstrated mild weakness of deltoids, supraspinatus, and biceps, anddepressed right biceps and brachioradialis jerks.

Lyme ELISA was strongly positive (4 times negative cutoff). Westernblot demonstrated one of three IgM bands and eight of 10 IgG bands.CSF demonstrated 15 lymphocytes/2L, protein concentration of 85 mg/dL,normal glucose concentration, and CSF to serum Lyme antibody indexof 2.0 (ie, CSF-specific antibody was proportionately twice that in serumafter normalization for IgG concentration). The patient received 4 weeksof oral doxycycline, and symptoms resolved completely.

Comment. Lyme disease causes severe radicular-type pain in about5% of patients. Although pain is typically dermatomal, careful evaluationoften demonstrates somewhat more widespread involvement. Dependingon location, pain can be misdiagnosed as visceral or mechanical radicular.Serologies are usually positive and CSF is often inflammatory. Symptomsare usually rapidly responsive to appropriate antibiotics.

Case 5-2The identical twin brother of the patient in Case 5-1 presented with5 months of identical symptoms, a negative Lyme ELISA, IgM Westernblot with three of three bands, and IgG blot with one of 10 bands. CSFwas normal except for a protein concentration of 85 mg/dL. His fastingblood glucose concentration was 195. Oral hypoglycemics were started,and his pain was treated symptomatically. No antibiotics were given.Symptoms subsided during the next 4 months.

Comment. Serologic test results should be invariably positive in apatient with neuroborreliosis that has been symptomatic for 5 months.With a negative ELISA, Western blots are of no value. In patients withdisease of months duration, a Western blot with solely IgM bands isundoubtedly a cross-reaction and not evidence of B. burgdorferi infection,past or present.


The entity referred to as Lyme en-cephalopathy, a manifestation oftenerroneously confused with encephalo-myelitis, has caused more than its fairshare of confusion among physiciansand patients alike.29Y31 Early in the evo-lution of our understanding about Lymedisease, it became apparent that manypatients with active systemic inflamma-tory disease, arthritis in particular butother manifestations as well, describedan accompanying sense of cognitiveslowing and memory difficulty thatinterfered with day-to-day functioning(Case 5-3 and Case 5-4). Early studiesshowed that few of these patients hadanything to suggest actual nervous sys-

tem infection. Neurologic examinationsand brain MRIs were generally normal,as were CSF examinations. Rather, thisappeared to be analogous to the toxic-metabolic encephalopathy experi-enced by patients with innumerableother infections, such as pneumonia orurinary tract infections, or other activeinflammatory disorders, such as rheu-matoid arthritis, presumably mediatedby cytokines or other molecules capa-ble of crossing the blood-brain barrierand altering neurologic function with-out damaging the CNS. Unfortunately,the notion that this might reflect un-derlying brain damage became wide-spread, often supported by unreliable

KEY POINTS

h Encephalomyelitis mostcommonly involves thespinal cord at the levelof a radiculopathy andis usually apparenton MRI scans andaccompanied byinflammatory CSF;involved areas arehypermetabolic onPET scans.

h Many patients withactive systemicinflammatory disease,Lyme arthritis inparticular but othermanifestations as well,have described anaccompanying sense ofcognitive slowingand memory difficulty.

h Early studies showedthat few patients withLyme encephalopathyhad anything tosuggest actual nervoussystem infection. Thisappeared to beanalogous to thetoxic-metabolicencephalopathyexperienced by patientswith innumerableother infections, suchas pneumonia or urinarytract infections, orother active inflammatorydisorders such asrheumatoid arthritis.

Case 5-3A 52-year-old man who frequently golfed in a Lyme-endemic areapresented to a rheumatologist with a 1-year history of episodic,unprovoked, recurrent painful swelling of one knee or the other. Oneach occasion the knee became red, painful, and swollen; remainedsymptomatic for several weeks; and then subsided. He had been treatedwith nonsteroidal anti-inflammatories as well as steroid injections, noneof which provided more than temporary relief. During this time, hereported, he had felt run down and cognitively slowed. When he arguedin court as an attorney, he found his reasoning less rapid than before.He had no other neurologic complaints and recalled no erythema migransor tick bites, although his high golf handicap frequently took him offthe greens to pursue errant balls. His rheumatologist found an extremelyelevated Lyme ELISA (6 times the upper limit) with nine bands on IgGWestern blot. The patient had had a brain SPECT interpreted as showingmultifocal hypoperfusion consistent with encephalitis; yet his brain MRIwas normal. The patient was then referred to a neurologist for possiblenervous system Lyme disease.

On neurologic examination, Mini-Mental State Examination and allother testing were normal. A lumbar puncture demonstrated normalCSF with a CSF to serum Lyme index of 0.5. The patient was treatedwith 4 weeks of oral doxycycline. During the next 5 months he notedthat his arthritis subsided and his cognitive function returned to normal.

Comment. Patients with active systemic inflammatory disease (eg,urinary infections, pneumonia) often describe fatigue and problemswith memory and mental focus. Presumably related to remote effectsof cytokines, these are not evidence of brain disease and typicallyresolve as the broader illness resolves. Qualitative brain SPECT scans areused by some in this context. There is no evidence supporting the notionthat the described abnormalities reflect brain disease, and the tests shouldprobably not be performed.


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tests such as qualitative brain SPECTscans, reinforcing patients fears thatLyme disease causes an irreversibleand debilitating neurologic disorder.In fact, the very rare instances of Lymeencephalomyelitis are usually easilydifferentiated from this encephalop-athy; the latter patients need to be re-assured that their symptoms are neitherirreversible nor evidence of brain damage.

Much attention has focused on pa-tients who have persisting fatigue andcognitive difficulty after being treated

for Lyme disease with regimens thatshould be highly effective even in severeinfections, a disorder often referred toas postYLyme syndrome. Data are un-equivocal that repeated or longercourses of antibiotics do not cure thesepatients,12 although the anti-inflammatoryeffects of some (eg, tetracyclines) or neu-roactive effects of others (ceftriaxonehaving significant effects on glutamateneurotransmission) may cause transient,unsustained improvements in symp-toms during treatment that disappear

Case 5-4A cousin of the patient in Case 5-3 was a 55-year-old man who playedtennis and had always lived in North Dakota. He had a 5-year history ofintermittent right knee pain, somewhat improved after arthroscopicsurgery, which found severe meniscus damage. During the year prior to hisarthroscopic procedure, he described feeling run down and cognitivelyslowed. When he argued in court as an attorney, he found his reasoningwas less rapid than before. He had no other neurologic complaints andrecalled no erythema migrans or tick bites. His rheumatologist found anegative Lyme ELISA but three bands on his IgM Western blot and noneon the IgG blot. He had not improved with 3 months of IV ceftriaxone, andhis Lyme disease laboratory testing was unchanged. A brain SPECT scanwas interpreted as showing multifocal hypoperfusion consistent withencephalitis; yet his brain MRI was normal. The patient was referred toa neurologist for possible nervous system Lyme disease.

On neurologic examination, Mini-Mental State Examination and allother testing were normal. A lumbar puncture demonstrated normal CSF.The patient was given reassurance that he had neither a CNS disease norLyme disease. The patient ultimately explained that he had always been ahyperachiever and his recent knee problems prevented him from enjoyinghis usual recreational activities and practicing law as vigorously as hewould like. Physical therapy and a brief course of cognitive-behavioraltherapy were arranged. Within 4 months he became more physically activeand felt more like himself.

Comment. Patients with Lyme arthritis invariably have very highconcentrations of antiYB. burgdorferi antibody in peripheral blood. Thenegative serology here effectively excludes the diagnosis. If that were notsufficient, he lived in an area where the potential for exposure to thisinfection is nonexistent. His knee symptoms differed from his cousins inthat, in this case, the same joint was always affected, and mechanicaldamage related to repeated athletic injuries was clearly present. Hissymptoms were nonspecific and in isolation would never warrant adiagnosis of Lyme disease or treatment with antibiotics. Isolated IgMbands on a Western blot with a negative ELISA, negative IgG blot, andlong-standing symptoms are clearly artefactual. Findings on brainqualitative SPECT are again uninterpretable.


rapidly with discontinuation of treat-ment. This pattern is the opposite ofthat typically seen when treating aninfection with antibiotics, in which sys-temic symptoms often improve mod-estly during treatment but then graduallyimprove more substantially over time asthe inflammatory response to the infec-tion gradually subsides.

Although some patients with postYLyme syndromemeet criteria for a diag-nosis of depression, this is by no meansinvariable and probably does not ex-plain this state. Recent work suggeststhat some individuals aremore at risk ofthis disorder following any of a numberof stressors, including the physiologicand psychological stress of a significantillness.32,33 Although patients often con-sider the suggestion of a role for psy-chological factors as either dismissive orpejorative, it is nothing of the sort. It isonly natural that anybody with a chronic

illness, particularly somebody who isused to high levels of activity and achieve-ment uninterrupted by distractions, willhave a psychological response to thisunwanted disruption. How people re-spond is a function of their underlyingpersonality traits. Studies suggest thatindividuals with high negative and lowpositive affect are predisposed to thesechronic persistent symptoms.

TREATMENTB. burgdorferi remains sensitive in vitroto many common antibiotics. Clinicalstudies have shown that oral doxycy-cline, ampicillin, and cefuroxime axetilare highly effective in most patients,including those with arthritis (Table 5-2).IV ceftriaxone, high-dose penicillin, andcefotaxime have been used in patientswith severe disease, particularly nervoussystem infection, and in patients whohave not responded to oral regimens.

KEY POINTS

h Data are unequivocalthat repeated or longercourses of antibiotics donot cure patients withpostYLyme syndrome.

h Recent work suggeststhat some individualsare more at risk ofpostYLyme syndromefollowing any of anumber of stressors,including thephysiologic andpsychological stressof a significant illness.

TABLE 5-2 Recommended Antibiotic Regimensa

Setting Regimenb Adult Dose Pediatric Dosec

Parenchymal CNS, othersevere disease, or failureof oral medications

Ceftriaxone

OR

2 g/d IV 50 mg/kg/d to 75 mg/kg/d IV,single dose

Cefotaxime

OR

2 g every 8 hours IV 150 mg/kg/d to 200 mg/kg/dIV in three divided doses

Penicillin G 3 million U to 4 millionU every 4 hours IV

200,000 U/kg/d to 400,000U/kg/d IV in six divided doses

CNS (meningitis, radiculoneuritis,cranial neuritis)

As aboveORDoxycyclined 100 mg twice daily 4 mg/kg/d in two divided doses

All other Doxycyclined

OR100 mg twice daily 4 mg/kg/d in two divided doses

AmoxicillinOR

500 mg 3 times daily 50mg/kg/d in three divided doses

Cefuroximeaxetil 500 mg, twice daily 30mg/kg/d in three divided dosesa All regimens should be implemented for 2 to 4 weeks.b All regimens are oral unless otherwise stated.c Pediatric weight-based doses not to exceed adult doses.d Doxycycline should not be prescribed to children younger than 8 years of age because of its detrimental effect on bones and teeth.


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European studies have shown that oraldoxycycline, which achieves spiroche-tocidal concentration in the CNS, ishighly effective in Lyme meningitis,cranial neuritis, and radiculoneuri-tis.19,34 Although this has not beenstudied in the United States, the anti-biotic sensitivities of the three prev-alent Borrelia responsible for Lymedisease are sufficiently similar thatthere is no reason to doubt that thiswould be effective. Amoxicillin andcefuroxime axetil have not been testedin CNS disease, largely because oftheoretic concerns about their poorCNS penetration of uninflamed menin-ges. However, the absence of a signifi-cant number of cases of Lyme meningitisamong children initially treated withthese two agents for disseminated butnon-neurologic disease strongly suggeststhat these regimens eliminate any spi-rochetes that might have entered theCNS (Table 5-2).

CONCLUSIONSLyme disease affects the peripheral andcentral nervous systems in about 15% ofpatients. Other than a benign form oflymphocytic meningitis, CNS involve-ment rarely causes significant impair-ment. Cranial and peripheral nerves areinvolved more often and can be quitesymptomatic. Antimicrobial therapy,even with oral doxycycline, is usuallyhighly effective.

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KEY POINTS

h Oral doxycycline,ampicillin, andcefuroxime axetil arehighly effective in mostpatients with Lymedisease, includingthose with arthritis.

h Oral doxycycline, whichachieves spirochetocidalconcentration in theCNS, is highly effectivein Lyme meningitis,cranial neuritis, andradiculoneuritis.


17. Halperin JJ, Luft BJ, Anand AK, et al. Lymeneuroborreliosis: central nervous systemmanifestations. Neurology 1989;39(6):753Y759.

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21. Feder HM Jr, Hoss DM, Zemel L, et al.Southern Tick-Associated Rash Illness (STARI)in the North: STARI following a tick bite inLong Island, New York. Clin Infect Dis2011;53(10):e142Ye146.

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23. Shah SS, Zaoutis TE, Turnquist J, et al.Early differentiation of Lyme fromenteroviral meningitis. Pediatr Infect DisJ 2005;24(6):542Y545.

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26. Halperin JJ, Golightly M. Lyme borreliosisin Bells palsy. Long Island Neuroborreliosis

Collaborative Study Group. Neurology1992;42(7):1268Y1270.

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28. Kalina P, Decker A, Kornel E, Halperin JJ.Lyme disease of the brainstem.Neuroradiology 2005;47(12):903Y907.

29. Halperin JJ, Krupp LB, Golightly MG,Volkman DJ. Lyme borreliosisYassociatedencephalopathy. Neurology 1990;40(9):1340Y1343.

30. Krupp LB, Masur D, Schwartz J, et al.Cognitive functioning in late Lymeborreliosis. Arch Neurol 1991;48(11):1125Y1129.

31. Logigian EL, Kaplan RF, Steere AC. Successfultreatment of Lyme encephalopathy withintravenous ceftriaxone. J Infect Dis1999;180(2):377Y383.

32. Hassett AL, Sigal LH. The psychology ofpost Lyme disease syndrome and notLyme. In: Halperin JJ, ed. Lyme diseaseVanevidence-based approach. Wallingford, UK:CABI, 2011.

33. Hassett AL, Radvanski DC, Buyske S, et al.Psychiatric comorbidity and otherpsychological factors in patients withchronic Lyme disease. Am J Med2009;122(9):843Y850.

34. Halperin JJ, Shapiro ED, Logigian EL, et al.Practice parameter: treatment of nervoussystem Lyme disease (an evidence-basedreview): report of the Quality StandardsSubcommittee of the American Academyof Neurology. Neurology 2007;69(1):91Y102.


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