treatment of nervous system lyme disease

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

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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 post–Lyme 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 (1983–2003) 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 post–Lyme syndrome (Level A). NEUROLOGY 2007;69:1–1

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 E–Pub at www.neurology.org.

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 atwww.neurology.org

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

SPECIAL ARTICLE

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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 triad—meningitis, 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 neuropa-thy3,4; or (d) encephalopathy (alteration of cognitivefunction of varying severity, with or without evi-dence of brain infection). Most well performedstudies have focused on (a), the group in which thediagnosis is most clear-cut and treatment responseis most straightforward to assess.

Parenchymal CNS involvement is quite rare, andstudies of treatment of these individuals havelargely been anecdotal (Class IV). Similarly, only alimited number of small studies have addressed (c)or (d); all are Class III or IV.

A separate entity, defined differently by differentauthors, often referred to as “post-Lyme syn-drome,” occurs in patients who have had Lyme dis-ease, but, after treatment that would normally beexpected to be effective, have continued to have re-sidual chronic symptoms, including one or more ofthe following: musculoskeletal pain (without frankarthritis; fibromyalgia-like), fatigue, and “neuro-psychiatric” symptoms. The latter typically consistof perceived memory or cognitive difficulty, irrita-bility, sleep disturbance, depression, headache, limbor other paresthesias—all in the absence of clinicalor laboratory evidence of focal or inflammatorycentral or peripheral nervous system involvement.5-7

Thus, this entity is often included in discussions ofneuroborreliosis, even though there is no evidenceof CNS infection in such individuals. Although onlythree published studies have addressed this disor-der, all have been Class I.

ADULT NEUROBORRELIOSIS Long before thecharacterization of Lyme disease, anecdotal re-ports8,9 indicated that erythema migrans-associatedmeningitis was responsive to penicillin. The firsttreatment trial,10 published in 1983, compared out-comes in 12 US patients with Lyme meningitis

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treated with high dose IV penicillin to those in agroup of patients evaluated previously and treatedonly with prednisone. Symptoms resolved far morequickly in penicillin-treated patients. No penicillin-treated patients had relapses following treatment,although several had residual symptoms. One even-tually was retreated for persistent rheumatologicsymptoms. The same year a Swedish study11 re-ported 21 patients with chronic meningitis, subse-quently shown to be due to B burgdorferi, whoresponded to IV penicillin. No control group wasincluded; since these patients’ illnesses had been un-remitting prior to treatment, the authors consideredthe patients’ pretreatment course as equivalent to anhistorical control. Although these studies weresmall and Class III, they indicated that neuroborre-liosis was antibiotic responsive, just as other studieshad shown that Lyme disease in general was antibi-otic responsive.12 Therefore no studies of treatmentof neuroborreliosis have included placebo-treatedpatients.

Subsequent studies have compared the efficacyof various regimens. In 1988, ceftriaxone and IVpenicillin were first shown13 to be comparably effec-tive. Ceftriaxone doses of 2 g/day were shown to beas effective as 4 g/day (Class III). The same year, aconsecutive series of 113 patients14 with neuroborre-liosis (Class IV), including 15 with encephalitis,treated with parenteral penicillin, doxycycline, orcefuroxime, was shown to have generally excellentresponses (no comparisons among regimens). Sub-sequent studies compared parenteral doxycycline(200 mg/day for 2 days, then 100 mg/day for 8 days;n � 39) to parenteral penicillin (20 MU/day for 10days, n � 36) (Class II with regard to CSF abnor-malities; Class III clinical)15; cefotaxime (2 g, 3 timesdaily for 10 days) vs penicillin (5 MU 4�/day for 10days) (Class III)16; cefotaxime (3 g, twice daily � 10days; n � 69 of whom 49 had neuropathy) vs peni-cillin (20 MU/day � 10 days; n � 66, 44 with neu-ropathy) (Class III)17; and ceftriaxone (2 g/day � 10days; n � 17) to cefotaxime (2 g every 8 hours x 10days; n � 16) (Class II with regard to CSF abnor-malities; Class III clinical).18 In each study, bothregimens demonstrated comparable rates ofefficacy.19-22

Although most studies have focused on patientswith Lyme meningoradiculitis, two have assessedtreatment response in patients with Lyme encepha-lopathy, defined as objectively demonstrable cogni-tive abnormalities on formal mental status testingor neuropsychological testing. In the first23 (ClassIII), 27 adults with Lyme encephalopathy, polyneu-ropathy, or both were treated with ceftriaxone, 2 gIV daily for 2 weeks. Response to therapy, as mea-

sured by clinical signs and symptoms, CSF analyses,and neuropsychologic testing, was gradual and typ-ically was not apparent until several months follow-ing completion of treatment. Six months followingtreatment, 17 (63%) had improved, 6 (22%) im-proved but relapsed, and 4 (15%) were unchanged.Since symptoms had been prolonged and unremit-ting prior to treatment, this was believed to be dueto the effect of treatment, even though no controlgroup was included for direct comparison. A secondstudy, in which CSF abnormalities were present in89%, demonstrated efficacy of ceftriaxone (2 g dailyfor 30 days) in 18 adult patients with Lyme enceph-alopathy (Class III).24 In this study, at 12 to 24months follow-up, all patients were somewhat im-proved (2 patients; 11%), greatly improved (9 pa-tients; 50%), or normal (7 patients; 39%).

While most studies demonstrated excellent re-sponses to a wide range of antimicrobial regimens,several have raised the possibility that a significantnumber of patients may have residual difficulties. Inone25 (Class IV), 50 patients were identified whohad intrathecal production of anti-B burgdorferi an-tibody. Of the 44 who were studied, 31 had cranialneuropathies, 12 radicular weakness, 12 other formsof weakness, 29 had pain, 11 had headache (multi-ple findings in most). At post-treatment follow-up,half the patients reported headache and concentra-tion problems, although their neurologic deficitswere better. The authors believed this representedan increase in subjective symptoms, despite im-provement in objectively demonstrable abnormali-ties, similar to findings reported earlier.26 However,in the earlier study fewer than 10% had residualcognitive complaints and the remaining individualshad symptoms suggestive of sequelae of disease,rather than ongoing infection. In another study27

(Class IV) 25% of the patients assessed 5 years fol-lowing treatment reported persistent “neurologic”difficulties. However, in this study, sequelae ap-peared to reflect neurologic damage at the time ofinfection, not ongoing infection or antibiotic treat-ment failure. Similarly, in a study of 36 patients28

(Class IV) treated for Lyme meningitis, many de-scribed continued problems at 1 year follow-up.However, none appeared to develop new neurologicor arthritic signs or symptoms. Rather, symptomsranged from nonspecific (headaches, myalgias) toresidua of prior cranial or peripheral neuropathies.

Importantly, none of these follow-up studies in-cluded a control population. When this was done ina large case control study of patients (primarily withnon-neurologic Lyme disease) in Connecticut,29 pa-tients who had been diagnosed with Lyme diseasereported having increased difficulties and multiple

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symptoms, but in fact these symptoms occurred justas frequently in uninfected, age-matched controls.

Finally, two Finnish studies argued that longercourses of treatment might be necessary. One30

(Class (III) described 60 patients treated for 100days, half receiving 2 weeks of ceftriaxone followedby oral amoxicillin, the other half with oral ce-fixime for the entire period. Clear case definitionswere not provided and the rationale for prolongedtreatment was not clear; at 1 year follow-up 29/30patients in each group were considered cured. Nocomparison group treated with conventionalcourses was included. A second study31 describedfailure of conventional courses of ceftriaxone. Diag-nostic criteria were not explicitly described in thisarticle and a major criterion of treatment successwas disappearance of symptoms, perhaps resultingin the conclusion that conventional treatment wasineffective based on premature assessment of symp-tom resolution.

Although numerous studies have demonstratedefficacy of parenteral antibiotic regimens in neu-roborreliosis, there is also substantial evidence sup-porting the role of oral agents, particularlydoxycycline. Pharmacologic studies32 have demon-strated that in patients taking 200 mg of oral doxycy-cline daily, the CSF concentration exceeds theMIC formany but not all B burgdorferi strains. At least 10studies have addressed the outcomes of treatingneuroborreliosis with doxycycline.12,14,15,19-22,27,33-35

All but two14,34 used oral doxycycline; since bloodlevels achieved are comparable whether this drug isgiven orally or IV, data from these studies of IVdoxycycline have been included. All studies wereperformed in Europe; most patients underwent CSFexamination and were shown to have a CSF pleocy-tosis. No studies in US patients with neuroborrelio-sis have explicitly compared treatment response tooral doxycycline vs parenteral regimens. In the vastmajority of studied patients, the clinical manifesta-tion of neuroborreliosis was meningitis, facial nervepalsy, or radiculitis. A very few patients had evi-

dence of parenchymal spinal cord or brain involve-ment. None of the studies was blinded; not all wererandomized or prospective. To compensate for thislack of blinding, many used sequential lumbarpunctures, using a decline in CSF mononuclearpleocytosis as an objective marker of treatment suc-cess. In one study,19 in which outcome was judgedby CSF improvement as well as clinical criteria,doxycycline (200 mg orally daily for 14 days; n �

31) was shown to be comparable to IV penicillin (3 gevery 6 hours for 14 days; n � 23) in patients withLyme meningitis with or without other associatednervous system involvement (Class II). A non-randomized comparison of patients with meningitisdemonstrated comparable CSF and clinical re-sponses to ceftriaxone (2 g/day, 10 to 14 days, n �

29, and oral doxycycline 400 mg/day, 10 to 14 days,n � 36) (Class III).20

Other studies, without comparison groups, haveshown high rates of efficacy with doxycycline (200to 400 mg/day, 9 to 17 days, 34 patients with menin-gitis, facial palsy; no comparison group) (ClassIII)21; doxycycline (200 mg/day in most, one with100 mg/day, one with two initial days of 400 mg,treatment duration 10 to 28 days; 6 with encephalo-myelitis, 63 with meningitis/cranial neuritis/radicu-litis) (Class IV)22; and doxycycline (200 to 400 mg/day � 10 to 19 days; 37 patients with meningitiswith or without other abnormalities, including 7with myelopathy, in a manuscript submitted forpublication, but not yet accepted) (Class III).36

Altogether, these studies provide data on 300 pa-tients with definite neuroborreliosis, treated withdoxycycline. In no study were outcomes demonstra-bly different whether patients received doxycyclineor parenteral beta-lactam regimens. Fifteendoxycycline-treated patients were retreated for per-sistent symptoms; none developed late neurologicsequelae, even though follow-up for some was aslong as several years. Aggregating the data from theeight studies that compared doxycycline to paren-teral regimens (figure), the overall response rate todoxycycline was 98.6% of the response rate to par-enteral penicillin or ceftriaxone (95% CIs 94.8% to102.5%). Given the very narrow CI, it is highly un-likely that there is a clinically or statistically signifi-cant difference between these regimens.

Although only two of these studies were Class IIand none Class I, they do appear to demonstrate thelow probability of developing late neurologic se-quelae following treatment with oral doxycycline.Similarly, at least one US study37 demonstrated nolong-term adverse health outcomes in childrentreated for Lyme disease associated facial palsy(84% treated with oral doxycycline or amoxicillin,

Figure Relative efficacy of doxycycline vsparenteral treatment

Relative efficacy ofdoxycycline vs parenteraltreatment (ratio of responserate to doxycycline toresponse rate to parenteralpenicillin or ceftriaxone; RRof 1.0 indicating identicalresponse rates with theagents being compared) ineight studies, and inaggregate. Responses inmost studies were judgedclinically; in study 6, CSFcriteria were used as well. Forsummed data, RR is 0.986(95% CIs 0.948 to 1.025).Additional analyses ofdoxycycline vs parenteralpenicillin or ceftriaxoneindividually and of parenteralpenicillin vs ceftriaxonesimilarly showed nosignificant differences. Keyto studies: #127; #219; #315;#434; #514; #620; #733; #835.



16% with ceftriaxone). Interpretation of such nega-tive findings in relatively small studies must be tem-pered, though, with an appreciation of the generallybenign long-term outcome in many patients withacute neuroborreliosis. A 1990 German study34

compared outcomes in 66 antibiotic-treated patientswith neuroborreliosis to outcomes in 57 patientsevaluated before the identification of the infectiouscause of this syndrome and therefore never treated.The majority of patients in both groups (59% ofuntreated, 62% treated) were asymptomatic atlong-term follow up; no patients in either group hadevidence of recurrent or progressive disease.

Although it is likely that US patients with thesame manifestations of neuroborreliosis will simi-larly be doxycycline responsive, there are differ-ences between the B burgdorferi strains and speciesprevalent in the United States and Europe; hence thedata may not be fully applicable. However, Euro-pean studies38,39 assessing the susceptibility of differ-ent Borrelia strains to multiple antimicrobials,including doxycycline, have found no significantdifferences in minimal inhibitory concentrationsamong the different species. Minimal bactericidalconcentrations (MBCs) have been more variable39

but for doxycycline were comparable for all species.In light of these observations, treatment responsesmight be expected to be comparable in US and Eu-ropean patients; however, this remains untested.

In the United States in particular, there has beena general reluctance to treat CNS B burgdorferi in-fections with oral regimens. Since several studieshave shown40,41 that many patients with nervoussystem Lyme disease have a vigorous CSF pleocyto-sis without symptoms of meningitis, some recom-mend routinely examining CSF in patients withsuspected neuroborreliosis (e.g., Lyme disease asso-ciated facial nerve palsy), and treating those with apleocytosis with parenteral regimens. Since no ClassI studies, with good long-term follow-up, prove thatoral treatment of Lyme meningitis is as effective asparenteral therapy with beta-lactam agents, particu-larly in patients infected with US strains of B burg-dorferi, treatment with parenteral beta lactamagents is reasonable. However, given the absence ofevidence of late CNS complications following oralantibiotic treatment of Lyme meningitis in all trialsperformed to date, coupled with the potential forgreater morbidity associated with parenteral regi-mens, initial treatment with oral doxycycline, with-out a lumbar puncture, also appears to be a safe andvalid approach to treatment—at least of facial nervepalsy.42

Notably, the only oral regimen that has beenshown to be effective in neuroborreliosis is doxycy-

cline—a drug with good CNS penetration. Amoxi-cillin and cefuroxime axetil, which are useful innon-neurologic Lyme disease, may be useful in neu-roborreliosis patients who cannot take doxycycline,but data in support of this are purely inferential—namely, the absence of observed long-term sequelaein individuals treated with these medications,37 anobservation subject to the previously notedlimitations.

The role of corticosteroids in patients with neu-roborreliosis remains unclear. No prospective trialshave addressed this question. The issue arises mostfrequently in patients with facial nerve palsy, sincesome guidelines for treatment of idiopathic facialnerve palsy43 but not others44 recommend their rou-tine use. Early anecdotal observations suggestedthat patients with Lyme arthritis who received ste-roids were more difficult to cure13,45; however, ste-roids may well have been used in these patientsbecause they already had more severe disease. Insome animal models, nervous system disease ismore pronounced if corticosteroids are adminis-tered.46 In contrast, anecdotal studies have sug-gested outcomes in patients with severe radicularpain47 or encephalomyelitis48 may be improved ifcorticosteroids and antibiotics are administeredconcurrently. One large retrospective review49 of101 patients with Lyme disease-associated facialnerve palsy found no significant difference in out-come regardless of treatment (antibiotics in 37, ste-roids alone or in combination with antibiotics in 44,no treatment in the remainder), although the onlypatient in the group with severe residua had re-ceived steroids. In a 10- to 20-year follow-up studyof patients with Lyme disease,50 including 31 pa-tients with facial nerve palsy, there was no differ-ence in long-term outcome between those who hadreceived steroids and those who had not. In sum, thelimited available data suggest no clear beneficial orharmful effect of steroids in patients with neurobor-reliosis who are treated with appropriate antimicro-bial therapy.

PEDIATRIC NEUROBORRELIOSIS A wide rangeof Lyme disease-associated neurologic disorders hasbeen described in children, including cranial neu-ropathies, headache, seizures, meningitis, meningo-encephalitis, encephalopathy, focal neurologicsigns, ataxia, vertigo, chorea, and transverse myeli-tis. Information comes from case reports, small se-ries of patients, and from studies mainly focused onrheumatologic aspects of the disease, conductedshortly after Lyme disease was recognized as a dis-tinct clinical entity.51-53 More recent studies in bothEurope and the United States addressing neurologic



involvement in cohorts of larger size show facialnerve palsy and meningitis to be the most frequentneurologic syndromes in children.41,51,54 In contrastto adult Lyme disease patients, Bannwarth’s syn-drome (meningoradiculitis) and mild radiculoneuri-tis are uncommon and encephalopathy rare.51

As in adults, there are relatively few studies spe-cifically assessing efficacy of treatment of neurobor-reliosis in children. Only one study identified in theliterature review was rated as Class I (but did notaddress clinical treatment response). In this study,75 children with Lyme neuroborreliosis were ran-domized to receive IV treatment with either penicil-lin G or ceftriaxone.55 On the 10th day of treatment,paired samples of serum and CSF were tested to de-termine the antibiotic concentration in each sample.CSF concentrations of both drugs exceeded the min-imal inhibitory concentration, though, not surpris-ingly, the duration for which this was true wassubstantially greater for ceftriaxone (�24 hours)than for penicillin. The authors concluded that bothdrugs likely would be effective for treating Lymeneuroborreliosis, but no specific treatment responsedata were provided. In the only Class II study,56 23children with Lyme neuroborreliosis were random-ized to receive 14 days of IV treatment with eitherpenicillin G or ceftriaxone. All children did well andnone had sequelae at follow-up �6 months later.The investigators concluded that treatment with ei-ther drug was highly effective.

All of the remaining studies were categorized aseither Class III or Class IV. Most were case seriesalthough there was one cross-sectional survey withcontrols, an observational study of 169 childrenwith Lyme neuroborreliosis54 (facial nerve palsy:55%; meningitis: 27.2%; Bannwarth’s syndrome:3.6%; meningoencephalitis: 3.6%; “Guillain-Barre”: 1.8%) in Lower Saxony in Germany. Al-though the focus of the study was on theepidemiology and the diagnosis of neuroborreliosis,virtually all of the children were treated IV withpenicillin for 10 to 14 days and all had excellent out-comes. In a Swedish study, 203 children with Lymeneuroborreliosis were treated IV with penicillin (53children), ceftriaxone (109 children), or cefotaxime(19 children) or orally with doxycycline (22 chil-dren).35 At follow-up, symptoms and signs resolvedin 58% of the children by the end of treatment, in92% by 2 months and in all children by 6 monthsafter treatment (three were lost to follow-up). In aretrospective Austrian study of 160 children withLyme disease (45 [28%] with meningitis, facialpalsy, or both33), 33 received ceftriaxone IV, 7 re-ceived benzylpenicillin IM, and 5 received doxycy-cline orally. All were treated for 10 to 21 days. All

151 children seen at 3-month follow-up recoveredcompletely. In a series of 187 Danish patients withLyme neuroborreliosis, 40 (21%) were children.40

Most received penicillin G IV and all apparently didwell at follow-up months to years later. In a USstudy, children with Lyme neuroborreliosis57 (facialnerve palsy n � 6; meningitis n � 4, overlap notspecified) were identified prospectively from a co-hort of 201 children with Lyme disease. The chil-dren were treated with a variety of antibioticregimens. Ceftriaxone IV was administered to threechildren with meningitis, two with facial nervepalsy, and one with facial nerve palsy and meningi-tis. The other children received orally administeredantibiotics (amoxicillin, doxycycline, erythromycin,or penicillin). At follow-up none reported sequelae.

Nine Swedish children with Lyme neuroborrelio-sis were treated with penicillin G IV.58 All but one (achild whose facial palsy persisted for 3 months) hadprompt improvement and cure of their illnesses. Atfollow-up 3 months later all were asymptomaticand appeared to be cured. Although one report offollow-up of 63 children with erythema migranswas identified by our search,53 only one of the chil-dren had neuroborreliosis (facial nerve palsy). Inany case, all of the children in the report were wellat follow-up. Finally, 43 children with facial nervepalsy due to Lyme disease were assessed 7 to 161months (mean: 49 months) after infection.37 Ofthese, 84% had been treated orally with either doxy-cycline or amoxicillin; the remainder had receivedceftriaxone. Twenty of the patients underwent neu-ropsychological testing and all had average or aboveaverage scores on a large battery of tests. Althoughchildren with facial nerve palsy were more likelythan normal matched controls to report musculo-skeletal pain, changes in behavior, and numbness,reports of problems with activities of daily livingwere similar among affected patients and matchedcontrols. The investigators concluded that the long-term neuropsychological and health outcomes ofchildren with facial nerve palsy due to Lyme diseasewere comparable to those who did not have Lymedisease.

Conclusions. Based on four Class II studies antibi-otic regimens have been established as probably safeand effective for both children and adults. OneClass I and one Class II study suggest that paren-teral regimens are probably safe and effective forsevere neurologic disease but two Class II studies15,19

and numerous Class III and IV studies suggest thatoral treatment, particularly with doxycycline, iscomparably safe and effective in many situationsnot involving parenchymal CNS involvement. Al-though the evidence is stronger in adults than chil-



dren, all available evidence indicates that theresponses to oral treatment are comparable inadults and children. However, it must be empha-sized that no definitive data exist to establish thesuperiority—or lack thereof—of either oral or par-enteral treatment. Specific regimens are listed in ta-bles 1 and 2.

POST–LYME DISEASE Post-Lyme syndrome. Asdiscussed above, patients who have received ac-cepted antibiotic regimens for various forms ofLyme disease sometimes have residual chronicsymptoms, referred to variably as post-Lyme syn-drome (PLS), post-Lyme disease syndrome, post-treatment chronic Lyme disease (PTCLD), or evenchronic Lyme disease. There has been controversyas to whether PLS is a form of active infection inwhich the organism is difficult or impossible toeradicate from various “privileged” sites vs a postin-fectious or noninfectious type of chronic fatiguesyndrome, in which there is no ongoing infection.Arguments offered to support the possibility of per-sistent active infection derive from the apparentsimilarity between these symptoms and patients’perceptions of the cognitive difficulty and fatiguenoted with untreated or partially treated Lyme dis-ease; however, in patients with untreated or incom-pletely treated Lyme disease, these symptoms aretypically associated with objective abnormalities onphysical or laboratory examination, and symptomsand abnormal findings clearly respond, frequently

with symptom resolution, to a 2- to 4-week courseof IV antibiotics.24,59

Most available data argue against persistent Bburgdorferi infection in patients who have receivedwhat are normally curative courses of antimicrobialtherapy. First, antibiotic resistance has not beendemonstrated in this genus.60-62 Second, persistentsymptoms do not correlate with any objective mea-sure of nervous system disease or with laboratorymeasures of inflammation.5,63 Third, there is no pre-cedent for such a phenomenon in other spirochetalinfections.64 Fourth, anti-B burgdorferi antibodyconcentrations often decline, even to undetectablelevels, despite persistent symptoms.5,63,65 Such a de-cline in antibody in the face of persistent infectionappears to be without precedent in other bacterialinfections. Fifth, Lyme disease lacks characteristicsof other infections that justify longer treatmentcourses, such as infections in which available anti-microbials have poor in vitro activity against the or-ganism, infections caused by an intracellularpathogen, or infections involving a biofilm. Finally,patients with PLS do not respond to a further courseof IV antibiotics. Anecdotally, some experience asubjective improvement while on antibiotics, withsymptoms recurring rapidly following medicationdiscontinuation, suggesting a placebo effect. Still,based on a transient improvement in symptoms,some physicians have treated patients with PLS withvarious antibiotic regimens for months to years.

Table 1 Antimicrobial regimens used in treatment of nervous system Lyme disease

Medication Adult dose Pediatric dose Classification

Oral regimens

Doxycycline* (preferred) 100 (–200) mg BID �8 yo: 4 (–8) mg/kg/d in 2 divided doses;max 200 mg/dose

B

Amoxicillin (whendoxycyclinecontraindicated)†

500 mg TID 50 mg/kg/d in 3 divided doses; max 500mg/dose

C

Cefuroxime axetil (whendoxycyclinecontraindicated)†

500 mg BID 30 mg/kg/d in 2 divided doses; max 500mg/dose

C

Parenteral regimens

Ceftriaxone 2 g IV daily 50–75 mg/kg/d in 1 dose, max 2 g B

Cefotaxime 2 g IV Q8H 150–200 mg/kg/day in 3–4 divided doses;max 6 g/day

B

Penicillin G‡ 18–24 MU/d,divided doses Q4H

200–400,000 U/Kg/d divided Q4H, max18–24 MU/day

B

For all, recommended duration is 14 days, although published studies have used courses ranging from 10 to 28 days, without sig-nificantly different outcomes.*Tetracyclines are relatively contraindicated in children �8 years of age or in pregnant or lactating women.†These two oral regimens are effective in non-nervous system Lyme borreliosis. There are no data demonstrating efficacy in neu-roborreliosis but large numbers of patients have been treated with these regimens for other forms of Lyme disease without obvi-ous subsequent onset of nervous system involvement. As such they may be an oral alternative in individuals who cannot takedoxycycline.‡The antibiotic dosage should be reduced for patients with impaired renal function.



To address this controversy, three randomized,double-blind placebo-controlled trials of antibiotictherapy in PLS have been published in adults withwell-documented Lyme disease who had previouslyreceived accepted initial courses of antibiotics foracute disease but who had residual symptoms typi-cal of PLS.

The first pair of trials, with a combined total of129 patients, was reported initially in a single arti-cle, in which patients were divided into two groups:one seropositive, one seronegative. Treatment re-sponse, reported in each group as a separate trial,was measured using the physical and mental health-related quality of life components of the MedicalOutcomes Study 36-item short form general healthsurvey (SF-36) as the primary outcome measure.5 Asecond article7 assessed whether neurocognitivechanges occurred in the same population, measur-ing attention, memory, and executive functioningusing a battery of neuropsychological tests as oneset of primary outcome measures. Mood and otherpsychiatric symptoms were assessed using the BeckDepression Inventory (BDI) and the Minnesota

Multiphasic Personality Inventory (MMPI-2) as anadditional set of primary outcome measures. En-trance criteria were symptoms of classic Lymedisease, physician-documented recommended treat-ment of Lyme disease, and typical musculoskeletalor cognitive PLS symptoms often accompanied byfatigue that had begun within 6 months of the initialinfection, and that had been present for at least 6months (but less than 12 years). Patients could beeither seropositive or seronegative, but were ex-cluded if they had previously received IV antibioticsfor 60 or more days, had known hypersensitivity tostudy medications, had active synovitis or positivePCR for B burgdorferi gene segments in CSF orblood. Patients were evaluated at baseline, wererandomized to receive either placebo or IV ceftriax-one 2 g/day for 30 days followed by oral doxycy-cline 200 mg/day for 60 days, and then re-evaluatedat 1, 3, and 6 months.

For the combined group of 129 patients, at base-line the physical component of the SF-36 score wasabout 1.5 SD below and the mental componentabout 0.5 SD below that of age-matched norms, in-dicating significant impairment in health-relatedquality of life.5 By contrast, although the baselineBDI showed mild to moderate depression, there wasno significant difference in neuropsychological testmeasurements in the combined patient group vsage-matched norms.7 There was also no significantdifference in baseline SF-36, BDI, or neuropsycho-logical test measurements in seropositive vs sero-negative patients.

At 6 months, there was no significant differencein the SF-36,5 neuropsychological test, and BDImeasurements7 between patients who had receivedplacebo vs antibiotic therapy. Notably, about 40%of patients in each group (i.e., placebo and antibi-otic) improved in the total SF-36 summary score at 6months, while about 30%were unchanged and 30%were worse. Similarly, several neuropsychologicaltest and BDI measurements improved at 6 months inboth placebo- and antibiotic-treated patients.

The other trial6 investigated potential changes infatigue, cognitive function, and CSF clearance of Bburgdorferi antigen in 55 patients with PLS. Theprimary outcome measures were (a) improvementin fatigue on a global fatigue severity measure (FSS-11); (b) improvement in mental speed on the A-Atest, a computerized reaction time task of cognitiveprocessing speed; and (c) CSF clearance of B burg-dorferi OspA antigen. Entrance criteria werephysician-documented erythema migrans, or aCDC-defined late manifestation of Lyme diseaseconfirmed by positive ELISA and Western blot,completion of a recommended course of antibiotic

Table 2 Syndromes and treatment options

Syndrome Treatment options

Meningitis Parenteral,particularly ifsevere*

Doxycycline PO†

Any neurologic syndrome with CSFpleocytosis

Parenteral,particularly ifsevere*

Doxycycline PO†

Peripheral nerve (radiculopathy,diffuse neuropathy, mononeuropathymultiplex, cranial neuropathy; normalCSF)

Doxycycline PO†

Parenteral iftreatment failure orif severe

Encephalomyelitis Parenteral

Encephalopathy Parenteral

Post-treatment Lyme syndrome No antibioticsindicated;symptomaticmanagement only

*Available data in European neuroborreliosis indicate that oraldoxycycline and parenteral ceftriaxone are equally effective inLyme meningitis, and anecdotal data from the United Statesindicate that in patients with Lyme disease–associated facialpalsy, response to oral treatment is sufficient that CSF exami-nation may be unnecessary. Although none of these studies isClass I, it was the consensus of the panel that, in the absenceof brain or spinal cord involvement, oral treatment of neurobor-reliosis is an acceptable option in appropriate circumstances.†Studies assessing oral treatment of neuroborreliosis have onlyused doxycycline. Other agents such as amoxicillin or cefu-roxime axetil may be effective in individuals who cannot toler-ate doxycycline but relevant data are lacking.



treatment, and severe persistent fatigue (typicallyaccompanied by other musculoskeletal or neuropsy-chiatric symptoms of PLS) coincident with initial in-fection. Patients were excluded if they had knowncephalosporin hypersensitivity or a confoundingmedical or severe psychiatric disorder. Patients wereevaluated at baseline, were randomized to receiveeither placebo or IV ceftriaxone 2 g/day for 28 days,and then re-evaluated at 1 and 6 months.

At 1 month, fatigue improved in both antibiotic-and placebo-treated groups. At 6 months, there wasa significant improvement in the FSS-11 fatiguescore in patients treated with ceftriaxone comparedto placebo, with no improvement in mental speed(or any of the other secondary neuropsychologicaltests) or in clearance of CSF antigen (although anti-gen was detected in CSF of only 16% of the patientsat baseline) in the antibiotic vs placebo group. Sub-group analysis showed that improvement in the fa-tigue score after ceftriaxone particularly occurred inpatients who had received an initial oral rather thanIV course of antibiotics for acute Lyme disease. Ofnote, patients in the ceftriaxone group more oftenguessed that they were on active treatment than didthe placebo patients, suggesting that blinding of pa-tients may have been compromised and that im-provement in fatigue in the ceftriaxone group mayhave been due to placebo effect. Importantly, theauthors point out that the adverse events associatedwith parenteral antibiotic therapy do not justifysuch therapy for fatigue, a problem which might re-spond to safer symptomatic management.

An additional controlled treatment trial66 pre-sented to date only in abstract form evaluated 10weeks of ceftriaxone treatment vs placebo in a totalof 37 patients. Preliminary findings appear to indi-cate lack of sustained improvement in cognitivefunction in the antibiotic-treated patients at 14weeks post-treatment follow-up. Although this is amuch anticipated, NIH-funded trial, since it has notyet been published, its methodology, detailed con-clusions and validity cannot be assessed, and it hasnot been included in the analysis.

In summary, published antibiotic treatment tri-als of PLS provide compelling Class I evidence thatPLS is not due to active Borrelia infection and is notresponsive to further antibiotic therapy, particularlywith respect to overall health-related quality of lifeand cognitive and depressive symptoms. Whetherprofound fatigue in PLS is antibiotic responsive isstill an open question but the data on this point arepartially confounded and, as noted above, the au-thors of the study of fatigue in PLS do not endorsefurther antibiotic therapy for this symptom. Theavailable studies confirm the importance of placebo

effect that obscures interpretation of symptom im-provement in individual patients with PLS treatedwith antibiotics.

Finally, in PLS there is dissociation between per-ceived problems with cognition and memory (whichare often also present in association with depressivesymptoms) and normal neuropsychological testing.7

In contrast to individuals with PLS, patients withprior untreated or partially treated Lyme diseasewith late cognitive symptoms (which typically aremilder than in PLS) often have abnormalities onneuropsychological testing, CSF, or imaging stud-ies. The latter patients may well have active infec-tion (e.g., Lyme encephalopathy), and often respondto IV ceftriaxone with resolution of symptoms.

Conclusions. Several Class I studies indicate that thedisorder referred to as post-Lyme syndrome doesnot respond to prolonged courses of antibiotics andthat such treatment can be associated with seriousadverse events (see below).

RECOMMENDATIONS

1) Parenteral penicillin, ceftriaxone, and cefo-taxime are probably safe and effective treat-ments for peripheral nervous system Lymedisease and for CNS Lyme disease with or with-out parenchymal involvement (Level Brecommendation).

2) Oral doxycycline is probably a safe and effectivetreatment for peripheral nervous system Lymedisease and for CNS Lyme disease without pa-renchymal involvement (Level B recommenda-tion). Amoxicillin and cefuroxime axetil mayprovide alternatives but supporting data arelacking.

3) Prolonged courses of antibiotics do not improvethe outcome of post-Lyme syndrome, are poten-tially associated with adverse events, and aretherefore not recommended (Level Arecommendation).

COMMENT ON TREATMENT SAFETY Althoughthe antimicrobial regimens discussed are widelyused and generally well tolerated, none is withoutpotential side effects. In one of the studies of post-Lyme syndrome,6 12 of the 28 patients receivingceftriaxone developed diarrhea, while 4 developedallergic reactions (1 anaphylaxis, 3 minor). Becauseof its biliary excretion, ceftriaxone tends to causepseudolithiasis (precipitation of the drug in the gallbladder), and may be associated with pseudomem-branous colitis more frequently than other antimi-crobials. Of the 55 patients (treated and placebo)who had indwelling IV access catheters, 3 developed



line sepsis (1 of 28 on ceftriaxone). One othertreated patient in this study developed anaphylaxiswhile 10 developed less severe adverse events. In theother published pair of long-term treatment trials,5

27 of 129 patients developed adverse effects (16 of64 receiving ceftriaxone), 2 of which (both patientson ceftriaxone) were life threatening (1 pulmonaryembolism, 1 fever and GI bleed). Combining treatedpatients in these three studies, life-threatening com-plications occurred in 1 per 23, while overall, ad-verse events occurred in about 1 of every 3 treatedpatients.

Although oral doxycycline avoids issues relatedto line infections, the drug is associated with gastricirritation and with photosensitization. The latter isparticularly problematic since most acute manifes-tations of Lyme disease occur in summer and au-tumn. Tetracyclines also cause abnormalities ofdeveloping bones and teeth in the fetus and in chil-dren under age 8.

RECOMMENDATIONS FOR FUTURE RESEARCHQuestions remain regarding the preferred therapeu-tic approach in early neuroborreliosis, particularlyamong US patients. The efficacy of oral doxycyclinecompared to a parenteral regimen such as ceftriax-one needs to be clearly established, as does the pre-dictive value of CSF abnormalities. Assuming oraldoxycycline is shown to be effective, it would thenbe helpful to assess the relative efficacy of other oralregimens such as amoxicillin or cefuroxime axetil.

Similarly, the optimal approach to the very rareentity of parenchymal CNS neuroborreliosis re-mains undefined. An assessment of preferred treat-ment duration, as well as a clear determination ofthe correct metrics of successful treatment, wouldbe very helpful.

Although it is clear that prolonged antimicrobialtherapy is not helpful in the treatment of post-Lymesyndrome, this entity will remain problematic untilits pathophysiology is better understood.

MISSION STATEMENT OF QSS

The mission of the QSS is to prioritize, develop, and publish evidence-based practice parameters related to the diagnosis, treatment, and prog-nosis of neurologic disorders. The QSS is committed to using the mostrigorous methods available within our budget, in collaboration withother available AAN resources, to most efficiently accomplish thismission.

DISCLAIMER

This statement is provided as an educational service of the American Acad-emy of Neurology. It is based on an assessment of current scientific andclinical information. It is not intended to include all possible propermethodsof care for a particular neurologic problem or all legitimate criteria forchoosing to use a specific procedure. Neither is it intended to exclude anyreasonable alternativemethodologies. The AAN recognizes that specific pa-

tient care decisions are the prerogative of the patient and the physician car-ing for the patient, based on all of the circumstances involved.

CONFLICT OF INTEREST STATEMENT

The American Academy of Neurology is committed to producing inde-pendent, critical and truthful clinical practice guidelines (CPGs). Signifi-cant efforts are made to minimize the potential for conflicts of interest toinfluence the recommendations of this CPG. To the extent possible, theAAN keeps separate those who have a financial stake in the success orfailure of the products appraised in the CPGs and the developers of theguidelines. Conflict of interest forms were obtained from all authors andreviewed by an oversight committee prior to project initiation. AANlimits the participation of authors with substantial conflicts of interest.The AAN forbids commercial participation in, or funding of, guidelineprojects. Drafts of the guidelines have been reviewed by at least threeAAN committees, a network of neurologists, Neurology peer reviewers,and representatives from related fields. The AAN Guideline AuthorConflict of Interest Policy can be viewed at www.aan.com.

APPENDIX 1Quality standards subcommittee members: Jacqueline French,MD, FAAN (Co-Chair); Gary S. Gronseth, MD (Co-Chair);Charles E. Argoff, MD; Stephen Ashwal, MD, FAAN (ex-officio); Christopher Bever, Jr., MD, MBA, FAAN; John D.England, MD, FAAN; Gary M. Franklin, MD, MPH (ex-offi-cio); Gary H. Friday, MD, MPH, FAAN; Larry B. Goldstein,MD, FAAN; Deborah Hirtz, MD (ex-officio); Robert G. Hollo-way, MD,MPH, FAAN; Donald J. Iverson, MD, FAAN; LeslieA. Morrison, MD; Clifford J. Schostal, MD; David J. Thur-man, MD, MPH; William J. Weiner, MD, FAAN; SamuelWiebe, MD.

APPENDIX 2AAN classification of evidence for therapeutic interventionClass I: Prospective, randomized, controlled clinical trial withmasked outcome assessment, in a representative population.The following are required:

(a) primary outcome(s) clearly defined(b) exclusion/inclusion criteria clearly defined(c) adequate accounting for drop-outs and cross-overs with

numbers sufficiently low to have minimal potential for bias(d) Relevant baseline characteristics are presented and sub-

stantially equivalent among treatment groups or there is appro-priate statistical adjustment for differencesClass II: Prospective matched group cohort study in a represen-tative population with masked outcome assessment that meetsa–d above OR a RCT in a representative population that lacksone criterion a–d.Class III: All other controlled trials (including well-defined nat-ural history controls or patients serving as own controls) in arepresentative population, where outcome is independently as-sessed, or independently derived by objective outcomemeasurement.*Class IV: Evidence from uncontrolled studies, case series, casereports, or expert opinion.*Objective outcome measurement: an outcome measure that isunlikely to be affected by an observer’s (patient, treating physi-cian, investigator) expectation or bias (e.g., blood tests, admin-istrative outcome data)

APPENDIX 3Classification of recommendations

A � Established as effective, ineffective, or harmful for thegiven condition in the specified population. (Level A rat-ing requires at least two consistent Class I studies.)



B � Probably effective, ineffective, or harmful for the givencondition in the specified population. (Level B rating re-quires at least one Class I study or at least two consistentClass II studies.)

C � Possibly effective, ineffective, or harmful for the givencondition in the specified population. (Level C rating re-quires at least one Class II study or two consistent Class IIIstudies.)

U � Data inadequate or conflicting; given current knowledge,treatment is unproven.

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

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