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Guideline Summary
Guideline Title
EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis.
Bibliographic Source(s)
Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I, European Federation of Neurological Societies. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. 2010 Jan;17(1):8-16, e1-4. [122 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)
  • European Lyme neuroborreliosis (LNB, early and late)
  • Post-Lyme disease syndrome (PLDS)
Guideline Category
Diagnosis
Evaluation
Management
Treatment
Clinical Specialty
Family Practice
Infectious Diseases
Internal Medicine
Neurology
Pediatrics
Intended Users
Physicians
Guideline Objective(s)

To present evidence-based recommendations for diagnostic evaluation and management of European Lyme neuroborreliosis (LNB)

Target Population

Adults and children with suspected European Lyme neuroborreliosis (LNB)

Interventions and Practices Considered

Diagnosis/Evaluation

  1. Assessment of neurological symptoms
  2. Polymerase chain reaction (PCR) in very early Lyme neuroborreliosis or patients with immunodeficiency
  3. Culture in specific situations, including atypical presentation or patients with immune deficiency
  4. Investigation of serum (enzyme-linked immunosorbent assay [ELISA] or ELISA followed by immunoblot [IB]) and cerebrospinal fluid (CSF) for Borrelia burgdorferi (Bb)-specific antibodies, intrathecal antibody production and signs of CSF inflammation

Note: The following tests were considered but not recommended due to insufficient evidence: microscope-based assays, chemokine CXCL13, antigen detection, immune complexes, lymphocyte transformation test, cyst formation, lymphocyte markers.

Management/Treatment

  1. Oral doxycycline (contraindicated in children <8 years [in some countries 9 years])
  2. Intravenous ceftriaxone
  3. Intravenous penicillin
  4. Intravenous cefotaxime
Major Outcomes Considered
  • Sensitivity and specificity of diagnostic tests
  • Effectiveness of treatment in neurological improvement and complete recovery

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Data were collected by searching MEDLINE, EMBASE, the Cochrane databases and other evidence-based guidelines and reviews, including the practice parameters proposed by the American Academy of Neurology and the Infectious Diseases Society of America guidelines. The search terms Lyme disease and Lyme neuroborreliosis (LNB) were cross-referenced with encephalopathy, meningitis, peripheral nervous system (PNS) disease, peripheral facial palsy, laboratory test, diagnosis and treatment. Review articles and book chapters were also included if they were considered to provide comprehensive reviews of the topic. The final choice of literature and the references included were based on the Task Force Panel judgement of their relevance to this subject.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).

Evidence Classification Scheme for a Therapeutic Intervention

Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:

  1. Randomization concealment
  2. Primary outcome(s) is/are clearly defined
  3. Exclusion/inclusion criteria are clearly defined
  4. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
  5. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment.

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

The classification for evidence levels for diagnostic and therapeutic interventions was made according to the guidance for the preparation of neurological management guidelines by European Federation of Neurological Societies (EFNS) scientific task forces (see the "Rating Scheme for the Strength of the Evidence" field and "Availability of Companion Documents" field).

Methods Used to Formulate the Recommendations
Expert Consensus (Delphi)
Description of Methods Used to Formulate the Recommendations

Two authors independently assessed quality of treatment trials. Recommendations were reached by consensus of all Task Force participants by a modified Delphi method and were also based on the Task Force members' own awareness and clinical experience. Where there was lack of evidence but consensus was clear, the Task Force members have stated their opinion as good practice points (GPP).

Rating Scheme for the Strength of the Recommendations

Rating of Recommendations for a Diagnostic Measure

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.

Good Practice Points (GPPs) Where there was lack of evidence but consensus was clear the Task Force members have stated their opinion as good practice points.

Rating of Recommendations for a Therapeutic Intervention

Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.

Good Practice Points (GPPs) Where there was lack of evidence but consensus was clear the Task Force members have stated their opinion as good practice points.

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

The guidelines were validated according to the European Federation of Neurological Societies (EFNS) criteria (see the "Availability of Companion Documents" field).

Recommendations

Major Recommendations

The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Points) are defined at the end of the "Major Recommendations" field.

Diagnostic Evaluation

Laboratory Tests

Microscope-Based Assays

There is not enough evidence to recommend any of the microscope-based assays as a routine diagnostic tool.

Polymerase Chain Reaction (PCR)

PCR on cerebrospinal fluid (CSF) samples has a low sensitivity, but may be useful in very early Lyme neuroborreliosis (LNB) with negative antibody index (AI), or in patients with immunodeficiency (GPP). Because of low sensitivity and unknown specificity, PCR cannot be recommended as a diagnostic method in patients with chronic symptoms or for follow-up of therapy.

Cultivation

Because of its low sensitivity, slow growth and restriction to a few specialized laboratories, culture of Borrelia burgdorferi sensu lato (Bb) is limited to special indications such as atypical clinical presentation or patients with immune deficiencies (GPP).

Bb-Specific Antibodies in Serum and CSF

Antibody tests for serum (enzyme-linked immunosorbent assay [ELISA] or ELISA followed by immunoblot [IB] if ELISA is positive) (GPP) and CSF (AI) are useful in the diagnosis of LNB (level B), but are hampered by a low sensitivity in patients with symptom duration <6 weeks, and by low specificity, if judged without other criteria. Because of the low specificity, antibody results can only be interpreted together with clinical data and CSF inflammation parameters. Therefore, antibody testing should only be carried out in patients with symptoms suggestive of LNB.

Chemokine CXCL13

There is not enough evidence to recommend CXCL13 test as a routine diagnostic tool or in follow-up after treatment.

Antigen Detection

There is not enough evidence to recommend antigen detection assays as a routine diagnostic tool or in follow-up after treatment.

Detection of Antibodies That Bind in Circulating Immune Complexes

There is not enough evidence to recommend immune complex tests as a routine diagnostic tool.

Lymphocyte Transformation Test (LTT)

There is not enough evidence to recommend LTT as a routine diagnostic tool or in follow-up after treatment.

Cyst Formation

There is not enough evidence to recommend examination for cyst formation as a diagnostic tool.

CD57+/CD3- Lymphocyte Subpopulation

There is not enough evidence to recommend examination for lymphocyte subpopulations as a diagnostic tool.

Choice of Laboratory Methods

  1. Investigation of CSF/serum pair for Bb-specific antibodies, intrathecal antibody production and signs of CSF inflammation is obligatory for laboratory diagnosis of LNB (level B).
  2. Culture and PCR may be corroborative in very early LNB (GPP).
  3. At present, no further methods are recommendable.

Diagnostic Criteria

The Task Force members recommend (GPP) the following criteria for definite and possible LNB (see also Table 2 in the original guideline document):

Definite LNB. The following three criteria are fulfilled: (I) neurological symptoms suggestive of LNB (with other causes excluded); (II) CSF pleocytosis; (III) Bb-specific antibodies in CSF (produced intrathecally).

Possible LNB. Two out of these three criteria are fulfilled. If criterion III is lacking, after a duration of 6 weeks, there has to be found Bb-specific antibodies in the serum.

These criteria apply to all subclasses of LNB except for late LNB with polyneuropathy where the following should be fulfilled for definite diagnosis:

(I) Peripheral neuropathy

(II) Clinical diagnosis of acrodermatitis chronica atrophicans (ACA)

(III) Bb-specific antibodies in serum.

Treatment

Early LNB

Early LNB with Manifestations Confined to the Peripheral Nervous System (PNS) and Meninges

Adult patients with definite or possible early LNB with symptoms confined to the meninges, cranial nerves, nerve roots or peripheral nerves (Bannwarth syndrome) should be offered a single 14-day course of antibiotic treatment.

  1. Oral doxycycline or intravenous (IV) ceftriaxone or IV penicillin or IV cefotaxime are effective and safe treatments (level B).
  2. Oral doxycycline (200 mg daily) and IV ceftriaxone (2 g daily) for 14 days are equally effective (level A).

The advantages of doxycycline are the oral route of administration and the lower costs. Doxycycline is relatively contraindicated during pregnancy or lactation.

Early LNB with Central Nervous System (CNS) Symptoms

Adult patients with definite or possible early LNB with CNS manifestations (myelitis, encephalitis, vasculitis) should be treated with IV ceftriaxone (2 g daily) for 14 days (not enough evidence: GPP).

Late LNB

  1. Adult patients with definite or possible late LNB with peripheral neuropathy and ACA should be treated with oral doxycycline (200 mg daily) or IV ceftriaxone (2 g daily) for 3 weeks (not enough evidence: GPP).
  2. Adult patients with definite or possible late LNB with CNS manifestations (myelitis, encephalitis, vasculitis) should be treated with IV ceftriaxone (2 g daily) for 3 weeks. (not enough evidence: GPP).

Post-Lyme Disease Syndrome (PLDS)

Antibiotic therapy has no impact on PLDS (level A).

Paediatric Neuroborreliosis

Paediatric patients with definite or possible early LNB with symptoms confined to the meninges, cranial nerves, nerve roots or peripheral nerves (Bannwarth syndrome) should be offered a single 14-day course of antibiotic treatment.

  1. Oral doxycycline or IV penicillin or IV ceftriaxone or IV cefotaxime is effective and safe treatments (level B).
  2. Oral doxycycline (200 mg daily) and IV ceftriaxone (2 g daily) for 14 days are equally effective (level B). The advantages of doxycycline are the oral route of administration and the lower costs. Doxycycline is contraindicated in those <8 years (in some countries 9 years).
  3. Paediatric patients with CNS manifestations (myelitis, encephalitis, vasculitis) should be treated with IV ceftriaxone (2 g daily) for 14 days (not enough evidence: GPP).

Definitions:

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy.

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation.

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls).

Evidence Classification Scheme for a Therapeutic Intervention

Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:

  1. Randomization concealment
  2. Primary outcome(s) is/are clearly defined
  3. Exclusion/inclusion criteria are clearly defined
  4. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
  5. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment.

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

Rating of Recommendations for a Diagnostic Measure

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.

Good Practice Points (GPPs) Where there was lack of evidence but consensus was clear the Task Force members have stated their opinion as good practice points.

Rating of Recommendations for a Therapeutic Intervention

Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.

Good Practice Points (GPPs) Where there was lack of evidence but consensus was clear the Task Force members have stated their opinion as good practice points.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for selected recommendations (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate diagnosis and management of European Lyme neuroborreliosis

Potential Harms

Ceftriaxone was associated with one case of anaphylaxis in one study.

Contraindications

Contraindications

Doxycycline is relatively contraindicated during pregnancy or lactation and is contraindicated in children <8 years (in some countries 9 years) of age.

Qualifying Statements

Qualifying Statements

This guideline provides the view of an expert task force appointed by the Scientific Committee of the European Federation of Neurological Societies (EFNS). It represents a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.

Implementation of the Guideline

Description of Implementation Strategy

The European Federation of Neurological Societies has a mailing list and all guideline papers go to national societies, national ministries of health, World Health Organization, European Union, and a number of other destinations. Corporate support is recruited to buy large numbers of reprints of the guideline papers and permission is given to sponsoring companies to distribute the guideline papers from their commercial channels, provided there is no advertising attached.

Implementation Tools
Staff Training/Competency Material
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I, European Federation of Neurological Societies. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. 2010 Jan;17(1):8-16, e1-4. [122 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2010 Jan
Guideline Developer(s)
European Federation of Neurological Societies - Medical Specialty Society
Source(s) of Funding

European Federation of Neurological Societies

Guideline Committee

European Federation of Neurological Societies Task Force on the Diagnosis and Management of European Lyme Neuroborreliosis

Composition of Group That Authored the Guideline

Task Force Members: Å Mygland, Department of Neurology, Department of Rehabilitation, Sørlandet Sykehus, Kristiansand, and Department of Clinical Medicine, University of Bergen, Bergen, Norway; U. Ljøstad, Department of Neurology, Sørlandet Sykehus, Kristiansand, Norway; V. Fingerle, Bavarian Health and Food Safety Authority, Oberschleißheim; T. Rupprecht, Department of Neurology, Ludwig-Maximilians University, Munich, Germany; E. Schmutzhard, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria; I. Steiner, Neurological Sciences Unit, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel

Financial Disclosures/Conflicts of Interest

Åse Mygland, Unn Ljøstad, Tobias Rupprecht, Volker Fingerle and Israel Steiner have no conflicts of interest.

Erich Schmutzhard has received fees or grants from Novo Nordisk, Bayer, Actelion, KCI and ALSIUS.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies Web site External Web Site Policy.

Print copies: Available from Å. Mygland, Department of Neurology, Sørlandet Sykehus, Serviceboks416, N-4604 Kristiansand S, Norway; Phone: +47 380 73914; Fax: +47 380 73911; E-mail: aase.mygland@sshf.no.

Availability of Companion Documents

The following are available:

  • Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K, Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific Committee. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81. Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies (EFNS) Web site External Web Site Policy.
  • Continuing Medical Education questions available from the EFNS Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI on August 4, 2011. The information was verified by the guideline developer on October 3, 2011.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the Blackwell-Synergy copyright restrictions.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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