Practice Parameter: Treatment of Nervous System Lyme Disease (An Evidence-Based Review) American Academy of Neurology (AAN) Quality Standards Subcommittee J.J. Halperin, MD; E.D. Shapiro, MD; E. Logigian, MD; A.L. Belman, MD; L. Dotevall, MD; G.P Wormser, MD; L. Krupp, MD; G. Gronseth, MD; C.T. Bever, Jr., MD American Academy of Neurology © 2007

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Presentation Objectives To identify key issues in the treatment of nervous system Lyme disease and post Lyme syndrome in adults and children. To make evidence-based recommendations American Academy of Neurology © 2007

Overview Epidemiology and Background Gaps in care AAN guideline process Analysis of evidence Summary Recommendations for future research American Academy of Neurology © 2007

Epidemiology Lyme disease: A multisystem disease caused by the tick-borne spirochete Borrelia burgdorferi which often affects the nervous system Symptoms: (some or all may be present) –Meningitis –Cranial neuritis –Radiculoneuritis American Academy of Neurology © 2007

Epidemiology Post Lyme Syndrome: Chronic symptoms in patients diagnosed with Lyme disease and who received treatment that was expected to be effective Symptoms: –Musculosketetal pain (without frank arthritis, fibromyalgia-like) –Fatigue –Neuropsychiatric symptoms American Academy of Neurology © 2007

Background Earliest treatment regimen for Lyme disease in US was prednisone 1983 American study: – B burgdorferi infection responsive to IV penicillin – Symptoms resolved far more quickly in penicillin- treated patients compared to earlier experience in those treated only with prednisone – Penicillin-treated patients had no relapses, but some had residual symptoms American Academy of Neurology © 2007

Background 1983 Swedish study: –B burgdorferi responsive to IV penicillin –Prior to treatment, illness was unremitting More recent studies show B burgdorferi is responsive to a variety of antimicrobials American Academy of Neurology © 2007

Gaps in Care Patient receives continued antibiotic treatment beyond 2 weeks despite lack of data to support the treatment course. American studies show treatment with parenteral antibiotics while European studies demonstrate comparable efficacy with oral doxycycline. Lack of clarity regarding which syndromes associated with Lyme disease reflect nervous system infection, which are a consequence of infection outside the nervous system, and which are post-infectious. American Academy of Neurology © 2007

AAN Guideline Process Clinical Question Evidence Conclusions Recommendations American Academy of Neurology © 2007

Clinical Question Question should address an area of quality concern, controversy, confusion, or variation in practice Question must be answerable with sufficient scientific data –Potential to improve clinical care and patient outcomes American Academy of Neurology © 2007

Literature Search/Review: Rigorous, Comprehensive, Transparent Complete Relevant American Academy of Neurology © 2007 Search Review abstracts Review full text Select articles

AAN Classification for Evidence All studies rated Class I, II, III, or IV Therapeutic Studies –Randomization, control, blinding Diagnostic Studies –Comparison to gold standard; spectrum Prognostic Studies American Academy of Neurology © 2007

AAN Level of Recommendations A = Established as effective, ineffective, or harmful for the given condition in the specified population B = Probably effective, ineffective, or harmful for the given condition in the specified population C = Possibly effective, ineffective, or harmful for the given condition in the specified population U = Data is inadequate or conflicting; given current knowledge, treatment is unproven American Academy of Neurology © 2007

AAN Level of Recommendations A = Requires two consistent Class I studies B = Requires one Class I study or two consistent Class II studies C = Requires one Class II study or two consistent Class III studies U = Studies not meeting criteria for Class I through Class III American Academy of Neurology © 2007

Clinical Questions Which antimicrobial agents have been shown to be effective or ineffective in the treatment of nervous system Lyme disease? Are different regimens preferred for different manifestations of neuroborreliosis? What duration of therapy is needed? American Academy of Neurology © 2007

Methods Literature Search –Ovid MEDLINE, Pubmed, and EMBASE At least two authors reviewed each full article Any disagreements were arbitrated by a third reviewer Disclosures were made Risk of bias determined using the AAN Classification of Therapeutic Evidence for each study (Class I – IV) Strength of practice recommendations linked directly to level of evidence (Level A – U) American Academy of Neurology © 2007

Literature Search/Review 37 articles American Academy of Neurology © articles Exclusion criteria: -Articles that did not address treatment of neuroborreliosis -Articles not peer- reviewed -Articles that were off topic -Review articles

Literature Search/Review Studies were divided into three groups: –Adult Lyme disease –Pediatric Lyme disease –Post Lyme disease Relevant studies graded as Class I – IV using the AAN Classification of Therapeutic Evidence Four studies were Class I Four studies were Class II All four of the Class II studies would be considered Class III with regard to clinical outcomes, for which assessments were not masked. All other studies were Class III or IV American Academy of Neurology © 2007

Clinical Question 1. Which antimicrobial agents have been shown to be effective or ineffective in the treatment of nervous system Lyme disease? American Academy of Neurology © 2007

Treatment for Peripheral Nervous System Lyme Disease and CNS Lyme Disease With or without CNS parenchymal involvement –Good evidence supports as probably safe and effective (Level B): Parenteral ceftriaxone, cefotaxime, penicillin Without parenchymal involvement –Good evidence supports as probably safe and effective (Level B): Oral doxycycline, parenteral ceftriaxone, cefotaxime, penicillin –Amoxicillin and cefuroxime axetil may provide alternatives but supporting data are lacking (Level B) American Academy of Neurology © 2007

Table 1. Antimicrobial Regimens Used in Treatment of Nervous System Lyme Disease Medication Adult Dose Child Dose Classification Oral Regimens Doxycycline 100 (-200) mg BID ≥8 yo (-8) mg/kg/d in B (preferred) divided doses, max 200 mg/dose Amoxicillin (when 500 mg TID 50 mg/kg/d in 3 divided C doxycycline contraindicated) doses; max 500 mg/dose Cefuroxime axetil (when 500 mg BID 30 mg/lg/d in 2 divided C doxycycline contrainticated) doses; max 500 mg/dose Parenteral Regimens Ceftriaxone 2 g IV daily mg/kg/d in 1 dose; B max 2 g Cefotaxime 2 g IV Q8H mg/kg/d in 3 – 4 B divided doses; max 6 g/day Penicillin G 18 – 24 MU/day, ,000 U/Kg/d divided Q4H; B divided doses Q4H max 18 – 24 MU/day American Academy of Neurology © 2007

Conclusions Based on four Class II studies, antibiotic regimens have been established as probably effective for both children and adults. American Academy of Neurology © 2007

Clinical Question 2. Are different regimens preferred for different manifestations of neuroborreliosis? American Academy of Neurology © 2007

Table 2. Syndromes and Treatment Options Syndrome Treatment Options Meningitis Parenteral, particularly if severe Doxycycline PO Any neurologic syndrome with CSF Parenteral, particularly if severe pleocytosisDoxycycline PO Peripheral nerve: radiculopathy, diffuseDoxycycline, PO neuropathy, mononeuropathy multiplex,Parenteral, if treatment failure or if cranial neuropathy; normal CSFsevere EncephalomyelitisParenteral EncephalopathyParenteral Post-treatment Lyme syndrome No antibiotics indicated; symptomatic management only American Academy of Neurology © 2007

Conclusions One Class I and one Class II study suggest that parenteral regimens are probably safe and effective for severe neurologic disease. Two Class II studies and numerous Class III and IV studies suggest that oral treatment with doxycycline is comparably safe and effective where there is no parenchymal CNS involvement. All studies were done in Europe, where strains of borrelia causing Lyme disease differ slightly. American Academy of Neurology © 2007

Conclusions Although the evidence is stronger in adults than children, all available evidence indicates that the response to oral treatment is comparable in adults and children. No definite data exist to establish the superiority, or lack thereof, of either oral or parenteral treatment. (See Tables 1. & 2.) American Academy of Neurology © 2007

Clinical Question 3. What duration of therapy is needed? American Academy of Neurology © 2007

Treatment of Post Lyme Syndrome Strong evidence supports: –Prolonged courses of antibiotics (of up to 12 weeks) do not improve outcome of post-Lyme syndrome, are potentially associated with adverse events, and are, therefore, not recommended (Level A). American Academy of Neurology © 2007

Duration of Therapy For both oral and parenteral regimens, the recommended duration is 14 days. Some published studies used courses of treatment from 10 to 28 days without significantly different outcomes. Prolonged parenteral antibiotic use can lead to severe diarrhea, blood stream infections, and other serious side effects. It is not recommended for longer than four weeks. American Academy of Neurology © 2007

Summary Treatment for Peripheral Nervous System Lyme Disease and CNS Lyme Disease With or without parenchymal involvement: –Good evidence supports as probably safe and effective (Level B): Parenteral ceftriaxone, cefotaxime, penicillin Without parenchymal involvement: – Good evidence supports as probably safe and effective (Level B): Oral doxycycline, parenteral ceftriaxone, cefotaxime, penicillin –Amoxicillin and cefuroxime axetil may provide alternatives but supporting data are lacking (Level B) American Academy of Neurology © 2007

Summary Treatment of Post Lyme Syndrome –Strong evidence supports that prolonged courses of antibiotics (of up to 12 weeks) do not improve outcome of post-Lyme syndrome, are potentially associated with adverse events, and are, therefore, not recommended (Level A). American Academy of Neurology © 2007

Summary The recommended duration of treatment for both oral and parenteral antibiotic regimens is 14 days. Oral doxycycline is generally well-tolerated. However, tetracyclines are relatively contraindicated in children <8 years of age and in pregnant or lactating women. Long-term treatment with parenteral antibiotics may cause severe diarrhea, blood stream infections, and other serious side effects. American Academy of Neurology © 2007

Future Research The efficacy of oral doxycycline compared to a parenteral regimen such as ceftriaxone needs to be clearly established, as does the predictive value of CSF abnormalities. If oral doxycycline is an effective treatment, it would be helpful to assess the relative efficacy of other oral regimens such as amoxicillin and cefuroxime axetil. For the optimal approach to parenchymal CNS nueroborreloisis, an assessment of treatment duration and the clear determination of the correct metrics of successful treatment would be beneficial. American Academy of Neurology © 2007

To access the full guideline please visit: AAN.com/Guidelines Published in Neurology, July 3, :91-102

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