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DESCRIPTIONLyme disease (LD) is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi transmitted by the bite of an infected ixodid tick endemic to Northeastern, North Central, and Pacific coastal regions of the United States. The disease is characterized by stages, beginning with localized infection of the skin (erythema migrans) followed by dissemination to many sites. Manifestations of early disseminated disease may include lymphocytic meningitis, facial palsy, painful radiculoneuritis, atrioventricular nodal block, or migratory musculoskeletal pain. Months to years later, the disease may be manifested by intermittent oligoarthritis, particularly involving the knee joint, chronic encephalopathy, spinal pain, or distal paresthesias. While most manifestations of LD can be adequately treated with oral antibiotics, intravenous (IV) antibiotics are indicated in some patients with neurologic involvement or atrioventricular heart block. However, overdiagnosis and overtreatment of LD is common due to its nonspecific symptoms, lack of standardization of serologic tests, and difficulties in interpreting serologic tests. In particular, patients with chronic fatigue syndrome or fibromyalgia are commonly misdiagnosed as possibly having LD and undergo inappropriate IV antibiotic therapy. The purpose of this policy is to provide diagnostic criteria for the appropriate use of IV antibiotic therapy. The following paragraphs describe the various manifestations of LD that may prompt therapy with IV antibiotics and the various laboratory tests that are used to support the diagnosis of LD.
Neurologic Manifestations of Lyme Disease (Neuroborreliosis)
Lymphocytic meningitis, characterized by head and neck pain, may occur during the acute disseminated stage of the disease. Analysis of the cerebrospinal fluid (CSF) is indispensable for the diagnosis of Lyme meningitis. If the patient has LD, the CSF will show a lymphocytic pleocytosis (lymphocyte count greater than normal) with increased levels of protein. Intrathecal production of antibodies directed at spirochetal antigens is typically present. A normal CSF analysis is strong evidence against Lyme meningitis. Treatment with a 2- to 4-week course of IV antibiotics, typically ceftriaxone or cefotaxime, is recommended.
Cranial neuritis, most frequently Bell’s palsy, may present early in the course of disseminated LD, occasionally prior to the development of antibodies, such that a LD etiology may be difficult to rule in or out. While Bell’s palsy typically resolves spontaneously with or without treatment with oral antibiotics, some physicians have recommended a lumbar puncture and a course of IV antibiotics if pleocytosis in the CSF is identified, primarily as a prophylactic measure to prevent further neurologic symptoms.
A subacute encephalopathy may occur months to years after disease onset, characterized by subtle disturbances in memory, mood, sleep, or cognition accompanied by fatigue. These symptoms may occur in the absence of abnormalities in the electroencephalogram (EEG), magnetic resonance imaging (MRI), or CSF. In addition, the symptoms are nonspecific and overlap with fibromyalgia and chronic fatigue syndrome. Thus diagnosis of Lyme encephalopathy may be difficult and may be best diagnosed with a mental status exam or neuropsychological testing. However, treatment with IV antibiotics is generally not indicated unless CSF abnormalities are identified.
Much rarer, but of greater concern, is the development of encephalomyelitis, characterized by spastic paraparesis, ataxias, cognitive impairment, bladder dysfunction, and cranial neuropathy. CSF examination reveals a pleocytosis and an elevation in protein. Selective synthesis of antispirochetal antigens can also be identified. A course of IV antibiotics with 3 to 4 weeks of ceftriaxone is suggested when CSF abnormalities are identified.
A variety of peripheral nervous system manifestations of LD have also been identified. Symptoms of peripheral neuropathy include paresthesias, or radicular pain with only minimal sensory signs. Patients typically exhibit electromyographic (EMG) or nerve conduction velocity abnormalities. CSF abnormalities are usually seen only in those patients with a coexistent encephalopathy.
Cardiac Manifestations of Lyme Disease
Lyme carditis may appear during the early dissemination stage of the disease; symptoms include atrioventricular heart block, tachyarrhythmias, and myopericarditis. Antibiotics are typically given, although no evidence proves that this therapy hastens the resolution of symptoms. Both oral and IV regimens have been advocated. Intravenous regimens are typically used in patients with a high degree atrioventricular block or a PR interval on the electrocardiogram (EKG) of greater than 0.3 second. Patients with milder forms of carditis may be treated with oral antibiotics.
Lyme arthritis is a late manifestation of infection and is characterized by an elevated IgG response to B. burgdorferi and intermittent attacks of oligoarticular arthritis, primarily in the large joints such as the knee. Patients with Lyme arthritis may be successfully treated with a 30-day course of oral doxycycline or amoxicillin, but care must be taken to exclude simultaneous central nervous system (CNS) involvement requiring IV antibiotic treatment. In the small subset of patients that do not respond to oral antibiotics, an additional 30-day course of oral or IV antibiotics may be recommended.
Fibromyalgia and Chronic Fatigue Syndrome
Fibromyalgia and chronic fatigue syndrome are the diseases most commonly confused with LD. Fibromyalgia is characterized by musculoskeletal complaints, multiple trigger points, difficulty in sleeping, generalized fatigue, headache, or neck pain. The joint pain associated with fibromyalgia is typically diffuse, in contrast to Lyme arthritis, which is characterized by marked joint swelling in one or a few joints at a time, with few systemic symptoms. Chronic fatigue syndrome is characterized by multiple subjective complaints, such as overwhelming fatigue, difficulty in concentration, and diffuse muscle and joint pain. In contrast to LD, both of the above conditions lack joint inflammation, have normal neurological test results, or have test results suggesting anxiety or depression. Neither fibromyalgia nor chronic fatigue syndrome has been shown to respond to antibiotic therapy.
The antibody response to infection with B. burgdorferi follows a typical pattern. During the first few weeks after the initial onset of infection, there is no antibody production. The specific IgM response characteristic of acute infection peaks between the third and sixth week. The specific IgG response develops only after months and includes antibodies to a variety of spirochetal antigens. IgG antibodies produced in response to LD may persist for months or years. Thus detection of IgG antibodies only indicates exposure, either past or present. In LD endemic areas, underlying asymptomatic seropositivity may range up to 5%–10%. Thus, as with any laboratory test, interpretation of serologic tests requires close correlation with the patients’ signs and symptoms. For example, patients with vague symptoms of LD, chronic fatigue syndrome, or fibromyalgia may undergo multiple serologic tests over many weeks to months in an effort to establish the diagnosis of LD. Inevitably, in this setting of repeat testing, one enzyme-linked immunosorbent assay (ELISA) or test, whether IgG or IgM, may be reported as weakly positive or indeterminate. These results most likely represent false positive test results in the uninfected patient who has had long-standing symptoms from a different condition and previously negative test results.
Currently, the Centers for Disease Control and Prevention (CDC) recommends a two-step method for the serologic diagnosis of LD:
Other tests include:
Polymerase Chain Reaction (PCR)
In contrast to the above 2 serologic tests, which only indirectly assess prior or present exposure to B. burgdorferi, PCR directly tests for the presence of the spirochete. Because PCR technology involves amplification of DNA from a portion of B. burgdorferi, there is a high risk of exogenous contamination, resulting in false positive results. Positive results in the absence of clear clinical indicators or positive serology are not definitive for diagnosis. In addition, the test cannot distinguish between live spirochetes or fragments of dead ones. The PCR technique has been studied using a variety of specimens. PCR has the best detection rates for skin biopsies from patients with erythema migrans and for synovial tissue (and synovial fluid, to a lesser extent) from patients with lyme arthritis. CSF may be positive by PCR during the first two weeks of infection, but thereafter the detection rate is low. PCR is not recommended for urine or blood specimens.
Borrelia PCR also provides information on which of the three major species pathogenic for humans has been found in the specimen tested (genotyping).
T-Cell Proliferative Assay
T-lymphocyte proliferation assays are not recommended as diagnostic tests; they are difficult to perform and standardize, and their sensitivity is not well characterized.
Evaluation of the Cerebrospinal Fluid (CSF)
Aside from the standard evaluation of CSF for pleocytosis, protein levels, and glucose levels, various tests are available to determine whether anti-B. burgdorferi antibodies are being selectively produced within the central nervous system. Techniques include a variety of immunoassays. For example, intrathecal antibody production can be detected by the CSF/serum index of B. burgdorferi antibodies. CSF and serum samples diluted to match the total IgG concentration in CSF are run in parallel in an IgG ELISA. Excess Borrelia-specific antibody in CSF indicates a positive result. As noted, PCR can also be used to detect the spirochete in the CSF, most successfully within the first 2 weeks of infection.
Treatment of Lyme Disease
As noted above, treatment with IV antibiotics is generally indicated only in those patients with symptoms and laboratory findings consistent with CNS or peripheral neurologic involvement, and in a small subset of patients with heart block or documented Lyme arthritis who have not responded to oral antibiotics. Typical IV therapy consists of a 2- to 4-week course of ceftriaxone or cefotaxime, both third-generation cephalosporins, or penicillin or chloramphenicol. No data suggest that prolonged or repeated courses of IV antibiotics are effective. Lack of effect should suggest an incorrect diagnosis or slow resolution of symptoms, which is commonly seen in LD. In addition, some symptoms may persist after treatment, such as Lyme arthritis; this phenomenon may be related to various self-sustaining inflammatory mechanisms rather than persistent infection.
POLICYTreatment of LD consists of oral antibiotics, except for the following indications:
Objective neurologic findings include:
Lyme disease may be documented either on the basis of serologic testing or by clinical findings of erythema migrans in early infection. Documentation of CSF abnormalities is required for suspected CNS infection, as indicated above.
Serologic documentation of infection requires:
Documented CSF abnormalities include ALL of the following:
PCR-based direct detection of B. burgdorferi in CSF samples may be considered medically necessary in patients with a short duration of neurologic symptoms (<14 days) during the window between exposure and production of detectable antibodies.
PCR-based direct detection of B. burgdorferi in the blood when results of serologic studies are equivocal.
Intravenous antibiotic therapy is considered not medically necessary in the following situations:
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY1/1994: Approved by Medical Policy Advisory Committee (MPAC)
5/1/2002: Type of Service and Place of Service deleted
3/25/2004: Reviewed by MPAC, Policy title “Lyme Disease Treatment” renamed “Intravenous Antiobiotic Therapy for Lyme Disease”, Description and Policy sections revised to be consistent with BCBSA policy # 5.01.08, intravenous antibiotic therapy changed from investigational to medically necessary for certain indications, investigation definition added, Sources updated, tables added to Code Reference section
5/5/2004: Code Reference section completed
3/13/2006: Policy reviewed, no changes
9/12/2006: Coding reviewed. ICD9 2006 revisions added to policy
11/13/2006: Code Reference section updated: CPT codes 87475, 87476, and 87477 deleted from policy
4/24/2007: Policy reviewed, policy statement rewritten for clarification
6/21/2007: Policy reviewed, description updated. Policy statement revised; IV antibiotic therapy is not medically necessary for uncomplicated cranial nerve palsy associated with Lyme disease and antibiotic-refractory Lyme arthritis
7/19/2007: Reviewed and approved by MPAC
7/10/2009: Policy reviewed, no changes
12/15/2009: Coding Section revised with 2010 CPT4 and HCPCS revisions
02/23/2011: Added the following to the policy statement: Determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment is considered investigational. No changes to other policy statements. Removed deleted HCPCS codes J0530, J0540, and J0550 from the Code Reference section.
02/24/2012: Add the following policy statement: A single 2- to 4-week course of IV antibiotics may be considered medically necessary in patients with Lyme carditis, as evidenced by positive serologic findings (defined above) and associated with a high degree of atrioventricular block or a PR interval of greater than 0.3 second. Documentation of Lyme carditis may include PCR-based direct detection of B burgdorferi in the blood when results of serologic studies are equivocal. The last policy statement was revised to state that other diagnostic testing is considered investigational including but not limited to C6 peptide ELISA or determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment. It previously stated that determination of levels of the B lymphocyte chemoattractant CXCL13 for diagnosis or monitoring treatment is considered investigational. Deleted outdated references from the Sources section.
11/28/2012: Policy reviewed; no changes.
SOURCE(S)Blue Cross Blue Shield Association policy # 5.01.08
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.