Introduction

Lyme disease (LD) remains a significant world-wide public health problem, affecting well over 50,000 people per year, based on CDC and European data, and remains a particular concern to pediatric rheumatologists because of the higher prevalence of Lyme arthritis in children. Recent advances have been made in the understanding of the pathogenesis of Lyme arthritis [1] and neuroborreliosis [2], while diagnostic testing and treatment recommendations have not changed dramatically over the past 15 years. This brief review will supplement the recently published European guidelines on the diagnosis and treatment of Lyme disease by Dressler et al [3], and will focus on several areas: 1) diagnosis, 2) treatment, 3) central nervous system Lyme disease (neuroborreliosis), 4) Lyme arthritis mimicking septic arthritis, and 5) Lyme advocacy groups, and their internet sites.

Diagnosis

The diagnosis of Lyme disease depends on either the presence of erythema migrans, of at least 5 cm in diameter, or serologic confirmation in association with typical clinical features, such as lymphocytic meningitis, cranial nerve palsy, high-grade atrioventricular conduction defect, or episodic large joint oligoarthritis. The typical screening assay is an automated ELISA assay directed against whole, sonicated borrelia (in North America, usually the B31 strain of B. burgdorferi). According to the 1995 ASTPHLD guidelines, a positive screening test should be followed by immunoblotting [4]. During the first month of illness, Lyme Western blotting should reveal at least two of the following three IgM bands: 23, 39, and 41 kilodaltons. Following one month of symptoms, the IgG response should be used to support a diagnosis of LD. At least 5 bands are required for a positive IgG blot, since healthy children and children with other rheumatic disorders rarely have more than a single band [5]. In Lyme arthritis, a robust immune response is typically seen, with 9-10 out of 10 bands positive in a commercial Western blot, while university labs may reveal up to 20 bands present.

Kalish et al [6] reported that 15% of their patients with Lyme arthritis continued to have a late IgM response for unclear reasons. Others, including this author, have found that some children with vague chronic complaints may have a positive Lyme IgM Western blot, without clinical support for a diagnosis of Lyme disease. Because of this, the Food and Drug Administration came out with a public health advisory in 1997. One of their recommendations was that “a positive IgM anti-Bb result alone is not recommended for supporting a diagnosis of Lyme disease in persons with illness of greater than one month duration”.

Other diagnostic tests include polymerase chain reaction (PCR), C6 peptide antibodies, and urinary antigen assay. Lyme PCR has limited clinical utility at this point. As a tool for early CNS disease, CSF Lyme PCR has less sensitivity than the combination of CSF pleocytosis and serum antibodies. CSF in late Lyme encephalopathy will only rarely be positive by PCR (2/110 CSF samples were positive in our hands, unpublished data). A positive PCR on a persistent joint effusion may be indicative of ongoing infection, rather than an autoimmune basis for the persistent arthritis. Lyme PCR testing of blood samples is not indicated.

The C6 peptide assay is an IgG ELISA that uses a peptide in the sixth invariant region of the VlsE lipoprotein of B. burgdorferi, and may appear sooner than the standard Lyme ELISA. Its precise role in the clinic is yet to be defined. One private laboratory, up until recently, was promoting its urinary antigen assay. Several physicians in Connecticut, who are known for treating patients with prolonged courses of antibiotics, seem to utilize this particular laboratory, IgeneX of Palo Alto, California. Klempner and colleagues sent blinded samples of urine from healthy individuals to IgeneX for their Lyme urine antigen test, and found that most of the samples tested were reported as positive [7].

Treatment

Treatment guidelines have been recently published by the Infectious Diseases Society of America [8] and the Red Book of the American Academy of Pediatrics [9]. Doxycycline (for ages 8 and older) and amoxicillin are still the preferred oral agents for uncomplicated Lyme disease. Cefuroxime and azithromycin may be substituted in the allergic child. For erythema migrans (EM), treatment is recommended for 14-21 days. Fourteen days is probably adequate for EM without systemic symptoms, while the longer 21 days may be advisable for the child with EM, fever, and malaise. Wormser et al [1]) found that 10 days of doxycycline was just as effective as 20 days in adults with EM, although the high drop-out rate in his study questioned the validity of his findings. A single 200 mg dose of doxycycline after a known Ixodes tick bite seemed to reduce the likelihood of contracting Lyme disease in a Lyme endemic area [11].

Lyme arthritis is usually successfully managed with 30 days of oral antibiotics: doxycycline 100 mg bid, or amoxicillin 50 mg/kg/d in 2 or 3 divided doses. We have found that approximately 20% of our Lyme arthritis patients will relapse, requiring a second course of antibiotics, either repeating oral agents, or switching to intravenous ceftriaxone for 1 month. If there is any hint of neurologic involvement, I would be more inclined to go the IV route for the second course. With relapse, or with persistence of the original episode of arthritis, it may be useful to check the child for HLA-DR4 (as a surrogate marker for antibiotic resistance) and HLA-B27 (as a marker for reactive arthritis, no longer infective). In general, intra-articular steroids should be delayed until the child has had a reasonable course of antimicrobials. Recent data, however, suggests that supplemental oral corticosteroids during acute septic arthritis may be protective [12]. Simple joint aspiration without steroid injection should be avoided in known Lyme disease, since fluid rapidly re-accumulates.

Neuroborreliosis

Invasion of the central nervous system with borrelia burgdorferi is the single complication of Lyme disease that warrants immediate and aggressive action. Most of the children I see with late Lyme encephalopathy (headaches, fatigue, neurocognitive abnormalities, elevated CSF Lyme antibodies, occurring months after disease onset), in hindsight, had early neurologic symptoms, especially fever and mild meningismus. Early lumbar puncture, with demonstration of a lymphocytic CSF pleocytosis (average cell count: 80 cells), followed by 2-4 weeks of IV ceftriaxone, could conceivably prevent some of the late CNS disease, which can turn an “A” student into one with transient learning disabilities.

While late CNS disease can be treated [13, 14], late treatment is not as simple. Specifically, some of the patients so treated may continue to have low grade complaints, such as headache and school difficulties. This raises the question as to whether ongoing neurologic complaints are due to borrelia invasion, tissue damage from the earlier infection, cross-reactive antibodies (molecular mimicry), persistent inflammatory mediators, or other reasons. [15].

The question of whether prolonged antibiotic therapy is useful for patients with Lyme disease and persistent symptoms, especially neurologic symptoms, was recently addressed [16]. Klempner and colleagues found that the combination of 30 days IV therapy plus 60 days oral therapy did not provide any benefit beyond placebo in a large group of adults with Lyme disease and ongoing complaints.

Do all Lyme patients with Bell palsy (7^th nerve palsy) require a lumbar puncture? Bell palsy without headache, fever, or neck stiffness, can probably be safely treated with oral antibiotics, preferably doxycycline because of its superior CNS penetrability. Yet, an LP should be performed to rule out central, or “nuclear” 7^th nerve paralysis. In addition to the classic triad of CNS Lyme (cranial neuropathy, meningitis, radiculitis), psychiatric symptoms, such as depression, panic attacks, and paranoia, may be seen but their exact relationship to borrelia infection remains a matter of controversy [17].

Pseudo-septic Arthritis

Lyme arthritis, when it first occurs, may mimic septic arthritis, especially when it involves the hip or knee [18]. Low grade fever, non-weight bearing, elevated sed rate, and mild leukocytosis may all be seen during early stages of Lyme arthritis. According to a widely used orthopedic algorithm [19], this child would have a 99.6% likelihood of having a septic joint. Even with elimination of the leukocytosis criteria (admittedly, uncommon in Lyme), the above patient would still have a 93% chance of having a pyogenic joint. Thus, if an orthopedist sees this child first, and has not considered Lyme disease, the child would be whisked off to surgery for lavage, unnecessary in Lyme arthritis. To add to the confusion, synovial fluid (SF) cell counts may overlap between the two conditions, with some cases of Lyme arthritis having SF WBC’s of over 100,000 cells/cu mm. For some reason, cartilage degradation is extremely unlikely in Lyme disease, despite the similarities in cell counts. In Lyme endemic areas like Connecticut, there are 10 children with Lyme arthritis for every single case of septic arthritis.

Lyme arthritis is differentiated from septic arthritis by demonstrating the presence of serum Lyme antibodies, and a negative blood and synovial fluid culture. Clinically, Lyme arthritis of the knee has more swelling and less pain than a septic knee. While waiting for the lab results to come back, a combination of IV ceftriaxone and vancomycin would be reasonable, to cover Lyme and methicillin-resistant staph aureus, respectively.

Lyme Advocacy Groups

New diseases, especially those popular with the media, often generate new support groups. Professionally-run groups, like the Arthritis Foundation, provide useful support, education, advocacy, and funds for research. Grass-roots groups may have other agendas, such as challenging scientific dogma and evidenced-based medicine, pressuring politicians to protect those physicians who do not adhere to standards in Lyme disease care, altering state legislation to block insurers’ efforts to control antibiotic usage, and to raise funds for selected investigators. There are some highly credible organizations, such as the American Lyme Disease Foundation (ALDF), which has a respected board of scientific advisors. Other groups, unfortunately, often spread fear and misinformation, and have created a cottage industry of Lyme physicians who get their patients referred from Lyme groups, and often diagnose sero-negative Lyme disease.

A recent survey of Lyme internet sites has shown some widely differing levels of accuracy. Cooper and Feder [20] scored 19 web sites according to standard knowledge about Lyme disease. Popular sites, such as the Lyme Foundation and Lyme Disease Association (LDA), scored poorly. The Lyme Foundation presented inaccurate information in 6 of the 8 domains tested, while LDA failed all 8 domains! The American Lyme Disease Foundation, FDA, CDC, and Johns Hopkins School of Medicine all scored well.

Summary

Lyme disease is an important disease for the pediatric rheumatologist to understand. Diagnosis and treatment have not changed much recently and are straight-forward if guidelines are followed. Diagnosing neuroborreliosis and distinguishing a septic joint from a pseudoseptic Lyme joint are challenging, particularly if physicians are not that familiar with Lyme. Pediatric rheumatologists should be aware of the Lyme advocacy groups and which ones provides better resources and help.

References

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