“An Approach to Lyme Disease”
Wesley P. Kozinn, M.D., F.A.C.P.
The management of Lyme disease remains controversial despite the recent publication of guidelines for diagnosis and treatment in the peer-reviewed medical literature. Failure to recognize typical clinical symptoms and false-negative testing procedures foster underdiagnosis. Anxiety about persistence of Lyme disease, misinterpretations serologic tests, and concerns about progression to a chronic illness foster overdiagnosis and overtreatment. In the absence of definitive diagnostic studies, physicians must cope with clinical uncertainties in the management of these patients. This balancing act requires careful clinical evaluation, patient education, empowerment of the patient in management decisions, and treatment that avoids harm. Physicians must update their knowledge and recognize that much is not known about the pathogenesis and optimal management of Lyme disease.
Lyme borreliosis is a disease of varied manifestations caused by the spirochete Borrelia burgdorferi. It has been characterized as an emerging infectious disease, and it is the most common vector-borne infection in the U.S. Infection is transmitted by the bite of Ixodid ticks, which concurrently can transmit other infectious agents, such as Babesia spp. and Ehrlichia spp. The distribution of the disease parallels the habitat of its tick vectors. The majority of U.S. cases are reported from the Mid-Atlantic States, southern New England, Wisconsin, Minnesota, Oregon and California . The disease occurs in Europe and Asia as well. Exposure to borrelial infection may therefore occur in areas not ordinarily considered endemic or as a result of travel to endemic areas.
For the primary physician as well as the specialist, Lyme disease remains a complex clinical problem. In the absence of definitive diagnostic tests and well-designed prospective studies that define optimal treatment for all stages of Lyme disease, practitioners must cope with uncertainty in the management of patients. The management of Lyme borreliosis has become polarized into two camps: academic medicine and Lyme treating physicians and their advocacy groups. The purpose of this paper is to help physicians develop a bridging strategy for managing patients when data for optimal treatment is often lacking.
The diagnosis of Lyme and other tick borne diseases can be difficult, especially when cases occur outside of Lyme endemic areas. Like Treponema pallidum, B. burgdorferi can cause symptoms involving the skin, nervous system, heart, joints, musculoskeletal system, eye, gastrointestinal tract, and other organs . Lyme disease can cause a variety of typical or non-specific presenting symptoms. Serologic tests for B. burgdorferi antibodies are important adjuncts to diagnosis. Unfortunately, standard enzyme immunoassay screens and Western blots lack the desired sensitivity, and specificity for diagnostic confirmation, especially early in disease . Under the best of laboratory circumstances, serologic evidence of Lyme disease can be missed, because of false-negative results, in up to 10% of late neurological Lyme disease and Lyme arthritis cases . False-positive tests, often caused by antibody to the p-41 flagellar protein, are especially problematic when the pre-test probability of Lyme disease is low. Serologic testing by enzyme immunoassay and Western blots can therefore result in both overdiagnosis and underdiagnosis . Ultimately, an accurate clinical diagnosis of Lyme disease requires comprehensive analysis of symptoms and signs, laboratory studies, epidemiology of the patient’s environment, and travel history.
Most helpful in diagnosis is presence of the erythema migrans (EM) rash, which can have a variable appearance. EM is reportedly recognized in 60-80% of patients with early Lyme disease4. However, other reports suggest that EM is seen far less frequently, perhaps because clinicians fail to make a diligent search for less obvious lesions in the scalp, groin, feet, perineum, and axillae. Other findings typical of early Lyme disease include facial palsy, especially bilateral, other cranial neuropathies, heart block, transient arthritis, or lymphocytic aseptic meningitis seen during the warm weather months in Lyme endemic areas. The development of an oligoarticular, large joint, migratory arthritis months to years after EM can also readily be recognized as Lyme arthritis.
Characteristic neurologic syndromes are also readily identifiable, when a history of tick bite or EM, or prior Lyme disease is obtained. These patients can have painful radiculopathy, cranial neuropathy, plexopathy and disseminated polyneuropathy. Mononeuritis multiplex is an important presentation, with multiple lesions in a throughout the peripheral nervous system. The cerebrospinal fluid (CSF) is almost always abnormal in these patients. CSF pleocytosis and the demonstration of intrathecal antibody production against B. burgdorferi are diagnostic of neurological Lyme disease.
In sum, patients with Lyme disease usually have recognizable clinical syndromes, and a careful clinical history will reveal epidemiological links to tick borne infection. B. burgdorferi antibody testing of blood, CSF, or joint fluid is an adjunct to the clinical diagnosis. The most challenging patients are those who present with non-specific symptoms such as fatigue, arthralgias, headache, muscle stiffness, memory disturbance, or impaired cognition. Lyme disease must be distinguished from fibromyalgia, chronic fatigue syndrome, multiple sclerosis, connective tissue diseases, and depression. Testing for Lyme disease is often done even though the pre-test probability of Lyme disease is low. The clinician must then cope with results yielding weakly positive B. burgdorferi antibody screens, and negative or inconclusive Western blot tests. Seronegative cases are unusual in longstanding Lyme disease, and they present the greatest difficulty in diagnosis. A history of tick exposure, Lyme disease in family members or pets, serologic evidence of other tick-borne infections, or a history of prior Lyme disease may sway the clinician to diagnose and treat for Lyme disease. For patients previously treated for Lyme disease, it is essential to determine if that diagnosis was originally correct, and if so, whether treatment was adequate.
Hopefully, tests that are in development will improve diagnosis, particularly in early infection, but none have as yet been validated for routine use. The most promising is the C 6 peptide detector, which has a higher sensitivity early in disease. Western blot testing independent of B. burgdorferi EIA studies may occasionally be helpful, as are direct tests for B. burgdorferi DNA by PCR in joint fluid, blood and cerebrospinal fluid. Brain MRI scans show non specific white matter abnormalities in CNS Lyme borreliosis, but this study can be very helpful in the appropriate clinical setting and epidemiology. Functional brain imaging may have a role in detecting cerebral perfusion abnormalities due to Lyme disease or other brain vasculopathies. The Lyme urinary antigen test was discredited because of high rates of false positives, lack of independent validation and reproducibility. The test was removed from the market and replaced by a dot blot urinary antigen test, but its usefulness has not been validated. The test is not approved by the food and drug administration, and is not recommended by the Centers for Disease Control and Prevention. Nevertheless, some physicians continue to advocate this test for evaluation of ‘seronegative’ Lyme disease or to determine Lyme disease activity, and patients may demand such testing.
The media have popularized Lyme disease as an incurable affliction, which does not respond completely to currently recommended antibiotic regimens. The published literature shows just the opposite. Recently, the Medical Letter and the Infectious Diseases Society of America (IDSA) published conservative guidelines for Lyme disease treatment using oral or intravenous antimicrobials for 2-4 weeks. However, the recommendations for the treatment of early Lyme disease, without neurologic involvement or A-V block, are the only ones based on at least one properly randomized controlled trial (evidence category A-I). The treatment guidelines for early neurologic disease, Lyme arthritis, Lyme carditis, and late neurologic disease are supported by category B-II and B-III evidence (moderate published evidence and expert opinion).
Management of late nervous system Lyme disease is the most problematic, because treatment guidelines are based on small, uncontrolled case series . The optimal treatment regimen for neurological Lyme disease is not known , but most patients respond well. Progressive recovery may take several months after treatment is completed.
The IDSA expert consensus is that neurological Lyme disease can be successfully treated with 2-4 weeks of I.V. ceftriaxone, cefotaxime, or penicillin G. Despite these and previously published similar recommendations, many physicians rely on more protracted courses of treatment. Of 92 Connecticut physicians responding to a survey of Lyme disease treatment practices, 43% treated post-erythema migrans Lyme disease for 3 months or more. For ‘chronic Lyme disease’, 24% of respondents treated for 6 months or more . An anecdotal treatment protocol published on the Internet and presented at Lyme Disease Foundation meetings has promoted the use of combination antimicrobial therapy, pulse therapy several days a week, cyclically protracted antimicrobial therapy, and the use of drugs such as vancomycin, metronidazole, plaquenil, and imipenem.
Prolonged antimicrobial therapy for Lyme disease carries risks, which physicians and patients must be aware of. Vascular catheters used for I.V. therapy can become clogged or infected. Ceftriaxone therapy is associated with a risk of biliary sludging, biliary colic, and acute cholecystitis . Superinfections with Clostridium difficile and Candida spp. may occur, despite ‘probiotic’ regimens. Allergic reactions, hematologic toxicity, and nephrotoxicity may accompany courses of parenteral or oral antibiotics. Finally, all antibiotic usage, to some extent, promotes the emergence of antimicrobial resistance. Physicians must be accountable for exacerbating this problem when they prescribe antibiotics inappropriately.
There is no convincing evidence that prolonged or cyclical antibiotic treatment courses are necessary or beneficial in preventing relapses. Nevertheless, some patients and physicians have developed strong belief systems concerning the persistence of B. burgdorferi infection despite ‘conventional’ treatment 27,19. Prolonged post-treatment symptoms such as fatigue, arthralgias, headaches, and cognitive disturbance encompass the spectrum of ‘chronic Lyme disease.’ Symptoms were persistent in 53% of 215 patients evaluated 1 year after treatment for a confirmed diagnosis of Lyme disease . Furthermore, fibromyalgia can follow Lyme disease, and it does not seem to respond to repeated courses of antimicrobial therapy.
The fear is that persistent symptoms are a sign of inadequately treated infection. Advocates of protracted antimicrobial therapy cite animal studies , in vitro studies, case series , and anecdotal reports to suggest that B. burgdorferi infection can persist as a chronic infection . On the opposite pole in this controversy, the IDSA has declared in its guidelines that there is insufficient evidence to support the concept of chronic Lyme disease as a distinct diagnostic entity 22.
Sigal suggests that persistent symptoms following treatment are due to a variety of mechanisms encompassing ‘Post-Lyme disease syndromes’. Least likely is persistent infection. Proposed mechanisms for protracted symptoms include post-infectious immunoreactive phenomena, sterile inflammation caused by dead organisms, permanent tissue injury that does not respond to antibiotics, and misdiagnosis of Lyme disease . These explanations may not sit well with patients whose illness and symptoms persist. Many seek continued treatment after thorough evaluation and advice against further antimicrobial therapy. A recently published prospective, double-blind placebo-controlled study comparing a month of I.V. ceftriaxone followed by 60 days of oral doxycycline for patients with ‘post-treatment chronic Lyme disease’ (PTCLD) showed no benefit of antibiotic treatment compared to placebo . The study did document the severe impairments of function caused by Lyme disease in these patients, but it suggested that the symptoms do not respond to protracted courses of antibiotics.
Another explanation for severe or persistent symptoms is tick-borne co-infection with the red blood cell parasite, Babesia microti . Patients with concurrent or sequential infections have a higher incidence of headache, chills and sweats. Symptomatic parasitemia may persist, despite treatment with clindamycin and quinine. The combination of azithromycin and atovaquone is a promising treatment for human babesiosis. Simultaneous or sequential infection with B. burgdorferi and the rickettsial agent of human granulocytic ehrlichiosis (Anaplasma phyagocytophila) also occurs. Patients with ehrlichiosis may have more fever and chills, but co infection may be indistinguishable from Lyme borreliosis alone. Ehrlichiosis can also cause life-threatening disease, with fever >38oC, pneumonia, leukopenia, thrombocytopenia, and hepatitis. Doxycycline is a preferred first line drug for the treatment of Lyme disease because it is also effective for the treatment of ehrlichia infection.
Developing an Approach
Given the number of uncertainties in the management of Lyme disease and the amount of anxiety about the condition, the physician must validate the patient’s concerns, and affirm that differing points of view exist. A successful patient encounter can be expected when the physician takes a thorough, non-judgmental history, carefully reviews available laboratory data, and performs a comprehensive physical examination. This approach adds to the patient’s confidence that an appropriate diagnosis and treatment plan will be attained. The role of the physician is not only to diagnose or exclude Lyme disease, but also to consider and evaluate alternative explanations for patient’s symptoms. Patient education is important to explain lab results, review published data, and engage in a dialogue to agree upon range of diagnostic treatment options.
The physician must improve his/her understanding and knowledge about this and associated tick-borne infections. As a practical matter, referral to an expert can be beneficial to the patient and the referring physician. By engaging patients in the decision making process, by accepting their anxieties, and by keeping an open mind, the physician can better cope with the varied viewpoints and uncertainties in the management of this complex disease entity. With an understanding that persistent symptoms can occur after effective treatment for Lyme disease, the patient can avoid the potential harm of unnecessary and protracted antimicrobial therapy.
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