The Long-Term Clinical Outcomes of Lyme Disease: A Population-Based Retrospective Cohort Study

Lyme borreliosis is a tick-borne infection caused by the spirochete Borrelia burgdorferi [1-3]. The disease usually begins with erythema migrans accompanied by viral-like or meningitis-like symptoms. Weeks later meningitis, facial palsy, atrioventricular nodal block, or migratory musculoskeletal pain may develop, followed months to years later by episodes of frank arthritis, encephalopathy, polyneuropathy, or acrodermatitis [4]. Lyme disease is now the most common vector-borne disease in the United States; nearly 50 000 patients have been diagnosed with it since 1982 [5]. Musculoskeletal and neurologic sequelae may occur from Lyme disease. Some of the late consequences of Lyme disease, such as oligoarticular arthritis, axonal polyneuropathy, or active encephalopathy, are thought to be caused by persistent spirochetal infection and are amenable to antibiotic treatment [6-8]. Other syndromes such as persistent arthritis, fibromyalgia, subtle joint pain, or mild encephalopathy do not improve with antibiotic treatment, suggesting a mechanism other than active infection [9-12]. We studied persons residing in an endemic coastal area of Massachusetts who were previously infected with B. burgdorferi in the early 1980s [13]. They contracted Lyme disease while the clinical syndromes and optimal antibiotic therapies were still evolving, which offered a natural experiment for the identification of risk factors for Lyme disease sequelae. We ascertained the prevalence of persistent symptoms in unselected patients with a history of Lyme disease; ascertained their rheumatologic, neurologic, and health status outcomes; and identified potential risk factors for these long-term sequelae. Methods Participants In February l991, we did a follow-up analysis of residents of Argylla Road in Ipswich, Massachusetts, an endemic coastal area for Lyme disease. The incidence and clinical course of Lyme disease among residents of this area have been reported previously [13]. Participants were recruited by calling consecutive households located in the Argylla Road area, the epicenter of infection, to ask if they would be interested in enrolling in a study about Lyme disease in their area. Potential participants were told that the study involved a history, physical examination, and serologic analysis for Lyme disease. Information about whether a person ever had a previous diagnosis of Lyme disease was obtained and used to assign tentative status (with or without Lyme disease) for study participants. We recruited participants until we had 50 tentative persons with Lyme disease and 50 tentative controls. Once the potential Lyme disease group was filled, calls were made consecutively to fill the potential control group. Residents 18 years of age or older were invited to participate in the study. This protocol was approved by the Brigham & Women's Hospital Committee for the Protection of Human Subjects. Confirmation of Lyme Disease For inclusion in the Lyme group, persons needed a previous diagnosis of Lyme disease by a physician and needed to fulfill the Centers for Disease Control and Prevention (CDC) criteria for Lyme disease (a history of physician-documented erythema migrans or a late manifestation of Lyme disease confirmed by a positive Lyme serologic test result, or both [14]). This information was obtained through patient interview and then medical record review to determine if patients fulfilled criteria for Lyme disease. Previous study records, local physician reports, and previous serologic test results were available for confirmation of Lyme disease. Persons without a previous clinical history of Lyme disease were classified as controls. The status of the participants (with or without Lyme disease) was determined independent of the clinical assessment, using a protocol that did not include any outcome data. Assessment of Clinical Outcomes A blinded investigator determined outcomes in a standardized manner independent of Lyme disease status. All patients completed a standardized questionnaire, had electrocardiography, and had a neuropsychological battery of tests. The questionnaire included data on demographics, comorbidity, education, review of systems, medications, memory and cognitive function, and the Short Form-36 health status measure (a reliable, previously validated measure of physical, psychological, social, and role functions [15]). A physical examination was done by one observer blinded to Lyme disease status. It included a joint examination (the American College of Rheumatology Glossary examination) that measured swelling and pain through passive range of motion [16] and a neurologic evaluation of strength and deep tendon reflexes, light touch, and vibration sensation with a 128-Hz tuning fork (at the elbow, wrist, fibula, and ankles). Pain and swelling indices from the joint examination (the American College of Rheumatology Glossary examination) were summed and recorded as a global score. A vibration test result of a distal gradient was considered present if the participant reported diminished vibratory sensation at a distal compared with proximal site. Each participant had an electrocardiographic study that was interpreted blindly by a cardiologist uninvolved with the clinical assessment. All outcomes were determined by one investigator who had no knowledge of whether participants were in the Lyme or control groups. The neuropsychological battery of tests measured immediate and delayed verbal memory, attention, conceptualization, fine motor dexterity, and perceptual discrimination. Tests included the California Verbal Learning Test [17], Wechsler Memory Scale (visual reproduction and verbal paired associates subtests [18]), Shipley abstraction subtest [19], Stroop test [20], Trailmaking test [21], and Purdue Pegboard Test [22]. The California Verbal Learning Test measures verbal memory. Participants are asked to learn a list of 16 words during five trials; recall on the fifth trial is recorded (trial 5). This is then followed by a distracter list. The original list is recalled after the distracter list is learned (short recall) and then recalled again after a 20-minute delay (long recall). This is a challenging test of memory for patients with superior premorbid experience. Normative values are available for young and elderly adults [17]; the range of normal is between 11 and 15 words for trial 5 and is between 10 and 15 words for the long-recall subtest for persons between 45 and 54 years of age. A clinically significant change in the California Verbal Learning Test would be recalling 4 more words or 4 fewer words. All tests were administered according to published procedures. Test scores were transformed into standard scores calculated from published, age-corrected normative data. Participants with a score of 2 or more SDs from age-adjusted means were considered impaired. All results were reviewed by a neuropsychologist (RK) who was not involved with the participant's evaluation, to determine those patients who were in need of further clinical evaluation. Participants with swelling or pain (joint examination test result), evidence of a distal gradient (vibration test result) or persistent symptoms of paresthesias in an extremity, or impairment on two or more neurocognitive tests were sent for further clinical evaluation. Nine patients were evaluated at the Lyme disease clinic at Tufts-New England Medical Center and 4 were evaluated by other neurologist or rheumatologist consultants to determine if these abnormal screening test results were accompanied by objective findings. This evaluation included lumbar puncture, electrophysiologic studies, magnetic resonance imaging, detailed neuropsychological tests [8], joint radiographs, or arthrocentesis. Serologic Evaluation All patients had serologic testing after the history and examination. Serum samples were stored at 70C and were tested for IgG antibodies to B. burgdorferi by indirect enzyme-linked immunosorbent assay (ELISA [23]); for IgM, IgG, and IgA antibodies to the spirochete by antibody-capture enzyme immunoassays [24]; and for the pattern of IgG reactivity to spirochetal polypeptides by Western blotting. In general, Western blot reactivity varied with the degree and duration of dissemination of Lyme disease. For example, patients with early localized infection or erythema migrans might react to only 2 to 8 B. burgdorferi polypeptides, those with meningitis might react to at least 8 to 14 polypeptides, and those with arthritis or late central nervous system disease might react to as many as 18 to 25 polypeptides (Berardi VP. Personal communication). The isolate used for antigen preparations was the B. burgdorferi G39/40 strain obtained through low passage [24]. Indirect ELISA titers greater than 400 and ELISA capture ratios (sample optical density/control optical density) of 1.0 or more were considered as increased test results. Western blot reactivity to five or more B. burgdorferi-specific polypeptides indicated previous infection [25]. Silver Stain Method The Dieterle silver impregnation stain used was a modification made by one of us (PHD) in 1985 [26]. This standard approach has yielded a constant clean yellow background of cerebral cortex sections with no silver impregnation of anatomic neural processes and dendrites. Spirochetes are easily seen as black to blue-black cells against the yellow tissue. Specificity for nonstaining of normal tissue fibers (procollagen, elastin, basement membrane material, and neural dendrites and filaments) and documentation of the cytologic structure of Borrelia spirochete strains were further tested in a large extended study [27]. Controls routinely used in each stain assay consisted of NP40 strain that was injected into human normal breast tissue removed for cosmetic surgery and was paraffin-embedded in the usual manner (negative control), and rat gonad tissue infected with the Reiter strain of treponemal spirochetes (positive c