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Summary of the first 100 patients seen at a Lyme disease referral center
F Summary of the First 100 Patients Seen at a Lyme Disease Referral Center LEONARDH. SIGAL,M.D., New Brunswick, New.lersey
PURPOSE AND PATIENTS AND METHODS: Lyme disease is a major clinical problem in a number of endemic areas in the United States. In areas where anxiety about the disease is high, patients and physicians often ascribe clinical concerns to Lyme disease. Incorrect diagnosis often leads to unnecessary antibiotic treatment (often prolonged or repeated intravenous therapy). This report summarizes the cases of the first 100 patients referred to the Lyme Disease Center at Robert Wood Johnson Medical School. RESULTS: I n o n l y 37 of the patients referred was Lyme disease, either current or preceding, the explanation for the complaints. Many of the patients had another definable arthropathy. Twenty-five of the patients had fibromyalgia, which has not previously been reported in Lyme disease. Three of these patients had active Lyme disease at the time of evaluation, and 17 had a history suggesting preceding Lyme disease. Approximately half of the 91 courses of antibiotic therapy given to these 100 patients before referral were probably unwarranted. CONCLUSIONS:Anxiety about possible late manifestations of Lyme disease has made Lyme disease a "diagnosis of exclusion" in m~ny endemic areas. Persistence of mild to moderate symptoms after adequate therapy and misdiagnosis of fibromyalgia and fatigue may incorrectly suggest persistence of infection, leading to further antibiotic therapy. Attention to patient anxiety and increased awareness of these musculoskeletal problems after therapy should decrease unnecessary therapy of previously treated Lyme disease.
From the Departments of Medicine and Molecular Genetics and Microbiology and the Lyme Disease Center, Robert Wood Johnson Medical School, New Brunswick, New Jersey. Requests for reprints should be addressed to Leonard H. Sigal, M.D., Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, MEB 484, New Brunswick, New Jersey 08903-0019. Manuscript submitted November 8, 1989, and accepted in revised form March 21, 1990.
L
Yme disease is a multi-system inflammatory disease with protean manifestations [1], which has reached epidemic proportions in certain Northeastern and Midwestern communities. Increasing press coverage has led to increased knowledge but also to increased anxiety in both patients and physicians. Awareness of the various manifestations of the disease and the difficulty in making a clinical or serologic diagnosis have compounded the apprehension in endemic communities. A number of medical centers and practitioners have attempted to respond to the need for expert clinical care. This is a report based on our experience with the first 100 patients seen at the Lyme Disease Center at Robert Wood Johnson Medical School. After evaluation, the majority of patients seen were thought not to have Lyme disease. Most patients referred for evaluation of Lyme disease had a variety of misdiagnosed inflammatory and non-inflammatory rheumatologic conditions unrelated to Lyme disease. In addition, fibromyalgia represents a clinical entity which, in an area endemic for Lyme disease, led to the frequent misdiagnosis of Lyme-related arthritis or neurologic disease. The result was inappropriate and unnecessary long-term therapy with intravenous or oral antibiotics. Fibromyalgia has not previously been reported in Lyme disease, but it may be part of the spectrum of musculoskeletal manifestations of Borrelia burgdorferi infection. PATIENTS AND METHODS
The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School is located in north-central New Jersey, an area endemic for Lyme disease. Referrals to our clinics are typically drawn from New Jersey, New York, and Pennsylvania. All patients included in this report were seen by the author at the Lyme Disease Center at the Robert Wood Johnson Medical Center between September 1988 and July 1989. Patients were seen by referral of local physicians, including internists, family practitioners, rheumatologists, neurologists, and obstetricians. The only exceptions to this "referral-only" rule were: (1) patients (three in number) who, after review of the initial telephone contact by our nursing staff and the author, had a rash compatible with erythema chronicum migrans; these patients were seen as soon after initial contact as possible; (2) patients who had no local physician and thought they had Lyme disease (12 in number); or (3) patients who thought they had Lyme disease complicating pregnancy (one patient). A retrospective review of the charts was done after 100 patients had been seen. Two patients had been treated and cured of their Lyme disease while attending our clinic and subsequently developed a rash compatible with erythema chronicum migrans. In both patients, increases in Lyme disease serologies supported June 1990 The American Journal of Medicine Volume88
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PATIENT REFERRAL FOR LYME DISEASE / SIGAL
TABLE I Final DiagnosticImpressionin the First 100 PatientsSeenat the Lyme DiseaseCenter at Robert WoodJohnsonMedicalSchool
Lyme disease Stage I Lyme disease Lyme arthritis Tertiary neuroborreliosis Definite/probable Recrudescent Lyme disease* Residual symptoms of Lyme disease after therapyt Other Osteoarthritis Rheumatoid arthritis Undifferentiated connective tissue disease Seronegative spondylarthropathy Mechanical joint disease of the knee Traumatic soft tissue injury of the wrist Septic arthritis of the knee* Inflammatory bowel disease-Crohn's disease Sinusitis Atypical migraine headache Fibromyalgia
Patient did not return for follow-up No specific diagnosis
Female (n -- 68)
Male (n -- 32)
9 1 4/2
7 0 O/1
4 7
0 2
1 2 1 2 2 1 1 0 0 1 23
2 2 0 2 2 0 0 2 1 0 2
1 6
1 8
* Patients who had received seeminglyadequate doses and duration of appropriate antibiotics but experiencedrecrudescenceof their earlier symptoms, All responded to retreatment with oral antibiotics during their follow-up period at the Lyme Disease Center. t Patientswith no evidenceof ongoingLyme diseaseor of any inflammatorydisease;all had receivedappropriatetypes and durationsof antibiotictherapy. * Patientwith dermatitis-arthritissyndromesecondaryto Neisseriameningococcus(positive synovialfluid culture).
the clinical impression of a new second exposure to B. burgdorferi; these second episodes are not included in this analysis. The diagnosis of Lyme disease was based on (1) the presence of the pathognomonic skin rash erythema chronicum migrans at the time of evaluation or by history; or (2) serologic evidence of preceding exposure to B. burgdorferi plus clinical findings suggestive of Lyme disease [2]. Prior to referral, many of the patients had been tested for serum antibodies to B. burgdorferi in various commercial laboratories. These are reported here as either positive or negative, according to that laboratory's interpretation. IgM and IgG anti-B, burgdorferi antibodies are measured in our laboratory using enzyme-linked immunosorbent assay techniques [3]. In addition, erythrocyte sedimentation rate, C-reactive protein, and a complete blood cell count were done on patients seen at the Lyme Disease Center. RESULTS Presenting Complaints or Referral Diagnosis Sixty-eight of the patients were females and thirtytwo were males. The mean age of the sample was 35.1 years; the mean age of the females was 33.9 years (median = 32, range, 4 to 77; 11 were less than 15 years of age) and the mean age of the males was 37.4 years (median = 38, range, 6 to 68 years; five were less than 15 years of age). Fourteen females and eleven males were seen with skin rash and/or symptoms suggestive of stage I Lyme disease.
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Lyme arthritis was the referral diagnosis in more than half of the patients. Of the 38 females in this category, 12 had a history of a skin rash compatible with erythema chronicum migrans, and 30 had a serology positive for Lyme disease. Two of the 13 males had a history of probable erythema chronicum migrans and seven had positive Lyme serology. Neurologic complaint (including concentration and memory loss, headache, irritability, peripheral neuropathies, and previous diagnosis of multiple sclerosis) thought to be due to Lyme neurologic disease was the reason for referral in nearly one quarter of our patients. Of the 15 female patients, seven were seropositive for Lyme disease and three had a history of probable erythema chronicum migrans; of the eight males, four were seropositive and none had a history of erythema chronicum migrans. Combined neurologic and articular complaints were reported in 12 patients. Overall, 54 females (79.4% of the females) and 21 males (65.6% of the males) complained of one or more of three major complaints: fatigue, neurologic disease, or articular disease. The duration of complaints ranged from i week to 9 years, the latter being a man referred for possible Lyme arthritis. Of the 18 patients with a chief complaint of fatigue, one had a history of a skin rash compatible with erythema chronicum migrans and 10 had elevated levels of antibodies to B.
burgdorferi. Final Diagnostic Impression It was our impression that 37 of the 100 patients actually had Lyme disease as the cause of their presenting or referral complaints (Table I). Sixteen of the 25 patients seen for possible stage I disease were thought to have Lyme disease, while only eight of the 60 seen for possible late manifestations of Lyme disease were thought to have Lyme disease. Four of these 60 patients had recrudescent disease after prior therapy. Nine patients had persisting non-specific symptoms following appropriately treated Lyme disease, including fatigue, malaise, difficultywith concentration and/ or memory, or musculoskeletal complaints. History, physical, and laboratory examination did not reveal any evidence of inflammation, fibromyalgia, or any other organic disease. In three patients, these symptoms slowly resolved during the period of follow-up (between 3 and 7 months). One quarter of the patients referred to the Lyme Disease Center had classic fibromyalgia by generally accepted criteria [4]. All patients had at least 3 months of musculoskeletal complaints and multiple trigger points but no evidence of synovitis or of a systemic condition, to explain these complaints (except Lyme disease in three patients; see later). All patients reported difficulty with sleep (difficulty falling asleep, frequent awakening in the middle of the night, or nonrestorative sleep), generalized fatigue, and/or neck pain. Most patients reported headache, which was a major complaint in 17 of these patients. Subjective swelling, especially of the hands, was reported by about half of the patients; none of our patients reported complaints suggestive of irritable bowel syndrome or Raynaud's phenomenon [4]. In no case was there laboratory evidence to suggest an occult inflammatory condition.
PATIENT REFERRAL FOR LYME DISEASE / SIGAL
Of the 25 fibromyalgia patients (Table II), 17 were thought to have fibromyalgia following Lyme disease. In nine patients, erythema chronicum migrans preceded the musculoskeletal complaints by a mean of 13 months (median: 6 months, range: 1 to 48 months). Three patients were thought to have fibromyalgia associated with Lyme disease present at the time of evaluation. None of these had preceding erythema chronicum migrans, but all were IgG seropositive (IgM negative) in our laboratory and had a history of an illness prior to the onset of their fibromyalgia that was compatible with stage I Lyme disease [2]. Seven patients were thought to have fibromyalgia unrelated to Lyme disease (two had a history of erythema chronicure migrans, one of whom had erythema chronicum migrans after the onset of the musculoskeletal complaints). In this group, one of five tested prior to referral was positive; in our laboratory, five of the seven patients were found to be seropositive for IgG, but not IgM, suggesting that this was not recent seroconversion. On closer review of several cases, the symptoms of fibromyalgia preceded the syndrome thought by the referring physician to be the onset of Lyme disease. Fatigue and/or "arthritis" were the presenting complaints in all of these cases. All patients with fibromyalgia reported difficulty with sleep; we did not inquire about the quality of sleep in all patients seen for possible Lyme disease, so the frequency of this complaint in the total population is not known. However, the parents of three of our pediatric Lyme disease patients noted that these children had the new onset of sleep problems (including difficulty falling asleep or awakening in the middle of the night) during the course of their confirmed Lyme disease. In none of the cases was the child in pain or systemically ill, and in all cases the sleep disorder resolved with antibiotic therapy. Prior to referral, all but one of the fibromyalgia patients had received antibiotic therapy. This therapy, including intravenous penicillin and ceftriaxone, was given in order to treat "Lyme arthritis" or other late manifestations of Lyme disease in 13 patients. Multiple courses of oral therapy were given to nine patients whose musculoskeletal symptoms did not resolve promptly. There was no clinical response to the antibiotic therapy in any of the fibromyalgia patients. Two of the three patients in whom fibromyalgia occurred during Lyme disease had received antibiotics prior to referral. Therapy initiated at the Lyme Disease Center included antibiotics, amitriptyline (25 mg orally at bedtime), and exercise with resolution of fibromyalgia within 4 to 6 months. Two patients did not return after their first visit, and no clear diagnosis could be made. In an additional 14 patients who completed the evaluation, no definite diagnosis was made; all of these patients were seronegative at commercial laboratories prior to referral and were negative in our testing. The presenting complaints of these patients included arthritis/arthralgias (in three), neurologic disease (in three), fatigue (in two), and a skin rash not typical of erythema chronicum migrans (in two). None of the four patients seen because of concern about the possibility of having Lyme disease (precipitated by a family member's recent diagnosis of Lyme disease [in two] or their own vague sense of anxiety that they might have the dis-
TABLEII Summary of Patientswith Fibromyalgia Fibromyalgia'sRelationshipto LymeDisease Previous 15)
(n = Female/Male Complaints Fatigue Arthritis/arthralgia Duration of complaints (in months) Mean Range Median Sleep disorder present* Seropositive prior to visit to Center Prior antibiotic therapy§ Oral Penicillin Doxycycline Tetracycline Amoxicillin Erythromycin Cefuroxime Intravenous Penicillin Ceftriaxone
13/2
Coincident (n = 3)
Unrelated (n = 7)
3/0
7/0
13 15
2 2
6 5
10.5 3-36 8.5 15 13t
10.3 7-12 12 3 3
29.9 6-96 24 7 1*
3 5 5 4 3 1
0 0 1 1 0 0
0 4 1 0 1 0
1 8
0 ]
0 0
* Beginningprior to or coincidentwith new musculoskeletalcomplaints;includeddifficulty failing asleep,awakeningin the middleof the sleep, or awakeningin the morningunrefreshed. t Bothpreviouslyseronegativepatientstestedpositivein our laboratory. t Fiveof the sevenpatientsweretestedprior to referralto the LymeDiseaseCenter, one of whom was positive. § Six had received two courses and one each had receivedfour and six courses of antibiotics.
ease [in three]) was thought to actually have Lyme disease. Previous Antibiotic Treatment Prior to referral, most of the patients had received antibiotic therapy. These included 75 courses of oral antibiotics (penicillin G, semi-synthetic penicillins [with or without probenecid], tetracyclines, erythromycin, and cefuroxime), one course of intramuscular penicillin G benzathine, and 15 courses of intravenous antibiotics (penicillin in one, ceftriaxone in 14). Multiple courses were given frequently (mean number of courses: 1.5, median: 2, range: 2 to 6). Approximately half of these courses of antibiotics were given for clinical problems that were thought, by us, to be unrelated to infection with B. burgdorferi. Four patients had a history compatible with recrudescence of their stage I manifestations after seemingly effective oral antibiotic therapy; one patient was retreated with intravenous ceftriaxone. All of these patients were re-treated at the Lyme Disease Center with four weeks of either tetracycline 250 mg or amoxicillin 500 mg four times/day for 4 weeks with resolution of all symptoms. Nine patients were seen who had a preceding history of Lyme disease and previous successful therapy, but the nonspecific symptoms had returned. These patients' conditions were refractory to further courses of antibiotics. Because of the small number of patients in the groups with recrudescent and residual complaints and the referral nature of this population, no conclusions can be drawn about the efficacy of the various antibiotic regimens used.
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PATIENT REFERRALFOR LYME DISEASE/ SIGAL COMMENTS
Lyme disease has become a serious public health problem in many areas of the United States. With the dissemination of information about the disease by the press, patients are now insisting that Lyme disease be considered in the differential diagnosis of many of their complaints. Patients and families are aware of the possible late manifestations of Lyme disease and are increasingly anxious about possible long-term and irreversible damage that might result if the diagnosis of Lyme disease is missed. Diagnostic serologic testing is often not definitive [5] and has not been standardized [6]. The possibility exists that patients may have Lyme disease and never seroconvert [7]. Unfortunately, Lyme disease has become a common "diagnosis of exclusion" where the signs and symptoms have not led the physician to a specific diagnosis. Asymptomatic infection with B. burgdorferi complicates the problem. In endemic areas, a small but significant percentage of the population may be seropositive with no history of Lyme disease [8]; seropositivity does not ensure that the current clinical problem is necessarily due to Lyme disease [4,9]. Patients may have levels of serum antibodies sufficient to be diagnostic of Lyme disease but have clinical problems, including chronic fatigue, not due to Lyme disease. The desire to make a diagnosis of a treatable disease has led to many misdiagnoses and to many unnecessary courses of antibiotics. These concerns are reflected in this summary of the first 100 patients seen at the Lyme Disease Center at Robert Wood Johnson Medical School. We are located in an area endemic for Lyme disease, where many people are very concerned (occasionally overly concerned) about Lyme disease. The most common reasons for referral were possible arthritis or neurologic disease or chronic fatigue as a late manifestation of Lyme disease. After a complete evaluation, our impression was that most of our patients did not have Lyme disease. In fact, only 25% had a history explicitly suggestive of Lyme disease. Final diagnoses included osteoarthritis (in three), rheumatoid arthritis (in four), seronegative spondyloarthopathies (in four), and mechanical disease of the knee (in four). These diagnoses were not considered by the referring physicians; all the patients were thought to have refractory Lyme disease. None of the clinical problems was, in fact, related to Lyme disease and none is currently thought to be amenable to antibiotic therapy. Approximately half of the preceding courses of antibiotic therapy were probably unnecessary. Fibromyalgia was the diagnosis in one fourth of the patients referred (Tables I and II). In 18 of these, the patient also had a history compatible with Lyme disease; in 15 cases preceding Lyme disease precipitated fibromyalgia and in three others fibromyalgia was present during Lyme disease. This unexpectedly high incidence of fibromyalgia raises a number of questions: Is fibromyalgia related to Lyme disease or is this a mere coincidence? Is fibromyalgia a part of or a complication of Lyme disease? If there is a relationship, what is the mechanism underlying the association? Sleep disorder is often a part of primary fibromyalgia and may be involved in its pathogenesis [10]. The discomfort felt during Lyme disease may interfere with sleep sufficiently to precipitate fibromyalgia. Many patients referred for evaluation of possible Lyme disease are convinced that they have an ongoing infection that they fear may lead to permanent dam580
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age; increased a n x i e t y may also lead to sleep disturbance. A few parents noted the new onset of sleep problems in their children during the active phase of Lyme disease, which ceased after antibiotic therapy. We now routinely ask the parents of patients with Lyme disease if the child has new sleep problems. About one third of all the pediatric cases of Lyme disease we see have an antibiotic-treatable sleep disorder, even in the absence of discomfort that might predictably interfere with sleep. Sleep disorder has recently been reported in children with Lyme disease [11]. It is, of course, possible that these children were more uncomfortable than their parents appreciated and that this discomfort was the cause of their sleep problems. Alternatively, sleep disorder may be a part of Lyme disease, representing an aspect of mild encephalopathy not previously appreciated. None of the patients reviewed by Steere et al [12] had symmetric trigger points suggestive of fibromyalgia. The patients reviewed began to experience their musculoskeletal pain 1 day to 8 weeks (mean: 2 weeks) after the onset of their Lyme disease; our patients were, in general, seen after a longer duration of symptoms (Table II). It is possible that fibromyalgia in Lyme disease may take a longer period of time to emerge. Proof of a link between Lyme disease and fibromyalgia awaits prospective studies with the appropriate control groups. Fibromyalgia is frequent in a general rheumatologic population, occurring in 4% [13] to 7.5% [14] of patients. Secondary fibromyalgia occurs in 5% to 10% of rheumatologic disorders [4,13]. Anxiety about previously active inflammatory joint disease was probably part of the pathogenesis of fibromyalgia in patients with fibromyalgia complicating rheumatoid arthritis [15]. In one series, 10% of fibromyalgia patients had a "viral syndrome" immediately before the onset of their musculoskeletal symptoms; "fibromyalgia may be a common musculoskeletal response to a variety of infectious and non-infectious agents" [16]. Fibromyalgia is more common in females, many of whom experience fatigue and numbness and/or swelling of their hands and feet [4]; this, as well as the near universality of sleep disorder, was the case in our patients. Our patients were concerned that fatigue, "arthritis," and "neurologic disease" were caused by chronic Lyme disease, with the promise of permanent joint or neurologic damage. Missing the diagnosis of fibromyalgia led to unnecessary antibiotic therapy for presumed Lyme arthritis or neurologic disease and a delay in diagnosis and appropriate therapy. In discussing secondary fibromyalgia due to preceding but inactive, inflammatory joint disease, Yunus [15] cautions against treating the original, but now inactive, disease; this may be of relevance to physicians seeing patients for possible Lyme disease. Treatment should be addressed to the secondary fibromyalgia [15]. In summary, patients seen at a Lyme disease referral center have an array of specific and non-specific complaints. Most of the patients seen in consultation did not have Lyme disease and many never had Lyme disease. In most patients without Lyme disease, a specific diagnosis could be made. Fibromyalgia was very common in our population. It may be another musculoskeletal manifestation of Lyme disease, perhaps due to a sleep disorder caused by Lyme disease, and may occur in the aftermath of Lyme disease. In our commu-
PATIENT REFERRAL FOR LYME DISEASE / SIGAL
nity, fibromyalgia was often misdiagnosed as arthritis, leading to increased anxiety about debility from the late manifestations of infection with B. burgdorferi, and to unnecessary courses of antibiotic therapy. Over-diagnosis of Lyme disease appears to be common in endemic areas. This probably occurs because of the absence of strict clinical criteria for the diagnosis of Lyme disease as well as because of the difficulties in interpreting currently available, non-standardized diagnostic tests [6] and increasing concern among physicians and patients that late stages of Lyme disease not be overlooked. The end result is improper care and unnecessary anxiety and antibiotic therapy. ACKNOWLEDGMENT
I thank Dr. Mark Taragin and the other members of the staff for assistance in patient care in the Lyme Disease Center; to Sondra Patella, Debbie McCIoskey, and Marcia Anderson for their expert assistance in the clinic and their sensitivity in addressing patients' concerns; to Robin Radziewiczfor her expertise in performing the Lyme serologic testing in our laboratory; to Pat Hanasand EileenWolfensonfor their assistance in scheduling our patients; and to Drs. Barbara K. Snyder and Randall M. Stevens for their review of this manuscript and their helpful suggestions.
REFERENCES
, _
1. Sigal LH: Lyme disease: a worldwide borreliosis. Clin Exp Rheumatol 1989; 6: 411-421. 2. Steere AC: Lyme disease. N Engl J Med 1989; 321: 586-596.
3. Magnarelli LA, Meegan JM, Anderson JF, Chappell WA: Comparison of an indirect fluorescent-antibody test with an enzyme-linked immunosorbent assay for serological studies of Lyme disease. J Clin Microbiol 1984; 20: 181-184. 4. Goldenberg DL: Fibromyalgia syndrome: an emerging but controversial condition. lAMA 2987; 257: 2782-2787. 5. Sigal LH: Lyme disease, 1988: Immunologic manifestations and possibleimmunopathogenetic mechanisms. Semin Arthritis Rheum 1989; 18: ]51-167. 6. Schwartz BS, Goldstein MD, Ribeiro JMC, Schulze TL, Shahied SI: Antibody testing in Lyme disease: a comparison of results in four laboratories, lAMA 1989; 262: 3431-3434. 7. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG: Dissociation of specific T- and B-lymphocyte responses to B. burgdorferi. N Engl J Med 1988; 319: 1441-1446. 8, Lastavica CC, Wilson ML, Berardi VP, Spielman A, Deblinger RD: Rapid emergence of a focal epidemic of Lyme disease in coastal Massachusetts. N EnglJ Med 1989; 320: 133-137. 9. Sigal LH: Responses of mononuclear cells to Borrelia burgdorferi. Ann Intern Med 1985; 103: 808-809. 10. Moldofsky H, Scarisbrick P, England R, Smythe H: Musculoskeletalsymptoms and non-REMsleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom Med 1975; 37: 341-351. 11. Belman AL, Romero J, Volkman D, Dattwyler R: Neurologic manifestations of Lyme disease in children. Pediatr Res 1989; 25: 353A. 12. Steere AC, Schoen RT, Taylor E: The clinical evolution of Lyme arthritis. Ann Intern Med 1987; 107: 725-731. 13. Wolfe F: Fibrositis, fibromyalgia, and musculoskeletal disease:the current status of the fibrositis syndrome. Arch Phys Med Rehabil 1988; 69: 527-531. 14. Muller W: The fibrositis syndrome: diagnosis, differential diagnosis and pathogenesis. Scand J Rheumatol [Suppl] 1987; 65: 40-53. 15. Yunus M, MasiAT, Calabro JJ, Miller KA, FeigenbaumSL: Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 1981; 11: 151-171. 16. Gordenberg DL: Fibromyalgia and other chronic fatigue syndromes: is there evidence for chronic viral disease? Semin Arthritis Rheum 1988; 18: 111-120.
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PURPOSE AND PATIENTS AND METHODS: Lyme disease is a major clinical problem in a number of endemic areas in the United States. In areas where anxiety about the disease is high, patients and physicians often ascribe clinical concerns to Lyme disease. Incorrect diagnosis often leads to unnecessary antibiotic treatment (often prolonged or repeated intravenous therapy). This report summarizes the cases of the first 100 patients referred to the Lyme Disease Center at Robert Wood Johnson Medical School. RESULTS: I n o n l y 37 of the patients referred was Lyme disease, either current or preceding, the explanation for the complaints. Many of the patients had another definable arthropathy. Twenty-five of the patients had fibromyalgia, which has not previously been reported in Lyme disease. Three of these patients had active Lyme disease at the time of evaluation, and 17 had a history suggesting preceding Lyme disease. Approximately half of the 91 courses of antibiotic therapy given to these 100 patients before referral were probably unwarranted. CONCLUSIONS:Anxiety about possible late manifestations of Lyme disease has made Lyme disease a "diagnosis of exclusion" in m~ny endemic areas. Persistence of mild to moderate symptoms after adequate therapy and misdiagnosis of fibromyalgia and fatigue may incorrectly suggest persistence of infection, leading to further antibiotic therapy. Attention to patient anxiety and increased awareness of these musculoskeletal problems after therapy should decrease unnecessary therapy of previously treated Lyme disease.
From the Departments of Medicine and Molecular Genetics and Microbiology and the Lyme Disease Center, Robert Wood Johnson Medical School, New Brunswick, New Jersey. Requests for reprints should be addressed to Leonard H. Sigal, M.D., Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, MEB 484, New Brunswick, New Jersey 08903-0019. Manuscript submitted November 8, 1989, and accepted in revised form March 21, 1990.
L
Yme disease is a multi-system inflammatory disease with protean manifestations [1], which has reached epidemic proportions in certain Northeastern and Midwestern communities. Increasing press coverage has led to increased knowledge but also to increased anxiety in both patients and physicians. Awareness of the various manifestations of the disease and the difficulty in making a clinical or serologic diagnosis have compounded the apprehension in endemic communities. A number of medical centers and practitioners have attempted to respond to the need for expert clinical care. This is a report based on our experience with the first 100 patients seen at the Lyme Disease Center at Robert Wood Johnson Medical School. After evaluation, the majority of patients seen were thought not to have Lyme disease. Most patients referred for evaluation of Lyme disease had a variety of misdiagnosed inflammatory and non-inflammatory rheumatologic conditions unrelated to Lyme disease. In addition, fibromyalgia represents a clinical entity which, in an area endemic for Lyme disease, led to the frequent misdiagnosis of Lyme-related arthritis or neurologic disease. The result was inappropriate and unnecessary long-term therapy with intravenous or oral antibiotics. Fibromyalgia has not previously been reported in Lyme disease, but it may be part of the spectrum of musculoskeletal manifestations of Borrelia burgdorferi infection. PATIENTS AND METHODS
The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School is located in north-central New Jersey, an area endemic for Lyme disease. Referrals to our clinics are typically drawn from New Jersey, New York, and Pennsylvania. All patients included in this report were seen by the author at the Lyme Disease Center at the Robert Wood Johnson Medical Center between September 1988 and July 1989. Patients were seen by referral of local physicians, including internists, family practitioners, rheumatologists, neurologists, and obstetricians. The only exceptions to this "referral-only" rule were: (1) patients (three in number) who, after review of the initial telephone contact by our nursing staff and the author, had a rash compatible with erythema chronicum migrans; these patients were seen as soon after initial contact as possible; (2) patients who had no local physician and thought they had Lyme disease (12 in number); or (3) patients who thought they had Lyme disease complicating pregnancy (one patient). A retrospective review of the charts was done after 100 patients had been seen. Two patients had been treated and cured of their Lyme disease while attending our clinic and subsequently developed a rash compatible with erythema chronicum migrans. In both patients, increases in Lyme disease serologies supported June 1990 The American Journal of Medicine Volume88
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PATIENT REFERRAL FOR LYME DISEASE / SIGAL
TABLE I Final DiagnosticImpressionin the First 100 PatientsSeenat the Lyme DiseaseCenter at Robert WoodJohnsonMedicalSchool
Lyme disease Stage I Lyme disease Lyme arthritis Tertiary neuroborreliosis Definite/probable Recrudescent Lyme disease* Residual symptoms of Lyme disease after therapyt Other Osteoarthritis Rheumatoid arthritis Undifferentiated connective tissue disease Seronegative spondylarthropathy Mechanical joint disease of the knee Traumatic soft tissue injury of the wrist Septic arthritis of the knee* Inflammatory bowel disease-Crohn's disease Sinusitis Atypical migraine headache Fibromyalgia
Patient did not return for follow-up No specific diagnosis
Female (n -- 68)
Male (n -- 32)
9 1 4/2
7 0 O/1
4 7
0 2
1 2 1 2 2 1 1 0 0 1 23
2 2 0 2 2 0 0 2 1 0 2
1 6
1 8
* Patients who had received seeminglyadequate doses and duration of appropriate antibiotics but experiencedrecrudescenceof their earlier symptoms, All responded to retreatment with oral antibiotics during their follow-up period at the Lyme Disease Center. t Patientswith no evidenceof ongoingLyme diseaseor of any inflammatorydisease;all had receivedappropriatetypes and durationsof antibiotictherapy. * Patientwith dermatitis-arthritissyndromesecondaryto Neisseriameningococcus(positive synovialfluid culture).
the clinical impression of a new second exposure to B. burgdorferi; these second episodes are not included in this analysis. The diagnosis of Lyme disease was based on (1) the presence of the pathognomonic skin rash erythema chronicum migrans at the time of evaluation or by history; or (2) serologic evidence of preceding exposure to B. burgdorferi plus clinical findings suggestive of Lyme disease [2]. Prior to referral, many of the patients had been tested for serum antibodies to B. burgdorferi in various commercial laboratories. These are reported here as either positive or negative, according to that laboratory's interpretation. IgM and IgG anti-B, burgdorferi antibodies are measured in our laboratory using enzyme-linked immunosorbent assay techniques [3]. In addition, erythrocyte sedimentation rate, C-reactive protein, and a complete blood cell count were done on patients seen at the Lyme Disease Center. RESULTS Presenting Complaints or Referral Diagnosis Sixty-eight of the patients were females and thirtytwo were males. The mean age of the sample was 35.1 years; the mean age of the females was 33.9 years (median = 32, range, 4 to 77; 11 were less than 15 years of age) and the mean age of the males was 37.4 years (median = 38, range, 6 to 68 years; five were less than 15 years of age). Fourteen females and eleven males were seen with skin rash and/or symptoms suggestive of stage I Lyme disease.
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Lyme arthritis was the referral diagnosis in more than half of the patients. Of the 38 females in this category, 12 had a history of a skin rash compatible with erythema chronicum migrans, and 30 had a serology positive for Lyme disease. Two of the 13 males had a history of probable erythema chronicum migrans and seven had positive Lyme serology. Neurologic complaint (including concentration and memory loss, headache, irritability, peripheral neuropathies, and previous diagnosis of multiple sclerosis) thought to be due to Lyme neurologic disease was the reason for referral in nearly one quarter of our patients. Of the 15 female patients, seven were seropositive for Lyme disease and three had a history of probable erythema chronicum migrans; of the eight males, four were seropositive and none had a history of erythema chronicum migrans. Combined neurologic and articular complaints were reported in 12 patients. Overall, 54 females (79.4% of the females) and 21 males (65.6% of the males) complained of one or more of three major complaints: fatigue, neurologic disease, or articular disease. The duration of complaints ranged from i week to 9 years, the latter being a man referred for possible Lyme arthritis. Of the 18 patients with a chief complaint of fatigue, one had a history of a skin rash compatible with erythema chronicum migrans and 10 had elevated levels of antibodies to B.
burgdorferi. Final Diagnostic Impression It was our impression that 37 of the 100 patients actually had Lyme disease as the cause of their presenting or referral complaints (Table I). Sixteen of the 25 patients seen for possible stage I disease were thought to have Lyme disease, while only eight of the 60 seen for possible late manifestations of Lyme disease were thought to have Lyme disease. Four of these 60 patients had recrudescent disease after prior therapy. Nine patients had persisting non-specific symptoms following appropriately treated Lyme disease, including fatigue, malaise, difficultywith concentration and/ or memory, or musculoskeletal complaints. History, physical, and laboratory examination did not reveal any evidence of inflammation, fibromyalgia, or any other organic disease. In three patients, these symptoms slowly resolved during the period of follow-up (between 3 and 7 months). One quarter of the patients referred to the Lyme Disease Center had classic fibromyalgia by generally accepted criteria [4]. All patients had at least 3 months of musculoskeletal complaints and multiple trigger points but no evidence of synovitis or of a systemic condition, to explain these complaints (except Lyme disease in three patients; see later). All patients reported difficulty with sleep (difficulty falling asleep, frequent awakening in the middle of the night, or nonrestorative sleep), generalized fatigue, and/or neck pain. Most patients reported headache, which was a major complaint in 17 of these patients. Subjective swelling, especially of the hands, was reported by about half of the patients; none of our patients reported complaints suggestive of irritable bowel syndrome or Raynaud's phenomenon [4]. In no case was there laboratory evidence to suggest an occult inflammatory condition.
PATIENT REFERRAL FOR LYME DISEASE / SIGAL
Of the 25 fibromyalgia patients (Table II), 17 were thought to have fibromyalgia following Lyme disease. In nine patients, erythema chronicum migrans preceded the musculoskeletal complaints by a mean of 13 months (median: 6 months, range: 1 to 48 months). Three patients were thought to have fibromyalgia associated with Lyme disease present at the time of evaluation. None of these had preceding erythema chronicum migrans, but all were IgG seropositive (IgM negative) in our laboratory and had a history of an illness prior to the onset of their fibromyalgia that was compatible with stage I Lyme disease [2]. Seven patients were thought to have fibromyalgia unrelated to Lyme disease (two had a history of erythema chronicure migrans, one of whom had erythema chronicum migrans after the onset of the musculoskeletal complaints). In this group, one of five tested prior to referral was positive; in our laboratory, five of the seven patients were found to be seropositive for IgG, but not IgM, suggesting that this was not recent seroconversion. On closer review of several cases, the symptoms of fibromyalgia preceded the syndrome thought by the referring physician to be the onset of Lyme disease. Fatigue and/or "arthritis" were the presenting complaints in all of these cases. All patients with fibromyalgia reported difficulty with sleep; we did not inquire about the quality of sleep in all patients seen for possible Lyme disease, so the frequency of this complaint in the total population is not known. However, the parents of three of our pediatric Lyme disease patients noted that these children had the new onset of sleep problems (including difficulty falling asleep or awakening in the middle of the night) during the course of their confirmed Lyme disease. In none of the cases was the child in pain or systemically ill, and in all cases the sleep disorder resolved with antibiotic therapy. Prior to referral, all but one of the fibromyalgia patients had received antibiotic therapy. This therapy, including intravenous penicillin and ceftriaxone, was given in order to treat "Lyme arthritis" or other late manifestations of Lyme disease in 13 patients. Multiple courses of oral therapy were given to nine patients whose musculoskeletal symptoms did not resolve promptly. There was no clinical response to the antibiotic therapy in any of the fibromyalgia patients. Two of the three patients in whom fibromyalgia occurred during Lyme disease had received antibiotics prior to referral. Therapy initiated at the Lyme Disease Center included antibiotics, amitriptyline (25 mg orally at bedtime), and exercise with resolution of fibromyalgia within 4 to 6 months. Two patients did not return after their first visit, and no clear diagnosis could be made. In an additional 14 patients who completed the evaluation, no definite diagnosis was made; all of these patients were seronegative at commercial laboratories prior to referral and were negative in our testing. The presenting complaints of these patients included arthritis/arthralgias (in three), neurologic disease (in three), fatigue (in two), and a skin rash not typical of erythema chronicum migrans (in two). None of the four patients seen because of concern about the possibility of having Lyme disease (precipitated by a family member's recent diagnosis of Lyme disease [in two] or their own vague sense of anxiety that they might have the dis-
TABLEII Summary of Patientswith Fibromyalgia Fibromyalgia'sRelationshipto LymeDisease Previous 15)
(n = Female/Male Complaints Fatigue Arthritis/arthralgia Duration of complaints (in months) Mean Range Median Sleep disorder present* Seropositive prior to visit to Center Prior antibiotic therapy§ Oral Penicillin Doxycycline Tetracycline Amoxicillin Erythromycin Cefuroxime Intravenous Penicillin Ceftriaxone
13/2
Coincident (n = 3)
Unrelated (n = 7)
3/0
7/0
13 15
2 2
6 5
10.5 3-36 8.5 15 13t
10.3 7-12 12 3 3
29.9 6-96 24 7 1*
3 5 5 4 3 1
0 0 1 1 0 0
0 4 1 0 1 0
1 8
0 ]
0 0
* Beginningprior to or coincidentwith new musculoskeletalcomplaints;includeddifficulty failing asleep,awakeningin the middleof the sleep, or awakeningin the morningunrefreshed. t Bothpreviouslyseronegativepatientstestedpositivein our laboratory. t Fiveof the sevenpatientsweretestedprior to referralto the LymeDiseaseCenter, one of whom was positive. § Six had received two courses and one each had receivedfour and six courses of antibiotics.
ease [in three]) was thought to actually have Lyme disease. Previous Antibiotic Treatment Prior to referral, most of the patients had received antibiotic therapy. These included 75 courses of oral antibiotics (penicillin G, semi-synthetic penicillins [with or without probenecid], tetracyclines, erythromycin, and cefuroxime), one course of intramuscular penicillin G benzathine, and 15 courses of intravenous antibiotics (penicillin in one, ceftriaxone in 14). Multiple courses were given frequently (mean number of courses: 1.5, median: 2, range: 2 to 6). Approximately half of these courses of antibiotics were given for clinical problems that were thought, by us, to be unrelated to infection with B. burgdorferi. Four patients had a history compatible with recrudescence of their stage I manifestations after seemingly effective oral antibiotic therapy; one patient was retreated with intravenous ceftriaxone. All of these patients were re-treated at the Lyme Disease Center with four weeks of either tetracycline 250 mg or amoxicillin 500 mg four times/day for 4 weeks with resolution of all symptoms. Nine patients were seen who had a preceding history of Lyme disease and previous successful therapy, but the nonspecific symptoms had returned. These patients' conditions were refractory to further courses of antibiotics. Because of the small number of patients in the groups with recrudescent and residual complaints and the referral nature of this population, no conclusions can be drawn about the efficacy of the various antibiotic regimens used.
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PATIENT REFERRALFOR LYME DISEASE/ SIGAL COMMENTS
Lyme disease has become a serious public health problem in many areas of the United States. With the dissemination of information about the disease by the press, patients are now insisting that Lyme disease be considered in the differential diagnosis of many of their complaints. Patients and families are aware of the possible late manifestations of Lyme disease and are increasingly anxious about possible long-term and irreversible damage that might result if the diagnosis of Lyme disease is missed. Diagnostic serologic testing is often not definitive [5] and has not been standardized [6]. The possibility exists that patients may have Lyme disease and never seroconvert [7]. Unfortunately, Lyme disease has become a common "diagnosis of exclusion" where the signs and symptoms have not led the physician to a specific diagnosis. Asymptomatic infection with B. burgdorferi complicates the problem. In endemic areas, a small but significant percentage of the population may be seropositive with no history of Lyme disease [8]; seropositivity does not ensure that the current clinical problem is necessarily due to Lyme disease [4,9]. Patients may have levels of serum antibodies sufficient to be diagnostic of Lyme disease but have clinical problems, including chronic fatigue, not due to Lyme disease. The desire to make a diagnosis of a treatable disease has led to many misdiagnoses and to many unnecessary courses of antibiotics. These concerns are reflected in this summary of the first 100 patients seen at the Lyme Disease Center at Robert Wood Johnson Medical School. We are located in an area endemic for Lyme disease, where many people are very concerned (occasionally overly concerned) about Lyme disease. The most common reasons for referral were possible arthritis or neurologic disease or chronic fatigue as a late manifestation of Lyme disease. After a complete evaluation, our impression was that most of our patients did not have Lyme disease. In fact, only 25% had a history explicitly suggestive of Lyme disease. Final diagnoses included osteoarthritis (in three), rheumatoid arthritis (in four), seronegative spondyloarthopathies (in four), and mechanical disease of the knee (in four). These diagnoses were not considered by the referring physicians; all the patients were thought to have refractory Lyme disease. None of the clinical problems was, in fact, related to Lyme disease and none is currently thought to be amenable to antibiotic therapy. Approximately half of the preceding courses of antibiotic therapy were probably unnecessary. Fibromyalgia was the diagnosis in one fourth of the patients referred (Tables I and II). In 18 of these, the patient also had a history compatible with Lyme disease; in 15 cases preceding Lyme disease precipitated fibromyalgia and in three others fibromyalgia was present during Lyme disease. This unexpectedly high incidence of fibromyalgia raises a number of questions: Is fibromyalgia related to Lyme disease or is this a mere coincidence? Is fibromyalgia a part of or a complication of Lyme disease? If there is a relationship, what is the mechanism underlying the association? Sleep disorder is often a part of primary fibromyalgia and may be involved in its pathogenesis [10]. The discomfort felt during Lyme disease may interfere with sleep sufficiently to precipitate fibromyalgia. Many patients referred for evaluation of possible Lyme disease are convinced that they have an ongoing infection that they fear may lead to permanent dam580
June 1990 The American Journal of Medicine Volume88
age; increased a n x i e t y may also lead to sleep disturbance. A few parents noted the new onset of sleep problems in their children during the active phase of Lyme disease, which ceased after antibiotic therapy. We now routinely ask the parents of patients with Lyme disease if the child has new sleep problems. About one third of all the pediatric cases of Lyme disease we see have an antibiotic-treatable sleep disorder, even in the absence of discomfort that might predictably interfere with sleep. Sleep disorder has recently been reported in children with Lyme disease [11]. It is, of course, possible that these children were more uncomfortable than their parents appreciated and that this discomfort was the cause of their sleep problems. Alternatively, sleep disorder may be a part of Lyme disease, representing an aspect of mild encephalopathy not previously appreciated. None of the patients reviewed by Steere et al [12] had symmetric trigger points suggestive of fibromyalgia. The patients reviewed began to experience their musculoskeletal pain 1 day to 8 weeks (mean: 2 weeks) after the onset of their Lyme disease; our patients were, in general, seen after a longer duration of symptoms (Table II). It is possible that fibromyalgia in Lyme disease may take a longer period of time to emerge. Proof of a link between Lyme disease and fibromyalgia awaits prospective studies with the appropriate control groups. Fibromyalgia is frequent in a general rheumatologic population, occurring in 4% [13] to 7.5% [14] of patients. Secondary fibromyalgia occurs in 5% to 10% of rheumatologic disorders [4,13]. Anxiety about previously active inflammatory joint disease was probably part of the pathogenesis of fibromyalgia in patients with fibromyalgia complicating rheumatoid arthritis [15]. In one series, 10% of fibromyalgia patients had a "viral syndrome" immediately before the onset of their musculoskeletal symptoms; "fibromyalgia may be a common musculoskeletal response to a variety of infectious and non-infectious agents" [16]. Fibromyalgia is more common in females, many of whom experience fatigue and numbness and/or swelling of their hands and feet [4]; this, as well as the near universality of sleep disorder, was the case in our patients. Our patients were concerned that fatigue, "arthritis," and "neurologic disease" were caused by chronic Lyme disease, with the promise of permanent joint or neurologic damage. Missing the diagnosis of fibromyalgia led to unnecessary antibiotic therapy for presumed Lyme arthritis or neurologic disease and a delay in diagnosis and appropriate therapy. In discussing secondary fibromyalgia due to preceding but inactive, inflammatory joint disease, Yunus [15] cautions against treating the original, but now inactive, disease; this may be of relevance to physicians seeing patients for possible Lyme disease. Treatment should be addressed to the secondary fibromyalgia [15]. In summary, patients seen at a Lyme disease referral center have an array of specific and non-specific complaints. Most of the patients seen in consultation did not have Lyme disease and many never had Lyme disease. In most patients without Lyme disease, a specific diagnosis could be made. Fibromyalgia was very common in our population. It may be another musculoskeletal manifestation of Lyme disease, perhaps due to a sleep disorder caused by Lyme disease, and may occur in the aftermath of Lyme disease. In our commu-
PATIENT REFERRAL FOR LYME DISEASE / SIGAL
nity, fibromyalgia was often misdiagnosed as arthritis, leading to increased anxiety about debility from the late manifestations of infection with B. burgdorferi, and to unnecessary courses of antibiotic therapy. Over-diagnosis of Lyme disease appears to be common in endemic areas. This probably occurs because of the absence of strict clinical criteria for the diagnosis of Lyme disease as well as because of the difficulties in interpreting currently available, non-standardized diagnostic tests [6] and increasing concern among physicians and patients that late stages of Lyme disease not be overlooked. The end result is improper care and unnecessary anxiety and antibiotic therapy. ACKNOWLEDGMENT
I thank Dr. Mark Taragin and the other members of the staff for assistance in patient care in the Lyme Disease Center; to Sondra Patella, Debbie McCIoskey, and Marcia Anderson for their expert assistance in the clinic and their sensitivity in addressing patients' concerns; to Robin Radziewiczfor her expertise in performing the Lyme serologic testing in our laboratory; to Pat Hanasand EileenWolfensonfor their assistance in scheduling our patients; and to Drs. Barbara K. Snyder and Randall M. Stevens for their review of this manuscript and their helpful suggestions.
REFERENCES
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1. Sigal LH: Lyme disease: a worldwide borreliosis. Clin Exp Rheumatol 1989; 6: 411-421. 2. Steere AC: Lyme disease. N Engl J Med 1989; 321: 586-596.
3. Magnarelli LA, Meegan JM, Anderson JF, Chappell WA: Comparison of an indirect fluorescent-antibody test with an enzyme-linked immunosorbent assay for serological studies of Lyme disease. J Clin Microbiol 1984; 20: 181-184. 4. Goldenberg DL: Fibromyalgia syndrome: an emerging but controversial condition. lAMA 2987; 257: 2782-2787. 5. Sigal LH: Lyme disease, 1988: Immunologic manifestations and possibleimmunopathogenetic mechanisms. Semin Arthritis Rheum 1989; 18: ]51-167. 6. Schwartz BS, Goldstein MD, Ribeiro JMC, Schulze TL, Shahied SI: Antibody testing in Lyme disease: a comparison of results in four laboratories, lAMA 1989; 262: 3431-3434. 7. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG: Dissociation of specific T- and B-lymphocyte responses to B. burgdorferi. N Engl J Med 1988; 319: 1441-1446. 8, Lastavica CC, Wilson ML, Berardi VP, Spielman A, Deblinger RD: Rapid emergence of a focal epidemic of Lyme disease in coastal Massachusetts. N EnglJ Med 1989; 320: 133-137. 9. Sigal LH: Responses of mononuclear cells to Borrelia burgdorferi. Ann Intern Med 1985; 103: 808-809. 10. Moldofsky H, Scarisbrick P, England R, Smythe H: Musculoskeletalsymptoms and non-REMsleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom Med 1975; 37: 341-351. 11. Belman AL, Romero J, Volkman D, Dattwyler R: Neurologic manifestations of Lyme disease in children. Pediatr Res 1989; 25: 353A. 12. Steere AC, Schoen RT, Taylor E: The clinical evolution of Lyme arthritis. Ann Intern Med 1987; 107: 725-731. 13. Wolfe F: Fibrositis, fibromyalgia, and musculoskeletal disease:the current status of the fibrositis syndrome. Arch Phys Med Rehabil 1988; 69: 527-531. 14. Muller W: The fibrositis syndrome: diagnosis, differential diagnosis and pathogenesis. Scand J Rheumatol [Suppl] 1987; 65: 40-53. 15. Yunus M, MasiAT, Calabro JJ, Miller KA, FeigenbaumSL: Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 1981; 11: 151-171. 16. Gordenberg DL: Fibromyalgia and other chronic fatigue syndromes: is there evidence for chronic viral disease? Semin Arthritis Rheum 1988; 18: 111-120.
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