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Lyme disease
REVIEWS
Lyme Disease
JOHN MEYERHOFF, M.D. Baltimore,
Maryland
Lyme disease is a recently described disease of unknown cause that may involve the skin, joints, heart, or nervous system with characteristic symptoms. The disease follows a bite from an lxodes tick. Symptoms are generally self-limited and despite the varied and sometimes protracted manifestations, the outcome of the disease is favorable. The epidemiologic, clinical, and laboratory features and treatment of Lyme disease are reviewed. Lyme disease, a recently described disease of unknown cause that may involve the skin, joints, heart, or nervous system [ 11, occurs most commonly in certain regions of the country: New England, Minnesota, and Wisconsin [2,3]. However, persons with Lyme disease who presumably contracted the disease on travel to areas of infestation by the vector have been reported to the Centers for Disease Control from Texas, California, New Jersey, and the District of Columbia [3]. The disease is not rare; the Centers for Disease Control recently reported 226 cases with onset in 1980 alone [3]. Although reports of the individual manifestations of Lyme disease have been published [ 1,4-81, no comprehensive review of this disease has yet appeared. A recent case with “classic” findings at our hospital prompted this review of the epidemiologic, clinical, and laboratory features and treatment of Lyme disease. TYPICAL CASE
From the Departments of Medicine, Sinai Hospital and Johns Hopkins University School of Medicine, Baltimore, Maryland. Requests for reprints should be addressed to Dr. John Meyerhoff, 2435 West Belvedere Avenue, Baltimore, Maryland 21215. Manuscript accepted November 9, 1982.
The patient, a 34-year-old white man without prior medical problems, went camping in Cecil County, Maryland, July 1 to 3, 1981. On July 6, he noticed a “pustular” lesion on his left scapula. This lesion expanded over the next week, and the patient experienced myalgias, fevers, chills, and a left temporal headache. On July 13, he visited his physician and was noted to have an oral temperature of 103.2OF. The lesion was noted to be dusky red, with a lighter colored, indurated center. The patient was treated with clindamycin, 150 mg every four hours, for approximately 24 hours, but did not improve. The patient was admitted to Sinai Hospital on July 15, 1981. On admission, the patient was febrile, with an oral temperature of 38.6’C. He was noted to have posterior cervical and sublingual lymphadenopathy. The lesion on the left scapula was warm to the touch and was 6 X 15 cm in size. There was a 4 X 1 cm central area that was desquamating (Figure 1). The rest of the findings on physical examination were normal. Routine laboratory studies all gave normal results, as did chest roentgenography and electrocardiography. Skin biopsy of the lesion showed a dense lymphocytic infiltration around the dermal blood vessels of the superficial and deep plexus. As shown in Figures 2 and 3, there were foci of epidermal spongiosis and edema
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Figure 1. Len scapular lesion on initial admission (photograph courtesy of Dr. Michael Levin).
of the papillary dermis (histologic description by Violet Jiji, M.D., Department of Pathology, Sinai Hospital). The patient was not treated with any specific medications, and his temperature became normal. He was discharged four days after admission, feeling better, with the skin lesion resolving. One week later, he had a recurrence of the skin lesion, with multiple lesions on the palms, arms, legs, and back. Twenty-four hours later, a headache and fever developed. Six days later, he noticed numbness of the tongue, followed by pain behind the left ear the next day. That evening, seven days after the recurrent skin lesions appeared, a facial droop developed, and he was readmitted to Sinai Hospital. On admission, he was afebrile and had left peripheral facial palsy and multiple erythematous skin lesions. Lumbar puncture yielded slightly hazy fluid with an opening pressure of 250 mm. The white blood cell count in the fluid was 180/mm3; 97 percent were monocytes. The protein level was 42 mg/dl, and the glucose value was 57 mg/dl. Gram stain, India ink preparation, and a Duo-fast stain for acid-fast organisms showed nothing. The patient was treated with 15 mg of prednisone, every six hours, and 250 mg of erythromycin, every six hours, over the next four days. He became afebrile on the fifth hospital day, and the prednisone dose was
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decreased to 55 mg per day. On the following day, he was discharged. Erythromycin was continued for a total of 10 days while the prednisone was decreased by 5 mg per day. During the next several weeks, the patient’s palsy resolved, and he has done well since. HISTORICAL BACKGROUND The “discovery” of Lyme disease began in 1975 when the Connecticut State Health Department and the Yale University Rheumatology Division were informed of an apparently unusual number of cases of arthritis in the town of Old Lyme, Connecticut. During the investigation of these reports, it was recognized that the persons affected had a distinct pattern of symptoms that probably represented a previously undescribed disease entity [4,5]. Further cases were then discovered elsewhere in Connecticut and New England. It was then recognized that the skin lesions of Lyme disease were identical to erythema chronicurn migrans. Erythema chronicurn migrans and the neurologic manifestations associated with it are well known in Europe, having been initially reported in 1909 [I] and 1922 [6], respectively. The initial reports of erythema chronicurn migrans in the United States date only to 1970 [9] and 1976 [lo]. Both reports came from areas (Wisconsin and Connecticut) in which Lyme disease is now recognized to occur frequently. The association
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Figure 2. Skin biopsy specimen of left scapular area showing dense perivascular lymphocytic infiltrate throughout all layers of the dermis with edema of the papillary dermis (hematoxylin and eosin stain; original magnification X 760, reduced by 30 percent; photograph courtesy of Dr. Violet Jiji).
Figure 3. Skin biopsy specimen of left scapular area showing perivascular lymphocytic infiltrate in the dermis with intracellular and extracellular edema in the epidermis and an area of hyperkeratosis (hematoxylin and eosin stain; original magnification X 160, reduced by 30 percent: photograph courtesy of Dr. Violet Jiji).
between erythema chronicurn migrans and bites of the lxodes genus of ticks has been reported in Europe, where the nervous system disease is called “tick-borne meningopolyneuritis” [6]. To investigate if there was a similar association between ticks and Lyme disease, epidemiologic studies of the patient [ 1 I] and tick [ 121 populations in eastern Connecticut were undertaken in 1977.
river or the other. The preference of this tick for the eastern bank of the Connecticut River is thought to be due to climatic factors.
EPIDEMIOLOGY During 1977, the incidence of Lyme disease was 30 times greater on the eastern bank of the Connecticut river than on the western shore [ 111. The majority of cases of Lyme disease occurred in children and young adults. Case-control studies of patients and their neighbors revealed that the patients did not have more outdoor activities than the control subjects. However, they were more likely to have a cat or farm animals, more likely to have a pet with ticks, and more likely to have had a tick bite in the year of the study. Since the hosts of the lxodes tick are mice and deer, these and other small mammals were trapped on both sides of the Connecticut River [ 121. The most common was the white-footed mouse, the preferred host of the immature tick. lxodes scapularis ticks were 12 times as abundant on these mice from the eastern shore as on those from the western shore. As the tick matures, its preferred host becomes the white-tailed deer. Although this species of deer is equally common on both sides of the river, eastern deer were found to have 16 times as many ticks as western deer. No other species of ticks was found to predominate on one side of the
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CLINICAL MANIFESTATIONS Although the early reports of this disease focused on the articular symptoms [4,5], arthritis is just one manifestation of Lyme disease [ 11. Dermatologic [ 11, neurologic [6], and cardiologic [7] involvement are also common and may predominante. Figure 4 illustrates the relationship of these manifestations.
NEUROLOGIC MANIFESTATIONS MANIFESTATIONS
Figure 4. Representation of the relationship of the clinical manifestations of Lyme disease. The size of the shapes and amount of overlap are approximate only.
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The most common of the clinical Dermatoiogic. manifestations is the skin rash, erythema chronicum migrans. The rash begins four to 20 days after a tick bite [ 11, which the patient may not remember. This may be due in part to the small size of the tick. An erythematous macule or papule forms at the site of the bite and then rapidly expands to form an annular lesion. The usual location is the trunk or proximal extremity, and the average diameter is 16 cm, but lesions up to 52 cm in diameter have been reported. The outer border is usually erythematous and flat, although it may be indurated. There is clearing in the middle of the lesion, while induration and erythema may occur in the center. The lesion is usually hot to the touch and may burn, prickle, or itch. The average duration of the initial skin lesion is about three weeks, with a range of two days to eight weeks. Multiple lesions can occur but are usually preceded by a single lesion. Recurrent attacks usually occur in the first year of the disease and were reported by 19 percent of the patients in one series [ 131. The skin lesions are often associated with systemic symptoms. The most common are malaise, fatigue, headache, and stiff neck, followed by arthraigias, myalgias, backache, sore throat, nausea, and vomiting. The most common physical findings are fever and lymphadenopathy [ 11. Some of these signs and symptoms may represent a milder, more transient form of meningoencephalitis, which later develops in some patients [6]. Fourteen percent of 226 patients in one series had transient meningeal symptoms [3]. Further articular, cardiac, or neurologic manifestations occurred in 61 percent of 409 patients with erythema chronicurn migrans in another series [ 21. Rheumatoiogic. The most common of the other manifestations of Lyme disease is the arthritis, which occurs in approximately half of the patients [3,13]. Some patients have the arthritis without having had a prior episode of erythema chronicum migrans. In twothirds of patients with erythema chronicurn migrans and arthritis, the arthritis develops within six months of the onset of erythema chronicum migrans [ 131. The initial attack of arthritis may be a mono-, oligo-, or poiyarticular episode, the knee being the most commonly affected joint-84 percent of patients in one series [4], with other joints involved much less frequently. Although swelling occurs frequently with involvement of the knee, pain on motion without obvious swelling or warmth is common in other joints [ 11. The usual duration of the first episode is one week [4]. Among the initial 51 patients described, 35 (69 percent) had recurrent attacks [4]. The median number of recurrent attacks was three, and the median number of joints involved in all attacks was also three. During recurrent attacks, there are usually more joints involved than in the initial episode. Recurrent
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attacks last about one week, with intervals of one week to two years between attacks and variation in the frequency and severity of each recurrence. In 1979, Steere et al [ 141 reported that a chronic arthritis had occurred in 10 of 102 patients whose arthritis had developed between 1974 and 1976 (14). Nine of the 10 patients had had a previous episode of erythema chronicurn migrans. Four of the patients had involvement of both knees, whereas the other six had monoarticular knee disease. Chronic arthritis usually developed a year after the initial manifestation of Lyme disease, although three patients had onset within six months. The knees were usually painful, and walking was difficult. Swelling fluctuated, but was often very intense, although less painful than expected from its degree. Pseudothrombophlebitis developed in three patients with ruptured Baker’s cysts. None of these patients had findings suggestive of rheumatoid arthritis (e.g., symmetric polyarthritis, morning stiffness, subcutaneous nodules, or rheumatoid factor), nor did they have signs or symptoms of Reiter’s disease (e.g., urethritis, conjunctivitis, and/or mucocutaneous lesions). Cardiac. Ten percent of the cases of Lyme disease with an onset in 1980 reported by the Centers for Disease Control had cardiac manifestations [3]. Twenty patients with cardiac abnormalities were reported on by Steere et al [7] in 1980. Manifestations of cardiac involvement began at a median of three weeks after the skin lesions first appeared, with a range of four to 83 days. The one patient without preceding erythema chronicum migrans had migratory polyarthralgias three weeks before the onset of heart block. These patients were not elderly, the two oldest patients being 40 and 58 years old. The most common abnormality, which occurred in 18 patients, was atrioventricular block, often characterized by rapid fluctuation in the degree of block. Some patients went from first-degree to complete block and back in a matter of minutes. Two other patients had S-T segment and T wave abnormalities without atrioventricular block. Eight of the 20 patients in Steere’s series had firstdegree block only. Of these eight, two had palpitations; the rest were asymptomatic. Of the other 10 patients with higher degrees of atrioventricular block, all had multiple degrees of block (first-degree and/or Wenckebach and/or complete block). All 10 of these patients were symptomatic, with syncope (five patients), shortness of breath (two patients), palpitations (two patients), or dizziness (one patient). Bundle of His recordings indicated that the atrioventricular block was proximal to the bundle of His. Additional findings of cardiac disease included T wave inversion in 10 patients and S-T segment depression in two patients. Four of nine patients who un-
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derwent radionuclide scanning showed mild decreases in ejection fraction, and one patient had a pericardial friction rub. These findings probably represent myocardial and pericardial inflammation in addition to atrioventricular nodal involvement. Neurologic. Meningitis alone was reported in 14 percent of the patients with onset in 1980 [3]. Encephalitis and cranial or radicular symptoms were reported in 19 percent of the same group. In 1979, Reik et al [ 6] reported the results of a prospective study of patients with neurologic involvement in addition to the previously mentioned transient symptoms that accompany erythema chronicurn migrans. Eighteen patients were included in their analysis. Fourteen had preceding erythema chronicurn migrans, whereas one had the characteristic arthritis. In three others, arthritis developed after the neurologic disease. In some patients, the transient meningeal symptoms did not resolve but became chronic; in six others, the neurologic involvement began one to six weeks after resolution of the erythema chronicurn migrans. There were several patterns of neurologic involvement. Three patients had encephalitis (one patient) or cranial neuropathy (two patients) only. The remaining 15 had multiple manifestations-meningitis (14 patients), encephalitis (12 patients), and cranial or radicular neuritis (eight patients each). One patient also had myelitis. Nine patients had a single episode lasting two to 12 weeks. The other nine had multiple episodes, with a range of two to six episodes per person, lasting two days to three months per episode. Most of the patients were relatively asymptomatic between episodes. Meningitis commonly presented with headache and stiff neck, often associated with nausea and vomiting and photophobia. These symptoms occurred intermittently for weeks with a mild headache present between attacks. This symptom complex lasted for up to nine months in one patient. Five patients had temporarily blurred vision attributed to increased intracranial pressure. Encephalitis was associated with somnolence, emotional liability, depression, poor memory and concentration, or behavioral changes. Ten of 13 patients with encephalitis had nonspecific abnormal electroencephalographic results. Chorea developed in three children. Cranial neuropathy occurred in eight patients, six of whom had a facial palsy. Half of the patients had more than one cranial nerve involved. Cranial nerve manifestations began four days to two months after the onset of disease and usually resolved in two weeks to five months. Three patients did continue to have a residual facial palsy after five months. Eight patients had a radiculopathy that was either motor or sensory, except in one patient who had both. All five patients with motor neuropathy had involvement
of the shoulder girdle. Symptoms began with pain, followed by weakness several days later. Radiculopathy began six to 12 weeks after the onset of Lyme disease and usually improved or resolved within a month. Three patients, however, still had weakness after three months. LABORATORY MANIFESTATIONS
Routine Studies. The most usual abnormality among “routine” laboratory results in Lyme disease is an elevated erythrocyte sedimentation rate [ 1,6,7]. Other routine studies have not given consistently abnormal results in any series of these patients. Body Fluids. Examination of synovial fluid in patients with acute arthritis usually shows inflammatory fluid; white blood cell counts from 500 to 98,000/mm3 have been reported [ 1,4]. The differential usually reveals a predominance of granulocytes, but this is not constant. Complement levels are variable, but complement depletion relative to serum levels is unusual. Synovial fluid white blood cell counts in patients with chronic arthritis range from 500 to 76,000, with granulocytes predominating [ 141. Twelve patients with meningitis, described by Reik et al [6], had cerebrospinal fluid leukocytosis, with a count ranging from 27 to 450/mm3 and 40 to 100 percent lymphocytes. In four of the five patients studied, the cerebrospinal fluid glucose level was less than two-thirds the serum level. Immune Complexes. Because immune complexes might be formed in response to an antigen or antigens in the tick, immune complexes were assayed by Hardin et al [ 151. The Clq binding assay, which utilizes the binding of Clq to the Fc portion of immunoglobulin molecules, was used. Within two months of the onset of Lyme disease, the serum of 14 of 18 patients with skin disease, 25 of 37 patients with arthritis, and 11 of 12 patients with neurologic or cardiac disease gave a positive reaction in the Clq assay. Thus, most of the patients with Lyme disease studied had circulating immune complexes in their serum soon after the onset of their disease. When patients whose disease was still active two to six months after onset were studied, two important observations were noted. First, no patient still had active skin lesions. Secondly, statistically more patients who had active cardiac or neurologic disease still had circulating immune complexes compared with the patients who had active joint disease. Moreover, when the Clq binding by synovial fluid and serum was measured simultaneously in 21 patients with articular complaints, there was always greater Clq binding in the synovial fluid than in the serum. Thus, immune complexes were present in the blood of patients at the time of disease onset, but cleared in those patients in whom cardiac or
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neurologic disease did not develop. The articular disease appeared to be associated with localization of Clq binding activity in the joints. Cryeglobulins. Another unusual property of the serum of these patients was the frequent presence of cryoglobulins. Forty-five percent of 97 serum samples from 48 patients in one study [ 161 showed cryoglobulins. IgM cryoglobulins were found significantly more often in patients (19 of 22, 86 percent) with manifestations of Lyme disease other than erythema chronicurn migrans than in those patients (five of 26, 19 percent) with erythema chronicurn migrans alone. Conversely, other symptoms were more likely to develop in patients with IgM cryoglobulins. Twenty-two of the 27 (81 percent) patients with erythema chronicurn migrans and predominantly IgM cryoglobulins had further disease, compared with only three of 21 (14 percent) patients without such proteins. Cryoglobulin localization to synovial fluid occurred in those patients with articular symptoms. Although only six of the 18 patients with active arthritis had serum IgM cryoglobulins when assayed, all had cryoglobulins in the synovial fluid. Curiously, these cryoglobulins were predominantly IgG, rather than IgM. In six patients with both synovial and serum cryoglobulins, the synovial fluid contained at least five times as much cryoprecipitable protein as did the serum cryogolobulins. Histologic Studies. Biopsy specimens of the central portion of the skin lesion show a mononuclear cell infiltrate around the blood vessels and skin appendages, but without the polynuclear cell infiltrate, dermal hemorrhage, or fibrinoid necrosis of vasculitis [ 11. There is edema of the papillary dermis, with intra- and extracellular edema and increased keratin in the epidermis. At the peripheral edges of the lesion, only the dermal, not the epidermal, changes are found. This lack of epidermal alteration at the expanding edge of the lesion is characteristic of an arthropod bite. The synovium from the patients with acute arthritis reveals the nonspecific findings of an inflammatory arthritis, with a mononuclear cell infiltrate that is mostly small lymphocytes and plasma cells [ 11. The stalks of synovium show edema, congestion, and vascular proliferation. These changes are consistent with an inflammatory arthritis and are not diagnostic of any specific form of arthritis. In those patients with chronic arthritis, there are similar changes, with pannus formation after a period of time [ 141. PATHOGENESIS There is now abundant evidence to suggest that it is a bite of the lxodes tick that initiates the development of erythema chronicurn migrans. However, erythema chronicurn migrans does not develop in every person
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bitten by this tick, nor does every patient with erythema chronicurn migrans get further manifestations of Lyme disease. The current working hypothesis for the pathogenesis of Lyme disease is illustrated in Figure 5. In some persons who are bitten by the tick, erythema chronicurn migrans develops through an immune complex-mediated mechanism. The development of erythema chronicurn migrans in some persons after a tick bite may relate to a relative inability to clear the presumed immune complexes from the blood or to the particular type of immune complexes that are formed. Continued failure to clear these complexes after erythema chronicurn migrans develops may then lead to cardiac or neurologic disease, whereas localization of complexes to the synovium results in joint disease. In certain persons, the noncutaneous manifestations of Lyme disease develop without an episode of erythema chronicurn migrans. This could be due to the ability to clear those complexes that are involved in erythema chronicurn migrans, but not those that cause the other findings. Attempts to isolate viral or rickettsial organisms from the ticks have failed [ 121, as have most attempts to show an infectious agent in these patients [ 11. However, a recent report has described the presence of spirochetal organisms in lxodes ticks [ 171. Nine patients with active or inactive Lyme disease had high titers of antibodies to the spirochete as demonstrated by indirect immunofluorescence. Confirmation of this report by additional studies would support the proposition that these spirochetal organisms or some portion of them is the putitive antigen in the presumed immune complexes. TREATMENT Since erythema chronicurn migrans has been reported to respond to penicillin, penicillin G, 250,000 units four times a day (or 250 mg of erythromycin or tetracycline four times a day in allergic persons), for 10 days was compared with no treatment [ 131. Penicillin resulted in a statistically shorter duration of erythema chronicurn migrans than no therapy, as did tetracycline, but erythromycin did not. Although penicillin and tetracycline were both better than erythromycin, neither was more effective than the other. The median duration of untreated skin lesions was 10 days, compared with four days with penicillin (and two days with tetracycline, but only five patients received this drug). Antibiotic-treated patients remained free of arthritis longer than those who were untreated [ 141. At six months, 79 percent of the treated patients were free of arthritis versus 56 percent of the untreated patients.
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ARTHRITIS
LOCALIZATiON OF IC TO SYNOVIUM
FAILURE TO FORM PATHOGENIC IC NO SEOUELEA
FOR:hO”
OR . RAPID
CLEARANCE OF IC
TICK BITE
l
ERYTHW CHRONtCtJU MIGRANS
FAILURE
CLEARANCE OF IC c
RESOLUTION
TO CLEAR
IGFROM
BLOOD
CARDIAC OR NEUROLOGIC MANIFESTATIONS
Figure 5.
Proposed relationship
of tick bites, immune complexes (IC), and Lyme disease.
Treated patients also had a significantly shorter duration of arthritis. No prophylactic effect was demonstrated in regard to cardiac or neurologic manifestations. On the basis of these observations and the recent report of the presence of spirochetes in lxodes ticks [ 171, it seems reasonable to treat patients who have erythema chronicum migrans with either penicillin or tetracycline for seven to 10 days, to hasten the resolution of the skin lesions and reduce the frequency of subsequent arthritis. The reason these drugs may be effective is unknown. Treatment of the arthritis, carditis, and neuritis has been empiric. The self-limited nature of the acute arthritis obviates the need for any analgesics other than acetaminophen or the nonsteroidal anti-inflammatory drugs. Patients with chronic arthritis have usually been treated conservatively with nonsteroidal anti-inflammatory agents, partial weight-bearing, and intra-articular steroids [ 131. Strenuous activity may prolong active disease. Three patients at Yale had resolution of their chronic arthritis after 12 to 16 months of disease [ 131. In five other patients who required synovectomy because of functional impairment, there has been no recurrence of arthritis. A recent case of chronic arthritis that responded to hydroxychloroquine has been reported
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Six of the eight patients with complete atrioventricular block had temporary transvenous pacemakers; all the pacemakers were removed within a week [7]. After one of these patients had a prompt response to prednisone, eight other patients received it, in divided doses totaling 40 to 60 mg per day. Within 24 to 48 hours, the degree of atrioventricular block decreased in all patients. The rest of the cardiac abnormalities resolved completely within one to two weeks. Prednisone was then tapered in increments of 5 to 10 mg per week. More rapid decreases in prednisone led to flares of articular or neurologic disease in some patients. The other 11 patients with atrioventricular block in this series were treated with aspirin. The three with complete block had resolution within one week, whereas firstdegree block resolved in one to six weeks. Prednisone has been used in the treatment of the inflammatory meningitis and encephalitis in a dose of 40 mg daily in adults and 20 mg in children [6]. Meningeal symptoms often respond within 24 hours, but the encephalitic symptoms do not respond as well. In one series, four patients had improvement within one week; three did not improve; 1 had progression of neurologic deficit; and chorea developed in one [6]. Cranial nerve and radicular symptoms probably do not resolve more quickly with treatment than without prednisone.
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In summary, Lyme disease is a recently characterized disease that appears to be related to bites of the lxodes genus of ticks. There is a characteristic and, to date, specific skin lesion, erythema chronicurn migrans, which may be followed by articular, cardiac, or neurologic manifestations, all of which are usually self-limited. Infrequently, these manifestations of Lyme disease may not be preceded by erythema chronicurn migrans, nor do they develop in all patients with erythema chronicurn migrans. The pathogenesis of the tick bite and its relationship to the further manifestations of Lyme disease have yet to be elucidated. There is sufficient evidence to suggest that this is an immune complex-mediated disease. This disease may be a new disease or the recent recognition of this particular symptom complex. Cases from outside New England and Minnesota and Wisconsin may occur in persons who have traveled to endemic areas or, as in our case, may occur in an area that harbors the lxodes tick and its natural hosts. Physicians throughout the United States (and North America) need to be able to recognize this disease, particularly so that patients can be reassured of the generally self-limited nature of this illness.
ACKNOWLEDGMENT I would like to thank Dr. Karl Grossman for allowing me to describe his patient and Dr. Richard Aach for reviewing this manuscript.
ADDENDUM The initial findings of Burgdorfer et al [ 171 concerning the role of spirochetal organisms in Lyme disease have been expanded to include larger numbers of patients and control subjects [ 19,201. The yet unnamed spirochete has been cultured from various sites in only five of 92 patients. In contrast, more than 90 percent of 135 patients have elevated levels of either IgG or IgM antibodies directed against the spirochete. Those patients in whom noncutaneous manifestations later developed usually demonstrated a decreased IgM titer and an increased IgG titer of antispirochetal antibodies at the time of these complications compared with earlier levels [ 191. These studies support the suggestion that this spirochete plays an important role in this disease. In addition, changes in antibody titers may prove to be helpful in the diagnosis of less obvious cases of Lyme disease.
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Steere AC, Malawi&a SE, Hardin JA, Ruddy S, Askenase PW, Andiman WA: Erythema chronicurn migrans and Lyme arthritis. Ann Intern Med 1977; 86: 685-698. Steere AC, Malawista SE: Cases of Lyme disease in the United States: locations correlated with distribution of lxodes damnini. Ann Intern Med 1979; 91: 730-733. Centers for Disease Control: Lyme disease-United States, 1980. Morbid Mortal Weekly Rep 1981; 30: 489-497. Steere AC, Malawista SE, Snydman DR. et al: Lyme arthritis. Arthritis Rheum 1977; 20: 7-17. Steere AC, Malawista SE, Snydman DR. Andiman WA: A cluster of arthritis in children and adults in Lyme, Connecticut (abstr). Arthritis Rheum 1976; 19: 824. Reik L. Steere AC, Battenhagen NH, Shope RE, Matawista SE: Neurologic abnormalities of Lyme disease. Medicine (Baltimore) 1979; 58: 281-294. Steere AC, Batsford WP, Weinberg M, et al: Lyme carditis: cardiac abnormalities of Lyme disease. Ann Intern Med 1980; 93: 8-16. Dryer RF, Goellner PG, Carney AS: Lyme arthritis in Wisconsin. JAMA 1979; 241: 498-499. Scrimenti RJ: Erythema chronicurn migrans. Arch Dermatol 1970; 102: 104-105. Mast WE, Burrows WM: Erythema chronicurn migrans in the United States. JAMA 1976; 236: 859-860. Steere AC, Broderick TF, Malawista SE: Erythema chronicurn migrans and Lyme arthritis: epidemiologic evidence for a tick vector. Am J Epidemiol 1978; 108: 312-321.
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Wallis RC, Brown SE, Kloter KO, Main AJ: Erythema chronicum migrans and Lyme arthritis: field study of ticks. Am J Epidemiol 1978; 108: 322-327. Steere AC, Malawista SE, Newman JH, Spieler PN, Bartenhagen NH: Antibiotic therapy in Lyme disease. Ann Intern Med 1980; 93: l-8. Steere AC, Gibofsky A, Patarryo ME, Winchester RJ, Hardin JA, Malawista SE: Chronic Lyme arthritis. Ann Intern Med 1979; 90: 896-901. Hardin JA, Steere AC, Malawista SE: Immune complexes and the evolution of Lyme arthritis. N Engl J Med 1979; 301: 1358-1363. Steere AC, Hardin JA. Ruddy S, Mummaw JG, Malawi& SE: Lyme arthritis. Correlation of serum and cryoglobulin IgM with activity, and serum IgG with remission. Arthritis Rheum 1979; 22: 471-483. Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP: Lyme disease-a tick borne spirochetosis. Science 1982; 216: 1317-1319. Coblyn JS, Taylor P: Treatment of chronic Lyme arthritis with hydroxchloroquine. Arthritis Rheum 1981; 24: 15671569. Steere AC, Grodzicki RL. Kornblatt AN, et al: The spirochetal etiology of Lyme disease. N Engl J Med 1983; 308: 733740. Benach JL, Bosler EM, Hanrahan JP. et al: Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med 1983; 308: 740-742.
Lyme Disease
JOHN MEYERHOFF, M.D. Baltimore,
Maryland
Lyme disease is a recently described disease of unknown cause that may involve the skin, joints, heart, or nervous system with characteristic symptoms. The disease follows a bite from an lxodes tick. Symptoms are generally self-limited and despite the varied and sometimes protracted manifestations, the outcome of the disease is favorable. The epidemiologic, clinical, and laboratory features and treatment of Lyme disease are reviewed. Lyme disease, a recently described disease of unknown cause that may involve the skin, joints, heart, or nervous system [ 11, occurs most commonly in certain regions of the country: New England, Minnesota, and Wisconsin [2,3]. However, persons with Lyme disease who presumably contracted the disease on travel to areas of infestation by the vector have been reported to the Centers for Disease Control from Texas, California, New Jersey, and the District of Columbia [3]. The disease is not rare; the Centers for Disease Control recently reported 226 cases with onset in 1980 alone [3]. Although reports of the individual manifestations of Lyme disease have been published [ 1,4-81, no comprehensive review of this disease has yet appeared. A recent case with “classic” findings at our hospital prompted this review of the epidemiologic, clinical, and laboratory features and treatment of Lyme disease. TYPICAL CASE
From the Departments of Medicine, Sinai Hospital and Johns Hopkins University School of Medicine, Baltimore, Maryland. Requests for reprints should be addressed to Dr. John Meyerhoff, 2435 West Belvedere Avenue, Baltimore, Maryland 21215. Manuscript accepted November 9, 1982.
The patient, a 34-year-old white man without prior medical problems, went camping in Cecil County, Maryland, July 1 to 3, 1981. On July 6, he noticed a “pustular” lesion on his left scapula. This lesion expanded over the next week, and the patient experienced myalgias, fevers, chills, and a left temporal headache. On July 13, he visited his physician and was noted to have an oral temperature of 103.2OF. The lesion was noted to be dusky red, with a lighter colored, indurated center. The patient was treated with clindamycin, 150 mg every four hours, for approximately 24 hours, but did not improve. The patient was admitted to Sinai Hospital on July 15, 1981. On admission, the patient was febrile, with an oral temperature of 38.6’C. He was noted to have posterior cervical and sublingual lymphadenopathy. The lesion on the left scapula was warm to the touch and was 6 X 15 cm in size. There was a 4 X 1 cm central area that was desquamating (Figure 1). The rest of the findings on physical examination were normal. Routine laboratory studies all gave normal results, as did chest roentgenography and electrocardiography. Skin biopsy of the lesion showed a dense lymphocytic infiltration around the dermal blood vessels of the superficial and deep plexus. As shown in Figures 2 and 3, there were foci of epidermal spongiosis and edema
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Figure 1. Len scapular lesion on initial admission (photograph courtesy of Dr. Michael Levin).
of the papillary dermis (histologic description by Violet Jiji, M.D., Department of Pathology, Sinai Hospital). The patient was not treated with any specific medications, and his temperature became normal. He was discharged four days after admission, feeling better, with the skin lesion resolving. One week later, he had a recurrence of the skin lesion, with multiple lesions on the palms, arms, legs, and back. Twenty-four hours later, a headache and fever developed. Six days later, he noticed numbness of the tongue, followed by pain behind the left ear the next day. That evening, seven days after the recurrent skin lesions appeared, a facial droop developed, and he was readmitted to Sinai Hospital. On admission, he was afebrile and had left peripheral facial palsy and multiple erythematous skin lesions. Lumbar puncture yielded slightly hazy fluid with an opening pressure of 250 mm. The white blood cell count in the fluid was 180/mm3; 97 percent were monocytes. The protein level was 42 mg/dl, and the glucose value was 57 mg/dl. Gram stain, India ink preparation, and a Duo-fast stain for acid-fast organisms showed nothing. The patient was treated with 15 mg of prednisone, every six hours, and 250 mg of erythromycin, every six hours, over the next four days. He became afebrile on the fifth hospital day, and the prednisone dose was
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decreased to 55 mg per day. On the following day, he was discharged. Erythromycin was continued for a total of 10 days while the prednisone was decreased by 5 mg per day. During the next several weeks, the patient’s palsy resolved, and he has done well since. HISTORICAL BACKGROUND The “discovery” of Lyme disease began in 1975 when the Connecticut State Health Department and the Yale University Rheumatology Division were informed of an apparently unusual number of cases of arthritis in the town of Old Lyme, Connecticut. During the investigation of these reports, it was recognized that the persons affected had a distinct pattern of symptoms that probably represented a previously undescribed disease entity [4,5]. Further cases were then discovered elsewhere in Connecticut and New England. It was then recognized that the skin lesions of Lyme disease were identical to erythema chronicurn migrans. Erythema chronicurn migrans and the neurologic manifestations associated with it are well known in Europe, having been initially reported in 1909 [I] and 1922 [6], respectively. The initial reports of erythema chronicurn migrans in the United States date only to 1970 [9] and 1976 [lo]. Both reports came from areas (Wisconsin and Connecticut) in which Lyme disease is now recognized to occur frequently. The association
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Figure 2. Skin biopsy specimen of left scapular area showing dense perivascular lymphocytic infiltrate throughout all layers of the dermis with edema of the papillary dermis (hematoxylin and eosin stain; original magnification X 760, reduced by 30 percent; photograph courtesy of Dr. Violet Jiji).
Figure 3. Skin biopsy specimen of left scapular area showing perivascular lymphocytic infiltrate in the dermis with intracellular and extracellular edema in the epidermis and an area of hyperkeratosis (hematoxylin and eosin stain; original magnification X 160, reduced by 30 percent: photograph courtesy of Dr. Violet Jiji).
between erythema chronicurn migrans and bites of the lxodes genus of ticks has been reported in Europe, where the nervous system disease is called “tick-borne meningopolyneuritis” [6]. To investigate if there was a similar association between ticks and Lyme disease, epidemiologic studies of the patient [ 1 I] and tick [ 121 populations in eastern Connecticut were undertaken in 1977.
river or the other. The preference of this tick for the eastern bank of the Connecticut River is thought to be due to climatic factors.
EPIDEMIOLOGY During 1977, the incidence of Lyme disease was 30 times greater on the eastern bank of the Connecticut river than on the western shore [ 111. The majority of cases of Lyme disease occurred in children and young adults. Case-control studies of patients and their neighbors revealed that the patients did not have more outdoor activities than the control subjects. However, they were more likely to have a cat or farm animals, more likely to have a pet with ticks, and more likely to have had a tick bite in the year of the study. Since the hosts of the lxodes tick are mice and deer, these and other small mammals were trapped on both sides of the Connecticut River [ 121. The most common was the white-footed mouse, the preferred host of the immature tick. lxodes scapularis ticks were 12 times as abundant on these mice from the eastern shore as on those from the western shore. As the tick matures, its preferred host becomes the white-tailed deer. Although this species of deer is equally common on both sides of the river, eastern deer were found to have 16 times as many ticks as western deer. No other species of ticks was found to predominate on one side of the
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CLINICAL MANIFESTATIONS Although the early reports of this disease focused on the articular symptoms [4,5], arthritis is just one manifestation of Lyme disease [ 11. Dermatologic [ 11, neurologic [6], and cardiologic [7] involvement are also common and may predominante. Figure 4 illustrates the relationship of these manifestations.
NEUROLOGIC MANIFESTATIONS MANIFESTATIONS
Figure 4. Representation of the relationship of the clinical manifestations of Lyme disease. The size of the shapes and amount of overlap are approximate only.
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The most common of the clinical Dermatoiogic. manifestations is the skin rash, erythema chronicum migrans. The rash begins four to 20 days after a tick bite [ 11, which the patient may not remember. This may be due in part to the small size of the tick. An erythematous macule or papule forms at the site of the bite and then rapidly expands to form an annular lesion. The usual location is the trunk or proximal extremity, and the average diameter is 16 cm, but lesions up to 52 cm in diameter have been reported. The outer border is usually erythematous and flat, although it may be indurated. There is clearing in the middle of the lesion, while induration and erythema may occur in the center. The lesion is usually hot to the touch and may burn, prickle, or itch. The average duration of the initial skin lesion is about three weeks, with a range of two days to eight weeks. Multiple lesions can occur but are usually preceded by a single lesion. Recurrent attacks usually occur in the first year of the disease and were reported by 19 percent of the patients in one series [ 131. The skin lesions are often associated with systemic symptoms. The most common are malaise, fatigue, headache, and stiff neck, followed by arthraigias, myalgias, backache, sore throat, nausea, and vomiting. The most common physical findings are fever and lymphadenopathy [ 11. Some of these signs and symptoms may represent a milder, more transient form of meningoencephalitis, which later develops in some patients [6]. Fourteen percent of 226 patients in one series had transient meningeal symptoms [3]. Further articular, cardiac, or neurologic manifestations occurred in 61 percent of 409 patients with erythema chronicurn migrans in another series [ 21. Rheumatoiogic. The most common of the other manifestations of Lyme disease is the arthritis, which occurs in approximately half of the patients [3,13]. Some patients have the arthritis without having had a prior episode of erythema chronicum migrans. In twothirds of patients with erythema chronicurn migrans and arthritis, the arthritis develops within six months of the onset of erythema chronicum migrans [ 131. The initial attack of arthritis may be a mono-, oligo-, or poiyarticular episode, the knee being the most commonly affected joint-84 percent of patients in one series [4], with other joints involved much less frequently. Although swelling occurs frequently with involvement of the knee, pain on motion without obvious swelling or warmth is common in other joints [ 11. The usual duration of the first episode is one week [4]. Among the initial 51 patients described, 35 (69 percent) had recurrent attacks [4]. The median number of recurrent attacks was three, and the median number of joints involved in all attacks was also three. During recurrent attacks, there are usually more joints involved than in the initial episode. Recurrent
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attacks last about one week, with intervals of one week to two years between attacks and variation in the frequency and severity of each recurrence. In 1979, Steere et al [ 141 reported that a chronic arthritis had occurred in 10 of 102 patients whose arthritis had developed between 1974 and 1976 (14). Nine of the 10 patients had had a previous episode of erythema chronicurn migrans. Four of the patients had involvement of both knees, whereas the other six had monoarticular knee disease. Chronic arthritis usually developed a year after the initial manifestation of Lyme disease, although three patients had onset within six months. The knees were usually painful, and walking was difficult. Swelling fluctuated, but was often very intense, although less painful than expected from its degree. Pseudothrombophlebitis developed in three patients with ruptured Baker’s cysts. None of these patients had findings suggestive of rheumatoid arthritis (e.g., symmetric polyarthritis, morning stiffness, subcutaneous nodules, or rheumatoid factor), nor did they have signs or symptoms of Reiter’s disease (e.g., urethritis, conjunctivitis, and/or mucocutaneous lesions). Cardiac. Ten percent of the cases of Lyme disease with an onset in 1980 reported by the Centers for Disease Control had cardiac manifestations [3]. Twenty patients with cardiac abnormalities were reported on by Steere et al [7] in 1980. Manifestations of cardiac involvement began at a median of three weeks after the skin lesions first appeared, with a range of four to 83 days. The one patient without preceding erythema chronicum migrans had migratory polyarthralgias three weeks before the onset of heart block. These patients were not elderly, the two oldest patients being 40 and 58 years old. The most common abnormality, which occurred in 18 patients, was atrioventricular block, often characterized by rapid fluctuation in the degree of block. Some patients went from first-degree to complete block and back in a matter of minutes. Two other patients had S-T segment and T wave abnormalities without atrioventricular block. Eight of the 20 patients in Steere’s series had firstdegree block only. Of these eight, two had palpitations; the rest were asymptomatic. Of the other 10 patients with higher degrees of atrioventricular block, all had multiple degrees of block (first-degree and/or Wenckebach and/or complete block). All 10 of these patients were symptomatic, with syncope (five patients), shortness of breath (two patients), palpitations (two patients), or dizziness (one patient). Bundle of His recordings indicated that the atrioventricular block was proximal to the bundle of His. Additional findings of cardiac disease included T wave inversion in 10 patients and S-T segment depression in two patients. Four of nine patients who un-
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derwent radionuclide scanning showed mild decreases in ejection fraction, and one patient had a pericardial friction rub. These findings probably represent myocardial and pericardial inflammation in addition to atrioventricular nodal involvement. Neurologic. Meningitis alone was reported in 14 percent of the patients with onset in 1980 [3]. Encephalitis and cranial or radicular symptoms were reported in 19 percent of the same group. In 1979, Reik et al [ 6] reported the results of a prospective study of patients with neurologic involvement in addition to the previously mentioned transient symptoms that accompany erythema chronicurn migrans. Eighteen patients were included in their analysis. Fourteen had preceding erythema chronicurn migrans, whereas one had the characteristic arthritis. In three others, arthritis developed after the neurologic disease. In some patients, the transient meningeal symptoms did not resolve but became chronic; in six others, the neurologic involvement began one to six weeks after resolution of the erythema chronicurn migrans. There were several patterns of neurologic involvement. Three patients had encephalitis (one patient) or cranial neuropathy (two patients) only. The remaining 15 had multiple manifestations-meningitis (14 patients), encephalitis (12 patients), and cranial or radicular neuritis (eight patients each). One patient also had myelitis. Nine patients had a single episode lasting two to 12 weeks. The other nine had multiple episodes, with a range of two to six episodes per person, lasting two days to three months per episode. Most of the patients were relatively asymptomatic between episodes. Meningitis commonly presented with headache and stiff neck, often associated with nausea and vomiting and photophobia. These symptoms occurred intermittently for weeks with a mild headache present between attacks. This symptom complex lasted for up to nine months in one patient. Five patients had temporarily blurred vision attributed to increased intracranial pressure. Encephalitis was associated with somnolence, emotional liability, depression, poor memory and concentration, or behavioral changes. Ten of 13 patients with encephalitis had nonspecific abnormal electroencephalographic results. Chorea developed in three children. Cranial neuropathy occurred in eight patients, six of whom had a facial palsy. Half of the patients had more than one cranial nerve involved. Cranial nerve manifestations began four days to two months after the onset of disease and usually resolved in two weeks to five months. Three patients did continue to have a residual facial palsy after five months. Eight patients had a radiculopathy that was either motor or sensory, except in one patient who had both. All five patients with motor neuropathy had involvement
of the shoulder girdle. Symptoms began with pain, followed by weakness several days later. Radiculopathy began six to 12 weeks after the onset of Lyme disease and usually improved or resolved within a month. Three patients, however, still had weakness after three months. LABORATORY MANIFESTATIONS
Routine Studies. The most usual abnormality among “routine” laboratory results in Lyme disease is an elevated erythrocyte sedimentation rate [ 1,6,7]. Other routine studies have not given consistently abnormal results in any series of these patients. Body Fluids. Examination of synovial fluid in patients with acute arthritis usually shows inflammatory fluid; white blood cell counts from 500 to 98,000/mm3 have been reported [ 1,4]. The differential usually reveals a predominance of granulocytes, but this is not constant. Complement levels are variable, but complement depletion relative to serum levels is unusual. Synovial fluid white blood cell counts in patients with chronic arthritis range from 500 to 76,000, with granulocytes predominating [ 141. Twelve patients with meningitis, described by Reik et al [6], had cerebrospinal fluid leukocytosis, with a count ranging from 27 to 450/mm3 and 40 to 100 percent lymphocytes. In four of the five patients studied, the cerebrospinal fluid glucose level was less than two-thirds the serum level. Immune Complexes. Because immune complexes might be formed in response to an antigen or antigens in the tick, immune complexes were assayed by Hardin et al [ 151. The Clq binding assay, which utilizes the binding of Clq to the Fc portion of immunoglobulin molecules, was used. Within two months of the onset of Lyme disease, the serum of 14 of 18 patients with skin disease, 25 of 37 patients with arthritis, and 11 of 12 patients with neurologic or cardiac disease gave a positive reaction in the Clq assay. Thus, most of the patients with Lyme disease studied had circulating immune complexes in their serum soon after the onset of their disease. When patients whose disease was still active two to six months after onset were studied, two important observations were noted. First, no patient still had active skin lesions. Secondly, statistically more patients who had active cardiac or neurologic disease still had circulating immune complexes compared with the patients who had active joint disease. Moreover, when the Clq binding by synovial fluid and serum was measured simultaneously in 21 patients with articular complaints, there was always greater Clq binding in the synovial fluid than in the serum. Thus, immune complexes were present in the blood of patients at the time of disease onset, but cleared in those patients in whom cardiac or
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neurologic disease did not develop. The articular disease appeared to be associated with localization of Clq binding activity in the joints. Cryeglobulins. Another unusual property of the serum of these patients was the frequent presence of cryoglobulins. Forty-five percent of 97 serum samples from 48 patients in one study [ 161 showed cryoglobulins. IgM cryoglobulins were found significantly more often in patients (19 of 22, 86 percent) with manifestations of Lyme disease other than erythema chronicurn migrans than in those patients (five of 26, 19 percent) with erythema chronicurn migrans alone. Conversely, other symptoms were more likely to develop in patients with IgM cryoglobulins. Twenty-two of the 27 (81 percent) patients with erythema chronicurn migrans and predominantly IgM cryoglobulins had further disease, compared with only three of 21 (14 percent) patients without such proteins. Cryoglobulin localization to synovial fluid occurred in those patients with articular symptoms. Although only six of the 18 patients with active arthritis had serum IgM cryoglobulins when assayed, all had cryoglobulins in the synovial fluid. Curiously, these cryoglobulins were predominantly IgG, rather than IgM. In six patients with both synovial and serum cryoglobulins, the synovial fluid contained at least five times as much cryoprecipitable protein as did the serum cryogolobulins. Histologic Studies. Biopsy specimens of the central portion of the skin lesion show a mononuclear cell infiltrate around the blood vessels and skin appendages, but without the polynuclear cell infiltrate, dermal hemorrhage, or fibrinoid necrosis of vasculitis [ 11. There is edema of the papillary dermis, with intra- and extracellular edema and increased keratin in the epidermis. At the peripheral edges of the lesion, only the dermal, not the epidermal, changes are found. This lack of epidermal alteration at the expanding edge of the lesion is characteristic of an arthropod bite. The synovium from the patients with acute arthritis reveals the nonspecific findings of an inflammatory arthritis, with a mononuclear cell infiltrate that is mostly small lymphocytes and plasma cells [ 11. The stalks of synovium show edema, congestion, and vascular proliferation. These changes are consistent with an inflammatory arthritis and are not diagnostic of any specific form of arthritis. In those patients with chronic arthritis, there are similar changes, with pannus formation after a period of time [ 141. PATHOGENESIS There is now abundant evidence to suggest that it is a bite of the lxodes tick that initiates the development of erythema chronicurn migrans. However, erythema chronicurn migrans does not develop in every person
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bitten by this tick, nor does every patient with erythema chronicurn migrans get further manifestations of Lyme disease. The current working hypothesis for the pathogenesis of Lyme disease is illustrated in Figure 5. In some persons who are bitten by the tick, erythema chronicurn migrans develops through an immune complex-mediated mechanism. The development of erythema chronicurn migrans in some persons after a tick bite may relate to a relative inability to clear the presumed immune complexes from the blood or to the particular type of immune complexes that are formed. Continued failure to clear these complexes after erythema chronicurn migrans develops may then lead to cardiac or neurologic disease, whereas localization of complexes to the synovium results in joint disease. In certain persons, the noncutaneous manifestations of Lyme disease develop without an episode of erythema chronicurn migrans. This could be due to the ability to clear those complexes that are involved in erythema chronicurn migrans, but not those that cause the other findings. Attempts to isolate viral or rickettsial organisms from the ticks have failed [ 121, as have most attempts to show an infectious agent in these patients [ 11. However, a recent report has described the presence of spirochetal organisms in lxodes ticks [ 171. Nine patients with active or inactive Lyme disease had high titers of antibodies to the spirochete as demonstrated by indirect immunofluorescence. Confirmation of this report by additional studies would support the proposition that these spirochetal organisms or some portion of them is the putitive antigen in the presumed immune complexes. TREATMENT Since erythema chronicurn migrans has been reported to respond to penicillin, penicillin G, 250,000 units four times a day (or 250 mg of erythromycin or tetracycline four times a day in allergic persons), for 10 days was compared with no treatment [ 131. Penicillin resulted in a statistically shorter duration of erythema chronicurn migrans than no therapy, as did tetracycline, but erythromycin did not. Although penicillin and tetracycline were both better than erythromycin, neither was more effective than the other. The median duration of untreated skin lesions was 10 days, compared with four days with penicillin (and two days with tetracycline, but only five patients received this drug). Antibiotic-treated patients remained free of arthritis longer than those who were untreated [ 141. At six months, 79 percent of the treated patients were free of arthritis versus 56 percent of the untreated patients.
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ARTHRITIS
LOCALIZATiON OF IC TO SYNOVIUM
FAILURE TO FORM PATHOGENIC IC NO SEOUELEA
FOR:hO”
OR . RAPID
CLEARANCE OF IC
TICK BITE
l
ERYTHW CHRONtCtJU MIGRANS
FAILURE
CLEARANCE OF IC c
RESOLUTION
TO CLEAR
IGFROM
BLOOD
CARDIAC OR NEUROLOGIC MANIFESTATIONS
Figure 5.
Proposed relationship
of tick bites, immune complexes (IC), and Lyme disease.
Treated patients also had a significantly shorter duration of arthritis. No prophylactic effect was demonstrated in regard to cardiac or neurologic manifestations. On the basis of these observations and the recent report of the presence of spirochetes in lxodes ticks [ 171, it seems reasonable to treat patients who have erythema chronicum migrans with either penicillin or tetracycline for seven to 10 days, to hasten the resolution of the skin lesions and reduce the frequency of subsequent arthritis. The reason these drugs may be effective is unknown. Treatment of the arthritis, carditis, and neuritis has been empiric. The self-limited nature of the acute arthritis obviates the need for any analgesics other than acetaminophen or the nonsteroidal anti-inflammatory drugs. Patients with chronic arthritis have usually been treated conservatively with nonsteroidal anti-inflammatory agents, partial weight-bearing, and intra-articular steroids [ 131. Strenuous activity may prolong active disease. Three patients at Yale had resolution of their chronic arthritis after 12 to 16 months of disease [ 131. In five other patients who required synovectomy because of functional impairment, there has been no recurrence of arthritis. A recent case of chronic arthritis that responded to hydroxychloroquine has been reported
/181.
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Six of the eight patients with complete atrioventricular block had temporary transvenous pacemakers; all the pacemakers were removed within a week [7]. After one of these patients had a prompt response to prednisone, eight other patients received it, in divided doses totaling 40 to 60 mg per day. Within 24 to 48 hours, the degree of atrioventricular block decreased in all patients. The rest of the cardiac abnormalities resolved completely within one to two weeks. Prednisone was then tapered in increments of 5 to 10 mg per week. More rapid decreases in prednisone led to flares of articular or neurologic disease in some patients. The other 11 patients with atrioventricular block in this series were treated with aspirin. The three with complete block had resolution within one week, whereas firstdegree block resolved in one to six weeks. Prednisone has been used in the treatment of the inflammatory meningitis and encephalitis in a dose of 40 mg daily in adults and 20 mg in children [6]. Meningeal symptoms often respond within 24 hours, but the encephalitic symptoms do not respond as well. In one series, four patients had improvement within one week; three did not improve; 1 had progression of neurologic deficit; and chorea developed in one [6]. Cranial nerve and radicular symptoms probably do not resolve more quickly with treatment than without prednisone.
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In summary, Lyme disease is a recently characterized disease that appears to be related to bites of the lxodes genus of ticks. There is a characteristic and, to date, specific skin lesion, erythema chronicurn migrans, which may be followed by articular, cardiac, or neurologic manifestations, all of which are usually self-limited. Infrequently, these manifestations of Lyme disease may not be preceded by erythema chronicurn migrans, nor do they develop in all patients with erythema chronicurn migrans. The pathogenesis of the tick bite and its relationship to the further manifestations of Lyme disease have yet to be elucidated. There is sufficient evidence to suggest that this is an immune complex-mediated disease. This disease may be a new disease or the recent recognition of this particular symptom complex. Cases from outside New England and Minnesota and Wisconsin may occur in persons who have traveled to endemic areas or, as in our case, may occur in an area that harbors the lxodes tick and its natural hosts. Physicians throughout the United States (and North America) need to be able to recognize this disease, particularly so that patients can be reassured of the generally self-limited nature of this illness.
ACKNOWLEDGMENT I would like to thank Dr. Karl Grossman for allowing me to describe his patient and Dr. Richard Aach for reviewing this manuscript.
ADDENDUM The initial findings of Burgdorfer et al [ 171 concerning the role of spirochetal organisms in Lyme disease have been expanded to include larger numbers of patients and control subjects [ 19,201. The yet unnamed spirochete has been cultured from various sites in only five of 92 patients. In contrast, more than 90 percent of 135 patients have elevated levels of either IgG or IgM antibodies directed against the spirochete. Those patients in whom noncutaneous manifestations later developed usually demonstrated a decreased IgM titer and an increased IgG titer of antispirochetal antibodies at the time of these complications compared with earlier levels [ 191. These studies support the suggestion that this spirochete plays an important role in this disease. In addition, changes in antibody titers may prove to be helpful in the diagnosis of less obvious cases of Lyme disease.
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