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Conferences and Reviews Lyme Disease DANIEL W. RAHN, MD, and STEPHEN E. MALAWISTA, MD, New Haven, Connecticut

Lyme disease is a tick-borne immune-mediated inflammatory disorder caused by a newly recognized spirochete, Borrelia burgdorferi. Over the past 15 years it has progressed from a medical curiosity to the most frequently recognized vector-borne illness in the United States. Its clinical hallmark is an early expanding skin lesion, erythema chronicum migrans, that may be followed weeks to months later by a spectrum of systemic features with joint, neurologic, and cardiac abnormalities predominating. The clinical manifestations are protean; symptoms may refer to any involved organ system alone or in combination. All stages of Lyme disease may respond to antibiotics, but treatment of early disease is the most successful. Although cases of the illness are concentrated in certain endemic areas, foci of Lyme disease are widely distributed within the United States and Europe. History Lyme arthritis was recognized in November 1975 because of an unusual geographic cluster of children with inflammatory arthropathy in the region of Lyme, Connecticut.' Its early elucidation-natural history,`6 immunopathogenesis,7-" epidemiology,"2-"5 pathology,2'411 and therapy16"-9-was carried out primarily at Yale University by Steere and Malawista and their colleagues. It soon became clear that this was a multisystem disorder (Lyme disease2-6) occurring at any age, in both sexes, and often preceded by a characteristic expanding skin lesion, erythema chronicum migrans (ECM). Recognition of this skin lesion provided an important link to disorders previously recognized in Europe. Erythema chronicum migrans had been described in 190920 and subsequently connected with the bite of the sheep tick, Ixodes ricinus,2" and with tick-borne meningopolyneuritis.2223 These syndromes are now often subsumed under the name, Lyme disease. In the Lyme region, a closely related deer tick, Ixodes dammini (a member of the so-called Ixodes ricinus complex), was implicated as the principal disease vector on epidemiologic grounds.`2`15 In 1982, Burgdorfer and associates24 isolated the spirochete that bears his name from I dammini collected on Shelter Island, New York, and linked it serologically to patients with Lyme disease. Within months this organism had been cultured from specimens of blood, skin, and cerebrospinal fluid of patients, and specific IgM and IgG antibody re§ponses had been delineated.25 26 Because of its infectious cause but inflammatory or "rheumatic" expression, Lyme disease, beyond intrinsic interest as a new nosologic entity, presents a unique human model for an infectious cause of a chronic rheumatic disease.27

Pathogenesis By morphology, physiology, and DNA composition, the spirochetes found in tick vectors and in patients with Lyme disease have been classified as Borrelia rather than Leptospira or Treponema, the other two spirochetes pathogenic for man. Clinical isolates in the United States and Europe have to date all belonged to a single species: Borrelia burgdorferi. 28 Unlike pathogenic treponemes, however, B burgdorferi can be cultured in artificial media in vitro. This organism is also responsible for some cases of an early skin lesion, benign lymphocytoma,29 and for a late one, acrodermatitis chronica atrophicans (ACA),29'30 both seen at present primarily in Europe. Characterization of clinical isolates has revealed several immunodominant proteins expressed during human infection; th-ese include a flagellar antigen and two outer surface proteins, ospA and ospB.3133 The antigenic reactivities of outer surface proteins may differ among isolates and can vary with serial passages of a single isolate in vitro.34 European isolates have been more heterogeneous than American ones, particularly with respect to ospA. Molecular weights and immunoreactivity of ospB have differed among both American and European isolates.35 Variation in protein composition could eventually explain differences in the clinical expression of Lyme disease in Europe and America. Compared with American disease, B burgdorferi infection in Europe is characterized by milder but more prolonged early disease, less frequent occurrence of multiple skin lesions and arthritis, and more frequent occurrence of meningoradiculitis and ACA. Continuous cultivation of B burgdorferi in vitro results in a loss of pathogenicity as evidenced by its inability to infect the white-footed mouse, Peromyscus leucopus, the primary reservoir of B burgdorferi in the wild in the northeastern United States. This change occurred after 11 to 15 serial passages and was associated with the disappearance of ospB from the surface of the organism.34 Similar alterations in the expression of surface proteins may occur during human infection,36 which could explain how the organism evades immunologic destruction in the presence of a mature immune response. Recovery of B burgdorferi is straightforward from the tick vector (see below) but generally difficult from patients, in part because of a relative paucity of organisms in most clinical specimens. An exception is its isolation from biopsy specimens of ECM cultured in improved media: for example, 6 of 14 in one study37; 9 of 13 in another. 30 Nevertheless, positive cultures have been reported at all stages of the illness-from blood (early),25'26'38 secondary annular lesions,30 meningitic

(Rahn DW, Malawista SE: Lyme disease. West J Med 1991 Jun; 154:706-714) From the Department of Internal Medicine. Section of Rheumatology, Yale University School of Medicine, New Haven, Connecticut. Reprint requests to Daniel W. Rahn, MD, Dept of Internal Medicine, Section of Rheumatology, Yale Univ School of Medicine, 333 Cedar St, New Haven, CT 06510.

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ABBREVIATIONS USED IN TEXT ACA = acrodermatitis chronica atrophicans ECM = erythema chronicum migrans ELISA = enzyme-linked immunosorbent assay

cerebrospinal fluid,25 heart,39 joint fluid,40 and even from an ACA lesion that had been present for more than ten years.30 Spirochetes have also been identified by silver stain or by immunofluorescence in some histologic sections of ECM4' and rarely of secondary annular lesions,42 synovium,43 brain,44'45 eye,46 heart,47 striated muscle,48 liver,49 spleen, kidney, and bone marrow.50 From these data, considered in the context of the clinical and epidemiologic features of Lyme disease (see below), the following pathogenetic sequence can be proposed. Borrelia burgdorferi is transmitted to the skin of the parasitized host by the tick vector. After an incubation period,6 the spirochetes migrate outward in the skin (causing ECM), spread in lymph (regional adenopathy), or disseminate in blood to other skin sites (secondary annular lesions) or organs (central nervous system, joints, heart, and presumably liver, spleen, and kidney). Maternal-fetal transmission has occurred but appears to be distinctly uncommon.50' 5 Although organisms are hard to find in later stages of Lyme disease, it is likely that live spirochetes are driving the illness throughout its course. Evidence for this interpretation includes the responsiveness of many patients to antibiotics; the rare sightings of spirochetes in affected tissues and fluids; possibly the antigen-specific proliferation of lymphocytes from these fluids52 53; and an expansion of the antibody response to additional spirochetal antigens over time.36 Lyme disease is associated with characteristic immune abnormalities.7-10 At disease onset (ECM), most patients have evidence of circulating immune complexes.9"l0 At that time, the findings of elevated serum IgM levels and cryoglobulins containing IgM predict subsequent nervous system, heart, or joint involvement7'8; that is, early humoral findings have prognostic significance. Serial determinations of serum IgM can be a helpful laboratory indicator of risk of future disease activity. These abnormalities tend to persist during neurologic or cardiac involvement, but by the time arthritis is present, serum IgM levels are more often normal. By then, immune complexes are usually lacking in serum but are present uniformly in joint fluid, 10 where their titers correlate positively with the local concentration of polymorphonuclear leukocytes.54 Mononuclear cells from peripheral blood show increasing proliferative responses to spirochetal antigens as the disease progresses, but the greatest reactivity is seen in synovial fluid cells from inflamed joints.52 Mononuclear cells exposed to spirochetes produce interleukin- 1, and interleukin-l has been found in fluid from inflamed joints.55 On biopsy a proliferative synovium is seen, often replete with lymphocytes and plasma cells that presumably are capable of producing immunoglobulin locally. Thus, an initially disseminated, immune-mediated inflammatory disorder becomes in some patients localized and propagated in joints. In addition to factors related to the pathogenicity of specific isolates of B burgdorferi, immunogenetic makeup may play a role in whether infected persons are able to rid themselves of spirochetes. Patients with chronic arthritis have been reported to have an increased frequency of the B-cell alloantigens DR4 and sometimes DR356 or DR2,57 and per-

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sons with another late manifestation, ACA, have an increased frequency of DR2.`8

Epidemiology Lyme disease is the most commonly reported vectortransmitted disease in the United States and has essentially worldwide distribution. In the United States, there are three distinct foci: the Northeast, from Massachusetts to Maryland; the upper Midwest, in Wisconsin and Minnesota; and the West, in coastal California and Oregon. 14.59 The illness, however, has been reported to occur in 43 states, as well as throughout Europe, Asia, and in Australia.59'60 The earliest known cases in the United States occurred on Cape Cod in 1962 and in Lyme, Connecticut, in 1965'4; reported cases in the US now exceed 13,000.60 Lyme disease can occur at any age and in either sex."5 The onset of illness is generally between May 1 and November 30; the peak is in June and July.6 The primary vectors of Lyme disease are tiny hard ticks of the Ixodes ricinus complex. Major foci of disease correspond to the distribution of I dammini (Northeast and Midwest),14'59 Ixodes pacificus (West),'4'59 I ricinus (Europe and western USSR),59'6' and Ixodes persulcatus (Japan, China, and Asian parts of USSR).6"62 Lyme disease, however, occurs in Australia despite the absence of ixodid ticks.63 Other vectors, including the Lone Star tick, Amblyomma americanum, are likely in some areas of the United States.64'65 Biting insects have been proposed as possible secondary vectors, but evidence to support transmission of disease by them is lacking.66 The rising incidence of Lyme disease in recent years in the United States may be explained by multiple factors, including an increase in the number of ixodid ticks, the outward migration of residential areas into previously rural woodlands (habitats favored by ixodid ticks and their hosts), an exploding deer population, and increased recognition. Study of the two-year life cycle of I dammini, the eastern deer tick, helps explain the ecology of B burgdorferi and the epidemiology of Lyme disease (Figure 1).6 68 Adult female ticks, having gorged on a blood meal the preceding fall or winter (generally on deer, their preferred host), deposit as many as several thousand fertilized eggs in early spring. Larvae emerge six to eight weeks later and feed once for two days in mid- to late summer on a variety of small mammals or passerine birds, but preferentially on the white-footed mouse. After molting to nymphs the next spring, they ingest a second blood meal for three or more days in late spring or early summer. Unlike many ticks, nymphal Idammini are not at all fastidious in selecting a host; in addition to the preferred white-footed mouse, they are known to feed on a broad range of small mammals and birds.69 After feeding, nymphs molt to adults later in the same season. Both adult males and females attach primarily to deer, but males probably do not feed; mating occurs while the females feed. Deer occupy a pivotal position in the ecology of Lyme disease because of the narrow host range of adult ixodid ticks; in one study on Great Island, Massachusetts, the number of I dammini ticks was reduced through the virtual elimination of deer.70 Fertilized eggs are laid again the following spring and the cycle begins anew.-'`67-7 In one study in the United States, 31% of 314 patients with early Lyme disease recalled a tick bite at the skin site where ECM developed days to weeks later.6 The six ticks that were saved and examined were all identified as nymphal Idammini, whose peak questing period occurs from

708

LYME DISEASE

LYME

DISEASE

Eggs lad

Uarva develop 's in

done month

L4rva

feneck

Year I-Spuing Adults

mate

Fal and Wmiier

Sumner

arefa

ormant

Nynph

May through July. Subsequent epidemiologic studies have established nymphal ixodid ticks to be the stage primarily responsible for transmission of the causative spirochete.67 In areas endemic for Lyme disease, the incidence of B burgdorferi in nymphal I dammini ranges from about 20% to more than 60%, but the infection rate in larvae is much lower24'25 65 (compare I pacificus: nymphs 0.9% to 2%72). Field studies have shown that ticks acquire spirochetes by feeding on a previously infected reservoir host, most commonly the white-footed mouse, which is almost universally infected with B burgdorferi in summer months.73 Vertical transmission of the causative organism is rare both in ticks and in mice.74 The establishment of an endemic focus therefore requires not only a tick vector in proximity with humans but also a reservoir host capable of becoming infected with B burgdorferi and of transmitting this agent to ticks. The low infection rate in Ipacificus compared with I dammini may be explained by the preference of larvae and nymphs of this TABLE 1.-Early Symptoms and Signs of Lyme Disease' 4lb

Symptoms

Malaise, fatigue, and lethargy Headache

.............

.............

80 64

Fever and chills ........... 59

Stiff neck

48

............. Arthralgias Myalgias

48

Backache

26

.............

.............

.............

43

Anorexia .............

23

Sore throat .............

17

Nausea

17

............. Dysesthesia ............. Abdominal .......... .............

Vomiting

pain

Photophobia

.............

Hand stiffness

............

11

10 8 6 5

Dizziness

............. Cough .............

Chest pain

Ear pain Diarrhea

.............

............. .............

5 4

Figure 1.-The life cycle of Ixodes dammini spans 2 years. In the spring of the first year (top), eggs hatch and larvae emerge. In the summer, the larvae feed once. They acquire Borrelia burgdorferi, the spirochete that causes Lyme disease, from their preferred host, the white-footed mouse. The next spring (bottom), the larvae molt into nymphs, which feed once again. Again, mice are the preferred host; humans, to whom the ticks transmit Lyme disease, are not necessary for maintenance of the tick's life cycle. The nymphs molt into adults that mate while the female is feeding on a deer; eggs are laid the next spring and the cycle is repeated (from Rahn and Malawista68).

species for lizards rather than small rodents.75 Lizards are not competent reservoirs for B burgdorferi and cannot transmit spirochetes to ticks that parasitize them. Borrelia burgdorferi has been isolated, or specific antibody found, in blood or tissue specimens of a wide variety of large and small animals, including domestic dogs (which can develop arthritis) and birds.76-80 Whether birds can function as reservoir hosts is currently disputed,69 8' but they clearly may favor the spread of infection through the transport of infected ticks to new locales. Clinical Characteristics Lyme disease has been divided by convention into three clinical stages with considerable overlap (Table 1), but most patients do not exhibit all of them and, in fact, seroconversion can occur in asymptomatic persons.8283 The illness usually begins with ECM and associated symptoms (stage 1), sometimes followed weeks to months later by neurologic or cardiac abnormalities (stage 2) and weeks to years later by arthritis (stage 3). Chronic neurologic and skin involvement may occur years after disease onset.

4%

Signs

Erythema chronicum migrans............ Multiple annular lesions. Lymphadenopathy Regional .......... Generalized ....... Pain on neck flexion..... Malar rash ............ Erythematous throat..... Conjunctivitis .......... Right upper quadrant tenderness .......... Splenomegaly .......... Hepatomegaly......... Muscle tenderness ...... Periorbital edema....... Evanescent skin lesions . . Abdominal tenderness Testicular swelling ...... .

...

10OOt 48

41 20 17 13 12 11

8 6 5

4

3 3 2 1

4 2

'These figures were derived from the study of 314 patients reported in Steere and Bartenhagen.6 tErythema chronicum migrans was required for inclusion in this study.

Early Manifestations Erythema chronicum migrans, the unique clinical marker for Lyme disease, begins as an erythematous macule or papule at the site where the tick vector had gorged.26 The interval between tick bite and onset of ECM varies from 3 to 32 days.6 The area of redness gradually expands to an average diameter of about 15 cm (range 3 to 68 cm). The outer borders are generally flat and without scale. There is usually partial central clearing, but centers may be red and indurated, vesicular, or even necrotic. Variations occur-many smaller rings within a single larger lesion, for example. The thigh, groin, and axilla are common sites. The lesion is warm to touch but not often sore or pruritic and easily missed if out of sight. Routine histologic findings are not specifically diagnostic and are compatible with an arthropod bite: a heavy dermal infiltrate of mononuclear cells, without epidermal change except at the site of the tick bite itself. A few days after the onset of ECM, about half of the

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patients in the United States have the development of multiple secondary lesions resulting from hematogenous spread of infection from a primary lesion. Secondary lesions resemble ECM itself but are generally smaller, migrate less, and lack indurated centers. Individual lesions may come and go, and their borders sometimes merge. (Benign lymphocytoma cutis, an erythematous papule at the site of a tick bite, usually on the nipple or ear lobe, has been reported as an early manifestation ofinfection in Europe.29) Erythema chronicum migrans and secondary lesions fade in three to four weeks (range, 1 day to 14 months) but may recur. Skin involvement is often accompanied by flulike symptoms: malaise and fatigue, headache, stiff neck, fever and chills, myalgia, and arthralgia.2 6 Some patients have evidence suggesting meningeal irritation with episodes of excruciating headache, neck pain, and stiffness typically varying over hours at this stage of the illness. Spinal fluid examination, which may reveal lymphocytic pleocytosis later in the illness, is typically normal during ECM, and objective neurologic deficits are lacking.3 Except for fatigue and lethargy, which are often constant, the signs and symptoms of early Lyme disease are typified by their intermittent and changing nature. For example, a patient may have meningitic attacks for several days, and then a few days of improvement, followed by the onset of migratory musculoskeletal pain. The pain may involve muscles and periarticular sites (tendons, bursae, and ligamentous attachments) as well as joints. Joint swelling is uncommon within the first few weeks of illness. The pain tends to affect only one or two sites at a time and to last a few hours to several days in a given location. The various systemic symptoms of early Lyme disease may precede ECM (or occur without it) and last for days to months (especially fatigue and lethargy) after the skin lesions have disappeared. In Europe, untreated ECM more commonly has a prolonged course and less commonly is associated with multiple annular lesions or prominent systemic symptoms. Similarly, laboratory abnormalities and subsequent arthritis are less common in Europe than in the United States.84 Later Manifestations Neurologic involvement. Within several weeks to months of disease onset (usually after ECM and associated symptoms have resolved), about 15% of patients in the United States will have neurologic abnormalities develop, including meningitis, encephalitis, chorea, cranial neuritis (including bilateral facial palsy), motor and sensory radiculoneuritis, mononeuritis multiplex, or diffuse peripheral sensorimotor neuropathy in various combinations.38586 A common pattern of neurologic involvement, occurring within the first few months of illness, is fluctuating meningoencephalitis, often with superimposed cranial nerve (particularly facial) palsy or peripheral radiculoneuropathy, but Bell's palsy may occur alone. After the first few weeks of illness, patients with meningitic symptoms have lymphocytic pleocytosis (averaging 0.001 x 106 per liter [100 cells per Al] in cerebrospinal fluid). Borrelia burgdorferi has been cultured from cerebrospinal fluid during meningitis.25 Lyme meningitis is often accompanied by irritability, photophobia, and impaired concentration indicative of mild encephalitis, which may be reflected in diffuse slowing on electroencephalography. Although patients complain of neck stiffness, Kernig and Brudzinski signs are typically absent, as is the case with

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other nonpurulent meningitides. Neurologic abnormalities last for months but usually resolve completely even without antibiotic therapy; they may recur (late neurologic complications are noted later in the article). Cardiac involvement. During the same stage of illness in which acute neurologic abnormalities occur, carditis develops in about 8% of patients in the United States, most often characterized by fluctuating atrioventricular (AV) block, which may vary rapidly from first-degree to Mobitz type 1 second-degree AV block (Wenckebach) or even complete heart block.5 Less commonly, patients have evidence of more diffuse myopericarditis with electrocardiographic changes (ST-T wave changes and/or ventricular or supraventricular arrhythmias) and radionuclide evidence of left ventricular dysfunction or, rarely, frank cardiomegaly. Patients with Lyme carditis may seek medical attention because of unexplained syncope or presyncope or occasional complaints only of palpitations. Cardiac complaints may be the presenting manifestations of Lyme disease. Gallium scan-positive myocarditis8" and, in one fatal case, spirochete-positive pancarditis47 have been reported. One patient described recently had convincing evidence of diffuse myocarditis proved by culture of a specimen of myocardium obtained by transvenous endomyocardial biopsy. This was associated with longstanding congestive cardiomyopathy that did not reverse with antibiotic therapy.39 No patients have had significant valvular involvement (compare acute rheumatic fever).' Cardiac involvement is usually brief, ranging from a few days to six weeks, and resolves in most patients even without specific antibiotic therapy. Arthritis. Lyme arthritis, although the first recognized clinical manifestation of this illness, actually occurs relatively late in the course of the disease. Symptoms varying from migratory musculoskeletal pain to overt inflammatory arthritis develop from a few weeks to as long as two years after the onset of illness. About 60% of patients with Lyme disease eventually have frank arthritis2'4'1' characterized by intermittent, asymmetric oligoarticular swelling and pain affecting primarily large joints, especially the knee. Both large and small joints may be affected, however, and a few patients have had symmetric polyarthritis. A typical attack of Lyme arthritis begins with sudden swelling of the affected joint (usually one), often out of proportion to pain. When the knee is involved, as in 80% of cases, the swelling, because it often occurs in active young adults or children, is commonly initially attributed to trauma. Knee effusions may have volumes of 100 ml or more and lead to the formation of popliteal cysts (Baker's cysts) that may rupture. An attack of arthritis may last from a few days to months. Recurrences are frequent in the first year after onset; they decrease with time but may recur for years. Overall, attacks cease in 10% to 20% of patients per year.88 Fatigue commonly accompanies active joint involvement, but fever or other systemic symptoms are unusual at this stage. Joint fluid leukocyte counts have varied from 0.5 to 110 x 106 per liter (500 to 110,000 cells per 1l), with an average of about 25 (25,000) cells, mostly polymorphonuclear leukocytes.2 Total protein levels have ranged from 30 to 80 grams per liter (3 to 8 grams per dl) but are generally normal to mildly elevated. Joint fluid complement and glucose levels are usually normal. During Lyme arthritis, immune complexes are often concentrated in joint fluid and not increased in peripheral blood.79

710

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6._ 0

-o6C.

-0

1I 8

0

16

24

Weeks Time After Onset of Symptoms

In about 10% of patients with arthritis, large-joint involvement may become chronic, with pannus formation. Erosions of cartilage and bone and permanent joint disability have occurred in a minority of these patients. " Synovial histologic features have mimicked those of rheumatoid arthritis: surface deposits of fibrin, villous hypertrophy, vascular proliferation, and a heavy infiltration of mononuclear cells (T and B cells intermixed).2,4"' Rarely, there may be obliterative endarteritis with spirochetes in perivascular areas demonstrable by monoclonal antibody or silver staining.43'89 Synovial biopsies have been performed primarily in those patients with more severe joint involvement so the pathology of the early lesion is less well characterized. Borrelia burgdorferi potently stimulates mononuclear cells to produce interleukin-1. Levels of this lymphokine have been elevated in synovial fluids.90 Synovium removed from one patient with chronic Lyme arthritis, when grown in tissue culture, produced large amounts of collagenase and prostaglandin E2. Thus, in chronic Lyme arthritis, the joint fluid cell counts, immune reactants (except for rheumatoid factor), synovial histology, amounts of synovial enzymes released, and resulting destruction of cartilage and bone may be similar to those in rheumatoid arthritis. Radiographic findings in Lyme arthritis have varied according to the clinical picture.9" Patients with intermittent arthritis have most often had only joint effusions, occasionally accompanied by periarticular soft tissue edema and enthesopathic changes, including even ossification of insertion sites of tendons and ligaments. Later changes in patients with chronic arthritis have included juxta-articular osteoporosis, cartilage loss, and marginal erosions. Fewer patients have had postinflammatory degenerative changes such as cartilage loss, subarticular sclerosis, and osteophyte formation. "

Late Manifestations Other late findings (years) associated with this infection include the chronic skin lesion, acrodermatitis chronica atrophicans,29'30 well known in Europe but still rare in the United States. This is an infiltrated plaque or nodule, especially on an extensor surface, that may eventually become atrophic; the active lesions contain spirochetes.30 There may be underlying joint changes affecting the same extremity as ACA. Uncommon late chronic neurologic manifestations include a variety of lesions of the central and peripheral nervous system. Demyelinating encephalopathy with multiple white matter lesions seen on magnetic resonance imaging scan and a multiple sclerosis-like clinical picture have occurred rarely. The documentation for this disorder has in-

________ ________ 2 3 Years

Figure 2.-The typical antibody response is shown in persons with untreated Lyme disease. Specific IgM antibodies usually become detectable 2 to 4 weeks after onset of disease. The subsequent appearance of specific IgG antibodies is frequently concurrent with systemic manifestations. IgM antibody levels typically decline over 4 to 6 months, even in untreated patients; a persistence of high IgM antibody levels is predictive of later manifestations of disease. IgG antibodies are almost always elevated during late disease (from Rahn and Malawista68).

cluded its occurrence in persons with a history of previous early Lyme disease, immunoreactivity against B burgdorferi in both serum and cerebrospinal fluid, and resolution following antibiotic therapy. It should be emphasized, however, that serologic and cerebrospinal fluid screening of patients from multiple sclerosis clinics in areas endemic for Lyme disease have not revealed any relationship, in general, between B burgdorferi infection and demyelinating disease.92 The same may be said about B burgdorferi infection and amyotrophic lateral sclerosis.93 A diffuse sensory neuropathy has also been described as a chronic manifestation of Lyme disease.86 This lesion is described electrophysiologically as a mild axonal polyneuropathy. Symptoms have been limited to peripheral paresthesias; the evidence favoring a relationship of this lesion to B burgdorferi infection has consisted of both serologic data and response to antibiotic therapy. Transverse myelitis has also been reported to occur.9495 Mild memory impairment, subtle mood changes, and chronic fatigue states are under investigation as chronic neurologic syndromes.95 "Progressive Borrelia encephalomyelitis"96 is currently recognized more frequently in Europe than in the United States.

Laboratory Diagnosis The diagnosis of Lyme disease is based on the recognition of clinical features of the illness in a patient with a history of possible exposure to the causative organism. Culture of B burgdorferi from patients is definitive but has rarely been successful except from skin biopsy specimens.25'30'37 Recently the organism was isolated from blood in a significant minority of patients with systemic manifestations of early disease.38 Special tissue-staining techniques41-43.45 generally have a low yield and are not readily available. Determination of specific antibody titers is currently the most helpful diagnostic test for Lyme disease. IgM antibodies against B burgdorferi usually appear two to four weeks after disease onset and reach a peak between the third and sixth week; specific IgG antibody titers rise more slowly and are generally highest months later when arthritis is present (Figure 2).2597 Persons with Lyme disease of more than six weeks' duration can be expected to have detectable specific antibodies. The tests used, however, are not yet standardized, and results from different commercial laboratories may vary.98 Although either immunofluorescence assays or enzyme-linked immunosorbent assays (ELISA) are offered, the ELISA technique offers the advantages of being more reproducibile, less subjective, and automatable. Such assays, however, cannot distinguish patients with active infection from those with previous immunologic exposure but without current infection. In our experience, the vast majority of

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with Lyme arthritis have a positive serologic reand this finding makes antibody titers against B burgdorferi particularly useful in differentiating Lyme disease from other rheumatic syndromes, especially when ECM has been missed, forgotten, or absent. Antibodies against B burgdorferi can cross-react with other spirochetes, including Treponema pallidum, but patients with Lyme disease do not have positive VDRL tests.69' False-positive results can also occur in patients with high-titer rheumatoid factors and during infectious mononucleosis. Currently Lyme serologic studies are frequently obtained in circumstances in which the risk of Lyme disease by clinical and epidemiologic criteria is slight. In this setting, when the pretest likelihood of disease being present is slight, a significant percentage of positive results will be falsely positive regardless of the specificity of the test. It is extremely important, therefore, to consider the clinical context when interpreting the result of a Lyme serologic study. Positive T-cell blastogenic responses to B burgdorferi can suggest that the host has encountered the Lyme spirochete sometime in the past,99 but their specificity is currently in question,10I and patients with active disease usually have positive antibody titers.99 Other tests under development seek to identify spirochetal material in host fluids or tissues. They include a test for spirochetal protein in urine10l and the use of the polymerase chain reaction to detect spirochetal DNA in host material'02; neither has been perfected for clinical use as of this writing. Several commonly performed laboratory tests may be abnormal early in the illness. The erythrocyte sedimentation rate is often modestly increased. The level of serum aspartate aminotransferase (AST or SGOT) is often mildly elevated during ECM, particularly in patients with prominent systemic symptoms. The level of this enzyme generally returns to normal within several weeks of disease onset. Total serum IgM levels are also often increased early in disease; a persistent increase of IgM, which correlates with specific IgM antibody levels, is a predictor of an increased risk of subsequent disease manifestations.2'7 Patients may be mildly anemic early in the illness and occasionally have elevated leukocyte counts with a left shift in the differential. A few patients have had transient microscopic hematuria, sometimes with mild proteinuria (dipstick), but renal function has been normal. Throughout the illness, serum complement levels are generally normal or elevated. Tests for rheumatoid factor and antinuclear antibodies are usually normal. persons sponse,

Differential Diagnosis Erythema chronicum migrans is the unique herald lesion of Lyme disease. When present in its classic form, there is little else that might be confused with it. Many patients, however, are unaware of having had ECM; in others, the lesion may be atypical in appearance. When multiple skin lesions are present, the appearance may suggest erythema multiforme, but blistering, mucosal lesions and involvement of the palms and soles (all features of erythema multiforme) are not features of Lyme disease. Rarely, patients with early Lyme disease have a malar rash suggesting systemic lupus erythematosus. Generalized urticaria has occurred and may suggest the diagnosis of the prodromal phase of hepatitis B infection or serum sickness. Finally, evanescent blotches and circles may resemble erythema marginatum, a cutaneous

711

manifestation of acute rheumatic fever, but evanescent lesions in Lyme disease do not expand. Lyme disease may be difficult to diagnose definitively early if flulike symptoms predominate, especially when ECM is absent or inapparent at the time of presentation. Severe headache and stiff neck may resemble aseptic meningitis, and, indeed, cerebrospinal fluid findings in Lyme meningitis are identical to those of viral meningitis. One helpful feature in this regard may be that the headache of Lyme disease tends to be intermittent. When generalized lymphadenopathy is present, particularly with splenomegaly, various diseases are suggested, including infectious mononucleosis and lymphoproliferative disorders. In later stages, Lyme disease may mimic other systemic inflammatory disorders. Like rheumatic fever, Lyme disease may be associated with sore throat (rarely a prominent feature) followed by migratory polyarthritis and carditis, but without evidence of valvular involvement or of a preceding streptococcal infection. With isolated joint involvement, the clinical picture can be indistinguishable from reactive arthritis. Isolated peripheral seventh cranial neuropathy may mimic idiopathic Bell's palsy, but Lyme disease is one of the few causes (along with Guillain-Barre syndrome and sarcoidosis) of bilateral Bell's palsy. Late neurologic involvement may suggest multiple sclerosis (transverse myelitis), Guillain-Barr6 syndrome (symmetric peripheral neuropathy), or brain tumor. In children, the attacks of arthritis, although generally shorter, may be identical to those seen in the oligoarticular form of juvenile rheumatoid arthritis, but without iridocyclitis. Treatment The major goal of therapy in Lyme disease is to eradicate the causative organism. Like other spirochetal diseases, Lyme disease is most responsive to antibiotics early in its course. Treatment regimens have evolved over time, based on both controlled clinical data and on clinical experience. Because of the difficulty in proving that bacteria have been eradicated and the common persistence of some symptoms long after treatment, the end point of antibiotic therapy is not always clear. The treatment regimens presented here represent guidelines that will no doubt be refined in time (Table 2).

Early Lyme Disease If patients are treated early with oral antibiotics, ECM typically resolves promptly, and major later sequelae (myocarditis, meningoencephalitis, or recurrent arthritis) usually do not occur.17 Prompt treatment is therefore important, even though such patients may be susceptible to reinfection.103 For adults, antibiotic choices in order of preference include oral doxycycline, 100 mg twice a day; amoxicillin, 250 to 500 mg three times a day; or erythromycin, 250 mg four times a day; each for 10 to 20 days depending on the rapidity of clinical response. Failures are more common with erythromycin use than with the other two agents. In children younger than 9 years, amoxicillin, 30 mg per kg per day (not less than 1 gram or more than 2 grams per day), is given in divided doses for the same period or, in cases of penicillin allergy, erythromycin, 30 mg per kg per day, in divided doses for 10 to 20 days. About 10% of patients with early Lyme disease experience a Jarisch-Herxheimer-like reaction (higher tempera-

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LYME DISEASE

LYME

TABLE 2.-Antibiotic Regimens for Various Manifestations of Lyme Disease' Length of

Lyme Disease

Drug

Early disease ..... Doxycycline Amoxicillin Erythromycin Neurologic manifestations Facial palsy alone

........

Doxycycline

Amoxicillin Erythromycin Other (such as meningitis) ...... Penicillin G Ceftriaxone Lyme carditis Mild

Course,

........

Daily Dosage

10-21 10-21 10-21

100 mg 2x/d 500 mg 3x/d 250 mg 4x/d

10-21 10-21 10-21

20 million units IV 2 grams IV

14-21 14-21

2x/d

Doxycycline

100

Penicillin G Ceftriaxone Doxycycline Amoxicillin and probenecid Penicillin G Ceftriaxone

20 million units IV 2 grams IV 100 mg 2x/d 500 mg of each 4x/d

14-21 14-21 30 30

20 million units IV 2 grams IV

14 14

mg

Moderate to severe

........

Lyme arthritis

IV= intravenous

....

days

100 mg 2x/d 500 mg 3x/d 250 mg 4x/d

30

'Current antibiotic regimens are based on both controlled clinical studies and clinical and will no doubt be refined in time. Antibiotic failures occur at all stages of disease, but, in general, the illness is most responsive to antibiotic therapy early in its course.

experience

ture, redder rash, or greater pain) during the first 24 hours of antibiotic therapy.'7 Whichever drug is given, 30% to 50% of patients have brief (hours to days) recurrent episodes of head-

ache, musculoskeletal pain, and fatigue that may continue for extended periods.17 The cause of these symptoms is unclear; they may result from undegraded spirochetal antigen(s) rather than persistence of live spirochetes. It is clear, however, that the risk of delayed resolution is greatest in persons with disseminated manifestations of disease (multiple skin lesions, headache, fever, lymphadenopathy, or Bell's palsy) before the institution of antibiotic therapy.17 Later Lyme

Disease For Lyme meningitis, with or without other neurologic manifestations (cranial neuropathy or radiculoneuropathy), intravenous penicillin G, 20 million units a day in six divided doses for ten days, is effective therapy. 18 Headache and stiff neck usually begin to subside by the second day of therapy and disappear by seven to ten days; motor deficits and radicular pain frequently require seven to eight weeks for complete recovery but do not require longer antibiotic courses. For Bell's palsy alone, oral regimens may suffice, but these patients may be at higher risk of later sequelae than are persons with early disease without neurologic dissemination. Although not studied systematically, carditis also responds rapidly (in days) to this regimen. The use of prednisone, 40 to 60 mg a day in divided doses, has, in the past, seemed to hasten resolution of high-grade heart block, but one should hesitate to institute glucocorticoid therapy during antibiotic administration as it may impede the eradication of infecting organisms.5 For patients with allergy to penicillin, doxycycline, 100 mg twice a day, is reasonable but unevaluated. If second- or third-degree heart block is present, patients should be admitted to hospital for cardiac monitoring; temporary pacing is occasionally required for complete heart block.

DISEASE

In clinical practice, ceftriaxone (2 grams a day for 14 to 21 days) has largely replaced penicillin for the treatment of disseminated Lyme disease. Arguments in favor of this practice are a once-a-day administration schedule that is amenable to outpatient intravenous antibiotic programs and improved penetration of the cerebrospinal fluid in comparison with penieillin.t04.105 Penicillin and cefotaxime have been found equally effective for the treatment of acute neurologic Lyme disease (meningitis or radiculitus) in a group of patients studied in Germany. 106

Late Lyme Disease Lyme arthritis has been successfully treated with both oral and parenteral antibiotics, but failures occur with any regimen chosen. Unless central nervous system involvement coexists, first-line treatment with a month-long course of doxycycline, 100 mg two times a day, or amoxicillin plus probenecid, 500 mg each four times a day, is recommended. Either of these regimens has a 70% cure rate, although complete response can be delayed as long as three months or more following completion of therapy.106 During treatment, the affected joint should be kept at rest and effusions drained by needle aspiration as for any infected joint. In a double-blind placebo-controlled trial, 7 of 20 patients given intramuscular benzathine penicillin, 2.4 million units a week for three weeks, were cured (mean follow-up 33 months) versus none of 20 control patients.19 This regimen provides low serum levels of penicillin for about six weeks. High-dose intravenous penicillin G (above), which yields much higher serum levels over its ten-day course, cured 11 of20 patients, including 2 in whom benzathine penicillin therapy had failed. 19 In one comparative trial, ceftriaxone (2 grams a day for 14 days) outperformed intravenous penicillin, but failures have occurred with both agents.t051 07 In patients in whom one course or more of antibiotics fail, arthroscopic synovectomy can result in a long-term response and perhaps cure. Optimal therapy for the later neurologic complications of Lyme disease is also not yet clear. The frequency of subtle chronic encephalopathy and peripheral neuropathy is debated at present. These disorders, when suspected, should be carefully documented through neurologic, neuropsychological, and electrophysiologic testing before aggressive or prolonged antibiotic therapy is instituted. Although some current thinking favors longer periods of the highest tolerated oral doses of amoxicillin (with probenecid), doxycycline, or even intravenous antibiotics in difficult cases, there is no controlled experience with courses of antibiotics longer than one month for any manifestation of Lyme disease. The infiltrative lesions of ACA are usually cured by three weeks of oral phenoxymethyl penicillin, 2 to 3 grams a day in divided doses. 108

Pregnancy Because the spirochetes that cause relapsing fever and syphilis can cross the placenta, there has been concern regarding this possibility in Lyme disease. Maternal-fetal transmission of B burgdorferi resulting in either neonatal death or stillbirth has been reported in rare instances in which symptomatic early Lyme disease occurred early in pregnancy and was either untreated or inadequately treated.50-51 In follow-up studies conducted by the Centers for Disease Control, maternal Lyme disease was not directly implicated as a cause of fetal malformations.109 There have been no cases of

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o

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fetal infection occurring when currently recommended antibiotic regimens for Lyme disease have been used during pregnancy. A lower threshold for initiating therapy for suspected Lyme disease in pregnancy is understandable, but women acquiring the illness during pregnancy should be reassured that the vast majority of infants born to women in these circumstances have been entirely well.

Tick Bites

regards the advisability of adminantibiotics prophylactically to persons sustaining ixodid tick bites in endemic areas. The single study completed to date has not supported this common practice."10 Because nymphal ixodid ticks must, in general, feed for a day or more before transmitting spirochetes (at least in mice"I1), ticks removed before this time are unlikely to have transmitted B burgdorferi even if infected. Tick-bite sites should be observed for the development of ECM and patients cautioned regarding the common associated symptoms of early Lyme A final treatment issue

istering

disease. REFERENCES

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Yale J Biol Med 1984; 57:463-471 30. Asbrink E, Hovmark A: Successful cultivation of spirochetes from skin lesions of patients with erythema chronicum migrans Afzelius and acrodermatitis chronica atrophicans. Acta Pathol Microbiol Immunol Scand [B1 1985; 93:161-163 31. Coleman JL, Benach JL: Identification and characterization of an endoflagellar antigen of Borrelia burgdorferi. J Clin Invest 1989; 84:322-330 32. Barbour AG, Tessier SL, Todd WJ: Lyme disease spirochetes and ixodid tick spirochetes share a common surface antigenic determinant defined by a monoclonal antibody. Infect Immun 1983: 41:795-804 33. Barbour AG. Tessier SL, Hayes SF: Variation in a major surface protein of Lyme discase spirochetes. Infect Immun 1984: 45:94-100 34. Schwan TG, Burgdorfer W, Garon C: Changes in infectivity and plasmid profile of the Lyme disease spirochete, Borrelia burgdorferi, as a result of in vitro cultivation. Infect Immun 1988; 56:1831-1836 35. Barbour AG, Heiland RA, Howe TR: Heterogeneity of major proteins in Lyme disease Borrelia: A molecular analysis of North American and European isolates. J Infect Dis 1985; 152:478-484 36. Craft JE, Fischer DK, Shimamoto GT, Steere AC: Antigens of Borrelia burgdorferi recognized during Lyme disease: Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest 1986; 78:934-939 37. Berger BW, Kaplan MH, Rothenberg IR, Barbour AG: Isolation and characterization of the Lyme disease spirochete from the skin of patients with erythema chronicum migrans. I Am Acad Dermatol 1985; 3:444-449 38. Nadelman RB, Pavia CS, Magnarelli LA, Worsmer GP: Isolation of Borrelia burgdorferi from the blood of seven patients with Lyme disease. Am J Med 1990; 88:21 39. Stanek G, Klein J, Bittner R, Glogar D: Isolation of Borrelia burgdorferi from the myocardium of a patient with long-standing cardiomyopathy. N Engl J Med 1990; 322:249-252 40. Snydman DR, Schenkein DP, Berardi VP, et al: Borrelia burgdorferi in joint fluid in chronic Lyme arthritis. Ann Intern Med 1986; 104:798-800 41. Berger BW, Clemmensen OJ, Ackerman AB: Lyme disease is a spirochetosis: A review of the disease and evidence for its cause. Am J Dermatopathol 1983; 5: 111-124 42. Berger BW: Erythema chronicum migrans of Lyme disease. Arch Dermatol 1984; 120:1017-1021 43. Johnston YE, Duray PH, Steere AC, et al: Lyme arthritis: Spirochetes found in synovial microangiopathic lesions. Am J Pathol 1985; 118:26-34 44. MacDonald AB: Borrelia in the brains of patients dying with dementia (letter). JAMA 1986; 256:2195-2196 45. Pachner AR, Duray P, Steere AC: Central nervous system manifestations of Lyme disease. Arch Neurol 1989; 46:790-795 46. Steere AC, Duray PH, Kauffman DJ, Wormser GP: Unilateral blindness caused by infection with the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985; 103:382-384 47. Marcus LC, Steere AC, Duray PH, Anderson AE, Mahoney EB: Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis-Demonstration of spirochetes in the myocardium. Ann Intern Med 1985; 103:374-376 48. Atlas E, Novak SN, Duray PH, Steere AC: Lyme myositis: Muscle invasion by Borrelia burgdorferi. Ann Intern Med 1988; 109:245-246 49. Goellner MH, Agger WA, Burger JJ, Duray PH: Hepatitis due to recurrent Lyme disease. Ann Intern Med 1988; 108:707-708 50. Schlesinger PA, Duray PH, Burke BA, Steere AC: Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985; 103: 67-68 51. WeberK, Bratzke HJ, Neubert U, Wilske B, Duray PH: Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 1988; 7:286-289 52. Sigal L, Steere AC, Freeman DH, DwyerJM: Proliferative responses of mononuclear cells in Lyme disease. Arthritis Rheum 1986; 29:761-769 53. Pachner AR, Steere AC, Sigal LH, Johnson CJ: Antigen-specific proliferation of CSF lymphocytes in Lyme disease. Neurology 1985; 35:1642-1644 54. Hardin JA, Steere AC, Malawista SE: The pathogenesis of arthritis in Lyme disease: Humoral immune responses and the role of intra-articular immune complexes. Yale J Biol Med 1984; 57:589-593 55. Habicht GS, Beck G, Benach JL: The role of interleukin- I in the pathogenesis of Lyme disease. Ann NY Acad Sci 1988; 539:80-86 56. Steere AC, Feld J, Winchester R: Association of chronic Lyme arthritis with increased frequencies of DR4 and 3 (Abstr). Clin Res 1988; 36:600A 57. Dwyer E, Steere AC, Winchester R: Distinctive molecular basis of susceptibility to chronic Lyme arthritis (Abstr). Clin Ret 1990; 38:409a 58. Kristoferistch W, Mayr WR, Partsch H, Neuman R, Stanek G: HLA-DR in Lyme borreliosis (Letter). Lancet 1986; 2:278

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59. Schmid GP: The global distribution of Lyme disease. Rev Infect Dis 1985; 7:41-50 60. Tsai TF, Bailey RE, Moore PS: National surveillance of Lyme disease, 19871988. Conn Med 1989; 53:324-327 61. Dekonenko EJ, Steere AC, Berardi VP, Kravchuk LN: Lyme borreliosis in the Soviet Union: A cooperative US-USSR report. J Infect Dis 1988; 158:748-753 62. Burgdorfer W: Vector/host relationships of the Lyme disease spirochete, Borrelia burgdorferi. Rheum Dis Clin North Am 1989; 15:775-787 63. Fraser JRE: Lyme disease challenges Australian clinicians-The implications of Australia's first reported case of Lyme arthritis. Med J Aust 1982; 1:101-102 64. Schulze TL, Bowen GS, Bosler EM, et al: Amblyomma americanum: A potential vector of Lyme disease in New Jersey. Science 1984; 224:601-603 65. Magnarelli LA, Anderson JF, Apperson CS, Fish D, Johnson RC, Chappell WA: Spirochetes in ticks and antibodies to Borrelia burgdorferi in white-tailed deer from Connecticut, New York State, and North Carolina. J Wildlife Dis 1986; 22: 178-188 66. Magnarelli LA, Anderson JF, Barbour AG: The etiologic agent of Lyme disease in deer flies, horse flies, and mosquitoes. J Infect Dis 1986; 154:355-358 67. Spielman A, Wilson ML, Levine JF, Piesman J: Ecology of Ixodes damminiborne human babesiosis and Lyme disease. Annu Rev Entomol 1985; 30:439-460 68. Rahn DW, Malawista SE: Clinical judgment in Lyme disease. Hosp Pract 1990; 25:39-50 69. Anderson J: Ecology of Lyme disease. Conn Med 1989; 53:343-346 70. Wilson ML, Telford SR, Piesman J, Spielman A: Reduced abundance of immature Ixodes dammini following elimination of deer. J Med Entomol 1988; 25: 224-228 71. Steere AC, Malawista SE, Craft JE, Fischer DK, Garcia-Blanco M (Eds): First International Symposium on Lyme Disease. Yale J Biol Med 1984; 57:445-713 72. Burgdorfer W, Lane RS, Barbour AG, Gresbrink RA, Anderson JR: The western black-legged tick, lxodes pacificus: A vector of Borrelia burgdorferi. Am J Trop Med Hyg 1985; 34:925-930 73. Mather TN, Wilson ML, Moore SI, RibeiroJMC, Spielman A: Comparing the relative potential of rodents as reservoirs of the Lyme disease spirochete. Am J Epidemiol 1989; 130:143-150 74. Piesman J, Donahue JG, Mather TN, et al: Transovarially-acquired Lyme disease spirochetes in field-collected larval ixo(les daimmini. J Med Entomol 1986; 23:2 19 75. Lane RS, Loye JE: Lyme disease in California: Interrelationship of Ixodes pacificus (Acari: Ixodidae), the western fence lizard (Sceloporus occidentalis), and Borrelia burgdorferi. J Med Entomol 1989; 26:272-278 76. Bosler EM, Coleman JL, Benach JL, et al: Natural distribution of the Ixodes dammini spirochetes. Science 1983; 220:321-322 77. Magnarelli LA, Anderson JF, Burgdorfer W, Chappell WA: Parasitism by Ixodes daminini (Acari: Ixodidae) and antibodies to spirochetes in mammals at Lyme disease foci of Connecticut, USA. J Med Entomol 1984; 21:52-57 78. Anderson JF, Johnson RC, Magnarelli LA, Hyde FW: Identification of endemic foci of Lyme disease. Isolation of Borrelia burgdorferi from feral rodents and ticks (Dermacentor variabilis). J Clin Microbiol 1985; 22:36-38 79. Kornblatt AN, Urband PH, Steere AC: Arthritis caused by Borrelia burgdorferi in dogs. J Am Vet Med Assoc 1985; 186:960-964 80. Anderson JF, Johnson RC, Magnarelli LA, Hyde FW: Involvement of birds in the epidemiology of the Lyme disease agent Borrelia burgdorferi. Infect Immun 1986; 51:394-396 81. Mather TN, Telford SR, MacLachlan AB, Spielman A: Incompetence of catbirds as reservoirs for the Lyme disease spirochete (Borrelia burgdorferi). J Parasitol 1989; 75:66-69 82. Hanrahan JP, Benach JL, Coleman JL, et al: Incidence and cumulative frequency of endemic Lyme disease in a community. J Infect Dis 1984: 150:489-496 83. Steere AC, Taylor E, Wilson MW, Levine JF, Spielman A: Longitudinal assessment of the clinical and epidemiological features of Lyme disease in a defined population. J Infect Dis 1986; 154:295-300 84. Asbrink E, Olsson I: Clinical manifestations of erythema chronicum migrans Afzelius in 161 patients-A comparison with Lyme disease. Acta Derm Venereol (Stockh) 1985; 65:43-52

LYME DISEASE 85. Pachner AR, Steere AC: The triad of neurologic manifestations of Lyme disease: Meningitis, cranial neuritis, and radiculoneuritis. Neurology 1985; 35:47-53 86. Halperin JJ, Little BW, Coyle PK, Dattwyler RJ: Lyme disease: Cause of a treatable peripheral neuropathy. Neurology 1987; 37:1700-1706 87. Alpert LI, Welch P, Fisher N: Gallium-positive Lyme disease myocarditis. Clin Nucl Med 1985; 10:617 88. Steere AC, Schoen RT, Taylor E: The clinical evolution of Lyme arthritis. Ann Intern Med 1987; 107:725-731 89. Steere AC, Duray PH, Butcher EC: Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Arthritis Rheum 1988; 31:487 90. Habicht GS, Beck G, Benach JL, Coleman JL, Leichtling KD: Spirochetes induce human and murine interleukin- 1 production. J Immunol 1985; 134:3147-3154 91. Lawson J, Steere AC: Lyme arthritis: Radiologic findings. Radiology 1985; 154:37-43 92. Halperin JJ, Luft BJ, Anand AK, et al: Lyme neuroborreliosis: Central nervous system manifestations. Neurology 1989; 39:753-759 93. Mandell H, Steere AC, Reinhardt BN, et al: Lack of antibodies to Borrelia burgdorferi in patients with amyotrophic lateral sclerosis. N Engl J Med 1989; 320:255-256 94. Reik L Jr, Smith L, Khan A, Nelson W: Demyelinating encephalopathy in Lyme disease. Neurology 1985; 35:267-269 95. Pachner AR: Spirochetal diseases of the CNS. Neurol Clin 1986; 4:207-222 96. Ackermann R, Gollmer E, Rehse-Kupper B: Progressive Borrelien-Enzephalomyelitis. Chronische Manifestation der Erythema-chronicum-migrans-Krankheit am Nervensystem. Dtsch Med Wochenschr 1985; 26:1039-1042 97. Craft JE, Grodzicki RL, Steere AC: The antibody response in Lyme disease: Evaluation of diagnostic tests. J Infect Dis 1984; 149:789-795 98. Schwartz BS, Goldstein MD, Ribeiro JMC, Schultz TL, Shahied SI: Antibody testing in Lyme disease. JAMA 1989; 262:3431-3434 99. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG: Seronegative Lyme disease-Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med 1988; 319:1441-1446 100. Padula S, Fister RD: Lyme disease synovial fluid cells show a significantly greater response to Borrelia burgdorferi antigens than peripheral blood cells (Abstr). Clin Res 1988; 36:535a 101. Hyde FW, Johnson RC, White TJ, Shelburne CE: Detection of antigens in urine of mice and humans infected with Borrelia burgdorferi, etiologic agent of Lyme disease. J Clin Microbiol 1989; 27:58-61 102. Rosa PA, Schwan TG: A specific and sensitive assay for the Lyme disease spirochete Borrelia burgdorferi using the polymerase chain reaction. J Infect Dis 1989; 160:1018-1029 103. Shrestha M, Grodzicki RL, Steere AC: Diagnosing early Lyme disease. Am J Med 1985; 78:235-240 104. Dattwyler RJ, Halperin JJ, Pass H, Luft B: Ceftriaxone-Effective treatment in refractory Lyme disease. J Infect Dis 1987; 155:1322-1325 105. Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ: Treatment of late Lyme borreliosis-Randomised comparison of ceftriaxone and penicillin. Lancet 1988; 1:1191-1194 106. Pfister HW, Preac-Mursic V, Wilske B, Einhaupl KM: Cefotaxime vs penicillin G for acute neurologic manifestations in Lyme borreliosis. Arch Neurol 1989; 46:1190-1193 107. Liu NY, Dinerman H, Levin RE, et al: Randomized trial of doxycycline versus amoxicillin/probenecid for the treatment of Lyme arthritis: Treatment of nonresponders with iv penicillin or ceftriazone. Arthritis Rheum 1989; 32:S32 108. Asbrink E, Hovmark A, Hederstedt B: Serological studies of erythema chronicum migrans Afzelius and acrodermatitis chronica atrophicans with indirect immunofluorescence and enzyme-linked immunosorbent assays. Acta Derm Venereol

(Stockh) 1985; 65:509-514 109. Markowitz LE, Steere AC, Benach JL, Slade JD, Broome CV: Lyme disease during pregnancy. JAMA 1986; 255:3394-3396 110. Costello CM, Steere AC, Pinkerton RE, Feder HM: A prospective study of tick bites in an endemic area for Lyme disease. J Infect Dis 1989; 159:136-139 111. Piesman J, Mather TN, Sinsky RJ, Spielman A: Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol 1987; 25:557-558

Lyme disease.

706 Conferences and Reviews Lyme Disease DANIEL W. RAHN, MD, and STEPHEN E. MALAWISTA, MD, New Haven, Connecticut Lyme disease is a tick-borne immun...
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