lyme disease (lyme borreliosis)

5

Lyme disease (Lyme borreliosis)

Juliane K. Franz MD

Department of Rheumatology and Clinical Immunology, Charite University Hospital, Berlin, Germany

Andreas Krause* MD

Professor of Rheumatology

Rheumaklinik Berlin-Wannsee, Berlin, Germany

Lyme borreliosis (Lyme disease) is a systemic infectious disease with a wide spectrum ofsymptoms affecting the skin, the heart, and the nervous and musculoskeletal systems.Lyme borreliosis is caused by the spirochaete Borrelia burgdorferi and transmitted by ticks. Thedisease occurs in endemic pockets with an incidence of from 50 to more than 100 cases per100 000 inhabitants.

Despite increasing knowledge about the virulence factors of the spirochaetes and theimmune response of the host, many aspects of the pathogenesis, for example of chronictreatment-resistant disease, are still a matter of debate.

The diagnosis is based on clinical findings and confirmed by serology. Diagnostic problems arisefrom patients with non-specific symptoms and a positive IgG serology.

In about 80% of the patients, the disease can be cured by adequate antibiotic therapy.Evidence-based guidelines for treatment have been recently published. The only vaccine toprevent Lyme disease, licensed in the USA, has been discontinued due to disappointing salesdespite good efficacy and tolerability.

Key words: Lyme disease; Lyme borreliosis; epidemiology; pathogenesis; natural outcome;diagnosis; therapy; co-infections; vaccine; prevention; post-Lyme syndrome; web information.

The disease was named after the town of Old Lyme, Connecticut, where, in 1975, therewas an accumulation of 12 cases of arthritis in children in a rural community.Originally suspected as juvenile chronic polyarthritis, it soon became obvious through asurveillance study that 25% of the patients had had an erythema migrans and recalled atick bite prior to the development of arthritis. Since 1910, it has been known thaterythema migrans is caused by an infective organism transmitted by ticks.1 Moreover,an association of erythema migrans with neurological symptoms has also been knownfor decades. Thus, in 1922, Garin-Bujadoux described a sensory radiculitis withmeningitis after an erythema migrans.2 In 1941, Bannwarth reported pain,paraesthesias, Bell’s palsy, and lymphocytic pleocytosis of cerebrospinal fluid afterhaving a tick bite and an erythema migrans.3

1521-6942/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.

Best Practice & Research Clinical RheumatologyVol. 17, No. 2, pp. 241–264, 2003doi:10.16/S1521-6942(02)00129-8, www.elsevier.com/locate/jnlabr/yberh

* Corresponding author. Tel.: þ49-30-80-505-292; Fax: þ49-30-80-505-299.E-mail address: [email protected] (A. Krause).

http://www.elsevier.com/locate/yberh

In addition to arthritis, skin and neurological symptoms, novel features of thedisease, such as cardiac conduction abnormalities, have been observed.4

In 1981, Burgdorfer et al. isolated a spirochaete from ticks in an endemic area.This spirochaete could also be cultured from skin, blood and cerebrospinal fluid frompatients with Lyme disease and was named Borrelia burgdorferi.5

EPIDEMIOLOGY

Lyme borreliosis is the most common vector-borne disease in USA6 and has become animportant infectious disease in Europe and Asia.7 Approximately 15 000 cases of Lymedisease are reported every year in USA.6 Lyme disease occurs in endemic pockets, withover 90% of the cases reported from eight states along the Atlantic Coast and fromWisconsin. In these regions, the annual reported incidence may exceed 100 cases per100 000 inhabitants. In some areas, such as Old Lyme, the incidence reaches 1000 casesper 100 000 inhabitants. The incidence in children aged 5–10 years is approximatelytwice as high as in adults (Table 1).6

In Europe, the disease is most prevalent in forested areas such as Scandinavia andCentral Europe. In southern Sweden, a population-based, prospective survey revealedan annual incidence of 69 cases per 100 000 population. In some highly endemic areas,the annual incidence reached 160 per 100 000.8 A similar study in southern Germanyfound an annual incidence of 111 per 100 000.9 In both European studies, the incidencein children was higher than in adults (Table 1).

AETIOLOGY

Lyme disease is caused by B. burgdorferi sensu lato, a Gram-negative spirochaete.B. burgdorferi undergoes enzootic cycles between ixoid ticks — Ixodes ricinus in Europeand I. scapularis and I. pacificus in the USA — and small mammal reservoirs. Ticks mayalso transmit infectious agents such as the FMSE virus, Babesia microti or the agent ofhuman granulocytic ehrlichiosis in addition to B. burgdorferi. Only recently, Bartonellahenselae has been described as a novel co-infecting agent in patients whose centralnervous system (CNS) is infected by B. burgdorferi.10

Table 1. Incidence in the USA for the year 2000

(Hayes N., personal communication).

Chlamydia 702 093

Neisseria gonorrhoeae 385 995

HIV (AIDS) 40 758

Salmonella 39 574

Treponema pallidum 31 575

Varicella 27 382

Shigella 22 922

Borrelia burgdorferi sensu lato 17 730

Mycobacterium tuberculosis 16 377

Hepatitis A virus 13 397

242 J. K. Franz and A. Krause

Among clinicians, the causative agent of Lyme borreliosis is known as B. burgdorferi.However, B. burgdorferi sensu lato is quite heterogeneous and, so far, 11 differentBorrelia species have been isolated from ticks.11

At least three species are pathogenic in humans: B. burgdorferi sensu stricto, B. gariniiand B. afzelii (reviewed in Ref. 11). In the USA only B. burgdorferi sensu stricto occurs,whereas all three species can be found in Europe. These different species preferentiallyinvade different organs (organotropism) which may explain at least in part the slightlydifferent clinical picture of Lyme disease in the USA as compared with Europe. Thus, thelate dermatological manifestation Acrodermatitis chronica atrophicans (ACA), mostly butnot exclusively associated with B. afzelii, can be observed in Europe but rarely, if ever, inthe USA. Neuroborreliosis is frequently caused by B. garinii. All three species can causeLyme arthritis, which occurs more frequently in North America than in Europe.7,12,13

PATHOGENESIS

Upon transmission, the spirochaete invades several host tissues. The spirochaetes firstencounter cells of the innate immune system (predominantly polymorphonuclear cellsand monocytes, but also innate T cells, such as NK T cells and gd T cells) as a first linedefence against the spirochaetes.14 The binding of B. burgdorferi lipoproteins to Toll-likereceptors induces a variety of pro-inflammatory mediators,15 that account for theinflammatory reaction in the infected host tissue. There is also a strong but delayedadaptive immune response provided by B and T cells. Despite the innate and adaptiveimmune response of the host, about 80% of infected persons develop a systemicdisease. Several properties of the spirochaetes, as well as host factors, are involved inthe pathophysiology of the disease. When the B. burgdorferi genome was sequenced,16

no specific virulence factor was detected. One of the most important findings was thatB. burgdorferi is not able to produce lipopolysaccharides but possesses a huge number ofgenes encoding lipoproteins. These proteins are anchored to the outer membrane viatheir lipid moieties and are called outer surface proteins (Osps). The differentexpression of these surface antigens as well as the antigenic variation within the vlsEexpression cassette17 enables the spirochaetes to evade the host immune response.An important virulence factor facilitating the dissemination of the infective agent isthe strong adhesion to various host extracellular-matrix proteins, glycosaminoglycansand integrins. In particular, the high affinity for matrix components may account forthe long-term survival of spirochaetes in connective tissue of the joints.Furthermore, spirochaetal lipoproteins are strong inducers of pro-inflammatorycytokines and chemokines.18 Host metalloproteinases are secreted and induced byB. burgdorferi.19,20 Recently, evidence for a spirochaetal carboxyl-terminal processingprotease (CtpA) has been reported.21 Specific anti-borrelial antibodies may not bedetected in sera from patients with Lyme disease before 3–4 weeks after the infection.Lytic antibodies are critical for eradicating the spirochaetes. In a recent study, surfaceproteins of B. burgdorferi with a high affinity for host complement control proteins(CRASP) have been identified and may reflect one mechanism of survival of thespirochaetes (personal communication).

There is only limited cross-reactivity of antibodies among different species ofB. burgdorferi. Therefore, the humoral immune response may not be protective andre-infections do occur even in patients with high titres of antibodies.

The pathogenesis of chronic persistent Lyme disease, in particular, is still a matter ofdebate. Most patients with Lyme arthritis recover completely after antibiotic therapy;

Lyme disease 243

however, in ,10% of patients with Lyme arthritis, the inflammation persists even afterrepeated courses of antibiotic therapy.7 Both persistent infection and induction ofimmunopathology by the spirochaetes are currently discussed. The following factssupport the concept of a persistent infection. Even at late stages of the disease,spirochaetes can be isolated from involved tissues (e.g. from ACA tissue after 10 years).The B. burgdorferi genome can be detected by polymerase chain reaction (PCR) insynovial tissue.22 Ultrastructural studies of synovial membranes from patients withchronic arthritis, and studies with a three-dimensional in - vitro model of Lyme arthritis,have revealed the presence of spirochaetes not only in tissues with a low turn-overrate, such as within bundles of collagen fibres,23 but also within macrophages andresident synovial fibroblasts.

On the other hand, in chronic therapy-resistant Lyme arthritis, the histologicallesions of affected synovial tissues resembling those found in rheumatoid arthritis,7 therare isolation of viable spirochaetes from patients with chronic disease, theunresponsiveness to antibiotic treatment in these patients and the association withHLA DR4 and DR2 point to the pathogenetic role of immunopathological processesinduced by the spirochaetes. Cross-reactivity between OspA and a self-antigen hasbeen discussed as a cause of treatment-resistant Lyme arthritis.7,13,24,25 An alternativeexplanation for the development of treatment-resistant Lyme arthritis would behypersensitivity that develops to traces of persistent antigen. Cytokines producedby cells of the innate immune system, such as the interleukins IL-1b, IL-6, IL-10, IL-11,IL-12, IL-17 and TNF-a, have been implicated in the regulation of arthritis severity inpatients or animal models.13 Altogether, it is likely that non-antigen-specificmechanisms mediate, perhaps in synergy with antigen-specific mechanisms,the immunopathology that finally leads to treatment-resistant Lyme arthritis insusceptible patients.7,25

CLINICAL FEATURES

The clinical manifestations of Lyme disease have been reviewed in a recent series ofexcellent articles.7,26–28

For systematic reasons, most textbooks group Lyme disease into three stages.However, the disease may become manifest at any stage, stages might be skipped ormay coincide. Therefore, for daily clinical practice, it is more useful to distinguishbetween early disease or acute phase (erythema migrans, acute neuroborreliosis,

Research agenda

In the pathogenesis of Lyme disease, more information is needed on:† properties of the organism: different expression of Osps, antigenic variation,

attachment to extracellular matrix and host-cell-surface molecules, inductionof pro-inflammatory cytokines and chemokines, induction of hostmetalloproteinases

† host factors: delayed humoral response, association to HLA DR 4 and 2,hypersensitivity to bacterial fragments

† in chronic persistent disease, persistent infection and induction ofimmunopathology


carditis, early arthritis) and late or chronic (persistent) disease (arthritis, acroderma-titis).

The general clinical manifestations of Lyme borreliosis are similar worldwide and willbe described in detail below. However, there are some regional variations in frequencyand appearance of certain symptoms between Europe/Eurasia and America that aresummarized in simplified form in Table 2.

Dermatoborreliosis

In most patients, Lyme disease begins with the pathognominic skin lesion, the erythemamigrans, and can be accompanied by signs of systemic inflammation such as low-gradefever, chills, arthralgias, myalgias, and malaise (‘flu-like illness’). Headaches andparaesthesias may reflect early neurological dissemination.

Erythema migrans starts as a red macule or papule at the site of the tick bite. After anincubation period of a few days up to 8 weeks, the lesions gradually expands(‘migrates’), sometimes reaching a size so large that the margins of an erythemaoriginating on the abdomen may meet at the back of the patient. In Europe, less often inAmerica, lesions lasting for a longer period will clear in the central part leaving ademarcated ring and a small red spot inside which the initial tick bite had taken place(Figure 1). The typical site of the erythema is the belt region, the posterior thigh,popliteal fossa or hairy areas such as the groin, axilla or hair on the head, especially inchildren. Even without antibiotic treatment, erythema migrans will resolve within 4–12weeks; however, in many cases, bacteria will persist at other sites and will causesubsequent Lyme manifestations.

Half of the American patients, but not the European patients, develop multiplesecondary erythema skin lesions resembling primary lesions, but smaller in size andexpansion. An additional dermatological manifestation in the early phase is thelymphocytoma cutis, especially in Europe, usually presenting as a purplish nodule atthe ear lobe, the nose (Figure 2), the forehead or the nipple.

Chronic borreliosis of the skin is a rare event in the USA, but quite common inuntreated European patients. ACA occurs after more than 12 months after the initialinfection and is characterized by a unilateral extended distal atrophic skin lesionfrequently preceded by an inflammatory, oedematous violaceous stage. A cigarette-paper-like appearance with a wrinkled violet thin skin without hair and with translucentveins (Figure 3) is typical. Frequently it is associated with pain in the joints underneaththe skin lesion (usually the PIP joints or toes) and is, therefore, sometimes called‘arthrodermatitis’. Diagnosis is quite easy owing to the typical skin manifestation and

Practice points

† for clinical practice, Lyme disease should be staged into early disease,disseminated disease and chronic-persistent disease

† pathognomonic features are erythema migrans, lymphadenosis cutis benigna,ACA and the meningoradiculitis Bannwarth

† all other symptoms are not restricted to Lyme disease (‘great imitator’) anddeserve careful differential diagnosis

† general symptoms are similar worldwide, but regional variations occur, partlydue to the organotropism of B. burgdorferi

Lyme disease 245

Table 2. Clinical manifestations of Lyme borreliosis in Eurasia and North America.7,29,30

Organ system Clinical feature Europe/Eurasia (Borrelia afzelii, Borrelia garinii,

Borrelia burgdorferi sensu stricto)

North America (Borrelia burgdorferi

sensu stricto)

Skin

Acute phase Erythema migrans Slower spreading, less intensely inflamed, and

of longer duration; less frequent haematogeneous

dissemination, but possible regional or contiguous

spread to other sites

Central clearing ,35%; systemic symptoms

common; frequent, possibly widespread

haematogeneous dissemination

Borrelial lymphocytoma Rarely and predominantly seen in children and

scarcely in adults

None reported

Chronic phase Acrodermatitis chronica

atrophicans

Caused primarily by Borrelia afzelii Rarely reported

Circumscribed scleroderma

and Lichen sclerosus et

atrophicus

Reports about the isolation of Borrelia afzelii

from lesional skin and improvement after

antibiotic therapy in single cases

None reported

Nervous system

Acute phase Meningopolyradiculo-neuritis

(Bannwarth), cranial nerve palsy

Severe radicular pain, meningitis more severe in

children, intrathecal pleocytosis and antibody

production, caused primarily by Borrelia garinii

Meningitis, less prominent radiculoneuritis

Chronic phase Encephalytis; encephalomyelits;

cerebral vasculitis; peripheral

neuropathy

Subtle sensory neuropathy within areas affected

by acrodermatitis. Severe encephalomyelitis,

spasticity, cognitive abnormalities, marked

intrathecal antibody production

Subtle sensory polyneuropathy without

acrodermatitis. Subtle encephalopathy, cognitive

disturbance, slight intrathecal antibody production

Heart

Acute phase Carditis Atrioventricular block and subtle myocarditis Atrioventricular block and subtle myocarditis

Chronic phase Dilated cardiomyopathy Isolation of Borrelia burgdorferi sensu lato from endomyocardial

biopsies in only a few cases

None reported

Musculoskeletal

Acute phase Arthritis Less frequent oligoarticular arthritis, less intense

joint inflammation

More frequent oligoarticular arthritis, more

intense joint inflammation

Chronic phase Arthritis; myositis; bursitis Persistent arthritis less frequent Treatment-resistant arthritis in about 10% of

patients, probably due to immunopathology

Antibody response Expansion of response to fewer borrelial antigens Expansion of response to many borrelial antigens

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usually an extremely marked immune response upon serology. If recognized early,treatment results in a resolution of the skin lesion; however, in prolonged cases,atrophic changes may remain. Moreover, acrodermatitis may lead to severe scarring ofaffected skin areas. This is of special interest because there is some evidence that a smallproportion of morphea cases (localized scleroderma) are also associated withB. burgdorferi infections.31

Figure 1. Erythema migrans. The lesion starts as a red macule or papule (A) at the site of the tick bite andthen slowly expands. (B) Central clearance may or may not be present.

Figure 2. Borrelial lymphocytoma: typical painless bluish-red nodule of the nose. Kindly provided byProfessor W. Sterry, Department of Dermatology, Charite University Hospital, Berlin, Germany.

Lyme disease 247

Neuroborreliosis

In a minority of patients (about 15%), typical neurological symptoms develop withinweeks or months after the tick bite: cranial neuropathy (most commonly involving thefacial nerve, Bells’s palsy, Figure 4); meningitis, especially in children; and radiculoneuro-pathy alone or in combination. The radiculoneuropathy accompanied by meningitis istermed Bannwarth’s syndrome. A recent study revealed similarities in the generalclinical picture of neuroborreliosis in Sweden, Germany and the USA.32

Figure 3. Acrodermatitis chronica atrophicans. Starting with a bluish-red discoloration, usually on theextensor surface of the extremities, the affected skin slowly becomes atrophic.


Radiculoneuropathy is usually a very painful acute condition, frequently with asignificant increase in pain at night. It may affect any dermatome, or several contiguousdermatomes, and is frequently mixed up with a ‘slipped disk’, even prompting surgery.Further symptoms include paresthesia, sensory deficits and motor weakness.

Facial palsy may even be bilateral, especially in children. It may occur when theerythema migrans is still present, or subsequently after a few weeks. In particular, arelationship to Lyme disease in endemic areas should be considered in children and intick-exposed individuals such as forest workers, house-wives working in the garden,farmers and hunters. Even in these risk groups, however, idiopathic facial palsy is moreprevalent than Lyme-associated neuropathy; clinically, however, a distinction is notpossible. Other manifestations include the paresis of the abducent nerve (5%).Clinically overt Lyme meningitis may be found in children, only rarely in adults, and ischaracterized by initial headaches, neck stiffness and additional signs of mildencephalopathy, while meningism is rare. All acute manifestations may eventuallyremit without treatment; however, in a significant number of patients, mild symptomsmay last for years in non-treated patients.36

In all suspected cases of neuroborreliosis, cerebrospinal fluid (CSF) analysis isnecessary to establish the diagnosis. The CSF is characterized by a lymphocyticpleocytosis with a cell number up to 1000 ml and elevated protein levels (1–2 g/l).The ratio of immunoglobulins to albumin might be elevated in the CSF compared withblood levels, and points to an intrathecal production of immunoglobulins. Oligoclonalelectrophoretic bands within the CSF reflect an immunological process.

However, in early cases of neuroborreliosis, spinal fluid findings may still be negative,and in cases of chronic disease, only mild elevations of protein may persist. Especially inthese circumstances, detection of B. burgdorferi DNA by PCR may be important toestablish the diagnosis.

Figure 4. Facial nerve palsy in acute neuroborreliosis.

Lyme disease 249

The rare manifestations of chronic neurological Lyme disease occurring months toyears after infection include distal symmetric polyneuropathy (often associated withacrodermatitis), mononeuritis multiplex, stroke-like disorders (caused by a cerebralvasculitis), chronic encephalitis, encephalomyelitis or meningoencephalomyelitis.The latter are characterized by slowly progressive courses with increasing spasticpara-, tetra- or hemiparesis. Some rare cases of demyelinating encephalopathyresembling multiple sclerosis have been described.33

Other manifestations include cognitive defects, memory loss and concentrationdeficits. The diagnosis has to be made with great caution and under strict criteriabecause the latter symptoms are particularly difficult to discriminate fromneuropsychiatric or neurotic diseases.

Ocular manifestations of Lyme disease

Ophthalmological changes are relatively rare and may include conjunctivitis and allvarieties of uveitis (anterior, intermedia and posterior and panuveitis). Meningitis maylead to a papillar oedema. In the chronic stage, uveitis, keratitis and episcleritis mayevolve. The recognition of Lyme borreliosis as a cause of ocular conditions is importantbecause treatment with antibiotics usually results in resolution of the disease.

Lyme carditis

Lyme carditis is a rather rare entity occurring in about 5% of patients. It frequentlydevelops after a preceding erythema migrans. Many patients also have concomitantneurological symptoms and arthralgias. Typical manifestations are conductionabnormalities with varying degrees of atrioventricular block, right or left bundleblock, atrial fibrillations or tachycardias. In Particluar, Lyme carditis should be suspectedin younger individuals showing conduction abnormalities without other apparent riskfactors. In Europe, rare instances of a chronic Lyme carditis have been described thatresult only in cardiomyopathy, even with a fatal course. However, cardiac involvementusually subsides spontaneously within a few weeks and does not recur. Spirochaeteshave been successfully cultured from cardiac biopsies. Therapy is symptomatic togetherwith antibiotic treatment — which usually results in prompt resolution. In cases ofconduction abnormalities, steroids have been added.

Articular manifestations

In the USA, arthritis is the predominant manifestation of disseminated B. burgdorferiinfection, with about 60% of untreated patients developing joint manifestations usuallyweeks to years after the initial infection. In Europe, a smaller proportion of patientsexperience arthritis — which may either occur in early disseminated disease or, moretypically, in late stages of disease. The clinical course is usually intermittent with acuteattacks and transient-seeming ‘remissions’. left untreated, it may go on for months oryears. In most cases, there is a mono- or oligoarticular course predominantly affectingthe knees, ankles and sometimes elbows, usually with massive effusions (Figure 5).

In our experience, only a minority of patients will remember a tick bite or anerythema migrans, and arthritis may be the only presentation of Lyme disease.Therefore, the diagnosis of Lyme arthritis is one of the greatest the challenges inrheumatology.


Popliteal (Baker’s) cysts are common, and — if present — dactylitis and achillestendon involvement can be helpful as diagnostic signs if reactive arthritis, psoriaticarthritis and spondyloarthropathies have been ruled out. Involvement of the sacroiliacjoints or the spine does not occur in Lyme borreliosis and is therefore most valuable fordifferentiating Lyme arthritis from the latter arthritides. Otherwise, Lyme arthritiscannot be distinguished from reactive arthritis or other acutely presentingoligoarticular diseases on clinical grounds alone. Joint fluid analysis usually showsnon-specific inflammatory changes, with a cell count of about 25 000 cells/mm3,predominantly granulocytes. Histological investigations of the synovial membrane haveconcentrated on chronic cases and have documented changes similar to those inrheumatoid arthritis, with a hyperplasia of the lining and lymphocytic infiltration.While it is generally difficult to culture B. burgdorferi from intra-articular sites, PCRanalysis of the joint fluid and synovial biopsies have shown the presence of spirochaetes.Therefore, PCR investigations may be helpful in unclear cases (see below).

In some cases, there is no overt arthritis, and the disease is characterized by non-specific arthralgias, myalgias and periarticular pain, making the differential diagnosisdifficult with regard to functional syndromes and fibromyalgia, especially in seropositiveindividuals living in endemic areas.

The prognosis of the disease is usually good. Joint destruction, even in long-standingcases, is rare. After adequate therapy, more than 80% of patients are cured, even after asingle course of antibiotic therapy. In some patients, repeated therapy is necessary.The success of antibiotic treatment often cannot be evaluated before several weeksafter completion of treatment because symptoms usually fade slowly and completerecovery may take several months.

A small proportion of patients with Lyme arthritis do not respond even to repeatedcourses of antibiotic treatment. In our (European) experience, these therapy-resistantpatients are rare, while in the USA a proportion of 10% has been described.

Figure 5. Lyme arthritis of the right knee.

Lyme disease 251

The incidence is lower in children than in adults. Treatment with steroids, especiallygiven intra-articularly, before adequate antibiotic treatment significantly increases therisk of developing treatment-resistant Lyme arthritis. While some of these cases may bedriven by intra-articular persistence of B. burgdorferi, there is some evidence that othersare maintained by infection-induced immunopathology, including autoimmunemechanisms.

Extra-articular manifestations in the musculoskeletal system

Compared with arthritis, other rheumatological manifestations are much rarer.These consist of tenosynovitis and bursitis. Despite frequent myalgias, overt myositis ordermatomyositis has only been described in rare cases — which could, however,be confirmed by a positive culture from a muscle biopsy. Also, three cases of apolymyalgia-like disease have been reported after an erythema migrans with a goodresponse to antibiotic therapy.

Post-Lyme syndrome

Clinical problems arise in a small percentage of patients who have been appropriatelytreated for Lyme disease but who still complain about multiple, mostly non-specific,symptoms, including fatigue, myalgias, arthralgias and cognitive impairment.This so-called ‘post-Lyme disease syndrome’ may be severely disabling, with asubstantially reduced health-related quality of life, and it has many features in commonwith chronic fatigue syndrome and fibromyalgia. The frequency, pathogenesis, diagnosisand treatment of this syndrome have been a highly contentious issue for more than adecade. Two recently published studies34,35 tested the effect of long-term therapy inpatients with well-documented Lyme disease and who had various persisting symptomsdespite an average of three previous courses of antibiotics. Patients received either 2 gceftriaxone daily for 30 days followed by 200 mg doxycycline daily for another 60 days,or placebo. The study was stopped prematurely because there was no differencebetween the treatment group and the placebo group, and therefore it was highlyunlikely that even this massive antibiotic therapy was of any benefit. Taken together,especially in patients with late stages of Lyme disease, it may be necessary to give two orsometimes even three courses of antibiotics with the antibiotics, dosages and durationsrecommended above.34 Despite this therapy, there is a small group of patients with

Practice points

Characteristics of Lyme arthritis:† often in North America, less frequent in Europe† occurs usually in later stages of Lyme disease† huge effusion possible† frequent recurrence† no systemic inflammation† no involvement of the sacroiliac joints

Problem: arthritis is the only manifestation, tick bite and/or erythema migrans arenot recalled


ongoing, so-called treatment-resistant arthritis or various, sometimes disablingsymptoms of post-Lyme syndrome. While we do not know the optimum treatmentfor these patients yet, it is obvious that prolonged antibiotic treatment should beavoided because it is not only ineffective but also expensive, and is burdened with anumber of severe and sometimes lethal side-effects.

NATURAL HISTORY AND LONG-TERM OUTCOME

The long-term outcome of Lyme borreliosis has been addressed by several studies.Shadick et al.,35 reported more joint pain, memory impairment and poorer functionalstatus in 186 patients who had Lyme disease (6 years after infection) compared with167 controls. However, no significant examination differences could be found betweenthe groups.

In 2001, Kalish et al. published a follow-up study of 84 randomly selected patients10–20 years after infection and 30 controls.36 The groups did not differ in currentsymptoms or neuropsychological tests. However, in patients with neuroborreliosiswho had not received antibiotic treatment, more residual neurological deficits, morejoint pain and sleeping disturbances occurred. Reviewing the current data on thelong-term outcome, the prognosis of Lyme disease is excellent.

CO-INFECTIONS

Ticks may serve as vectors for additional pathogens, such as Babesia microti andAnaplasma phagocytophila, the agent of human granulocytic ehrlichiosis (HGE).Human co-infection may occur from a single tick bite that transmits multiple pathogensor from multiple tick bites.

The first co-infection with B. burgdorferi and B. microti was reported in 1983,37 andthe first co-infection of B. burgdorferi and A. phagocytophila in 1997.38 Severalprospective studies analysed the clinical symptoms of co-infections. A total of 671persons in an endemic region of New York revealed no seroconversion to two or moreinfective agents during the 1-year follow-up39, although five patients had initial signs ofco-infection. Co-infections (any combination of borreliosis, babesiosis, HGE) werefound in 75/192 (39%) patients with either erythema migrans or flu-like symptoms inConnecticut and Block Island over a 6-month period.40 The most frequent co-infectionwas B. burgdorferi and B. microti. Co-infection was associated with a higher percentage offlu-like illness. Another prospective study conducted from 1996 to 1997 found only 4%

Practice points

Long-term outcome of Lyme disease:† patients report more joint pain, memory impairment and poorer functional

status, but tests did not unreveal significant differences compared with normalcontrols

† patients not receiving antibiotic therapy exhibit more residual symptoms

Lyme disease 253

of patients with evidence for a co-infection.41 Therefore, the risk of acquiring co-infections appears to be rather low in endemic areas.

Although either of the co-infecting organisms may cause severe disease, they mostcommonly result in asymptomatic infection. A retrospective study on the long-termoutcome of Lyme borreliosis and babesiosis co-infection on Nantucket Island revealedno increased disease severity or persistent symptoms,42 the same was found forco-infection with B. burgdorferi and A. phygocytophila.43

In daily clinical practice, a complete blood smear should be performed in patientssuspected to have co-infections, especially in patients with erythema migrans andflu-like symptoms. Leucocytopenia (HGE), anaemia (babesiosis) and thrombocytopenia(both) support the diagnosis of co-infection (Belongia E, personal communication).

Recently, Bartonella henselae has been described as a novel co-infecting agent inpatients whose CNS is infected with B. burgdorferi.10

For further reading, we recommend an excellent review on tick-borne co-infectionsby Thompson et al.44

LYME DISEASE IN CHILDREN

Originally described in children, arthritis remains the most common manifestation ofLyme disease in the USA. In endemic regions, the incidence of Lyme arthritis is twice ashigh in children compared with adults. In general, Lyme arthritis appears to be lesspainful in children. The long-term outcome in children is excellent; there are no reportsof chronic persistent Lyme arthritis in children.

In European children, erythema migrans and lymphocytic meningitis (facial palsy) arethe major clinical manifestations.45

Recently, involvement of the optical nerve has been described in children.46

This might be due to inflammation or increased intracranial pressure;47 it causedbilateral blindness in one case.46

DIFFERENTIAL DIAGNOSIS

The characteristic appearance of the erythema migrans can hardly be misdiagnosed.However, the differential diagnosis of atypical cases includes all other erythematous skin

Practice points

Co-infections may occur with:† FMSE virus (Europe)† Babesia microti† Anaplasma phygocytophila† Bartonella henselea

Frequency is rather low (,5%), and infections are mostly asymptomatic† for clinical practice, complete blood smear (anaemia, leucopenia, thrombope-

nia) is recommended in patients with erythema migrans combined with flu-likesymptoms


diseases such as erythema gyratum repens, erythema anulare and the erythemanecrolyticum migrans. There are usually no laboratory abnormalities in early Lymedisease except for rare elevations of the ESR, mild anaemia, leukocytosis and slightelevations of liver enzymes. At this stage of the disease, only 50% of patients developserological signs of a B. burgdorferi infection (see below).

If fever and flu-like symptoms are the predominant findings, Lyme borreliosis canhardly be distinguished from viral infections. However, rhinitis, sore throat or cough donot belong to the clinical spectrum of Lyme disease.

In later stages, Lyme disease can manifest with a variety of cardiac, neurological andarthritic symptoms which are not specific for Lyme disease. Lyme carditis can beconfused with viral carditis or with rheumatic fever.

Neurological symptoms may simultaneously or sequentially involve multiple levels ofthe central and peripheral nervous system with a wide array of possible differentialdiagnoses. However, CSF analysis usually permits diagnosis of Lyme disease or rules itout. Although most cases remain ‘idiopathic’, Lyme disease is the most commonrecognized cause of Bell’s palsy, especially if it occurs bilaterally.

Lyme arthritis may resemble reactive arthritis. A remarkable finding in Lyme arthritisis the frequent absence of systemic inflammatory signs. Thus, despite massive effusions,ESR and CRP values are often normal or only slightly elevated. Therefore, if, forexample, a knee swelling is the initial symptom — especially in a younger athletic person— acute meniscopathy may be a wrong diagnosis if Lyme arthritis is not considered. Onthe other hand, reactive arthritis is normally characterized by significant elevations ofthe ESR and CRP. In contrast to spondyloarthropathies, Lyme arthritis is not associatedwith HLA-B27 and axial involvement is missing. In severe cases of Lyme arthritis,rheumatoid factor and antinuclear antibodies may be positive, making the differentialdiagnosis of Lyme disease difficult — especially in rare cases of a polyarticular or erosivecourse of disease. An important disease to consider is Lofgren’s syndrome whichfrequently presents with acute arthritis of the lower extremities. The erythemanodosum and bihilar lymphadenopathy will help to distinguish this condition from Lymearthritis.

DIAGNOSIS

Diagnosis depends largely on recognition of a characteristic clinical picture, whileserological tests confirm the diagnosis.

A typical erythema migrans can be diagnosed only by appearance. In all other cases,the diagnosis of Lyme borreliosis is based on clinical grounds and supported by

Practice points

Differential diagnosis:† skin: erythema gyratum repens, erythema anulare, erythema necrolyticum

migrans† heart: viral myocarditis, rheumatic fever† musculoskeletal system: fibromyalgia, polymyalgia rheumatica† arthritis: reactivearthritis, gout, atypical rheumatoidarthritis, Lofgren’s syndrome† peripheral and central nervous system: cranial neuropathy, meningitis, radiculo-

neuropathy; rarely: symmetric polyneuropathy, mononeuritis multiplex, stroke-like disorders (vasculitis), meningoencephalitis

Lyme disease 255

laboratory analyses, especially Lyme serology. A history of exposure to ticks, or a tickbite in an area that is endemic for Lyme disease, symptoms characteristic for, or at leastcompatible with, Lyme disease, and the detection of specific antibodies againstB. burgdorferi are the most important diagnostic hallmarks. In Lyme neuroborreliosis,the diagnosis may be confirmed by the detection of CSF pleocytosis and intrathecalantibody production against borrelial antigens. In contrast, the diagnosis of Lymearthritis is difficult to establish. Patients usually present with non-specific symptoms andoften do not remember having had specific early Lyme manifestations. The directdetection of the spirochaete is still difficult, and positive serology does not necessarilydifferentiate between previous or ongoing infection. Therefore, it is often possible togive only a probable diagnosis of Lyme arthritis after having ruled out other forms ofarthritis.

The European Concerted Action Against Lyme Borreliosis (EUCALB) and theCenters for Disease Control (CDC) have published case definitions for Lyme diseasewhich combine clinical and laboratory data (URL http://www.dis.strath.ac.uk/vie/LymeEU/).48,49 These may be used for public health surveillance and studies on Lymedisease.

Serology

Serology is usually performed when Lyme disease is suspected. Specific IgM antibodiesagainst B. burgdorferi first become detectable 3–4 weeks after the infection, peak after6–8 weeks and usually decline subsequently. IgG antibodies appear 6–8 weeks after theinfection and remain detectable for many years.7 For diagnostic purposes, it isimportant to keep in mind that both IgG and IgM responses can persist for over 10years, even after successful antibiotic treatment.7 Two-tiered testing is currentlyrecommended. The most commonly used screening tests are ELISAs. Western blottingprocedures are applied for the confirmation of positive ELISA results.7,27,48 False-positive ELISA results can be caused by other bacteria (e.g. Treponema denticulata) or bya polyclonal B cell stimulation.

The sensitivity, specificity and reproducibility of the currently available commercialtests vary greatly. Guidelines for the appropriate use of serodiagnostic tests for Lymedisease in the USA have been developed by the American College of Physicians.50

According to these guidelines, serological testing is useful only when the pre-testprobability of Lyme disease is 0.20–0.80. In clinical practice, Lyme serology should beperformed only in patients with signs and symptoms compatible with Lyme disease. Aspositive serology alone is not sufficient to make the diagnosis, differential diagnosesneed to be ruled out in parallel. Usually, highly positive serology in an ELISA does notneed to be confirmed by an immunoblot. Cross-reactivities with syphilis tests do occur

Practice points

Diagnosis of Lyme disease:† based on clinical and geographical data† confirmed by serology: two-step approach

– screening: ELISA (IgG and IgM)– confirmation: immunoblot

† Borrelia PCR (urine, cerebrospinal fluid, synovial fluid) in special cases


http://www.dis.strath.ac.uk/vie/LymeEU/


but they are only rarely of clinical relevance. If so, it is much more likely that positiveLyme serology leads to false-positive syphilis serology than vice versa.

A significant advance in serology appears to be the development of an IgG ELISAusing a conserved vlsE peptide of the spirochaete.51 This test has a high specificity andsensitivity, becomes positive prior to the IgG response detected by Western blot andmight also be of value in European Lyme borreliosis caused by B. afzelii and B. garinii.

Direct detection methods

The culture of B. burgdorferi from patient specimens would prove the diagnosis of Lymedisease. Unfortunately, it is difficult to perform, insensitive and slow, and thereforerarely attempted for diagnostic purposes, except for unclear skin manifestations ofLyme borreliosis.7

PCR-based assays detecting B. burgdorferi DNA have shown increasing significanceon the basis of their high sensitivity, specificity and capability for typing andquantification of spirochaetes in specimens; however, they are currently not considereda routine method — partly because there is considerable interlaboratory variation inthe results.7 B. burgdorferi DNA can be detected in synovial fluid22,52 or synovial tissue22

from patients with Lyme arthritis, and in the CSF from patients with early CNSmanifestations of Lyme disease.53

Positive serology in asymptomatic patients

In areas endemic for Lyme disease, many inhabitants are seropositive yet lack anyhistory or symptoms of Lyme disease.7 The frequency of asymptomatic infection maybe considerable and further complicates the interpretation of serological data. Duringthe 2-year observation period of the clinical trial of the Lyme vaccine, 137 of theplacebo recipients seroconverted on Western blotting. Twenty-eight of those (20%) didnot show any clinical symptoms of Lyme disease.54 A retrospective Swedish study evenfound that more than half of the people who were seropositive by ELISA could notrecall any symptoms suggestive of Lyme disease.55

TREATMENT

Antibiotic treatment

There is no need to treat persons with positive Lyme serology but without anysymptoms of Lyme disease. Treatment decisions should always be based on clinicalsigns. All manifestations of Lyme borreliosis should be treated with antibiotics asearly as possibly to shorten the clinical course and prevent the progression of thedisease. Detailed, essentially comparable and evidence-based recommendations havebeen issued by EUCALB (URL http://www.dis.strath.ac.uk/vie/LymeEU/) and by theInfectious Disease Society of America.56 Therapeutic decisions depend on duration,stage and symptoms of the disease. Amoxicillin, doxycycline and third-generationcephalosporins are the drugs of choice.7,26–28 Doxycycline has the advantage of beingalso effective against the agent of human granulocytic ehrlichiosis which may be co-transmitted by ticks. In early infections, azithromycin and oral cephalosporines arealso effective and may serve as alternatives if the first-line drugs are contraindicated.However, their efficacy has not been proven in later stages of disease. Penicillin G is

Lyme disease 257


also recommended for disseminated infections but has the disadvantage of shortdosage intervals. Erythromycin is less effective than the recommended compoundsand therefore regarded as the last choice.

Doxycyline must not be prescribed for children or for pregnant or nursing mothersbecause of the discoloration of the child’s teeth. Patients taking doxycycline have to betold that the therapy causes photosensibility.

The duration of treatment ranges from 2 to 4 weeks. Details are given in Table 3.Uncomplicated Lyme arthritis, i.e. without neurological or any other organ

manifestations, may be treated orally with amoxicillin or doxycycline. However, onestudy found the subsequent development of neuroborreliosis in patients treated with

Table 3. Treatment of Lyme borreliosis.

Condition Drug Dose/day (dosages for childrena) Duration

Early infection Doxycycline 1 £ 200 mg or

2 £ 100 mg orally

14–21 days

Amoxicillin 3 £ 500–750 mg

or 2 £ 1000 mg

orally (50 mg/kg)

14–21 days

Azithromycinb 2 £ 500 mg orally 1st day

500 mg 2nd to 5th day

Cefuroxime

acetylb2 £ 500 mg orally 14–21 days

Acute

neuroborreliosiscCeftriaxone 1 £ 2 g i.v. (50 mg/kg) 14–21 days

Cefotaxime 3 £ 2 g i.v. (100 mg/kg) 14–21 days

Penicillin G 4 £ 5 MioU i. v.

(500 000 U/kg)

14–21 days

Doxycyclined 1 £ 200 mg or

2 £ 100 mg orally

14–21 days

Carditise Ceftriaxone 1 £ 2 g i.v. 14 days

Cefotaxime 3 £ 2 g i.v. 14 days

Penicillin G 4 £ 5 MioU i.v. 14 days

Arthritis,

acrodermatitis

Doxycycline 1 £ 200 mg or

2 £ 100 mg orally

30–40 days

Amoxicillin 3 £ 500–750 mg or

2 £ 1000 mg orally

30–40 days

Ceftriaxone 1 £ 2 g i.v. 14–21 days

Cefotaxime 3 £ 2 g i.v. 14–21 days

Lyme borreliosis

during pregnancy

Amoxicillin 3 £ 500–750 mg or

2 £ 1000 mg orally

14–21 days

Penicillin G 4 £ 5 MioU i. v. 14–21 days

Ceftriaxonef 1 £ 2 g i.v. 14 days

Cefotaximef 3 £ 2 g i.v. 14 days

a Dosages for adults are the maximum dosages.b Only in cases of doxycyclin and amoxicillin allergy or contraindications.c In chronic neuroborreliosis, intravenous therapy only for 14–28 days.d Only in cases with facial palsy alone.e In patients with first-degree atrioventricular block, oral therapy for 14–21 days may be sufficient.f Should be used with caution in the first trimester because of lack of data on safety.


doxycycline but not in those primarily treated with ceftriaxone. If the oral regimen wasnot effective, which may occur in some 20% of patients, or in cases with symptoms ofneurological or other organ involvement, parenteral therapy with ceftriaxone orcefotaxime should be given. In patients with persistent symptoms, a second parenteralantibiotic therapy should be given, again following the evaluated approaches forparenteral treatment. There is no need to change the drug because borreliae do notbecome resistant to any of the recommended antibiotics. Similarly, other therapeuticregimens such as high-dose pulse therapy or long-term antibiotic treatment are neithernecessary nor evaluated and may be associated with a substantial risk of seriousside-effects.

The important treatment study of post-Lyme syndrome34 is discussed in the sectionabove. Using the recommended therapeutic approach, the prognosis of Lyme disease isexcellent. Almost all early infections are rapidly cured without sequelae. In later stages ofdisease, especially in Lyme arthritis, symptoms often wane slowly and clinicalimprovement is observed only several weeks after therapy. It should be kept in mindthat there are several potential reasons for treatment failures or incomplete responsesto therapy, including misdiagnosis and irreversible tissue damage caused by the infection.However, about 10% of patients with Lyme arthritis in the USA and probably a smallerpercentage of European patients do not respond sufficiently even to repeated courses ofantibiotic treatment. The pathogenesis of this so-called treatment-resistant Lymearthritis has not been fully elucidated yet but there is some evidence thatinfection-induced immunopathology plays a major role in most of these cases(see above).

Additional therapy

As no controlled therapeutic studies, for example with disease-modifying antirheumaticdrugs, have yet been performed, symptomatic treatment with anti-inflammatory agentsshould be given. In patients with persistent monoarthritis, especially with proliferativesynovialitis, synovectomy can be beneficial. A recent study reported the successfulsymptomatic treatment of neuropathic pain in late-stage Lyme borreliosis by gabapentin(Weissbacher S, personal communication).

C vaccine

Immunization with several different B. burgdorferi proteins, including OspA, can inducespecific neutralizing antibodies. OspA is expressed on B. burgdorferi in the mid-gut ofthe tick and is down-regulated after migration to the salivary gland of the tick andinjection into the human host. During the blood meal, the anti-OspA antibodies killthe spirochaetes within the mid-gut of the tick prior to transmission of thespirochaetes.57 A vaccine consisting of recombinant lipidated OspA (LYMErixw) wasfound to be safe and effective in a large clinical trial involving more than 10 000participants aged 15–70 years who lived in areas of the USA where Lyme disease isendemic.54 In 1998, this vaccine was approved by the Food and Drug Administration foruse in persons older than 16 years. The OspA vaccine was not tested in Europe, basedon the heterogeneity of OspA sequences found in European Borrelia isolates and theexpected limited efficacy.

Since vaccine licensure, about 1.49 million doses have been distributed.Besides hypersensitivity reactions, no severe side-effects have been described inthe post-marketing reports.58 The induction of arthritis was a major concern owing to

Lyme disease 259

reports on cross-reactivity between OspA and human antigens, but no anti-OspA-induced synovitis has been reported. However, in February 2002, GlaxoSmithKlinediscontinued manufacturing the LYMErix vaccine due to disappointing demands andsales.

Prophylaxis

Exposure prophylaxis

Prophylactic measures for avoiding tick bites include simple physical measures such aswearing long sleeves and long pants that are tucked into the socks, the completeavoidance of wooded areas, and drastic measures such as area application ofinsecticides. One popular recommendation is the use of tick and insect repellents.However, to maintain effectiveness, DEET (N,N-diethylmetatoluamide)-containingrepellents need to be applied every 1–2 h. Moreover, their use may result in severecomplications, including encephalopathy, seizures, coma and death in children.13

Permethrin kills ticks and can be sprayed on to clothing, but skin exposure should beavoided due to its possible carcinogenicity. In infested areas, daily careful screening fortick bites and the rapid removal of ticks appears to be the most realistic and usefulprophylactic measure.7 Experimental and observational data indicate that transmissionof B. burgdorferi occurs only after ticks have been attached to the host for at least 24 toover 50 h.13 Persons who have been bitten by a tick should be informed about earlyLyme disease manifestations and advised to seek immediate treatment in case of thedevelopment of respective symptoms.

Secondary prevention

The risk of acquiring B. burgdorferi infection through a tick bite is low and variesbetween 1.2 and 3.2%. It increases, however, to greater than 25% when someone hasbeen bitten by an infected tick.59 Transmissions rarely occur within the first 24 h of thetick bite and can take place only when the tick has become at least partially engorgedwith blood. Weighing the low risk and the possible side-effects of doxycyclinetreatment, the Infectious Diseases Society of America has published a recommendationthat antibiotic treatment should not be administered routinely to persons who havebeen bitten by a tick.56 In a study performed in Westchester County NY, where theincidence of Lyme disease is probably the highest in the world, one dose of 200 mgdoxycycline p.o. administered within 72 h after a tick bite was 87% effective inpreventing Lyme disease.60 However, the observation period in that study was only 6weeks and the first symptoms of Lyme disease may occur much later. Only 3% of thosewho received placebo in this study developed Lyme disease. Thus, 40 doses ofdoxycycline had to be administered to prevent one case of Lyme disease. This numberwould be higher in areas with a lower incidence of Lyme disease. The efficacy ofprophylactic doxycycline administration is further reduced by the fact that most casesof Lyme disease result from unrecognized tick bites. Conversely, for many people,including physicians, it may be difficult to distinguish a tick bite from an insect bite sothat some patients would be treated unnecessarily. Taken together, routine antibioticprophylaxis is not recommended. Individuals with tick bites should be stratifiedaccording to their risk of infection by borreliae. Only in those rare patients who havereally been bitten by a tick and not, for example, by an insect, and who have a high risk ofinfection (i.e. nymphal tick from an endemic area, long duration of tick attachment, ticksat least partially engorged) may antibiotic prophylaxis be considered.


LYME DISEASE INFORMATION ON THE WEB

The web sites listed in Table 3 provide profound information on Lyme disease.61

† Clinical features and diagnosis:home page of the center of Disease Control (CDC on Lyme disease: http://www.cdc.gov/ncidod/dvbid/lyme/index.htm

† Pictoral diagnosis aid:http://www.journals.uchicago.edu/CID/journal/issues/v35n4/020270/020270.text.html

† EUCALB (European Concerted Action on Lyme Borreliosis)http://www.dis.strath.ac.uk/vie/LymeEU/index.htm

† On-line seminar from The Lancet:http://www.thelancet.com

† Education source for patients:The American Lyme Disease Foundation, http://www.aldf.com

SUMMARY

Lyme disease (syn.: Lyme borreliosis) is a complex, multisystem infectious diseasewith a wide and still expanding spectrum of clinical symptoms. Lyme borreliosis iscaused by the spirochaete B. burgdorferi and transmitted by infected ticks. Currently,three species of B. burgdorferi sensu lato are known to cause the disease in humans:B. burgdorferi sensu stricto (USA and Europe), B. garinii (Europe) and B. afzelii(Europe). The disease occurs in endemic pockets in large parts of Europe, NorthAmerica and Asia, with an annual incidence of 50–100 (in some endemic areas, even.300) cases per 100 000 inhabitants. Co-infections with B. microti andA. phagocytophila (human granulocytic ehrlichiosis) may occur, but the frequency israther low and they most commonly result in asymptomatic infections.

Host factors (late and insufficient immune response, hypersensitivity reaction) aswell as several properties of the organism (antigenic variation, evasion of host immuneresponse, induction of pro-inflammatory cytokines and metalloproteinases of the host)are involved in the pathophysiology of the disease. However, the mechanisms leading tochronic treatment-resistant Lyme arthritis are still a matter of debate. Novel insightsare expected from gene transfer experiments.

The diagnosis is based on clinical symptoms and endemic data, and confirmed byserology. Pathognomonic features are the erythema migrans, the lymphadenosiscutis benigna, the ACA and the meningoradiculitis Bannwarth. All other symptomsof Lyme borreliosis may also occur in other diseases and require careful differentialdiagnosis.

The general clinical picture of Lyme borreliosis is similar in the USA and Europe.However, at least in part due to the organotropism of the Borrelia species, there aresome differences concerning the frequency and appearance of leading symptoms.Problems in daily clinical practice arise from patients with positive serology but lackingtypical clinical signs of Lyme borreliosis and from patients with so-called post-Lymesyndrome. Lyme disease is usually cured by antibiotic treatment at any stage of thedisease. Therapy is easier and more successful the earlier it is started. Recently,evidence-based guidelines for antibiotic therapy have been provided by the InfectiousDisease Society of America.

Lyme disease 261

http://www.cdc.gov/ncidod/dvbid/lyme/index.htm

http://www.cdc.gov/ncidod/dvbid/lyme/index.htm

http://www.journals.uchicago.edu/CID/journal/issues/v35n4/020270/020270.text.html

http://www.journals.uchicago.edu/CID/journal/issues/v35n4/020270/020270.text.html

http://www.dis.strath.ac.uk/vie/LymeEU/index.htm

http://www.thelancet.com

http://www.aldf.com

The first and only vaccine to prevent Lyme disease was licensed in the USA in 1998.However, despite the good efficacy and tolerability in the post-marketing period,manufacturing was discontinued in February 2002, owing to disappointing demand forthe product and poor sales.

The overall prognosis of the disease is excellent. Despite the common concerns ofsome physicians, and of the general population, about Lyme disease as a dangerousillness with the risk of chronic sequelae, one should keep in mind that the disease istreatable (90%), non-fatal and non-contagious. From a scientific point of view, Lymearthritis may serve as a model system for rheumatic diseases with a known aetiology.

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