Lyme Disease

Current State of Knowledge

Background: Lyme disease is the most frequent tick-borne infectious disease in Europe. The discovery of the causative pathogen Borrelia burgdorferi in 1982 opened the way for the firm diagnosis of diseases in several clinical disciplines and for causal antibiotic therapy. At the same time, speculation regarding links between Borrelia infection and a variety of nonspecific symptoms and disorders resulted in overdiagnosis and overtreatment of suspected Lyme disease.
Method: The authors conducted a selective review of the literature, including various national and international guidelines.
Results: The spirochete Borrelia burgdorferi sensu lato is present in approximately 5% to 35% of sheep ticks (Ixodes ricinus) in Germany, depending on the region. In contrast to North America, different genospecies are found in Europe. The most frequent clinical manifestation of Borrelia infection is erythema migrans, followed by neuroborreliosis, arthritis, acrodermatitis chronica atrophicans, and lymphocytosis benigna cutis. Diagnosis is made on the basis of the clinical symptoms, and in stages II and III by detection of Borrelia-specific antibodies. In adults erythema migrans is treated with doxycycline, in children with amoxicillin. The standard treatment of neuroborreliosis is third-generation cephalosporins.
Conclusions: After appropriate antibiotic therapy, the outcome is favorable. In approximately 95% of cases neuroborreliosis is cured without long-term sequelae. When chronic borreliosis is suspected, other potential causes of the clinical syndrome must be painstakingly excluded.
Dtsch Arztebl Int 2009; 106(5): 72–82
DOI: 10.3238/arztebl.2009.0072
Key words: tick bite, antibiotic, borreliosis, laboratory diagnosis, Lyme disease

Lyme disease is the most common tick-borne infectious disease in Europe (1). The responsible pathogen, Borrelia burgdorferi, was discovered 26 years ago. This organism was found to be the cause of erythema chronicum migrans and of other disease manifestations as well, and the overarching entity of Lyme borreliosis was thereby defined. After the manifestations of neuroborreliosis had been wrongly ascribed, for decades, to an unknown virus, this discovery was a milestone in modern infectious disease medicine. The identification of the pathogen also opened up new possibilities for the etiological diagnosis of a variety of conditions due to Borrelia burgdorferi sensu lato (of which the main types are Borrelia burgdorferi sensu stricto, B. garinii, B. afzelii, and B. spielmanii), as well as new possibilities for pathogen-directed antibiotic therapy aimed at the cause of the disease.

Borrelia burgdorferi sensu lato, like Treponema pallidum and other pathogenic organisms, can cause chronic as well as acute infection (1). In persistent infections of the central nervous system (CNS), the bacterial count in the CNS is often low; bacterial constituents are released in small quantities over an extended period of time. Current research therefore addresses the question whether this might lead to stimulation of both the innate immune response (predominantly through the family of toll-like receptors) and the acquired immune response (by stimulating antigen-specific B and T cells), thereby maintaining a state of chronic inflammation. Furthermore, autoimmune processes are suspected to play a role in the development of chronic disease manifestations (2).

In parallel with the marked improvement of knowledge about the causative organism, clinical features, diagnosis, and treatment of Lyme disease in recent years, this disease entity has also become a collecting basin for speculations and fears about a possible link between tick-borne pathogens and a multiplicity of nonspecific complaints and conditions. One reason for this is the relatively high prevalence of antibodies against Borrelia burgdorferi (5% to 25%) even in healthy persons, depending on their prior exposure to tick bites in their occupational and leisure-time activities (1). The persistence of antibodies is not uncommonly misconstrued as evidence of florid infection, and thus the overdiagnosis and overtreatment of Lyme disease have become a significant problem. It is not surprising that worried physicians and patients often insist on treatment with antibiotics even in the absence of a clear indication.

Learning objectives: After reading this article, the reader should
- be acquainted with preventive measures against Borrelia infections,
- know when disease due to Borrelia burgdorferi is to be diagnosed, and
- know what kind of antibiotic treatment is appropriate, according to current knowledge.

Microbiology
The Gram-negative spirochetal bacterium Borrelia burgdorferi sensu lato is transmitted by the bite of an infected tick; in Germany, depending on the region, it is found in about 5% to 35% of ticks (e.g., in 25% of the ticks studied in southern Lower Saxony in the spring of 2007). The disease that it causes, Lyme borreliosis, has highly variable and often complex clinical manifestations and therefore must be included in the differential diagnosis of conditions belonging to many different medical specialties. Unlike the pathogen causing early summer meningoencephalitis, Borrelia burgdorferi is present throughout central Europe, in the same geographical area as its vector, the ixodid tick (Ixodes ricinus).

In Europe, unlike North America, there are several clinically relevant species of Borrelia burgdorferi causing human disease, which can be distinguished from each other genotypically (Borrelia burgdorferi sensu stricto, B. afzelii, B. garinii, B. spielmanii). Borrelia spielmanii has been described to date only as a cause of erythema migrans. Borrelia afzelii is the only known pathogen causing the chronic skin condition acrodermatitis chronica atrophicans (3). The other species can apparently give rise to all of the clinical manifestations of borreliosis (3). Borrelia garinii is found more often in cases of neuroborreliosis (4).

In view of the different spectrum of pathogens (the only pathogen causing Lyme disease in the USA is Borrelia burgdorferi sensu stricto), the findings of North American clinical studies are not automatically applicable to the situation in Europe.

The probability of transmission to a human being by a tick bite is low in the first 24 hours of adhesion and then increases markedly. It is only after contact with blood that the borrelia in the gut of the tick migrate to its salivary gland, so that they can be transmitted to the human victim through the puncture wound (1, 5).

Preventive measures against infection include the following:

- Wearing appropriate protective clothing
- Carefully inspecting the skin for ticks
- Removing the ticks rapidly.

In children, ticks are often found at the hairline. Forceps (tweezers) are a suitable instrument for removing them. Any superfluous manipulation of ticks, e.g., crushing them or covering them with oils or ointments, should be avoided, as these maneuvers may promote the regurgitation of blood and thereby increase the likelihood of borrelial transmission. Once the tick has been removed, the puncture site should be meticulously disinfected (5).

The prophylactic administration of antibiotics is not recommended as a routine measure (5). There is debate about whether this might be of benefit in certain exceptional cases, e.g., multiple tick bites in a highly endemic area for the disease, but the necessary duration of antibiotic treatment in such cases has not been adequately documented in clinical trials. The treatments that are sometimes given range from a single dose to a three-week course of antibiotics. The mere demonstration of borrelia in the tick does not constitute an indication for antibiotic treatment (5, 6).

After a tick bite, the rate of seroconversion—i.e., the probability that specific antibodies to Borrelia burgdorferi will be produced—is in the range of 3% to 6%. Clinically silent infection is common: clinically overt disease arises after only 0.3% to 1.4% of tick bites. In several prospective, regionally representative studies, the annual incidence of overt borreliosis in Germany was found to be 100 to 150 cases per 100 000 persons per year (7). In a study based in Würzburg (Bavaria) involving 313 cases over a period of 12 months, Borrelia burgdorferi infection manifested itself as erythema migrans in 89% of cases, as stage II neuroborreliosis in 3%, as borrelial lymphocytoma in 2%, as carditis in less than 1%, as arthritis in 5%, and as acrodermatitis chronica atrophicans in 1%. There was not a single case of chronic (Stage III) neuroborreliosis (7). Most cases arose between June and August; only 15% arose between November and April (7).

Clinical features
Lyme borreliosis can affect many different organs. The stage of the disease is classified as early or late, and the manifestations are classified as local or generalized. The frequency of the individual clinical manifestations is highly variable, depending on the age of the patient, the species of the pathogen, and other factors (1, 8).

Stage I (days to weeks after the tick bite): erythema migrans around the site of infection.

Stage II (weeks to six months after the tick bite): meningoradiculitis (inflammation of the meninges and nerve roots; Bannwarth syndrome), meningitis, peripheral facial palsy, encephalitis, myelitis, cerebral arteritis, multiple erythemas, arthritis, myalgia, borrelial lymphocytoma, myositis, myo- or pericarditis, iritis.

Stage III (longer than six months after the tick bite, perhaps years after it): encephalitis or encephalomyelitis, cerebral arteritis, polyneuropathy, mono- or oligoarthritis, acrodermatitis chronica atrophicans.

The course of the disease may skip any individual stage, e.g., a patient with neuroborreliosis need not have had erythema migrans in the past. Spontaneous recovery is the rule mainly in stages I and II. Stage III is differentiated from Stage II rather arbitrarily by a cut-off interval of six months from the day of the tick bite.

Stage I (early, localized): The typical, and by far the most common (> 80%), manifestation of early Borrelia infection is erythema migrans, which is usually seen one to two weeks after the tick bite (range, 3 to 30 days) (e1). The erythema spreads locally around the site of the puncture wound in a circular or oval configuration, and it may become quite large. The rash is painless but may itch. Two or more skin lesions appear in some cases, indicating early systemic dissemination of the bacteria. If left untreated, erythema migrans usually resolves spontaneously in a few days to weeks (median, 4 weeks).

In 10% to 30% of cases, erythema migrans is accompanied by nonspecific constitutional symptoms such as malaise, a subfebrile temperature, short-lasting migratory pains in the small joints, bursae, and tendons, and fatigability (1).

Stage II (weeks to six months after the tick bite, generalized): Meningoradiculoneuritis (Bannwarth syndrome) is the leading manifestation of this stage in adult patients. After erythema migrans, this is the second most common manifestation of acute Lyme disease in adults. Its main clinical features are lymphomonocytic meningitis, radiculitis (inflammation of the spinal nerve roots), cranial nerve deficits (most commonly a uni- or bilateral peripheral facial palsy), radicular pain, and paresis (1). The protein concentration in the cerebrospinal fluid (CSF) is often relatively high, a finding that distinguishes this condition from a viral infection of the central nervous system.

In children, the major finding is usually an acute peripheral facial palsy, usually associated with CSF pleocytosis, or else a lymphocytic meningitis without focal neurological manifestations (8, 9).

Borrelial carditis is a relatively rare complication in Europe (in contrast to North America), occurring in about 1% of all cases of illness due to Borrelia burgdorferi (7). It reportedly arises with a latency of four days to seven months after the tick bite (median, 21 days). It is often accompanied by other manifestations, such as erythema migrans or neurological deficits. Its symptoms are dizziness, palpitations, or syncope, caused by disturbances of intracardiac impulse generation or impulse conduction. The typical finding is an atrioventricular block of variable severity, which usually resolves within six weeks. Rarely, ST- and T-wave changes indicate the presence of myocarditis.

Borrelial lymphocytoma (also called lymphadenosis cutis benigna of Bäfverstedt) is the typical cutaneous manifestation of stage II disease, usually arising within 2 months of the tick bite. Its frequency is approximately 2%; it is often accompanied by erythema migrans (7). The lesion is a benign reddish-purple tumor that tends to appear on the earlobe in children, and on the nipples, scrotum, nose, or arms in adults (figure 1 jpg ppt).

Stage III (late or persistent disease): The typical manifestations are acrodermatitis chronica atrophicans of Herxheimer (ACA) and chronic Borrelia-induced arthritis.

Six months to several years after the tick bite, inflammatory skin lesions may arise that undergo a transition to an atrophic stage of ACA. These lesions tend to appear on the extensor surfaces of the limbs but are occasionally located on the face or trunk. They consist of parchment-like thinning of the skin with prominent venous markings and, sometimes, altered pigmentation. The patients complain of pain, pruritus, and hyperesthesia or paresthesia. ACA is occasionally associated with polyneuropathy.

In stage III, chronically progressive meningoencephalitis and multifocal cerebral vasculitis can arise (1). The term "chronically progressive meningoencephalitis" is used when irreversible neurological damage is present and the course of the illness is not self-limited, as it is in acute Borrelia-induced meningoencephalitis.

In a series of 18 patients (10), the following clinical manifestations were found:

- in 16 patients, spastic quadric- or paraparesis;
- in 11, cranial nerve deficits (figure 2 jpg ppt);
- in 9, bladder dysfunction;
- in 7, sensory disturbances;
- in 6, ataxia;
- in 4, altered personality;
- in 2, flaccid paresis;
- in 2, dysarthria.

Fewer than 5% of all patients with neuroborreliosis suffer from chronic progressive meningoencephalitis. Cerebral borrelial vasculitis, a rare condition, is an obliterating vasculitis with thickening of the vascular intima and adventitia and perivascular lymphocytic infiltrates (11, 12). Rare cases of extrapyramidal motor disease associated with Borrelia infection have been described (e2), but there is some question as to the causal relationship.

In untreated Lyme disease, joint manifestations can arise months to years after the tick bite, usually in the form of a chronic mono- or asymmetrical oligoarthritis. The knee and elbow joints are most commonly affected. A not very painful arthritis occurring in episodic attacks is typical, often associated with a voluminous effusion but only mild signs of inflammation. Each episode lasts for several days to weeks. In children, borrelial arthritis has a good prognosis and rarely becomes chronic, even when untreated (7, 8) (figure 3 jpg ppt).

Diagnostic evaluation
Borrelia burgdorferi sensu lato can be cultured from body fluids only in highly specialized laboratories, and, because of the low bacterial count in the fluids that are tested, the polymerase chain reaction (PCR) is of limited diagnostic sensitivity. Routine microbiological diagnostic testing therefore generally consists of an assay for Borrelia-specific antibodies. Lyme disease is a clinical diagnosis, i.e., clinical criteria (the history, symptoms, and signs) are decisive for the assignment of the diagnosis and the interpretation of the serological findings. The more typical the clinical features, the less important the serological findings. Serological examination should be performed immediately whenever an infection with Borrelia burgdorferi sensu lato is suspected on clinical grounds. If the findings are negative or ambiguous and the clinical suspicion remains, then the serological examination should be repeated in three weeks. If clinically evident erythema migrans is present, no serology need be obtained, because antibiotic treatment is indicated regardless of the laboratory findings.

The clinical findings and laboratory parameters are accordingly considered in the published case-definition criteria ([13, 14]; see also the box "Internet Addresses" gif ppt).

In Europe, microbiological testing for Lyme disease must take the heterogeneity of the causative organisms into account. The guidelines recommend a stratified serological diagnostic evaluation: first, a sensitive ELISA that differentiates IgG and IgM antibodies should be used as a screening test. Positive or borderline results should then be confirmed with an immunoblot, the interpretation of which is described in the guidelines (13). In case of doubt, a reference laboratory should check the specificity of the finding (14).

Antibodies against Borrelia are found in fewer than 50% of patients with erythema migrans (1). In contrast, when neurological manifestations arise, Borrelia-specific IgM or IgG antibodies are found in the serum of more than 90% of patients (9, 13). "Borrelia serology may be negative in the early phase of a borrelial infection, particularly if antibiotic treatment has been started early" (14). Serology together with the corresponding clinical manifestations has a high diagnostic specificity.

In neuroborreliosis, the CSF examination reveals pleocytosis, usually with a leukocyte concentration well below 1000/mL, in which lymphocytes predominate. The CSF protein concentration is often elevated to 1 g/L or higher. The clinical suspicion of neuroborreliosis is confirmed by the demonstration of CSF pleocytosis and intrathecally formed specific antibodies against Borrelia (antibody index, AI). The Borrelia-specific AI is determined for both IgG and IgM (box gif ppt).

A pathological Borrelia-specific AI is conclusive evidence of a current or previous episode of neuroborreliosis. In early stages of the disease, the Borrelia-specific AI can still be negative. CSF pleocytosis reflects the degree of activity of the inflammatory process in the central nervous system. Repeated determinations of the specific antibody titer in the serum and of the CSF/serum AI provide no valid information about the degree of activity of the disease or the response to treatment.

In summary, the detection of specific antibodies in the serum in the early phase of a Borrelia infection is neither a necessary criterion for the diagnosis (e.g., the sensitivity of this test in the early phase of erythema migrans is 50% at most) nor a sufficient criterion for it (as shown by the high prevalence of specific antibodies [<5% to more than 25%] in the general population). The less specific the patient's symptoms, the lower the predictive value of a positive serological finding. Conversely, if a borrelial infection has persisted for longer than eight weeks, Borrelia-specific antibodies must be detectable in the serum. An elevated Borrelia-specific AI is not proof of a fresh episode of neuroborreliosis; even when neuroborreliosis has been successfully treated, an elevated Borrelia-specific AI can be found for years afterward, long after the CSF leukocyte count has become normal again.

The direct demonstration of the infectious agent by laboratory culture or PCR should be attempted only when there are special indications for this, such as inconclusive clinical or serological findings. Direct demonstration requires especially careful preparation of the sample to be tested (skin biopsy, CSF, joint puncture or biopsy; sensitivity for skin, 50% to 70%; for joint puncture, 50% to 70% [PCR only]; for CSF, 10% to 30%). PCR is preferred because it can be performed much more rapidly than culture.

Neither antigen testing of body fluids nor PCR on urine samples is recommended, as these techniques have not been clinically validated. The same holds for the lymphocyte transformation test, which, in principle, should be able to detect very early Lyme disease and to distinguish active from no longer active infection. This method is particularly subject to false-positive results and is therefore not suitable for diagnostic use in its current stage of development (6, 15).

Treatment
Lyme disease has a good prognosis (14, 16, 17). Most of its clinical manifestations are self-limiting. Even in the pre-antibiotic era, and also afterward, for as long as neuroborreliosis was mistakenly considered to be a viral infection (i.e., until 1982), spontaneous cures were often observed. Antibiotic treatment shortens the clinical course and prevents complications and rare chronic infections (16, e3–e5). The long-term results of antibiotic treatment are very good (14, 16–18). When the disease is treated in accordance with published guidelines, recurrences are very rare. On the other hand, reinfection is possible after another tick bite. The development of antibiotic resistance of the pathogenic organism has not been demonstrated to date. Even after the pathogen has been eliminated, the clinical manifestations may take weeks to resolve. The effect of treatment should be judged from the clinical manifestations rather than the laboratory findings. Antibiotic treatment rapidly relieves pain in Bannwarth syndrome (14). 95% of patients with spinal radiculitis had severe pain at the beginning of treatment; after 14 days of treatment with ceftriaxone, the intensity of pain was markedly reduced in all patients. Stage II neuroborreliosis resolved completely, without any residual symptoms, in 90% of patients after 3 months and in 95% after 12 months; 5% still had a mild facial palsy. The neurological deficits resolve more slowly after antibiotic treatment of stage III neuroborreliosis, and the frequency of residual damage is higher: after 12 months, the pareses, ataxia, and bladder dysfunction had completely resolved in 10 of 15 patients (66%) (16). In neuroborreliosis, normalization of the CSF pleocytosis can be used as an additional measure of the response to treatment, alongside the clinical findings.

Because the serological findings can vary markedly, and because antibodies, including those formed in the central nervous system, can persist for a long time, serological follow-up testing is not a suitable means of monitoring the success of treatment.

An infection with Borrelia burgdorferi sensu lato is not followed by any lasting immunity.

The choice of antibiotic, its mode of administration, and the duration of treatment depend on the stage of the disease, the clinical manifestations, and the age of the patient (table gif ppt). The recommendations given here are based on treatment studies, on in vitro data regarding pathogen sensitivity, and on the pharmacokinetic parameters of the antibiotics that are used.

The pathogenic organisms causing borreliosis are highly sensitive in vitro to cefotaxime, ceftriaxone, and macrolides (minimal inhibitory concentration for the growth of 90% of strains [MIC₉₀], 0.06 to 0.12 mg/L) and somewhat less sensitive to amoxicillin, other aminopenicillins, and tetracyclines (MIC₉₀, 0.5 mg/L). The MIC₉₀ of penicillin is relatively high (4 mg/L).

The current standard of treatment in stage I in adult patients is doxycycline 100 mg po bid or amoxicillin 500 mg po tid for two weeks (evidence level A) (17). While taking doxycycline, patients should avoid exposure to the sun, because phototoxic side effects are otherwise common. Children under 9 years old should not take tetracyclines, because these can cause yellowish discoloration of the teeth; amoxicillin is usually given instead. Alternatively, cefuroximaxetil or (in case of allergy to beta-lactam antibiotics) macrolides can be given instead, but the effectiveness of these drugs seems to be less reliable (17).

In randomized studies involving patients with stage II neuroborreliosis, the following treatment regimes were found to be effective: penicillin 6 × 10⁶ U IV tid-qid (evidence level A), cefotaxime 2 g tid (A), ceftriaxone 2 g IV qd for 14 days (A), and doxycycline 100 mg po bid–tid for 2 weeks (B) (14, e6). The third-generation cephalosporins are recommended despite their higher daily treatment costs because of their low MIC₉₀ values. After the intravenous administration of 2 g of drug, equally high CSF concentrations of cefotaxime and ceftriaxone are achieved (19). Ceftriaxone 2 g IV qd for 14 days is the standard treatment because it needs to be given only once daily.

In stage III, ceftriaxone 2 g IV qd is given for 14 to 21 days (or for 14 to 28 days; for alternative treatments, see the table).

Prolongation of the treatment to more than 28 days is not indicated. On the contrary, this carries a high risk of side effects, including pseudomembranous colitis and the accumulation of ceftriaxone calcium salts in the gall bladder, which can also become symptomatic.

Chronic, nonspecific symptoms accompanied by a positive Borrelia serology
In addition to the clinical and laboratory findings described above that clearly fulfill the case-definition criteria, chronic, nonspecific symptoms accompanied by a positive Borrelia serology are sometimes thought to represent a form of Lyme disease. There is concern in such situations that chronic Lyme disease has arisen without the clinical signs of an acute infection ever having been observed previously. The authors consider this to be possible, in view of the fact that typical neuroborreliosis or borrelial arthritis can develop in the absence of prior erythema migrans. Nonetheless, an especially meticulous process of differential diagnosis is mandatory in such cases. In the guidelines of the German Neurological Society, the following is stated: "If Borrelia antibody tests are positive (...) and have been confirmed as positive by a reference laboratory (...), and if other causes have been excluded, then a single course of antibiotic treatment can be considered in individual cases (...). Failure of this empirical course of antibiotic treatment to relieve the patient's symptoms lastingly is evidence against the presence of chronic Lyme disease" (14).

Patients who have been through an episode of borreliosis that has resolved after adequate antibiotic treatment may have symptoms thereafter, most commonly impaired performance, fatigability, impaired concentration, or chronic pain (20). This symptom complex is often designated by the as yet inadequately defined terms "chronic Lyme disease" or "post-Lyme syndrome," implying the pathogenetic conception of a persistent infection or of a persistent secondary disease after eradication of the causative organism (18). In many studies that have been performed on such patients, the bacterium could no longer be demonstrated, and a reintroduction or prolongation of antibiotic therapy had the same effect as placebo treatment (21). In one study involving 55 patients who were still suffering from severe fatigability and exhaustion 6 months (or more) after adequate antibiotic treatment for borreliosis, a new 28-day course of ceftriaxone (2 g/day) improved their fatigability and exhaustion, but not the cognitive impairment that was simultaneously present (22). Moreover, controlled studies have shown that symptoms of this kind do not seem to arise any more often in patients who have had definitively documented Lyme disease than they do in normal control individuals (23). Nonetheless, prolonged antibiotic treatment is still postulated by some to be beneficial, mainly on the basis of case reports and nonrandomized studies. Such treatment generally lies within the sphere of "alternative medicine" (24).

New experimental data suggest that T-cell clones activated in a borrelial infection can react not only with Borrelia antigens, but also with endogenous proteins such as heat shock protein 90 (HSP90). This cross-reaction to exogenous and endogenous antigens might induce an autoimmune illness, which might in turn explain cases of antibiotic-resistant, chronic illness after borrelial infection (2, 25). Research is currently addressing the question whether a borrelial infection can induce an autoimmune reaction of rheumatic type that persists after the pathogen has been eliminated. There is much controversy over another question, i.e., whether borrelial infection can cause psychiatric disease.

The demystification of this infectious disease is urgently needed and can only be brought about by further, unambiguous scientific documentation of its long-term consequences.

Residual manifestations in the aftermath of Borrelia burgdorferi infections must be treated symptomatically, e.g., with anti-inflammatory drugs or antidepressants. On the other hand, in the authors' judgment, the administration of repeated cycles of antibiotic treatment is not indicated.

Conflict of interest statement
Professor Nau and Professor Eiffert have received support for their work on neuroborreliosis from the Else Kröner Fresenius Foundation. Professor Christen states that he has no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 23 May 2008; revised version accepted on
1 September 2008.

Translated from the original German by Ethan Taub, M.D.


Corresponding author
Prof. Dr. med. Roland Nau
Geriatrisches Zentrum
Evangelisches Krankenhaus Göttingen-Weende
An der Lutter 24
37075 Göttingen, Germany
[e-mail]


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