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Understanding Lyme Disease: A Complete Guide to Diagnosis and Treatment

Lyme borreliosis (Lyme disease) is a complex, multi-organ infection caused by Borrelia bacteria transmitted through tick bites.

21 min

Table of Contents

Key Points

  • Up to 50% of Lyme patients recall no tick bite; absence of rash does not rule out infection.
  • Negative antibody tests do not exclude Lyme disease, especially after early antibiotic treatment.
  • Lymphocyte transformation test (LTT) can indicate active infection when serology is inconclusive.
  • Early antibiotic treatment within 4 weeks of infection improves outcomes significantly.
  • Chronic Lyme disease may cause fatigue, neurological, joint, and skin symptoms lasting over 6 months.

Background: What Is Lyme Borreliosis?

Lyme borreliosis was first identified as a distinct disease in 1975 by Steere and colleagues, and the causative agent was discovered in 1981 by Willi Burgdorfer. Despite intensive research since then, there remains an inadequate scientific basis for the diagnosis and treatment of this condition, especially for chronic forms where evidence-based studies are lacking.

The disease occurs throughout Europe, and infection typically happens in the countryside, in one's own garden, or through contact with domestic and wild animals. Lyme borreliosis is classified in the ICD-10-GM Diagnosis Code under A 69.2 "Lyme disease, Erythema chronicum migrans due to B. burgdorferi" and under M 01.2 "Arthritis in Lyme Disease."

The earlier classification of the disease into three stages (Stage I with erythema migrans, Stage II with early organ manifestations, and Stage III with late manifestations) is now considered outdated because clinical signs of the various stages overlap. Today, doctors prefer to classify the disease into early and late manifestations, with "chronic Lyme borreliosis" being equivalent to what was formerly called Stage III.

Essential Features of Lyme Disease

Lyme borreliosis is known as a multiorgan disease because it can affect many different organs and systems in the body. This creates a wide range of differential diagnoses for the often numerous manifestations of the disease.

The essential features of Lyme borreliosis include:

  • Erythema migrans (EM) — the characteristic "bull's eye" rash, though this is not inevitable
  • Lymphocytoma (a reddened nodular swelling) and acrodermatitis chronica atrophicans (a skin condition in late stages)
  • Flu-like condition in the early stage, even without EM, as a sign of pathogen dissemination
  • Usually acute manifestations in various organ and tissue systems with a wide variety of symptoms
  • Chronic fatigue and rapid fatiguability, an episodic disease course with a strong feeling of illness, and symptoms that appear in different places

Characteristic of the late manifestations are chronic fatigue, rapid fatiguability, and symptoms that appear in different locations throughout the body. Many different organ-specific symptoms may also be present, which we will discuss in detail below.

Diagnostic Strategy in Daily Practice

In daily medical practice, doctors encounter several distinct situations when dealing with potential Lyme borreliosis. These include a recent tick bite, erythema migrans and lymphocytoma, early stage without erythema migrans, and chronic stage. Each situation requires a different diagnostic approach.

One of the most important facts to understand is that up to 50% of borreliosis patients deny having suffered a tick bite when their history is taken. This means that a negative history of tick bites does not rule out Lyme borreliosis. The longest latency period before the occurrence of symptoms of the disease was documented at 8 years.

What to Do After a Recent Tick Bite

If you have recently been bitten by a tick, the guidelines recommend observing the site of the bite for 4–6 weeks. If any reddening (erythema) occurs, you should consult a doctor immediately. It also makes sense to examine the tick itself for Borrelia using PCR testing, though a negative PCR result does not entirely rule out the infectiousness of the tick.

Serological testing (blood tests for antibodies) is recommended to confirm insurance claims, for patients with a history of Lyme borreliosis, and if it is planned to monitor the course of the disease. If antibodies against Borrelia are found in the blood at a check-up examination 6 weeks after a tick bite, infection has occurred. This can be proven only with a pair of serum samples taken at different times.

Patients themselves should keep a diary and record any cutaneous changes photographically. If the tick is still present, it is advisable to keep it for later testing for Borrelia by PCR.

Erythema Migrans and Lymphocytoma

Erythema migrans is considered evidential for Lyme borreliosis. The conclusion is clear: immediate antibiotic treatment is required. The earlier the antibiotic treatment is started, the better the infection can be controlled. Therapeutic success is distinctly poorer even 4 weeks after the start of infection.

Borrelia-specific antibodies do not appear until 2–6 weeks after the start of infection. Antibiotic treatment at an early stage can prevent the development of antibodies, meaning no seroconversion takes place. Therefore, seronegativity (negative antibody test) following early antibiotic treatment does not rule out Lyme borreliosis in any way.

If there is a corresponding history of tick exposure and a reddened nodular swelling is found — for example on the nipple, skin of the scrotum, bends of joints, and in children often on the external ear — this may be a lymphocytoma. A Borrelia lymphocytoma is evidential of Lyme borreliosis just as erythema migrans is, taking into consideration the differential diagnosis. This type of lymphocytoma is usually caused by Borrelia afzelii and sometimes forms in the centre of an erythema migrans in the region of the original tick bite. Borrelia can be isolated from all areas of an erythema migrans and of a Borrelia lymphocytoma.

Early Stage Without Erythema Migrans

In up to 50% of cases, no erythema migrans is observed in the early stage of Lyme borreliosis. In the absence of EM, the diagnosis is based on several criteria: the circumstances of the illness (time spent in one's own garden and in the countryside, tick bite), a thorough physical examination with inspection of the skin in search for EM (including those possibly with diameters less than 5 cm) and lymphocytomas, and laboratory diagnostic tests.

First manifestations of Lyme borreliosis sometimes do not occur for weeks to years after the start of infection. If appropriate symptoms are present, especially if tick bites are mentioned during history-taking, or if there is a high risk of infection, Lyme borreliosis must always be considered in the differential diagnosis.

The following may occur in the early stage:

  • Transient migratory arthritis, arthralgia (joint pain) and myalgia (muscle pain)
  • Bursitis (inflammation of bursae) and enthesitis (inflammation at tendon attachment sites)
  • Headaches
  • Radicular pain syndromes (known as Bannwarth's syndrome)
  • Cranial nerve symptoms, especially facial nerve paresis (weakness or paralysis)
  • Sensitivity disturbances (numbness, tingling)
  • Cardiac dysrhythmias, stimulus formation and stimulus conduction disorders (heart rhythm problems)
  • Ocular symptoms, such as double vision

Chronic Lyme Borreliosis

The time differentiation between the early and late stages is somewhat arbitrary. Disease manifestations of Lyme borreliosis which occur more than 6 months after the start of infection are designated in this guideline as late manifestations or as chronic.

Lyme borreliosis can lead to numerous symptoms in the chronic stage. The following are particularly frequent:

  • Fatigue (exhaustion, a chronic feeling of illness)
  • Encephalopathy (impaired cerebral function)
  • Muscular and skeletal symptoms
  • Neurological symptoms, including polyneuropathy (nerve damage)
  • Gastrointestinal symptoms
  • Urogenital symptoms
  • Ocular symptoms
  • Cutaneous (skin) symptoms
  • Heart diseases

A cutaneous manifestation indicative of the illness in its late stage is acrodermatitis chronica atrophicans (ACA), a skin condition characterized by thinning and discoloration of the skin. Chronic polyneuropathy, which often accompanies ACA, is also seen as a typical manifestation of the illness in its late stage.

Occupational Disease and Accident Insurance

Lyme borreliosis is classed as an occupational disease according to No. 3102 in Annex 1 to the Occupational Diseases Regulation in Germany. The only deciding factor is whether the tick bite (the infection) occurred in the course of one's work. For certain occupational groups at high risk of infection — including farmers, forestry workers, and veterinarians — a relationship between the tick bite and the disease is generally accepted as causal. For other occupational groups, this causal relationship must be demonstrated by the person affected.

Therefore, when a tick bite occurs during work and manifestations of the illness subsequently appear, the attending physician must carefully document the history, the examination findings, and the laboratory results. The same applies to a tick bite suffered by individuals who have taken out relevant accident insurance.

In the case of a tick bite during work or for those with accident insurance, a serological test for Borrelia should be performed as soon as possible after exposure, and the test system should be documented. Seroconversion, a significant rise in titre, or an increase in the bands in the immunoblot in the course of four to six weeks must be regarded as proof of a Borrelia infection.

Symptoms of Chronic Lyme Borreliosis

The symptoms of chronic Lyme borreliosis develop either seamlessly from the early stage, or only after a symptomless interval of months to years, or may indeed develop from the outset as chronic Lyme borreliosis without patients being aware of an early stage. The conclusion to draw from this is that chronic Lyme borreliosis may exist even in the absence of a history of tick bite and erythema migrans, if the circumstances of the illness, its manifestations, and the differential diagnostic analysis make this a reasonable assumption.

Inflammation of the knee joint (gonitis), after other causes have been excluded by differential diagnosis, is evidential of the late phase of chronic Lyme borreliosis.

The spread of Borrelia in the body leads to multiorgan or systemic disease with an exceptionally wide variety of possible manifestations. Beyond the most common symptoms mentioned above, the disease can affect:

  • Neurological and mental health: including cognitive difficulties, mood changes, and various neurological syndromes
  • Hormonal, vegetative and immunological manifestations: affecting the endocrine system and immune response
  • Muscular and skeletal systems: including arthritis and muscle pain
  • Cutaneous manifestations: various skin conditions beyond erythema migrans
  • Cardiovascular symptoms: including heart rhythm disturbances and inflammation
  • Ocular manifestations: affecting vision and eye structures
  • Manifestations during pregnancy: which require special attention

Laboratory Diagnostics

Lyme borreliosis-related laboratory diagnostic tests for Borrelia infection are indicated if there are symptoms or clinical findings present which are consistent with Lyme borreliosis. However, serological monitoring tests to assess the success of treatment are not useful in chronic Lyme borreliosis. The success of treatment must be assessed clinically.

Direct Identification of Borrelia

Lyme borreliosis is an infectious disease. Applying strict scientific criteria — especially in scientific studies — only the detection of Borrelia in culture with identification of the causative agent by PCR is considered proof of a Borrelia infection.

The identification of Borrelia DNA by a polymerase chain reaction (PCR for Borrelia) is also of major relevance. Although the sensitivity of this identification technique is poor, especially in the late manifestations of Lyme borreliosis, tests should nevertheless be conducted to identify the causative agent. This includes testing skin biopsy specimens when suspicious cutaneous changes are present, other biopsy specimens and puncture specimens (for example in cases of joint inflammation), and cerebrospinal fluid (CSF) in cases of acute neuroborreliosis. Importantly, negative results do not rule out Lyme borreliosis.

Borrelia Serology (Antibody Testing)

Borrelia serology is the basic diagnostic tool to answer the question of whether a Borrelia infection might be present. However, the test systems on the market (ELISA and immunoblotting) are not standardised, meaning findings from different laboratories can be compared to only a limited degree.

Testing for the presence of Borrelia-specific antibodies is possible only with an immunoblot. If a Borrelia infection is suspected, an IgG and IgM immunoblot for Borrelia should be carried out in all cases. The request note to the laboratory must therefore state: "Borrelia serology inc. immunoblotting for Borrelia." In addition, the clinical diagnosis or suspected diagnosis should be given as Lyme borreliosis.

The procedure recommended by the Robert Koch Institute (RKI) and prescribed by the Association of Health Insurance Funds — to conduct immunoblotting as a confirmatory test only if the ELISA is abnormal (a process known as stepwise diagnostics) — must be rejected because this leads to serologically false-negative results in up to a further 15% of patients. The reason for this is that the antigen spectrum present in the immunoblot is usually not identical to that included in the ELISA exploratory test. An ELISA and an immunoblot for Borrelia are two different test methods which can yield differing results in the individual case, even though they correlate with each other to a high degree.

The immunoblot detects antibodies against specific Borrelia antigens, each with different diagnostic significance:

  • p14, p18: High specificity, mainly in cases of B. afzelii
  • p21 (DbpA): High specificity, binds to decorin protein on host cells, especially in the skin
  • p22-25 (OspC): High specificity, most important marker of the early IgM response; 13 different OspC types have been described
  • p31 (OspA): High specificity, seven different OspA types are known, and the OspA type determines the species
  • p34 (OspB): High specificity, antibodies only appear late post-infection
  • p39 (BMPA): High specificity, antibodies usually appear early post-infection
  • p41 (Flagellin): Unspecific, cross-reactions with other spirochaetes and flagellated bacteria; IgM antibodies appear first and very early
  • p60 (Hsp6): Unspecific, antibodies often also appear in other bacterial infections
  • p66: Unspecific, antibodies common in bacterial infections
  • p75 (Hsp): Unspecific
  • p83/100: High specificity, antibodies usually only in the later stage of infection
  • VlsE: High specificity, IgG antibodies are possible even in the early stage; VlsE is expressed by Borrelia only in the host

A negative serological finding does not rule out Lyme borreliosis. There may be a disease requiring treatment even without the detection of antibodies. Causes include antibiotic treatment starting early but inadequate, treatment with immunodepressants including cortisone, exhaustion of the immune system, masking of the causative agents, and genetic disposition.

A positive serological finding means that the patient has acquired a Borrelia infection at some point in time. With a single serological test, it is not possible to decide whether this infection is active or latent. At best, this can be decided by the attending physician on the basis of its clinical development. It is not within the remit of a laboratory physician to evaluate a positive finding as a "serological relic" — that is, antibodies evidential of an earlier infection.

Examination of Cerebrospinal Fluid (CSF)

Diagnostic testing of the cerebrospinal fluid (CSF) is indicated in cases of acute inflammation of the nervous system, including:

  • Meningitis, meningo-encephalitis, encephalomyelitis, acute encephalitis
  • Acute meningoradiculitis (Bannwarth's syndrome), Guillain-Barré syndrome
  • Cerebral vasculitis, myelitis
  • Neuritis of cranial nerves, especially facial nerve paresis
  • Acute polyneuropathy

However, testing of the CSF is not indicated in the following disease states in relation to Lyme neuroborreliosis, because pathological results are not to be expected:

  • Encephalopathy in chronic Lyme borreliosis
  • Chronic polyneuropathy in the late stage
  • Cerebro-organic psychosyndrome

Pleocytosis (cell count over 5/μL), elevated protein level, and evidence of the intrathecal synthesis of Borrelia-specific antibodies (serum/CSF ratio) are indications of acute neuroborreliosis. However, if the neuroborreliosis occurs very soon after Borrelia infection and with late manifestations, Borrelia-specific antibodies will be absent from both the serum and the CSF, or will appear sooner in the CSF than in the serum, and vice versa.

The detection of intrathecally formed Borrelia-specific antibodies in the CSF is only very rarely possible in cases of Lyme borreliosis with neurological involvement. If acute neuroborreliosis is suspected, the treatment should not be made dependent on the laboratory results.

Lymphocyte Transformation Test (LTT)

As the cellular immune response (lymphocytes, monocytes) follows a more rapid dynamic than the relatively sluggish serological formation of antibodies, a lymphocyte transformation test (LTT) is faster to provide an indication of an active infection.

The following arguments support the use of cellular immunological methods in the laboratory diagnosis of Lyme borreliosis:

  1. The direct identification of the causative agent is proof of Lyme borreliosis, but the sensitivity of the methods for direct identification of Borrelia is technically inadequate at present for daily practice.
  2. A positive serological finding is not evidence of active Lyme borreliosis. On the other hand, a negative serological finding does not rule it out, especially when there are early manifestations of Lyme borreliosis.
  3. If there is no positive result available from a Borrelia culture or PCR for Borrelia, an LTT for Borrelia can provide an indication whether active Lyme borreliosis is present. A positive result from the LTT for Borrelia is suspicious, but not evidential, of an active Borrelia infection.
  4. The LTT for Borrelia is clearly positive even in the early stage of Borrelia infection (even if erythema migrans is present) and is generally negative or at least clearly regressive 4 to 6 weeks after the conclusion of successful antibiotic treatment.

The indications for an LTT for Borrelia are:

  • Evidence of an active Borrelia infection in seropositive patients with ambiguous symptoms
  • A seronegative result or result assessed serologically as borderline in patients with a strong clinical suspicion of Lyme borreliosis
  • To monitor therapy approximately 4–6 weeks after concluding a course of antibiotic treatment
  • To monitor progress if there is a clinical suspicion of a recurrence of Lyme borreliosis
  • A new infection

Certain laboratories offer different methods for the detection of Borrelia-specific activation of T lymphocytes, such as the EliSpot-Test-Borrelia®. In these methods, the induction of cytokine synthesis is measured at the cellular level. Although the EliSpot is well-established in the diagnosis of infectious diseases like tuberculosis, its importance in the diagnosis of borreliosis has yet to be tested by appropriate techniques.

CD57+ NK Cells

According to Stricker and Winger, CD57+ NK cells (a type of natural killer cell) are often markedly reduced in the blood of patients with chronic Lyme borreliosis. However, it is not possible to evaluate the CD57+ NK cells as a laboratory parameter in connection with Lyme borreliosis at present, on account of the insufficient data available.

Co-infections

Ticks can transmit multiple pathogens simultaneously, leading to co-infections that can complicate the clinical picture and treatment of Lyme borreliosis. Co-infections transmitted by ticks include various bacterial and parasitic agents that may require additional or different treatment approaches. Additionally, there are co-infections not transmitted by ticks that may be present in patients with Lyme borreliosis and should be considered in the differential diagnosis.

Antibiotic Treatment of Lyme Borreliosis

The recommendations for antibiotic treatment presented in this guideline differ significantly in some respects from the guidelines of other specialist societies. The patient must be made aware of this fact when treated according to this guideline. In addition, careful checks for side-effects must be carried out when long-term antibiotic therapy is conducted.

Early treatment is critical. The earlier antibiotic treatment is started after infection, the better the infection can be controlled. Therapeutic success is distinctly poorer even 4 weeks after the start of infection.

Unsuitable Antibiotics

Not all antibiotics are effective against Borrelia bacteria. The guidelines specifically identify certain antibiotics that are unsuitable for treating Lyme borreliosis and should not be used. Patients should be aware that receiving an inappropriate antibiotic may lead to treatment failure and progression of the disease.

Suitable Antibiotics

Several antibiotics have been shown to be effective against Borrelia burgdorferi and related species. The choice of antibiotic depends on the stage of the disease, the organs affected, and individual patient factors. Effective antibiotics in Lyme borreliosis include specific members of the tetracycline, penicillin, and cephalosporin classes, among others.

The guidelines provide detailed tables of effective antibiotics, their dosages, and routes of administration for different clinical situations.

Monotherapy Options

For many patients, treatment with a single antibiotic (monotherapy) may be sufficient. The guidelines provide specific recommendations for antibiotic monotherapy of Lyme borreliosis, including the drug of choice, dosage, and duration of treatment for different stages and manifestations of the disease. Early localized disease often responds well to oral antibiotics, while more advanced or neurological forms may require intravenous therapy.

Combined Therapy Options

In certain situations — particularly in chronic or complicated cases — a combined therapy using two or more antibiotics may be recommended. The guidelines provide specific recommendations for antibiotics used in combined therapy of Lyme borreliosis. This approach may be considered when monotherapy has failed, in cases of co-infection, or in severe or persistent manifestations of the disease.

Prevention Strategies

Prevention of Lyme borreliosis focuses primarily on avoiding tick bites and removing ticks promptly when they are found. The guidelines emphasize the importance of checking for ticks after spending time in tick habitats, using appropriate protective measures, and removing attached ticks properly and quickly.

After a tick bite, the site should be observed for 4–6 weeks for any reddening. If erythema occurs, immediate medical consultation is advised. Early antibiotic treatment at the time of erythema migrans can prevent the development of antibodies and control the infection effectively.

Limitations of Current Knowledge

Despite intensive research, there is as yet an inadequate scientific basis for the diagnosis and treatment of Lyme borreliosis. This is especially the case with the chronic forms, for which there is a lack of evidence-based studies. The guidelines acknowledge several important limitations:

  • Test systems for Borrelia serology are not standardised, limiting comparability between laboratories
  • Direct identification of Borrelia has poor sensitivity, especially in late manifestations
  • Negative serological findings do not rule out Lyme borreliosis
  • Positive serological findings cannot distinguish between active and latent infection
  • The CD57+ NK cell parameter cannot be evaluated at present due to insufficient data
  • The EliSpot test's importance in borreliosis diagnosis has yet to be tested by appropriate techniques

These limitations mean that clinical judgment remains essential in diagnosing and treating Lyme borreliosis, particularly in its chronic forms.

Recommendations for Patients

Based on this comprehensive guideline, patients should be aware of the following key recommendations:

  1. After a tick bite: Observe the bite site for 4–6 weeks. If any reddening occurs, consult a doctor immediately. Consider having the tick tested for Borrelia by PCR.
  2. If erythema migrans appears: Seek immediate antibiotic treatment. Early treatment is critical for successful outcomes.
  3. Be aware that absence of a tick bite history does not rule out Lyme disease: Up to 50% of patients do not recall a tick bite.
  4. Understand that negative antibody tests do not exclude Lyme disease: Especially in early stages or after early antibiotic treatment.
  5. Request comprehensive testing: If Lyme borreliosis is suspected, ask for Borrelia serology including immunoblotting, not just ELISA alone.
  6. Consider LTT testing: The lymphocyte transformation test can provide valuable information about active infection, especially when serology is inconclusive.
  7. For occupational exposure: Document tick bites occurring during work carefully, as Lyme borreliosis is a recognized occupational disease for certain high-risk groups.
  8. Monitor treatment success clinically: Serological monitoring to assess treatment success is not useful in chronic Lyme borreliosis; clinical assessment is the appropriate method.
  9. Be aware of co-infections: Ticks can transmit multiple pathogens, which may complicate diagnosis and treatment.
  10. Discuss treatment options thoroughly with your physician: The recommendations in this guideline differ in some respects from other specialist societies' guidelines, and patients should be informed of these differences.

This guideline emphasizes that Lyme borreliosis is a complex, multiorgan disease that requires careful clinical evaluation and individualized treatment. The chronic forms of the disease present particular challenges due to the lack of evidence-based studies and the limitations of current diagnostic methods.

Frequently Asked Questions

I had a tick bite but no rash. Can I still have Lyme disease?

Yes. Up to 50% of Lyme disease patients do not recall a tick bite, and erythema migrans (the typical rash) is absent in up to 50% of early cases. If you have symptoms consistent with Lyme disease, such as joint pain, headache, or facial nerve palsy, discuss testing with your doctor, even without a rash.

My Lyme disease antibody test was negative. Does that mean I don't have Lyme disease?

No. A negative antibody test does not rule out Lyme disease. Antibodies may not appear until 2–6 weeks after infection, and early antibiotic treatment can prevent antibody development. Also, the recommended stepwise testing (ELISA first, then immunoblot) can miss up to 15% of cases. If symptoms persist, ask about immunoblot testing or a lymphocyte transformation test (LTT).

What is the lymphocyte transformation test (LTT) for Lyme disease?

The LTT is a blood test that measures the cellular immune response to Borrelia. It can indicate an active infection, especially when antibody tests are negative or inconclusive. A positive LTT is suspicious but not proof of active Lyme disease. It is also used to monitor treatment success, as it usually becomes negative 4–6 weeks after successful antibiotic therapy.

What are the common symptoms of chronic Lyme disease?

Chronic Lyme disease (manifestations lasting more than 6 months) often causes fatigue, rapid fatiguability, encephalopathy (impaired brain function), muscle and joint pain, neurological symptoms like polyneuropathy, and various skin, heart, eye, and gastrointestinal issues. Symptoms may come and go and can affect many different parts of the body.

Can Lyme disease be treated with antibiotics?

Yes. Early antibiotic treatment is very effective. The guidelines recommend specific antibiotics (e.g., tetracyclines, penicillins, cephalosporins) for different stages. For chronic cases, long-term antibiotic therapy may be recommended, but this differs from other guidelines. Always discuss treatment options with your doctor, as the choice depends on the stage and organs affected.

Source Information

Original Article Title: Diagnosis and Treatment of Lyme borreliosis Guidelines

Organization: Deutsche Borreliose-Gesellschaft e. V. (German Borreliosis Society)

Publication Details: Revised 2nd edition, December 2010 (1st edition finalised April 2008)

Authors: Deutsche Borreliose-Gesellschaft e. V., Am Planetarium 12, D-07743 Jena, Germany

Note: This patient-friendly article is based on peer-reviewed research and clinical guidelines. The original guideline was prepared with great care, but no liability can be accepted for its accuracy, especially in relation to dosages, either by the authors or by the German Borreliosis Society. Patients should always consult with their healthcare provider regarding diagnosis and treatment decisions.

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