Multimodal therapy

Lyme disease, also known as Lyme borreliosis, is an infectious disease caused by  Borrelia burgdorferi, a type of bacteria from the spirochetes group. The name ‘Lyme’ comes from the town of Lyme in Connecticut, US, where this disease was first diagnosed in 1975 following increased incidence of arthritis associated with tick bites. The pathogen Borrelia burgdorferi is closely related to Treponema pallidum, which causes syphilis. Soon after infection, the Borrelia migrate from the bloodstream back into the tissue. Lyme disease can affect any organ, the nervous system, the joints or other tissue. This is why the illness is known as a multisystemic disease. The disease occurs in humans and all other mammals, as well as in birds. In Europe, transmission is primarily via the castor bean tick, or very rarely via mosquitoes or horseflies.

 

Discovery and naming of Lyme disease

Lyme borreliosis is named after LymeConnecticut, where the disease was first diagnosed in the 1970s, combined with the description of the disease as a borreliosis, based on the microbiological classification of the pathogen. The pathogen was named Borrelia burgdorferi after the Swiss-American Willy Burgdorfer, who discovered the bacterium in the US in 1981.

Borrelia burgdorferi

 

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Fig.1 Borrelia under the microscope

In the US, there is only one major Borrelia species of the disease-causing Borrelia bacterium. In Europe, there are six different types, all of which can cause disease in humans. Certain manifestations of the disease, such as acrodermatitis chronica atrophicans (ACA), are found in Europe but not in the US.

The types occurring in Europe are:

  1. burgdorferi,
  2. garinii,
  3. afzelii,
  4. valaisiana,
  5. lusitaniae, and
  6. spielmani (A14S).

Except for B. lusitaniae, all genospecies have also been found in ticks in Germany. The different types are considered to have differing complement resistance.

Statistics

Distribution

 

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Fig.2 Countries with reported cases of Lyme disease

Lyme disease is very widespread. Lyme disease is endemic in Germany, although the prevalence is higher in the south than the north of the country. While only 6–10% of ticks in northern Germany are infected with Borrelia burgdorferi, the prevalence in southern and central Germany is approximately 20–30%. In certain regions, the proportion of infected ticks can be up to 50%. However, these are only estimates, as accurate reporting is currently unavailable. Details of the pathogenesis of the disease, which would provide information on the course of the various disease manifestations and how best to treat them, are also lacking.

Risk of infection

Lyme disease is the most common tick-borne disease in Germany. In contrast to viral infections such as tick-borne encephalitis (TBE), infection with Lyme disease from a tick bite can even occur in cities, wherever people are in direct contact with bushes and trees in gardens and forests. However, not every tick bite results in infection with Borrelia or in symptomatic Lyme disease. According to estimates from the Robert Koch Institute, the probability is 1 in 300. In high-risk areas, however, the risk must be assumed to be much greater. As far as the ticks themselves are concerned, it can be assumed that the prevalence of their infection with Borrelia varies from around 5% to well over 40%. On average, the prevalence in Germany is approximately 20%, although in parts of southern Germany it is around 30–50%. Around 70% of all cases of Lyme disease occur between June and September. The risk of developing TBE, a dangerous tick-borne disease, is around 500 times lower.

The University of Heidelberg carried out a study to determine the risk of infection from a tick bite. They found that, on average, 3% of people bitten by ticks were infected. However, for people bitten by a tick infected with B. burgdorferi, the risk of infection was 27–35%.

In order to better estimate the risk of infection from a tick bite, it is possible to the have the tick tested for Borrelia infection by means of PCR. If the tick is found to be infected with Borrelia, this still does not mean that it will have transmitted the disease. This is because a certain amount of time is required for the tick to transmit Borrelia – unlike for the TBE virus. Estimates of the time required vary from 6 to 48 hours. Clearly, however, the longer a tick infected with Borrelia has remained attached to a person’s skin, the higher the risk of disease. There is also a significant risk of infection if the tick is not removed properly, for example, if it is squeezed. Ticks should be removed as soon as possible using special tweezers, which should preferably be made of stainless steel.

Transmission

 

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Fig. 3 Ixodes ricinus, or castor bean tick

Ixodes ricinus, also known as the castor bean tick, is one of the main carriers of Borrelia and a transmitter of more than 50 diseases. Other, rare transmitters of Borrelia include mosquitoes, horseflies and mites. Sexual transmission of Borrelia from person to person is possible, i.e. humans can be disease vectors in rare cases. If a pregnant woman is infected, there is a risk of stillbirth or harm to the unborn child. Transmission through blood products is considered to be possible, but unlikely.

Diagnosis

A major difficulty in diagnosing Lyme disease is the serological distinction between Lyme disease that has healed (residual titer) and Lyme disease that is still active and requires treatment. False negative and false positive serological findings are common. It is not possible to evaluate the course of the disease using this method. Of course, it can help to identify Lyme disease as a suspected cause of a patient’s symptoms, but whether this is sufficient evidence to begin treatment with antibiotics is questionable. False negative results also mean that, in Lyme disease, the reliability of serological testing is around 50%. Because of these diagnostic difficulties, many cases of Lyme disease are overlooked, especially in the early stages, as there are no measurable levels of antibodies against Borrelia antigens in the first few weeks following infection. This creates a diagnostic gap (= the time from infection to the start of antibody production), which is why, in the early stages, it is not advisable to wait for the result of the blood test. Instead, if there is clinical suspicion of Lyme disease, treatment with antibiotics should begin without delay, as the chance of full recovery is greatest with early treatment. The bull’s-eye rash known as erythema migrans must be treated immediately. Even with active disease, inflammatory markers such as ESR, CRP and other acute-phase proteins may remain normal. Thus, normal levels of these acute-phase proteins (inflammatory markers) do not rule out active disease. Newer inflammatory markers such as TNF-α, IL-6, NFkB and CD56/57 are more reliable.

The sensitivity of serological testing methods (ELISA) is usually higher in later stages. In the second stage, this is around 70% to 90%. If there is evidence of clinical neuroborreliosis, a lumbar puncture may be performed in order to test the cerebrospinal fluid. If inflammatory changes in the cerebrospinal fluid are present and evidence of Borrelia-specific intrathecal antibodies can be obtained, neuroborreliosis can be confirmed.[1] However, testing of cerebrospinal fluid for neuroborreliosis is associated with false negative results in approximately 30% of cases. In the early stages of neuroborreliosis, serum antibody titers are often negative. In these cases, the recently discovered chemokine CXCL13 (a B-cell-attracting protein) may be useful, as it is significantly increased in the cerebrospinal fluid of patients with neuroborreliosis even in early stages of the disease. According to studies carried out to date, the specificity of this marker is comparable to intrathecal antibody synthesis. Moreover, the concentration of CXCL13 in the fluid decreases rapidly under treatment, enabling active infection to be distinguished from a residual titer.

 

However, this marker is not yet well established in clinical diagnosis, and is only used for testing within studies (e.g. at LMU University of Munich). Lumbar puncture results may also be negative if only the peripheral nerves are involved. Some specialized laboratories and institutions perform a lymphocyte transformation test (LTT) if there is positive serology and unclear pathogen activity. A positive result indicates Borrelia-specific T-cells in the blood and supports the clinical suspicion of active disease. However, as yet there have been no large clinical trials looking into whether a close correlation exists between a positive LTT and disease activity. The LTT is also not covered by statutory health insurance. Polymerase chain reaction (PCR) testing is another diagnostic method by which active Lyme disease may be detected. In this method, bacterial DNA is processed and a Borrelia-specific fragment is replicated (amplified) by means of the polymerase chain reaction. While this test is highly specific, the sensitivity is strongly dependent on the type of tissue examined. For example, in cerebrospinal fluid with neuroborreliosis it is around 20–30%, in synovial fluid with Lyme arthritis and in skin with dermatoborreliosis it is approximately 70%. A negative result by no means rules out active disease.

Differential diagnosis

The differential diagnosis can be very broad, depending on the stage of the disease. Conditions that should be ruled out include other tick-borne diseases and other infections (including babesiosis, rickettsiosis, leptospirosis and bartonellosis).

Lyme disease can ‘mimic’ a variety of diseases, in a similar way to syphilis. If there are neurological symptoms, it is important to distinguish between Lyme disease and multiple sclerosis, in order to avoid serious misdiagnosis and incorrect treatment with steroids rather than antibiotics. If there is inflammation of the joints, differential diagnoses include osteoarthritis, rheumatoid arthritis and other forms of arthritis. It is often difficult to distinguish between Lyme encephalopathy and chronic fatigue syndrome.

Disease progression

 

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Erythema migrans as a result of a tick bite with borreliosis infection of the lower leg

Antibodies to Borrelia can be present following infection, without necessarily causing symptoms. The serology can be positive years after the disease has healed. Quite often, a definite diagnosis can only be made on the basis of symptoms, progression of the disease, medical history and laboratory findings. We have found the Burroscano score to be very valuable in these cases. This is a questionnaire with specific questions that are combined to give an overall score, which indicates whether chronic Lyme disease is likely. If the serology is also positive and the CD56/57 are low, chronic Lyme disease is likely and a treatment attempt is justified if the patient is unwell.

 

Sometimes a treatment attempt with antibiotics can bring clarity in these situations. However, if the symptoms respond to treatment with antibiotics this does not necessarily mean that active Lyme disease is present, and vice versa: non-response does not mean that the disease is healed. There is some controversy about the optimal therapy for Lyme disease, so we have taken a different path for some years, offering multimodal therapy for chronic Lyme disease. Our focus is on whole-body hyperthermia, in which the body temperature is increased to 41.6 to 41.8 °C/ 106.88 to 107.24 °F for a period of 120–180 minutes. The idea of including whole-body hyperthermia in the treatment program is based on two facts: the proven thermal lability of spirochetes such as Borrelia, and that the Borrelia are intracellularly located in the chronic phase and therefore are no longer accessible by means of antibiotic therapy.

 

Initial evidence of the high efficacy of thermotherapy in syphilis (Treponema pallidum spirochetes), which is related to chronic Lyme disease, was established by the Viennese physician and researcher Wagner-Jauregg in 1927, when he showed that an astonishing improvement could be achieved by means of regular fever therapy. The results were so impressive that he was awarded the Nobel Prize for his work. See below for a detailed description of our multimodal treatment approach.

Clinical symptoms of chronic Lyme disease

As a rule, Lyme disease is associated with severe symptoms that may worsen over the years. However, symptom-free latent periods are also possible. Disappearance of the symptoms thus does not necessarily mean that the disease has been eliminated. In early Lyme disease (stage 2) the symptoms are similar to flu (without a cough or runny nose). Symptoms at this stage include myalgia and arthralgia, which may be confused with fibromyalgia. These symptoms often do not respond to antibiotic treatment. However, if symptoms corresponding to fibromyalgia or chronic fatigue remain over time and there is no deterioration without antibiotic treatment, the possibility of chronic Lyme disease must be considered, especially if there is a history of primary symptoms typical of Lyme disease. This also applies to other non-specific symptoms such as:

chills,

fever,

joint and muscle pain,

exhaustion, and

depression.

Infection with Lyme disease does not result in lasting immunity, so repeat infection is possible.

Stages

There are a number of symptoms that are typical of the various disease stages. Lyme disease is also associated with a range of non-specific symptoms, such as:

fatigue,

headache,

fever,

neck stiffness,

visual problems,

dizziness,

nausea and vomiting, and

psychological changes.

1st stage: Local infection

After an incubation period of around 5–29 days following transmission of the disease, there may be local infection of the skin, which is accompanied by a characteristic bull’s-eye rash, known as erythema migrans [6].

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Fig. 5 Erythema migrans

The erythema sometimes disappears without treatment, but may last for months in some cases. A reduction in the erythema migrans does not mean that the infection has healed, as the bacteria may have spread. It usually expands slowly from the site of the tick bite. Erythema migrans (a bull’s-eye rash) is a clear symptom of infection with Lyme disease. However, it is absent in more than half of people infected. Lyme disease responds well to treatment with antibiotics (e.g., doxycycline) in the first stage the disease. The course of treatment must be sufficiently long and at a sufficiently high dose, although there are no fixed guidelines.

2nd stage: Spread of the bacteria

After around 4 to 16 weeks, the bacteria spread throughout the body. The incubation and latent periods may also be longer, however. In this stage, the patient suffers from flu-like symptoms such as fever and headache, which can make identification of the disease difficult. Excessive sweating is a characteristic symptom. As the bacteria spread through the body, various organs, joints and muscles as well as the central and peripheral nervous systems can be affected. Primary symptoms in this stage often include:

Garin-Bujadoux-Bannwarth syndrome with significant radiculopathy,

facial nerve paralysis, which can cause the face to appear lopsided,

arthritis and myalgia, which can move from one from joint to another,

changes in the sense of touch,

visual disturbances, and

heart problems with sinus tachycardia, hypertension and carditis.

In this stage, the immune system is often no longer able to fight off the infection. The bacteria only briefly remain in the blood, and quickly move to the connective tissue. In this stage, however, Borrelia can also be intracellularly located, where they are difficult to eliminate via the immune system and antibiotics, but can be treated by means of whole-body hyperthermia or passive fever. This is especially true for neuroborreliosis, which can contribute to various diseases of the peripheral nerves and the central nervous system. Borrelia release toxins that are lipophilic and particularly harmful to the brain and nervous system. Neuroborreliosis usually occurs in the early stage of the disease (up to around 10 weeks), when antibodies have not yet been produced. This is why a sufficient course of antibiotics should be given in this stage, and systemic whole-body hyperthermia should also be considered in order to achieve complete healing. The choice of antibiotic is based on the infection and form of the disease. We use tetracyclines, Rocephin (Cefatriaxon) and Metronidazole. If Lyme disease is not adequately treated in good time, the disease can progress and cause permanent organ damage, i.e., it can become a multisytemic disease.

3rd stage: Chronic infection

If Lyme disease is not treated in time, the bacteria may persist and lead to chronic infection (late manifestation). That is, the disease may recur (relapse) or symptoms may worsen. A symptom-free latent period of months or even years may be followed by subsequent recurrence of the disease. Acrodermatitis chronica atrophicans (ACA) often only develops years later. It can also lead to chronic recurrent Lyme arthritis with a range of symptoms, or involvement of the central and peripheral nervous systems (neuroborreliosis) with polyneuropathy, Borrelia meningitis, Lyme encephalomyelitis or encephalitis. Chronic disease may also affect the sense organs or the joints and muscles. Chronic Lyme disease affecting the joints is known as Lyme arthritis. Inflammatory bursitis or osteoarthritis may also occur. ACA is the primary dermatological symptom. If the brain is involved the hypothalamus and pituitary glands may also be affected, leading to impairment of other endocrine organs such as the thyroid, adrenal glands or sex organs.

The disease can present with a variety of symptoms. While in some patients primarily their joints are affected, others mainly report having neurological symptoms. There is also a group of patients who have heart problems, usually associated with vasculitis. Mixed forms also occur. Many patients with Lyme disease complain of unbearable fatigue, rapid exhaustion and chronic fatigue that cannot be relieved by adequate sleep. The following late manifestations of Lyme disease are described in the literature:

Chronic, recurrent Lyme arthritis

Arthritis with involvement of large joints

Tenosynovitis

Fasciitis

Osteomyelitis

Panniculitis, dactylitis, bursitis, etc.

Arthralgia, myalgia (fibromyalgia-like symptoms)

Neurological or neuropsychiatric conditions

Radiculitis of spinal and cranial nerves

Neuritis of peripheral nerves

Meningitis

Myelitis

Cerebral vasculitis

Myositis, dermatomyositis-like conditions

Encephalitis, encephalopathy (chronic-fatigue-like symptoms)

Acrodermatitis chronica atrophicans (ACA)

Erythromelalgia

Cigarette-paper-like atrophy of the skin

Sclerodermal hardening of the skin and fibrous nodules

Other possible delayed symptoms:

Post-treatment Lyme disease syndrome

Heart conditions including myocarditis and cardiomyopathy

Hearing conditions including tinnitus and hearing loss

Eye conditions including uveitis, keratitis, and episcleritis

Disease of liver, kidneys, and gastrointestinal tract

Endocrine disorders (hypothyroidism, Hashimoto’s disease), adrenal fatigue, sex hormone imbalance (anovulatory cycles, PMS, infertility, loss of libido, etc.)
Kind regards

Brigitte