Overview of Diagnosis and Treatment of LB
Table of contents
Lyme borreliosis (LB) is an infectious disease caused by borrelia, to wit the species B. burgdorferi. The pathogen was verified by Burgdorfer in 1982 (293). The infection is transmitted by ticks (in Europe: Ixodes ricinus, common name wood tick). Insight into the context of the disease and manifestations thereof is based on the works of AC Steere (43), who primarily made his observations in children in the town of Lyme near Long Island, New York. To differentiate between various borrelioses, the disease caused by B. burgdorferi is referred to as Lyme borreliosis.
Lyme borreliosis can affect a number of organs and organ systems (multi-organ or multi-system disease, respectively); the symptoms are just as diverse, resulting in extensive differential diagnosis among individual manifestations of the disease. It is especially difficult to diagnose Lyme disease in late stage, all the more so because there is no so-called positive disease marker, i.e. a technological medical examination process used for verification. Rather, diagnosis of Lyme borreliosis can be proved by erythema migrans or lymphocytoma in the early stage and acrodermatitis chronica atrophicans in the late stage. Also an acute Lyme neuroborreliosis with typical clinical picture and specific changes of the cerebrospinal fluid prove the disease. Also, proof of the pathogen agent by culture or PCR (Polymerase Chain Reaction) allows the diagnosis of LB, but the available methods are of low sensitivity and therefore do not belong to routine diagnostic procedures. In consequence, the diagnosis of LB largely relies on the entire corpus of data available, in particular symptoms, clinical results, and the distinction from other diseases, i.e. the differential diagnosis. The detection of Lyme borreliosis is thus largely a diagnosis of elimination. The differential diagnosis requires extensive knowledge of concurrent diseases in numerous specialty fields. This chapter aims to offer an introduction into the many problems posed in this area, and to convey an overview of the structure of Lyme borreliosis.
Because the tick Ixodes ricinus can only survive in a moderate climate, Lyme borreliosis is a disease of such climate zones between approximately the 40th and 60th northern parallels. The disease can be transmitted by different tick species, namely by Ixodes ricinus in Europe, and I. scapularis and I. pacificus in North America. In other areas (Far East, East Asia, Southeastern Europe) different species of ticks are the carriers.
In Europe, the disease is largely transmitted by 3 subspecies: Borrelia burgdorferi ss, B. garinii and B. afzelii, and primarily by B. burgdorferi ss in North America. Other subspecies can be carriers, although this is much less common. Examples include B. spielmanii, B. valaisiana, B. lusitaniae and B. bissettii. However, human pathogeneity of the latter 3 subspecies is uncertain.
The formation of the disease is based on the confrontation between pathogen and (human) immune system, and the resulting inflammatory processes with more or less extensive organ damage.
There are special issues from a treatment perspective, as Borrelia burgdorferi possesses special means of combating the immune system and the effect of antibiotics.
Data on incidence (annual new cases) and prevalence (number of Lyme borreliosis patients within a period of one year) show enormous discrepancies. Upon general observation, however, Lyme borreliosis is by no means a rare disease. It is to be assumed that around one million patients suffer from a manifestation of Lyme borreliosis in the Federal Republic of Germany every year.
Significant characteristics of Lyme borreliosis
Because Lyme borreliosis can affect many organs (so-called multi-organ and multi-system disease), there is a comprehensive differential diagnosis for the often numerous manifestations of the disease. Observing the pertinent characteristics of LB makes the differential diagnosis easier, and the misidentification of Lyme borreliosis is immensely prevented.
Characteristics of LB
The following situations are significant for the normal practice:
Fresh tick bite
Anamnestically, 50-70 % of LB patients deny having a tick bite. A negative tick bite anamnesis also does not rule out LB (173, 174, 175, 176).
If the tick is available, it should be inspected for infectiousness via PCR. However, a negative PCR result does not completely rule out the infection (1). After being bitten by a verifiably infectious tick and a sucking period of about 1-2 hours, the transmission of infection cannot be ruled out, and antibiotic treatment, as in the early stage, must be discussed (see section "Prevention").
Failure to inspect the tick can have the following consequences:
Erythema migrans (EM) (early-stage, stage I)
Erythema migrans verifies the disease (LB). There are 2 significant consequences of EM:
As antibodies first appear 2-6 weeks after the infection begins (2, 3, 4, 5, 6, 84), it is incorrect and irresponsible to begin antibiotic treatment of EM not immediately, but rather only after determination of a pathological, serological result.
The earlier the antibiotic treatment sets in, the better the infection can be controlled. The chance of treatment is much slimmer 4 weeks after the beginning of the infection (7, 251).
Early antibiotic treatment can prevent the development of antibodies, i.e. no seroconversion takes place. Seronegativity after early antibiotic treatment does not rule out LB, but rather the LB is verified by the EM.
Lymphocytoma is another skin manifestation of the early stage of the disease. Lymphocytoma is an erythematous swelling, primarily around well-circulated areas of the skin (earlobes, nipples, genitalia).
Early stage without Erythema migrans (EM) (stage I)
In 30-50 % of cases, no EM appears in the early stage of Lyme borreliosis (5, 7, 8, 9, 10, 11). The diagnosis must thus be based on other criteria:
Initial manifestations of Lyme borreliosis sometimes appear weeks or months after the infection begins (4, 13, 117, 124, 200). With corresponding symptoms, the LB must be considered with differential diagnosis. This especially applies to an anamnesis of tick bites or high risk of infection.
Chronic stage (late-stage, stage III)
Chronic Lyme borreliosis is identical to the late-stage manifestation (stage III).
Prior early-stage LB (EM, lymphocytoma, flu-like symptoms) is very important for the diagnosis of the disease in the late stage. However, about 50 % of cases of chronic LB entail no prior or previously known early stage (cf. 4, 7, 13, 117, 124, 200). The lack of an early stage also aids in the misidentification of Lyme borreliosis; regardless, the initial diagnosis of Lyme borreliosis is often significantly delayed (251, 252). The general reason for this is a misdiagnosis, i.e. the assumption of other, non-applicable diseases (252, 253, 254).
The identifying skin manifestation of the late stage is acrodermatitis chronica atrophicans (ACA), which however occurs in only 10 % of cases.
Chronic LB can lead to a number of symptoms (cf. Tab. 3.4). The following manifestations must especially be noted:
In accordance with the multitude of manifestations, chronic Lyme borreliosis requires extensive general and neurological examination.
Examinations in other areas are often also required, especially for purposes of conducting a variety of technological medical examinations.
Lab diagnosis of chronic Lyme borreliosis entails the following examinations:
Remark concerning occupational illness and accident insurance
Under definite circumstances Lyme disease is acknowledged as occupational disease. The only determining factor is whether the accident (tick bite with transmission of infection), i.e. the infection, occurred while working, namely the patient's proper occupation. For some occupational groups with a high risk of infection (e.g. farmers and forest workers, veterinarians) there is generally an assumed correlation between accident (tick bite) and disease (causal relationship). For other occupational groups this causal relationship must be verified by the patient. In case of a tick bite while on the job, and in the event of subsequent symptoms, it is thus required that the attending physician carefully documents the anamnesis, examination results, and lab results. The patients themselves should record journal entries and render photo documentation of skin changes.
Accident insurance claims also require that the Lyme borreliosis acquired on the job (tick bite with transmission of infection) results in subsequent impairment of the patient's health for a certain period of time. In conjunction with insurance claims, the causal relationship between occupation and infection (accident), as well as the subsequent disease (Lyme borreliosis), must be verified (cf. Chapter 3.1). The occupational illness and subsequent impairment must be verified by the patient (claimant). A proven causal relationship between the tick bite (accident) and occurrence of Lyme borreliosis and continued presence of late-stage Lyme borreliosis must be verified. Verification of current late-stage Lyme borreliosis requires proof of correlation with the accident (tick bite with borrelia infection). General overlapping symptoms between the accident and current disease situation provide a significant instrument for argumentation. It is not uncommon for the tick bite and resulting borrelia infection to be recognised as an occupational illness, however, the subsequent development of late-stage Lyme borreliosis is not acknowledged.
And so it is first necessary to verify the tick bite with transmission of borrelia infection (with likelihood), and also the damage, i.e. persistent late-stage Lyme borreliosis or damage resulting from Lyme borreliosis.
From a legal perspective, the following two aspects must be considered when verifying causality:
The external causation concerns the relationship between occupation and infection. The internal causation is that between infection and resulting late-stage Lyme disease.
Symptoms of Lyme borreliosis
Lyme borreliosis is traditionally categorised into 3 stages according to severity and progression:
An alternative division of stages can be considered for practical clinical reasons.
Alternative stage categorisation of LB
Modern stage categorisation
Recently it has become more common to categorise two stages:
The temporal threshold between these two stages is not clear. The limit of 6 months provided in literature is obsolete. From a practical perspective the early stage lasts about 4 weeks, and afterward the symptoms are to be categorised as late-stage.
Acute Lyme borreliosis and acute Lyme neuroborreliosis (previously stage II) are categorised as early-stage with a certain temporal tolerance.
The early stage is primarily characterised by the following manifestations:
For diagnostic, treatment-related, and prognostic reasons, the early stage is temporally defined and is based on the first 4 weeks after the infection begins. As presented above, antibiotic treatment within these 4 weeks is relatively successful. Serological findings after first-time infections appear at the end of this period at the earliest (2, 3, 4, 5, 6, 7, 84).
The early stage is mainly characterised by the disease-verifying EM, although this only occurs in 50-70 % of cases for first-time or new infections (5, 7, 8, 9, 10, 11). It is often accompanied by general flu-like symptoms.
If the pathogens spread throughout the entire organism after infection (inoculation), this dissemination may also lead to diseases of other organs. The thresholds between such a disseminated early stage and acute Lyme disease (stage II) or even a chronic stage (late stage, stage III) are fluid.
The EM may vary significantly in shape, size, and characteristics (4, 8, 9, 12, 13, 117, 124, 200). The traditional shape with margin and central blanching is only present in one-half of cases. That is why in cases of doubt EM should be diagnostically assumed for any erythema regardless of its appearance, especially when the erythema exhibits expansion or persistence over a period of weeks. The CDC (Centers for Disease Control and Prevention) currently note that EM is not present or observed in 30 % of cases, in over 50 % of cases the traditional anulare form is not present and shape variations are common, a macular form is present in 60 % of cases with livid colouration and vesicular changes are visible in the middle (290). It is difficult to demarcate a localised inflammatory reaction around the bite area with a maximum diameter of 2 cm which appears a short time after the tick bite. This inflammation is triggered by a secretion that the tick injects into the skin when biting, and is thus unrelated to borrelia. The demarcation of a so-called mini-erythema migrans with a diameter of less than 5 cm (12) is only possible with continued observation; the EM usually increases in size over time and exhibits a persistence of at least 2 weeks. In case of doubt, a skin biopsy should be conducted for purposes of pathogen verification by PCR.
The initially homogenous erythema can blanche in the middle; all that remains is an arch-shaped margin, and may entail itching and pain with changing characteristics from a span of weeks to many months. On average it heals abruptly after about 10 weeks. With antibiotic treatment the EM usually blanches within several days. Persistence signals inefficient antibiotic treatment and the necessity of switching antibiotics.
Lymphocytoma is equivalent to EM in terms of disease significance and the strategies described. Lymphocytoma entails an inflammatory swelling that can appear in all parts of the body, but especially around well-circulated tissues (earlobes, nipples, scrotum). There are also transitional and overlapping lymphocytoma and EM (so-called atypical EM (14)).
The possibility of a borrelia infection must essentially be assumed with the presence of erythema, of course under consideration of the differential diagnosis. In case of differential diagnostic uncertainties, erythema migrans must be assumed and the corresponding diagnostic and treatment measures taken. In such a situation, dermatological examination is indicated and possibly a skin biopsy for purposes of verifying the pathogen, usually via PCR.
All skin manifestations of Lyme borreliosis in the early and late stage are presented in Tab. 3.5.
Early-stage post-dissemination symptoms
In case of existing erythema or the lack of any skin manifestations, the expansion of the pathogen (dissemination) results in a more or less distinctive disease state. The acute manifestation is referred to as acute Lyme disease (stage II). In less acute courses the early stage may entail numerous organ manifestations (cf. Tab. 3.4) so that there is a seamless transition to the chronic stage. However, there is often a relatively or completely pain-free interval between the early stage and chronic LB (late stage).
Acute Lyme disease (stage II) usually occurs a few weeks or months after the beginning of the infection (inoculation). In accordance with early dissemination, such a disease state may also occur quickly in the presence of existing EM.
The severe disease state often requires inpatient diagnosis and treatment.
The serological findings for acute Lyme disease are generally pathological, although the lack or minor manifestation of the serological findings do not rule out the disease.
With regard to the multi-organ and multi-system disease, acute Lyme borreliosis is not uncommonly associated with nervous system manifestations, i.e. acute Lyme disease may entail acute Lyme neuroborreliosis, or may solely occur as acute neurological symptoms.
Manifestations of Lyme neuroborreliosis
The term "Lyme neuroborreliosis" (LNB) refers to the disease manifestations in the nervous system. It must be noted that Lyme neuroborreliosis is only one of a multitude of organ manifestations. Lyme neuroborreliosis its not an individual disease in and of itself, but rather a partial manifestation of Lyme disease within the entire organism. However, the neurological symptoms may be at the forefront to an extent, or may appear as the only disease phenomenon of Lyme borreliosis.
The manifestations of Lyme neuroborreliosis are presented in Table 3.1. The symptoms triggered by borrelia infection are very similar to neurological disease states with other causes. For example, peripheral facial nerve paralysis as part of Lyme borreliosis cannot be phenomenologically differentiated from so-called idiopathic facial nerve paralysis. With regard to the differential diagnostic observation of neurological infectious diseases, overall it can be determined that Borrelia burgdorferi exhibits relatively low virulence compared to other bacteria and some neurotropic viruses. The medical condition of meningitis as a result of infection with Streptococcus pneumoniae is thus more distinctive than is the case with Lyme neuroborreliosis. The same likewise applies to the often similarly severe course of early summer meningoencephalitis (Tick born encephalitis, TBE) which takes a far more dramatic course in terms of manifestation, mortality, and disease consequences than acute Lyme neuroborreliosis. However, Lyme neuroborreliosis may cause severe medical condition with sequelae.
Some symptoms of Lyme neuroborreliosis, however, are more or less typical. This is true for Neuroradiculitis (M. Bannwarth), for isolated temporary or non-progredient myelitis, a chronic form of myelitis with fluctuating manifestation and chronic encephalitis.
All major medical conditions that have special significance for Lyme neuroborreliosis, and [which] may be associated with a problematic differential diagnostic demarcation, are presented below (Tab. 3.1).
Acute Lyme neuroborreliosis
The following neurological symptoms arise from the various localisations of the inflammation in the nervous system (Tab. 3.2).
With cranial neuropathies, failures or functional impairments are usually induced by infectious inflammation in the respective nuclear areas, and so cranial neuropathies are categorised with neural radiculitides for pathological-anatomical purposes. The inflamed lesion may also sometimes occur distally to the subarachnoid space, i.e. peripherally (23). The corresponding impairments are listed below along with the respective cranial nerve number (Tab. 3.3). Refer to the special chapter for further literature.
Chronic Lyme neuroborreliosis
The symptoms of chronic Lyme neuroborreliosis (chronic LNB) largely correspond to the manifestation of acute Lyme neuroborreliosis. However, there are differences when it comes to manifestation of the disease over time and special characteristics with regard to the brain disorder:
With chronic encephalomyelitis the time-dependent variations go along with various motoric, sensitivity and coordinative disorders in phases of deterioration and intervals with only weak symptoms
(19, 24). The neurological deficits can develop into a progressive condition over time, one which may extend over years.
The phases of deterioration of chronic LNB usually last for weeks or months, and the alleviation of symptoms in the intervals is generally gradual, and for a similar period of time. These relatively long phases of deterioration and only gradual alleviation can allow for a certain degree of differentiation between chronic LNB and multiple sclerosis; however, the differential diagnosis between chronic LNB and MS is often difficult when considering the various technological medical examinations. Pertinent is the consideration of other chronic LB data: disease circumstances, manifestations in various other organs, and so not only in the CNS but also medical findings that indicate chronic LB. Instances in which the symptoms can be attributed to both chronic LNB and multiple sclerosis are rare. The McDonald criteria must be fulfilled in order to diagnose MS.
There is no positive disease marker for both multiple sclerosis and chronic LNB, i.e. there is no technological medical examination, let alone any lab test, that would be able to verify the disease with pathological findings. That is why diagnostic criteria were established for both diseases, which have been defined for MS (most recent revision in 2010) whereas this is not (yet) the case for late-stage (central) Lyme neuroborreliosis. Indeed there are diagnostic criteria for Lyme neuroborreliosis, although these concern (albeit unspokenly) acute Lyme neuroborreliosis and not the chronic manifestations with inflammations in the parenchyma of the central nervous system.
A cerebrovascular disease resulting from vasculitis with LB (17) is also attributed to chronic Lyme neuroborreliosis for practical considerations, although it is primarily a vascular disease. Vasculitis usually results in hemi-symptoms (25, 26) with a protracted and recurrent course.
Encephalopathy with chronic LB and LNB refers to an impairment of cognitive brain performance and mental impairments. Encephalopathy is a very common issue in relation to chronic Lyme borreliosis (27). Cognitive and mental impairments can result in significant disabilities with corresponding effects on social functions (cf. 28, 29, 30).
With encephalopathy the cerebral fluid is usually unremarkable or exhibits only minor changes, especially in the form of increased protein and albumin levels. Such a minor fluid change (blood-liquor barrier) is present in about 5 % of instances of encephalopathy with chronic Lyme borreliosis (28, 31, 32, 33). One frequent manifestation of chronic Lyme neuroborreliosis is chronic peripheral polyneuropathy (20, 21, 34). The lower extremities are mainly affected. This is usually a sensormotoric polyneuropathy of an axonal demyelinating type. The sensory impairment dominates, although motoric impairment may be extensive with the result of severe disability. The cerebral fluid results for chronic polyneuropathy in conjunction with LNB are generally unremarkable (35, 36, 37).
Neurodegenerative diseases (e.g. M. Alzheimer, M. Parkinson, dementia) have been shown in numerous studies to have a pathophysiological relationship with Lyme neuroborreliosis. In light of the constantly increasing neurodegenerative diseases among the aging population, such a relationship could be of significance, although it is not yet apparent to what degree.
Symptoms of chronic Lyme borreliosis
Like the term "early-stage" chronic Lyme disease should also be temporally defined. Disease manifestations of borreliosis that occur 4 weeks after the beginning of infection (inoculation) should be allocated to the condition of chronic Lyme borreliosis (late-stage Lyme disease, LB stage III).
The symptoms of chronic Lyme borreliosis [form] either seamlessly from the early stage, after a pain-free interval of months to years, or primarily form (chronic Lyme borreliosis without preceding early-stage form (4, 7, 13, 117, 124, 200)). The result is that chronic Lyme borreliosis must also be diagnosed if there is no tick bite and no EM if the circumstances, manifestations, and differential diagnosis analysis make it apparent.
Chronic Lyme borreliosis is a persistent infection with vital pathogens. It is not the result of a past infection or a condition after presumably successful antibiotic treatment of the pathogen. Accordingly, numerous studies show that pathogens are cultivated even after highly effective antibiotic treatment (11, 15, 24, 43, 50, 53, 57, 60, 62, 112, 121, 122, 125, 128, 139, 140, 141, 143, 150, 152, 156, 157, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 255, 256).
The inflammation of the knee joint (gonitis) is the outlying manifestation in the late-phase (chronic Lyme borreliosis) (43); after differential diagnostic elimination of other causes, gonitis is practically proof of late-phase chronic Lyme borreliosis. However, Lyme arthritis (gonarthritis) only occurs in about 40 % of cases (7). It is thus not at all obligatory for the late-stage manifestation, and lack thereof does not rule out LB.
Because the expansion of borrelia within the organism leads to multi-organ and multi-system diseases, there is an incredibly wide variety of symptoms. The extensive, practically complete set of symptoms of Lyme borreliosis is presented below by organs and organ systems.
The list of such a variety of manifestations also contains the hidden risk of lack of acceptance due to the seeming arbitrariness or lack of differential diagnostic precision. However, all manifestations listed below have been proven in the respective publications, although very rare phenomena (e.g. ALS-like diseases) have only been verified in individual instances.
A comprehensible overview is possible when the symptoms are ordered by most-affected organs and consideration of the general symptoms (Tab. 3.4).
Skin manifestations of LB
Skin manifestations of early- and late-stage LB can be found in Table 3.5 (12, 14, 50, 58, 205-221).
Erythema migrans (EM) and acrodermatitis chronica atrophicans (ACA) verify LB. ACA initially entails an oedematous-infiltrative early phase with livid colouration and swelling. Skin atrophy occurs with advanced progression. Dermatitis atrophicans maculosa is a special form of ACA. Other manifestations are stripe-shaped reddening, "pseudoscleroderma" (morphaea) in the form of ivory-coloured dermatosclerotic plates and juxta-articular fibroid nodes.
Erythema migrans, which verifies the disease, only occurs in about 50 % of cases. EM is not by any means obligatory for the diagnosis of Lyme borreliosis, and its absence does not rule out Lyme borreliosis. Erythema migrans is a visual diagnosis, although the pathogen can often be determined with a skin biopsy by means of PCR (see Chapter 22.17 and 22.18). Histologically, EM is characterised by a perivascular, lymphocytic infiltrate with few plasma cells and isolated eosinophils (cf. Tab. 7.1).
EM may vary significantly in shape and size. Mini-erythemae with a diameter of less than 5 cm are possible, and the pathogen can be verified via PCR. Of special significance is the fact that the erythema can appear in various shapes: anular (en cockade, bull's-eye shape) in about 50 % of cases, macular (more or less consistent reddening) also in about 50 % of cases. Furthermore, the skin around the erythema can exhibit further changes such as papules, vesicles, haemorrhaging, and others. It is not uncommon for the EM to take multiple forms (multiple erythemata migrantia, MEM). Because EM verifies the early stage, it is necessary to consider atypical manifestatons of EM in order to ensure prompt diagnosis and early antibiotic treatment.
In about 3 % of cases lymphocytma occurs in the early stage, and this also verifies the disease. Clinically lymphocytoma occurs as an inflammatory swelling, histologically it is considered a pseudolymphoma designated as borrelia lymphocytoma with reference to the aetiology. Predilection areas are parts of the skin with good blood circulation (e.g. nipples, earlobes, scrotum). Transitions between lymphocytoma and erythema migrans are also possible, and such a combination is categorised as "atypical EM".
Acrodermatitis chronica atrophicans (ACA) occurs in about 10 % of cases of late-stage Lyme borreliosis and verifies the late stage. This is differentiated into an inflammatory stage of the subcutis which progresses into skin atrophy with degeneration of the subcutis. Histologically ACA occurs in the inflammatory stage as a perivascular, lymphocytic infiltrate with isolated plasma cells and few eosinophils. In the atrophic stage there is a mingling of lymphocytic infiltrate with plasma cells, sweltering of the epidermis/dermis/subcutaneous rete ridges, atrophy of the adnexa, and loss of the rete ridges. Refer to Chapter 10.2 for further histological phenomena.
The duration of an erythema migrans can last for weeks or several years (264-285). With antibiotic treatment the erythema migrans abates within days or weeks; the success rate of treatment is 90-95 % (264-270). This equates to a failure rate of 5-10 %. However, there are no studies of collectives concerning persistence issues of EM after antibiotic treatment. All that is known is the failure of antibiotics in a fraction of cases and pathogen verification during skin infection (panniculitis) despite intensive antibiotic treatment (277). Upon failure of antibiotic treatment, persistence of the EM over months or even years is to be expected. The EM may transition into acrodermatitis chronica atrophicans (ACA) in its chronic state (272). The simultaneous presence of EM and ACA (typical late-stage manifestation) implies the potential of a long-term EM (283).
Other infections may be present alongside Lyme borreliosis, the pathological synergy of which either worsens the patient's condition or induces similar manifestations to LB. Such accompanying infections are referred to as coinfections.
Some coinfections, like LB, can be transmitted by ticks, i.e. a tick bite can cause multiple infections. Some coinfections are transmitted without ticks, or there are other ways aside from ticks for them to be transmitted.
The coinfections transmitted by ticks are listed in Table 3.6, and tick-independent coinfections in Table 3.7.
The coinfections make disease manifestations more distinct through modulation of the immune system, and are considered a significant reason for treatment resistance of Lyme borreliosis (188-203).
Bartonella henselae, verified in 40 % of ticks in Europe, is paid special consideration (222).
Bartonella henselae was found in the cerebral fluid of patients with diseases of the central nervous system, and without any prior cat-scratch disease (188). Furthermore, like Bb Bartonella henselae can induce a multi-organ disease (223).
Reactive arthritis is not a nosological entity. Rather it is an umbrella term for disease conditions with post-infectious arthritides. Diagnostic and pathophysiological categorisation is still uncertain. However, the pertinent literature is increasingly providing indications that so-called reactive arthritis is actually a persistent, infectious form of arthritis similar to stage III Lyme arthritis. Accordingly, antibiotic treatment is indicated.
Pathogens that induce reactive arthritis are listed in Tab. 3.9.
Yersiniosis is of particular differential diagnostic significance with regard to LB. Both diseases (LB, reactive arthritis with yersiniosis) typically entail joint inflammation in the lower extremities; the gonitis typical of LB can likewise indicate reactive arthritis with yersiniosis.
An interval of several days to several weeks should be noticed between the symptoms typical of infection and occurrence of reactive arthritis.
Acute reactive arthritis usually regresses spontaneously within 6 months. If this time period is exceeded then this indicates chronic reactive arthritis, which has a reported frequency of 4 - 19 %.
Treatment requires antiphlogistics (NSAR) or anti-TNF compounds.
Timely administration of antibiotics against the underlying infection can prevent the development of reactive arthritis to a degree. Various studies have shown that antibiotics cannot impact the progression of reactive arthritis, although this is solely based on chlamydia infections and a very restrictive antibiotic treatment (204).
Laboratory examinations available for diagnostic analysis of Lyme disease are documented in Table 3.10, examinations of cerebrospinal fluid in case of neuroborreliosis in Table 3.11 and further laboratory examinations indicated in various stages of LB in Table 3.12.
Antibodies are verifiable about 2-6 weeks after the infection begins (inoculation) (2, 3, 4, 5, 6, 84, 261). With a previously negative starting value, the appearance of antibodies verifies fresh
infection. In this regard it is prudent to determine a starting value immediately following the tick bite. If antibodies are verifiable at the starting point (as a result of past Bb infection),
the fresh, i.e. new, infection appears in the surge of serological findings (increased titer with ELISA, EIA, greater number of bands in the western blot).
Serological examination entails the quantitative determination of IgM and IgG antibodies as well as the verification of various Borrelia antigens via electrophoretic separation with the western blot method.
The verification of antibodies is proof of the presence of the infection, but not the disease (LB). Diagnosis of LB is solely based on clinical data: disease conditions, history, reported symptoms, and test results. A positive serological result is merely an indication of a causal relationship between the Borrelia infection and symptoms typical of LB. The serological result can neither verify nor rule out Lyme borreliosis.
Early antibiotic treatment often prevents seroconversion, i.e. the development of antibodies, although the Borrelia infection persists and morphs into chronic Lyme disease (late-stage Lyme disease). Regardless, seronegativity is present in up to 30 % of cases of chronic Lyme borreliosis.
Seronegativity thus does not rule out Lyme borreliosis, i.e. the verification of antibodies is not mandatory for the diagnosis of LB (46-63).
The presence of IgM antibodies is much less common than that of IgG antibodies. The IgM antibody, generally considered an early indicator, occurs in no more than 50 % of early-stage cases (64). In late-stage cases the frequency is only 15 % (65). Much like seronegativity in general, the absence of IgM antibodies does not contradict the diagnosis of a Borrelia infection and subsequent Lyme borreliosis.
The term "seroscar" describes the presence of antibodies after the disease (LB) has abated; this term is only applicable if there are no symptoms of Lyme borreliosis. It is also possible that the serological findings occur in a symptom-free interval period, in which case the relapse of the symptoms (thrust) would exclude the term "seroscar".
The western blot test is more sensitive than the screening tests (49, 66, 291). It is thus prudent to conduct screening tests and western blot simultaneously. Up to a certain point the two procedures both have benefits when it comes to quantification, namely the screening tests for titer levels and the western blot for the number of verifiable bands.
The Borrelia antigens verified with western blot vary in specificity and can also be categorised to different stages to a certain degree. Refer to Table 3.13 for the characteristics (67).
The lymphocyte transformation test (LTT, syn. lymphocyte proliferation test) is based on the measurement of the immunological memory of immune cells (persistent T- and B-memory lymphocytes). The
test was developed in 1979 (68, 69) and first used in relation to Lyme borreliosis in 1981 (70). The diagnostic significance of LTT has since been proven in numerous studies (70-84). Through
methodical development LTT has come to achieve a sensitivity equivalent to that of serological tests (84).
LTT has special significance with regard to seronegative Lyme borreliosis. LTT is positive in about 20 % of seronegative LB patients, and in this situation it is the only indication of a Borrelia infection. Furthermore, positive LTT is a strong indication of current presence of Borrelia within the organism.
As concerns the diagnostic significance of LTT, it is important whether false-positive LTT results are to be expected. This risk is clearly quite low, as shown by the overwhelming number of publications (83, 84).
The T-cell test also examines immunological memory, whereby the emission of cytokines is measured after stimulation of the immune cells with Borrelia antigens. There are currently no durable data for a measurable comparison between LTT and T-cell test.
LTT shows a much higher reactive speed than serological examinations. In the early stage LTT is positive before antibodies are detected. After a sucessful antibiotic treatment LTT becomes negative within 4-6 weeks. With relapse LTT mostly becomes positive again (67).
LTT is thus largely significant for diagnostic problems as a result of ambiguous symptoms, the efficiency test of antibiotic treatment, and monitoring, especially with regard to recurrence (Tab.
In a positive serological test the LTT and T-cell test may be negative, and vice versa.
LTT and T-cell test are, as with the serology, merely pertinent to the infection but not to the disease. Negative LTT and T-cell test thus do not rule out LB.
CD57+ NK cells are commonly reduced in case of chronic Lyme borreliosis and Lyme neuroborreliosis (85, 294). The current data do not allow for a definitive assessment.
Lab verification of Lyme borreliosis is based on the verification of Borrelia by culture or polymerase chain reaction (PCR). The cultural cultivation verifies the existence of vital Borrelia; PCR merely documents the genetic material of the borrelia that can theoretically also stem from devitalising microbes or microbe particles. However, from a practical perspective a positive PCR result is also considered pathogenic verification and proof of the presence of Lyme borreliosis.
Various lab tests are conducted for the different stages or disease circumstances. Refer to Table 3.12 for more detailed information.
Cerebro-spinal-fluid (CFS) diagnostics of Lyme neuroborreliosis differentiate between non-specific and specific results. Refer to Table 3.11 for more detailed information. Specific fluid findings verify intrathecal antibodies (formed in the CNS) through titer comparison between serum and liquor with the Reiber method, comparison of the western blot findings in the serum and liquor (number, type of bands), and specification of oligoclonal bands with ELISA. A positive antibody index (AI) indicates intrathecal AB formation, i.e. the AB titer in the liquor is (relatively) increased compared to the serum (considering the natural concentration differences of protein, albumin and IgG in the liquor and serum). Intrathecal antibodies often begin to develop many weeks after the onset of the Borrelia infection in the CNS. In some cases there are no intrathecal antibodies at all in the presence of Lyme neuroborreliosis. Furthermore, intrathecal antibodies may persist many years after regression of the Lyme borreliosis. The intrathecal antibodies' primary diagnostic significance lies in acute Lyme borreliosis, when they occur alongside corresponding symptoms and course of the disease. However, intrathecal antibodies are not proof of existing Lyme borreliosis or Lyme neuroborreliosis in the late stage. On the other hand, the lack of intrathecal antibodies does not by any means rule out stage III Lyme borreliosis, especially as Lyme borreliosis with inflammation of the central nervous system (immunological response by the CNS) only occurs in 5-10 % of cases, i.e. intrathecal antibodies are not to be expected in 90 % of patients with late-stage Lyme borreliosis.
The verification of OspA also verifies the presence of Borrelia burgdorferi s. l. in the CNS . Verification of the pathogen may sometimes occur directly via PCR, and rarely via culture. Certain chemokines, in particular CXCL 13, are likely significant in the determination of the early stage of acute LNB ; however, this method is currently not a component of routine diagnosis.
The intrathecal antibodies especially important for the diagnosis of acute LNB are only verifiable about 2 weeks after the onset of neurological symptoms. Furthermore, numerous publications show that intrathecal antibodies are not verifiable in a considerable fraction of cases despite typical clinical manifestation, inflammatory fluid results, and verification of the disease via pathogenic verification (86-105).
Furthermore, it is to be noted that there are usually no pathological liquor results in acute early-stage Lyme neuroborreliosis (LNB), so the diagnosis thereof cannot rely on liquor results. In one study of 799 patients with distinctly acute LNB, liquor changes according to the criteria of the pertinent guidelines (Epidemiological Bulletin of the Robert Koch Institute, Berlin, 38/2007) were present in only 42 cases (5.25 %). The bulletin states, "The lab diagnostic verification of early neuroborreliosis required for the current definition is only fulfilled in a very small number of conveyed neuroborreliosis cases, a problem that has already been noted in a previous report," (171).
Seronegativity in the serum also does not rule out LNB, as revealed by studies of clinically typical cases with pathogenic verification (106-110).
Other technical medical tests
Other testing methods pertaining to the musculoskeletal system, nervous system, heart, and eye are also used in the diagnostic clarification of Lyme borreliosis and Lyme neuroborreliosis. The various methods are listed in Table 3.15. The purpose of the methods is self-explanatory, although some characteristics must be noted: CCT and MRT serve to verify cerebral lesions and expanded, demyelinating clusters whereby these illustrative procedures cannot differentiate between LNB and MS (111-115). SPECT can reveal significant impairment of metabolic activity and circulation in various cerebral regions, including in the presence of encephalopathy (116). The skeletal scintigram serves to verify inflammations, including around the joints, that are highly significant when considering the differential diagnosis for diagnosing chronic Lyme borreliosis.Neuropsychological tests are utilised for encephalopathy; however, cognitive functional impairments are often not recorded while they are verifiable through subjective estimation (with corresponding tests) . An inconspicuous neuropsychological test does not rule out cognitive impairment as a result of encephalopathy with chronic LB. An ophthalmological test can reveal optical neuritis by assessing visual acuity and visual field; these tests are of special significance for retrobulbar optical neuritis, i.e. with normal fundus. VEP (visually evoked potential) allows for the objectification of such a disorder. Furthermore, the ophthalmological test records uveitis anterior, intermedia and posterior (177, 178), vitreitis (179), retinal vasculitis (180), and papilloedema (181, 182). Dermatological testing of skin biopses can histologically and microbiologically reinforce the diagnosis of LB-typical skin change (e.g. with ACA or persistent or recurring EM).
Antibiotic treatment of Lyme borreliosis
Because there have not yet been any evidence-based studies of the antibiotic treatment of chronic Lyme borreliosis, no guarantee can be made for the following recommended treatments of late-stage (stage III) Lyme borreliosis.
The following 2 facts are of special significance with regard to the efficacy of antibiotic treatment of LB:
The scientific basis for antibiotic treatment of LB remains insufficient, with the exception of the localised early stage (EM before dissemination). The significant deficits of the clinical-scientific analyses are reflected in the treatment guidelines, the recommendability and evidential basis of which are severely limited in the international literature (4, 13, 117, 118, 124, 200) and which do not meet the medical and healthcare policy requirements.
The following evidential criteria are at the basis of the international recommendations (4, 13, 117, 118, 124, 200):
I At least one randomised study
II At least one well-designed, non-randomised study
III Expert experience based on clinical expertise
The recommendability is based on the evidence level:
A. Good evidence
B. Some evidence
C. Weak evidence
Accordingly, the following levels of recommendability come from the international literature as represented by the IDSA (Infectious Disease Society of America) (118):
Localised early stage A-I
(Amoxicillin for children under the age of 8) B-II
Disseminated early stage B-II – B-III
(Independent of type of antibiotic and disease situation)
Late phase B-II – B-III
When categorising B-III, the expert opinion and clinical experience are equivalent to weak evidence based on non-randomised studies.
The treatment of chronic Lyme borreliosis (late-stage, stage III) is thus not based on a solid foundation, i.e. there are no randomised studies of these important issues.
The recommendations presented here are based on the scientific literature, clinical experience of physicians with expertise in borreliosis, and fundamental research, in particular in the fields of microbiology and immunology. Successful antibiotic treatment is only possible with an efficient immune system. With regard to antibiotic treatment, problems arise from natural or acquired resistance. The pathogen (Bb) can remove itself from the immune system with "escape mechanisms" (164, 183).
The treatment duration is of crucial significance for the efficiency of antibiotic treatment. In the early stage, i.e. the first 4 weeks after inoculation, a failure rate of 10 % is to be expected (119, 120, 121, 122), whereas this number is much higher in chronic manifestations and can be up to 50 % (4, 13, 117, 122, 123, 124, 125, 126, 127, 128, 200).Past works had already referred to the problem areas of chronic Lyme borreliosis and its limited response to treatment (4, 13, 117, 122, 124, 130-135, 200). In all of these studies the treatment duration was limited and usually lasted no longer than 4 weeks. Repeated treatment cycles during such a treatment period also showed considerable treatment failure rates (136, 137, 138).
Chronic Lyme borreliosis is defined as a disease and is precisely presented as such in the literature (139-143, 247, 248, 249, 250, 255, 256). This also corresponds to the fact that after abstaining from adequate antibiotic treatment for weeks or years, the pathogen was verified in various tissues as well as the blood, liquor, and synovial fluid. The clinical course of chronic Lyme borreliosis after untreated erythema migrans was presented in the early works of Steere et al., 1987 (262) and Szer et al., 1991 (263).
Some studies have since become available that verify the positive effect of long-term antibiotic treatment, partially with regard to single aspects (4, 13, 117, 144, 145, 122, 123, 146, 124, 130-135, 147, 148, 126, 127, 128, 149, 147, 139, 136, 137, 150, 151, 152, 141, 138, 153, 142, 143, 200).
The limited effect of antibiotic treatment is revealed in numerous studies: even after presumably highly effective antibiotic treatment, pathogens were cultivated (144, 121, 122, 154, 125, 155, 128, 139, 150, 156, 157). Other factors play a role in vivo under antibiotic treatment (162) that are based on the ability of Borrelia to withdraw from the immune system (167, 122, 159, 160, 161) and to resist antibiotics. After multiple antibiotic treatments (Ceftriaxon, Doxycycline, Cefotaxim) Borrelia could be isolated from the skin (121, 122, 130, 148, 150, 156, 163, 157). A considerable discrepancy between antibiotic sensitivity of the Borrelia in vitro versus in vivo was also verified (125).
The Borrelia's resistance to antibiotics is, among other things, attributed to the intracellular location of the Borrelia (292) and biologically largely inactive eukaryotic shapes (cyst form) (167, 133, 160, 161, 155, 140). Furthermore, a film of complement regulators on the surface of the pathogen was discovered in Borrelia, with the effect of complement resistance with typical "shedding" (159, 160, 161). Other mechanisms, e.g. the diversification of membrane lipoproteins, loss of plasmids, various processes for deactivating complement (167, 160, 161) assist with the "escape mechanism" verified in other bacteria as well, i.e. the ability of the pathogen to withdraw from the immune system. The pathogen's ability to down-regulate proteins (pore-forming protein) could also contribute to the impairment of antibiotic effectiveness (164, 165).
There are 4 randomised studies of chronic Lyme borreliosis that focused on the comparison of various antibiotics and the antibiotic treatment of encephalopathy. These studies primarily showed that Cephalosporins were superior to Penicillin (4, 13, 117, 124, 129, 133, 200). Another study was solely concerned with encephalopathy with Lyme borreliosis (150). Usual dosage of Doxycycline only results in relatively low serum levels and tissue concentrations whereas the concentrations are much higher with the Cephalosporins, i.e. as concerns the minimal inhibitor concentrations (MIC) the values of the Cephalosporins are at least ten times greater than those for Doxycycline (154). Because of these high tissue concentrations, the usage of Cephalosporins to treat chronic Lyme borreliosis is nearly unavoidable. One alternative to this end is Gemifloxacin, which also achieves very high tissue concentrations (184). A very wide treatment spectrum and high tissue concentration of the antibiotics are especially significant with regard to poorly circulated compartments, especially in the extracellular matrix of connective tissue structures (joint capsules, fasciae, tendons), as Borrelia have a particular affinity for such tissues.
Whereas the above mentioned discrepancies concerning the in vitro effect and clinical success were verified for some antibiotics, there is good accordance among the Betalactams, Carbapenems, Macrolides and Tetracyclines. The bactericidal effect is clearly less dependent on the concentration than on the reaction time. The genospecies exhibit variable susceptibility, and the sensitivity may vary within one species. Treatment failure is seen in practically all common antibiotics (125).
Other antibiotics, especially the Carbapenems and Telithromycin, are used clinically although usage thereof is based on test in vitro (125) and there are no clinical studies. The same applies to Tigecycline (185, 186).
The antibiotics effective against Borrelia are listed in Table 3.17. The intracellular effect, penetration into the cerebro-spinal-fluid (liquor/serum concentration in %), and the effectiveness period (plasma half-life) are also listed.
As explained above, Borrelia are capable of morphologically changing, i.e. forming so-called cystic forms that are resistant to most antibiotics. Normal, spirochaetal Borrelia can reform from the cystic forms in a favourable, especially antibiotic-free environment. As the table shows, only the substances Tinidazol, Metronidazol, and Hydroxychloroquin can influence the cystic forms, whereby Hydroxychloroquin also influences the mobile Borrelia while this is not the case for Metronidazol (140, 166). However, more recent tests show that Tinidazol and Metronidazol are also highly efficient against spirochaetal forms of Borrelia burgdorferi (288). Furthermore Hydroxychloroquin, as a lysomotropic substance, reinforces the effect of macrolides (140) and possibly also that of the tetracyclines.
Another major effect of Tinidazol and Metronidazol is their influence on the biofilm, which was also verified in Borrelia. Both substances proved themselves effective, although Tinidazol was much more effective (Tinidazol differs from Metronidazol with an SO2 molecule) (258, 259, 260).
Antibiotic treatment can either be in the form of monotherapy (Table 3.18) or synchronous combination treatment (Table 3.23 and 3.24).
The efficiency of antibiotic combination treatment has not yet been scientifically proven; this treatment method is based on microbiological findings and not yet systematically examined, empirical data.
A number of antibiotics have been proven to be ineffective in treating Lyme borreliosis (cf. 164) (Table 3.16).
The longer the infection lasts, the more difficult it is to treat Lyme borreliosis with antibiotics. Whereas the early stage before dissemination is susceptible to antibiotics, there are often considerable difficulties with chronic Lyme borreliosis (late stage, stage III).This is not only induced by dissemination, i.e. the spread of the pathogen throughout the entire organism, but is also a result of a progressive adaptation of the pathogen and its resulting ability to withdraw from the immune system and antibiotic effects.
The characteristics of the different antibiotics' effects are listed in Tab. 3.22.
The antibiotics that are effective against Borrelia are listed in Table 3.17 with listing intracellular effect, penetration into the CFS and duration of effectiveness (plasma half-life).
Azithromycin, which accumulates in various organ tissues, has special characteristics. This is especially the case for cerebral tissue. Upon oral application of 500 mg of Azithromycin, cerebral concentrations of about 2.5 µg/g are measured one day later. If one considers the maximum inhibitory concentration (MIC) measured in vitro or the maximum bactericidal concentration (MBC) (125), the cerebral concentration is 100 times that of the MIC and 5 times that of the MBC in vitro (286).
The most recent tests show that the antibiotic Tigecycline is also effective against cystic forms and biofilms (185, 293, 294). The substance is incredibly effective against Borrelia (186), exhibits intracellular effectiveness, possesses good penetration into the liquor and a long tissue half-life (cf. Table 3.17) so that a daily dosage of 50 mg may also suffice for chronic LB and LNB.
Treatment with Roxithromycin is solely recommended by Gasser and Dusleag, 1990 (153). Roxithromycin is not recommended by Hansen et al. based on their study (287) of treatment of Lyme borreliosis.
Monotherapy, i.e. treatment of LB with only one antibiotic in various stages of the disease, is presented in Table 3.18.
Antibiotic treatment should be adjusted to the patient's weight, especially for children and underweight patients.
Treatment with Cephalosporins of the third generation is also suitable after initially continuous treatment (subsequently) in the form of pulsed treatment; during pulsed treatment the medication is administered 3-4 days out of the week .
The administration of third-generation Cephalosporins is also viewed critically by physicians, as they fear aiding intracellular residence and cyst formation of Borrelia burgdorferi [168, 169].
Monitoring the blood count, ALAT, lipase and creatinine is required weekly at first, and then every 2-3 weeks. When using Ceftriaxon, sonographic monitoring of the gall bladder must be performed every 3 weeks to recognise formation of "sludge" in time. When using Macrolides, ECG monitoring is required in two-week intervals.
The risk of a Herxheimer reaction must be noted for any antibiotic treatment of Lyme borreliosis, regardless of the stage. Corticoids should thus only be applied for considerable symptoms (parenteral).
Temporary light to medium worsening of symptoms may occur in the first weeks of antibiotic treatment. A short break in treatment, namely 2 to 3 days, helps to distinguish between drug intolerance and Herxheimer reaction.
Probiotic treatment is necessary to protect the intestinal flora and supports the immune system during long-term antibiotic treatment (e.g. Mutaflor, Omniflora [cf. 224]). In case of severe diarrhea that is hard to treat (e.g. with Saccharomyces boulardii), antibiotic treatment must immediately be interrupted and it must be determined whether a Clostridium difficile infection is present. In case of mycosis in the gastrointestinal tract, antimycotic treatment is required parallel to antibiotic treatment, and for 1-2 weeks beyond the antibiotic treatment. Common antimycotic medications are used for oral and genital mycosis.
For purposes of a better overview, the antibiotics used in stages I, II and III are listed in tables (Tab. 3.19, 3.20, 3.21). The data of these tables coincide with those of Table 3.18.
To this end it is also noted that synchronous, combined antibiotic treatment is prudent for stage III Lyme borreliosis (cf. Tab. 3.23, 3.24, 3.25).
Antibiotic treatment of late-stage (stage III) Lyme borreliosis requires antibiotics with specific effectiveness characteristics: high tissue concentration, intracellular effectiveness and effectiveness in the CNS. Effectiveness against cystic forms and biofilm (Tab. 3.22).
As there are no antibiotics that meet all of these requirements for effective treatment, it is necessary to combine various antibiotics simultaneously and over a sufficient period of time. Stage III Lyme borreliosis thus requires synchronous, combined, long-term antibiotic treatment.
The principle of synchronous, combined antibiotic treatment is described with frequently utilised treatment plans (Tab. 3.23). Along with these examples, a range of other combinations and alternatives is presented in Tab. 3.24.
The antibiotics suitable for synchronous, combined, long-term antibiotic treatment, their dosage and the necessary treatment duration are compiled in the overview in Tab. 3.25.
Essentially, third-generation Cephalosporin should be used with one or two oral antibiotics. If the Cephalosporins are ineffective, the other Betalactams listed in Table 3.25 come into consideration.
Because Lyme borreliosis is primarily transmitted by Ixodes ricinus (wood tick) in Europe, the following prevention is based on this carrier. However, personal protection also considers other ticks, especially those found outside of Europe.
Prevention considers the following factors:
With regard to the risk of exposure it must be noted that ticks are found in grasses and shrubbery up to a height of 1 m above the ground. Upon contact the ticks are shed from the surface and reach the skin (beneath the clothes) of all areas of the body. Ticks prefer moisture and warm areas of the skin, although a tick bite can essentially occur anywhere on the body. A special risk arises from contact with wild animals and pets.
This information results in the following primary sources of risk:
Protective gear should prevent penetration by ticks, especially through sealing around the legs and arms. The easiest way to ensure this is to stick the ends of the trouser legs into the socks, or with thick hemming.
Safety suits have also been designed, primarily for children; permethrin is used to impregnate military uniforms.
Various repellants are also available which reduce the risk by spraying directly onto the skin before exposure, although it is not completely effective and the effectiveness is limited to a few hours.
After exposure, i.e. after spending time in open nature, showering is recommended; the body should then be searched for ticks. This is made difficult by the fact that the pre-stages of the adult ticks, the so-called nymphs, are only about 1 mm in size and are thus easy to overlook.
An attached tick must be removed as quickly as possible, as the risk of infection grows the longer the tick is sucking (cf. Chapter 5.2). Only tweezers, tongs, or a sling must be used to remove the tick, as other methods are unsuitable. Once the tick has been grasped with the tweezers or tongs, the tick is slowly and gently removed from the skin, and the bite area is disinfected. Other manipulations around the area of the bite must be avoided.
The benefit of antibiotic prevention after a tick bite correlates to the risk of infection. As this risk is evaluated differently by the studies described in the pertinent literature, there are controversial recommendations as to antibiotic prevention. The work by Nadelmann et al., 2001 concerning one-time administration of Doxycycline for purposes of prevention is particularly significant. In this study it was shown that one-time administration of 200 mg of Doxycycline within 72 hours after the tick bite reduces the risk of infection from 3.2 % to 0.4 %. The authors thus recommended a one-time prophylactic dosage based on these data. Details can be found in Chapter 23.22.
Pain, paresthesia, loss of sensitivity in the feet, legs, hands and arms