BORRELIA INFECTIONS – LYME DISEASE

A SUMMARY OF THE IMPORTANT FACTS & DIAGNOSTIC

PITFALLS,
THERAPY AND TREATMENT OPTIONS

By JACOB JASON DEMEDICI

SUMMARY

In this article the terms “Lyme disease”, “Borrelia infection”, “Lyme borreliosis” and “Borreliosis”
are used interchangeably and have the same meaning and refer to the same disease. IN
different publications these terms are used in different, non-coordinated fashion, but they all refer
to the same disease, which is the topic of this article.

Treatment options and after care are discussed at the end of this article.

The intent and purpose of this article is to give readers as well as medical professionals an
overview of typical symptoms, diagnostic pitfalls and treatment / therapy options of Lyme
disease, also known as Borreliosis or Borrelia infections.
Borrelia or Lyme borreliosis is mainly diagnosed by clinical diagnosis of skin symptoms,
neurological symptoms, joint discomfort and other symptoms. Very important are also the history
of a tick bite, a subsequent redness, a flu-like illness, the beginning and the duration of the
complaints. The detection of Borrelia antibodies serves to confirm the diagnosis. An immunoblot
study is used to confirm the ELISA, which is a screening test, and should be done in any case
with a positive ELISA. The interpretation of the results strongly depends on the given diagnosis
and the given history.
Borrelia infections are the most common tick-borne infections ever. About 4% of all tick bites
cause such an infection. As a rule, this infection is first visible through an erythema migrans at
the sting site, before it comes to a pathogen generalization.
By adequately removing ticks, many infections can be prevented.
The clinic of Borrelia infection is extremely diverse, in the late stage is a combination of general
symptoms such as night sweats and fatigue with symptoms of the musculoskeletal system
(myalgia, arthralgia) typical.
In addition to the clinical symptoms, the diagnosis is mainly based on serological test
procedures, the implementation and interpretation of which have since become standardized.
The Lyme disease can be successfully treated at any stage. In the case of a fresh infection, oral
therapy is sufficient; in the chronic stage intravenous therapy regimens are necessary.

SOME IMPORTANT KEY ASPECTS:

1. Doctors should not rely on a positive IgG Borrelia serology to equate to infection,
respectively used only serology to diagnose or to exclude a Borrelia infection.
2. Patients with a positive IgG Borrelia serology may not develop the disease at all.
Patients with a strong healthy immune system may be infected with the Borreliosis
pathogens, but never become ill.
3. A positive IgG Borrelia serology must not be the sole reason for initiating therapy
but rather visual and symptom confirmation is required.
4. A prophylactic antibiotic treatment after a tick bite with e.g. Doxycycline is
somewhat controversial and under dispute, but there is no doubt that initiating
antibiotic treatment based on perceived individual risk and suspected early
symptoms may indeed help. In fact in the case of an infection the earlier antibiotic
treatment is started the better for the patient.
5. It is said in some publications that a Borrelia infection can be cured in any phase.
That appears to be not true. Untreated Borrelia infection will become chronic and
in many cases will lead to severe secondary health complications, including but
not limited to inner organs as the disease propagates throughout the body.
Untreated Borreliosis may lead to severe health complications, disease and
possibly death.
6. Horseflies and certain mosquitos may also transmit Borreliosis, but without a
doubt the by far largest source of infections are ticks.

DIAGNOSTIC PITFALLS

Lyme disease is the most common arthropod-borne disease of the Northern

Hemisphere. Often there are doubts because of unspecific symptoms or unclear
laboratory findings, if there is a disease requiring treatment. This article should help to
correctly interpret the findings obtained in the laboratory.
Lyme disease is caused by the pathogen Borrelia (B.) burgdorferi. These Borrelia bacteria are
today referred to as B. burgdorferi sensu lato (sl) complex and distinguish themselves from the
relapsing fever Borrelia [1].
The symptoms decide
It can not be emphasized enough that Lyme disease in all its disease stages and manifestations
is initially a clinical (suspicion) diagnosis. Laboratory diagnostics help to substantiate or refute
this suspicion, depending on the stage of the disease. It should be noted that the sensitivity of
the available methods in early disease stages (eg erythema migrans, Borrelia lymphocytoma
and acute neuroborreliosis) is limited and therefore a negative test does not rule out Lyme
disease.
No test without concrete suspicion!
In order to better assess the validity of Borrelia tests, it is necessary to learn something about
the performance data of a test. The significance is usually given with the parameters sensitivity
and specificity. However, this is often a bit misleading in practice, so a calculation example:
Assuming that a test has a sensitivity of 95% and a specificity of 95% (the majority of borrelia
tests are significantly worse): the test would now be able to detect a disease with a prevalence
in the population of 100/100 000 inhabitants (the prevalence of Lyme -borreliosis is on this
scale). Will be arbitrarily tested 1000 people. With a sensitivity of 95%, he would surely find the
one sufferer. However, the 95% specificity will cause 50 people to be tested "false-positive". The
result is 51 positive test results, of which only one is really sick. The positive predictive value in
this example is just under 2%!
For that reason, it is pointless to just do a Borrelia study. The probability of false-positive results
is far too high. Only when symptoms and anamnesis speak for a certain disease probability, it
makes sense to perform such a test.
serology
Serology is still the mainstay of the diagnosis of borreliosis infections. Today, this is performed
as a two-step diagnostic, as recommended by professional societies [2].
In a first step, today IgG (immunoglobulin G) and IgM are determined by enzyme immunoassay
(EIA), more rarely by indirect immunofluorescence (IFT). If the result is borderline or positive, an
immunoblot is performed in a second step.
Enzyme immunoassay (EIA)
The enzyme immunoassay is most commonly used in borrelia diagnostics. In contrast to the IFT,
it is completely automatable and objectively readable.
Since Borrelia diagnostics are not standardized, tests with regard to the antigen used, the unit
and the standard range differ in some cases considerably. It is therefore difficult to compare the
results of different tests from different laboratories. Today, EIAs are either coated with lysate
antigens (obtained from the growth of Borrelia) or with recombinant antigens.
Immunoblots (IB)
In immunoblots (IB), the individual Borrelia antigens are present separately on a strip. A
distinction is made between tests with electrophoretically separated antigens (Western blots)
and so-called line assays or strip tests. In the strip tests, the antigens are sprayed at certain
points with a kind of inkjet printer. Strip tests have several advantages. The reading is much
easier, the arrangement of the bands can be chosen freely.
Unlike the EIA, which measures the amount of antibody, the immunoblot shows against which
antigens the immune response is directed. In the early phase of the infection, antibodies are
usually only formed against a few antigens ("early bands"), while with longer-lasting immune
responses additional bands are added and then also so-called "late bands" occur (FIGS. 1 and
2). It can be differentiated between "specific" and "less specific" antibodies. For these reasons,
it is necessary that the laboratory indicates not only the test result but also the detected bands
(possibly with intensity) on the findings.
Meaning of individual antigens
As already mentioned, bands can be classified according to their specificity and occurrence in
the course of the infection. IgM antibodies to OspC (outer surface protein C) are formed
early. They are also the most important antibodies of the early phase and must be well
recognized by all test systems. Some tests therefore contain the OspC of several strains. VlsE
is also an early and specific marker, especially in IgG test systems. Therefore, this antigen is
included in virtually all current tests. Figure 1 shows blot results from five patients with acute
Lyme disease.
With increasing disease duration (weeks to months), additional antibodies are added. Typical
"late antibodies" are directed against p100 and DbpA (decorin binding protein A). Antibodies to
p58, p60 and OspA are also produced during the course of infection. Fig. 2 shows blot strips of
patients with a longer lasting immune response. The immune response is directed here against
a variety of antigens.
Blot strips can now be objectively read and documented with blot readers. However, the immune
response of individual patients is very different and the result is not always as clear as in the
examples shown.
pathogen detection
The pathogen detection is reserved for the Lyme disease specific issues. In today's laboratory
diagnostics virtually only a nucleic acid amplifying technique (NAT) is used. As a rule, it is a PCR
(polymerase chain reaction). In addition to the NAT stands as "gold standard" nor the cultivation
available. Only with this method can the proof be given that they are living, reproducible
pathogens and not borrelia remnants. However, the cultivation is complex, takes a long time and
is therefore not a routine method.
Unfortunately, both culture and PCR have limited sensitivity, which can vary depending on the
material. So z. As a PCR from the blood using routine PCR techniques does not make sense,
as well as the study of urine [3]. Suitable examination materials are a skin biopsy (eg from the
edge of an erythema migrans or an acrodermatitis chronica atrophicans), synovial fluid or better
a synovial biopsy and cerebrospinal fluid. The sensitivities are between 20 and 80% [4].
Examination of ticks
 For some years, it has been possible to examine distant ticks for Borrelia infection. Several
laboratories offer this study. The meaningfulness of this investigation is controversially
discussed, since not every tick is noticed and therefore does not reliably protect this procedure
against a Lyme disease. In addition, not every single sting of a positive tick leads to an infection
or to a manifest illness.
Nevertheless, this study can be used for risk assessment. In the USA it could be shown that
short-term antibiotic prophylaxis significantly reduces the occurrence of an infection
[5]. Examination of the tick can significantly reduce the number of persons treated
prophylactically. Even if no prophylaxis is performed, the knowledge of an infected tick may
influence the further course of infection control. This examination of ticks is done by NAT. The
laboratory must be able to ensure that the relevant subspecies are detected with sufficient
sensitivity.
Evaluation of the results
In the general medical practice one will be confronted mainly with serological findings. It is
important to evaluate these in conjunction with the clinic and medical history. The following
statements should help the reader with the evaluation:
1. In the early phase of infection, lack of antibodies does not exclude infection. Early therapy may
result in antibody formation. When antibodies are formed, they often belong exclusively to the
IgM class.
2. In Z. n. Acute borreliosis isolated IgM antibodies persist for a long time. If one later encounters
these antibodies, this can lead to a misdiagnosis of "acute Lyme disease".
3. A serological follow-up, z. B. after three weeks, can help with unclear initial findings to ensure
the diagnosis. A therapy success check after acute infection is not possible by means of
serology.
4. If IgG antibodies have formed after an acute infection, this does not initially indicate a treatment
failure. However, the few treatment failures will be more likely to be found in patients with IgG
seroconversion.
5. The detection of Borrelia-specific antibodies without corresponding symptoms is not a
therapeutic indication.
6. Missing IgG antibodies make chronic infection unlikely.
7. Persistent IgM antibodies without simultaneously detectable IgG antibodies also do not speak
for a chronic infection.
8. In V. a. Chronic Lyme disease and proven IgG antibodies should not misunderstand IgM
antibodies as activity markers. Chronic Lyme disease is also possible without IgM antibodies.
9. For positive IgG antibodies, follow-up is only useful at long intervals. Optimal is a parallel test of
both samples with the same test.

In case of unclear constellations, the result should be discussed with a microbiologist or

laboratory doctor experienced in borrelia diagnostics. Unfortunately, there are still cases in which
a patient is not treated due to misinterpreted laboratory values. The opposite case, over-therapy,
is more common.

BORRELIA (LYME) SEROLOGY IN PRACTICE

Only 20 percent of patients experience seroconversion after the bite of a tick infected with
borrelia; only two percent develops erythema migrans. A positive Borrelia serology is not
to be equated with an infection; therefore finding other causes for the symptoms is
essential.
By Elisabeth Aberer et al. *

Austria is an endemic area for Lyme borreliosis - a disease that is transmitted by ticks. Patients
with early skin symptoms, erythema migrans, are primarily cared for by general
practitioners. These are also the focal point for other possible symptoms of Lyme disease - heart
problems, joint and muscle pain, neurological symptoms and headaches. Special skin symptoms
of Lyme borreliosis and neurological symptoms such as facial nerve palsy are usually treated by
a private specialist or at the clinic. The diagnosis of Lyme borreliosis is primarily clinical, by the
typical Hautbefund, other symptoms but also by the history of a tick bite.

Borrelia serology is a diagnostic test to confirm the diagnosis of clinical signs of Lyme
borreliosis. Positive results can be expected:
 Erythema migrans: 50 percent positive
 Borrelia lymphocytoma: 75 percent positive
 Acrodermatitis chronica atrophicans: 100 percent positive
 Lyme arthritis: 100 percent positive
 Neuroborreliosis: evidence of infection by positive CSF / serum antibody index, lymphocytic
pleocytosis and barrier disorder.

Of interest to the dermatologist is whether Morphea (circumscribed scleroderma) of lichen

sclerosus and malignant B-cell lymphoma are associated with Lyme borreliosis, as all of these
diseases have also been reported to be successful in antibiotic therapy. The serology gives a
reason for this. Other reported symptoms associated with Lyme disease include tinnitus, acute
hearing loss, uveitis, arthralgia, myalgia, neuropathies and sympathetic dystrophic reflex
syndrome. Therefore, Borrelia antibodies are examined in all possible complaints of the
patients.
Infestation of the population

Contact with Borrelia does not necessarily lead to a manifest illness. Seroconversion occurs in
20 percent of patients after biting of a borrelia-infected tick; Only two percent develop
erythema migrans. For many people, it can thus come to a "silent celebration"; they are very
healthy. Due to the high level of contamination of the population (ten percent of blood donors,
30 percent of forest workers, 70 percent of 70-year-old hunters) can be difficult to determine in
which patients actually proven Borrelia infection leads to symptoms and which are quite
different diseases behind it.

The University Clinic for Dermatology in Graz performs serological Borrelia diagnostics in the
Graz State Hospital. According to the guidelines, an ELISA is used as a screening test, which
should be confirmed by an immunoblot. By immunoblot antibodies are determined, from whose
pattern one can read an early or late infection. The problem with serology is that the antibodies
that are formed after infection are also detectable after therapy and also show healthy
individuals dependent on their tick exposure in a high percentage of antibodies without being
ill. Now, when these Borrelia antibodies are being studied for the various symptoms of Lyme
disease, it is helpful for the referring physician to provide an interpretation of the results from
the immunoblot pattern.

Interpretation and Correlation

Interpretation of Borrelia serology often offers several options. However, the evaluation of the
serology results from the result of the immunoblot (Table 1). Even if antibodies are positive in
the ELISA but can not be confirmed by the immunoblot, this is not evidence of infection.
Project: referrer survey

For one year, the University Clinic for Dermatology Graz has issued the immunoblot report with
a medical interpretation. To find out whether this interpretation is also helpful for the referring
physician, a referral survey was conducted in July 2011 and was given to various hospitals of
the LKH Graz (ENT, Rheumatology, Neurology, Children's Hospital, Pediatric Surgery,
Ophthalmology, Internal Medicine / Infectiology and to doctors at the University Hospital for
dermatology). Furthermore, 100 case histories of the clinic were examined to determine
whether the given interpretation fits the clinical picture. Out of the 60 questionnaires, 16
answered. Most referring physicians are content with an interpretation. In most cases the
interpretation is also helpful, but occasionally it does not match the clinical picture.

Early infections are characterized by IgM antibodies, such as those found in erythema
migrans. After one month, IgG seroconversion should be performed. Only when IgG antibodies
are formed can confirmation of Lyme disease occur. For isolated IgM antibodies without
developed IgG antibodies, the interpretation of the findings should be considered
unspecific. Table 2 shows that in erythema migrans the serology before therapy is only 35
percent positive. A new blood sample at one month would be required to confirm
seroconversion most commonly seen after therapy (50 to 70 percent positive test, IgM only or
IgM + IgG antibody).

Procedure for classic skin symptoms

Erythema migrans is always a clinical diagnosis (Figure 1). One must not wait for the
serology; the therapy must be done immediately. Performing a serology in this early form of
Lyme borreliosis is therefore not required. It is different in the Borrelia lymphocytoma and in the
Acrodermatitis chronica atrophicans. In both diseases, a histological confirmation of the
diagnosis must be made (exception: children with lymphocytone). In lymphocytoma can be
detected in about 75 percent, in acrodermatitis chronica atrophicans in 100 percent
antibodies. Procedure for other symptoms

In the clinical diagnosis of neuroborreliosis, the neurologist specifies the indication for
CSF. Borrelia antibody produced autochthonically in cerebrospinal fluid is determined by CSF /
serum index to confirm the diagnosis. Cardiac arrhythmia may be due to a titer movement in the
serology, the diagnosis of underlying Lyme borreliosis suspect. The history of a tick bite and the
exclusion of other diseases but also plays an important role here. Unilateral joint swelling and
migratory joint pain are heterogeneous. Again, the history of a tick bite or skin symptoms is
crucial for the diagnosis of Lyme arthritis.

Other symptoms (33 percent seropositive in our evaluation, 83 percent positive serology in
arthritis / arthralgia, myalgia, headaches, tinnitus and ocular symptoms such as uveitis) show a
certain percentage of Borrelia infection. Antibiotic therapy is therefore recommended. For a
longer time of infection, more than 30 days should be treated. If there are unclear symptoms
(27% seropositive, Table 2) and Borrelia IgG antibodies are present, we also propose a "Safety
Therapy" over 30 days.

For the given comments, the referring physicians would like a more accurate assignment of
proven bands, whether they correspond to an early or late infection. As the referring colleagues
rightly note, one must accept that antibody detection alone is not evidence of infection and that
the cultural pathogen can provide the only evidence. A PCR indicates that the DNA of the
pathogen is present, but not whether the pathogen is still capable of reproduction and not if it is
pathogenic and relevant to the disease. Our request to referring physicians is to have clues such
as the diagnosis, history of tick bites (when?), Erythema migrans (when?), And previous
antibiotic therapy for Lyme borreliosis. This allows the interpretation to be optimized.

Historical introduction

Some clinical manifestations of Lyme disease have been known for more than a hundred
years. BUCHWALD described "diffuse idiopathic skin atrophy" as early as 1883, POSPELOW
(1886) spoke of "atrophy idiopathique de la peau", JUDASSOHN (1891) of "atrophia maculosa
cutis" and PICK 1894 of "erythromyelia." We recognize all of these syndromes today as variants
of the form of the Lyme disease acrodermatitis chronica atrophicans (ACA).
Also, the erythema migrans was described in 1910, the acute neurological form in 1941 by Garin
and Bujadoux. Only with the "rediscovery" of Lyme disease in 1975 in Lyme / Connecticut but
the disease was gradually understood as an entity and with the discovery of the pathogen by
Burgdorfer 1982, the foundation for diagnosis.

1 By the way, POSPELOW is the source of the cited "cigarettes-paper-like pleating of the skin"
in acrodermatitis chronica atrophicans
Borrelia in the natural cycle
Borrelia are transmitted primarily by shield ticks (in our case Ixodes ricinus, the wood buck)
between different mouse generations.
Here, a special feature of the mouse immune system plays a role: the mouse does not suffer
from the Borrelia infection, it even allows a lifelong bacteremia. This allows the circulating in the
mouse blood Borrelia be resumed by ticks at any time.
The tick is only about 1% already transovariantly infected with Borrelia. The first stage of
development, the larva, absorbs Borrelia from mice at their first blood meal. Then she skins off
to the nymph. These nymphs are already 15-25% infected with Borrelia. After another blood
meal, it will re-skinned and become an adult animal. Only the adult females then need another
blood meal before oviposition.
Since ticks need two or three blood meals in their life cycle, the pathogen can be repeatedly
taken up and passed on.

The red-eared mouse, one of the major reserves for Borrelia

Humans actually play no part in the natural cycle of the Borrelia, from the point of view of the
pathogen it is even an epidemiological dead end. Immunologically, humans are different from
the mouse: they do not tolerate the pathogen but attack it. The price is that the person is clinically
ill. On the other hand, bacteremia in humans will only be possible for a short time, so that the
pathogen can not be taken up again from peripheral blood and passed on. Therefore, a Lyme
disease in humans is not transmitted by blood contacts or sexually transmitted.

Lyme Disease: Epidemiology

Borrelia are transmitted exclusively by tick bites. The pathogen is located in the midgut of the
tick. Like the tick itself, the Borrelia have to survive long food-free intervals and can slow down
their metabolism during this time. After the start of the blood meal food substrate is available,
now the Borrelia bacteria start to increase their metabolism and actively migrate into the salivary
glands of the tick after about 14 hours, from where they can be transferred to the puncture wound
with saliva secretions. This usually happens after at least 14 hours. If you remove a tick during
this time, it usually comes not to infection, if the tick is not squeezed at the distance and so
intestinal contents get into the wound.
Note: Never squeeze the tick when removing it! Tweezers, ticks and similar instruments are
therefore unsuitable.
Better suited is a scalpel of the form 11, whose finely extended tip is pushed into the gap between
the skin and the body of the tick. Then the tick is pushed up by leverage and pulled out (see
picture)

Tick removal with scalpel

On average, about 15% of ticks that suck humans are infected with borrelia (Oehme et
al.,). Interestingly, 80% of these ticks were nymphs, the middle stage of development. These
nymphs are only about 1.5-2.5mm tall. Why adult ticks are rarely found on humans is
unknown. The investigations of Oehme have shown that in borrelium-containing ticks in every
fourth case came to the transmission of the pathogen. One can therefore open the following bill:
15% of the ticks contain Borrelia, but only 4% of all tick bites lead to a Borrelia infection.

In view of these figures, we reject (Landesarbeitsgruppe tick-borne diseases Baden-

Württemberg, Anm. Of the author) from a general antibiotic prophylaxis after tick bite from and
recommend a study of the tick by PCR for Borrelia. Only with positive evidence, we consider an
antibiotic prophylaxis justified, otherwise 96% of all patients would be treated unnecessarily.

Prospective own investigations have shown that in endemic areas about 500 per 100 000
inhabitants annually become ill with a Lyme disease (Hassler, HabilSchr.). This morbidity rate
could be reduced to 85 per 100,000 by adequate tick removal.
It is estimated that there are tens of thousands of new cases every year in Germany due to such
prospective investigations. This number could be significantly reduced by adequate tick removal.
The disease begins: Erythema migrans
After transmission of the pathogen during the tick bite, the Borrelia in the skin multiply and
actively migrate from the sting site to the periphery at a speed of 3-6mm / day. The generation
time in Borrelia is 12-36 hours, on average 24 hours. The multiplication of the pathogens
happens very slowly, so that usually after 7-14 days the number of pathogens is so great that a
detectable immune reaction begins. Then lymphocytes and plasma cells enter the infected area
and cause visible discoloration of the skin, the erythema migrans.

The "seven-day rules"

Everything that becomes visible at the sting site before the seventh day is part of the "primary
sting reaction". This is triggered by mechanical irritations, such as in the tick removal, or by
foreign body reactions to tick parts or tick saliva. An erythema migrans becomes visible at the
earliest after seven days.

Picture: The erythema migrans is the visible cellular immune reaction (here about 21 days after
the tick bite)
Erythema migrans is a visual diagnosis! We never find eczematous changes, the epidermis
remains intact.

A special case of erythema migrans is the borrelia lymphocyte (BL). Sometimes we see in the
center of an erythema migrans a slightly denser cell infiltration, which represents a
lymphocytoma. This can also be solitary, especially in children's ears. The reason is simply that
the Borrelia have their limits when they spread peripherally to the ear, so that a clearer local
infiltrate can form. Pathophysiologically and histologically, the transitions from EM to BL are
fluid. However, we have observed that a solitary lymphocytoma can often occur as part of re-
infections. In these cases, the immune reaction starts a little earlier and more violently than at
the first infection, so that a denser infiltrate of defense cells is formed in a small space.
In both erythema migrans and lymphocytoma, we generally do not find any serologically
detectable antibodies. The therapy should therefore never be made dependent on the antibody
status!

Picture: Lymphocytoma on the ear of a child

The pathogen begins to spread: the generalization phase

When passing through the skin, Borrelia sooner or later encounters blood vessels whose walls
they wander through. Then the bacteremia begins in the sense of a pathogen
generalization. This can be completely subclinical but also be accompanied by severe general
symptoms such as fatigue, feeling flu, night sweats and palpitations. The number of pathogens
and the severity of the immune reaction determines the intensity of the clinical symptoms.

Now the immune reaction sets in, antibodies are formed, macrophages fight the borrelia, so that
the phase of the clinically recognizable bacteremia usually lasts only a few days. Nevertheless,
the pathogen dispersal may have occurred previously and lead to organ involvement.

If it comes to the CSF invasion, lymphocytic meningitis occurs (about 3-5% of all cases), the full
screen is the combination of meningitis with neuritis peripheral nerves ("Bannwarth syndrome".
Cardiac involvement can lead to conduction abnormalities, intermittent tachyarrhythmias and
myocarditis. Rarely can this run protracted and cause cardiomyopathy.

Nests of Borrelia escape the immune system: the chronification

Borrelia have a special affinity to collagen fiber. In these fibers they can escape the attacks of
the immune system and cause a persistent infection. In these "immunologically privileged
places" the Borrelia can survive for a long time and after months to years initiate symptoms of
the late stage. In the chronic phase, especially tissues of the supporting apparatus, ie tendons,
cartilage and bones are affected. As a result, patients often suffer from arthralgia and myalgia,
tendon pain, and increased periosteum sensitivity.

The actual Lyme arthritis is not uncommon. It usually affects the larger joints, especially the more
mechanically loaded such as knee and ankle joints. Often massive effusions occur, sometimes
so violently that rupture of baker cysts occurs. Often the affected joints change at fairly short
intervals.

Even in the chronic stage it comes in phases of disease activity quite regularly to accompanying
general symptoms: Patients feel extremely beaten off and tired, often sweat at night violently
and complain of palpitations. Such relapses are often reported one to four times a month.

Late effects due to pathogen persistence: neuropathy and ACA

After some years, some patients develop sensory polyneuropathy, which is triggered by axonal
degeneration of peripheral nerves. Motor failure is extremely rare.
Finally, due to their optimum temperature of 32-34 ° C, Borrelia can concentrate on the cooler
claws. Occasionally, acrodermatitis chronica atrophicans (ACA) with blue-red discoloration of
the skin may appear. Borrelia can easily be cultured from these areas, which proves the
persistence of chronic borreliosis.

Picture: ACA with pillow-like infiltrates and areas with pronounced atrophy of the
epidermis
Do different Borrelia species have distinct disease patterns?

Due to a work by van Dam (##), it is repeatedly stated that the different types of Borrelia cause
different clinical pictures. For example, Borrelia afzelii is particularly likely to cause skin
involvement, especially ACA, B. garinii is said to have a special affinity for the nervous tissue,
and B. burgdorferi is most frequently responsible for Lyme arthritis. This acceptance must be
questioned because the distribution of Borrelia species in the Benelux countries is different than,
for example, in southern Germany. Leading species in the Netherlands is B. garinii, in our
investigations in southern Germany we found the most common with 44% B. afzelii. At least in
individual cases, all species could be detected in all disease patterns.

Diagnostics

The diagnosis of Borrelia infections rests on several pillars: clinical, serological and direct
pathogen detection.
In the case of fresh infection, only the clinical picture is decisive. An erythema migrans is a gaze
diagnosis and must be treated in principle, even if the serology is still negative.
In the case of an already generalized infection, serologically detectable IgM antibodies will
usually be expected. IgG antibodies are to be expected in the later stages. Even during acute
relapses of the late stage, the IgM does not have to be positive again, often only IgG antibodies
are detectable.

Therefore, the clinical picture determines the procedure.

► Erythema migrans is generally treated without serology, pathogen detection by PCR or culture
from skin biopsies would be possible, but is usually not necessary.
► If Borrelia infection is suspected in the generalization phase, serology is often helpful but may
be negative at the beginning. Therefore, if necessary repeat after two to three weeks.
► If neuroborreliosis (with CNS involvement) is suspected, CSF evidence with evidence of
autochtonous antibody formation is evident.
► For chronic infections with symptoms of the late stage, especially in joint involvement, IgG
antibodies are mandatory to justify the diagnosis of Lyme disease, but there are no seronegative
late-stage borreliosis. The pathogen detection succeeds, however, only in exceptional cases,
most likely from synoviabiopsia.
► In the case of acrodermatitis, pathogen detection by PCR or culture is easily possible from
skin biopsies. This technique also allows therapy control in ACA.
Interpretation of Borrelia serology

Today, a two-stage test procedure is generally used. For technical reasons, an addiction test
(IFT or Elisa format), which can be carried out largely automatically, is initially carried out. If a
positive result is obtained with this test, the specificity of the antibodies is confirmed by Western
blot (= immunoblot). Thus, nonspecific cross-reactions of the addictive tests and thus false-
positive results can be detected.
The principle of Western blot works like this: Borreliae cultured in the laboratory are broken down
into their individual proteins, which are separated electrophoretically from a nitrocellulose strip
and sorted by molecular weight. Then this strip is incubated with patient serum. When antibodies
to the individual proteins are present, they bind and are visualized via a color reaction. The
resulting pattern is similar to a barcode and immediately shows which of the Borrelia proteins
are "recognized" by the patient serum. Some of the proteins are completely nonspecific and
therefore highly cross-reactive (about 41kD flagellin, a common protein in the bacterial world in
all flagelliferous bacteria). Others, such as 31kD OSP A and the 94kD protein, are highly specific.
Since all Borrelia species are highly cross-reactive, one can in principle carry out a western blot
with each species, but in general B. afzelii strains are used for the diagnosis. Nevertheless, B.
garinii infections can be detected with these tests.

Fig: Western blot with detection of multiple bands (strong 31 kD IgG band, also 41 kD, 58 kD
and 94 kD are IgG positive) in a patient with Lyme arthritis

The lymphocyte transformation test

The principle of LTT is intriguing: you confront a patient's living lymphocytes with an antigen and
see if they respond to it by measuring the metabolic activity of incorporating 3H-thymidine.
Unfortunately, this test is subject to strong fluctuations and often gives false-positive results. The
currently available on the market LTT tests are not sufficiently validated and therefore not
currently recommended.

THERAPY
The treatment of Lyme disease as well as the diagnosis is stage-dependent. The fresh infections
(erythema migrans and lymphocytomas) in adults are treated with doxycycline 3x100 mg daily
for 20 days. Alternatives are: Amoxicillin 3x750mg to 4x1g / 20 days; Cefuroxime axetil 2-3x500
mg / 20 days or azithromycin 500 mg / 10 days.
Erythromycin has performed significantly worse in all studies and can no longer be
recommended; roxithromycin is also not recommended.
In children and adolescents, treatment with amoxicillin or cefuroximaxetil (weight-adjusted, 20
days), as doxycycline can not be used in children. Alternative is azithromycin for at least 10 days.

Borrelia infections in the stage of generalization with general symptoms can be treated in
principle just like early infections. For CNS involvement, intravenous therapy should be used (in
adults, cefotaxime 2x3g daily / 15 days or ceftriaxone 2g daily / 15 days, in children weight-
adjusted). For cephalosporin allergy, only penicillins or imipenem remain.

In the chronic stage, oral therapy attempts are futile, only the intravenous therapy regimens (see
above) are definitely effective.

TODAY’S THERAPY RECOMMENDATIONS

Phase 1: Local infection ("Stage 1")
(Erythema migrans and Borrelia lymphocytoma)
In adults: doxycycline 2-3x100 mg / 20 days
Alternatives: Amoxicillin 3x750-4x1000 mg / 20 days
Cefuroxime axetil 2-3x500 mg / 20days
Azithromycin 500 mg / 10 days
In children: amoxicillin (3-4xtgl 15mg / kgKG),
Cefuroxime axetil (2-3x daily 6mg / kgKG),
Azithromycin (1xtgl 6mg / kgKG)
In pregnant women: amoxicillin, cefuroxime axetil (as above)

Phase 2 (bacteremia phase)

See above, alternatively IV therapy with cefotaxime or ceftriaxone
In case of CNS involvement (Bannwarth syndrome): iv cephalosporins

Phase 3 (chronic stage)

Cefotaxime 2x3 to 2x4 g / 15-21 days iv
Ceftriaxone 2-4g / 14-21 days iv
For a prolonged therapy over more than 20 days there is no proof of a benefit, but the side
effects increase considerably.
There is no evidence of efficacy for oral therapy with doxycycline in the chronic stage.

ASPECTS OF AFTER-CARE
After treatment with erythema migrans, routine serology is routinely checked after three
months. If IgG seroconversion does not occur then the disease is considered cured. Residues
of IgM antibodies may be detectable for a longer time, this is not disturbing.

After treatment for chronic Lyme disease, at least four serological and clinical controls are
generally performed at six-monthly intervals. Then you can usually detect a slow disappearance
of the specific immune response. However, the clinic clearly has priority in the assessment of
therapeutic success: usually the first to disappear the general symptoms such as fatigue and
night sweats, joint pain relieves usually hesitant for weeks and months, neuropathy often leave
a defect healing.

Because Borrelia has no resistance to commonly used antibiotics, every therapy reduces the
number of Borrelia by a few orders of magnitude. So you can always count on at least a
temporary improvement. Recurrences announce themselves at the earliest after 10-12 weeks
by a recurrence of the original symptoms. A completely lacking therapeutic success should
therefore always be the occasion to critically question the diagnosis again.

Generally speaking: Borreliosis can be cured at any stage.

Our own figures from more than 1500 patients with chronic Lyme disease show the following
results: 82% were permanently cured with one treatment cycle, 18% required a second, 8% a
third and a fourth cycle 3%. Only in three patients with allergies to penicillins and cephalosporins
no curative therapy was possible.