Introduction
Lyme borreliosis (LB) is a multisystemic infectious disease that
is caused by the arthropod-borne spirochete Borrelia burgdorferi sensu lato
(Bb). In Europe, about 80% of all cases of LB represent skin manifestations,
all together named dermatoborrelioses (DB). There are three characteristic
manifestations of DB, in which the etiopathogenic role of Bb, most often
the subtype Borrelia afzelii (1,2), is proven by cultivation of the spirochete
from lesional skin. These manifestations are erythema migrans (EM), borrelial
lymphocytoma (BL), and acrodermatitis chronica atrophicans. In this article,
clinical and diagnostic aspects of EM and BL will be discussed, based on
our experience with more than 1,000 DB patients, seen at the Department of
Dermatology in Graz, Austria between 1993 and 2000.
Erythema migrans
Epidemiology and transmission of Borrelia burgdorferi
EM, the hallmark of early LB, is the most frequent manifestation
of LB at all. It is found in endemic areas (clusters) all over the northern
hemisphere, including the Alpe-Adria-region (3). The incidence of EM in Styria,
the southeastern-most state of Austria is estimated to be 50/100.000 per
year. EM affects both sexes and all age groups equally and shows seasonal
variations with a peak incidence between May and September, although several
cases also occur regularly during the winter months. EM develops at the site
of an infectious tick bite in most cases, but in a small percentage of patients
EM lesions develop distantly to a tick bite. In accordance with the most
frequent sites of tick bites (higher body temperature), the location of EM
is usually the calf/popliteal fossa region, or the thigh/groin/buttock region,
or the armpit/shoulder region. A tenet in the etiopathogenesis of EM has
been that an attachment period of at least 24 hours is necessary for the
tick to transmit enough spirochetes into the human skin to produce EM. In
our patients, the average attachment period is between 12 and 72 hours, but
many patients also give a reliable history of a shorter attachment period.
EM develops after an incubation period of 4-180 days (median, 14 days) following
the tick bite. A still debatable question is, whether or not arthropods other
than ticks are able to transmit Bb. Over the last eight years, about 10%
of our patients, who could specifically recall an arthropod bite at the site
where EM developed later, were sure that this arthropod was a flying insect.
Figure 1. Solitary annular type of erythema migrans.
Figure 2. Solitary macular type of erythema migrans.
Clinical types of erythema migrans
There are different clinical types of EM:
(i) Solitary macular and
(ii) solitary annular EM comprise 43% and 38% of all EM lesions,
respectively, and are round to oval, sharply demarcated, red to bluish-red
erythemas with a diameter of at least 5 cm (4,5). The difference between
these two types is that annular lesions are ring-like (Fig. 1), whereas macular
lesions show no central clearing, but remain homogenous. The latter is characterized
by a pronounced inflammatory edge in most cases (Fig. 2). EM usually lacks
epidermal changes, although vesicles or minimal scaling have been observed
in a few patients. EM lesions on the calf tend to develop a hemorrhagic component
due to stasis. Local symptoms are generally mild (itching or burning sensations)
or absent.
Figure 3. Bull's eye type of erythema migrans.
Figure 4. Atypical variant of solitary erythema migrans. Note that the erythematous
ring is incomplete.
(iii) The bull's eye type (2%) is a variant of solitary annular EM that is characterized by a target-like morphology with a peripheral bright red rim that is separated from a central bluish-red patch by a ring of normally appearing skin (Fig. 3).
(iv) Another type of EM is the minimal size EM, which is defined as EM lesion with a diameter of less than 5 cm on presentation (6). We have observed 52 patients with such lesions in a series of 957 consecutive EM patients. In 21 of these patients, EM remained in this size also 7-10 days after the first visit without antibiotic treatment, whereas EM expanded beyond a diameter of 5 cm over time in the other 31 patients. Thus, in around 3% of patients, EM is smaller than 5 cm ("true minimal size EM"). In our 21 patients, the sex ratio m:f was 10:11 and the median age of the patients was 45 years. Twelve of the lesions were macular, nine annular. Of interest, 66% of all these EM lesions were located on the lower extremities. The mean disease duration before start of antibiotic treatment was 13.6 days (range, 6-50 days). Extracutaneous signs and symptoms, in particular fatigue, were present in 5/21 (24%) patients. Serum anti-Bb IgG and/or IgM antibodies were found in 16/21 (76%) patients by a standard ELISA test.
(v) Five percent of EM lesions are atypical (Fig. 4). Among these
lesions there are the combined BL and EM lesions, which we have defined as
the occurrence of the two manifestations of DB together at the same site
of the body (7). We scrutinized our patients files for bluish-red nodules
or plaques in the center of an EM and found such combined lesions in 15/1,007
(1.5%) patients. The sex ratio of m:f was 8:7 and a median age of 51 years.
Twelve of the 15 (73%) combined lesions were localized on the upper part
of the body. Interestingly, Borrelial lymphocytoma (BL) preceded EM in all
15 patients by 2-8 weeks. Extracutaneous signs and symptoms were present
in 3/15 (20%) of patients and occurred simultaneously with the beginning
of EM, indicating that the development of EM around BL may represent the
transition from a primarily localized into a disseminated manifestation of
DB.
Figure 5. Disseminated erythema migrans.
Figure 6. Borrelial lymphocytoma on the earlobe.
(vi) The development of more than one EM lesions in one patient
(multilocular EM) has been observed in 9% of our patients. The mean total
number of lesions per patient was four, with a range from 2-36. The underlying
pathogenic mechanism in many patients is hematogenous dissemination of the
spirochete, in which case there is a primary EM with a typical clinical aspect,
followed by a median of six secondary lesions all over the body after a latency
period of a few days. Secondary lesions are generally smaller an less inflammatory
(Fig. 5). These patients are affected more often by extracutaneous signs
and symptoms than patients with solitary lesions and are more often seropositive.
This kind of disseminated EM is less frequent in Europe than in the USA (8),
and the number of lesions per patient is smaller in European patients. Besides
this disseminated form of EM, there are also patients in whom the occurrence
of multiple lesions is due to more than one infectious arthropod bites or
to local spread of Bb.
Erythema migrans in children
EM in children is most frequently located in the head-neck region
and often displays an atypical (band-like or gyrated) morphology. These lesions
are very transient (few days) and variable in intensity over time. Neuropediatricians
sometimes see children who are suffering from an ipsilateral peripheral facial
palsy along with an EM lesion on the face, which may point to a neurotropic
spread of Bb. Disseminated EM is found more often in children than in adults.
Extracutaneous signs and symptoms
Extracutaneous signs and symptoms occur in up to 40% of all EM patients,
in which case the disease has to be classified as major form of EM. These
signs and symptoms are unspecific and usually mild. The most common features
associated with EM are elevated temperature, headache, arthralgias, myalgias,
fatigue, malaise, regional or generalized lymphadenopathy, and sore throat.
These signs and symptoms occur along with EM and are usually transient, generally
lasting for a few days only. In many cases, they have already disappeared
before initiation of antibiotic treatment, but may indicate that (hematogenous)
dissemination of Bb has taken place. It must be clear that these signs and
symptoms are not due to another etiology or primary disease. They must also
be distinguished from signs and symptoms indicating another organ manifestation
of LB (e.g., neuroborreliosis, cardioborreliosis) on the one hand and from
features of ehrlichiosis on the other hand. Ehrlichiosis, in Europe usually
human granulocytic ehrlichiosis, is caused by the HGE agent that is transmitted
by the same ticks as Bb. Co-infection with Bb and the HGE agent is found
in about 20% of borreliosis patients in Austria (9).
Differential diagnoses
The differential diagnoses of solitary EM comprise unspecific insect
bite reactions, which develop more rapidly and will clear from the periphery
within a few days without antibiotic therapy, erysipelas, which is usually
accompanied by high fever and chills, morphea, which has an ivory-like whitish
center that is surrounded by a lilac ring and has an increased consistency
on palpation. Granuloma annulare, which may also be caused by Bb infection,
has a small elevated border consisting of multiple confluent papules. Tinea
lesions are scaling and eryispeloid is located on the hand or fingers in
most cases. The most important differential diagnoses for multilocular EM
are urticaria, multilocular fixed drug eruption, erythema annulare centrifugum,
and erythema infectiosum.
Diagnosis
The diagnosis of EM is primarily made on clinical grounds, which may be supported by the history of an arthropod bite. Analysis of IgG and IgM antibodies to Bb in the serum of patients should be performed using an ELISA; an additional immunoblot test (two-test approach) should be carried out to prove the specificity of a positive or undetermined ELISA result in clinically difficult situations. It must be kept in mind that neither a positive result can prove the diagnosis of EM unequivocally, nor does a negative result exclude EM, because of seroprevalence, cross-reactions etc. Interpretation of positive test results must include the following possibilities: acute EM, EM during or shortly after antibiotic therapy, seroprevalence (15-20% in Styria), persistent titer after appropriate antibiotic treatment that may result from a polyclonal B-cell activation and does not require further treatment when the patient is disease-free, cross reaction with other antigens (e.g., EBV, mumps (12), varicella zoster virus, etc.). Vaccination titers are currently no problem in Europe, as there is no vaccination available so far, but need already to be considered in the USA.
Interpretation of negative test results must include the following possibilities: false clinical diagnosis (skin lesion does not represent EM), no seroconversion (analysis too early in the course of the disease), antibiotic pre-treatment. Histopathology from lesional skin is a very helpful adjunct to the diagnosis of EM. In a biopsy specimen from the edge of the lesion, the most important finding will be a superficial (and deep), perivascular (and interstitial) mononuclear infiltrate composed mostly of lymphocytes and histiocytes with a variable admixture of plasma cells (13).
The gold standard for diagnosing EM is the direct detection of the infectious agent from the rash by cultivation. A 3 mm punch biopsy specimen must be obtained from the leading edge of EM under sterile conditions and has to be directly transferred into a tube with BSK-H medium. Cultivation has to be carried out at 34°C in an incubator. Assessment of spirochete growth is performed weekly with a dark field microscope. Under optimal conditions, sensitivity of this method may reach 80%. However, the procedure is laborious and it may take several weeks for Bb to grow in the medium. Because of this delay of culture results, it is not a suitable method, when therapeutic decisions have to be made. Moreover, cultivation of Bb is only available in specialized laboratories. Polymerase chain reaction (PCR) is able to detect Bb specific DNA in biopsy samples from lesional skin. As LB is a "paucibacillary"disease, which means that only few spirochetes are present at the site of infection/inflammation.
PCR is a very advantageous technique, because it amplifies the (small
amounts of) DNA present in the skin lesion. It should be kept in mind, however,
that in contrast to cultivation, no viable spirochetes but only DNA is detected.
The advantages of PCR are high sensitivity as well as specificity and that
the results are available very quickly. Also, it may be used with archival
(formalin-fixed, paraffin-embedded) samples (14). The sensitivity is 70-90%
depending on the sample source (archival versus frozen tissue). False positive
results due to contamination may be a problem. PCR from serum or urine are
also feasible, but currently not used as routine diagnostic procedures.
Borrelial lymphocytoma
BL is a subacute cutaneous manifestation of LB that has been defined as a stage 2 (early disseminated infection) manifestation, but may also occur directly at the site of a tick bite (15). Thus, BL can also represent a stage 1 (early localized infection) manifestation of LB. BL is the least common manifestation of LB (5%) and occurs more often in children than in adults. Extracutaneous signs and symptoms are very infrequent. BL is a solitary lesion in most patients. It is a bluish-red nodule or plaque with a size between 1-5cm, sharply demarcated, and often with a slightly atrophic surface.
On palpation, BL is a soft and non-tender lesion. BL is located typically on the earlobe (Fig. 6), breast (nipple, areola), and less frequently on the scrotum or the (anterior) axillary fold.
The diagnosis is based primarily on the clinical aspect, but histopathology, which reveals a B-cell pseudolymphoma, is mandatory for the definite diagnosis of BL, in particular to rule out B-cell lymphoma of the skin. For this differentiation, it is sometimes necessary to perform additional immunohistochemical and PCR studies to exclude monoclonality. Although some patients with BL may be seronegative, Bb IgG and/or IgM antibodies are found in the serum of 80% of all BL patients. Direct detection of Bb or Bb specific DNA in lesional skin by culture or PCR are helpful addition to the diagnosis.
Differential diagnoses of BL include insect bite reactions, cutaneous
lymphoma, foreign body granuloma, sarcoidosis, cutaneous metastasis, keloid,
perichondritis, and granulomatous contact dermatitis due to golden earrings.