Early LB, clinical aspects Glinica[ aspects and dwgnDsis of e,ytliema m-igrans and borrelial lymphocytoma R.R. Milllegger SUMMARY There are three distinct cutaneous manifestations of Lyme borreliosis {LB), erythema migrans {EM), borrelial lymphocytoma {BL), and acrodermatitis chronica atrophicans. EM, the hallmark of early LB, is the most frequent manifestation of LB and develops within 4-180 days (median, 14 days) after an infectious tick bite. There are five different clinical types of EM. Solitary macular and solitary annular EM comprise more than 80% of all EM lesions. Less frequent vari- ants are the bull's eye type, the minimal size EM, the combined BL and EM, and the multilocular EM. EM in children is most frequently located in the head-neck region and often displays an atypical morphology. It may be associated with an ipsilateral peripheral facial palsy. Extracutaneous, usually mild and tran- sient, signs and symptoms occur in up to 40% of all EM patients {major form of EM). They must not be confused with features of human granulocytic ehrlichiosis that is found in about 20% of LB patients in Austria. The diagnosis of EM is primarily made on clinical grounds. Serologic test results are often false negative or positive. Histopathology from lesional skin is a helpful adjunct to the diagnosis. Direct detec- tion of B. burgdorferi {DNA) by cultivation or PCR can prave the diagnosis. BL is a subacute cutaneous manifestation of LB that has been defined as a stage 2 {early disseminated infection) manifestation, but may-also occur during early localized infection. It usually represents a soli- tary lesion in stereotypical locations {ear, nipple) and represents a B cell pseudolymphoma. Introduction Lyme borreliosis (LB) is a multisystemic infectious disease that is caused by the arthropod-borne spirochete Eoi-relia hurgd01'.f'eri sensu lato (Eh). In Europe, about 80% of ali cases ofLB represent skin manifestations, ali together namecl clermatoborrelioses (DB). There are three characteristic manifestations of DB, in which the etiopathogenic role of Eh, most often the subtype Eor- relia qf'zelii (1 ,2), is proven by cultivation of the spiro- chete from lesional skin. These manifestations are erythema migrans (EM), borrelial lymphocytoma (BL), and acroclermatitis chronica atrophicans. In this article, clinical and diagnostic aspects of EM ancl BL will be Clni ca l study Lyme borreliosis, iBorrelia burgdorferi, ;erythema migrans, borrelial lymphocytoma 152 - - - - ---- --- --- - - ----------------Acta Dermatoven APA Vol 10, 2001, No 4 Early LB, clinical aspects discussed, based on our experience with more than 1,000 DB patients, seen at the Department of Derma- tology in Graz , Austria between 1993 and 2000. Erythema migrans Epidemiology and transmission oj Borrelia burgdorjeri • 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 ofEM 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 Figure 1. Solitary annular type of erythema severa! cases also occur regularly during the winter migrans. 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 accor- dance 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 Figure 2. Solitary macular type of erythema region, or the armpit/ shoulder region. A tenet in tbe migrans. etiopathogenesis of EM has been that an attachment period of at least 24 hours is necessary for tbe tick to transmit enougb 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 pe- riod. EM develops after an incubation period of 4-180 days (median, 14 days) following the tick bite. A stil! debatable question is , whether or not arthropods other than ticks are able to transmit Bb. Over the last eigbt years, about 10% of our patients, who could specifi- cally recall an arthropod bite at the site where EM de- veloped later, were sure that tbis arthropod was a fly- ing insect. Clinical types oj 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 diam- eter of at least 5 cm C 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). Clnical stud y 1J4 ~--- - ----------------- ----- -------~ Acta Dermatoven APA Vol 10, 2001, No 4 Clnical stud y Early LB, clinical aspects Figure 3. Bull's eye type of erythema migrans. Figure 4. Atypical variant of solitary erythema migrans. Note that the erythematous ring is incomplete. EM usually lacks epidermal changes, although vesicles or minimal scaling have been observed in a few pa- tients. EM lesions on the calf tend to develop a hemor- rhagic component due to stasis. Local symptoms are generally mile! (itching or burning sensations) or ab- sent. (iii) The bull's eye type (2%) is a variant of solitary an- nular EM that is characterized by a target-like morphol- ogy 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 pa- tients. In 21 of these patients , EM remained in this size also 7-1 O days after the first visit without antibiotic treat- ment, whereas EM expanded beyond a diameter of 5 cm over tirne in the other 31 patients . Thus , in around 3% of patients , EM is smaller than 5 cm ("trne 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 fa- tigue , were present in 5/ 21 (24%) patients. Serum anti- Bh 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 w e 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. Interest- ingly, Borrelial lymphocytoma (BL) pr~ceded EM in all 15 patients by 2-8 weeks. Extracutaneous signs and symptoms w ere present in 3/ 15 (20%) of patients and occurred simultaneously with the beginning of EM, in- clicating that the development of EM arouncl BL may represent the transition from a primarily localizecl into a clisseminatecl manifestation of DB. Acta Dermatoven APA Vol 10, 2001, No 4 --------- ------ ------------------- JJJ Early LB, clinical aspects 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, w ith a range from 2-36. The underly- ing pathogenic mechanism in many patients is hematog- enous dissemination of the spirochete, in which case there is a primary EM with a typical clinical aspect, fol- lowed 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 extra- cutaneous signs and symptoms than patients with soli- tary 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 occur- rence of multiple lesions is due to more than one infec- tious 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 tran- sient (few days) and variable in intensity over tirne. Neuropediatricians sometimes see children who are suffering from an ipsilateral peripheral facial palsy along w ith 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 ofEM. These signs and symp- toms are unspecific and usually mild. The most com- mon features associated with EM are elevated tempera- ture , 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 indi- cate that (hematogenous) dissemination of B b has tak en place. It must be clear that these signs and symptoms Clnical stud y 1J6 -------------- - - ---- - -------------- Acta Dermatoven APA Vol 10, 2001, No 4 Clnical study are not due to another etiology or prima1y disease. They must also be clistinguishecl from signs ancl symptoms inclicating another organ manifestation of LB (e.g., neuroborreliosis, carclioborreliosis) on the one hancl ancl from features of ehrlichiosis on the other hand. Ehrlichiosis , in Europe usually human granulocytic ehrlichiosis, is causecl by the HGE agent that is trans- mittecl by the same ticks as Bb. Co-infection with Bb ancl the HGE agent is found in about 20% ofborreliosis patients in Austria (9). Differential diagnoses The clifferential diagnoses of solitary EM comprise unspecific insect bite reactions, which develop more rapidly and w ill clear from the periphe1y within a few clays w ithout antibiotic therapy, erysipelas, which is usually accompanied by high fever ancl chills, morphea, which has an ivory-like whitish center that is surrounded by a lilac ring and has an increased consistency on pal- pation. Granuloma annulare, which may also be causecl by Bb infection, has a small elevatecl borci er consisting of multiple confluent papules. Tinea lesions are scaling ancl e1yispeloid is locatecl on the band or fingers in most cases. The most important differential cliagnoses for multilocular EM are urticaria, multilocular fixed drug eruption, e1ythema annulare centrifugum, ancl e1ythema infectiosum. Diagnosis The cliagnosis of EM is primarily made on clinical grounds, which may be supportecl by the history of an arthropocl bite. Analysis of IgG and IgM antiboclies to Eh in the serum of patients should be performed using an ELISA; an additional immunoblot test (two-test ap- proach) should be carriecl out to prove the specificity of a positive or undetermined ELISA result in clinically difficult situations. It must be kept in mine! that neither a positive result can prove the diagnosis of EM un- equivocally, nor cloes a negative result exclude EM, because of seroprevalence, cross-reactions etc. Inter- pretation of positive test results must include the fol- lowing possibilities: acute EM, EM during or shortly af- ter 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 fi.uther treatme11t when the patient is clis- ease-free, cross reaction with other antigens (e .g., EBV, mumps (12), varicella zoster virus, etc.). Vacci11ation ti- ters are currently 110 problem in Europe, as there is no vaccination available so far, but need alreacly to be co11- sidered in the USA. Interpretation of negative test results must include Early LB, clinical aspects the following possibilities: false clinical cliag11osis (skin lesion cloes not represent EM), no seroconvers ion (analysis too early in the course of the disease), antibi- otic pre-treatme11t. Histopathology from lesional skin is a vety helpful acljunct to the cliagnosis of EM. In a bi- opsy specimen from the eclge of the lesion, tbe most important fincling will be a superficial (and cleep), perivascular (and interstitial) mononuclear infiltrate composed mostly of lymphocytes and bistiocytes w ith a variable aclmixture of plasma cells (13). Tbe gole! standard for diagnosing EM is tl1e clirect detection of the infectious agent from tbe rasb by culti- vation. A 3 mm punch biopsy specimen nrnst be ob- tainecl from the leacling edge ofEM under sterile condi- tions ancl has to be clirectly transferred into a tube witb BSK-H meclium. Cultivation bas to be carried out at 34°C in an incubator. Assessment of spirocbete growth is performed weekly witb a dark field microscope. Under optimal conditions, sensitivity of tbis metbod may reacb 80%. However, the procedure is laborious ancl it may take severa! weeks for Bb to grow in the medium. Be- cause of tbis delay of cul ture results, it is nota suitable methocl, wben therapeutic clecisions bave to be macle. Moreover, cultivation of Bb is only available in special- izecl laboratories . Polymerase chain reaction (PCR) is able to cletect Bb specific DNA in biopsy samples from lesional skin. As LB is a "paucibacilla1y"disease, wbich means that only few spirochetes are present at tbe site of infection/ inflammation. PCR is a ve1y aclvantageous technique, because it amplifies tbe (small amounts ot) DNA present in the skin lesion. It shoulcl be kept in mine!, bowever, tbat in contrast to cultivation, no viable spirochetes but only DNA is cletected . The advantages of PCR are higb sen- sitivity as well as specificity ancl that the results are avail- able vety quickly. Also, it may be used with archival (formali11-fixecl, paraffin-embeclcled) samples (14). Tbe sensitivity is 70-90% depencling 011 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 rou- tine diagnostic procedures. Borrelial lymphocytoma BL is a subacute cutaneous manifestation ofLB that bas been defi11ed asa stage 2 (early disseminated infec- tion) 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%) ancl occurs more often in cbildre11 than in aclults. Extra- cutaneous signs ancl symptoms are vety infrequent. BL is a solitary lesion in most patients. It is a bluish-red nodule or plaque with a size between 1-5cm, sbarply clemarcatecl, and often witb a slightly atrophic surface. Acta Dermatoven APA Vol 10, 2001, No 4 ------------------- ------ - - - -------1.57 Early LB, clinical aspects On palpation, BL is a soft and non-tender lesion. BL is located typically on the earlobe (Fig. 6), breast (nipple, areola), ancl less frequently on the scrotum or the (an- terior) axilla1y folcl. ies to exclude monoclonality. Although some patients with BL may be seronegative, Bb IgG ancl/ or IgM an- tiboclies are founcl in the serum of 80% of ali BL patients. Direct cletection of Bb or Bbspecific DNA in lesional skin by culture or PCR are helpful aclclition to the cliagnosis. The cliagnosis is basecl primarily on the clinical as- pect, but histopathology, which reveals a B-cell pseudo- lymphoma, is mandato1y for the definite cliagnosis of BL, in particular to rule out B-cell lymphoma of the skin. For this differentiation, it is sometimes necessa1y to perform additional immunohistochemical ancl PCR stucl- Differential cliagnoses of BL include insect bite re- actions, cutaneous lymphoma, foreign body granuloma, sarcoidosis, cutaneous metastasis, keloicl, perichonclri- tis, ancl granulomatous contact dermatitis due to golclen earrings. H, E FE ll EN C E S AUTHOR'S ADDRESS l. Zochling N, Miillegger RR, Schliipen EM, Stumpenhausen G, Soyer HP, Wienecke R, Hodi S, Volkenandt M, Ker! I-1. Molecular subtyping of Borrelia burgdorferi (Bb) in lesi ona! skin from Styrian (Austrian) patients with various manifestations of dermatoborreliosis (DB). J Invest Dermatol 1995;104: 687. 2. Picken RN, Strle F, Picken MM, Ruzic-Sabljic E, Maraspin V, Lotric-Furlan S, Cimperman J. Identifica- tion of three species of Bon·elia burgdorferi sensu lato (B. burgdoiferi sensu stricto, B. garinii, and B. aftelii) among isolates from acrodermatitis chronica atrophicans lesions. J Invest Dermatol 1998; 11 O: 211-4. 3. Stanek G. Lyme Borreliosis. Wien Med Wschr 1995;145: 155-61. 4. Wharton M, Chorba TL, Vogt RL, Morse DL, Bi.ihler JW. Case definitions for puhlic health surveillance. MMWR 1990;39: 1-43. 5. Stanek G, O'Connell S, Cimmino M, Aberer E, Kristoferitsch W, Granstrom M, Guy E, Gray J. European Union concerted action on risk assessment in Lyme borreliosis: clinical case definitions for Lyme borreliosis. Wien Klin Wochenschr 1996;108: 741-7. 6. Weber K, Neubert U, Bi.ichner SA. Erythema migrans and early signs and symptoms. In: Weber K, Burgdorfer W (editors). Aspects of Lyme borreliosis. Berlin: Springer, 1993; 105-21. 7. Mi.illegger RR, Weger W, Binder B, Ker! H. Combined borrelial lymphocytoma with erythema migrans. Retrospective study of a rare manifestation of dermatoborreliosis in 15 patients. J Eur Acad Dermatol Venereol 2000;14(Suppl.1): 48-9. 8. Miillegger RR, Brunner-Kohler G, Zochling N, Reiter H, Hodi S, Soyer HP, Ker! II. Erythema migrans multiloculare in Styria (Austria). Acta dermatovenerologica APA 1996;5: 13-6. 9. Mi.illegger RR, Weger W, Sixl W, Binder B, Aberer E, Marth E, Ker! H, Stiinzner D. Serologischer Nachweis von humaner granulozytarer Ehrlichiose (HGE) bei 19% von Patienten mit Dermatoborreliose (DB). Z I-Iautkr 2001; 76(Suppl.1): S6. 10. Asbrink E. Cutaneous manifestations of Lyme borreliosis. Clinical definitions and differential diag- noses. ScandJ Infect Dis 1991; Suppl.77: 44-50. 11. Hansen K. Laboratory diagnostic methods in Lyme borreliosis. Ciin Dermatol 1993;11: 407-14. 12. Millner MM, Schimek MG, Mi.illegger RR, Stanek G. Borrelia burgd01feri ELISA titres in children with recent mumps meningitis. Lancet 1990; 336: 125-6. 13. Hodi S, Soyer I-IP, Mi.illegger RR. Dermatopathologic diagnosis of Lyme borreliosis. Acta dermatovenerologica APA 1996; 5: 123-9. 14. Wienecke R, Neubert U, Volkenandt R. Molecular detection of Borrelia burgdorferi in formalin- fixed, paraffin-embedded lesions of Lyme disease. J Cutan Pathol 1993; 20: 385-8. 15. Asbrink E, Hovmark A, Olsson I. Lymphadenosis benigna cutis solitaria -borrelia lymphocytoma in Sweden. Zbl Bakt Hyg 1989; Suppl 18: 156-63. Robert R. Milllegger, MD, projessor oj dermatology, Department oj Dermatology, l(arl-Franzens-University School oj Medicine, Auenbruggerplatz 8,A-8036 Graz Austria, E-mail: robert.muellegger@kjunigraz.ac.at Clnical study JJ 8 - - ---- ------- ---- ------ ----------- Acta Dermatoven APA Vol 10, 2001, No 4