Clinical features of early erythema migrans disease and related disorders

Zbl. Bakt. Hyg. A 263, 209-228 (1986)

Dermatology Clinical Features of Early Erythema Migrans Disease and Related Disorders KLAUS WEBER 1 and UWE N EUBERT 2 1

2

Dermatologist and Allergo logist, Miinchen, FRG Department of Derm at ology, University of Miinchen, FRG

Summary 104 patients with eryth ema migrans disease (EM D), 7 patient s with borrelial lymphocyto ma (BL), an d 2 1 patients with acrodermatitis chro nica arrophi cans (ACA) were pro spectively followed for a median of 20, 14, and 12 month s, respectively. 99 pa tients with EMD and 6 with BL were treated with antibiotics early for their illness. 72 pat ients with EMD had 1 to 10 constitutional symptoms besides rhe erythema rnigra ns, 32 had erythema migrans alone, and a child with BL had urtic ar ia. Out of 39 patients with EM O, 23 acquire d a rthralgia, 18 signs a nd symptoms consistent with neurologic manifesta tio ns and 8 wit h card iac involvement before or after therapy. 4 patients with EMD and 1 with BL had up to 10 multiple erythema migra ns lesions. 3 patients with EMD experie nced a reinfection and 1 with ACA a relap se. Severa l pa tients with ACA developed signs and symptoms con sistent with neurol ogic, car diac and joint involvement, and 2 had a history of EMD . Elevated antibod y titers against Borrelia burgdorferi were present in 48% of 69 patients with EM D, 5 with BL and 11 with ACA, and in 93 % of ano ther group with EM D, 2 with BL and 10 with ACA, when tested agai nst other borr eliae. Increased values of the ESR, IgG, IgA and IgM were found in mo re pat ients with ACA th an with EMD . The median of IgA an d IgM was significan tly higher in ACA th an in EMD. Bor reliae were fou nd in brain and liver of a newborn . Earl y EMD app ears to be qui te similar to early Lyme diseas e.

Introduction Erythema (chronicum) migrans with or without meningitis has been thought of as an infectious disease years before Lyme disease has been described (15, 16,22, 39, 55, 56). In 1934, Stadelmann has reported on a patient with arthralgia, myalgia and fatigue from Marburg, Germany (41). Bannuiarth has noted fever, arthralgia and tachycardia in a few of his patients with meningoradiculitis (7). Hellerstrom has spoken of an "infective agent with allergizing properties" and he has included the meningitis in his considerations (18). In addition, fever, fatigue, headaches, meningitis and changes in the differential blood count have been taken as hint for an infectious disease process (55, 56). Neurologic manifestations have been known for a long time (7, 15, 22, 25) and erythema chronicum migrans meningitis was a term used in 1974 (55). 14 Zbl. Bakt. H yg. A 263. 1- 2

210

Klaus Weber and Uwe Neubert

Ne vertheless, it was the comprehensive description by Steere et aJ. of an infecti ous disease called Lyme disease (45- 51) which has led to broad acceptance of this disorder. The question rema ins how much the European and the American form s of the infectious diseases caused by Borrelia (B.) burgdorferi differ. It is believed that the European disea se is less severe (5, 30, 52, 59, 61). Because of the uncertainty whether both diseases are different or not and to keep up with European tradition, th e term eryth ema (chro nicum) migrans disease (EM D) has been used since 1981 (2, 57, 59, 61, 67). In this paper, we suggest that EMD with related disorders is quite similar to and onl y somewhat different from Lyme disease.

Patients and Methods

1. Patients. a) EMD. 73 consecutive patients appeared in the private practice of one of us (K. W.) between Decemb er 1978 and June 1985 (gro up A); 23 of those patients have been described in a pr evious pap er for which the cut-off time had been No vember 1981 (59); 18 additional patients out of the group of 73 had been observed until fall 1983 (61). 72 patients show ed up becau se of the skin lesion s, erythem a migr ans, or a histor y of it (in 3), and 1 patient because he believed to suffer from herpe s zoster after a tick bite ; 1 patient was first seen in a community hosp ital (E in 59), and 2 patients were follow ed-up after they were discharged from hospitals. In addition, 31 consecutive patients were personally seen by Dr. U. N. in the dermatological outpatient clinic or as a consultant in the Klinikum GroBhadern of the University of Miinchen between June 1982 and June 1985 (group B). 20 patients appe ar ed prim ar ily becau se of the ir erythema migr ans, and 11 patients staye d in the ho spit al for oth er reason s. Years of first visits were as follows : 1 patient in 1978, 9 in 1979, 9 in 1980,5 in 1981,21 in 1982, 17 in 1983, 33 in 1984, and 9 in 1985. b) Borr elial lymphocytorna (BL). 7 patients including the 4 previously reported ones (61,64) were seen between September 1982 and February 1985. c) Acrodermatitis chronica atrophicans (ACA). 21 patients including the 9 previ ously reported ones (61, 62) appeared between October 1979 and April 1985. Criteria for inclusion were the presence or the recent history of an erythema migrans, the pr esence of BL or ACA, and in the case of the patient with a tick bit e, radicular pain and arthralgia with subsequent rise of antibody titers. Additio nal crit erion for BL was an elevated antibody titer , either IgG type or IgM type or both . 2. The prospective program included a history (with a questionnaire being used at first visit in 52 group A patients and several patients with BL and ACA since September 1980), an examination of the (affected) skin and (regional) lymph node s, a gene ral ph ysical examination (only in 23 group A and 16 gro up B pat ient s, in 2 with BL, and in 12 with ACA), determination of antiborrelial anti bodie s, various other laboratory tests (often onl y in a part of the pat ients), and follo w-up as outlined below . 3. Serology. In 69 group A patients (blood was obtained in 2 additional patient s later), in 5 patients with BL, and in 11 patients with ACA, antibodies against Borrelia burgdorferi (11, 23) were sought for by an indirect immunofluorescence test according to th e method of Wi lske et al. (67); detailed result s in some patients were alread y reported (60-64, 67). In the other patients except 4 gro up B EM D pati ent s, evalu at ion of ant ibodies against severa l borrelia e obtained from alive mice was accomplished

Clinical Features of Early Erythema Migrans Disease

211

according to the method of Neubert et al. (31). Antib od y titers of ~ 1 : 64 were considered to be elevated in group A patients. 4. Laboratory tests included ESR (uncor rected Westergren method), protein-electrophoresis, serum immun oglobulins and complement determined by laser or rate nephelometry, urine analysis, hemoglobin, leukocytes, differential count, SGOT, SGPT, and LDH; uric acid, rheum atoid factor , anti -streptolysin test, and antinuclear antibodies were determined in 11 patients with joint involvement. 5. Special procedures. Electrocardiogram (in 26 patients with EMD most of whom had no other disea se), electroencephalogram , bone mar row exa mination (in 4 patients with ACA), psychiatric evaluation (in 2 with EMD ), chest X-ray, long-term EKG and radionuclid vent riculogra phy (in 2 with ACA, respectively) were performed as need ed or in selected patients. An attempt to isolate borreliae out of blood or 3 mm skin punch biopsies or both from 15 group A patients, 1 patient with BL, and 2 with ACA beginning in June 1982 was mad e by Dr. V. Preac-Mursic (33); attempts in the other patients are reported on elsewhe re (31). 6. Treatment. 5 patients with EMD and 1 with BL refused therapy. All ot her patients were treated with antibiotics at first visit or shortly afterwards (see 65). 7. Follow-up. Patients were usually seen about 2 weeks after initia tion of th erapy and more frequently if the y had more severe symptoms. Patients were told to report special complaints, particularl y neurologic, cardiac, and joint sympto ms. Several patient s did not report such symptoms unless they were interviewed agai n. All patients but 2 with EMD and 1 with ACA, who were lost for follow-up, were interviewed up to almo st 7 years after the beginning of the disease; the latest check-up was usually the spring of 1985, the cut-off time of this study. In EMD , the follow- up for group A patients was 21 (mean value 28) months (1- 71), for gro up B 14 (mean valu e 19) months (1- 36), and for all EMD patients 20 (mean value 27) months (1- 71) and 52 (mean value 49) months (24-71) in 33 patients followed for 2: 24 months. The follow up for Bl wa s 14 (mean value 13) months (3- 21) an d for ACA 12 (mean value (21) months (2- 68). 8. Definition. Arthralgia was defined as pain on mot ion (not present prior to EMD ). 9. Statistical analysis. Differences of qualitative data were examin ed by chi-squ ar e test and of quantitative data by median test. The median was chosen unless specified otherwise, with range in pare nth esis. Since hypotheses were generated by statistical testing after collection of the data of this stud y, they may need confirmation by another material.

Results 1. EMD

Age and Sex. There were 65 females and 39 males. The mean age was 44 years (16-75), the median age 42 years. First visits were during the wh ole year with a predominance in Jul y (Fig. 1). Tick bites occurred between Ap ril through O ctober (Fig. 2). 18 patients believed to have noted an insect sting.

Erythema migrans was present in 100 patients at first visit (T able 1); 3 additional patients had a history of an erythema migrans with sponta neo us clearing within 2 to 3 weeks. The duration of th e erythema migran s had to be guessed in several instances

212

Klaus Weber and Uwe Ne ubert r--J-J-J--

ro-

r0-

t--

ro-

f--

Jan Feb Ma r Ap r Ma y Jun Jul

Aug Sep Oct

Nov Dec

Figure 1. First visit in 104 pa tients with EMD.

Jan

Feb Mar Apr ,\ la y Jun

Jul

Au g Se p Oct

Figure2. Tickbite~in42 patientsandonsetoferythemamigrans D

Nov Dec in 103 patients with EMD.

Clinical Features of Early Erythema Migrans Disease

213

Table 1. Erythema migrans characteristics (n = 103) Characteristics Duration 2: 4 weeks < 4 weeks Symptoms asymptomatic pruritus pain, burning, heat Appearance (n = 100) ring-shaped homogeneous hemorrhagic Central lesions Multiple lesions Spontaneous clearing

n

84' 19 44 33

26 79 19 2 21 4 9

.\ 61 before therapy

because the beginning was not noted by these patients; in almo st all cases, the erythema migrans had reached a size of about 3 to 5 em in diameter when it was first recognized. Pain, burning, and/or feeling of heat within the erythema migran s were mor e often (P < 0.01) associated with joint, neurologic, and cardi ac manif estati on s (and to ta l duration of EMD, included or excluded) than asymptomatic or pruritic lesion s; th ere was no sta tistical differenc e between asymptomatic and pruritic lesion s, and the inten sity of the pruritus did not matter, to o. Most erythema migrans lesions were ring-shaped with a bright red bo rder usu ally 1 to 3 em in diameter and central clear ing or slight central violaceous discoloration. Early lesions were sometimes more hom ogeneous; a few of them could be observed to develop into ring-shape lesion s within a few da ys o r weeks. 2 patients had haemo rrhagi c or purpuric lesion s: a 35 -year old man had an unusally severe initial illness associated with fever, chills, fati gue, dizzine ss, coryza, conjunctivitis, diarrhea, stiff neck, headache, difficult y swallo wing, pain and itchiness within the skin lesion , and he develop ed constant arthralgia in both elbo ws 4 weeks later for th e next 6 month s despite therapy with oral penicillin; and a 2S-year old man had fever, chills, fati gue, severe headache , and pain within the erythema migrans and the surrounding tissues. The appearance of the cent ra l lesions var ied between small papul es 3 to 5 mm in diameter and more diffuse violaceous erythernas or indurated plaques up to 12 em in diameter. 2 patients with lar ger cent ral lesion s developed pol yneuritis after oral peni cillin and slight pulm on ary interstiti al edema (Dr. R. Rienmiill er, University of Miinchen ) during minoc ycline therapy, respecti vely, but th e ot hers had no sequel ae. Two patients had 2 erythema migrans lesions. 8 secondary lesions with a size of 10 to 50 em in diameter develop ed successively in a thi rd, and in a fourth pati ent, 10 with a size o f 3 to 10 em shortly after 40 mg tr iamcinolon had been injected for hay fever. The seco nda ry lesions were distributed on th e trunk an d extre mities and were asym ptomatic ap art o ne exception (one painful lesion of 2).

214

Klaus Weber and Uwe Neubert

Spontaneous clearing occurred in 9 patients, in 7 within 3 weeks (1- 3.5). 3 patients developed proven meningoradiculitis a few weeks later, one woman 2 short attacks of radicular pain in the affected leg, one man (with a spontaneous clearing after 25 weeks) arthralgia of the right knee, and 4 had no later symptoms. Onset of EMD was 2 months (1.5- 6) before therapy, and follow-up after therapy 9 months (1.5-45) in 7 cases and 36 months in two untreated women without sequelae. Somewhat peculiar lesions were present in 3 patients. A 66-year old man had a violaceous erythema 3 em in diameter for 3 months; in a 42-year old woman, a ca. 5 em lesion shrunk to a size of about 2 em for the next 6 weeks, then a patchy lesion with a few erythemas about 0.5 to 1.5 em in diameter in somewhat annular distribution spread from a size of 5 X 7 em to 17 x 21 em within the next 3 months; and a 43-year old man had a tick bite in May 1984, but it took 4 months before he noticed a lesion about 5 em in diamter around that tick bite; in all 3 cases, ring-shaped erythema migrans lesions finally developed. The maximum mean diameter of the erythema lesions was 20 em (3 to 65). 67 lesions were located on the legs, 12 on the arms, and 21 on the trunk. Symptoms are listed in Table 2. Headaches were excruciating in 3 patients and fatigue profound in several patients. Myalgia was generalized in 3 or localized either in the musclesadjacent to the erythema migrans or migratory in a few instances. Fever did

Table 2. Symptoms (n = 104) n

Headaches Fatigue, malaise Lesional pruritus Lesional pain, heat, burning Arthralgias Myalgia Fever Sensory disturbances Chills Sore throat Dizziness Stiff neck Profuse sweating Palpitations Sleeplessness Diarrhea Hoarseness Difficulty concentrating Double vision Cough Weight loss Vomiting Nasea Chest pain Eye pressure *

sometimes after antibiotic therapy

39 33 33

26 19

18 17 10 10

9 9 8 5 5 5*

3 3

3" 2 2 2* 2 2 1 1

Clinical Features of Early Erythema Migrans Disease

215

not exceed 39 °C and chills were usually characrerized as shivering, not as coarse shaking; fever lasted a single day to several weeks and recurred in a few patients. Sore throat was usually of mild to moderate intensity. Diarrh ea and hoarseness in 2 patients lasted a few days, but one patient had tracheolaryngitis sometimes associated with aphony for 3 months (D in 59). The cough was dry and lasted up to 4 weeks. Weight loss of up to 8 kg occurred in 2 patients with features of meningoencephalitis. The spectrum of symptoms varied. An erythema migrans alone was present in 32 patients. Besides the erythema migrans, 14 patients had one more symptom, 23 two, 16 three, 7 four, and 11 five to ten symptoms; the patient without erythema migrans had 5 symptoms. Findings are presented in Table 3. Lymph nodes reached a size of 1.5 em in diameter and were usually non-tender with 2 exceptions. Joints were usually not inflamed but sometimes sensitive to pressure, larger joints often only in limited areas. Pharyngitis consisted of diffuse redness. Ext raregional lymphadenopath y was usually limited to certain regions, in several instances to the nuchal region. Table 3. Findings (n = 104) n

Erythema migrans Regional lymphadenopathy Elevated temperature Tender joints on pressure Pharyngitis Extraregional lymphadenopathy Heart beat 80-100/min Multiple EM lesions Muscle tenderness Extrasystoles ,. Hoarseness Tracheolaryngitis Conjunctivitis Hypesthesia,.,. Pain on neck flexi on Bradycardia *.,

100 20 17 8 6 6 4

4 3 3

2 1 1 1 1 1

" in one man after therapy after therapy EM = erythema migrans **

Arthralgia was present in 23 patients (16 females and 7 males), in 18 prior to therapy (Table 4, Figures 3 and 4). The median age was 42 years (17- 63). Patients had intermittent or single attacks or both. Duration of attacks was longer in joints affected constantly (P < 0.01). Total duration did not differ significantly if joints affected intermittently and constantly were compared. Pain was present in 16 patients during quiescence, sometimes even more pronounced than on motion; 6 patients awoke during the night because of pain; the pain was severe in the hip of one man, and in the knee of another man after initiation of therap y. Pain was sometimes of varying intensity in joints affected constantly. 6 patients reliably

} week s

5 (1-3 2) 0.5 (ho urs-B) 2 (0.1- 12 ) 5.5 (0.1-47) 10 (2- 60) 2 (1- 14 ) 10 4 2 7 2

Intermittent (n =' 10)

6 5

-

3 (0.2-1 8) 1 1 (1-22) 7 2

-

3 (0-8 ) 10 (1-72)

Constant (n = 7)

a

Upper 6 lines are medians (ra nge) and lower 5 lines are numbers of pati ents duration per joint EM = erythema migrans

Onset aft er tick hitefEM Duration of attacks Interval between attacks Total duration (mo nths)" Number of attacks Number of joints Pain Swelling Redness Impairment o f motion Local relation to EM

Table 4. Joint characteristics

7 (0- 52) 1 (hours-I) 2.5 (0.2- 10) 24 (5- 35) 23 (10-75 0 ) 2 (1- 10) 6

4 2

-

2.5 (0.1- 7 ) 1 2 (1-3)

-

8.5 (4-20 ) 10 (0.5- 28)

Intermittent and constant (n = 6) Intermitr. Const.

6 (0-52 ) I (hours-72) 2 (0. 1-12) 6 (0.1-47 ) 13 (1-750 ) 2 (1- 22) 23 6 2 17 9

Total (n = 23 )

;:"

n

0-

C

~

~

ll>

::l 0..

n

~ ..,0-

In

C

Zl

::-::

N ...... o-,

Clinical Features of Early Erythema Migrans Disease

217

Kn ee Elbow PIP Shoulder Ankl e

Mep Wr is t

t.f~f

Pai n and swe ll i n g

~

Pain

T emporo mandibular Hi p DIP

6

2

12

10

8

pati ents

Figure 3. Distribution of joints among 23 patients with EMD, joints of the same kind counted as groups. PIP: proximal interphalangeal; MCP: metacarpophalangeal; DIP: distal interphalangeal joint.

PIP Kn ee Elbow DIP Sh oul d er A nkl e ~' C P

Wi{

Pain and swe lli ng

~

Pain

Wr i st

T emporomand ib ula r Hi p

12

16

20

211

28

joi n ts

Figure 4. Number of affected joints in 23 patients with EMD, each joint counted individually. PIP, DIP, and MCP as in Figure 3.

218

Klaus Weber and Uwe Neubert

recorded swelling and 2 additional patients believed to have noti ced a slight swelling (swelling of these was not included in Table 4 and in the Figures). Redness was lackin g prior to therapy but occcurred in 2 pat ients sho rtly after therapy. Impairment of motion was due to pain but onl y durin g extreme motion s. Symptoms and signs consistent with neurologic involvement (in 18 patients) included stiff neck in 8, radicular pain in 6, prov en meningoradiculitis and severe headaches in 3, respectively, generaliz ed paresthesia, pa resis, diplopi a, difficulty concentrating, and longlasting lesional pa in in 2, respectively, and eye pr essure, par esthesia/hypesthesia of all fingers, and a depressive phase (the wom an had the first phase 3 years previously) in one pat ient , respectively. Th ere were 11 females and 7 males. The median age wa s 46 years. 5 of the patients were hospitalized. Symptoms in the remaining 13 patients were either of short duration or not so severe. Some of the findings were confirmed by neu rologists, but oth er patients did not seek evaluatio n by a specialist. Symtpoms and signs suggestive of cardiac invo lvement were found in 6 women and 2 men (median age 42 years ), not includ ing 4 additio nal patients who experienced attacks of palpitation s, dizziness, and/or nausea a few days after initiation of the rapy (see 65); heart involvement cannot be excluded in the latter. Attacks of palpitations and dizziness were pr esent in 3, occurred usuall y together in the same patient, and lasted onl y a few minut es to one hour. Extrasysto les were noted by physicians in 2 patients and by on e medical student in himself. On e patient had inte rmittent stings in the heart , and a 45-year old woman had 4 episodes of severe pain extending from the heart into the teeth and both upper arms lasting up to 30 minutes each only during the 6-months period of her erythema migrans (there was a follow-up of 2 112 years in her). Two patients had 1,4, and 5 attac ks, respectively, one had 8, and ano ther mor e th an 10 att acks. Two syncopes leading to unconsciousness up to 5 minutes occurred in a 54year old man 4 weeks after onset of an erythema migrans, but his case was not includ ed in the group of 8 because the cardiac origin of his atta cks could not be p roved; he also had difficulty concent rating and developed a pa resis of the left foot 9 months later. Unfortun ately, EKGs could not be performed in any patient during attac ks; after or betw een attacks, EKGs were repo rted to be norm al. However, a 57-year old woman (E in 59) developed prolongation of QTc to 0.46 s (122% ; normal up to 115 % ) 14 days after initiation of int ravenous penicillin therapy and bra dycardia of 49 beat s/min 5 days later after initiation of subsequent intravenous tetr acycline therapy (the wo man was a patient of Dr. A. Puzik and the 4 EKGs taken during EMD and an additiona l previous one were reevaluated by Dr. W. Baedecker). The intervals from tick bite to onset of erythema migra ns wer e 1.5 weeks (0.5- 16), from tick bite or on set of erythema migrans to cardi ac involvement 2 weeks (> 0-12), to neurologic involvement 4 weeks (> 0-20), to arthralgia 6 weeks (> 0-32), and to first extradermal symptoms in 39 patients 4 weeks (0- 32) and in 4 of the 39 patients > 12 weeks. Com binations of manifestations occurred in 10 patients. Arth ralgia was associated with severe heada che, proven meningoradiculitis, and sensory disturbances in 2 patient s, respectively, with palp itations, Prinzmetal angina, or slight inter stiti al edema of the lung in 3 others, respectively, and syncope was followed by paresis in 1 more patient. Arthralgia began 1 week (0- 9) after onset of erythema migrans, in 4 instances simultaneously. Dur ation of special man ifestations and erythem a migrans disease is listed in tabl e 5. Intermittent symptoms lasted sometimes only minutes to hours, but the whole involvement including interv als was counted.

Clinical Features of Early Erythema Migrans Disease

219

Table 5. Duration of special manifestations and disease

Erythema migrans (n = 103) Cardiac symptoms" (n = 8) Neurologic symptoms (n = 18) Arthralgia (n = 23) EMD totally (n = 104)

Before therapy

After therapy

Total

1.5 5 1.5 1 1.4

0.5 0.5 3 6 0.7

1.8 2.5 2.3 6 2.5

(0.1-10)

(> 0-8)' (> 0-4)'

(0.3-10)g (0.1-10)

(0.1-5)' (0.2-0.5)d (0.5-28/ (0.1-46)h (0.1-46)

(0.3-10) (> 0-8) (0.5-28) (0.1-47) (0.5-48)

Values are medians (range) of months n = 92 patients with new symptoms after therapy excluded n=7 n=4 n = 11 n = 12 n = 18 n = 21

5 patients remained untreated. They could be followed-up for 30 months(8-60). Two patients developed palpitations (one attack of 30 minutes in 1 patient) or intermittent chest pain for 8 months shortly after onset of EMD. Two group A patients showed an increase of the IgM antibody titers up to 1 : 128 and 1 : 64, respectively; in addition, one of these patients also had elevated IgG antibody titers of 1 : 128 or 1 : 64 for 5 years, but both had no later symptoms (follow-up 3 and 5 years, respectively). The patient with the persistent IgG antibodies had a tick bite without erythema migrans, radicular pain for 3 weeks and arthralgia for 2 months in the initial phase of EMD. Two patients acquired no symptoms related to EMD. Elevated antibody titers against B. burgdorferi (group A) or against other borreliae (group B) were present in 59 of 97 patients (Table 6). In group A, an at least fourfold increase of IgM antibody titers up to 1: 256 could be observed in 6 patients, of IgG antibody titers up to 1 : 256 in 2 patients, and an at least fourfold decrease of IgM in 16 (after therapy in 14) within 7.5 months (0.7-44) and of IgG antibody titers in 9 patients after therapy within 18 months (1-37). For results of group B patients, see (31). After therapy, 28 out of 33 group A patients with elevated titers could be

Table 6. Elevated antiborrelial antibody titers group A (n = 69) %

group B (n = 28) %

IgM IgG IgM and IgG

20

5

(29) (12) (7)

4 7 15

(14) (25) (54)

Total

33

(48)

26

(93)

Antibody type

8

Methods for group A in reference (67) and for group B in (31)

220

Klaus Weber and Uwe Neubert

controlled serologicall y. Ant ibody titers remained elevated in one for 41 months (IgG type, no sequelae) and in 3 others for 0.7, 1 or 19 months (lgM type, no clinical sequelae). 28 A pa tient s did not develop a rise of IgG or IgM antibody titers, although the y had a mean of 1.8 sero logical controls (1- 4) for 5.5 months (0.3-48) after therapy. Further 8 A patients were negative, but had no serological control or ha d their first bloo d drawn after therapy. IgG antibody titers of the group A patients with joint, neuro logic, or car diac symptoms and of the 2 patients with the tracheolaryngitis and the int erstitial edema of the lung taken together were significantly higher (P < 0.05) compa red to the IgG antibody tit ers of group A patients with erythema migrans alone; ther e was no statisticial difference among IgM antibody tite rs of gro up A pa tient s and among group B pa tients. Most abnormal laboratory findings are listed in Table 7. The ESR was ~ 20 rnrn/h in 5 patients, the median in the 72 patients 6 mm/h (2- 27) . The leukocy tosis of 12900 was observ ed in a wom an with lesional pain for 30 months . 2 pa tien ts had an ab solute lymph openia of 1184 an d 876 cells/rnrrr', respectively, 4 and 0.5 weeks after on set of EMD, but relative lymphocytosis was present starting in the 4th week after ons et of EMD. 3 patients had a serum IgG of > 1500 mg/dl (2550, 1670, 1530) . The media n (n = 89) of IgG was 1080, of IgM 134, an d of IgA 208 mg/dl. A few pa tients had a slight elevation of SGOT and /or SGPT. Results of the electrophoresis and several other laborato ry values were presented in part in previous papers (56, 59, 61); the findings were mostl y negative, normal , or non -specific as were the special tests in the 11 patients with joint involvement, the attempts to isolate borreli ae from group A patients, and the special procedures, unless specified otherwise. Reinfec tions occurred in 3 patients. Two of them were treated with oral penici llin within 2 to 3 month s for the first EMD and did not have an increase of .antiborrelial an tibody titers during and after second EMD 5 and 7 years later, respectively. The thi rd patient (of group B) was not treated; one year later she develope d an erythema migrans around a tick bite, later a pro ven meningo radicul itis, 8 secondary erythema

Tab le 7. Abnormal laboratory findings in EMD

ESR Leukocytes

Patients tested

Patient s with Media n of abn. values (%) abn. values

Range of abo . values

Normal values

72

14' (19) 1 ( 4)

19 12900

11-27

< 10 mm/h 4 l_1OJ /mmJ

78

77-78

26 57 14 8 6 2

26 53- 68 12-1 6

< > < >

1410 283 380

1329-2550 252- 39 5 352- 400

26

i

Neutrophils

t Lymphocy tes 32 Monocytes Eosinophi ls Basophil s Serum IgG Serum IgM Serum IgA a

89 89 89

i

t

2 2 5 2 3 2 5

( 6) ( 6) (10) ( 6) ( 9) ( 6) (16)

15 (17) 9 (10) 6 ( 7)

8- 10 5-6 2

Patients with ob vious othe r causes excluded ; abn. = abnormal

70 35 50 20 ::; 6 ::; 4 ::; 1

%

< 1320 mg/dl < 25 0 mg/dl < 35 0 mg/dl

Clinical Features of Early Erythema Migrans Disease

221

migrans lesions, and elevated antiborrelial IgM and IgG antibody titers of 1 : 40 and 1: 160, respectively. Three women were pregnant. One woman was treated with propicillin during the 12th week of pregnancy for an erythema migrans of one-week duration, had negative antibody titers at first visit and 2 months after therapy, delivered a normal child, but the child died 23 hours after delivery; post mortem examination (Drs. H. Bratzke and M. Eder, University of Miinchen) revealed signs of aspiration in the lung and mild hemorrhage in the brain; borreliae were found in brain and liver by silver stain and/or immunofluorescence with monoclonal antibodies (with Dr. P. H. Duray, Yale University). A second woman contracted EMD 2 weeks before term and delivered a normal child which did not show any clinical signs of infection or elevated antibody titers up to the age of 9 months. A third woman had a tick bite during the 26th week of pregnancy and was treated with propricillin 2 weeks later for an erythema migrans of a few days duration; at the cut-off time, she was doing well. Comparison of group A and group B revealed similar median values for the age of the patients. Female/male ratio was 44/29 versus 21110. Arthritic, neurologic, and cardiac symptoms were distributed as follows: 18:5, 11:7, and 7:1. Comparison of ESR and immunoglobulins showed no statistically significant difference. Serological results were different (Table 6) as were the methods. "Severe" EMD. The 12 patients with 5 and more symptoms at first visit (erythema migrans excluded) had a total duration of the illness of 20 months (1-36), and 11 of the 12 had arthralgia or neurologic symptoms or both. They did not differ from the other patients regarding age and sex ratio. 3 had elevation of serum IgG (median = 1350 mg/dl), 2 of IgM (median = 268), and 3 of ESR (median = 22 rnm/h). Out of 10 group A patients, 7 had elevated IgM (median = 1 : 64) and 4 elevated IgG antibody titers (median = 1: 128).

2. BL. 7 patients with BL had a median age of 10 years (2.5-29). There were 5 children and 2 adults. The total duration until resolution was 8 months (3-12). 6 had their lesions on the ear, one on the arm. Regional lymphadenopathy was present in 5, 6 secondary erythema migrans lesions in 1, and urticaria and fever in 1 for 3 weeks prior to treatment. Elevated IgG antibody titers of up to 1 : 256 were found in 6 patients and IgM titers of up to 1: 512 in 4. Out of 5 patients seen by K. W., 3 had an at least fourfold decline (of IgG type in 2, of IgM type in 1) 17 months (8-20) after therapy; one patient had no decline after 14 months, and another no serological control.

3. ACA 21 patients with ACA had a median age of 59 years (36-77). There were 11 females and 10 males. The duration until first visit was 12 months (4-60). The ACA was located on the leg in 14 patients, on the arm in 12, and on the face in 3. Regional lymphadenopathy was observed in 6 patients, fibrous nodules in 5, neuropathy in 5, joint involvement in 4 (one had a history of arthralgia, one had more a periarticular inflammation, one developed arthralgia of the ankle of the affected leg 4 months after therapy with tetracycline, when ACA was still present, and one had intermittent arthralgia in the knee and ankle of the affected leg prior to therapy), cardiac symptoms in 3, a history of erythema migrans in 2, and pseudosclerosis in 1.

222

Klaus Weber and Uwe Neubert

The abnormal laboratory values are listed in table 8. IgM antibod y titers were negative in all 11 group A patients examined according to the method in (67); for results in the other 10 patients, see (31). The IgG antibod y titers of group A patients showed an at least fourfold rise in 5 patients 18 months (0.5- 24) after the first serological control despite initial therapy with oral (in 4) or parenteral penicillin, and an at least fourfold decline in 5 patients 23 months (11-43 ) after therapy. The ESR was 2: 20 mrn/h in 10 patients (median = 29) and serum IgG > 1500 mg/dl in 9 patients (median = 1840). The median of all values available (n = 19) was 20 for ESR, 1460 for IgG, 201 for IgM, and 281 for 19A. Significantly higher values than in EMD were found for ESR (P < 0.1, borderline difference), 19A (P < 0.01), IgM (P < 0.05), and median IgG antibody titers of group A patients (1 : 512 versus 1 : 16). Significantly more patients with ACA than with EMD had elevated ESR, IgG, IgA (P < 0.01 each), and IgM (P < 0.05). Table 8. Abnormal laboratory findings in ACA

ESR

Serum IgG Serum IgM Serum IgA

Patients tested

Patients with Median of abn. values ('Yo) abo. values

Range of abo. values

Normal values

19 19 19 19

12 ( 10 ( 5( 6(

< < < <

19G antibody titers' 21 A patients 11 B patients 10

63) 53) 26) 32)

27 1800 351 430

15-80 1460-2650 279-579 355- 536

11 (100) 10 (100)

512 240

64-4000 80-640

10 rnrn/h 1320 mg/dl 250 rng/dl 350 mg/dl

::5 64 ::5 10

Methods for A patients in reference (67), for B in (31 ); abn. = abnormal reciprocal values

a

Discussion In this prospective study, 39 out of 104 consecutive patients with early EMD developed special manifestations such as arthralgia, signs and symptoms consistent with neurologic or cardiac involvement, slight pulmonary interstitial edema, syncopes, or tracheolaryngitis (the latter 3 manifestations only in a single patient each). 32 patients had erythema migrans alone without any symptoms. Combination of special manifestations occurred in 10 patients and 12 patients had 5 to 10 constitutional symptoms initially. These observations were made although 99 patients received antibiotic treatment at or shortly after first visit. Erythema migrans ist the hallmark of EMD (59). Age and seasonal distribution, sex ratio, appearance, and variation of occurrence over the years have been known for some time (16, 11, 37,59 ). Our present findings were in agreement with these observations. Haemorrhagic, multiple, and recurrent lesions arc uncommon in Europe (5, 30, 39, 59). Multiple lesions occur frequently in Lyme disease (9, 38, 45, 50) in which recurrent, haemorrhagic, and even ulcerated lesions have been described (9, 45, 50). Recurrent lesions have been noted by others (5,21, 37) but not in our current series. However, reinfection could be observed in 3% of our patients similar to the experience

Clinical Features of Early Erythema Migrans Disease

223

of others (5,21); 2 of our patients with reinfection have been presented in some detail (63, 66). Erythema migrans may be lacking, as has been observed in the neurologic literature (22, 24, 25) and in Lyme disease (45). Peculiar lesions such as the 3 seen by us may hamper a correct clinical diagnosis. Homogeneous lesions often represent early forms (5, 16) as was shown in a few of our cases. Erythema migrans may last less or more than 4 weeks. It has been proposed to call only the latter form erythema chronicum migrans (59). Such lesions may last up to 2 years (10) and seem to be rather common in Europe (5, 16,21,37,59). On the other side, lesions lasting less than 4 weeks have often been reported to be followed by neurologic manifestations (4, 22, 24, 25). As a few of our cases showed, early spontaneous clearing was not always a bad prognostic sign. Asbrink and Olsson have found that significantly more patients with an erythema migrans of ~ 3 weeks duration compared to 2: 3 weeks duration had general symptoms (5); we could not substantiate this result in our material, even if 4 weeks were taken as borderline. We found that pain, burning, and/or a feeling of heat within the erythema migrans were significantly more frequently associated with the development of special manifestations than pruritic or asymptomatic lesions. EMD and Lyme disease can be accompanied by a rather long list of signs and symptoms (45,50,59). Our findings were in agreement with this. Others have found higher (38) or lower (5, 52) percentages of general symptoms and manifestations than were represented by our 72%. Our 12 patients with 6 and more initial signs and symptoms showed a prolonged course and almost all developed special manifestations which is in agreement with previous observations in Lyme disease (discussion in 65). The percentage of patients having erythema migrans alone was higher in our series (31 %) than in one report (38), or similar (9). Signs and symptoms (apart from dysesthesia, diarrhea, dizziness, and muscle tenderness) have been observed more frequently in Lyme disease (50) than in our previous (59) or present report. Furthermore, some signs and symptoms were not observed by us such as malar rash, splenomegaly, hepatomegaly, or testicular swelling (50). Joint involvement was present in 22% of our patients. This is less than in Lyme arthritis (27,45,48,50), more than in other European studies (5, 43, 52), and similar to our own previous reports (28, 30, 59, 61). In one series of our previous publications, 10 (59) and later 17 (61) group A patients with joint involvement have been presented. This paper omits 3 of the original patients with arthralgia (F, I, and M in 59) because they had been seen retrospectively. According to our present observations, the knee ranked now first in the distribution of joints amounting to almost 50% of the patients affected, which was still less than in Lyme arthritis (27, 45). The distribution of joints among our patients was similar compared to Lyme arthritis (45). We did not have the opportunity to observe longstanding frank arthritis in our patients, although 6 gave a reasonable record of swelling and 2 additional ones of redness shortly after antibiotic therapy. We cannot rule out that at least these 8 patients had arthritis sometimes, but we found it safer to denote the joint involvement in all patients as being arthralgic. 18 of our patients had arthralgia before and 21 after therapy with antibiotics (65). The course of the arthralgia in our patients varied considerably as it does in Lyme arthritis (45,46). In 8 of our patients, arthralgia lasted only a few days up to 1 month, but in 14 patients the duration was 6 months and more; several patients had joints involved for different periods. The time of onset of the arthralgia was similar to that reported for Lyme arthritis (46).

224

Klaus Weber and Uwe Neubert

Contrary to our previous report (61) and in agreement with Steere et al., the arthralgia of most of our patients was intermittent. The reason for this seemingly different finding is that some of our new patients had this type of involvement and that several patients originally listed as having single attacks developed intermittent attacks after the cut-off time of a previous report (61). Our 8 patients with a duration of more than 18 months all had an intermittent involvement in a given joint but 4 had single joint involvement in addition. Some of the details presented in a previous paper (59) differ from the present ones because we used the median now instead of the mean values previously. Furthermore, our statements regarding the percentage of arthralgia varied between the present 22 % and the previous 35% because there were more cases seen in 1982 (6 out of 11 group A and 3 out of 1 group B patients) compared to 2 out of 17 in 1983 and 3 out of 33 cases in 1984; such a variation over the years has already been observed in Lyme arthritis (48) but may occur incidentally. Neurologic manifestations have been described in detail in the European literature, mainly focusing on the meningoradiculitis of Bannwarth (4, 7,15,22,24,25). Patients with meningitis without peripheral neuropathy or with a suspicion of meningoencephalitis have also been presented (17, 20, 35, 53, 55). The spectrum of neurologic involvement is similar in Lyme disease (32). We made observations which fit into these descriptions. It was, however, noteworthy that our prospective study included some patients who developed symptoms and signs which were so short or so mild, that the affected patients would not seek special medical care. The frequency of neurologic involvement was similar to that found previously (59) and elsewhere (43). Cardiac manifestations have first been observed by Steere et al. in Lyme disease (45, 49). In Europe, signs and symptoms of a few cases have been described (13, 22a, 59) or mentioned (30, 61). Our 8 patients had signs and symptoms which fit into the clinical description of Lyme carditis (49). We are not aware of a description of a Prinzmetal type angina associated with EMD. The prolongation of QT c occurring in a patient after therapy has been discussed elsewhere (65). The woman with the slight pulmonary interstitial edema on chest X-ray, fever, and lethargy appearing a few days after initiation of therapy had 2 preceding erythema migrans lesions (following a tick bite each) within 4 weeks, an ESR of 13 mm/h, a serum IgM of 395 mg/dl, a serum IgG of 2550, and a rise of the IgM antibody titers from 1 : 16 to 1 : 64 within 2 weeks. So far, non-productive cough has been noted in Lyme disease and EMD (38, 50, 59, this study) and a more severe pulmonary involvement only in another borreliosis (40). Single observations such as the latter cases or the case with the tracheolaryngitis are somewhat problematic since unrelated causes were not detected but cannot be excluded. European experience with untreated patients has been quite limited outside the neurologic literature. However, several smaller series (5, 19, 54) and case reports (26 and 59, with literature) have mainly focused on arthralgia or arthritis. Two groups have described 2 patients with proven conduction abnormalities (13, 22a); 2 of our patients also had symptoms suggestive of heart involvement during early illness, and a 54-year old man had 2 syncopes before antibiotic therapy but a cardiac origin could not be proven. Three of our women were pregnant. One was still pregnant at the cut-off time of this study, and one having contracted EMD shortly before term delivered a normal child. The newborn of the third woman had a few borreliae in brain and liver despite antibiotic therapy during pregnancy. Congenital heart disease has been reported recently (36).

°

Clinical Features of Early Erythema Migrans Disease

225

The serological results were different in groups A and B, but the methods applied were different, too. One of us (U. N.) and co-workers using borreliae obtained from alive mice found positive serological results more frequently than other European authors (28, 31) with the exception of Ackermann (1). The serological findings in the 69 group A patients were more like the ones reported by others and by a part of our group using cultured borreliae as antigen (2, 38, 43, 60, 61, 67), but were less frequently positive than in selected patients with Lyme disease (8,14,34,51). Changes of various laboratory values in EMD and related disorders have been observed for many years (7,16,39,56,61). Steere et al. extended these findings (45, 46,50).33% of patients with Lyme disease have an elevation of the serum IgM but only 4 to 7% in two European investigations (52,59) and 10% in our present study; however, Asbrink and Olsson have found 17% (5). The percentage of IgG values> 1500 mg/dl has been 3% in Lyme disease (50) and our study. We found no correlation between elevation of IgM and arthralgia as Steere et al. have observed for arthritis (46). Changes in the differential blood count including monocytosis, eosinophilia, lymphopenia (in 1 patient with early EMD), plasma-cell like lymphocytes, and relative lymphocytosis have been reported (56, 59) and were corroborated by our present study. An absolute lymphopenia has recently been observed in early Lyme disease (38) and now by us, too. In 1983, we have reported on elevated antibody titers in lymphocytoma (60, 61). To separate lymphocytomas with and without antiborrelial antibodies, we used the designation spirochetal lymphocytoma (61). When the borrelial nature of the spirochete detected by Burgdorfer et al. (11) became clear (23), we specified the name to borrelial lymphocytoma (64). Caflisch et al. added another case (12), and we now included 3 more cases. One of our children had urticaria for 3 weeks, a finding not yet reported in BL but in Lyme disease (9,50). ACA is now generally thought of as a late manifestation of the infectious disease caused by B. burgdorferi (6, 44,61,62). Persistence of a then unknown bacterium had been postulated in 1981 (58), a 100% elevation of IgG antibody titers has been found (3, 6, 43, 60-62, 67), and borreliae have been isolated from the skin (6, 42, 68). Erythema migrans may precede ACA (6,16,37,61); we added now our second case to this. In addition to our previous observations (61, 62), we now found additional patients with peripheral neuropathy, joint involvement, pseudosclerosis, and elevation of ESR and immunoglobulins. The median age and the median ESR, IgM, and IgA of our patients with ACA were significantly higher than in our patients with EMD. In conclusion, early EMD and early Lyme disease are quite similar, but EMD seems to be less severe. BL as observed in our patients is a part of the early disease, and ACA is a late manifestation. Later symptoms and signs are not prevented by certain antibiotics (65).

Acknowledgement. We are indebted to Drs. G. Schierz, B. Wilske, V. Preac-Mursic, P. Herzer, C.-D. Reimers, and H. E. Krampitz (University of Miinchen), to Drs. W. Baedecker and R. Thurmayr (Technical University of Miinchen), and to Dr. T. Becker, laboratory specialist, Miinchen, for invaluable help. Dr. R. Thurmayr kindly performed the statistical analysis. 15 Zbl. Bakt. Hyg. A 263.1-2

226

Klau s Weber a nd Uwe Neubert

R ef erences

1. Ackermann, R.: Erythema chronicum migrans und dur ch Zecken iibertragene Meningopol yneuritis (C arin-Bujado ux-Bannwa rrh): Borrelien-Infe ktionen? Dtsch. Med . Wschr. 108 (1983) 577- 58 0. 2. Ackermann, R., j. Kabatzei, H. P. Boisten, A. C. Steere, R. L. Crodzicki, S. Hartung, and U. Runne: Spirochaten-Atiologie der Erythema-chronicum-migrans-Krankheit. Dtsch. Med . Wschr. 109 (1984) 92-97. 3. Ackermann, R., H. P. Boisten, j. Kabatzki, U. Runne, K. Kriiger, and W. P. Herrmann : Serumanrikorper gegen Ixodcs-ricinu s-Spirochate bei Acrodermatit is chronica at rophicans (H erxheimer). Dt sch. Med . Wschr. 109 (1984) 6-10. 4. Ackermann, R., P. Horstrup, and R. Schmidt: T ick-borne menin go polyneuritis (Garin-Bujado ux, Bannwarth), Yale J. BioI. Med . 5 7 (1984) 485-490. 5. Asbrink, E. and I . Olsson: Clinical manifestations of erythema chro nicu m migrans Afzelius in 161 pa tients. Acta Derm. Vener eol. (Stockh.). 65 (1985) 43-52. 6. Asbrink, E., A. Houmarh, and B. Hederstedt: Th e spirochetal etio logy of acro derm atitis ch ronica atroph icans He rx heimer. Acta Derm . Venereo l. (Stockh.). 64 (1984) 506- 5 12. 7. Bannuiarth, A.: Chronische Iyrnphocytare Menin gitis, entziindliche Polyneuritis und " Rheurnatisrnus" . Arch. Psychi atr. Ncrvenkr. 113 (194 1) 284-376. 8. Barbour, A. G., W. Burgdorfer, E. Grunuialdt, and A. C. Steere: Ant ibodies of patients wit h Lyme disease to components of the Ixodes dammini spiro chete. J. Clin . Invest. 72 (1983) 5 04-515. 9. Berger, B. W.: Erythema chronicum migrans of Lyme disease. Arch. Derrnatol. 120 (1984) 101 7-1021. 10. Bruder, K.: Zur Kenntnis des Erythem a chronicum migrans (Lipsch urz). Derrnatol. Wschr. 121 (1950) 337- 344. 11. Burgdorfer, W., A. G. Barbour, S. F. Hayes, J. L. Benach, E. Grunu/aldt, and J. P. Davis: Lyme disease - a rick-borne spirochetosis? Science 21 6 (1982 ) 131 7-1 319 . 12. Cailiscb, U., O. U. B. Schaad, A. Aescblimann, W. Burgdorfer: Die Zecken-Meningoradiku litis - eine Spiroch atose. Schw eiz. med. Wsch r. 114 (1984) 630- 634. 13. Cornuau, C, M. Bardet, P. Baudoin, P. L. Daumas, B. Oblet, G. Poirot, and M. Valois: Bloc auri culo-ventriculaire aigu, syncopal, au cours de la mal adie de Lyme. La Presse Medicale 13 (19 84 ) 888 . 14. Craft, J. E., R. L. Grodzicki, and A. C. Steere: Antib od y response in Lyme disease: evalu ation of diagnostic tests. J. Infect. Dis. 149 (1984 ) 789-795 . 15. Erbsloh, F. and K. Kohlmeyer: Uber polytope Erkrank ungen des per ipheren Nervensysrerns be i lymphocytarer Menin gitis. Fortschr. Neural. Psychia t. 36 (196 8) 321-3 42. 16. Hauser, W.: Wahrscheinliche Infekti on skrankheiten der Haut. Handbuch Haut- und Ces ch lechtsk rankheiten IV 1 A, Springer, Berlin (196 5) 556 -629. 17. Hellerstrom, S.: Erythema chranicum migra ns Afzelii. Acta Derm . Venereol. (Stockh.) 11 (1930) 315-321. 18. Hellerstrom, S.: Erythema chronicurn migrans Afze1ius with menin gitis. Acta Derm. Venereol. (Stockh.) 31 (195 1) 227- 234 . 19. Herzer, P., M. Schattenkircbner, and N . Zollner: Lyme-Art hritis - eine zu selten bedachte Diagnose? Verhandlungen Dtsc h. Ges. Inn. Med. 89 (1983) 299 -302. 20. Hallstrom, E.: Successful treatment of erythem a migr an s Afzelius. Acta Derm . Venereol. (Stockh.) 31 (195 1) 235 -243 . 21. Hoilstrom, E.: Penicillin trea tment of erythema chronicum migrans Afzelius. Acta Derm. Venereol. (Stockh.) 38 (195 8) 285-289. 22. Horstrup, P. and R. Ackermann: Durch Z ecken ub errragene Men ingop olyneuritis (Ga rinBujadoux, Bannwa rth ). Fortsc hr . Neurol. Psychiatr. 41 (197 3) 583-606. 22 a Houu/erzyl, j., f. J. Root, and f. A. Hoogkamp-Korstanie: A case of Lyme disease with cardiac involveme nt in the Ne therlands (letter). Infection 12 (1984) 358. 23. Johnson, R. G. P. Schmid, F. W. Hyde, A. G. Steigerwalt, and D . J. Brenner: Borrelia

t s«.

c,

Clinical Features of Early Erythema Migrans Disease

22 7

burgdorferi sp. nov.: etiologic agent of Lyme disease. Intern. J. System. Bact. 34 (1984) 496--497. 24. Kristoferitsch, W., G. Spiel, and P. Wessely: Zur Meningopolyneuritis (Garin-Bujadoux, Bannwarth). Nervenarzt 54 (1983) 640-646. 25. Meyer-Rienecker, H. j. , B. Hitzschke: Lymphocytic meningoradiculiris. Handbook Clin. Neurol. 34 (1978) 571-586. 26. Muller, W.: Die Lyme-Arthritis (Erythema-migrans-Arthritis). Schweiz. med. Wschr. 114 (1984) 265-269. 27. Lawson,}. P. and A. C. Steere: Lyme arthritis: radiologic findings. Radiology 154 (1985) 37--43. 28. Neubert, U.: Zur Ariologiedes Eryhtema chronicum migrans. In Tropenmed. Tagung. Ed. J. Boch. Frankfurt, Lang (1984) 353- 358 29. Neubert, U. and H. E. Krampitz: Spirochaetal antibodies in patients with erythema chronicum migrans, meningoradiculitis Bannwarth and acrodermatitis chronica atrophicans (abstract). J. Invest. Derm. 82 (1984) 544-5 45. 30. Neubert, U.: Zur Atiologie von Erythema-migrans-Krankheit und Lyme-Erkrankung. Hautarzt 35 (1984) 563-570. 31. Neubert, U., H. E. Krampitz, and H. Engl.: Microbiological findings in erythema chronicum migrans, acrodermatitis chronica atrophicans and lymphadenosis cutis benigna. Zbl. Bakt, Hyg. A 263 (1986) 237-252. 32. Pachner, A. R. and A. C. Steere: The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology 35 (1985) 47-53 . 33. Preac-Mursic, V., G. Schierz, H.-W. Pfister, K. Einhaupl, B. Wilske, and K. Weber: Isolierung einer Spirochare aus Liquor cerebrospinalis. Munch. med. Wschr. 126 (1984) 275- 276. 34. Russell, H., j. S. Sampson, G. P. Schmid, H. W. Wilkinson, and B. Plikaytis: Enzyme-linked immunosorbent assay and indirect immunofluorescence assay for Lyme disease.]. Infect. Dis. 149 (1984) 465--470. 35. Schirduan, M.: Verdacht auf Toxoplasmose bei Meningitis nach Erythema chronicum migrans bullosum. Arch. Derrn, Syph. 192 (1950) 256-260. 36. Schlesinger, P. A., P. H. Duray, B. A. Burke, A. C. Steere, and T. Stillman: Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann. Int. Med. 103 (1985) 67-68 . 37. Sedlacek, V.: Erythema chronicum migrans - poznarnky ke klinice, etioparogenezi a zarazeni. Cs. dermato logie 35 (1960) 386-399. 38. Sbrestha, AI., R. L. Grodzicki, A. C. Steere: Diagnosing early Lyme disease. Am.]. Med. 78 (1985) 235-240. 39. Sonck, C. E.: Erythema chronicum migrans with multiple lesions. Acta Derm. Venereol. (Stockh.) 45 (1965) 34-36 . 40. Southern, P. M. and j. P. Sanford: Relapsing fever. Medicine 48 (1969) 129-149. 41. Stadelmann, R.: Ein Beitrag zum Krankheitsbild des Erythema chronicum migrans Lipschutz. Dissertation, Marburg, 1934. 42. Stanek, G.: Lyme disease and related disorders Microbiol. Sciences 2 (1985) 231-234. 43. Stanek, G., G. Wewalka, V. Groh, R. Neumann, and W. Kristoferitsch: Differences between Lyme disease and European arthropod-borne borrelia infections (letter). Lancet I (1985) 401. 44. Steigleder, G. K.: Ixodes-ricinus-Spirocharen: wahrscheinlich Ursache der Acrodermatitis chronica atrophicans Herxheimer. Dtsch. Med. Wschr. 109 (1984) 3-5. 45. Steere, A. c., S. E. Malawista , t. A. Hardin, S. Ruddy, P. W. Askenase. W. A. Andiman: Erythema chronicum migrans and Lyme arthri tis: the enlarging clinical spectrum. Ann. Intern. Med. 86 (1977) 685-698. 46. Steere, A. C, ] . A. Hardin, S. Ruddy.], G. Mummaw, and S. E. Malawista: Lyme arthritis. Arthritis and Rheumatism 22 (1979) 471--483. 47. Steere, A. c. A. Gibofsky, M. E. Patarroyo, R. j. Winchester,}. A. Hardin, S. E. Malawista: Chronic Lyme arthritis: clinical and immunogenetic differentiation from rheumatoid arthritis. Ann. Intern. Med. 90 (1979) 896- 901.

228

Klau s Weber and Uwe Neubert

c., S. E. Malawista,]. H. Newman, P. N . Spieler, N. H. Bartenhagen: Antibiot ic ther apy in Lyme disease. Ann. Intern. Med. 93 (1980) 1-8. 49. Steere, A. c, W. P. Batsford, M. Weinberg,]. Alexander, H. ]. Berger, S. Wolfson, and S. E. Malawista: Lyme carditis: cardiac abnorma lities of Lyme disease. Ann. Intern. Med . 93 (1980 ) 8-16. 50. Steere, A. c., N. H. Bartenhagen,]. E. Craft, G. ]. Hutchinson, ]. H. Newman, D. W. Rahn, L. H. Sigal, P. N . Spieler, K. S. Stenn, and S. E. Malawista: The early clinical manifestations of Lyme disease. Ann. Intern. Med. 99 (1983) 76-82. 48. Steere, A.

51. Steere, A. c., R. L. Grodzicki, A. N. Kornblatt,]. E. Craft, A. G. Barbour, W. Burgdorfer, G. P. Schmidt, E. johnson, and S. E. Malawista: The spirochetal etiology of Lyme disease. N. Eng!. J. Med . 308 (1983) 733- 740.

52. Stiernstedt, G., G. Eriksson, W. Enfors, H. [orbech, B. Suenungsson, B. Skoldenberg, M. Granstrom: Erythema chroni cum migrans in Sweden. Scand. J. Infect. Dis. (1985). 53. Stiernstedt, G., B. SkOidenberg, A. Garde, G. Kolmodin, H.[orbech , B. Svenungsson, and A. Carlstrom: On the role of Ixodes ricinus spirochete in infectious disease of the nervous system.

54. Stiernstedt, G. and M. Granstrom: Ixodes ricinus spirochere infection as the cause of postinfectious arthritis in Sweden. Scand. J. Rheumatol. (1985) in press.

55. Weber, K.: Erythema-chronicum-migrans Meningitis - eine bakterielle Infektionskrankheit? M unch. Med. Wochenschr. 116 (1974) 1993-1998.

56. Weber, K. and O . Braun-Falco: Blutbildverand erungen bei Erythema chro nicum migrans. H aut arzt 25 (1974) 611-613 .

57. Weber, K.: Erkrankungen nach ZeckenbiK Z. Allgemeinmed. 57 (198 1) 1158-1163. 58. Weber, K.: Treatment of Lyme disease (letter). Ann. Intern . Med. 94 (1981) 137. 59. Weber, K., A. Puzik, T. Becker: Erythema-migran s-Krankh eit: Beitrag zur Klinik und Beziehung zur Lyme-Krankh eit. Dtsch. Med. Wochen schr. 108 (1983) 1182-1190.

60. Weber, K., G. Scbierz, B. Wilske, V. Preac-Mursic, W. Burgdorfer, and A. G. Barbour:

61. 62. 63. 64. 65. 66. 67.

68.

Antibodies against Ixodes damm ini and Ixodes ricinus spirochetes in tick-born e disorders. 11th ADF meeting, Kiel, November 12, 1983 (abstract). Arch. Dermatol. Res. 276 (1984) 260 . Weber, K., G. Schierz, B. Wilkse, and V. Preac-Mursic: European erythema migrans disease and related disorder s. Yale J. BioI. Med. 57 (1984) 463-471. Weber, K., G. Scbierz, B. Wilske, and V. Preac-Mursic: Zur Klinik und Atiologie der Acrod ermatitis chronica atrophicans. Hautarzt 35 (1984) 571-577 . Weber, K., G. Schierz, B. Wilske, U. Neubert, A. G. Barbour, and W. Burgdorfer: Reinfektion bei Erythema-migrans-Krankheit (abstract). Zbl. Hautkr. 150 (1985) 628- 629. Weber, K., G. Scbierz, B. Wilske, and V. Preac-Mursic: Das Lymphozytom - eine Borreliose? Z. Hau tkr . 60 (1985) 1585-1 598. Weber, K., U. Neubert, and R. Thurmayr: Antibiotic therapy in early erythema migrans disease and related disorders. Zbl. Bakt. Hyg. A (1986) this volume. Weber, K., G. Schierz, B. Wilske, U. Neubert, H . E. Kramp itz, A. G. Barbour, and W. Burgdorfer: Reinfection in erythema migrans disease. Infection 14 (1986) 32- 35. Wilske, B., G. Schierz, V. Preac-Mursic, K. Weber, H.-W. Pfister, and K. Einhiiupl: Serological diagnosis of erythema migrans disease and related disorder s. Infection 12 (1984) 33 1-337. Preac-Mursic, V., B. Wilske, P. Herzer, G. Scb ierz, and M. Bauer: Acrodermatitis chron ica atrophi cans - eine Borreli ose! Hautarz t 36 (1985) 69 1-693 .

Dr. K. Weher, Rcsenstrafe 6, D-8000 Miinchen 2, FRG