JOURNAL of the

AmeRICaN

Acarserrrv OF

DerMaTOLOGY VOLUME 23 NUMBER 3

PART 1

SEPTEMBER 1990

Continuing medical education The many faces and phases of borreliosis II. Donald C. Abele, MD, and Kenya H. Anders, MD Augusta, Georgia Borrelia burgdorferi, the etiologic agentof Lymedisease, has alsobeen associatedwith other cutaneousconditions. Acrodermatitis chronicaatrophicansand lymphadenosis benigna cutis are also caused by B. burgdorferi. Recent evidence links some cases of progressive facial hemiatrophyof Parry-Romberg, benign lymphocytic infiltrateof the skin (Jessner-Kanof), lichensclerosus et atrophicus, morphea, and Shulman syndrome with borreliae. This article reviews the manifestations of the diseases definitely linked to borreliosis and the evidence linking borreliae to progressive facial hemiatrophy, benign lymphocytic infiltrate, lichen sclerosus et atrophicus, morphea, and Shulmansyndrome. (J AM ACAD DERMATOL 1990;23: 401-10.)

In recent years, species of Borrelia have been recognized as the etiologic agents of several apparently diverse diseases, including erythema chronicum migrans (ECM); Lyme disease (LD); acrodermatitis chronica atrophicans (ACA); lymphadenosis benigna cutis (LBC), originally called Spiegler-Fendt sarcoid; and possibly some types of morphea, lichen sclerosus et atrophicus (LSA), progressive facial hemiatrophy of Parry-Romberg (PFH), benign lymphocytic infiltrate ofthe skin (J essner-Kanof) (BLI), and Shulman syndrome (eosinophilic fasciitis). Lyme disease was reviewed in Part I of this series.' ACA, LBC, LSA, PFH, BLI, and Shulman syndrome have been linked in varying degrees with borreliae and are the subject of this review. ACRODERMATITIS CHRONICA ATROPHICANS

ACA has been widely recognized in Europe for many years but is rarely reported in the United ORTHO

The CME articlesare madepossible through an educational

~ grant from the Dermatological Division, Ortho Pharma-

W

ceutical Corporation. From the Departmentof Dermatology, Medical College of Georgia. Reprint requests: Donald C. Abele, MD, Departmentof Dermatology, Medical Collegeof Georgia, 1521 Pope Ave., Augusta,GA 30912.

16/2/20307

States.? Although described earlier, Herxheimer and Hartman- coined the name ACA in 1902. Untreated ACA is characterized by a chronic progressive course that consists of an inflammatory and an atrophic stage. Lesions most commonly involve the distal extremities and slowly enlarge, particularly over the extensor surfaces. Early lesions are erythematous nodules or plaques that often show central clearing. This inflammatory stage may last for months or years; however, while the margins expand, central areas may show atrophic changes with loss of hair and poikiloderma (Fig. 1). Periarticular subcutaneous nodules or fibrous bands may develop and result in limitation of joint movement. 4 At times the disorder may be misdiagnosed as a peripheral vascular disorder, particularly as venous insufficiency.t The histopathologic findings in 32 patients have been extensivelyreviewed by Asbrink et a1. 6 During the early inflammatory stage, telangiectasia and dermal edema with a predominantly perivascular infiltrate of lymphocytes and plasma cells are observed. In the later stages the epidermis becomes atrophic and there is destruction of epidermal appendages and sclerosis suggestive of morphea. In nine cases the epidermis was atrophic but had hyperkeratosis; four of these nine cases had lique-

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Journal of the Americ an Academy of Dermatology

Fig. 1. Acrodermatitis chronicum atrophicans. (Courtesy Denny L. Tuffanelli, MD , San Francisco, Calif.) Fig. 2. Lymphadenosis benigna cutis. (Courtesy Kenneth E. Greer, MD, Charlottesville, Va.)

faction degeneration and two cases had a lichenoid appearance suggestive of lichen planus. One patient with clinical scleroderma-like skin lesions had biopsy findings of dermal sclerosis that could not be distinguished from scleroderma. Five patients had LSAlike lesions that histologically could not be differentiated from LSA although lesions from two patients had numerous plasma cells, a finding not seen in LSA. Other reports of LSA-like genital lesions associated with ACA include those of Gans,? Schweitzer and Layman.I and Aberer et a1. 9 Systemic complaints are often associated with ACA. Hopfl D• II described a peripheral polyneuropathy in many patients. In a series of 41 patients Asbrink" reported that approximately two thirds of patients complained of dysesthesias, cramps, and pain in the affected extremities or lumbar region. Some patients also had weight loss, arthralgias, deforming arthritis, and periosteal changes. In addition, one patient had scleroderma-like lesions and five had LSA-like lesions." Kristoferitsch et a1. 12 reported that approximately two thirds of 50 patients with ACA had evidence of peripheral sensory neuropathy or polyneuropathy. The neurologic deficits were chiefly distal sensory deficits in areas affected by ACA. Nerve biopsy specimens from four patients showed mononuclear inflammation around epineurial vessels but no evidence of necrotizing vasculitis.

Spirochetes were not found with Warthin-Starry . silver staining. Some perineurial IgA and IgM deposition was found. These findings were similar to those seen in meningopolyneuritis of Garin-Bujadoux-Bannworth (MPN-GBB), although not as severe.P i!" An infectious origin for ACA has long been suspected. Svartzl! treated patients with penicillin in 1946. Thyressonl'' reported the successful treatment of 57 patients with penicillin in 1949. ACA has been transmitted from person to person. 17. 18 An association of the disease with tick exposure was suggested by Hauser'? in 1955 and Danda/" in 1963. Case reports of ECM preceding or in association with ACA 19,21 -25 and the demonstration of spirochetes in skin from ECM and ACA25 reinforced the possibility that ACA was of borrelial origin. The demonstration of high serum antibody titers and successful cultivation of borreliae from lesions of ACA were reported by Asbrink and Hovmark'" in 1985 and provide the final evidence that ACA is due to barrelial infection. These findings have recently been confirmed by Kaufman et al.,27 who reported two cases of ACA from North America. Although antibiotic therapy appears to be beneficial for ACA, there are questions about the best therapeutic agents and their effectiveness. Asbrink et a1. 28 advise phenoxymethyl penicillin, 3 gm/day,

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for 3 weeks for the inflammatory skin lesions but suggest that intravenous penicillin may be required for patients who also have neurologic or joint symptoms . Weber et al. 29 reviewed numerous reports of therapy and reported 34 patients with ACA whom they had treated. They were unable to ascertain superiority of any antibiotic regimen over another (penicillin or its derivatives versus tetracycline) and noted that not all patients' skin lesions responded, that peripheral neuropathy might manifest or develop after antibiotic therapy, and that other late manifestations such as arthralgias and musculoskeletal pain might develop despite therapy. LYMPHADENOSIS BENIGNA CUTIS

Spiegler'" and Fendt" described cutaneous lesions that histologically resembled sarcoma but followed a benign clinical course. The lesions are asymptomatic, erythematous or violaceous nodules or plaques on the head (especially the ear lobes), the trunk (with predilection for areolae), and the extremities (Fig. 2). Bafverstedt-? proposed the name lymphadenosis benigna cutis (LBC) and classified the disorder into the more common solitary form and a disseminated form. Histologically, the lesions are characterized by a dense infiltration of the dermis with lymphocytes and histiocytes that form a follicular pattern similar to the architecture of a lymphoid follicle (Fig. 3). Appendages and blood vessels are not involved by the infiltrate. Occasional eosinophils can be present. The epidermis is normal and separated by a grenz zone from the dermal infiltrate. The major histologic differential diagnoses include arthropod bite reactions and lymphoma cutis. 33 No definitive therapy has been described although the lesions are radiosensitive. Intralesional and topical steroids, as well as penicillin, have produced remissions. 34- 37 Many reports have suggested an infectious agent as the cause of LBe. An association of LBC with tick bites has been reported. 38-4O LBC has also been associated with ECM, 32, 40·~2 polyradiculitis." and ACA,35 Paschoud'P tr ansferred LBC from one person to another by inoculation and observed the development of ECM. Spirochete-like organisms in lesions of LBC have been detected by mercury- and silver-stained sections of skin .25,44 Increased serum titers of antiborre1ial antibodies were reported by Asbrink and Olsson" and Weber et a1. 45 Hovmark et aJ.46 strengthened the borreliallink with their report of 10 patients with LBC; four re-

Fig. 3. Lymphadenosis benigna cutis. (Hematoxylineosin stain; X3.5.) (Courtesy James L. O'Quinn, MD, Augusta, Ga.)

called tick bites before the lesions developed, five had ECM near the site of LBC lesions, six had elevated antibody titers to B. burgdorferi spirochetes, one had meningitis and facial nerve palsy, and spirochetes were cultured from the lesions in one patient. The LBC lesions cleared with penicillin therapy. LICHEN SCLEROSUS ET ATROPHICUS AND MORPHEA Conflicting reports exist about B. burgdorferi as a possible etiologic agent in some forms of morphea and LSA. Several clinical observations suggest a possible relation between morphea and ACA. 47-49 Aberer et al.50,51 reported that as many as 50% of studied patients with morphea had serum antibodies to B. burgdorferi as assayed by enzymelinked immunosorbent assay (ELISA) techniques. They emphasized that ACA, recognized as being caused by B. burgdorferi, and morphea had many similar clinical and histopathologic features; both disorders begin with a blue-red edematous phase and evolve into sclerosis (morphea) or atrophy (ACA), both may be associated with neuromuscular complaints, and both may respond to penicillin therapy. In 1987 Aberer and Stanek52 reported the presence of spirochetes in skin biopsy specimens from some patients with morphea and LSA; with an avidin-biotin-immunoperoxidase method they detected spi-

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rochetes in 4 of 13 patients with morphea as in 6 of 13 patients with LSA. In another study these authors-? reported elevated antibodies to B. burgdorferi in 8 of 15 patients with morphea; in addition, spirochetes were cultured from one patient's lesions and demonstrated in histologic sections from three of eight patients by immunoperoxidase methods. Two patients had negative serologic tests for B. burgdorferi although spirochetes were found in their lesions. Clinical improvement in early inflammatory lesions occurred after penicillin therapy. Other reports indicate that 20% to 50% of patients with morphea have antibodies to borreliae. 54,55 One case of generalized morphea with a positive serologic test was reported by Maleville et al. 56 Aberer et al.57 reported neurologic findings in nine patients with morphea and in two patients with LSA who had either elevated antibody titers or spirochetes demonstrated in biopsy specimens; spirochetes were cultured from one patient with morphea. Ten patients had neurologic findings that included hyperesthesias, paresthesias, dysesthesias, weakness, muscular atrophy, facial palsy, and myalgias.V These findings are similar to those seen in LD and ACA. They also reviewed other reports of neurologic symptoms in patients with morphea, including one patient who had facial hemiatrophy. Coexistent ACA and morphea have also been reported. 58 Jablonska-? mentioned that among 431 cases of ACA reported by Gottron, pseudosclerodermatous changes were present in 54. She also stated that the indurations in ACA may be impossible to distinguish from localized scleroderma.59 Other investigators have failed to confirm these positive serologic findings and no cases of morphea caused by borreliosis have been reported as yet in the United States. 6D-65 Halkier-Sorensen et a1. 64 used the B. burgdorferi flagellum ELISA method'i"- 67 to detect antibodies, which may be a more specific and sensitive serologic test than previous ones that use whole-cell antigen preparatlons.P- 69 Uitto et al.70 reported 10 patients with cutaneous lesions clinically typical of morphea and LSA who had histopathologic changes of both disorders; they suggested that these lesions were part of a spectrum of histologic changes that could represent similar etiologic events or a closely related pathologic process. Connelly and Winkelmann71 reported patients with simultaneous LSA, morphea, and lichen planus and commented on the concurrent or sequential relationships of LSA and morphea. However, Patter-

Journal of the American Academy of Dermatology

son and Ackerman 72 concluded that the LSA-like lesions in patients with morphea are different from true LSA. The classification and etiology of morphea, LSA, and similar disorders are obviously unclear and it is difficult to reconcile these divergent reports. The histologic changes reported in these disorders may be part of a spectrum of nonspecific pathologic responses that may have many causes and the same end-stage result. Halkier-Sorensen et al.64 suggested this possibility and cited instances of localized sclerodermatous changes in ACA that require clinical, histopathologic, and serologic findings for diagnosis; in some patients these findings may be ACA with sclerosis rather than idiopathic morphea.t?' 73 As in syphilis and other infectious diseases, serologic tests are indirect means of diagnosis, full of pitfalls that include specificity, sensitivity, cross-reactivity, appropriateness of antigens used in the tests, and prevalance of antibodies in the population. Because spirochetes have been demonstrated in tissue and by culture in some patients with morphea and LSA, it would not seem reasonable at this time to dismiss them as causative agents even in patients with a negative serology. In syphilis, late manifestations are not always associated with positive serologic tests; it is conceivable that serologic tests for Borrelia might also be negative late in the course. In an editorial about the possible relationships of morphea and LSA, TuffaneUi74 suggested that patients with early morphea and morphea associated with LSA should have antibody studies and that patients with positive ELISA titers should be treated with antibiotics. He also suggested that patients with negative ELISA but positive immunofluorescent antibody (IFA) titers should be considered for therapy, particularly patients with early morphea, including children with linear scleroderma of the extremities, extensive lesions, or facial lesions with a poor cosmetic outcome. PROGRESSIVE FACIAL HEMIATROPHY (PARRY -ROMBERG SYNDROME)

Parry and Romberg are credited with the first descriptions ofPFH.75-77The onset usually begins in the first two decades of life with irregular pigmentary changes (hypopigmentation or hyperpigmentation) on one side of the face. Muscular spasms or neuralgia may be present. These changes are followed by a slowly evolving (months to years) progressive atrophy of the skin, subcutaneous fat, mus-

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Figs. 4 and 5. A 5-year-old girl with progressive facial hemiatrophy. There was loss of dermal and subcutaneous tissue and hyperpigmentation and hypopigmentation on left side of face, extending from beneath the eye to the neck and chin. Hypopigmentation of the left eyebrow and lashes is present. Skin is atrophic with prominent vessels and a sclerotic band in malar area along the nose.

cle, and even bone. The skin becomes dry, thin, and atrophic but usually remains mobile. Scarring fibrosis may be present in some areas. The atrophy may be confined to the distribution of one divisionof the trigeminal nerve or involve the entire side of the face. It rarely is bilateral and very rarely involves half the body, usually, but not always, the ipsilateral side. The atrophy in such cases may begin on the extremities or trunk with later involvement of the face. 78 Histopathologically, the changes are similar to those seen in scleroderma.I'- 77, 79-81 There is variable dermal thickening with sclerosis of the collagen bundles and loss of skin appendages. The fat is replaced by fibrous tissue and muscles may be atrophic, edematous, and vacuolated with focal inflammation and loss of striations. The cause of PFH is uncertain although many believe it is related to various systemic collagenvascular disorders, especially scleroderma or linear morphea. 82,83 Other reports of positive AN As in PFH can be found. 77• 8o, 84 In addition to cutaneous atrophy, numerous ocular and neurologic complications have been reported. Ophthalmologic complications include keratitis.T' iritis," iridocyclitis," cataracts,75,85 ip-

silateral enophthalmia,"? optic nerve atrophy,75,8S Horner's syndrome," heterochromic irides" and uveitis. Neurologic abnormalities reported include trigeminal neuralgia,"? paresthesia.i'' muscular spasms.I? contralateral Jacksonian seizures,75-77 ipsilateral migraine headache, 80. 81 ipsilateral cerebral calcifications,75,76 facial palsy, and dysesthesia. Although the scleroderma-like histologic findings and reports of findings positive for AN As suggest an association of PFH with collagen-vascular disease, there are other possible interpretations of these reports. The skin in PFH is usually atrophic yet pliable and not as sclerotic as in morphea or scleroderma. In addition, the depth ofthe atrophy and fibrosis that often involves fascia, muscle, and bone is not common in scleroderma or morphea (except for linear morphea). In fact, the clinical appearance and histopathologic changes reported in PFH may be viewed as more akin to the changes in ACA, clearly a disorder caused by B. burgdorferi infection. Falsepositive ANAs and serologic tests for syphilis have been associated with borreliosis.?" Of particular interest is that one patient with morphea and antibody to B. burgdorferi also had facial hemiatrophy.F A patient with PFH and elevated titers of antibodies to Borrelia has been reported recently.P A

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406 Abele and Anders

J

I

I Fig. 6. Morphologic features of Borrelia-like microorganisms. A, Elongated, loosely coiled, and intensely argyrophilic microorganism (arrow) in derrnis. (Steiner silver impregnation; X870.) Inset, Fluorescent, partially coiled, and fragmented form (arrow) in wall of dermal capillary. (Indirect immunofluorescence with monoclonal antibody against Borrelia species, X870.) B, Elongated, noncoiled, fragmented filamentous forms (arrows) in subcutaneous tissue. (Steiner silver impregnation; X870.) (From Abele DC, BedingfieldRB, Chandler FW, et al. J AM ACAD DERMATOL 1990;22:532.)

5-year-old girl had sustained trauma under the left eye 1 year previously. Some discoloration persisted after the swelling resolved. Three months later, an erythematous, painful "bump" on her arm was observed that developed "red streaks" going up the arm. She had been treated empirically with amoxicillin because of the possibility of a "brown spider bite." Several months later, uneven tanning was noted on the left side of her face and slight asymmetry of her smile was noted. Rapidly progressive thinning, hypopigmentation, and atrophy of the tissues of the left side of the face developed, extending to the chin and neck (Figs. 4 and 5). A rapid plasma reagin test was positive, VDRL was reactive at 1:1 dilution, and a microhemagglutin- Treponema pallidum test (MHA-TP) was nonreactive. Borrelia antibody titer was greater than 1:128. Steiner silver stains of the skin biopsy specimen revealed rare spirochetes suggestive of a Borrelia species (Fig. 6). IFA with monoclonal antibody specific for Borrelia (genus level only) revealed rare organisms. Treatment with oral penicillin was begun. After 1 month of therapy, the skin of the left cheek was nearly normally pigmented and fuller with reduced prominence of blood vessels. BENIGN LYMPHOCYTIC INFILTRATION OF THE SKIN (JESSNER-KANOF) BLI was described in 1953 as "flat, discoid, more or less elevated, pinkish to reddish brown, starting as

small papules, expanding peripherally, sometimes clearing in the center, sometimes showing a circinate arrangemem.t"? (page 447) The lesions occur more commonly in men. 88 Familial cases have been reported.s" 90 The face, ear lobes, and neck are most frequently involved, although the trunk, extremities, and scrotum have been involved.P!- 92 The lesions are usually asymptomatic but may be pruritic; they may persist from weeks to 30 years (average 5 years) with spontaneous remissions and exacerbations.P They can recur in the same or other areas. Resolution occurs without scarring. No specific therapy is known. Histopathologically, the main finding is a perivascular lymphocytic infiltration of the dermis. Occasional plasma cells and histiocytes may be present. The epidermis is usually normal in appearance. 93 The clinical differential diagnosis includes discoid lupus erythematosus (DLE), polymorphic light eruption, lymphoma cutis, sarcoid, tuberculosis cutis, and drug eruption. Most of these can be readily excluded by histologic criteria. Some authorities believe BLI is a form of DLE though it heals without scarring, does not have hyperkeratosis or follicular plugging, has no basal cell degeneration, and has negative tissue immunofluorescence.P" In addition, the cells in the infiltrate of BLI have been shown to be predominantly T cells 95-97 with different characteristics from those in D LE. 97-99 Van Hale and Winkelmann 100 reported equal num-

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bers of helper and suppressor T cells. Konttinen et al. 101 reported that the infiltrate does not have the characteristics of lymphoproliferative disorders but suggest that T cells are accumulated from the circulation. Other reports about the T cell population in lesions of BLI are available. 102-105 Abele et al. 106 reported the case of a patient with BLI thought to be due to B. burgdorferi infection (Fig. 7). The patient was diagnosed in 1981 with clinical lesions of BLI supported by a characteristic lymphocytic infiltration from the biopsy specimen. Eight years later, he reported a 3-year history of recurrent annular and polycyclic erythematous lesions on his back, which were clinically suggestive of ECM. He reported frequent exposure to ticks, vague knee arthralgias, and had borderline first-degree atrioventricular heart block with nonspecific T wave changes. Serum for IgG antibodies to B. burgdorferi was positive by IFA at a titer of 1:128. A biopsy specimen of the back lesions was compatible with ECM. Steiner stains and immunofluorescence stains on the ECM lesions showed spirochetal forms. The facial lesions of lessner-Kanof were still present in 1989 but cleared along with the ECM after tetracycline therapy for his LD. Steiner silver stains done on the tissue block saved from 1981 revealed spirochetal structures suggestive of a Borrelia species. Immunofluorescence staining was positive with a species-specific monoclonal antibody to the Borrelia species (genus level only). The authors'P" suggest that the patient had ECM with BLI, which may be another manifestation of borreliosis.

EOSINOPHILIC FASCIITIS (SHULMAN SYNDROME) Shulman syndrome (eosinophilic fasciitis) was described in 1974 as a painful swelling and induration of the extremities that produces limitation of motion.I'" The disorder often appears after trauma or strenuous exertion. Histologically, dermal sclerosis with inflammation and fibrosis of the fat and deep fascia is present. Clinical improvement can be produced with corticosteroids, but some cases have subsided spontaneously and others have evolved into scleroderma. 108 Recent reports have implicated B. burgdorferi infection as a possible etiologic agent for this disorder on the basis of a history of antecedent tick bites, positive serologic studies for borreliae, and demonstration of spirochetes in tissue. 109, 110

Borreliosis II 407

Fig. 7. Lymphocytic infiltration of the skin (JessnerKanof) in patient who had spirochetes identified in these lesions.

One of these cases of Shulman syndrome was later questioned because of lack of eosinophilia or hypergammaglobulinemia, failure to respond to corticosteroids, and nonspecific histologic find-

ings.'!' Another report suggests a relation among Shulman syndrome, borreliosis, and carpal tunnel syn-' drome. A woodsman with frequent tick bites had morphea-like lesions and diffuse swelling of both forearms. 112 A biopsy specimen was consistent with morphea that involved the deep fascia. The induration and morphea-like lesions regressed after treatment with penicillin. Three years later residual induration of his arms was noted but his major complaints were paresthesias in the fingers and nocturnal palmar pain. Laboratory findings included ANA titer of 1:160, 8% peripheral eosinophilia, hypergammaglobulinemia, and elevated titers of antiborrelial antibodies. Despite treatment with penicillin, the symptoms worsened and surgical correction of the carpal tunnel syndrome was required.

CONCLUSION Although B. burgdorferi has not yet rivaled its cousin T. pallidum's reputation as "the great imitator," it can present with numerous manifestations. In the first article of this series, the many manifestations of Lyme disease were discussed. 1 This second

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article reviewed two disease processes, ACA and LBC, clearly related to B. burgdorferi in Europe. Some cases of LSA, BU, PFH, and eosinophilic fasciitis seem to be linked to Borrelia. These latter processes may represent a nonspecific reaction pattern to more than one causative agent. When a treatable etiologic agent such as Borrelia can be identified, a range of therapeutic options can be considered. Presently, however, the duration of and optimal agent for treatment have not been established for these non-Lyme borrelioses. Physicians must carefully interpret serologic tests in light of the clinical situation. REFERENCES 1. Abele DC, Anders KH. The many faces and phases of borreliosis I. Lyme disease. J AM ACAD DERMATOL 1990;23:. 2. Lavoie PE, Wilson AJ, Tuffanelli DL. Acrodermatitis chronica atrophicans with antecedent Lyme disease in a Californian. Zentralbl Bakt Hyg A 1986;263:262-5. 3. Herxheimer K, Hartman K. Dber acrodermatitis chronica atrophicans. Arch Dermatol (Berlin) 1902;61:57-76. 4. Asbrink E. Erythema chronicum migrans Afzelius and acrodermatitis chronica atrophicans, Acta Derrn Venereal Suppl (Stockh) 1985;118:1-63. 5. Fagrell B, Stiernstedt G, Ostergren J. Acrodermatitis chronica atrophicans Herxheimer can often mimic a peripheral vascular disorder. Acta Med Scand 1986;220: 485-8. 6. Asbrink E, Brehmer-Andersson E, Hovrnark A. Acrodermatitis chronica atrophicans--a spirochetosis. Am J Dermatopathol 1986;8:209-19. 7. Gans O. Acrodermatitis atrophicans, Z Hautler 1933; 45:678. 8. Schweitzer SE, Layman CWo Acrodermatitis chronica atrophicans. Arch Dermatol 1935;31:196-212. 9. Aberer E, Neumann R, Lubec G. Acrodermatitis chronica atrophicans with lichen sclerosus et atrophicans: tubulointerstitial nephritis and urinary excertion of spirochete-like organisms. Acta Derm Venereal (Stockh) 1987;67:62-5. 10. HopfHCR. Acrodermatitis chronica atrophicans (Herxheimer) und nervensystem. Monographien aus dem gesamtgebiete der neurologie und psychiatrie 1966;114:1130. 11. Hopf HCR. Peripheral neuropathy in acrodermatitis chronica atrophieans (Herxheimer). J Neurol Neurosurg Psychiatry 1975;28:452-8. 12. Kristoferitsch W, Sluga E, Graf M, et at. Neuropathy associated with acrodermatitis chronica atrophicans: clinical and morphological features. Ann N Y Acad Sci 1988;539:35-45. 13. Camponovo F, Meier C. Neuropathy ofvasculitic origin in a case of Garin-Bujadoux-Bannwarth syndrome with positive Borrelia antibody response. J Neurol 1986;233: 69-72. 14. Vallat JM, Hugou J, Lubeau M. et al. Tick bite meningoradiculoneuritis: clinical, electrophysiologic, and histologic findings in 10 cases. Neurology 1987;37:749-53. 15. Svartz N. Penicillinbehandlung vid dermatitis atrophicans. Herxheimer Nord Med 1946;32:2783.

16. Thyresson N. The penicillin treatment of acrodermatitis chronica atrophicans (Herxheimer). Acta Derm Venereal (Stockh) 1949;29:572-621. 17. Golz H. Die acrodermatitis chronica atrophicans Herxheirner als infektionslerankheit. Hautarzt 1955;6:244-52. 18. Zmegac Z. Zur frage der aetiologie der acrodermatitis chronica atrophicans unter besonderer berucksichtigung der implantationsversuche von Gotz. Hautarzt 1966; 7:293-8. 19. Hauser W. Zur klinik, atiologle und pathogenese der akrodermatitis chronica atrophicans. Hautarzt 1955;6:7780. 20. Danda J. Die weltfrequenz der akrodermatitis chronica atrophicans, Hautarzt 1963;14:337-40. 21. Ludwig E. Erythemachronicum migrans im fruhstadium der acrodermatitis chronica atrophicans Herxheimer. Hautarzt 1956;7:41-2. 22. Weber K, Schierz G, Wilske B, et at. Zur klinikund atiologic der acrodermatitis chronica atrophicans. Hautarzt 1984;35:571-7. 23. Steurer J, Bensley G, Greminger P, et al. Acrodermatitis chronica atrophicans und Lymesche erkrankung. Internist 1987;28:693-7. 24. Frithz A, Lagerholm B. Acrodermatitis chronica atrophicans, erythema chronicum migrans and lymphadenosis benignacu tis-e-spirochetal diseases? Acta Derm Venereol (StocJch) 1983;63:432-6. 25. Asbrink E, Hovmark A, Hederstedt B. The spirochetal etiology of acrodermatitis chronica atrophicans Herxheimer. Acta Derm Venereal (Stockh) 1984;64:506-12. 26. Asbrink E, Hovmark R. Successful cultivation of spirochetes from skin lesionsof patients with erythema chronicum migrans Afzelius and acrodermatitis chronica atrophieans. Acta Pathol Microbiol Immunol Scand [Sect B] 1985;93:161-3. 27. Kaufman LD, Gruber BL, Phillips ME, et at. Late cutaneous Lyme disease: acrodermatitis chronica atrophicans. Am J Med 1989;86:828-30. 28. Asbrink E, Hovmark A, Olsson r. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bakt Hyg A 1986;263:251-61. 29. Weber K, Preac-Mursic V, Neubert D, et at. Antibiotic therapy of early European Lyme borreliosis and acrodermatitis chronica atrophicans. Ann N Y Acad Sci 1988; 539:324-45. 30. Spiegler E. Uber die sogenennte sarcomatosis cutis. Arch Derm Syph 1894;27:163. 31. Fendt H. Beitrage zur Kenntnis der sognannten sarcoiden. Geschwultse der Haut. Arch Derm Syph 1900;53:213. 32. Bafverstedt 8. Uber lymphadenosis benigna cutis, eine klinische and pathologich-anatomische studie. Stockholm: PA Nordstedt & Soner, 1943. 33. Lever WF, Schaumburg-Lever G. Histopathology of the skin. Philadelphia: J8 Lippincott, 1983;753-6. 34. Bianchi G E. Die penicillinbehandlung der lymphozytome. Dermatologica 1950;100:270-3. 35. Bavferstedt B. Lymphadenosis benigna cutis (LABC)its nature, course and prognosis. Acta Dcrm Venereal (Stockh) 1960;40:10-18. 36. Bafverstedt B. Unusual forms of lymphadenosis benigna cutis (LABC). Acta Derm Venereal (Stockh) 1962:42:3-

10. 37. Buchner SA, Fluckiger B, Rutli T. Infiltrative lymphadenosis benigna cutis als borreliose der haut, Hautarzt 1988;39:77-81. 38. Jordan P, Holtschmidt J. Traumatisches zeckenbiss-

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