Early Studies- Part 2

N Engl J Med. 1988 Dec 1;319(22):1441-6.

Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi.

Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG.

Department of Medicine, State University of New York, School of Medicine, Stony Brook 11794-8161.

Comment in:

N Engl J Med. 1989 May 11;320(19):1279-80.

The diagnosis of Lyme disease often depends on the measurement of serum antibodies to Borrelia burgdorferi, the spirochete that causes this disorder. Although prompt treatment with antibiotics may abrogate the antibody response to the infection, symptoms persist in some patients. We studied 17 patients who had presented with acute Lyme disease and received prompt treatment with oral antibiotics, but in whom chronic Lyme disease subsequently developed.

Although these patients had clinically active disease, none had diagnostic levels of antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity against B. burgdorferi in serum from these patients was no greater than that in serum from normal controls. The patients had a vigorous T-cell proliferative response to whole B. burgdorferi, with a mean ( +/- SEM) stimulation index of 17.8 +/- 3.3, similar to that (15.8 +/- 3.2) in 18 patients with chronic Lyme disease who had detectable antibodies.

The T-cell response of both groups was greater than that of a control group of healthy subjects (3.1 +/- 0.5; P less than 0.001). We conclude that the presence of chronic Lyme disease cannot be excluded by the absence of antibodies against B. burgdorferi and that a specific T-cell blastogenic response to B. burgdorferi is evidence of infection in seronegative patients with clinical indications of chronic Lyme disease.

PMID: 3054554 [PubMed - indexed for MEDLINE]

Ann N Y Acad Sci. 1988;539:324-45.

Antibiotic therapy of early European Lyme borreliosis and acrodermatitis chronica atrophicans.

Weber K, Preac-Mursic V, Neubert U, Thurmayr R, Herzer P, Wilske B, Schierz G, Marget W.

Department of Microbiology, University of Munich, Federal Republic of Germany.

In a study on 121 consecutive patients with erythema migrans, 65 patients obtained oral penicillin, 36 tetracyclines, and 20 amoxicillin-clavulanic-acid. Follow-up was carried out for a median of 29, 17, and 7 months, respectively. In another limited trial on 29 patients with acrodermatitis chronica atrophicans (ACA), 14 patients received oral penicillin, 9 parenteral penicillin, and 6 tetracyclines. There was no statistically significant difference among treatment groups in both therapeutic trials, with the exception of different follow-ups due to the nonrandomized study design and different occurrence of the Jarisch-Herxheimer reaction in patients with erythema migrans.

Later extracutaneous manifestations developed in 27% of the patients with erythema migrans and in 47% of the patients with ACA despite antibiotic therapy. We could not prove the superiority of any antibiotic tested in either early or late European Lyme borreliosis.

PMID: 3056202 [PubMed - indexed for MEDLINE]

Rev Neurol (Paris). 1988;144(12):765-75.

[Multiple neurologic manifestations of Borrelia burgdorferi infection]

[Article in French]

Dupuis MJ.

Clinique St-Pierre, Ottignies, Belgique.

The neurological spectrum of Borrelia burgdorferi infections is still enlarging. We review epidemiological, pathological and serological data of Lyme disease. The course of the disease is divided in three stages: stage 1 during the first month is characterised by erythema chronicum migrans and associated manifestations; stage 2 includes not only the classical European meningoradiculitis but also less specific neurological symptoms: isolated lymphocytic meningitis with an acute or even relapsing course, apparently idiopathic facial palsy, neuritis of other cranial nerves, polyneuritis cranialis, Argyll-Robertson sign, peripheral nerve involvement, acute transverse myelitis, severe encephalitis, myositis.

During stage 3, three to five months or longer after the onset of the disease, chronic arthritis, acrodermatitis chronica atrophicans and various neurological symptoms can be observed: chronic neuropathy with mainly sensory or motor signs, recurrent strokes due to cerebral angiopathy and progressive encephalomyelitis; this third stage the central nervous system involvement is characterised by slowly progressive or fluctuating course during months or years, ataxic or spastic gait disorder, bladder disturbances, cranial nerve dysfunction including optic atrophy and hypoacusia, dysarthria, focal and diffuse encephalopathy.

This chronic central nervous system disease can mimic multiple sclerosis, anorexia nervosa, psychic disorders or subacute presenile dementia. It is often associated with pleiocytosis, abnormal EEG and evoked potentials, sometimes multifocal and mainly periventricular white matter lesions visualised by CT or MRI, and as a rule high antibody titers against Borrelia burgdorferi.

High doses of penicillin can halt the disease, sometimes induce spectacular regression of symptoms or sometimes be inefficient; ceftriaxone could be a more powerful therapy. Similarities between syphilis and Borreliosis are multiple: both of these spirochetes contain plasmids, can be transmitted through the placenta and progress for many years through successive stages, with multiorgan symptoms, including parenchymatous and vascular lesions of the central nervous system. Borrelia burgdorferi is the new great imitator.

PMID: 3070690 [PubMed - indexed for MEDLINE]

Ann N Y Acad Sci. 1988;539:346-51.

Treatment of erythema chronicum migrans of Lyme disease.

Berger BW.

Department of Dermatology, New York University School of Medicine, New York 10016.

Between June 1981 and July 1987 the efficacy of antibiotic treatment of 215 patients with erythema chronicum migrans of Lyme disease was evaluated in terms of the necessity for retreatment and the prevention of the late manifestations of Lyme disease. The principal antibiotics utilized to treat 161 patients through 1986 were varying doses of tetracycline, or penicillin alone or in combination with probenecid. Two of 80 patients with a minor form of the illness and 17 of 81 patients with a major form of the illness required retreatment. There were four patients who did not respond to retreatment with their original medication. A 15- to 30-day course of amoxicillin (500 mg q.i.d.) and probenecid (500 mg q.i.d.) or doxycycline (100 mg t.i.d.), and on three occasions ceftriaxone (2-4 g/day i.v.), were used to treat 54 patients in 1987. Although it is too early to judge the efficacy of treatment in these patients, increases in the incidence of Herxheimer reactions and drug eruptions were observed. Strict compliance with treatment protocols and the possibility of reactions to medications should be thoroughly discussed with patients.

PMID: 3190102 [PubMed - indexed for MEDLINE]

Scand Audiol. 1989;18(4):205-10.

Brainstem response audiometry in chronic Lyme borreliosis.

Sandström M, Bredberg G, Asbrink E, Hovmark A, Holmkvist C.

Department of Audiology, Södersjukhuset, Stockholm, Sweden.

Auditory brainstem responses (ABR) were investigated in 26 patients with acrodermatitis chronic atrophicans, which is a late manifestation of Lyme borreliosis. Nine of the patients showed pathological ABR, four of them unilaterally and five bilaterally. The main pathological findings were: 1) Poor reproducibility of waves IV-V or of wave V; 2) Increased latency of wave V. After antibiotic treatment, ABR was improved in eight of the nine patients, and in three of them it was normal. In the five patients who did not completely recover, the improvement consisted in better reproducibility and a tendency towards normal wave V latencies. The results of this study indicate that the central nervous system may become involved in patients with acrodermatitis chronica atrophicans.

PMID: 2609097 [PubMed - indexed for MEDLINE]

Am J Clin Pathol. 1989 Jan;91(1):95-7.

Spirochetes in the spleen of a patient with chronic Lyme disease.

Cimmino MA, Azzolini A, Tobia F, Pesce CM.

Istituto Scientifico di Medicina Interna, Università di Genova, Italy.

A 54-year-old man had intermittent evening fever, arthralgia, transient erythematous macular eruption on the skin, and splenomegaly of two year's duration. Immunofluorescence tests for Borrelia burgdorferi serum antibodies had positive results, but G-penicillin treatment was ineffective. Splenectomy with lymph node biopsy was performed to rule out lymphoproliferative disorders. Borrelia-like spirochetes were identified histologically in the spleen; this finding was consistent with persistence of B. burgdorferi organisms in inner organs in chronic Lyme disease.

PMID: 2910019 [PubMed - indexed for MEDLINE]

Monatsschr Kinderheilkd. 1989 Feb;137(2):101-4.

[Neuroborreliosis: progressive encephalomyelitis with cerebral vasculitis]

[Article in German]

Lock G, Berger G, Gröbe H.

Kinderklinik, Stadt Nürnberg.

Encephaloborreliosis is described in a 16 year old patient. Besides the progressive encephalopathy this case presents symptoms and findings of a cerebral vasculitis. During and after antibiotic treatment all clinical symptoms and pathological changes in the cerebrospinal fluid almost completely disappeared.

PMID: 2716736 [PubMed - indexed for MEDLINE]

Trends Neurosci. 1989 May;12(5):177-81.

Lyme disease.

Pachner AR.

Lyme disease is of interest to the neurologist and neuroscientist for a variety of reasons. As more arthropod hosts throughout the world are infected with the causative organism, Borrelia burgdorferi, the illness in humans is becoming more prevalent; in addition, recognition of the disease in humans and susceptible animals is increasing. The neurological manifestations include acute and chronic forms, and it has become clear that B. burgdorferi has joined Treponema pallidum, herpes simplex virus, and human immunodeficiency virus (HIV) as an agent of persistent infection of the brain.

Recent strides in the understanding of antigenic variation in Borrelia have provided insights into how this agent may survive in the human host. Preliminary work in animal models has provided information about the relationships between strain-dependent tropisms, spirochetemia, the development of specific antibody, and nervous system invasion. Finally, the history of the development of understanding of the disease has been a fascinating mixture of parental concern, serendipitous discovery, and correlation of clinical syndromes and serological evaluations across continents.

PMID: 2472690 [PubMed - indexed for MEDLINE]

N Engl J Med. 1989 Aug 31;321(9):586-96.

Lyme disease.

Steere AC.

Division of Rheumatology/Immunology, Tufts University School of Medicine, New England Medical Center, Boston, MA 02111.

Comment in:

N Engl J Med. 1990 Feb 15;322(7):474-5.

Within the last decade, Lyme borreliosis has emerged as a complex new infection whose distribution is worldwide. The disorder is caused by a recently recognized spirochete, B. burgdorferi, transmitted by ticks of the I. ricinus complex. Certain species of mice are critical in the life cycle of the spirochete, and deer appear to be crucial to the tick. Although the disorder's basic outlines are similar everywhere, there are regional variations in the causative spirochete, animal hosts, and clinical manifestations of the illness. In the United States, Lyme disease commonly begins in summer with a characteristic skin lesion, erythema migrans, accompanied by flu-like or meningitis-like symptoms. Weeks or months later, the patients may have neurologic or cardiac abnormalities, migratory musculoskeletal pain, or arthritis, and more than a year after onset, some patients have chronic joint, skin, or neurologic abnormalities. After the first several weeks of infection, almost all patients have a positive antibody response to the spirochete, and serologic determinations are currently the most practical laboratory aid in diagnosis. Treatment with appropriate antibiotics is usually curative, but longer courses of therapy are often needed later in the illness, and some patients may not respond.

PMID: 2668764 [PubMed - indexed for MEDLINE]

Rev Infect Dis. 1989 Sep-Oct;11 Suppl 6:S1518-25.

A perspective on the treatment of Lyme borreliosis.

Luft BJ, Gorevic PD, Halperin JJ, Volkman DJ, Dattwyler RJ.

Department of Medicine, University of New York, Stony Brook 11794-8153.

Lyme borreliosis has become the most common tick-borne infection in the United States. Although both beta-lactam and tetracycline antibiotics have been shown to be effective in the treatment of this spirochetosis, the development of optimal therapeutic modalities has been hampered by the lack of reliable microbiologic or immunologic criteria for the diagnosis or cure of this infection. In vitro sensitivity studies have been performed by several laboratories, but there has been no standardization of the methodology for measuring either inhibitory or bactericidal levels.

Clinical studies have documented the efficacy of antibiotics, but therapy has failed in as many as 50% of cases of chronic infection. Although new antibiotic regimens appear promising, the optimal treatment of this infectious disease remains to be determined. In this report we review the clinical and experimental rationale for the antibiotic regimens that we currently use and the need for a more standardized approach to treatment trials.

PMID: 2682965 [PubMed - indexed for MEDLINE]

Rev Infect Dis. 1989 Sep-Oct;11 Suppl 6:S1487-93.

Clinical pathologic correlations of Lyme disease.

Duray PH.

Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.

The multisystem effects caused by Borrelia burgdorferi in Lyme disease are multiple, varied, and unpredictable. In some patients, the full extent of the infection consists of a stage I acute systemic viral-like illness. Stage II primarily involves the cardiovascular system (myocarditis) and/or the central nervous system (CNS) (meningoencephalitis, polyradiculitis). More inflammatory cells are found in the heart and nervous system structures during this intermediate stage than are found in any tissues involved during stage I. Stage III is characterized by peripheral neuropathy and CNS disorders such as dementia or transverse myelitis and arthritis and synovitis of large joints such as the knee. Chronic Lyme disease is also associated with multiple and seemingly unrelated cutaneous manifestations such as acrodermatitis chronica atrophicans, sclerodermoid-like reactions, lichen sclerosus et atrophicus, subcuticular fibrous nodules, eosinophilic fasciitis-like lesions of the extremities, and, possibly, granuloma annulare. With care, spirochetes can be recovered or demonstrated by silver staining in most of the above lesions. Spirochetes have yet to be seen in the tissues of autonomic ganglia or peripheral nerves.

PMID: 2814170 [PubMed - indexed for MEDLINE]

Infection. 1989 Nov-Dec;17(6):355-9.

Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis.

Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, Prokop J.

Neurologische Klinik Grosshadern, München, FR Germany.

The persistence of Borrelia burgdorferi in patients treated with antibiotics is described. The diagnosis of Lyme disease is based on clinical symptoms, epidemiology and specific IgG and IgM antibody titers to B. burgdorferi in serum. Antibiotic therapy may abrogate the antibody response to the infection as shown in our patients. B. burgdorferi may persist as shown by positive culture in MKP-medium; patients may have subclinical or clinical disease without diagnostic antibody titers to B. burgdorferi. We conclude that early stage of the disease as well as chronic Lyme disease with persistence of B. burgdorferi after antibiotic therapy cannot be excluded when the serum is negative for antibodies against B. burgdorferi.

PMID: 2613324 [PubMed - indexed for MEDLINE]

Rheum Dis Clin North Am. 1989 Nov;15(4):649-56.

Lyme disease: musculoskeletal manifestations.

Kolstoe J, Messner RP.

Section of Rheumatology, University of Minnesota School of Medicine, Minneapolis.

A previously unrecognized musculoskeletal syndrome led to the recognition of this "new" infectious disease. Several distinct patterns of musculoskeletal involvement can be seen throughout the course of untreated Lyme disease. Diffuse, nonspecific muscle achiness and stiffness can be seen early to be followed by characteristically brief, recurrent episodes of LIMP and transient arthritis that help to differentiate LD from other arthropathies. Chronic oligoarticular arthritis is seen in a few. Lyme arthropathy most closely resembles the reactive arthropathies. In a few cases, LD has mimicked other connective tissue disorders such as juvenile rheumatoid arthritis, rheumatoid arthritis, myositis, and scleroderma. It would appear that the full spectrum of musculoskeletal LD is still being defined.

PMID: 2685923 [PubMed - indexed for MEDLINE]

Rheum Dis Clin North Am. 1989 Nov;15(4):679-90.

Lyme disease in children.

Belani K, Regelmann WE.

Lyme disease is an increasing health risk for children. Pediatricians should become familiar with the different clinical syndromes caused by the Borrelia burgdorferi. Appropriate antibiotic therapy must be initiated and follow-up of these children should be a part of the management as some may develop (tertiary) chronic borreliosis. Lyme disease should be considered in the diagnostic work-up of heart block, childhood arthritis and in undiagnosed peripheral and central nervous system disease. Serologic tests appear to be quite specific and sensitive in children with late stage disease in our experience. Newer diagnostic tests to detect infection during the early stage will optimize the management of Lyme disease and further decrease the incidence of long-term sequelae.

PMID: 2685925 [PubMed - indexed for MEDLINE]

Rheum Dis Clin North Am. 1989 Nov;15(4):691-710.

Histopathology of clinical phases of human Lyme disease.

Duray PH.

Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Acute, subacute, or chronic persistent human Lyme borreliosis is an inflammatory disorder composed pathologically of lymphocytes, plasma cells, macrophages, and mast cells. The lymphoplasmocellular infiltrates can at times be seen in the skin, subcutaneous tissues, lymph nodes, spleen, liver, myocardium, brain, autonomic ganglia, and peripheral nerves. The joints in arthritic cases have proliferative synovitis, fibrinaceous deposits, lymphoplasmocellular aggregates, and mast cells. Varying degrees of vascular damage does occur in these sites; however, usually only in late, chronic disease. Spirochetes are present in most sites, in an extracellular location, but are sparse.

PMID: 2685926 [PubMed - indexed for MEDLINE]

Ann Neurol. 1989 Dec;26(6):732-7.

Molecular mimicry and Lyme borreliosis: a shared antigenic determinant between Borrelia burgdorferi and human tissue.

Aberer E, Brunner C, Suchanek G, Klade H, Barbour A, Stanek G, Lassmann H.

Department of Dermatology II, University of Vienna, Austria.

Comment in:

Ann Neurol. 1990 Aug;28(2):195-6.

The pathogenesis of chronic manifestations in Lyme borreliosis, a disease induced by Borrelia burgdorferi, is at present unresolved. By testing monoclonal antibodies directed against various borrelia antigens, we found an antigenic determinant shared by the 41 kDa flagella protein and human tissue, especially prominent on myelinated fibers of human peripheral nerve, on nerve cells and axons of the central nervous system, as well as on certain epithelial cells (including joint synovia) and on heart muscle cells. Immune reactions against such a shared antigen could play a pathogenetic role in chronic organ manifestations of Lyme borreliosis.

PMID: 2481425 [PubMed - indexed for MEDLINE]

Rheum Dis Clin North Am. 1989 Nov;15(4):635-47.

Nervous system manifestations of Lyme disease.

Halperin JJ.

Department of Neurology, State University of New York, Stony Brook.

Neurologic involvement is commonplace in Lyme borreliosis. Neuropathies can be acute or chronic, focal or disseminated, but are predominantly axonal. CNS infection can also be acute or indolent, focal or disseminated; meningitis, encephalitis, and cranial nerve palsies occur. A mild encephalopathy is also common, but only occasionally due to CNS infection.

PMID: 2555847 [PubMed - indexed for MEDLINE]

Rev Infect Dis. 1989 Sep-Oct;11 Suppl 6:S1460-9.

Epidemiology and clinical similarities of human spirochetal diseases.

Schmid GP.

Division of Sexually Transmitted Diseases, Centers for Disease Control, Atlanta, Georgia 30333.

Lyme disease, first identified in 1975, is the most recently recognized of the seven human spirochetal diseases; the evolving clinical picture of Lyme disease indicates it shares many features with the other diseases. These similarities are striking in view of the diverse epidemiology of the seven diseases, which are caused by Treponema species (spread by human-to-human contact) or Leptospira or Borrelia species (zoonoses). These similarities include the following: (1) skin or mucous membrane as portal of entry; (2) spirochetemia early in the course of disease, with wide dissemination through tissue and body fluid; and (3) one or more subsequent stages of disease, often with intervening latent periods. Lyme disease shares with many spirochetal diseases a tropism for skin and neurologic and cardiovascular manifestations, whereas chronic arthritis is unique to Lyme disease. These similarities and dissimilarities offer opportunities to discover which properties unique to the pathogenic spirochetes are responsible for clinical manifestations and suggest that certain clinical features of patients with spirochetal diseases other than Lyme disease may someday be recognized in patients with Lyme disease.

PMID: 2682958 [PubMed - indexed for MEDLINE]

Rheum Dis Clin North Am. 1989 Nov;15(4):747-55.

Treatment of Lyme borreliosis.

Luft BJ, Dattwyler RJ.

Department of Medicine, State University of New York, Stony Brook.

The infectious process of Lyme disease can appear as chronic dermatologic, rheumatologic, or neurologic. To rationally select a treatment regimen, the physician must have an appreciation of the clinical manifestations of the illness and of the systemic nature of the infection. The authors discuss the proper treatment protocols for each stage in the progression of Lyme disease.

PMID: 2555849 [PubMed - indexed for MEDLINE]

Rheum Dis Clin North Am. 1989 Nov;15(4):747-55.

Treatment of Lyme borreliosis.

Luft BJ, Dattwyler RJ.

Department of Medicine, State University of New York, Stony Brook.

The infectious process of Lyme disease can appear as chronic dermatologic, rheumatologic, or neurologic. To rationally select a treatment regimen, the physician must have an appreciation of the clinical manifestations of the illness and of the systemic nature of the infection. The authors discuss the proper treatment protocols for each stage in the progression of Lyme disease.

PMID: 2555849 [PubMed - indexed for MEDLINE]

Lucy Barnes