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LYME DISEASE AND MULTIPLE SCLEROSIS: TRICKY AND SERIOUS MEDICINE

I am not an expert in either disorder. I try to read passionately and study both. Here is my concern. First, the routine labs used to diagnosis Lyme and the common other tick infections Bartonella, Babesia and Ehrlichia are really poor and have been dummied down to meet some pre-determined frequency. Very smart and sincere neurologists and infection physicians are expecting a solid large national lab to be as good with these tests as they are with other types of tests. The fact is they are often exceptional with some types of lab testing, and most are terrible at tick and flea-borne infection testing. I am sorry to find this and I take no pride or joy in reporting this is my finding when I test patients with a certain infections and the blinded lab misses it — sometimes up to 6x.

Lyme disease is very common and it can easily cause antibodies against the myelin sheath or the fat around nerves. Multiple Sclerosis is a real and serious illness.

Finally, it is possible in some patients both are present.

The material below is just meant to increase reflection so that a quick diagnosis does not happen to anyone, and any diagnosis is constantly revisited each year, since the treatments differ profoundly for each illness.


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Erratum in:
  • J Neurol. 2008 May;255(5):782.

CSF B--lymphocyte chemoattractant (CXCL13) in the early diagnosis of acute Lyme neuroborreliosis.

Ljżstad U, Mygland A.

Dept. of Neurology, Sżrlandet Sykehus HF, Kristiansand Serviceboks 416, 4604 Kristiansand, Norway. unn.ljostad@sshf.no

Recent studies have suggested a diagnostic role of the B-lymphocyte attracting chemokine (CXCL13) in the cerebrospinal fluid (CSF) in Lyme neuroborreliosis (LNB). Our aim was to evaluate diagnostic accuracy of CSF CXCL13 in a cohort of 59 consecutive patients referred to hospital for suspected LNB. Thirty-seven patients were classified as definite LNB and used as the reference standard. Seven were classified as probable, and seven as possible LNB. Eight patients did not fulfil case definitions and were used as controls.At presentation, CSF CXCL13 was elevated in all patients with definite LNB, as compared to a positive CSF B. burgdorferi (Bb) antibody index (AI) in 33 of 37. Pre-treatment sensitivity of elevated CSF [corrected] Bb Al [corrected] was 100 % (95 % CI = 91-100) and 89 % [corrected] (95 % CI = 75-96) respectively (p = 0.053). Among the eight control patients, CSF CXCL13 was normal in five and only slightly elevated in three, and Bb AI was negative in five. Specificity of CSF CXCL13 and Bb AI was similar 63 % (95 % CI = 31-86) (p = 1.0).CSF CXCL13 was elevated in 6/7 patients with probable LNB and 3/7 patients with possible LNB. Bb AI was negative in all these 14 patients.An additional control group consisted of 31 patients with multiple sclerosis (MS), 11 with non-inflammatory neurological diseases, and ten with verified non-Lyme meningitis and high CSF cell count. CSF CXCL13 was slightly elevated in 15 MS patients, and in nine meningitis patients. Mean CSF CXCL13 was higher in definite LNB (3524 ng/g CSF protein) than in MS (27 ng/g) and non-Lyme meningitis (23 ng/g) (p < 0.001).Four months post-treatment CSF CXCL13 was normalized in 82 % of patients with definite LNB, as compared to a negative Bb AI in 10 % (p < 0.001).CSF CXCL13 may be a useful supplement in early diagnosis of acute LNB.

Publication Types:
PMID: 18344056 [PubMed - indexed for MEDLINE]

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Hypothesized role of galactocerebroside and NKT cells in the etiology of multiple sclerosis.

Blewett MM.

Harvard College, 1129 Harvard Yard Mail Center, Cambridge, United States. mblewett@fas.harvard.edu

According to the molecular mimicry theory, multiple sclerosis (MS) develops when the immune system mistakenly attacks a component of the myelin sheath that is structurally similar to a foreign epitope. The glycolipid galactocerebroside (GalC) is a major component of myelin. As lipids comprise between 70% and 85% of myelin, glycolipids should be investigated as candidate autoantigens in MS. GalC displays broad structural similarities to the Borrelia burgdorferi glycolipid antigen BbGL-2 and to the Sphingomonas antigen GalAGSL. In principle, therefore, these bacteria may induce an autoimmune attack on the myelin sheath. GalC is also structurally similar to natural killer T (NKT) cell ligand alpha-galactosylceramide (alpha-GalCer). Further studies must be performed to clarify the role of GalC in the activation of NKT cells and the development of MS.

PMID: 17889444 [PubMed - indexed for MEDLINE]

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Lyme borreliosis and multiple sclerosis are associated with primary effusion lymphoma.

Batinac T, Petranovic D, Zamolo G, Petranovic D, Ruzic A.

Department of Dermatovenerology, Rijeka University Hospital, Kresimirova 42, 51000 Rijeka, Croatia.

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by chronic inflammation and demyelination. Studies suggested that the viral, especially Epstein-Barr virus infection, and bacterial infections, especially Borrelia burgdorferi infection, play a role in etiology of MS. MS prevalence parallels the distribution of the Lyme disease pathogen B. burgdorferi. Criteria used for diagnosis of MS can also be fulfilled in other conditions such as Lyme disease, a multisystem disorder resulting from infection by the tick-borne spirochete, B. burgdorferi. In the late period of Lyme disease demyelinating involvement of central nervous system can develop and MS can be erroneously diagnosed. A Lyme borreliosis can mimick central nervous system lymphoma. Also, B. burgdorferi has been implicated not only in etiology of MS, but also in etiology of lymphoma. Studies suggested that there is an increased risk of non-Hodgkin lymphoma in patients, who had a history of autoimmune diseases such as MS and that both non-Hodgkin's lymphomas and Hodgkin's disease were associated with Epstein-Barr virus infection. A small group of lymphomas called primary effusion lymphomas (PEL) is a recently individualized form of non-Hodgkin's lymphoma (WHO classification) that exhibit exclusive or dominant involvement of serous cavities, without a detectable solid tumor mass. These lymphomas have also been linked to Epstein-Barr virus and human herpes virus type 8 infections but virus negative cases have been described. Therefore, we propose that MS and neuroborreliosis are linked to central nervous system primary effusion lymphomas. As a first step in confirming or refuting our hypotheses, we suggest a thorough study of CSF in the patients suspected for the diagnosis of MS and Lyme borreliosis.

PMID: 17197115 [PubMed - indexed for MEDLINE]

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Motion-onset and pattern-reversal visual evoked potentials in diagnostics of neuroborreliosis.

Kubov‡ Z, Szanyi J, Langrov‡ J, Kreml‡cek J, Kuba M, Honegr K.

Department of Pathophysiology, Charles University in Prague, Faculty of Medicine in Hradec Kr‡lovŽ, Czech Republic. kubova@lfhk.cuni.cz

Neuroborreliosis is a form of borreliosis that affects the central and/or peripheral nervous system. Although it can mimic neurologic and ophthalmologic disorders such as multiple sclerosis and optic neuritis, visual evoked potential (VEP) examination is usually not used in neuroborreliosis diagnostics. Combined VEP testing (pattern-reversal VEPs and VEPs produced in response to linear and radial motion) was performed in 81 patients with neuroborreliosis verified by laboratory results (positive polymerase chain reaction or intrathecal antibodies production). Thirty-four patients reported diplopia or blurred vision related to borreliosis. In 33 (40%) patients the VEPs were delayed: motion-onset VEPs were pathologic in 22 (27%) patients, reversal VEPs in 5 (6%) patients, and both VEP types in 6 (7%) patients. The findings suggest that VEP testing (especially the motion-onset VEP testing) can confirm CNS involvement. Much higher sensitivity of motion-onset VEPs in comparison with reversal VEPs can result from rather selective (earlier) involvement of the magnocellular system or the dorsal stream of the visual pathway.

Publication Types:
PMID: 17016151 [PubMed - indexed for MEDLINE]

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Immunophenotypic patterns of T-cell activation in neuroinflammatory diseases.

Heinrich A, Ahrens N, Schmidt S, Khaw AV.

Department of Neurology, University of Greifswald, Greifswald, Germany. alexander.heinrich@bkh-guenzburg.de

OBJECTIVES: We aimed to gain insights into the pathogen-specific differences in early adaptive immune responses following central nervous system infections with Borrelia burgdorferi and viral pathogens by studying the immunophenotypic patterns of T-cell activation. Moreover, we wished to determine whether the expression of T-cell activation markers reflects disease activity in multiple sclerosis (MS). METHODS: Proportions of cerebrospinal fluid T-cells expressing the markers HLA-DR, CD25 and CD38 were determined in patients with MS (n = 40), acute viral meningomyeloradiculoneuritis (VID, n = 26), early neuroborreliosis (NB, n = 23) and non-inflammatory neurologic diseases (n = 51) by using flow cytometry. In relapsing-remitting MS, disease activity was assessed by clinical examination and magnetic resonance imaging. RESULTS: For each of the surface markers that were examined, significant differences in T cell proportions were found between patient groups. The proportion of HLA-DR+ T cells was higher and that of CD25+ T cells lower in NB compared with VID. These differences were attributable only to the early phase of the disease (< or = 6 days after symptom onset). Among MS patients, there was a trend for higher proportions of T cells expressing activation markers in patients with gadolinium-enhancing lesions. CONCLUSIONS: The decreased CD25 expression in NB may reflect immunomodulatory effects of B. burgdorferi facilitating persistent infection. Larger prospective studies of T-cell activation markers for ascertaining the association between cellular markers and clinical surrogates of disease activity in MS are warranted.

PMID: 16542164 [PubMed - indexed for MEDLINE]

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Neuralgia and demyelinating plaques: MS or lyme disease?

Savely G.

South Austin Family Practice Clinic, Austin, Texas, USA.

Publication Types:
PMID: 16152811 [PubMed - indexed for MEDLINE]

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Relevance of immunological variables in neuroborreliosis and multiple sclerosis.

Bedn‡rov‡ J, Stourac P, Adam P.

Department of Clinical Microbiology, Faculty Hospital, Masaryk University, Brno, Czech Republic.

OBJECTIVES: The aims were to investigate the frequency of intrathecal synthesis of specific antibodies against measles (M), rubella (R) and varicella zoster (Z) viruses (MRZ reaction) as a diagnostic marker between multiple sclerosis (MS) and neuroborreliosis (NB) groups and to postulate the most typical cerebrospinal fluid (CSF) variables profile of these entities. METHODS: Three cohorts of patients were investigated: MS (n = 42), NB (n = 27) and other neurological diseases (OND) (n = 15). Measles, rubella, varicella zoster and borrelia-specific IgG antibodies were measured by ELISA, Q(alb) (CSF/serum albumin ratio) as a marker of blood-CSF barrier function and specific antibody indices (AI) were calculated according to relevant formulae. IgG oligoclonal bands (OB) were detected by isoelectric focusing and immunoenzymatic staining. RESULTS: Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive anti-borrelia AI. Eighty-nine percent of NB patients had positive anti-borrelia AI and two patients had individually anti-measles and rubella positive AI. MS-CSF variables profile included the presence of IgG OB in 81%, elevated Q(alb) in 31% and normal cell count in 66.7%. Of NB patients IgG OB were positive in 74%, elevated Q(alb) in 81.5% and normal cell count in 7.4%. CONCLUSION: MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB. Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.

PMID: 16008535 [PubMed - indexed for MEDLINE]

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Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis.

Cepok S, Rosche B, Grummel V, Vogel F, Zhou D, Sayn J, Sommer N, Hartung HP, Hemmer B.

Department of Neurology, Heinrich Heine-University, Duesseldorf, Germany.

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology. Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation in multiple sclerosis patients.

Publication Types:
PMID: 15800022 [PubMed - indexed for MEDLINE]

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Diagnosis of Lyme borreliosis using enzyme immunoanalysis.

Cermakova Z, Ryskova O, Honegr K, Cermakova E, Hanovcova I.

Department of Clinical Microbiology, Faculty of Medicine in Hradec Kr‡lovŽ, Charles University of Prague, Czech Republic. cermakovaz@fnhk.cz

BACKGROUND: Antiborrelia antibodies in Lyme borreliosis (LB) are mostly detected by enzyme immunoassay (EIA), confirmed by immunoblot (the "two-step system"). In indicated cases, direct evidence of Borrelia burgdorferi is obtained with the PCR method, electron microscopy and cultivation. The "one-step system" of testing for IgM and IgG antibodies in LB is economically preferably, but it requires an EIA kit with more than 90% sensitivity and specificity. MATERIAL/METHODS: 90 blood samples were collected, 54 from patients with clinically defined LB and 36 samples from individuals free of LB. IgM and IgG antibodies against Borrelia burgdorferi were detected in parallel with five different EIA kits from various producers. The results were verified clinically in all cases, in disputable cases with additional immunoblot (BAG-Med), and analyzed statistically. RESULTS: Specificity and sensitivity were calculated from the measured values, and diagnostic efficiency was determined for each EIA kit. EIA kits for antiborrelia antibody assay with high specificity have low sensitivity and vice versa. In 9 samples from patients with clinical diagnoses (multiple sclerosis, Parkinson disease, epilepsy, rheumatoid arthritis) we found false positives in EIA and WB tests. CONCLUSIONS: The best results for a "one-step system" of examinations for antiborrelia antibodies were obtained with the Abbot and Euroimmun EIA kits in our set. A "two-step system" of serological examination could be composed from the basic IgM and IgG examination with a high sensitivity EIA kit (Viroimmun, Test-Line) followed with confirmation of positives by specific immunoblot.

PMID: 15795690 [PubMed - indexed for MEDLINE]

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Chronic Lyme borreliosis at the root of multiple sclerosis--is a cure with antibiotics attainable?

Fritzsche M.

Clinic for Internal and Geographical Medicine, Soodstrasse 13, 8134 Adliswil, Switzerland. markus.fritzsche@gmx.ch

Apart from its devastating impact on individuals and their families, multiple sclerosis (MS) creates a huge economic burden for society by mainly afflicting young adults in their most productive years. Although effective strategies for symptom management and disease modifying therapies have evolved, there exists no curative treatment yet. Worldwide, MS prevalence parallels the distribution of the Lyme disease pathogen Borrelia (B.) burgdorferi, and in America and Europe, the birth excesses of those individuals who later in life develop MS exactly mirror the seasonal distributions of Borrelia transmitting Ixodes ticks. In addition to known acute infections, no other disease exhibits equally marked epidemiological clusters by season and locality, nurturing the hope that prevention might ultimately be attainable. As minocycline, tinidazole and hydroxychloroquine are reportedly capable of destroying both the spirochaetal and cystic L-form of B. burgdorferi found in MS brains, there emerges also new hope for those already afflicted. The immunomodulating anti-inflammatory potential of minocycline and hydroxychloroquine may furthermore reduce the Jarisch Herxheimer reaction triggered by decaying Borrelia at treatment initiation. Even in those cases unrelated to B. burgdorferi, minocycline is known for its beneficial effect on several factors considered to be detrimental in MS. Patients receiving a combination of these pharmaceuticals are thus expected to be cured or to have a longer period of remission compared to untreated controls. Although the goal of this rational, cost-effective and potentially curative treatment seems simple enough, the importance of a scientifically sound approach cannot be overemphasised. A randomised, prospective, double blinded trial is necessary in patients from B. burgdorferi endemic areas with established MS and/or Borrelia L-forms in their cerebrospinal fluid, and to yield reasonable significance within due time, the groups must be large enough and preferably taken together in a multi-centre study.

PMID: 15617845 [PubMed - indexed for MEDLINE]

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[Virological and immunological indices in patients with multiple sclerosis]

[Article in Russian]

Agafonov AP, Kameneva SN, Agafonova OA, Neverov AA, Ignat'ev GM.

The level of specific antibodies to viruses of measles, parotitis, type-6 herpes, Epstein-Barr, tick-borne encephalitis and Borrelia burgdorferi as well as presence of genetic samples and antigens of the above infectious antigens were studied in patients with multiple sclerosis (MS). The cytokines Th1 and Th2 parameters were investigated in blood serum of patients at different MS stages. The titer of antibodies to measles virus was noted to be increasing in MS patients with age and disease aggravation. The level of antibodies to any of the studied infectious agents, except for the type-6 herpes virus, was not dynamically changing for as long as 9 months. The viral genetic samples (measles RNA) were detected just once in 2 patients; the detection time coincided in both cases with MS aggravation. The cytokines dynamics failed to correlate with MS aggravation or exacerbation while the total index of all studied cytokines was decreased. A high MMPw 9 content in blood serum correlated with MS exacerbation in 1 patient.

Publication Types:
PMID: 15455682 [PubMed - indexed for MEDLINE]

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Comment in:
Comment on:
Lyme borreliosis: perspective of a scientist-patient.

Hamlen R.

rhamlen@iximd.com <rhamlen@iximd.com>

Publication Types:
PMID: 15451481 [PubMed - indexed for MEDLINE]

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Isolated monolateral neurosensory hearing loss as a rare sign of neuroborreliosis.

Iero I, Elia M, Cosentino FI, Lanuzza B, Spada RS, Toscano G, Tripodi M, Belfiore A, Ferri R.

Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging, Via Conte Ruggero 73, I-94018 Troina (EN), Italy. ivaniero@oasi.en.it

Lyme disease, or borreliosis, is a zoonosis transmitted by Borrelia burgdorferi which also involves the central nervous system (CNS), in 15% of affected individuals, with the occurrence of aseptic meningitis, fluctuating meningoencephalitis, or neuropathy of cranial and peripheral nerves. Encephalopathy with white matter lesions revealed by magnetic resonance imaging (MRI) scans in late, persistent stages of Lyme disease has been described. In this report, we describe a patient with few clinical manifestations involving exclusively the eighth cranial nerve, monolaterally and diffuse bilateral alterations of the white matter, particularly in the subcortical periventricular regions at cerebral MRI. This single patient study shows that the search for antibodies against Borrelia burgdoferi should always be performed when we face a leukoencephalopathy of unknown origin. An isolated lesion of the eighth cranial nerve can be the only neurologic sign in patients with leukoencephalopathy complicating Lyme disease.

Publication Types:
PMID: 15060815 [PubMed - indexed for MEDLINE]

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Intrathecal antibody production against Borrelia burgdorferi in a patient with relapsing-remitting multiple sclerosis.

Hartmann M, Pfadenhauer K.

Publication Types:
PMID: 14641530 [PubMed - indexed for MEDLINE]

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Geographical and seasonal correlation of multiple sclerosis to sporadic schizophrenia.

Fritzsche M.

Clinic for Internal Medicine, Soodstrasse 13, 8134 Adliswil, Switzerland. markus.fritzsche@bluewin.ch

BACKGROUND: Clusters by season and locality reveal a striking epidemiological overlap between sporadic schizophrenia and multiple sclerosis (MS). As the birth excesses of those individuals who later in life develop schizophrenia mirror the seasonal distribution of Ixodid ticks, a meta analysis has been performed between all neuropsychiatric birth excesses including MS and the epidemiology of spirochaetal infectious diseases. RESULTS: The prevalence of MS and schizophrenic birth excesses entirely spares the tropical belt where human treponematoses are endemic, whereas in more temperate climates infection rates of Borrelia garinii in ticks collected from seabirds match the global geographic distribution of MS. If the seasonal fluctuations of Lyme borreliosis in Europe are taken into account, the birth excesses of MS and those of schizophrenia are nine months apart, reflecting the activity of Ixodes ricinus at the time of embryonic implantation and birth. In America, this nine months' shift between MS and schizophrenic births is also reflected by the periodicity of Borrelia burgdorferi transmitting Ixodes pacificus ticks along the West Coast and the periodicity of Ixodes scapularis along the East Coast. With respect to Ixodid tick activity, amongst the neuropsychiatric birth excesses only amyotrophic lateral sclerosis (ALS) shows a similar seasonal trend. CONCLUSION: It cannot be excluded at present that maternal infection by Borrelia burgdorferi poses a risk to the unborn. The seasonal and geographical overlap between schizophrenia, MS and neuroborreliosis rather emphasises a causal relation that derives from exposure to a flagellar virulence factor at conception and delivery. It is hoped that the pathogenic correlation of spirochaetal virulence to temperature and heat shock proteins (HSP) might encourage a new direction of research in molecular epidemiology.

PMID: 12537588 [PubMed - as supplied by publisher]

PMCID: PMC149400


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Comment in:
Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders.

Muraro PA, Wandinger KP, Bielekova B, Gran B, Marques A, Utz U, McFarland HF, Jacobson S, Martin R.

Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, MD 20892-1400, USA. murarop@ninds.nih.gov

T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.

Publication Types:
PMID: 12477694 [PubMed - indexed for MEDLINE]

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Multiple sclerosis and Lyme borreliosis.

Schmutzhard E.

Department of Neurology, University Hospital, Innsbruck, Austria. erich.schmutzhard@uibk.ac.at

In a deductive approach the two disease entities of multiple sclerosis and chronic progressive neuroborreliosis are discussed. Various clinical features, seroepidemiology, neuroimaging, CSF findings, CSF serology, specific proteins within the CSF and antibodies against neuronal structures as well as the most recent findings of different dendritic cells within the CSF are discussed as a means of differentiating these two disease entities.

Publication Types:
PMID: 12422598 [PubMed - indexed for MEDLINE]

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Bacterial infection as a cause of multiple sclerosis.

Wolfson C, Talbot P.

Department of Epidemiology and Biostatistics, McGill University, and Centre for Clinical Epidemiology and Community Studies, Lady Davis Institute for Medical Research, Quebec, Montreal, Canada. tinaw@epid.jgh.mcgill.ca

PMID: 12241771 [PubMed - indexed for MEDLINE]

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[The Multiple Sclerosis Documentation System MSDS. Discussion of a documentation standard for multiple sclerosis]

[Article in German]

Pette M, Eulitz M.

Neurologische UniversitŠtsklinik, Klinikum Carl Gustav Carus, Technische UniversitŠt Dresden, Fetscherstrasse 74, 01307 Dresden.

The MSDS (multiple sclerosis documentation system) has been developed at the Department of Neurology, Technical University of Dresden, Germany, during the last 4 years. The first version of this database application has been in use since October 2000. The MSDS manages information on MS patients, their treating physicians, patient history (symptoms, other diseases, biographical history, family history, habits, medication), clinical signs, results of laboratory examinations (blood chemistry, autoantibodies, borrelia serology, evoked potentials, cranial and spinal cord magnetic resonance imaging), clinical scores relevant for MS, and biosamples. In principle, MSDS allows online data input and semiautomatically generates reports to all general practitioners and neurologists treating the respective patient. Patient information sheets and internal treatment guidelines are part of the system. During a 3-month evaluation, the first version of MSDS was tested at eight university multiple sclerosis ambulatory care units and one general neurology hospital. The overall judgement was favorable. Suggestions for changes and improvements, as well as practical experiences, were considered when developing MSDS 2.0, which will be available by the end of 2001.

Publication Types:
PMID: 11975090 [PubMed - indexed for MEDLINE]

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[Multiple sclerosis. Chlamydia hypothesis in debate]

[Article in German]

Derfuss T, Hohlfeld R, Meinl E.

Abteilung fźr Neuroimmunologie, Max-Planck-Institut fźr Neurobiologie, Am Klopferspitz 18A, 82152 Martinsried.

Recently, an association between multiple sclerosis and Chlamydia pneumoniae infection has been suggested. Because standardized PCR protocols are lacking, a series of studies could not clarify whether C. pneumoniae is present in brain tissue and CSF of MS patients. Therefore, other studies focused on the humoral immune response against C. pneumoniae: 24% of MS patients, but only 5% of the control patients showed intrathecally produced antibodies against C. pneumoniae. If an infection with C. pneumoniae was involved in the pathogenesis of MS, one would expect that, in analogy to other infections of the CNS, the oligoclonal bands in the CSF of MS patients would recognize the responsible agent. However, the results we obtained by affinity-mediated immunoblots showed that the oligoclonal bands in the CSF of MS patients are not directed against Chlamydia antigen. In contrast to this, we found that the immunoglobulins in the CSF of neuroborreliosis patients reacted strongly against Borrelia antigen in the affinity-mediated immunoblots. In light of these results we assume that the intrathecal immunoglobulin production against C. pneumoniae is part of a polyspecific immune response. Thus, it is not likely that C. pneumoniae is causally linked to the pathogenesis of multiple sclerosis.

Publication Types:
PMID: 11688186 [PubMed - indexed for MEDLINE]

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Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry?

Benoist C, Mathis D.

Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Place, Boston, MA, USA. cbdm@joslin.harvard.edu

Autoimmune diseases remain one of the mysteries that perplex immunologists. What makes the immune system, which has evolved to protect an organism from foreign invaders, turn on the organism itself? A popular answer to this question involves the lymphoid network's primordial function: autoimmunity is a by-product of the immune response to microbial infection. For decades there have been tantalizing associations between infectious agents and autoimmunity: beta-hemolytic streptococci and rheumatic fever; B3 Coxsackieviruses and myocarditis; Trypanosoma cruzi and Chagas' disease; diverse viruses and multiple sclerosis; Borrelia burgdorfii and Lyme arthritis; and B4 Coxsackievirus, cytomegalovirus or rubella and type 1 diabetes, to name the most frequently cited examples. In addition, animal models have provided direct evidence that infection with a particular microbe can incite a particular autoimmune disease. Nonetheless, many of the associations appear less than convincing and, even for those that seem to be on solid footing, there is no real understanding of the underlying mechanism(s).

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PMID: 11526389 [PubMed - indexed for MEDLINE]

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Use of serum immune complexes in a new test that accurately confirms early Lyme disease and active infection with Borrelia burgdorferi.

Brunner M, Sigal LH.

Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

The present recommendation for serologic confirmation of Lyme disease (LD) calls for immunoblotting in support of positive or equivocal ELISA. Borrelia burgdorferi releases large quantities of proteins, suggesting that specific antibodies in serum might be trapped in immune complexes (ICs), rendering the antibodies undetectable by standard assays using unmodified serum. Production of ICs requires ongoing antigen production, so persistence of IC might be a marker of ongoing or persisting infection. We developed an immunoglobulin M (IgM) capture assay (EMIBA) measuring IC-derived IgM antibodies and tested it using three well-defined LD populations (from an academic LD referral center, a well-described Centers for Disease Control and Prevention (CDC) serum bank, and a group of erythema migrans patients from whose skin lesions B. burgdorferi was grown) and controls (non-Lyme arthritis inflammatory joint disease, syphilis, multiple sclerosis, and nondisease subjects from a region where LD is endemic, perhaps the most relevant comparison group of all). Previous studies demonstrated that specific antigen-antibody complexes in the sera of patients with LD could be precipitated by polyethylene glycol and could then be disrupted with maintenance of the immunoreactivity of the released antibodies, that specific anti-B. burgdorferi IgM was concentrated in ICs, and that occasionally IgM to specific B. burgdorferi antigens was found in the IC but not in unprocessed serum. EMIBA compared favorably with commercial and CDC flagellin-enhanced enzyme-linked immunosorbent assays and other assays in confirming the diagnosis of LD. EMIBA confirmed early B. burgdorferi infection more accurately than the comparator assays. In addition, EMIBA more accurately differentiated seropositivity in patients with active ongoing infection from seroreactivity persisting long after clinically successful antibiotic therapy; i.e., EMIBA identified seroreactivity indicating a clinical circumstance requiring antibiotic therapy. Thus, EMIBA is a promising new assay for accurate serologic confirmation of early and/or active LD.

Publication Types:
PMID: 11526153 [PubMed - indexed for MEDLINE]

PMCID: PMC88321


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Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.

Derfuss T, Gźrkov R, Then Bergh F, Goebels N, Hartmann M, Barz C, Wilske B, Autenrieth I, Wick M, Hohlfeld R, Meinl E.

Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany.

Chronic intrathecal immunoglobulin (Ig) production is a hallmark of multiple sclerosis characterized by the presence of oligoclonal IgGs and, in addition, polyspecific recognition of different pathogens such as measles, rubella and herpes zoster virus. While the antigen specificity of the oligoclonal IgGs in multiple sclerosis is largely unknown, the oligoclonal IgGs arising during CNS infectious diseases are reactive against the specific pathogen. Recently, a link between Chlamydia pneumoniae and multiple sclerosis has been claimed. To test the possible role of C. pneumoniae in multiple sclerosis, we analysed (i) whether there is intrathecal IgG production against C. pneumoniae in multiple sclerosis and (ii) if the oligoclonal IgGs in the CSF of multiple sclerosis patients recognize C. pneumoniae. By studying paired serum-CSF samples from 120 subjects (definite multiple sclerosis, 46; probable multiple sclerosis, 12; other inflammatory neurological diseases, 35; other neurological diseases, 27) by enzyme-linked immunosorbent assay, we found that 24% of all patients with definite multiple sclerosis, but only 5% of patients with other inflammatory or non-inflammatory diseases, produced IgGs specific for C. pneumoniae intrathecally (definite multiple sclerosis versus other inflammatory neurological diseases: P = 0.027). The presence of intrathecal IgGs to C. pneumoniae was independent of the duration of disease and relatively stable over time. The major CSF oligoclonal IgG bands from multiple sclerosis patients with an intrathecal Ig production to C. pneumoniae did not react towards purified elementary bodies and reticulate bodies of C. pneumoniae on affinity-mediated immunoblot following isoelectric focusing (IEF-western blots). In contrast, the IgGs in the CSF of control patients with neuroborreliosis strongly reacted with their specific pathogen, Borrelia burgdorferi, by IEF-western blot analysis. Concomitant analysis of the CSF of 23 patients with a nested polymerase chain reaction for C. pneumoniae was negative in all cases. Together, our findings strongly suggest that the immune response to C. pneumoniae is part of a polyspecific intrathecal Ig production, as is commonly observed with other pathogens. This argues against a specific role for C. pneumoniae in multiple sclerosis.

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PMID: 11408328 [PubMed - indexed for MEDLINE]

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Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study.

Chmielewska-Badora J, Cisak E, Dutkiewicz J.

Department of Occupational Biohazards, Institute of Agricultural Medicine, Jaczewskiego 2, 20-090 Lublin, Poland.

A total of 769 adult neurological patients hospitalised in clinics and hospitals situated in the Lublin region (eastern Poland) were examined during the years 1997-2000 with ELISA test for the presence of anti-Borrelia burgdorferi sensu lato antibodies. A statististically significant (p=0.0422) relationship was found between the clinically confirmed diagnosis of multiple sclerosis and the positive serologic reaction with Borrelia antigen. Ten out 26 patients with multiple sclerosis (38.5%) showed positive serologic reaction to Borrelia, whereas among the total number of examined neurological patients the frequency of positive findings was twice as low (19.4%). The result suggests that multiple sclerosis may be often associated with Borrelia infection

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PMID: 11153045 [PubMed - indexed for MEDLINE]

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Mechanisms of immunomodulation by glatiramer acetate.

Gran B, Tranquill LR, Chen M, Bielekova B, Zhou W, Dhib-Jalbut S, Martin R.

Cellular Immunology Section, Neuroimmunology Branch, NINDS, NIH, Bethesda, MD 20892, USA.

OBJECTIVE: To define the mechanism of action of glatiramer acetate (GA; formerly known as copolymer-1) as an immunomodulatory treatment for MS. BACKGROUND: The proposed mechanisms of action of GA include 1) functional inhibition of myelin-reactive T cells by human leukocyte antigen (HLA) blocking, 2) T-cell receptor (TCR) antagonism, and 3) induction of T helper 2 (Th2) immunomodulatory cells. In this report, the authors examined the effects of GA on the functional activation of human T-cell clones (TCC) specific for myelin basic protein (MBP) and for foreign antigens. Several questions were addressed: Is the inhibitory effect of GA specific for autoantigens? Is it mediated by blocking the interaction between peptide and HLA molecule? Is GA a partial agonist or TCR antagonist, or does it induce anergy? Does it induce Th2 modulatory T cells? METHODS: The effects of GA on antigen-induced activation of human TCC specific for MBP, influenza virus hemagglutinin, and Borrelia burgdorferi were studied by proliferation and cytokine measurements, TCR downmodulation, and anergy assays. GA-specific TCC were generated in vitro from the peripheral blood of patients and healthy controls by limiting dilution. RESULTS: GA more strongly inhibited the proliferation of MBP, as compared with foreign antigen-specific TCC; in some MBP-specific TCC, the production of Th1-type cytokines was preferentially inhibited. In addition to HLA competition, the induction of anergy, but not direct TCR antagonism, was observed. Numerous GA-specific TCC were generated from the peripheral blood of both MS patients and normal controls, and a fraction of these showed a Th2 phenotype. CONCLUSIONS: This study confirms a preferential inhibitory effect of GA on autoreactive TCC. With respect to cellular mechanisms, although HLA competition appears to play the most important role in functional inhibition in vitro, a direct effect on the TCR may be involved at least in some autoreactive T cells as shown by anergy induction. Although not confirmed at the clonal level, it is demonstrated further that GA induces T cells that crossreact with myelin proteins. GA-specific, Th2-modulatory cells may play an important role in mediating the effect of the drug in vivo.

Publication Types:
PMID: 11113226 [PubMed - indexed for MEDLINE]

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Chorea as a symptom of neuroborreliosis: a case study.

Piccolo I, Thiella G, Sterzi R, Colombo N, Defanti CA.

Division of Neurology, Hospital Niguarda Ca' Granda, Milan, Italy.

Borrelia burgdorferi (Bb) can cause a large number of neurological symptoms. Although extrapyramidal disturbances are rare (representing less than 2% of all neurological complications), diffuse choreic dyskinesias have been described during the course of mild encephalitis. The data published in the literature suggest that there are clinical and neurological analogies between neuroborreliosis and multiple sclerosis (MS). The presence of specific anti-Bb antibodies in cerebrospinal fluid is a discriminating factor that allows a diagnosis of neuroborreliosis to be made. We describe the case of a patient with Lyme disease, characterised by widespread chorea and behavioural disturbances. Emphasis is placed on the atypical onset and evolution, the difficulties encountered in formulating a diagnosis, and the uncertainties concerning the pathophysiology and clinical/neuroradiological correlations of the disease.

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PMID: 10933464 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi induces matrix metalloproteinases by neural cultures.

Perides G, Tanner-Brown LM, Eskildsen MA, Klempner MS.

Tupper Research Institute, Department of Medicine, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts. gperides@caregroup.harvard.edu

Matrix metalloproteinases (MMPs) are associated with chronic neurologic diseases such as multiple sclerosis and senile dementia. Lyme disease is a multisystemic infection involving the nervous system, skin, joints, and heart. Neurologic manifestations of chronic Lyme disease include encephalopathy and cranial and peripheral neuropathy. Borrelia burgdorferi, the spirochaete causing Lyme disease, has been cultured from the cerebrospinal fluid (CSF), and B. burgdorferi DNA is frequently detected in the CSF of patients with Lyme neuroborreliosis. We used cerebral and cerebellar primary cultures to determine whether B. burgdorferi induces the production of MMPs by primary neural cultures. B. burgdorferi in a dose- and time-dependent manner induced the expression of MMP-9 by primary neural cultures but had no effect on the expression of MMP-2. Human and rat type I astrocytes expressed MMP-9 when incubated with B. burgdorferi in the same manner as primary neural cultures. This response may play a role in the symptomatology and the pathogenesis of Lyme neuroborreliosis. Copyright 1999 Wiley-Liss, Inc.

Publication Types:
PMID: 10583909 [PubMed - indexed for MEDLINE]

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[Eye involvement in circumscript scleroderma--manifestation of borreliosis?]

[Article in German]

Framme C, Dietrich J, Lohmann CP, Sachs HG.

Augenklinik und Poliklinik, Klinikum, UniversitŠt Regensburg.

BACKGROUND: The circumscript cutaneous sclerosis is an inflammato-edematous erythema of the skin, usually leading to a plaque-like sclerosis and cutaneous atrophy. The etiology of this disease remains unknown, but some authors presume a systemic infection with Borrelia burgdorferi as the underlying pathological condition. PATIENT: We present a case of a 66-year-old male patient who suffered from episcleritis of his left eye. Funduscopy showed an unilateral papillary edema. Visual acuity was 1.0. The patient had multiple erythemata of the skin of the body-trunk and the arms. On histological examination the lesions were compatible with circumscript sclerosis. Neurological examination was normal. Brain imaging (MRI), CSF examination and serology showed no pathological findings, although the patient presented with raised antibodies against Borrelia burgdorferi (IgG positive, IGM negative). Intravenous antibiotic treatment and topical steroids for three weeks resulted in a complete recovery of the scleritis, but had no effect on the papillary edema. CONCLUSION: Inflammatory pathological findings of the eye can be associated with circumscript sclerosis, a disease, that is normally limited to the skin. The pathological mechanism remains unclear. The presumption of an underlying borreliosis could not be confirmed in this case.

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PMID: 10572891 [PubMed - indexed for MEDLINE]

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Cross-reactivity of Borrelia burgdorferi and myelin basic protein-specific T cells is not observed in borrelial encephalomyelitis.

Pohl-Koppe A, Logigian EL, Steere AC, Hafler DA.

Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, 02115, USA. Annette.Pohl-Koppe@kk-i.med.uni-muenchen.de

Borrelial encephalomyelitis, a rare manifestation of Lyme borreliosis, may present as a multiple sclerosis (MS)-like disease. It is postulated that in MS, inflammation of the white matter is caused by a T-cell response directed to myelin antigens. Here, we examined whether a T-cell autoimmune response may play a pathogenetic role in Borrelia-associated white matter disease mediated by cross-reactivity between myelin basic protein (MBP) and B. burgdorferi. We generated a total of 1760 short-term T-cell lines against B. burgdorferi or MBP from two patients with Borrelial encephalomyelitis and compared these with three patients with late Lyme disease, one patient with transverse myelitis, eight patients with MS, and four healthy controls. While a few T-cell lines recognized both B. burgdorferi and MBP, T-cell clones from these lines responded only to the antigen of the original stimulation. Thus, our data do not provide evidence for cross-reactivity between MBP and B. burgdorferi. Copyright 1999 Academic Press.

PMID: 10357888 [PubMed - indexed for MEDLINE]

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The underdiagnosis of neuropsychiatric Lyme disease in children and adults.

Fallon BA, Kochevar JM, Gaito A, Nields JA.

Department of Psychiatry, Columbia University Medical Center, New York, New York, USA.

Lyme Disease has been called "The New Great Imitator," a replacement for that old "great imitator" neurosyphilis. This article reviews the numerous psychiatric and neurologic presentations found in adults and children. It then reviews the features of Lyme Disease, which makes it almost uniquely hard to diagnose, including the complexity and unreliability of serologic tests. Clinical examples follow that illustrate those presentations of this disease that mimic attention deficit hyperactivity disorder (ADHD), depression, and multiple sclerosis.

Publication Types:
PMID: 9774805 [PubMed - indexed for MEDLINE]

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Neuro-ophthalmic manifestations of Lyme disease.

Balcer LJ, Winterkorn JM, Galetta SL.

Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, USA.

Lyme disease is a multisystem disorder caused by infection with the Borrelia burgdorferi spirochete. The diagnosis of Lyme disease usually is based on several clinical criteria, with supportive data from laboratory testing. The presence of the bullseye skin lesion, erythema migrans, is the single pathognomonic criterion. In the 20 years since the initial description of Lyme disease in the United States, B. burgdorferi has been implicated as an etiologic agent in numerous ophthalmic and neuro-ophthalmic syndromes, involving most structures from the cornea to the cranial nerves. Neuro-ophthalmic and ocular manifestations of Lyme disease include meningitis with papilledema, cranial neuropathies, follicular conjunctivitis, nummular keratitis, and intraocular inflammation. Although an association with Lyme disease has been purported for numerous other syndromes, a definite causal relationship has not been proved in many cases. During a period of rapidly increasing awareness of Lyme disease, a high index of suspicion and poorly defined criteria for its presence have resulted in over-diagnosis of Lyme disease. In the authors' experience, the incorrect diagnosis of Lyme disease initially has been made in patients with allergic conjunctivitis, keratoconus, morning glory syndrome, craniopharyngioma, meningioma, CNS lymphoma, paraneoplastic syndrome, multiple sclerosis, sarcoid, syphilis, and functional illness. Nevertheless, this treatable infection must be an important consideration in the differential diagnosis of certain ocular or neurologic diseases.

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PMID: 9176782 [PubMed - indexed for MEDLINE]

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[Diagnosis and treatment of facial palsy]

[Article in Spanish]

Noya M, Pardo J.

Servicio de Neurolog’a, Hospital General de Galicia-Cl’nico Universitario, Santiago de Compostela.

The topographic diagnosis of facial nerve lesions is based on the symptoms that accompany paralysis, allowing lesions to be located in the protuberance, pontocerebellar angle, facial channel or trajectory distal to the stylomastoid foramen. Most cases of peripheral facial palsy have no apparent cause (idiopathic, or Bell's, peripheral facial palsy). However, facial palsy can sometimes be a manifestation of neuroborreliosis, multiple sclerosis, diabetes, HIV infection or neurinoma. Neurophysiologic studies complement physical examination to establish a prognosis; after the fifth day axonal degeneration related to incomplete recovery can be recognized. Magnetic resonance identifies nerve lesions but is useful only in atypical cases. Prednisone 1 mg/kg over 5 days, with gradual weaning, is the most widely accepted treatment for Bell's palsy. Acyclovir is indicated in Ramsay-Hunt syndrome. Early surgical decompression in cases with poor prognosis is not generally considered beneficial. Cases of permanent facial palsy have serious consequences, particularly because facial expression is altered.

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PMID: 9131909 [PubMed - indexed for MEDLINE]

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Borrelial fasciitis: diffuse fasciitis and peripheral eosinophilia associated with Borrelia infection.

Granter SR, Barnhill RL, Duray PH.

Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.

We present four cases of diffuse fasciitis (DF) associated with peripheral eosinophilia in which spirochetal organisms were identified. Two patients had borderline positive results on serologic evaluation for Borrelia burgdorferi. Deep biopsy showed dermal sclerosis associated with variable degrees of perivascular mononuclear inflammation. Diffuse fasciitis, septal panniculitis, and myositis with mononuclear cell infiltrates and varying numbers of eosinophils were observed. All cases showed a striking lymphocytic vasculopathy associated with atypical reactive endothelial cells. Using modified Dieterle and Steiner silver stains, multiple organisms were seen in one specimen, a single unequivocal organism detected in two specimens. In one case, no organisms were detected on silver stain; however, organisms were demonstrated using rabbit polyclonal antibodies against B. burgdorferi. B. burgdorferi-specific DNA was identified in one patient by the polymerase chain reaction. These results indicate that some cases of eosinophilic fasciitis are an expression of Lyme disease. We have previously proposed the more specific term "borrelial fasciitis" to describe such lesions.

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PMID: 8902092 [PubMed - indexed for MEDLINE]

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Intrathecal immune response in patients with neuroborreliosis: specificity of antibodies for neuronal proteins.

Kaiser R.

Department of Neurology, University of Freiburg, Germany.

Cerebrospinal fluid (CSF) and serum samples of 47 patients with serologically proven neuroborreliosis were examined by Western blotting for antibodies to a crude extract of human cortex (CNS) comprising a multitude (> 40) of protein bands. Intrathecal synthesis of total immunoglobulins was determined by the Reiber formula and of autoantibodies to CNS proteins by enzyme-linked immunoassay (ELISA) and by Western blotting. Employing ELISA, intrathecal synthesis of autoantibodies (IgG, IgM and/or IgA) was demonstrated in 40 of 47 patients with neuroborreliosis (85%), in 5 of 40 with multiple sclerosis (12%), and in 22 of 40 with viral meningoencephalitis (55%). Of 40, 35 and 15 patients with neuroborreliosis and an intrathecal synthesis of total IgG, IgM or IgA, 20 revealed an intrathecal production of IgG antibodies (50%), 24 of IgM antibodies (68%) and 6 of IgA autoantiodies (40%) in the CSF. The specificity of autoantibodies differed greatly between most patients. Of 24 different CNS proteins which elicited an immune response in various patients, identities could be determined only for the myelin basic protein (5 of 40) and for the three neurofilament proteins (NF-68, NF-150, NF-200) (13 of 40 patients). In this limited number of patients no significant correlation between individual clinical symptoms and certain autoantiodies could be detected. The higher frequency of intrathecally produced autoantibodies in patients with neuroborreliosis is assumed to result from mitogenic rather than specific activation of autoreactive B-cell clones by Borrelia burgdorferi. The pathogenic relevance of these autoantibodies remains to be determined.

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PMID: 7643141 [PubMed - indexed for MEDLINE]

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Multiple sclerosis and positive Lyme serology.

Lana-Peixoto MA.

Faculdade de Medicina da Universidade Federal de Minas Gerais, Brasil.

As Lyme neuroborreliosis (LNB) may clinically mimic multiple sclerosis (MS) the presence of antibodies to Borrelia burgdorferi in serum of patients with a MS-like disease in non-endemic areas for Lyme disease may be troublesome. We report the case of a 45-year-old white female with the diagnosis of relapsing/remitting form of MS due to a 15-year history of optic neuritis and recurrent episodes of motor and sensation disturbance in the upper right limb and in both lower extremities associated with bladder dysfunction. A magnetic resonance imaging of the brain revealed multiple high intensity periventricular white matter lesions. The patient had been exposed to ticks but did not recall the presence of erythema migrans. ELISA for Lyme disease was positive in two different laboratories and the positive serology was confirmed by Western blotting. No convincing response followed treatment with ceftriaxone. Although it is clear that the patient had been infect by Borrelia burgdorferi the relationship of this spirochetal infection with the neurological disease could not be ascertained.

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PMID: 7611954 [PubMed - indexed for MEDLINE]

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Polyclonal and oligoclonal IgA synthesis in the cerebrospinal fluid of neurological patients: an immunoaffinity-mediated capillary blot study.

Sindic CJ, Monteyne P, Bigaignon G, Laterre EC.

Laboratory of Neurochemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

An intrathecal synthesis of IgA has been reported in various neurological disorders. However, the frequency of its occurrence and the electrophoretic characteristics of the locally produced IgA remained a matter of controversy. We developed a sensitive immunoaffinity-mediated capillary blot technique for the detection of polyclonal and oligoclonal IgA in the CSF of 115 patients with various neurological disorders. Paired CSF and serum samples containing 50 ng IgA after appropriate dilutions were submitted to isoelectric focusing in agarose gels; IgA was then blotted onto a polyvinylidene difluoride sheet coated by an anti-IgA antiserum or by infectious antigens. The immunoblots were revealed by an alkaline phosphatase-conjugated anti-IgA antiserum. Only five samples displayed CSF-restricted oligoclonal IgA bands, including two out of 33 from MS patients. In herpetic encephalitis (n = 5) and varicella-zoster meningitis (n = 2), a strong intrathecal production of virus-specific IgA antibodies was detectable. In such cases, faint oligoclonal IgA antibodies were superimposed on a polyclonal background. A weak local production of anti-Borrelia burgdorferi IgA antibodies was present in two out of four cases of neuroborreliosis.

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PMID: 8294549 [PubMed - indexed for MEDLINE]

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Significance of reactive Lyme serology in multiple sclerosis.

Coyle PK, Krupp LB, Doscher C.

Department of Neurology, School of Medicine, SUNY.

Nineteen of 283 consecutive patients evaluated in the Multiple Sclerosis (MS) Comprehensive Care Center had a borderline or positive B. burgdorferi serology. In 8 patients a repeat serology was nonconfirmatory. Cerebrospinal fluid was examined in 10 seropositive patients and showed anti-B. burgdorferi antibodies without intrathecal production in 5 patients. Antibiotic treatment did not prevent subsequent neurological relapses. The finding of reactive Lyme serology in an MS patient with no suggestive features of the infection is unlikely to indicate neurological Lyme disease.

Publication Types:
PMID: 8239571 [PubMed - indexed for MEDLINE]

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The presence of anti-Borrelia burgdorferi antibodies in a group of multiple sclerosis patients in eastern Sicily. Preliminary data.

di Bella P, Calisto ML, Calimeri S, Squeri R, Anzalone C, Lo Giudice D, Bramanti P.

Department of Hygiene, Preventive Medicine and Public Health, University of Messina.

The authors evaluate the presence of anti-Borrelia burgdorferi antibodies in a group of polysclerotic patients of Eastern Sicily, in order to verify or dismiss a correlation between Borrelia infection and demyelinizing syndrome. 460 samples of serum were examined, of which 60 belonged to patients affected by definite multiple sclerosis; the other 400 were taken from a group of apparently healthy subjects. From the analysis of the data obtained it can be seen that of the 60 polysclerotic subjects examined, 12 equal to 20% were found to be positive for the presence of IgG anti-Borrelia burgdorferi, while in the control group 30 subjects were found to be positive, equal 7.5%.

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PMID: 8249668 [PubMed - indexed for MEDLINE]

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Oligoclonal IgG in cerebrospinal fluid detected by isoelectric focusing using PhastSystem.

Hansson LO, Link H, Sandlund L, Einarsson R.

Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden.

Identification of oligoclonal immunoglobulin G (IgG) in cerebrospinal fluid (CSF) is one of the major laboratory signs in multiple sclerosis (MS). Oligoclonal IgG can also be seen in other immunostimulating central nervous system diseases, e.g. meningitis caused by Borrelia spirochetes. A convenient isoelectric focusing (IEF) method combined with polyethyleneglycol-enhanced (PEG) immunofixation and silverstaining using PhastSystem for detection of oligoclonal IgG bands in serum and unconcentrated spinal fluid was developed. Serum and cerebrospinal fluid samples earlier investigated using agarose IEF combined with immunoblotting and avidin-biotin amplified double-antibody peroxidase staining (= A-IEF) were blindly re-analysed using PhastGel IEF 3-9 modified with addition of Pharmalyte 8-10.5 followed by immunofixation and silver staining (= PhastIEF). PhastSystem IEF using PhastGel had the same capability to separate and visualize oligoclonal IgG bands as the conventional agarose IEF. However, PhastIEF was more convenient and less time-consuming than A-IEF. PhastIEF combined with immunofixation and silver staining using application of standardized amounts of IgG for both the serum and CSF samples (40-60 ng IgG/lane is fast, well-standardized and reproducible. The method is sensitive and uses only a minute volume of unconcentrated cerebrospinal fluid for the investigation of CSF IgG pattern.

PMID: 8210971 [PubMed - indexed for MEDLINE]

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High-resolution 1H NMR spectroscopy of cerebrospinal fluid in spinal diseases.

Koschorek F, Offermann W, Stelten J, Braunsdorf WE, Steller U, Gremmel H, Leibfritz D.

University Clinic of Radiology, Kiel, Fed. Rep. of Germany.

Twenty-nine patients with disk herniations, 7 patients with intraspinal tumors, 4 patients with multiple sclerosis and one patient with infection by borrelia have been studied by CT, myelography and/or MR. To gain information on the metabolism of central nervous system disease (CNS), and thus, to improve diagnosis the cerebrospinal fluid (CSF) was studied in all cases using high-resolution 1H NMR spectroscopy at 360 MHz. Seventeen metabolites could be identified in CSF in addition to the usual clinical chemical parameters. As compared to a control group discrimination of tumors from inflammation was possible by means of different metabolites and/or metabolite concentration. The CSF in disk herniations differed in the concentration of acetate from the control group. In CSF of tumors, multiple sclerosis and of infection by borrelia distinct differences in the concentrations of putrescine, citrate, valine, alpha-alanine, acetate, creatinine, glucose, beta-hydroxy-butyric acid, glutamine and creatine have been observed both as compared directly and in comparison to the control group. Thus, high-resolution 1H NMR spectroscopy of CSF gives speedy information on metabolism, since a variety of metabolites, usually examined only in different tests, can be studied in one single step. Thus, high-resolution 1H NMR spectroscopy supports imaging, especially MR, as morphological changes in diseases may be differentiated by means of different metabolite profiles. This assumption needs further confirmation on a prospective study with a larger patient population.

PMID: 8127445 [PubMed - indexed for MEDLINE]

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Lyme neuroborreliosis manifesting as an intracranial mass lesion.

Murray R, Morawetz R, Kepes J, el Gammal T, LeDoux M.

Department of Surgery, University of Alabama, School of Medicine, Birmingham.

Lyme neuroborreliosis is one of the chronic manifestations of Lyme disease and is caused by the neurotropic spirochete, Borrelia burgdorferi. Two of the three stages of Lyme disease potentially involve the central nervous system: a second stage that may manifest as meningitis, cranial neuritis, or radiculoneuritis; and a third stage, or chronic neuroborreliosis, with parenchymal involvement. The tertiary stage may mimic many conditions, including multiple sclerosis, polyneuropathy, viral encephalitis, brain tumor, vasculitis, encephalopathy, psychiatric illness, and myelopathy. We report a 10-year-old child with signs, symptoms, and radiological manifestations of intracranial mass lesions, without previously recognized manifestations of Lyme disease. This proved to be Lyme neuroborreliosis, documented by histological and serological examination, which responded well to antibiotic therapy. The need to establish a tissue diagnosis of intracranial mass lesions is emphasized, and the utility of a computed tomographic-guided stereotactic system for this purpose is discussed.

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PMID: 1584393 [PubMed - indexed for MEDLINE]

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Neuroactive kynurenines in Lyme borreliosis.

Halperin JJ, Heyes MP.

Department of Neurology, SUNY, Stony Brook.

Although neurologic dysfunction occurs frequently in patients with Lyme borreliosis, it is rarely possible to demonstrate the causative organism within the neuraxis. This discordance could arise if neurologic symptoms were actually due to soluble neuromodulators produced in response to infection. Since immune stimulation is associated with the production of quinolinic acid (QUIN), an excitotoxin and N-methyl-D-aspartate (NMDA) agonist, we measured levels of CSF and serum QUIN, and lymphokines. Samples were obtained from 16 patients with CNS Borrelia burgdorferi infection, eight patients with Lyme encephalopathy (confusion without intra-CNS inflammation), and 45 controls. CSF QUIN was substantially elevated in patients with CNS Lyme and correlated strongly with CSF leukocytosis. In patients with encephalopathy, serum QUIN was elevated with corresponding increments in CSF QUIN. Lymphokine concentrations were not consistently elevated. We conclude that CSF QUIN is significantly elevated in B burgdorferi infection--dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA synaptic function--a receptor involved in learning, memory, and synaptic plasticity--may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients.

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PMID: 1531156 [PubMed - indexed for MEDLINE]

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Absence of antibodies to Borrelia burgdorferi in multiple sclerosis.

Rasmussen HB, Clausen J, Heltberg A.

Publication Types:
PMID: 1792860 [PubMed - indexed for MEDLINE]

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Central nervous system abnormalities in Lyme neuroborreliosis.

Halperin JJ, Volkman DJ, Wu P.

Department of Neurology, State University of New York, Stony Brook 11794.

Intrathecal production of anti-Borrelia burgdorferi antibody occurs frequently in CNS Lyme, yet reliable diagnosis of neuroborreliosis is still considered difficult and controversial. Therefore, we assessed the utility of this measurement in 103 Lyme patients. Among 15 patients with Lyme meningoradiculitis and 41 controls, diagnostic specificity was 93% and sensitivity 87%. Application of this method permits the identification of a rare B burgdorferi-associated multifocal encephalitis (brain infection) and its differentiation from a milder encephalopathy, or confusional state; the latter may not require CNS bacterial invasion. The encephalitis involves white matter more often than gray; severity varies widely. Of six patients with this antibiotic-responsive encephalitis, five were positive for HLA DQw3(DQw7). We conclude that (1) measurement of intrathecal antibody production is a reliable indicator of CNS infection, (2) North American neuroborreliosis includes the same spectrum of neurologic dysfunction as described in Europe, and (3) HLA typing may be useful in furthering our understanding of severe CNS involvement.

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PMID: 1922798 [PubMed - indexed for MEDLINE]

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[Diagnosis of Lyme neuroborreliosis. Detection of intrathecal antibody formation]

[Article in German]

Wilske B, Bader L, Pfister HW, Preac-Mursic V.

Max-von-Pettenkofer-Institut fźr Hygiene und Medizinische Mikrobiologie, UniversitŠt Mźnchen.

The most common neurological manifestation of Lyme disease is lymphocytic meningoradiculitis (Banwarth's syndrome, stage II). In rare cases, chronic progressive encephalomyelitis (stage III) with symptoms similar to multiple sclerosis is observed. Antibodies against Borrelia burgdorferi are detectable in 70-90% of stage II cases, with IgM-antibodies predominating in the first two weeks, and IgG-antibodies thereafter. Detection of specific intrathecal antibodies is the best serodiagnostic parameter for diagnosing neuroborreliosis. With the aid of a CSF/serum index determination (on the basis of a comparison of IgG-antibody ELISA titers in CSF and serum with identical IgG concentrations) involvement of the nervous system was shown in 64% and 77%, respectively, of 76 stage II cases (diagnostic significance 98% and 100%, respectively). In particular when tertiary forms of the disease are suspected immunoblot techniques (Western blot, IEF-affinity blot) are recommended confirmatory tests.

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PMID: 1937323 [PubMed - indexed for MEDLINE]

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Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain.

Reiber H, Lange P.

Neurochemisches Labor der Neurologischen Klinik, UniversitŠt Gšttingen, F.R.G.

Specific antibody synthesis in brain could be detected with maximal sensitivity by combining an advanced enzyme immunoassay with a sophisticated evaluation method that involves calculating the ratio between the cerebrospinal fluid (CSF)/serum quotients for specific antibodies (Qspec) and total IgG (QIgG). This Antibody Index (AI = Qspec/QIgG) discriminates between a blood-derived and a pathological, brain-derived specific antibody fraction in CSF and takes into account individual changes in blood/CSF barrier function. For local synthesis of polyclonal IgG in the central nervous system (QIgG greater than QLim), we propose the correction AI = Qspec/QLim (QLim represents that IgG fraction in CSF originating only from blood, calculated from the individual albumin quotient of a single patient). The normal reference range for the AI was between 0.7 and 1.3 (n = 250 control patients for each antibody species). Values of AI greater than or equal to 1.5 indicated a local specific antibody synthesis in the central nervous system. Sensitivity and precision were greatest if we analyzed the virus-specific antibodies in CSF and serum simultaneously with an enzyme immunoassay in continuous concentrations (arbitrary units) instead of titer steps. We have applied the method successfully to antibodies to measles, rubella, herpes simplex, varicella-zoster, human immunodeficiency virus (HIV), and cytomegalovirus, and to anti-Toxoplasma or -Borrelia antibodies. Clinical relevance is demonstrated for an acute zoster virus infection (monospecific response), chronic diseases such as HIV encephalitis with acute opportunistic Toxoplasma infection, and multiple sclerosis (secondary polyspecific response).

PMID: 1855284 [PubMed - indexed for MEDLINE]

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Immunological differentiation between neuroborreliosis and multiple sclerosis.

Heller J, Holzer G, Schimrigk K.

Department of Neurology, UniversitŠtsnervenklinik, Homburg/Saar, Federal Republic of Germany.

Neuroborreliosis, a tick-borne spirochaetosis of the central nervous system, is diagnosed by the presence of intrathecally synthesized Borrelia burgdorferi-specific antibodies. Multiple sclerosis and neuroborreliosis can show similarities in clinical symptoms as well as lymphocytic cell reactions and oligoclonal bands in the isoelectric focusing of cerebrospinal fluid. To differentiate between multiple sclerosis and neuroborreliosis we tested intrathecally synthesized IgM and virus antibodies. The IgM indices were higher for most of the neuroborreliosis patients studied than for those with multiple sclerosis, and cell counts were also significantly higher in the acute stage of the disease. In 84% of multiple sclerosis patients we were able to demonstrate intrathecal antibody production against measles, rubella or mumps virus. Neuroborreliosis patients had no intrathecal virus antibody synthesis. The specification of oligoclonal bands resulting from isoelectric focusing of cerebrospinal fluid with an ELISA for B. burgdorferi can further substantiate the diagnosis of neuroborreliosis or help to rule it out in multiple sclerosis patients with positive borrelia-specific serology.

PMID: 2074447 [PubMed - indexed for MEDLINE]

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Western immunoblot and flagellum enzyme-linked immunosorbent assay for serodiagnosis of Lyme borreliosis.

Karlsson M.

Department of Infectious Diseases, Danderyd Hospital, Sweden.

Western immunoblot with a whole-cell lysate was compared with an enzyme-linked immunosorbent assay with a purified flagellum antigen of Borrelia burgdorferi for serodiagnosis of Lyme borreliosis. The assays showed similar sensitivities and specificities in detecting immunoglobulin M and/or immunoglobulin G antibodies in sera from 68 patients with neuroborreliosis and 44 controls with meningitis and encephalitis or with multiple sclerosis. Flagellum enzyme-linked immunosorbent assay is more easily standardized and seems to be a more suitable diagnostic test in a routine laboratory.

Publication Types:
PMID: 2229399 [PubMed - indexed for MEDLINE]

PMCID: PMC268127


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MRI reveals pathology in neuro Lyme disease.

Egerter DE.

PMID: 10149360 [PubMed - indexed for MEDLINE]

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[Multiple sclerosis or Lyme disease? a diagnosis problem of exclusion]

[Article in Spanish]

Garc’a-Monc— JC, Mir— Jornet J, Fern‡ndez Villar B, Benach JL, Guerrero Espejo A, Berciano JA.

Department of Pathology, SUNY, Stony Brook.

There is no diagnostic biological marker in multiple sclerosis. Thus, its diagnosis is based on clinical criteria. These criteria can also be found in other conditions. Lyme disease is currently among them. In a late period of the disease demyelinating involvement of central nervous system can develop, and multiple sclerosis can be erroneously diagnosed. We have evaluated a series of 55 patients with a definite diagnosis of multiple sclerosis, and we have found evidence of infection by the causative organism of Lyme disease in three. We describe the three patients and we discuss the relationship between both conditions. We conclude that it is important to consider Lyme disease as a diagnostic possibility in patients with neurological disease of unknown etiology such as multiple sclerosis.

Publication Types:
PMID: 2388492 [PubMed - indexed for MEDLINE]

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[ELISA for specifying oligoclonal bands of isoelectric focusing of cerebrospinal fluid in patients with neuroborreliosis and multiple sclerosis]

[Article in German]

Heller J, Holzer G, Schimrigk K.

UniversitŠtsnervenklinik Neurologie, Homburg/Saar.

PMID: 2352572 [PubMed - indexed for MEDLINE]

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Comparison of flagellum and sonicate antigens for serological diagnosis of Lyme borreliosis.

Karlsson M, Stiernstedt G, Granstršm M, Asbrink E, Wretlind B.

Department of Infectious Diseases, Danderyd Hospital, Sweden.

A sonicate antigen and two concentrations of a purified flagellum antigen of Borrelia burgdorferi were compared for serological diagnosis of Lyme borreliosis by an enzyme immunoassay (EIA). Generally, the higher concentration of flagellum antigen was found to be superior to the lower concentration, which was diluted eight times compared to the higher concentration. The diagnostic sensitivity for IgG antibody detection increased from 13% in the sonicate EIA to 31% in the best flagellum EIA assay (p = 0.01) in sera from patients with erythema migrans (n = 70), and from 34% to 55% (p = 0.01) in sera from patients with neuroborreliosis (n = 77). However, the sensitivity for IgG in sera from patients with acrodermatitis chronica atrophicans (n = 20) was high in both assays: 90% in the sonicate EIA compared to 95% in the flagellum EIA. Regarding IgM, there was no significant difference between the sensitivity of the assays in sera from any of the patient groups. The sensitivity values for IgM and IgG in cerebrospinal fluid (CSF) from patients with neuroborreliosis were also without significant differences. Sera and CSF from patients with meningitis/encephalitis of non-Borrelia etiology (n = 35), multiple sclerosis (n = 9) or syphilis (n = 24), served as controls. The flagellum EIA showed a significantly improved specificity for IgG in CSF from controls with syphilis (p less than 0.01). It is concluded that purified Borrelia burgdorferi flagellum antigen is superior to a sonicate antigen, especially for serodiagnosis of the early stages of Lyme borreliosis.

Publication Types:
PMID: 2186910 [PubMed - indexed for MEDLINE]

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Management of Lyme disease.

Goodwin SD, Sproat TT, Russell WL.

College of Pharmacy, University of Florida, Gainesville.

The microbiology, transmission, epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Lyme disease are reviewed. Lyme disease, a tick-borne syndrome, was first described in 1975. The etiologic agent of Lyme disease is Borrelia burgdorferi, a slow-growing spirochete. Lyme disease is the most prevalent tick-borne disease in this country; endemic areas in the United States include the northeastern, north central, and western regions. Both infectious and immunologic mechanisms are important factors in the pathogenesis of Lyme disease. The primary mechanism, however, is thought to be infectious. Three stages of Lyme disease have been described; stage I, characterized by erythema chronicum migrans and flu-like symptoms; stage II, characterized by dermatologic, ophthalmologic, neurologic, and cardiac disorders; and stage III, characterized by arthritis, a multiple sclerosis-like syndrome, psychiatric disorders, and a chronic fatigue syndrome. Therapy with penicillin or tetracycline hastens the resolution of stage I symptoms. Treatment duration normally ranges between 10 days and three weeks. Tetracycline or doxycycline appears to be more effective than penicillin in preventing the development of late Lyme disease. Although intravenous penicillin G and ceftriaxone are both effective for the treatment of late Lyme disease, many clinicians consider ceftriaxone to be the agent of choice. Whether exposed patients from endemic areas should receive antimicrobial prophylaxis is controversial. Further clinical studies are needed to determine optimal therapy for the various stages of Lyme disease, particularly Lyme arthritis.

Publication Types:
PMID: 2180624 [PubMed - indexed for MEDLINE]

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[Differential diagnosis of atypical plasma cells in the cerebrospinal fluid]

[Article in German]

Kraft R, Altermatt HJ, Nguyen-Tran Q.

Abteilung fźr klinische Zytologie, UniversitŠt Bern.

2102 samples of lumbar cerebrospinal fluid (CSF) were examined by qualitative cytology for atypical plasma cells. Samples from seven patients contained such cells. Retrospective investigation of these patients revealed that four of them had had neuroborreliosis, one had multiple sclerosis, one herpes zoster and one malignant non-Hodgkin lymphoma. It is concluded that in a case of unexplained meningoradiculitis with lymphoplasmocytic reaction in the CSF, morphological analysis of the plasma cells can provide important diagnostic pointers.

Publication Types:
PMID: 2806105 [PubMed - indexed for MEDLINE]

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Neurologic manifestations of Lyme disease, the new "great imitator".

Pachner AR.

Department of Neurology, University Hospital, Georgetown University Medical School, Washington, D.C. 20007.

The causative agent of Lyme disease, Borrelia burgdorferi, is a highly neurotropic organism that not only can produce symptomatic neurologic disease but also can exist dormant within the central nervous system (CNS) for long periods. Two distinct types of neuroborreliosis occur at different stages of Lyme disease. Second-stage Lyme meningitis resembles aseptic meningitis and is often associated with facial palsies, peripheral nerve involvement, and/or radiculopathies. Lyme meningitis may be the first evidence of Lyme disease, occurring without a history of erythema chronicum migrans or flu-like illness. Third-stage parenchymal involvement causes a multitude of nonspecific CNS manifestations that can be confused with conditions such as multiple sclerosis, brain tumor, and psychiatric derangements. Manifestations of CNS parenchymal involvement in Lyme disease are generally associated, however, with a history of erythema chronicum migrans, meningitis, or carditis. Both second- and third-stage Lyme neuroborrelioses are commonly misdiagnosed because they are relatively uncommon and because they mimic many better-known disorders.

Publication Types:
PMID: 2682960 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi antibodies in multiple sclerosis patients.

Coyle PK.

Department of Neurology, SUNY, Stony Brook 11794.

Lyme disease is said to produce a late syndrome resembling multiple sclerosis. We analyzed serum antibodies to Borrelia burgdorferi in 100 patients referred for possible MS. All lived in an area endemic for Lyme disease. Only 1 of 89 definite MS patients and 2 of 11 non-MS patients were antibody positive. Infection with Borrelia burgdorferi is rare in MS, and Lyme disease is unlikely to play a significant role in the differential diagnosis of MS.

PMID: 2725867 [PubMed - indexed for MEDLINE]

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Comment in:
Lyme neuroborreliosis: central nervous system manifestations.

Halperin JJ, Luft BJ, Anand AK, Roque CT, Alvarez O, Volkman DJ, Dattwyler RJ.

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

We evaluated 85 patients with serologic evidence of Borrelia burgdorferi infection. Manifestations included encephalopathy (41), neuropathy (27), meningitis (2), multiple sclerosis (MS) (6), and psychiatric disorders (3). We performed lumbar punctures in 53, brain MRI in 33, and evoked potentials (EPs) in 33. Only patients with an MS-like illness had abnormal EPs, elevated IgG index, and oligoclonal bands in the cerebrospinal fluid. Twelve of 18 patients with encephalopathy, meningitis, or focal CNS disease had evidence of intrathecal synthesis of anti-B burgdorferi antibody, compared with no patients with either MS-like or psychiatric illnesses, and only 2/24 patients with neuropathy. MRIs were abnormal in 7/17 patients with encephalopathy, 5/6 patients with an MS-like illness, and no others. We conclude that (1) intrathecal concentration of specific antibody is a useful marker of CNS B burgdorferi infection; (2) Lyme disease causes an encephalopathy, probably due to infection of the CNS; (3) MS patients with serum immunoreactivity against B burgdorferi lack evidence of CNS infection with this organism.

Publication Types:
PMID: 2542840 [PubMed - indexed for MEDLINE]

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Total, anti-viral, and anti-myelin IgG subclass reactivity in inflammatory diseases of the central nervous system.

Mathiesen T, von Holst H, Fredrikson S, WirsŽn G, Hederstedt B, Norrby E, Sundqvist VA, Wahren B.

Department of Virology, National Bacteriological Laboratory, Stockholm, Sweden.

Total IgG subclass levels, anti-viral, anti-myelin basic protein (anti-MBP), and anti-ganglioside 1 (anti-GM1) IgG subclass levels were measured in 6 patients with herpes simplex virus encephalitis (HSVE), 16 with borreliosis, 8 with other bacterial infections, 12 with multiple sclerosis (MS), 13 with subacute sclerosing panencephalitis (SSPE), 5 with glioblastoma and 12 controls. Total IgG1 levels were elevated in cerebrospinal fluid (CSF) from all patient groups (but not in the controls), IgG2 in bacterial infections, IgG3 in HSVE and borreliosis and IgG4 in some SSPE patients. The anti-viral (anti-measles, varicella zoster virus and rubella) IgG antibodies in MS were restricted to IgG1, anti-measles IgG to IgG1 and sometimes IgG4 in SSPE, anti-borrelia IgG to IgG1, IgG2 and IgG3. In contrast to anti-viral antibodies, anti-MBP and GM1 antibodies belonged to IgG1, IgG3 or IgG4 in MS. The nature of the immunological activation appears to be reflected in the subclass patterns elicited in the central nervous system. Different IgG subclass patterns in infectious diseases and MS suggest a difference between antigen-specific and non-specific B-cell activation.

PMID: 2760636 [PubMed - indexed for MEDLINE]

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Lyme borreliosis and multiple sclerosis.

Schmutzhard E.

Department of Neurology, University Hospital, Innsbruck, Austria.

There is now general consensus that tertiary Lyme borreliosis affecting the central nervous system does exist. Clinical, neuropathologic, laboratory and epidemiologic features indicate clearly that tertiary Lyme borreliosis of the CNS is a distinct entity and there is no etiologic association with multiple sclerosis.

Publication Types:
PMID: 2686768 [PubMed - indexed for MEDLINE]

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Autoimmunity in Lyme disease: molecular cloning of antigens recognized by antibodies in the cerebrospinal fluid.

Schluesener HJ, Martin R, Sticht-Groh V.

Clinical Research Unit for Multiple Sclerosis, Max-Planck Society, Wuerzburg, F.R.G.

In inflammatory disease of the central nervous system (CNS), oligoclonal bands of immunoglobulin with restricted heterogeneity can often be observed in cerebrospinal fluid (CSF) samples. These antibodies can be directed against the disease inducing pathogen or might be autoreactive and involved in the process of brain inflammation and demyelination. We used a molecular biology approach to characterize these antibody responses in patients with Lyme disease. This disorder is caused by infections with the spirochete Borrelia burgdorferi which is transmitted by ticks. Lyme disease can be associated with neurological symptoms due to inflammation of the central and peripheral nervous system. Phage lambda gtll expression libraries from B. burgdorferi and human brain were screened with cerebrospinal fluid antibody probes from patients with Lyme disease. We obtained recombinant phage clones encoding antigenic proteins from both B. burgdorferi and human CNS libraries. Thus, in this study two patients with chronic Lyme disease produced antibodies against recombinant B. burgdorferi as well as against CNS proteins, and the generation of this transient autoimmune response might be essential to the development of demyelinating disease.

PMID: 2491615 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis.

Schmutzhard E, Pohl P, Stanek G.

Department of Neurology, University Hospital, Innsbruck, Austria.

Sera of 106 multiple sclerosis patients and 103 closely matched controls were examined for Borrelia burgdorferi antibodies. The prevalence rate in multiple sclerosis patients was 14.2%, in controls 25.2%. Overall prevalence was 20.1%. Mean IgG antibody level was insignificantly higher in controls than in multiple sclerosis patients. Patients with a chronic progressive course of multiple sclerosis had an insignificantly higher mean borrelia antibody level, when compared with those suffering from relapsing/remitting form of disease.

PMID: 3225603 [PubMed - indexed for MEDLINE]

PMCID: PMC1033030


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[Borrelia burgdorferi encephalomyelitis]

[Article in French]

DeprŽ A, Sindic CJ, Bukasa K, Bigaignon G, Laterre C.

Laboratoire de Neurochimie, Cliniques Universitaires Saint-Luc, UniversitŽ Catholique de Louvain, Bruxelles, Belgique.

We report two patients with chronic encephalomyelitis due to Borrelia burgdorferi in whom the definite diagnosis was delayed because of atypical clinical features. The first patient presented with chronic spastic paraparesis, slight ataxia and nystagmus of several years' duration. A tentative diagnosis of multiple sclerosis was made in spite of important abnormalities of the CSF biological characteristics. The second patient presented with an acute aphasia and a bilateral Babinski's sign. He was thought to suffer from benign herpetic meningoencephalitis. Several months later, as the patient experienced relapses with cerebellar and spinal cord involvement, falsely positive tests for syphilis were found and an antibiotic treatment was given. High protein content, low glucose levels, pleocytosis and oligoclonal bands were observed in all CSF samples, but the definite diagnosis was based on the detection of serum and CSF antibodies against B. burgdorferi.

Publication Types:
PMID: 3187297 [PubMed - indexed for MEDLINE]

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[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.

Publication Types:
PMID: 3070690 [PubMed - indexed for MEDLINE]

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Chronic progressive neurological involvement in Borrelia burgdorferi infection.

Weder B, Wiedersheim P, Matter L, Steck A, Otto F.

Five patients with chronic meningitis were hospitalized several times for progressive neurological symptoms. The clinical manifestations included cranial neuritis, radiculoneuritis, myelitis and encephalitis. In two cases cerebral infarction occurred. The course was commonly characterized by a tendency to deteriorate. From the clinical point of view, it was repeatedly difficult to exclude multiple sclerosis or tuberculous meningitis. Finally, specific antibodies against Borrelia burgdorferi were detected by indirect immunofluorescence assay. The diagnosis of a borreliosis was not considered initially because there was no history of tick-bite or erythema chronicum migrans, and the neurological involvement of the central nervous system seemed unusual. The latency between the first symptoms and diagnosis varied from 3 months to 5 years. After a parenteral, high-dose therapy with penicillin, there was a significant improvement in all patients. In two cases, there was evidence of intrathecally produced antibodies to myelin basic protein.

PMID: 3819785 [PubMed - indexed for MEDLINE]

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Borrelia arthritis in Sweden.

Stiernstedt G, Granstršm M.

Antibodies to Borrelia spirochetes were determined by an enzyme-linked immunosorbent assay (ELISA) in sera from 298 patients with postinfectious arthritis. Sera from healthy individuals, patients with acute infectious meningitis of proven etiology and patients with multiple sclerosis served as controls. Titers above the 100% percentile of controls were found in five of 298 (2%) arthritis patients. Two of the arthritis patients had higher titers than any titers previously found in Swedish patients with Borrelia meningitis. It is concluded that a Borrelia etiology should be considered in patients with reactive or postinfectious arthritis of unknown origin.

PMID: 3577488 [PubMed - indexed for MEDLINE]

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Anti-myelin antibodies in cerebrospinal fluid and serum of patients with meningopolyneuritis Garin-Bujadoux-Bannwarth and other neurological diseases.

Suchanek G, Kristoferitsch W, Stanek G, Bernheimer H.

Anti-myelin antibodies (AMA) of IgG, IgM, and IgA class were investigated by ELISA in CSF and serum from patients with meningopolyneuritis Garin-Bujadoux-Bannwarth (GBB), other inflammatory diseases of the nervous system (ID) comprising meningoencephalitis (ME), multiple sclerosis (MS), and Guillain-BarrŽ syndrome (GBS), and various noninflammatory neurological diseases (NID). Anti-Borrelia antibodies (ABA) were determined by ELISA in GBB patients. In CSF, a high incidence of IgG-AMA, IgM-AMA, and IgA-AMA was found in GBB as compared with ID and NID. On average, positive AMA titers were higher in GBB than in ID and NID, IgM-AMA titers in GBB being most prominent. In serum, AMA were found in all but 2 patients investigated. On average, IgM-AMA titers were higher in GBB and MS than in other diseases; IgG-AMA titers in GBB and ME were relatively low. Antibody indices, calculated from titer values and Ig concentrations in CSF and serum, indicate intrathecal synthesis mainly of IgG- and IgA-AMA, and of IgG- and IgM-ABA. Participation of AMA in the pathogenesis of GBB may be envisaged, but needs further confirmation.

Publication Types:
PMID: 3577478 [PubMed - indexed for MEDLINE]

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Spirochaetes and Lyme disease.

Benoit P, Dournon E, Destee A, Warot P.

Publication Types:
PMID: 2877362 [PubMed - indexed for MEDLINE]

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Relapsing fever/Lyme disease. Multiple sclerosis.

Kurtz SK.

Lyme Disease and Relapsing Fever caused by Borrelia burdorferi and Borrelia hermsii, respectively, have been generally considered curable if diagnosed early. However, it is becoming apparent that when these diseases are left undiagnosed and untreated they may cause severe problems for some people. They, in fact, may be one of the major causes of Multiple Sclerosis. These two Borrelia infections, when left untreated, are now known to be capable of causing neurological problems, cardiac problems, relapses as much as ten years later, increased IgG/albumin ratio and increased lymphocytes. These same things hold true for Multiple Sclerosis patients. This paper discusses the Borrelia spirochetes which cause Lyme Disease and Relapsing Fever and what correlation that may have with Multiple Sclerosis.

PMID: 3642202 [PubMed - indexed for MEDLINE]

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Multiple sclerosis and Borrelia burgdorferi.

Fumarola D.

Publication Types:
PMID: 2875306 [PubMed - indexed for MEDLINE]

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Multiple sclerosis associated with sinusitis.

[No authors listed]

Publication Types:
PMID: 2871364 [PubMed - indexed for MEDLINE]

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Diagnosis of spirochetal meningitis by enzyme-linked immunosorbent assay and indirect immunofluorescence assay in serum and cerebrospinal fluid.

Stiernstedt GT, Granstršm M, Hederstedt B, Skšldenberg B.

The antibody response against a spirochetal strain isolated from Swedish Ixodes ricinus ticks was determined by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay of cerebrospinal fluid (CSF) and serum specimens from 45 patients with chronic meningitis. Samples of CSF, serum, or both from patients with various infections of the central nervous system, multiple sclerosis, syphilis, or infectious mononucleosis and from healthy individuals served as control samples. Probable spirochetal etiology could be demonstrated for 41 of 45 (91%) patients with clinical symptoms of chronic meningitis. Approximately 25% of the patients had significantly elevated titers of antibody to the spirochete in CSF but not in serum. The highest diagnostic sensitivity, 91%, was demonstrated by measurement of CSF antibodies and calculation of a spirochetal CSF titer index, which is the ratio of (ELISA titer in CSF/ELISA titer in serum) to (albumin in CSF/albumin in serum) and which also considers the degree of blood-CSF barrier damage. The highest specificity, 98%, was obtained by calculation of a CSF titer index. Patients with short duration of disease were especially prone to be antibody negative in serum but positive in CSF. Significant rise in serum antibody titers was seldom demonstrated in patients treated with antibiotics. It is concluded that measurement of CSF antibodies, especially by ELISA, is a highly sensitive and specific method for the immunological diagnosis of spirochetal meningitis.

Publication Types:
PMID: 3889049 [PubMed - indexed for MEDLINE]

PMCID: PMC271789


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[Current status of spirochaete etiology of multiple sclerosis; Borrelia findings in a case of multiple sclerosis.]

[Article in German]

AHRENS CB, MUSCHNER K.

PMID: 13625985 [PubMed - OLDMEDLINE]

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[Detection of Borrelia in the central nervous system by disintegration with the thedane blue-potassium chlorate method; with a technical contribution to the checking of the spirochete etiology of multiple sclerosis.]

[Article in German]

SIMONS HC.

PMID: 13257395 [PubMed - OLDMEDLINE]


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