Dr James Schaller
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Spirochetes Neurology

Many varieties of spirochetes are very common all over the world. For example, Lyme disease is a powerful infection that is able to evade the immune system over 10 ways. It is often missed due to the invisibility of the period-sized brownish deer tick. Lyme disease spirals into most tissues and loves to enter the brain.

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Cerebral vasculitis and stroke in Lyme neuroborreliosis. Two case reports and review of current knowledge.

Topakian R, Stieglbauer K, Nussbaumer K, Aichner FT.

Department of Neurology, Academic Teaching Hospital Wagner-Jauregg, Linz, Austria. raffi.topakian@hotmail.com

We report on 2 patients with cerebral vasculitis and stroke due to Lyme neuroborreliosis (LNB). Both patients had a prodromal stage involving headaches, and showed meningeal enhancement in addition to ischemic infarctions on brain magnetic resonance imaging and diffuse vasculitis on vascular imaging. Serological and cerebrospinal (CSF) fluid studies confirmed the diagnosis of active LNB. Ceftriaxone for 3 weeks led to an excellent recovery and improvements in the CSF examination findings. Stroke physicians should be aware of this rare presentation of LNB. A review of the current knowledge on cerebral vasculitis due to LNB is provided. 2008 S. Karger AG, Basel.

Publication Types:
PMID: 18810231 [PubMed - indexed for MEDLINE]

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An exotic cause for confusion in the garden.

Williams F, Ginsberg L, Brenner R, Cohen A.

Department of Neurology, Royal Free Hospital, London, UK.

Publication Types:
PMID: 18644913 [PubMed - indexed for MEDLINE]

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IL-10 helps control pathogen load during high-level bacteremia.

Londoño D, Marques A, Hornung RL, Cadavid D.

Department of Neurology and Neuroscience and Center for Emerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.

During relapsing fever borreliosis, a high pathogen load in the blood occurs at times of peak bacteremia. Specific IgM Abs are responsible for spirochetal clearance so in absence of B cells there is persistent high-level bacteremia. Previously, we showed that B cell-deficient mice persistently infected with Borrelia turicatae produce high levels of IL-10 and that exogenous IL-10 reduces bacteremia. This suggested that IL-10 helps reduce bacteremia at times of high pathogen load by a B cell-independent mechanism, most likely involving innate immunity. To investigate this possibility, we compared B. turicatae infection in RAG2/IL-10(-/-) and RAG2(-/-) mice. The results showed that IL-10 deficiency resulted in significantly higher bacteremia, higher TNF levels, and early mortality. Examination of the spleen and peripheral blood showed markedly increased apoptosis of immune cells in infected RAG2/IL-10(-/-) mice. Neutralization of TNF reduced apoptosis of leukocytes and splenocytes, increased production of IFN-gamma by NK cells, increased phagocytosis in the spleen, decreased spirochetemia, and rescued mice from early death. Our results indicate that at times of high pathogen load, as during peak bacteremia in relapsing fever borreliosis, IL-10 protects innate immune cells from apoptosis via inhibition of TNF resulting in improved pathogen control.

Publication Types:
PMID: 18641346 [PubMed - indexed for MEDLINE]

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Relevance of the antibody index to diagnose lyme neuroborreliosis among seropositive patients.

Ljøstad U, Mygland A.

Publication Types:
PMID: 18606973 [PubMed - indexed for MEDLINE]

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Comment on:
Relevance of the antibody index to diagnose lyme neuroborreliosis among seropositive patients.

Lanska DJ.

Publication Types:
PMID: 18606972 [PubMed - indexed for MEDLINE]

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Erratum in:
  • Lancet Neurol. 2008 Aug;7(8):675.

Comment in:
Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial.

Ljøstad U, Skogvoll E, Eikeland R, Midgard R, Skarpaas T, Berg A, Mygland A.

Department of Neurology, Sørlandet Hospital HF, Kristiansand, Norway. unn.ljostad@sshf.no

BACKGROUND: Use of intravenous penicillin and ceftriaxone to treat Lyme neuroborreliosis is well documented, although oral doxycycline could be a cost-effective alternative. We aimed to compare the efficacy of oral doxycycline with intravenous ceftriaxone for the treatment of Lyme neuroborreliosis. METHODS: From April, 2004, to October, 2007, we recruited consecutive adult patients from nine hospitals in southern Norway into a non-inferiority trial. Inclusion criteria were neurological symptoms suggestive of Lyme neuroborreliosis without other obvious causes, and presence of any of the following: a CSF white-cell count of more than five per mL; intrathecal production of specific Borrelia burgdorferi antibodies; or acrodermatitis chronicum atrophicans. Patients were randomly allocated to receive 200 mg oral doxycycline or 2 g intravenous ceftriaxone once per day for 14 days, in a double-blind, double-dummy design. A composite clinical score (range 0 to 64, 0=best) was based on standardised interviews and clinical neurological examination. The primary outcome was reduction in clinical score at 4 months after the start of treatment. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00138801. FINDINGS: Of 118 patients who underwent randomisation, 102 completed the study (mean clinical score at baseline 8.5 [SD 4.1]). 4 months after the start of treatment, mean score improvement in the doxycycline group (n=54) was 4.5 (95% CI 3.6 to 5.5) points and that in the ceftriaxone group (n=48) was 4.4 (3.4 to 5.4) points (95% CI for difference between groups -0.9 to 1.1; p=0.84). 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery (95% CI for difference between groups -4% to 34%; p=0.13). Side-effects possibly related to treatment were reported in 21 (37%) and 26 (46%) patients in these groups, respectively (-28% to 9%; p=0.30). Three patients discontinued ceftriaxone treatment owing to adverse events. INTERPRETATION: Oral doxycycline is as efficient as intravenous ceftriaxone for the treatment of European adults with Lyme neuroborreliosis.

Publication Types:
PMID: 18567539 [PubMed - indexed for MEDLINE]

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Multiple cranial nerve involvement in Bannwarth's syndrome.

Vianello M, Marchiori G, Giometto B.

O.U. Neurology, Ca' Foncello Hospital, Piazza Ospedale 1, 31100, Treviso, Italy.

Bannwarth's syndrome is a tick-transmitted neurological disease caused by spirochetes of the Borrelia burgdorferi group. Neurological manifestations of the disease occur after skin erythema and include: neuritic pain, lymphocytic pleocytosis without headache and sometimes cranial neuritis. We present the case of a man who complained of a neurological syndrome without evidence of tick bite and concurrent manifestation of the infection, for whom serological analysis only revealed the infection after testing repetitive specimens. We discuss the need to start early therapy when clinical manifestations are suggestive of the disease in endemic areas.

Publication Types:
PMID: 18483708 [PubMed - indexed for MEDLINE]

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Viliuisk encephalomyelitis in Northeastern Siberia is not caused by Borrelia burgdorferi infection.

Storch A, Vladimirtsev VA, Tumani H, Wellinghausen N, Haas A, Krivoshapkin VG, Ludolph AC.

Department of Neurology, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. alexander.storch@neuro.med.tu-dresden.de

Viliuisk encephalomyelitis (VE) is an endemic neurological disease in Northeastern Siberia and generally believed to be a chronic encephalomyelitis of unknown origin. We investigated 17 patients with a clinical diagnosis of VE within the Viliuiski region of Sakha (Yakutian) Republic to explore the core clinical syndrome of chronic VE and subsequently whether VE is caused by Borrelia burgdorferi infection. We found a chronic myelopathy as the core of the syndrome, often following an acute phase with a meningo-radiculo-neuropathy, suggestive of chronic neuroborreliosis. A search for inflammatory parameters in a larger cohort in blood (39 VE patients and 41 controls) and CSF samples (10 VE patients and 7 controls) excluded an ongoing chronic infection, but revealed evidence for an immunological scar or a chronic inflammatory ("autoimmune") response in the CSF. In addition, we detected signs of a previous exposure to Borrelia burgdorferi antigens in a subset of chronic VE patients with positive serological results using ELISA/immunoblot in 54/10% and 22/0% of VE patients and controls, respectively (p values of 0.003/0.034; Fisher's exact test). However, CSF analyses did not show a link between exposure or at least immunological reaction against Borrelia and the risk of suffering from VE. Our data provide the first evidence of the presence of Borrelia burgdorferi or similar pathogens in Northeastern Siberia, but do not support a causative role of these pathogens in the aetiopathogenesis of VE.

Publication Types:
PMID: 18379734 [PubMed - indexed for MEDLINE]

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Diagnostic value of sural nerve biopsy in patients with suspected Borrelia neuropathy.

Schäfers M, Neukirchen S, Toyka KV, Sommer C.

Department of Neurology, University of Würzburg, Würzburg, Germany.

Peripheral neuropathy is a recognized but incompletely understood manifestation of borreliosis. As the pathology of this neuropathy has been described only in small case series, the value of nerve biopsy findings for the pathologic diagnosis of Borrelia-associated neuropathy is unclear. We collected and investigated 21 patients with peripheral neuropathy and with typical clinical and serologic signs of neuroborreliosis [Borrelia neuropathy (BN)]. Standard histology and immunohistochemistry were performed on sural nerve biopsies using antibodies to CD4, CD68 and membrane attack complex C5b-9, intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6. Nine patients with idiopathic vasculitic neuropathy (VN) and 14 with idiopathic axonal neuropathy (AN) served as disease controls. In BN, the characteristic histology was that of an AN with transmural or perivascular lymphocytic infiltration of nerve vessels. In BN, but less in VN and AN, perineurial thickening and neovascularization were observed. For BN but not for VN, this thickening correlated with increased perineurial immunoreactivity (IR) to TNF-alpha, C5b-9, and ICAM-1. In comparison to AN, both BN and VN displayed increased perineurial T-cell infiltration and human leukocyte antigen (HLA)-DR3-IR. In the endoneurium, cytokine (IL-1beta, IL-6, TNF-alpha), HLA-DR3, and ICAM-1 expression was more pronounced in VN but not in BN. The neuropathy in patients with neuroborreliosis resembles idiopathic VN but shows some distinctive features. None of the findings of this study are disease specific but as a pattern may help support the diagnosis of inflammatory neuropathy in patients with serological evidence for Borrelia infection.

Publication Types:
PMID: 18346234 [PubMed - indexed for MEDLINE]

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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.

Ljøstad U, Mygland A.

Dept. of Neurology, Sørlandet 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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Canalicular magnetic stimulation lacks specificity to differentiate idiopathic facial palsy from borreliosis in children.

Hufschmidt A, Müller-Felber W, Tzitiridou M, Fietzek UM, Haberl C, Heinen F.

Department of Neurology, Verbundkrankenhaus Bernkastel-Wittlich, Koblenzer Street 91, Wittlich, Germany. a.hufschmidt@kh-wittlich.de

OBJECTIVE: To investigate the role of transcranial magnetic stimulation (TMS) to differentiate between idiopathic facial nerve palsy (iFNP) and facial nerve palsy due to borreliosis (bFNP). PATIENTS AND METHODS: Transcranial and intracanalicular magnetic and peripheral electrical stimulation of the facial nerve together with clinical grading according to the House and Brackmann scale were performed in 14 children and adolescents with facial palsy (median age 11.5 yr, range 4.6-16.5 yr). Serum and cerebrospinal fluid (CSF) were evaluated for antibodies against Borrelia burgdorferi and CSF cell count, glucose and protein content were screened with methods of routine laboratory testing. Data of patients were compared with normal values established in 10 healthy subjects (median age 10.2 yr, range 5.1-15.3 yr). RESULTS: Patients with iFNP showed a significant decrease in MEP amplitude to canalicular magnetic stimulation compared with healthy controls (p=0.03). However, MEP amplitude did not discriminate sufficiently between the two groups, because the ranges of dispersion of MEP amplitudes overlapped. Patients with bFNP had normal MEP amplitudes to canalicular magnetic stimulation compared with normal subjects. CONCLUSION: Diagnostic assessment by TMS failed to provide a reliable diagnostic criterion for distinguishing between iFNP and bFNP in children and adolescents.

PMID: 18206409 [PubMed - indexed for MEDLINE]

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The pathogenesis of lyme neuroborreliosis: from infection to inflammation.

Rupprecht TA, Koedel U, Fingerle V, Pfister HW.

Department of Neurology, Ludwig-Maximilians University, Munich, Germany.

This review describes the current knowledge of the pathogenesis of acute Lyme neuroborreliosis (LNB), from invasion to inflammation of the central nervous system. Borrelia burgdorferi (B.b.) enters the host through a tick bite on the skin and may disseminate from there to secondary organs, including the central nervous system. To achieve this, B.b. first has to evade the hostile immune system. In a second step, the borrelia have to reach the central nervous system and cross the blood-brain barrier. Once in the cerebrospinal fluid (CSF), the spirochetes elicit an inflammatory response. We describe current knowledge about the infiltration of leukocytes into the CSF in LNB. In the final section, we discuss the mechanisms by which the spirochetal infection leads to the observed neural dysfunction. To conclude, we construct a stringent concept of the pathogenesis of LNB.

Publication Types:
PMID: 18097481 [PubMed - indexed for MEDLINE]

PMCID: PMC2148032


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[The clinical diagnosis and therapy of neurosyphilis]

[Article in Chinese]

Yang XS, Zhang LF, Xiao B.

Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.

OBJECTIVE: To study the clinical features, neuroimages, laboratory findings, therapy and prognosis of neurosyphilis. METHODS: The clinical features, neuroimages, laboratory findings and therapy of 18 patients with neurosyphilis were analyzed retrospectively. RESULTS: Interstitial neurosyphilis especially meningovascular syphilis was the most common type of which the clinical features varied widely. Treponema pallidum hemagglutination assay (TPHA) test of both serum and CSF samples might be positive, but the positive rate in CSF was lower than that in serum. MRI of syphilitic gumma was typical. Penicillin is the drug of first choice for effective treatment except syphilitic gumma, which should be treated with resectopn. The effective rate of penicillin is 93%. CONCLUSIONS: Patients with neurosyphilis may present diverse clinical symptoms at the beginning of the course, therefore it is misdiagnosed easily at the first visit. It is important to comprehend that positive syphilis antibody test in serum or CSF is specific for the diagnosis. Penicillin is the drug of first choice for effective treatment.

Publication Types:
PMID: 18028799 [PubMed - indexed for MEDLINE]

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PCR for bacterial 16S ribosomal DNA in multiple sclerosis cerebrospinal fluid.

Lindsey J, Patel S.

Department of Neurology, University of Texas Health Science Center at Houston, TX 77030, USA. john.w.lindsey@uth.tmc.edu

The cause of multiple sclerosis (MS) is currently unknown. The hypothesis of this study is that MS is caused by a chronic bacterial infection of the central nervous system (CNS) and the ensuing immune response. We developed a sensitive two-stage polymerase chain reaction method using nested or semi-nested primers specific for the bacterial 16S ribosomal DNA to test for the presence of bacterial DNA in cerebrospinal fluid. We designed seven sets of primers to amplify DNA from spirochetes , Campylobacter, Mycoplasma, Chlamydia, Bartonella, Mycobacteria and Streptococcus and tested cerebrospinal fluid from patients with relapsing-remitting MS, primary progressive MS, transverse myelitis and controls. We did not detect DNA from any of the groups of bacteria in patients or controls. We conclude that we were unable to find evidence for CNS infection with any of these seven groups of bacteria in MS.

Publication Types:
PMID: 17986505 [PubMed - indexed for MEDLINE]

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Comment in:
Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients.

Blanc F, Jaulhac B, Fleury M, de Seze J, de Martino SJ, Remy V, Blaison G, Hansmann Y, Christmann D, Tranchant C.

Department of Neurology, University Hospital of Strasbourg, Louis Pasteur University, Strasbourg, France. blanc.frdrc@free.fr

BACKGROUND: No consensual criteria exist to diagnose neuroborreliosis. The intrathecal anti-Borrelia antibody index (AI) is a necessary criterion to diagnose neuroborreliosis in Europe, but not in the United States. Previous studies to determine the diagnostic value of the AI found a sensitivity ranging from 55% to 80%. However, these studies included only typical clinical cases of meningitis or meningoradiculitis, and none had a control group with CSF anti-Borrelia antibodies. METHODS: We studied a sample of 123 consecutive patients with clinical signs of neurologic involvement and CSF anti-Borrelia antibodies. We determined the AI for all patients and a final diagnosis was made. Patients were then divided into three groups (neuroborreliosis, possible neuroborreliosis, control). RESULTS: Thirty of the 40 patients with neuroborreliosis had a positive AI (AI sensitivity = 75%). Two of the 74 patients with another neurologic diagnosis had a positive AI (AI specificity = 97%). CONCLUSION: The antibody index has a very good specificity but only moderate sensitivity. Given the lack of consensual criteria for neuroborreliosis and the absence of a "gold standard" diagnostic test, we propose pragmatic diagnostic criteria for neuroborreliosis, namely the presence of four of the following five items: no past history of neuroborreliosis, positive CSF ELISA serology, positive anti-Borrelia antibody index, favorable outcome after specific antibiotic treatment, and no differential diagnosis. These new criteria will need to be tested in a larger, prospective cohort.

PMID: 17785663 [PubMed - indexed for MEDLINE]

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Comment on:
Is the presence of antibodies in CSF sufficient to make a definitive diagnosis of Lyme disease?

Roos KL, Berger JR.

Publication Types:
PMID: 17785661 [PubMed - indexed for MEDLINE]

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Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis.

Ljøstad U, Skarpaas T, Mygland A.

Department of Neurology, Sørlandet Sykehus HF, Kristiansand, Norway. unn.ljostad@sshf.no

The aim of the study was to examine diagnostic sensitivity and temporal course of intrathecal Borrelia burgdorferi (Bb) antibody production in acute Lyme neuroborreliosis (LNB). We recruited consecutive adult patients with LNB diagnosis based on strict selection criteria. Serum and cerebrospinal fluid (CSFs) were obtained, and clinical examination was performed pre-treatment, and 13 days and 4 months post-treatment. Pre-treatment positive Bb antibody index (AI) was detected in 34 of 43 (79%). All nine pre-treatment Bb AI negative patients, and 26 of 34 pre-treatment Bb AI positive patients reported symptom duration <6 weeks. Eight patients, all Bb AI positive, reported symptom duration of 6 weeks or longer. Consequently, pre-treatment diagnostic sensitivity of Bb AI was 74% when symptom duration was <6 weeks, and 100% when 6 weeks or longer. Three patients converted from negative to positive Bb AI status post-treatment. The six patients who were persistently Bb AI negative had lower CSF cell count and protein at presentation, when compared with the patients with positive Bb AI. In conclusion, the diagnostic sensitivity of Bb AI is suboptimal in acute early LNB. Repeated post-treatment Bb AI testing, to confirm or reject LNB diagnosis, is unreliable, as the majority of initial Bb AI negative patients remained negative at follow-up.

Publication Types:
PMID: 17662007 [PubMed - indexed for MEDLINE]

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EEG with triphasic waves in Borrelia burgdorferi meningoencephalitis.

Eriksson B, Wictor L.

Division of Clinical Neurology, Lund University Hospital, Lund, Sweden. Bengt.B.Eriksson@skane.se

We describe a case of encephalopathy in which the clinical picture and triphasic waves in the EEG indicated a metabolic cause. However, the illness was caused by neuroborreliosis. The occurrence of triphasic waves in the EEG is a strong evidence of metabolic encephalopathy, but triphasic waves are not specific for metabolic encephalopathy. Triphasic waves have been described in a number of non-metabolic encephalopaties and structural brain lesions. To our knowledge, this is the first report of triphasic waves in Borrelia burgdorferi meningoencephalitis.

Publication Types:
PMID: 17661801 [PubMed - indexed for MEDLINE]

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Borrelia garinii induces CXCL13 production in human monocytes through Toll-like receptor 2.

Rupprecht TA, Kirschning CJ, Popp B, Kastenbauer S, Fingerle V, Pfister HW, Koedel U.

Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany.

Recent studies have suggested an important role for the B-cell-attracting chemokine CXCL13 in the B-cell-dominated cerebrospinal fluid (CSF) infiltrate in patients with neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB patients. It has not been clear, however, whether high CSF CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well. Furthermore, the mechanisms leading to the observed CXCL13 expression have not been identified yet. Here we describe similarly elevated CSF CXCL13 levels in patients with neurosyphilis, while pneumococcal meningitis patient CSF do not have high CXCL13 levels. In parallel, challenge of human monocytes in vitro with two of the spirochetal causative organisms, Borrelia garinii (the Borrelia species most frequently found in NB patients) and Treponema pallidum, but not challenge with pneumococci, induced CXCL13 release. This finding implies that a common spirochetal motif is a CXCL13 inducer. Accordingly, we found that the lipid moiety N-palmitoyl-S-(bis[palmitoyloxy]propyl)cystein (Pam(3)C) (three palmitoyl residues bound to N-terminal cysteine) of the spirochetal lipoproteins is critical for the CXCL13 induction in monocytes. As the Pam(3)C motif is known to signal via Toll-like receptor 2 (TLR2) and an anti-TLR2 monoclonal antibody blocked CXCL13 production of human monocytes incubated with B. garinii, this suggests that TLR2 is a major mediator of Borrelia-induced secretion of CXCL13 from human monocytes.

Publication Types:
PMID: 17562761 [PubMed - indexed for MEDLINE]

PMCID: PMC1951179


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Erratum in:
  • Neurology. 2008 Apr 1;70(14):1223.

Comment in:
Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, Krupp L, Gronseth G, Bever CT Jr; Quality Standards Subcommittee of the American Academy of Neurology.

Department of Neurosciences, Overlook Hospital, NYU School of Medicine, Summit, NJ, USA.

OBJECTIVE: To provide evidence-based recommendations on the treatment of nervous system Lyme disease and post-Lyme syndrome. Three questions were addressed: 1) Which antimicrobial agents are effective? 2) Are different regimens preferred for different manifestations of nervous system Lyme disease? 3) What duration of therapy is needed? METHODS: The authors analyzed published studies (1983-2003) using a structured review process to classify the evidence related to the questions posed. RESULTS: The panel reviewed 353 abstracts which yielded 112 potentially relevant articles that were reviewed, from which 37 articles were identified that were included in the analysis. CONCLUSIONS: There are sufficient data to conclude that, in both adults and children, this nervous system infection responds well to penicillin, ceftriaxone, cefotaxime, and doxycycline (Level B recommendation). Although most studies have used parenteral regimens for neuroborreliosis, several European studies support use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis (Level B), reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neurologic symptomatology, or failure to respond to oral regimens. The number of children (> or =8 years of age) enrolled in rigorous studies of oral vs parenteral regimens has been smaller, making conclusions less statistically compelling. However, all available data indicate results are comparable to those observed in adults. In contrast, there is no compelling evidence that prolonged treatment with antibiotics has any beneficial effect in post-Lyme syndrome (Level A).

Publication Types:
PMID: 17522387 [PubMed - indexed for MEDLINE]

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Pathogen specificity and autoimmunity are distinct features of antigen-driven immune responses in neuroborreliosis.

Kuenzle S, von Büdingen HC, Meier M, Harrer MD, Urich E, Becher B, Goebels N.

Clinical Neuroimmunology Unit, Department of Neurology, University Hospital Zürich, Frauenklinikstrasse 26, CH-8091 Zürich, Switzerland.

Neuroborreliosis (NB) is a chronic infectious disease of the central nervous system (CNS) caused by a tick-borne spirochete, Borrelia burgdorferi. In addition to direct effects of the causative infectious agent, additional immunity-mediated mechanisms are thought to play a role in the CNS pathology of NB. In order to further understand the involvement of humoral immune mechanisms in NB, we dissected the intrathecal antibody responses down to the single-plasma-cell level. Starting with single-cell reverse transcription-PCR of fluorescence-activated cell sorter-sorted cerebrospinal fluid plasma cells from an NB patient, we identified expanded clones and resurrected the antigen specificity of their secreted antibodies through recombinant expression of the correctly paired immunoglobulin heavy- and light-chain genes as monoclonal antibodies (MAbs). As expected, we found specificity for the causative infectious agent, B. burgdorferi, among the clonally expanded plasma cell (cePC)-derived MAbs. However, from an independent cePC of the same patient, we could derive MAbs specific for human CNS myelin, without detectable cross-reactivity with B. burgdorferi antigens. While reactivity against B. burgdorferi is a known feature of humoral immune responses in NB, we show (i) that immune responses specific for self antigens may be a distinct feature of CNS infections independent of pathogen reactivity and (ii) that humoral autoimmunity in NB (since found in cePC) is the result of a truly antigen-driven immune response. Our findings indicate that in NB mechanisms may be at play that induce distinct immune responses specific for pathogen and self antigens independent from "molecular mimicry."

Publication Types:
PMID: 17517881 [PubMed - indexed for MEDLINE]

PMCID: PMC1951992


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Coinfection with Borrelia turicatae serotype 2 prevents the severe vestibular dysfunction and earlier mortality caused by serotype 1.

Cadavid D, Garcia E, Gelderblom H.

Department of Neurology and Neuroscience and the Center for the Study of Emerging Pathogens, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA. cadavidi@umdnj.edu

BACKGROUND: Relapsing fever (RF) is a multisystemic spirochetal infection caused by different Borrelia species. Studies in our laboratory have shown that disease severity varies depending on the infecting serotype. However, the relative contribution of each serotype to pathogenesis during mixed infections is not known. To investigate this, we compared the outcome of infection with isogenic serotypes 1 (Bt1) or 2 (Bt2) of the RF agent B. turicatae alone or in combination. METHODS: B cell-deficient mice were used for these experiments, to avoid serotype clearance by the host's variable membrane protein-specific antibodies. Observers masked to infection status examined infected and uninfected control mice for clinical disease and functional impairment for up to 65 days. RESULTS: All mice developed persistent infection with the serotypes with which they were originally inoculated. Severe vestibular dysfunction developed in mice infected with Bt1 alone and was associated with increased morbidity and mortality. However, coinfection with Bt2 significantly reduced the severity of vestibular dysfunction and prevented earlier mortality. In contrast, coinfection with Bt1 had little effect on the severe arthritis caused by Bt2 infection. CONCLUSIONS: The manifestations of infection with B. turicatae are significantly influenced by the combination of serotypes present during mixed infection.

Publication Types:
PMID: 17471439 [PubMed - indexed for MEDLINE]

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Comment in:
Case records of the Massachusetts General Hospital. Case 11-2007. A 59-year-old man with neck pain, weakness in the arms, and cranial-nerve palsies.

Greer DM, Schaefer PW, Plotkin SR, Hasserjian RP, Steere AC.

Department of Neurology, Massachusetts General Hospital, USA.

Publication Types:
PMID: 17429088 [PubMed - indexed for MEDLINE]

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Tick-borne encephalitis with polyradiculitis documented by MRI.

Pfefferkorn T, Feddersen B, Schulte-Altedorneburg G, Linn J, Pfister HW.

Department of Neurology, Klinikum Grosshadern, University of Munich, Munich, Germany. thomas.pfefferkorn@med.uni-muenchen.de

Publication Types:
PMID: 17420411 [PubMed - indexed for MEDLINE]

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High production of CXCL13 in blood and brain during persistent infection with the relapsing fever spirochete Borrelia turicatae.

Gelderblom H, Londoño D, Bai Y, Cabral ES, Quandt J, Hornung R, Martin R, Marques A, Cadavid D.

Department of Neurology and Neuroscience and Center for Emerging Pathogens, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA.

Relapsing fever (RF) is a multisystemic borrelial infection with frequent neurologic involvement referred to as neuroborreliosis. The absence of an effective antibody response results in persistent infection. To study the consequences to the brain of persistent infection with the RF spirochete Borrelia turicatae, we studied B cell (Igh6-/-) and B and T (Rag1-/-) cell-deficient mice inoculated with isogenic serotypes 1 (Bt1) or 2 (Bt2). We found that Bt1 was more tissue tropic than Bt2, not only for brain but also for heart. Igh6-/- mice developed more severe clinical disease than Rag1-/- mice. Bt1-infected brains had widespread microgliosis/brain macrophage activation despite localization of spirochetes in the leptomeninges rather than the brain parenchyma itself. Oligoarray analysis revealed that CXCL13 was the most upregulated gene in the brain of Bt1-infected Igh6-/- mice. CXCL13 was also the most abundant of the chemokines we measured in infected blood. Persistent infection did not result in injury to the brain. Treatment with exogenous interleukin-10 reduced microgliosis in the brain and production of CXCL13 in the blood. We concluded that brain involvement in B cell-deficient mice persistently infected with B. turicatae is characterized by prominent microgliosis and production of CXCL13 without detectable injury.

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PMID: 17356382 [PubMed - indexed for MEDLINE]

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Neurosyphilis: the reemergence of an historical disease.

Gilad R, Lampl Y, Blumstein G, Dan M.

Department of Neurology, Wolfson Medical Center, Holon, Israel.

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PMID: 17348486 [PubMed - indexed for MEDLINE]

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The mammalian host response to borrelia infection.

Cadavid D.

Department of Neurology and Neuroscience and Center for the Study of Emerging Pathogens, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. cadavidi@umdnj.edu

Tick-borne relapsing fever (RF) and Lyme disease (LD) are spirochetal infections of humans caused by different Borrelia species in endemic areas throughout the world. Our laboratory is studying the response of mammalian hosts to borrelia infection in RF and LD. For this, we use mice and non-human primates infected with B. burgdorferi sensu stricto strain N40 (N40) and the Oz1 strain of Borrelia turicatae (Bt), agents of LD and RF in North America, respectively. Our results have revealed that outbred non-human primates are significantly less susceptible than outbred mice to persistent infection with N40. In contrast, the majority of mice inoculated with the RF agent B. turicatae clear the infection, with the notable exception of residual brain or blood infection in up to 25% of cases. Little if any tissue injury occurs in immunocompetent animals with either LD or RF. In contrast, impairment of specific antibody production results in significant tissue injury, most notably in the heart, in both LD and RF. The inflammatory infiltrate is rich in plasma cells, activated macrophages and T cells, and there is significant deposition of antibody and complement, including membrane attack complex, in inflamed tissues and spirochetes. Significant loss of cardiomyocytes with apoptosis and caspase activation was observed in the heart of immunosuppressed non-human primates infected with N40 and in B cell-deficient mice infected with B. turicatae. Unlike the heart, the brain of B cell-deficient mice infected with B. turicatae showed prominent microglial activation but no detectable tissue injury. Tissues from immunosuppressed non-human primates infected with N40 produce large amounts of immunoglobulin and the B cell chemokine CXCL13, both of which significantly correlate with the spirochetal load. We conclude that the main response of mammalian hosts in LD and RF is the production of specific antibody to clear the infection. Failure of this response leads to persistent infection, which can lead to tissue injury, most notably in the heart.

Publication Types:
PMID: 17160603 [PubMed - indexed for MEDLINE]

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Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum.

Marra CM, Colina AP, Godornes C, Tantalo LC, Puray M, Centurion-Lara A, Lukehart SA.

Department of Neurology, University of Washington School of Medicine, Seattle, WA 98104-2499, USA. cmarra@u.washington.edu

To determine whether the 23S rRNA mutation that confers macrolide resistance is present in >1 Treponema pallidum strain, 58 isolates collected between 2001 and 2005 were screened for this mutation and for an unrelated sequence that distinguishes between strains. The odds of identifying a macrolide-resistant strain increased over time (P=.006). In subjects who had received macrolides in the previous year, the relative risk of harboring a resistant strain was 2.2 (95% confidence interval, 1.1-4.4; P=.02). The macrolide-resistant strains were not identical. These findings suggest that macrolide resistance may be increasing in multiple strains in response to antibiotic pressure.

Publication Types:
PMID: 17109351 [PubMed - indexed for MEDLINE]

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Chronic polyneuropathy and Lyme disease.

Mygland A, Skarpaas T, Ljøstad U.

Department of Neurology, Sørlandet Sykehus, Kristiansand, Norway. aase.mygland@sshf.no

Infection of the peripheral nervous system with Borrelia burgdorferi can present as a cranial neuropathy or radiculopathy with cerebrospinal fluid (CSF) pleocytosis and intrathecal antibody production against B. burgdorferi, or as an asymmetric peripheral neuropathy with acrodermatitis chronica atrophicans (ACA) and normal CSF findings. According to North American studies, it can also present as a symmetric chronic polyneuropathy without ACA or other Lyme manifestations. Our purpose was to investigate the prevalence of B. burgdorferi antibodies in patients presenting with isolated chronic polyneuropathy (PN) in a European region with high incidence of Lyme disease. Sera from 209 PN patients and 247 healthy blood donors from Vest-Agder County, Norway, were examined. Borrelia burgdorferi antibodies were detected in 43 (21%) PN patients and in 45 (18%) healthy blood donors (P = 0.553). The prevalence of B. burgdorferi antibodies was similar (P = 0.311) in cryptogenic PN (24/102, 24%) and PNs of identified etiologies (19/107, 18%). PN patients with B. burgdorferi antibodies had normal spinal fluid white cell count and they did not differ clinically or electrophysiologically from PN patients without antibodies. None of 20 antibody-positive PN patients responded to antimicrobial treatment. The study shows that, in Europe, chronic distal PN without ACA or other Lyme manifestations is very rarely caused by a B. burgdorferi infection.

PMID: 17038034 [PubMed - indexed for MEDLINE]

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Interaction of a neurotropic strain of Borrelia turicatae with the cerebral microcirculation system.

Sethi N, Sondey M, Bai Y, Kim KS, Cadavid D.

Department of Neurology and Neuroscience, Center for the Study of Emerging Pathogens, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, MSB H506, Newark, NJ 07103, USA.

Relapsing fever (RF) is a spirochetal infection characterized by relapses of a febrile illness and spirochetemia due to the sequential appearance and disappearance of isogenic serotypes in the blood. The only difference between isogenic serotypes is the variable major outer membrane lipoprotein. In the absence of specific antibody, established serotypes cause persistent infection. Studies in our laboratory indicate that another consequence of serotype switching in RF is a change in neuroinvasiveness. As the next step to elucidate this phenomenon, we studied the interaction of the neurotropic Oz1 strain of the RF agent Borrelia turicatae with the cerebral microcirculation. During persistent infection of antibody-deficient mice, we found that serotype 1 entered the brain in larger numbers and caused more severe cerebral microgliosis than isogenic serotype 2. Microscopic examination revealed binding of B. turicatae to brain microvascular endothelial cells in vivo. In vitro we found that B. turicatae associated with brain microvascular endothelial cells (BMEC) significantly more than with fibroblasts or arachnoidal cells. The binding was completely eliminated by pretreatment of BMEC with proteinase K. Using transwell chambers with BMEC barriers, we found that serotype 1 crossed into the lower compartment significantly better than serotype 2. Heat killing significantly reduced BMEC crossing but not binding. We concluded that the interaction of B. turicatae with the cerebral microcirculation involves both binding and crossing brain microvascular endothelial cells, with significant differences among isogenic serotypes.

Publication Types:
PMID: 16940140 [PubMed - indexed for MEDLINE]

PMCID: PMC1695479


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Neuroborreliosis in an HIV-1 positive patient.

Cerný R, Machala L, Bojar M, Rozsypal H, Pícha D.

Department of Neurology, Charles University in Prague, 2nd Faculty of Medicine, V Uvalu 84, 15006 Praha 5, Czech Republic. rudolf.cerny@lfmotol.cuni.cz

Simultaneous co-infections of Borrelia burgdorferi sensu lato and HIV-1 are rare events, with only six published cases. A case of acute neuroborreliosis with facial palsy, meningoradiculitis (Bannwarth's syndrome) in an HIV-1 positive individual is described. Diagnosis was confirmed by Western immunoblot analysis of serum and CSF and by proof of intrathecal production of antibodies against B. garinii. The patient was successfully treated with cefotaxime. In all published HIV+ cases, the course of borreliosis did not differ from that of the HIV negative population and the prognosis in properly treated patients was good.

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PMID: 16703302 [PubMed - indexed for MEDLINE]

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Residual brain infection in relapsing-fever borreliosis.

Cadavid D, Sondey M, Garcia E, Lawson CL.

Department of Neurology and Neuroscience and Center for the Study of Emerging Pathogens, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103, USA. cadavidi@umdnj.edu

BACKGROUND: Neurological involvement is common in the spirochetal infection relapsing fever (RF) in both humans and experimental animals. RF is best known for antigenic variation caused by the sequential expression of variable outer membrane lipoproteins of 2 sizes, variable small (Vsp) and variable large (Vlp) proteins. Less understood is the persistence of RF borreliae in the brain after they are cleared from the blood, referred to as residual brain infection (RBI). Our goal was to investigate the phenomenon of RBI in RF. METHODS: We studied RBI in immunocompetent mice by culturing blood and perfused brain samples 1 month after intraperitoneal inoculation with Borrelia turicatae serotype 1 (Bt1). Mice deficient in Toll-like receptor 2 (TLR2-/-) or in B and T cells (scid) were included for comparison. RESULTS: All scid mice had persistent infection in blood and brain. RBI was found in 3 (19%) of 16 immunocompetent and TLR2-/- mice. RBI was caused by either persistence of the original serotype (Bt1) or newly emerged Vsp (n=1, renamed Bt3) or Vlp serotypes. The Vsp of Bt1 (Vsp1) and Bt3 (Vsp3) were 75% identical. CONCLUSIONS: RBI in RF is relatively frequent and can occur by persistence of the original or newly emerged serotypes.

Publication Types:
PMID: 16619194 [PubMed - indexed for MEDLINE]

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Adhesion of Borrelia garinii to neuronal cells is mediated by the interaction of OspA with proteoglycans.

Rupprecht TA, Koedel U, Heimerl C, Fingerle V, Paul R, Wilske B, Pfister HW.

Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany.

To study pathogenic mechanisms of Lyme meningoradiculitis, dorsal root ganglia (DRG) cells and two neuronal cell lines (B50, SH-SY5Y) were incubated with Borrelia garinii, the Borrelia species most frequently isolated from CSF of Lyme neuroborreliosis patients in Europe. We demonstrated that (I) OspA-positive B. garinii adhere to neuronal cells, (II) Borrelia adhesion can be blocked by a monoclonal antibody against OspA, (III) preincubation with proteoglycans interferes with the adhesion process and (IV) rOspA directly binds to the proteoglycans. This indicates that both OspA and the cell bound proteoglycans are involved in the attachment of B. garinii to neuronal cells.

Publication Types:
PMID: 16603253 [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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Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients.

Pfister HW, Rupprecht TA.

Department of Neurology, Ludwig-Maximilians-University, Klinikum Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany. hans-walter.pfister@med.uni-muenchen.de

The diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production. Patients with neuroborreliosis are usually treated with intravenous ceftriaxone for 2-3 weeks. In case of allergy, doxycycline may be used. Treatment efficacy is detected by the improvement of the neurological symptoms and the normalization of the CSF pleocytosis. The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue. There is no formal definition of the PLD syndrome, and its pathogenesis is unclear. Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies.

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PMID: 16524775 [PubMed - indexed for MEDLINE]

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Dementia due to neurosyphilis with persistently negative CSF VDRL.

Lee JW, Wilck M, Venna N.

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. jlee38@partners.org

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PMID: 16344539 [PubMed - indexed for MEDLINE]

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Central nervous system Lyme disease.

Halperin JJ.

Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA. halperin@nshs.edu

Nervous system infection with Borrelia burgdorferi frequently causes meningitis and rarely causes encephalomyelitis. Altered cognitive function also can occur in the absence of central nervous system infection. Recently developed serodiagnostic tools, such as the C6 assay, and appropriate use of Western blotting promise to improve diagnostic accuracy. Treatment trials have demonstrated the efficacy of relatively brief courses of oral antimicrobial agents, even in peripheral nervous system infection and meningitis. Several well-performed studies have clearly shown that prolonged antimicrobial treatment of "post-Lyme disease" is ineffective. Diagnosis and treatment of Lyme disease continue to improve.

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PMID: 16263055 [PubMed - indexed for MEDLINE]

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Cardiac apoptosis in severe relapsing fever borreliosis.

Londoño D, Bai Y, Zückert WR, Gelderblom H, Cadavid D.

Department of Neurology and Neuroscience and Center for the Study of Emerging Pathogens, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB H506, Newark, NJ 07103, USA.

Previous studies revealed that the heart suffers significant injury during experimental Lyme and relapsing fever borreliosis when the immune response is impaired (D. Cadavid, Y. Bai, E. Hodzic, K. Narayan, S. W. Barthold, and A. R. Pachner, Lab. Investig. 84:1439-1450, 2004; D. Cadavid, T. O'Neill, H. Schaefer, and A. R. Pachner, Lab. Investig. 80:1043-1054, 2000; and D. Cadavid, D. D. Thomas, R. Crawley, and A. G. Barbour, J. Exp. Med. 179:631-642, 1994). To investigate cardiac injury in borrelia carditis, we used antibody-deficient mice persistently infected with isogenic serotypes of the relapsing fever agent Borrelia turicatae. We studied infection in hearts 1 to 2 months after inoculation by TaqMan reverse transcription-PCR and immunohistochemistry (IHC) and inflammation by hematoxylin and eosin and trichrome staining, IHC, and in situ hybridization (ISH). We studied apoptosis by terminal transferase-mediated DNA nick end labeling assay and measured expression of apoptotic molecules by RNase protection assay, immunofluorescence, and immunoblot. All antibody-deficient mice, but none of the immunocompetent controls, developed persistent infection of the heart. Antibody-deficient mice infected with serotype 2 had more severe cardiac infection and injury than serotype 1-infected mice. The injury was more severe around the base of the heart and pericardium, corresponding to sites of marked infiltration by activated macrophages and upregulation of interleukin-6 (IL-6). Infected hearts showed evidence of apoptosis of macrophages and cardiomyocytes as well as significant upregulation of caspases, most notably caspase-1. We conclude that persistent infection with relapsing fever borrelias causes significant loss of cardiomyocytes associated with prominent infiltration by activated macrophages, upregulation of IL-6, induction of caspase-1, and apoptosis.

Publication Types:
PMID: 16239571 [PubMed - indexed for MEDLINE]

PMCID: PMC1273893



Bilateral facial nerve palsy in the course of neuroborreliosis in children-dynamics, laboratory tests and treatment.

M?odzikowska-Albrecht J, Zarowski M, Steinborn B, Winczewska-Wiktor A, Gurda B, Wigowska-Sowi?ska J.

Chair and Department of Developmental Neurology Pozna? University of Medical Sciences, Poland. albrecht@amp.edu.pl

PURPOSE: Presentation of four patients with bilateral peripheral facial nerve palsy as a clinical manifestation of neuroborreliosis in children--diagnostic, treatment and prognosis. MATERIAL AND METHODS: In 2002-2004 in The Chair and Department of Developmental Neurology, 24 children from the Wielkopolska region were admitted with diagnosis of borreliosis. Among all the children with borreliosis, confirmed by serologic examination, 4 (16.7%) demonstrated bilateral peripheral facial palsy (PFP). We investigated the presence of IgM class and IgG class specific antibodies in the sera and cerebrospinal fluid (CSF) of 4 patients with bilateral PFP. (Detected by immunoenzymatic methods--ELISA.) RESULTS: Before the occurrence of PFP all the children manifested unspecified systemic symptoms such as headaches, muscle and articulation pains, weakness and in two cases a mood depression. At first all patients demonstrated elevated IgM antibodies and proper levels of IgG antibodies. Control tests administered within 2-14 months later reduction of antibodies was indicated. Two patients demonstrated significant pleocytosis in CSF test, (without the meningeal symptoms). All children were treated with physiotherapeutic procedures and were administered antibiotic intravenously. CONCLUSIONS: PFP is one of the most frequent neurological symptoms of borreliosis in children. In case of acute PFP and especially the bilateral form of PFP, neuroborreliosis is the most probable diagnosis. All children reported PFP at one side first and after several weeks the paresis of the facial nerve on the opposite side usually appeared. The clinical state of children started to improve after the introduction of physiotherapy and this process usually lasted several months.

PMID: 16119630 [PubMed - indexed for MEDLINE]

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The cure of one of the most frequent types of dementia: a historical parallel.

Nitrini R.

Neurology, University of São Paulo School of Medicine, Brazil. rnitrini@uol.com.br

The year 2005 marks the centenary of the discovery of Treponema pallidum by Schaudinn and Hoffmann, an important milestone in a long process that culminated in the cure of general paralysis of the insane, probably the most frequent type of dementia up to the first half of the 20th century. Reflections on the process that achieved the virtual eradication of general paralysis of the insane may be important in developing approaches to manage Alzheimer disease, today's most prevalent type of dementia. Both for general paralysis of the insane and Alzheimer disease, it took time for them to be recognized as frequent causes of dementia. The hypothesis of the syphilitic origin of general paralysis of the insane instigated heated debates during the 19th century, even surpassing those between proponents of the amyloid cascade versus the tau protein hypotheses for Alzheimer disease. The results of the management of general paralysis of the insane warrant special reflection. Penicillin therapy arrests the disease, but many patients did not regain their previous cognitive performance. The treatment, to be completely efficient, must be accomplished in the phase of early syphilis or in the latent period, thereby preventing the evolution to general paralysis of the insane. The same probably will be true for Alzheimer disease-to be completely successful, treatment should be given before the disease has begun to damage the brain.

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PMID: 16118533 [PubMed - indexed for MEDLINE]

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Comment on:
Sublime diagnosis of Lyme neuroborreliosis.

Segal BM, Logigian EL.

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PMID: 16087895 [PubMed - indexed for MEDLINE]

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Mild leptospirosis with three-year persistence of IgG- and IgM-antibodies, initially manifesting as carpal tunnel syndrome.

Finsterer J, Stöllberger C, Sehnal E, Stanek G.

Department of Neurology, Krankenanstalt Rudolfstiftung, Vienna, Austria. duarte@aonmail.at

Long-term persistence of IgG- and IgM-antibodies against leptospira after mild leptospirosis has not been reported. In a 45-year-old female pet-shop worker with carpal tunnel syndrome, accompanied by arthralgias, coughing, repeatedly elevated temperature, followed by easy fatigability, personality change, memory and speech disturbance, blurred vision, myalgia and swollen lymph nodes, leptospirosis was diagnosed, based upon history, clinical findings, and serological investigations. After the described symptoms had disappeared following doxycyclin for 2 weeks, IgG- and IgM-antibodies against leptospira remained positive during the next three years. This case illustrates that leptospirosis may start as carpal tunnel syndrome and that the severity of leptospirosis does not seem to be related to the intensity of the humoral immune response against the causative agent.

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PMID: 16038755 [PubMed - indexed for MEDLINE]

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Comment in:
Reactive Lyme serology in optic neuritis.

Sibony P, Halperin J, Coyle PK, Patel K.

Department of Ophthalmology and Neurology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA. psibony@notes.cc.sunysb.edu

BACKGROUND: Establishing a causal relationship between optic neuritis and Lyme disease (LD) has been hampered by technical limitations in serologic diagnosis of LD. Even so, there is a general impression that optic neuritis is a common manifestation of LD. METHODS: Retrospective case analysis of Lyme serology in 440 patients with optic neuritis examined between 1993 and 2003 in a single neuro-ophthalmic practice at Stony Brook University Medical Center, Suffolk County, New York, a region hyper-endemic for LD. RESULTS: Lyme enzyme-linked immunosorbent assay (ELISA) was positive in 28 (6.4%) patients with optic neuritis, three of whom had syphilis with cross-reactive antibodies. Among the remaining 25 ELISA-positive patients, optic neuritis could be confidently attributed to LD in only one case, a patient with papillitis. The other 24 cases had reactive Lyme serologies related to a history of LD years earlier, asymptomatic exposure, false-positive results, or non-specific humoral expansion. The ELISA in these 24 cases were weakly positive and the Western blots were negative by Centers for Disease Control criteria. There were no significant clinical differences between the 25 seropositive optic neuritis cases and 50 seronegative optic neuritis cases. CONCLUSIONS: Based on these cases and a review of the literature, there is insufficient evidence for a causal link between LD and retrobulbar optic neuritis or neuroretinitis. There is sufficient evidence to establish a causal link between LD and papillitis and posterior uveitis.

PMID: 15937426 [PubMed - indexed for MEDLINE]

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Acute peripheral facial palsy in adults.

Ljøstad U, Økstad S, Topstad T, Mygland A, Monstad P.

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

OBJECTIVE: To collect epidemiological data of peripheral facial palsy, and especially to chart the incidence and clinical characteristics of Lyme associated facial palsy. MATERIAL AND METHODS: We included consecutive adult patients presenting with peripheral facial palsy in Vest-Agder County from January 1997 to December 1998. The facial palsy was graded according to the House and Brackman facial function scoring system,and cerebrospinal fluid and serum samples were examined for Borrelia burgdorferi antibodies and virus antibodies. Final outcome was evaluated by follow up visits or telephone interview. RESULTS: Sixty nine patients were included and followed until complete recovery, or for 5 years. Ten per cent were caused by Lyme disease, 17% by virus infection, 4% by other causes and 68% were classified as Bell's palsy. All patients with Lyme facial palsy had additional neurological symptoms, and 87% reported constitutional complaints. The overall final outcome was good with complete recovery in 77%, slight sequelae in 20% and moderate sequelae in 3%. No patients experienced severe sequelae. Two of 28 patients examined with neurography had absent compound muscle action potentials in orbicularis oculi. Both made good recovery with only slight sequelae. CONCLUSIONS: Peripheral facial palsy is a common disorder with a favourable prognosis. Lyme disease seems to be an infrequent cause of facial palsy in patients without constitutional symptoms or additional neurological findings.

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PMID: 15778908 [PubMed - indexed for MEDLINE]

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Delayed resolution of white matter changes following therapy of B burgdorferi encephalitis.

Steinbach JP, Melms A, Skalej M, Dichgans J.

Department of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, School of Medicine, Germany. joachim.steinbach@uni-tuebingen.de

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PMID: 15728315 [PubMed - indexed for MEDLINE]

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Severe neuroborreliosis: The benefit of prolonged high-dose combination of antimicrobial agents with steroids--an illustrative case.

Massengo SA, Bonnet F, Braun C, Vital A, Beylot J, Bastard J.

Department of Neurology, Centre Hospitalier de Mont de Marsan, 40000 Mont de Marsan, France. massengoserge@hotmail.com

Neuroborreliosis frequently occurs in endemic areas, whereas encephalomyelitis is uncommon. Treatment consists classically of 2 to 4 weeks of recommended antimicrobial agents with a generally good outcome. A severe case is reported combining an encephalomyelitis with an axonal polyneuropathy. Clinical improvement was observed only with the use of prolonged high dose of 2 antimicrobial agents combined with steroids.

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PMID: 15698718 [PubMed - indexed for MEDLINE]

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Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue.

Alaedini A, Latov N.

Department of Neurology and Neuroscience, Cornell University, 1300 York Ave., New York, NY 10021, USA. ara2004@med.cornell.edu

Neurological sequela of chronic Lyme disease include encephalopathy, myelopathy and peripheral neuropathy. These have generally been attributed to either persistent infection or pathogen-induced autoimmunity. In this study, we investigated the presence of cross-reactive human neural epitopes that share amino acid sequences with Borrelia burgdorferi OspA protein. Sequence similarity analysis was carried out by searching known cDNA sequences from brain tissue. The cDNA database search yielded three sequences that were identical to sequences in OspA. Corresponding peptides were synthesized and antibodies were generated against them in rabbits. Antibodies against two of the homologous OspA peptides were found to react with neurons in human brain, spinal cord and dorsal root ganglia by immunohistochemistry.

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PMID: 15652419 [PubMed - indexed for MEDLINE]

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Research opportunities on human neuroborreliosis.

Gelderblom H, Martin R, Marques AR.

Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

A workshop, sponsored by the National Institutes of Health, was convened in September 2001 to evaluate the current knowledge in neurological Lyme disease. The meeting was centered into discussion of both clinical and basic aspects of the disease. Participants included researchers from the fields of infectious diseases, neurology, rheumatology, autoimmunity and basic immunology, largely but not exclusively focused on Lyme disease. This report summarizes the presentations made at the meeting.

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PMID: 15631071 [PubMed - indexed for MEDLINE]

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Treponema pallidum strain-specific differences in neuroinvasion and clinical phenotype in a rabbit model.

Tantalo LC, Lukehart SA, Marra CM.

Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98104-2499, USA.

BACKGROUND: The relationship between neuroinvasion and other manifestations of syphilis and the infecting strain of Treponema pallidum is not known. METHODS: Six groups of 8 rabbits were intravenously infected with 1 x 108 organisms from 1 of 6 strains of T. pallidum. Rabbits were examined 2-3 times/week; blood and cerebrospinal fluid (CSF) were collected weekly and every 2 weeks, respectively, for 10-12 weeks. Degree of CSF pleocytosis and skin-lesion severity were estimated by the area under the white blood cell-versus-time and lesion-versus-time curves. RESULTS: Maximum serum Venereal Disease Research Laboratory test titers, time to maximum titer, degree of CSF pleocytosis, and severity of skin lesions differed significantly among infecting strains. Overall, T. pallidum was identified, by reverse-transcriptase polymerase chain reaction, in CSF from 13 (27.7%) of 47 rabbits and was never identified in CSF from rabbits infected with 1 of the strains. The time course of detection varied by infecting strain. Severity of skin lesions and of CSF pleocytosis were inversely correlated (P=.005). CONCLUSIONS: There are particularly neuroinvasive T. pallidum strains, and the clinical phenotype of infection varies with infecting strain. This information could ultimately be used to identify patients at increased risk for neuroinvasion and, thus, at risk for neurosyphilis.

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PMID: 15593006 [PubMed - indexed for MEDLINE]

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Neurosyphilis.

Marra CM.

University of Washington School of Medicine, Harborview Medical Center, Neurology, Box 359775, 325 9th Avenue, Seattle, WA 98104-2499, USA. cmarra@u.washington.edu

Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system early in the course of disease but causes persistent infection in only a subset of infected persons. Individuals with persistent infection or asymptomatic meningitis are at risk for developing symptomatic neurosyphilis if they are not treated with a drug regimen that achieves sufficient drug levels in cerebrospinal fluid to kill the organism. In this article, recent studies that address the risk, diagnosis, and management of neurosyphilis are discussed within the context of a brief review. Particular attention is given to current controversies. In the developed world, these issues are particularly relevant to persons who are infected with HIV.

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PMID: 15509443 [PubMed - indexed for MEDLINE]

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Cardiac involvement in non-human primates infected with the Lyme disease spirochete Borrelia burgdorferi.

Cadavid D, Bai Y, Hodzic E, Narayan K, Barthold SW, Pachner AR.

Department of Neurology and Neuroscience, UMDNJ-New Jersey Medical School, Newark, NJ, USA. Cadavidi@umdnj.edu

To investigate cardiac involvement in the non-human primate (NHP) model of Lyme disease, we inoculated 39 adult Macaca mulatta with Borrelia burgdorferi sensu stricto strains N40 (BbN40) by needle (N=22, 14 immunocompetent (IC), seven permanently immunosuppressed (IS), and four transiently immunosuppressed (TISP)) or by tick-bite (N=4, all TISP) or strain 297 (Bb297) by needle (N=2 IS), or with B. garinii strains Pbi (N=4, 2 TISP and 2 IS), 793 (N=2, TISP) or Pli (N=2, TISP). Five uninfected NHPs were used as controls. Infection and inflammation was studied in the hearts and the aorta removed at necropsy 2-32 months after inoculation by (1) H&E and trichrome-staining; (2) immunohistochemistry and digital image analysis; (3) Western blot densitometry; and (4) TaqMan RT-PCR. All NHPs inoculated with BbN40 became infected and showed carditis at necropsy. The predominant cells were T cells, plasma cells, and macrophages. There was increased IgG and IgM in the heart independent of immunosuppression. The B-cell chemokine BLC was significantly increased in IS-NHPs. There was increased deposition of the complement membrane attack complex (MAC) in TISP and IS-NHPs. The spirochetal load was very high in all BbN40-inoculated IS-NHPs but minimal if any in IC or TISP NHPs. Double-immunostaining revealed that many spirochetes in the heart of BbN40-IS NHPs had MAC on their membranes. We conclude that carditis in NHPs infected with B. burgdorferi is frequent and can persist for years but is mild unless they are immunosupressed.

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PMID: 15448708 [PubMed - indexed for MEDLINE]

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Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi.

Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH 3rd.

Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY 10022, USA. nol2002@med.cornell.edu

Neurological syndromes that follow vaccination or infection are often attributed to autoimmune mechanisms. We report six patients who developed neuropathy or cognitive impairment, within several days to 2 months, following vaccination with the OspA antigen of Borrelia burgdorferi. Two of the patients developed cognitive impairment, one chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy, one both cognitive impairment and CIDP, and one cognitive impairment and sensory axonal neuropathy. The patients with cognitive impairment had T2 hyperintense white matter lesions on magnetic resonance imaging. The similarity between the neurological sequelae observed in the OspA-vaccinated patients and those with chronic Lyme disease suggests a possible role for immune mechanisms in some of the manifestations of chronic Lyme disease that are resistant to antibiotic treatment.

PMID: 15363064 [PubMed - indexed for MEDLINE]

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[Eosinophilic fasciitis associated with Borrelia afzelii infection]

[Article in Japanese]

Kikuchi O, Murai H, Ikezoe K, Kawajiri M, Ohyagi Y, Isogai E, Kira J.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University.

A 58-year-old woman suffered from stiffness, swelling, rubor and muscle pain in the extremities one month after she climbed a mountain in Kyushu, an island in southern Japan. On admission, mild proximal weakness was present in the extremities. Her range of motion in the extremities was limited due to firm skin and subcutaneous stiffness which was similar to scleroderma. She showed peripheral blood eosinophilia and hypergammaglobulinemia as well as a high erythrocyte sedimentation rate. An IgM antibody against Borrelia afzelii was positive. MRI of the skeletal muscles demonstrated enhancing fascia around the biceps brachii muscle, and a biopsy specimen revealed perivascular infiltration of mononuclear cells within the hypertrophic fascia. Eosinophilic infiltration was absent. We treated the patient with prednisolone, doxycycline and amoxicillin, which alleviated the symptoms. This is the first report to show that Borrelia afzelii was involved in eosinophilic fasciitis.

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PMID: 15287514 [PubMed - indexed for MEDLINE]

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Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIV-infected individuals.

Marra CM, Tantalo LC, Maxwell CL, Dougherty K, Wood B.

Department of Neurology, University of Washington School of Medicine, Seattle, USA. cmarra@u.washington.edu

OBJECTIVE: To identify alternatives to the CSF-Venereal Disease Research Laboratory (VDRL) test for the diagnosis of neurosyphilis in HIV-infected individuals. METHODS: CSF fluorescent treponemal antibody (FTA) reactivity and % CSF lymphocytes that were B cells in fresh and frozen samples were determined for 47 HIV-infected cases with syphilis and 26 HIV-infected controls. As for serum, CSF fluorescent treponemal antibody reactivity > or =2+ was considered positive. Based on the results in controls and cases with normal CSF measures, cut-offs for elevated CSF B cells were proposed to be > or =9% in fresh and > or =20% in frozen samples. Neurosyphilis was defined as a reactive CSF-VDRL. RESULTS: CSF-FTA-ABS (absorbed) and CSF-FTA (unabsorbed and undiluted) were 100% sensitive for the diagnosis of neurosyphilis. Elevated % CSF B cells in fresh and cryopreserved samples was specific (100%) but not sensitive (40 and 43%) in post hoc analyses. The results of CSF-FTA and assessment of % CSF B cells together allowed 16% of cases with pleocytosis but nonreactive CSF-VDRL to be diagnosed with neurosyphilis and 26% to be diagnosed as not having neurosyphilis. CONCLUSION: When the CSF-VDRL is nonreactive, CSF-FTA and % CSF B cells may help exclude or establish the diagnosis of neurosyphilis.

Publication Types:
PMID: 15249615 [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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Comment in:
Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter?

Marra CM, Maxwell CL, Tantalo L, Eaton M, Rompalo AM, Raines C, Stoner BP, Corbett JJ, Augenbraun M, Zajackowski M, Kee R, Lukehart SA.

Department of Neurology, Division of Infectious Diseases, University of Washington School of Medicine, Seattle, Washington, USA. cmarra@u.washington.edu

To identify factors that affect normalization of laboratory measures after treatment for neurosyphilis, 59 subjects with neurosyphilis underwent repeated lumbar punctures and venipunctures after completion of therapy. The median duration of follow-up was 6.9 months. Stepwise Cox regression models were used to determine the influence of clinical and laboratory features on normalization of cerebrospinal fluid (CSF), white blood cells (WBCs), CSF protein concentration, CSF Venereal Disease Research Laboratory (VDRL) reactivity, and serum rapid plasma reagin (RPR) titer. Human immunodeficiency virus (HIV)-infected subjects were 2.5 times less likely to normalize CSF-VDRL reactivity than were HIV-uninfected subjects. HIV-infected subjects with peripheral blood CD4+ T cell counts of < or =200 cells/ mu L were 3.7 times less likely to normalize CSF-VDRL reactivity than were those with CD4+ T cell counts of >200 cells/ mu L. CSF WBC count and serum RPR reactivity were more likely to normalize but CSF-VDRL reactivity was less likely to normalize with higher baseline values. Future studies should address whether more intensive therapy for neurosyphilis is warranted in HIV-infected individuals.

Publication Types:
PMID: 15034833 [PubMed - indexed for MEDLINE]

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[Lyme disease]

[Article in Japanese]

Miyazaki K.

Department of Neurology, Neurological Institute, Tokyo Women's Medical University.

Publication Types:
PMID: 15011356 [PubMed - indexed for MEDLINE]

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[Neurosyphilis]

[Article in Japanese]

Nagano I, Abe K.

Department of Neurology, Okayama University Medical School.

Publication Types:
PMID: 15011355 [PubMed - indexed for MEDLINE]

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Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features.

Marra CM, Maxwell CL, Smith SL, Lukehart SA, Rompalo AM, Eaton M, Stoner BP, Augenbraun M, Barker DE, Corbett JJ, Zajackowski M, Raines C, Nerad J, Kee R, Barnett SH.

Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA. cmarra@u.washington.edu

OBJECTIVE: To define clinical and laboratory features that identify patients with neurosyphilis. METHODS: Subjects (n=326) with syphilis but no previous neurosyphilis who met 1993 Centers for Disease Control and Prevention criteria for lumbar puncture underwent standardized history, neurological examination, venipuncture, and lumbar puncture. Neurosyphilis was defined as a cerebrospinal fluid (CSF) white blood cell count >20 cells/ microL or reactive CSF Venereal Disease Research Laboratory (VDRL) test result. RESULTS: Sixty-five subjects (20.1%) had neurosyphilis. Early syphilis increased the odds of neurosyphilis in univariate but not multivariate analyses. In multivariate analyses, serum rapid plasma reagin (RPR) titer > or =1 : 32 increased the odds of neurosyphilis 10.85-fold in human immunodeficiency virus (HIV)-uninfected subjects and 5.98-fold in HIV-infected subjects. A peripheral blood CD4+ T cell count < or =350 cells/ microL conferred 3.10-fold increased odds of neurosyphilis in HIV-infected subjects. Similar results were obtained when neurosyphilis was more stringently defined as a reactive CSF VDRL test result. CONCLUSION: Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.

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PMID: 14745693 [PubMed - indexed for MEDLINE]

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Spinal cord involvement in the nonhuman primate model of Lyme disease.

Bai Y, Narayan K, Dail D, Sondey M, Hodzic E, Barthold SW, Pachner AR, Cadavid D.

Department of Neurology and Neuroscience, and Center for the Study of Emerging Pathogens, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.

Lyme borreliosis is a multisystemic disease caused by infection with various genospecies of the spirochete Borrelia burgdorferi. The organs most often affected are the skin, joints, the heart, and the central and peripheral nervous systems. Multiple neurological complications can occur, including aseptic meningitis, encephalopathy, facial nerve palsy, radiculitis, myelitis, and peripheral neuropathy. To investigate spinal cord involvement in the nonhuman primate (NHP) model of Lyme borreliosis, we inoculated 25 adult Macaca mulatta with B. burgdorferi sensu strictu strains N40 by needle (N=9) or by tick (N=4) or 297 by needle (N=2), or with B. burgdorferi genospecies garinii strains Pbi (N=4), 793 (N=2), or Pli (N=4) by needle. Immunosuppression either transiently (TISP) or permanently (IS) was used to facilitate establishment of infection. Tissues and fluids were collected at necropsy 7-24 weeks later. Hematoxylin and eosin staining was used to study inflammation, and immunohistochemistry and digital image analysis to measure inflammation and localize spirochetes. The spirochetal load and C1q expression were measured by TaqMan RT-PCR. The results showed meningoradiculitis developed in only one of the 25 NHP's examined, TISP NHP 321 inoculated with B. garinii strain Pbi. Inflammation was localized to nerve roots, dorsal root ganglia, and leptomeninges but rarely to the spinal cord parenchyma itself. T cells and plasma cells were the predominant inflammatory cells. Significantly increased amounts of IgG, IgM, and C1q were found in inflamed spinal cord. Taqman RT-PCR found spirochetes in the spinal cord only in IS-NHP's, mostly in nerve roots and ganglia rather than in the cord parenchyma. C1q mRNA expression was significantly increased in inflamed spinal cord. This is the first comprehensive study of spinal cord involvement in Lyme borreliosis.

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PMID: 14688796 [PubMed - indexed for MEDLINE]

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Frequent detection of Mycoplasma pneumoniae in Bell's palsy.

Völter C, Helms J, Weissbrich B, Rieckmann P, Abele-Horn M.

Department of Otorhinolaryngology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080 Wuerzburg, Germany. voelter.martinez@t-online.de

The cause of Bell's palsy (BP) remains unknown despite various hints to an infectious etiology. Mycoplasma pneumoniae is a common pathogen of the respiratory tract causing pharyngitis, tracheobronchitis or pneumonia. Neurological complications are the most frequent extrapulmonary manifestation. So far, only a few case reports suggested an association between cranial nerve palsy and M. pneumoniae infection. Patients with a BP who were admitted to the Department of Otorhinolaryngology or Neurology of the University of Wuerzburg between 2000 and 2002 were tested serologically for the presence of antibodies against Borrelia burgdorferi, herpes viruses (HSV-1/2, VZV) and M. pneumoniae. The diagnosis of mycoplasmal infection was made when at least one of the following criteria was met: a threefold rise or more in the titer of antibody of M. pneumoniae in paired sample or a microparticle agglutination assay (MAG) of > or =1:40 and the detection of IgA and/or IgM antibodies in the acute phase serum. Ninety-one consecutive patients could be included. Fifteen patients showed a reactivation of a VZV ( n=12) or of a HSV-1 ( n=3) infection. In six cases the immunoblot revealed specific antibody bands for B. burgdorferi. In 24 patients (26.4%) a seroconversion of M. pneumoniae could be detected. Only two patients complained of mild respiratory symptoms. According to our results, M. pneumoniae is frequently associated with Bell's palsy. Thus, a routine screening for this pathogen, even in the absence of respiratory symptoms, is necessary.

PMID: 14576947 [PubMed - indexed for MEDLINE]

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Magnetic resonance imaging of meningoradiculomyelitis in early disseminated Lyme disease.

Tullman MJ, Delman BN, Lublin FD, Weinberger J.

Departments of Neurology and Neuroradiology, Mount Sinai School of Medicine, New York, New York, USA. mark.tullman@mssm.edu

Lyme disease, a multisystem illness caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States. There are 3 clinical stages of Lyme disease: early localized, early disseminated, and late persistent disease. Neuroborreliosis, infection of the nervous system by B. burgdorferi, may occur during early disseminated or late persistent disease. Spinal cord involvement in early disseminated disease is extremely rare. In patients with early disseminated neuroborreliosis, treatment with antibiotics often leads to rapid recovery and may prevent further complications of Lyme disease. The authors present the clinical and radiographic findings, both before and after treatment, in a patient with meningoradiculomyelitis due to early disseminated Lyme disease.

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PMID: 12889175 [PubMed - indexed for MEDLINE]

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Asymptomatic intracranial gumma in a patient with syphilitic uveitis and human immunodeficiency virus infection.

Lana-Peixoto MA, Teixeira AL Jr, Tzelikis PF, Campos WR, Curi A, Oréfice F.

Department of Neurology, Federal University of Minas Gerais, Belo Horizonte, Brazil. lanapma@uol.com.br

The case is described of a 51-y-old man with uveitis as the first clinical manifestation of syphilis and in whom laboratory work-up disclosed human immunodeficiency virus infection and asymptomatic brain gummata. The case illustrates the need for a comprehensive work-up in previously asymptomatic patients with uveitis.

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PMID: 12875526 [PubMed - indexed for MEDLINE]

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Lyme disease and the peripheral nervous system.

Halperin JJ.

Department of Neurology, North Shore University Hospital, 300 Community Drive, Manhasset, New York 11030, USA. halperin@nshs.edu

Lyme disease, the multisystem infectious disease caused by the tick-borne spirochete Borrelia burgdorferi, causes a broad variety of peripheral nerve disorders, including single or multiple cranial neuropathies, painful radiculopathies, and diffuse polyneuropathies. Virtually all appear to be varying manifestations of a mononeuropathy multiplex. Diagnosis requires that the patient should have had possible exposure to the only known vectors, Ixodes ticks, and also have either other pathognomonic clinical manifestations or laboratory evidence of exposure. Treatment with antimicrobial regimens is highly effective. The mechanism underlying these neuropathies remains unclear, although interactions between anti-Borrelia antibodies and several peripheral nerve constituent molecules raise intriguing possibilities.

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PMID: 12872317 [PubMed - indexed for MEDLINE]

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Comment in:
Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial.

Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, Dattwyler R, Chandler B.

Department of Neurology, Stony Brook University Medical Center, Stony Brook, NY 11794-8121, USA. lkrupp@notes.cc.sunysb.edu

OBJECTIVE: To determine whether post Lyme syndrome (PLS) is antibiotic responsive. METHODS: The authors conducted a single-center randomized double-masked placebo-controlled trial on 55 patients with Lyme disease with persistent severe fatigue at least 6 or more months after antibiotic therapy. Patients were randomly assigned to receive 28 days of IV ceftriaxone or placebo. The primary clinical outcomes were improvement in fatigue, defined by a change of 0.7 points or more on an 11-item fatigue questionnaire, and improvement in cognitive function (mental speed), defined by a change of 25% or more on a test of reaction time. The primary laboratory outcome was an experimental measure of CSF infection, outer surface protein A (OspA). Outcome data were collected at the 6-month visit. RESULTS: Patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (rate ratio, 3.5; 95% CI, 1.50 to 8.03; p = 0.001). No beneficial treatment effect was observed for cognitive function or the laboratory measure of persistent infection. Four patients, three of whom were on placebo, had adverse events associated with treatment, which required hospitalization. CONCLUSIONS: Ceftriaxone therapy in patients with PLS with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection in this study. Because fatigue (a nonspecific symptom) was the only outcome that improved and because treatment was associated with adverse events, this study does not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued patients with PLS.

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PMID: 12821734 [PubMed - indexed for MEDLINE]

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The immune response at onset and during recovery from Borrelia burgdorferi meningoradiculitis.

Cepok S, Zhou D, Vogel F, Rosche B, Grummel V, Sommer N, Hemmer B.

Clinical Neuroimmunology Group, Department of Neurology, Philipps University, Marburg, Germany.

BACKGROUND: Borrelia burgdorferi causes a wide range of neurologic syndromes. In Europe, acute meningoradiculitis is the most common manifestation. OBJECTIVE: To address the nature of the immune response during the course of B burgdorferi meningoradiculitis, with special respect to the early and late changes in cerebrospinal fluid (CSF). METHODS: Serial immunophenotyping was performed and cytokine measurements were obtained in the peripheral blood and CSF of 12 European patients with definite B burgdorferi meningoradiculitis. RESULTS: Early during infection and before initiation of treatment, we observed high levels of interleukin (IL) 10, IL-6, and IL-8, and large numbers of B cells and plasma cells in the CSF of most patients. At the same time, we found a mainly unspecific intrathecal antibody synthesis. During resolution of the infection, cytokine levels normalized rapidly and plasma cells disappeared from the CSF. In parallel, the percentage of B cells in the CSF increased over several months, accompanied by rising levels of intrathecally produced B burgdorferi-specific antibodies. CONCLUSIONS: Our findings demonstrate that the early phase of B burgdorferi meningoradiculitis is characterized by a well-coordinated immune response involving specific cytokine release and plasma cell recruitment, followed by a long-lasting, antigen-specific B-cell response in the central nervous system.

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PMID: 12810490 [PubMed - indexed for MEDLINE]

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Clonal accumulation of activated CD8+ T cells in the central nervous system during the early phase of neuroborreliosis.

Jacobsen M, Zhou D, Cepok S, Nessler S, Happel M, Stei S, Wilske B, Sommer N, Hemmer B.

Department of Neurology, Philipps-University, Marburg, Germany.

Borrelia burgdorferi may cause an acute infection of the central nervous system (CNS) that rarely leads to chronic disease. To characterize host immunity to B. burgdorferi in humans, we performed serial T cell receptor (TCR) variable beta (TCRBV) chain analyses in blood and cerebrospinal fluid (CSF) samples from 10 patients with acute neuroborreliosis. In most patients, we found significant differences in TCRBV expression between CSF and peripheral blood T cells, predominantly involving CD8(+) T cells. T cells that accumulated in the CSF had a memory phenotype and expressed high levels of C-C chemokine receptor 5 and CD69. Serial studies demonstrated that CD8(+) T cell accumulation decreased continuously after resolution of the infection. In 2 patients, serial analysis of the TCR-alpha and -beta chain sequences revealed that overexpression of TCRBV in CSF was caused by extensive clonal expansion of CD8(+) T cells. Our findings support the role of CD8(+) T cells during the early host defense against spirochete infection of the CNS.

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PMID: 12660943 [PubMed - indexed for MEDLINE]

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Comment in:
Lyme disease and optic neuritis: long-term follow-up of seropositive patients.

Jacobson DM.

Departments of Neurology and Ophthalmology, Marshfield Clinic, Marshfield, WI, USA. jacobsod@mfldclin.edu

PMID: 12629255 [PubMed - indexed for MEDLINE]

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Intracerebral haemorrhage as a manifestation of Lyme neuroborreliosis?

Scheid R, Hund-Georgiadis M, von Cramon DY.

Day Clinic of Cognitive Neurology, University of Leipzig, Germany. scheid@cns.mpg.de

Lyme Neuroborreliosis (LNB) has repeatedly been reported to cause cerebral vasculitis. However, there is no reliable information about the incidence of cerebral vessel affection. The majority of reports deal with ischaemic consequences, and there are a few reports of subarachnoid haemorrhage (SAH). We report a case of otherwise unexplained intracerebral haemorrhage (ICH) where clinical and laboratory tests have shown LNB. Late stage LNB might not only cause ischaemic, but haemorrhagic stroke as well.

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PMID: 12535004 [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.

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PMID: 12422598 [PubMed - indexed for MEDLINE]

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Antibacterial therapy of neurosyphilis: lack of impact of new therapies.

Ali L, Roos KL.

Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

Neurosyphilis is caused by the spirochete Treponema pallidum. These organisms divide slowly, requiring long exposure to antibacterials for treatment success. In order for an antibacterial to be effective in the therapy of neurosyphilis, it must achieve treponemicidal concentrations in the CSF, have a long half-life and be given in a treatment regimen that favours compliance. Penicillin was first introduced for the treatment of syphilis in 1943, and despite interest in the use of amoxicillin, erythromycin, tetracycline, doxycycline, ceftriaxone and azithromycin, penicillin remains the only recommended antibacterial agent for neurosyphilis.

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PMID: 12421113 [PubMed - indexed for MEDLINE]

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Geniculate neuralgia as a manifestation of neuroborreliosis.

Frese A, Lüttmann RJ, Husstedt IW, Ringelstein EB, Evers S.

Department of Neurology, University of Münster, Germany.

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PMID: 12390649 [PubMed - indexed for MEDLINE]

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Peripheral neuropathy in acrodermatitis chronica atrophicans - effect of treatment.

Kindstrand E, Nilsson BY, Hovmark A, Pirskanen R, Asbrink E.

Karolinska Institute, Department of Neurology, Huddinge University Hospital, Stockholm, Sweden.

Forty-seven patients with the late borrelial manifestation acrodermatitis chronica atrophicans (ACA) and with objective neurological and/or neurophysiological findings were followed up after antibiotic treatment with dermatological, serological, neurological and neurophysiological controls. Despite a good therapeutic effect on ACA lesions, specific antibody values and symptoms of irritative nerve lesions, the objective neurological and neurophysiological findings of nerve deficit remained unchanged. There was no progress of neuropathy findings during the follow-up time. Our interpretation of the results is that the remaining neuropathy signs after treatment of ACA are neurological sequelae and not manifestations of persisting Borrelia infection.

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PMID: 12371917 [PubMed - indexed for MEDLINE]

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Lyme disease.

Coyle PK.

Department of Neurology, School of Medicine, State University of New York at Stony Brook, HSC, T-12 Room 020, Stony Brook, NY 11794-8121, USA. pcoyle@notes.cc.sunysb.edu

Lyme disease is due to infection with a tick-borne spirochete, Borrelia burgdorferi. Risk for infection is confined to regions that contain the Ixodid tick vector. Characteristic skin, musculoskeletal, cardiac, ocular, and neurologic disorders are associated with the local, early dissemination and late stages of infection. Neurologic involvement can be seen at all stages, and involves both central and peripheral nervous system syndromes. The inability to easily culture B. burgdorferi and the lack of a reliable active infection assay have contributed to controversies in diagnosis and management. Because the vast majority of patients are seropositive, however, antibody testing is helpful to support the diagnosis of Lyme disease. With appropriate antibiotics, most patients do well. This infection provides an important model system to understand how interactions between an organism, vector, and host lead to disease. It also provides a model to study how infectious agents lead to neurologic disease.

Publication Types:
PMID: 12359100 [PubMed - indexed for MEDLINE]

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Avidity determination of Borrelia burgdorferi-specific IgG antibodies in Lyme disease.

Rauer S, Beitlich P, Neubert U, Rasiah C, Kaiser R.

Department of Neurology, Albert Ludwig University, Freiburg, Germany. rauer@nz11.ukl.uni-freiburg.de

The avidity indices of Borrelia burgdorferi-specific IgG antibodies were estimated using ELISA in sera from patients with different stages of Lyme disease. In addition, sera from healthy students with proof of borrelial-specific IgG antibodies from standard serology were tested. Low avidity indices were detected predominantly in sera from patients with early-stage Lyme disease [erythema migrans (EM); n = 25]. High avidity indices were found in healthy students (n = 72) and in most of the patients with neuroborreliosis (NB; n = 44) and chronic late-stage Lyme disease [acrodermatitis chronica atrophicans (ACA); n = 36]. In conclusion, early-stage Lyme disease (EM) could be differentiated from advanced and chronic stages (NB, ACA) and from "seropositive" healthy persons using avidity determination in the majority of patients in this study.

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PMID: 11760158 [PubMed - indexed for MEDLINE]

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Incidence and prevalence of infection with human granulocytic ehrlichiosis agent in Germany. A prospective study in young healthy subjects.

Woessner R, Gaertner BC, Grauer MT, Weber K, Mueller-Lantzsch N, Hunfeld KP, Treib J.

Dept. of Neurology, Westpfalz Medical Center, Kaiserslautern, Germany.

BACKGROUND: Only limited data are available on incidence and prevalence of infection with the human granulocytic ehrlichiosis (HGE) agent in a healthy population. MATERIALS AND METHODS: In a prospective study, we tested 361 male soldiers (age 18-29 years) from southwestern Germany for the HGE agent immunoglobulin G (IgG) using an indirect immunofluorescence antibody assay and for Borrelia burgdorferi IgG with an ELISA at the beginning and the end of their 10-month military service. Using a standardized questionnaire, the subjects were asked about clinical symptoms at the beginning and the end of the observation period. RESULTS: Of these 361 subjects, 14.9% were HGE agent IgG positive at study entry. 19 participants (5.3%) seroconverted from IgG negative to positive during the observation period resulting in an incidence rate of 6.4% per year. 20 subjects converted from initially HGE agent IgG positive to negative resulting in a reconversion rate of 6.6% per year. Concurrence of Borrelia IgG and HGE agent IgG was observed in 21.1%, whereas 13.7% were HGE agent IgG positive but Borrelia IgG negative (not significant). Clinical symptoms associated with HGE were not present in seroconverting subjects. CONCLUSION: Infection with the HGE agent occurs frequently in southwestern Germany but was asymptomatic in these young subjects.

PMID: 11688905 [PubMed - indexed for MEDLINE]

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Bell's palsy: electrodiagnostics are not indicative of cerebrospinal fluid abnormalities.

Birkmann C, Bamborschke S, Halber M, Haupt WF.

Department of Neurology, University of Cologne, Germany.

Electrodiagnostic testing (electromyography, electroneuronography, and blink reflex) and cerebrospinal fluid (CSF) examination (cell count, immunoglobulins, and antigen-specific intrathecal immunoglobulin G synthesis against herpes simplex virus, varicella zoster virus, cytomegalovirus, and Borrelia burgdorferi sensu latu) were performed in 56 patients with Bell's palsy. The CSF was normal in 45 patients and abnormal in 11 patients. Acute borreliosis was the most common specific pathological CSF finding (4 of 11). Electromyography revealed abolished volitional activity in 22% of patients with normal CSF and in 36% with pathological CSF. Electroneuronographic tests with an amplitude decrease of more than 90% on the affected side or abolished responses were found in 20% of patients with normal CSF and in 18% with pathological CSF. Abolished orbicularis oculi reflexes were seen in 67% of patients with normal CSF and in 82% with pathological CSF Concerning electrodiagnostic testing, no statistically significant difference between patients with normal and abnormal CSF was found, so we conclude that electrodiagnostic testing has no indicative value for abnormal CSF in Bell's palsy.

PMID: 11407851 [PubMed - indexed for MEDLINE]

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Neurosyphilis showing transient global amnesia-like attacks and magnetic resonance imaging abnormalities mainly in the limbic system.

Fujimoto H, Imaizumi T, Nishimura Y, Miura Y, Ayabe M, Shoji H, Abe T.

First Department (Neurology) of Internal Medicine, Kurume University School of Medicine, Asahimachi.

We report a case of neurosyphilis with transient global amnesia (TGA)-like attacks on the first presentation. MRI abnormalities in bilateral limbic systems, including a few lesions in the basal ganglia and thalamus, were identified. Depression and dementia became apparent, accompanied by a high treponemal antibody titer and mild cortical atrophy. Antisyphilitic therapy brought about mild improvement, and the MRI abnormalities decreased.

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PMID: 11393420 [PubMed - indexed for MEDLINE]

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Cortical reflex action myoclonus in neurosyphilis.

Okuma Y, Tanaka R, Fujishima K, Kobayashi T, Mizuno Y.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. SGZ02202@nifty.ne.jp

Publication Types:
PMID: 11306871 [PubMed - indexed for MEDLINE]

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[Spirochetal infection]

[Article in Japanese]

Yamazaki M, Koh S.

Department of Neurology, Nagano Red Cross Hospital.

Publication Types:
PMID: 11212756 [PubMed - indexed for MEDLINE]

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Lyme borreliosis mimicking central nervous system malignancy: the diagnostic pitfall of cerebrospinal fluid cytology.

Kieslich M, Fiedler A, Driever PH, Weis R, Schwabe D, Jacobi G.

Department of Pediatric Neurology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany. mkieslich@zki.uni-frankfurt.de

We report two children with acute loss of neurological functions and signs of an increased intracranial pressure. Imaging techniques ruled out space occupying lesions, whereas CSF cytology indicated CNS involvement of a non-Hodgkin lymphoma in the form of abnormal lymphocytic pleocytosis with malignancy criteria fulfilling lymphoid cells. CSF protein electrophoresis and Borrelia burgdorferi serology revealed neuroborreliosis which was successfully treated with antibiotic therapy. The malignancy mimicking cytology is based on a blastoid transformation of B- and T-lymphocytes due to the antigenic stimulus of B. burgdorferi infection. Lymphoid cells in the CSF of a patient with acute or chronic neurological symptoms raise the differential diagnosis of inflammatory etiology versus CNS lymphoma. Monomorphism and higher quantity of the lymphoid cells point to CNS lymphoma. A lower quantity and polyclonal pattern of lymphoid cells associated with an elevated protein fraction caused by intrathecal immunoglobulin synthesis suggest an inflammatory etiology.

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PMID: 11185583 [PubMed - indexed for MEDLINE]

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Pachymeningitis luetica: a case report.

Joosten AA, Prevo RL, de Vos RA, Hendrix MG, Boomstra S, Jansen Steur EN.

Department of Neurology, Medisch Spectrum Twente, PO Box 50.000, 7500 KA Enschede, The Netherlands.

Pachymeningitis luetica is extremely rare in developed countries. We describe a 41-year-old male patient with pachymeningitis luetica, multiple ischaemic infarctions, and severe hydrocephalus. The delay in making the diagnosis contributed to patient's death. Rapid diagnosis is essential on the slightest suspicion of an infection by Treponema pallidum, because timely treatment with antibiotics is effective.

Publication Types:
PMID: 10996719 [PubMed - indexed for MEDLINE]

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Molecular mimicry in infectious encephalitis and neuritis: binding of antibodies against infectious agents on Western blots of human nervous tissue.

Birner P, Gatterbauer B, Drobna D, Bernheimer H.

Institute of Neurology, University of Vienna, Austria.

OBJECTIVES: To study the occurrence of cross-reactivities of antibodies against infectious agents with human nervous tissue. METHODS: Binding of 25 antibodies against 17 neurotropic pathogens comprising Borrelia burgdorferi, Toxoplasma gondii, and various DNA and RNA viruses to Western blots of human cortex and myelin from central and peripheral nervous system was investigated. RESULTS: Fourteen of the 25 antibodies tested showed binding to Western blots of human nervous tissue, suggesting the presence of shared epitopes. Binding of 11 antibodies against 10 pathogens to cortex and/or myelin correlated with the tissue targeted by neuropathological lesions. Three antibodies did not show such correlation; 11 antibodies did not bind at all. CONCLUSIONS: Our results suggest that shared epitopes between infectious agents and human nervous tissues are more common than previously expected. Thus, molecular mimicry should be considered more frequently as a possible pathogenetic mechanism, among others, inducing tissue damage in encephalitis and neuritis caused by various pathogens. Copyright 2000

PMID: 10942637 [PubMed - indexed for MEDLINE]

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The Erve virus: possible mode of transmission and reservoir.

Woessner R, Grauer MT, Langenbach J, Dobler G, Kroeger J, Mielke HG, Mueller P, Haass A, Treib J.

Dept of Neurology, Westpfalz Clinic, Kaiserslautern, Germany.

The Erve virus is suspected to cause severe headache in humans, lasting several days (thunderclap headache). Mice are characterized as a probable reservoir for the Erve virus. We tested 396 wild mice for Erve virus using an immunofluorescence test and found Erve virus antibodies in five cases, showing that small mammals form a reservoir for Erve virus. If ticks are the vector for the virus, a coincidence with borreliosis should exist. We were unable to confirm this in a homogeneous cohort of 955 young men, 62 of whom tested positive for borreliosis. This group did not test positive significantly more often in the immunofluorescence test than a gender- and age-matched control group.

PMID: 10879642 [PubMed - indexed for MEDLINE]

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The history of tabes dorsalis and the impact of observational studies in neurology.

Nitrini R.

University of São Paulo, Brazil.

It is common for a particular aspect of scientific knowledge to undergo a great advance in a brief period of time after the discovery of new investigational procedures that broaden research horizons. Knowledge of neurosyphilis increased markedly during the second half of the 19th century. As revealed by the example of tabes dorsalis, this progress was not related to new research methods but instead to the impetus of careful clinical observations.

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PMID: 10768641 [PubMed - indexed for MEDLINE]

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A comparison study of two therapeutic protocols for neurosyphilis.

Serragui S, Yahyaoui M, Hassar M, Chkili T, Bouhaddioui N, Soulaymani R.

Anti-Poison Centre of Morocco, National Health Institutes, Rabat, Morocco.

In Morocco, neurosyphilis is a serious public health problem. In the neurology service at the specialist hospital in Rabat, two drug treatments were used. Treatment A consisted of infusion over a period of 4 h of 20 MUI of penicillin G per day for 3 weeks. Treatment B consisted of infusion over a period of 6 h of 30 MUI of penicillin G per day for 10 days. Each treatment was tested on a group of eight neurosyphilitic patients as first-line treatment. On the first day of treatment, both blood and CSF pharmacokinetics were sampled for each patient. Blood and CSF were taken within 24 h. Penicillin G concentrations were determined by a microbiological method. The results obtained showed that perfusions of either 20 MUI or 30 MUI of penicillin allowed the achievement of high serum concentrations. These increased progressively until reaching their maximum at T4 h for treatment A (from 92.33 to 106.38 micrograms/ml). For treatment B, maximal concentration is obtained at T6 h (from 108 to 141.52 micrograms/ml). Penicillin concentrations decreased immediately after stopping the perfusion. At CSF levels, penicillin G concentrations were identical to serum concentrations. However, one difference was observed: a one-hour difference between the serum and CSF peaks. The CSF peak was achieved at T5 h for treatment A (0.063 to 2.25 micrograms/ml) and at T7 h for treatment B (0.92 to 2.94 micrograms/ml). The concentrations obtained were largely superior to the CMI of Treponema pallidum for both treatment A and treatment B, at 47 times and 82 times higher respectively. The recovery time of the patients was 14 h for treatment A and 24 h for B treatment. These results have shown that therapeutic method B was more efficient than A. Moreover, the evolution of penicillin G's diffusion in the CSF during treatment, of cell counts of protein level, of the VDRL test and of the gamma-globulin rate was studied.

Publication Types:
PMID: 10667099 [PubMed - indexed for MEDLINE]

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Is IgM of diagnostic value in case of delayed intrathecal production of IgG antibodies?

Pierer K, Stünzner D, Feichtinger M, Homann CN, Kleinert G, Kessler HH, Marth E.

Institute of Hygiene, Medical School, Karl Franzens University, Graz, Austria.

The neurological manifestations of Lyme borreliosis comprise a wide range of clinical signs. However, these symptoms might have other aetiologies. Therefore detection of intrathecal production of specific antibodies is necessary to confirm the clinical assumption of neuroborreliosis (NB). In case of delayed intrathecal production of specific IgG antibodies, detection of IgM could play a role in the early diagnosis of NB. To clarify whether IgM is of diagnostic value in such cases, paired CSF serum samples from 176 patients with suspected NB admitted to the department of Neurology, Karl Franzens University, Graz, Austria, were tested. Testing was performed with the IDEA Neuroborreliosis Kit (Dako, Denmark) and Enzygnost Borreliosis (Behring, Germany) and results of both methods were compared. According to well defined criteria 63 of the 176 patients had defined NB and 113 were regarded as possible NB. Twelve out of 63 patients with defined NB had delayed intrathecal IgG production. Only one patient with delayed IgG production had an intrathecal IgM production prior to IgG. In all patients with possible NB no intrathecal production of IgM was detected. At the time of the first lumbar puncture IgG intrathecal production could be detected with the IDEA seven times more often than with the Enzygnost Borreliosis. The determination of intrathecal production of IgM does not appear to be of diagnostic value in patients with delayed IgG antibody production. Therefore a consecutive lumbar puncture is more likely to confirm clinical assumption if there is strong clinical evidence of NB.

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PMID: 10666808 [PubMed - indexed for MEDLINE]

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Overdiagnosis and overtreatment of Lyme neuroborreliosis are preventable.

Prasad A, Sankar D.

Department of Neurology, New York University Medical Center, NY 10016, USA.

The problems of diagnosis and treatment of Lyme neuroborreliosis can be minimised by strictly following the clinical diagnostic criteria, and understanding the pitfalls of laboratory tests. The diagnosis is based solely on objective clinical findings, with serologic test results used only to confirm the diagnosis. It must be underscored that serologic testing, when ordered without regard for clinical presentation (i.e., used as a screen), may be misleading due to its extremely low positive predictive value. Enzyme-linked immunosorbent assay should always be confirmed by Western blot. The cerebrospinal fluid Borrelia burgdorferi antibody index is more meaningful than simple titres of specific antibody. Polymerase chain reaction is still a research tool and should not be utilised without clinical correlation. All serologic tests and polymerase chain reaction may remain positive long after successful treatment. Overdiagnosis and overtreatment can be minimised by following these guidelines.

Publication Types:
PMID: 10621874 [PubMed - indexed for MEDLINE]

PMCID: PMC1741416


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Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology.

Kaplan RF, Jones-Woodward L, Workman K, Steere AC, Logigian EL, Meadows ME.

Department of Neurology, Tufts University School of Medicine, Boston, Massachusetts, USA.

A small percentage of Lyme patients develop mild to moderate encephalopathic symptoms months to years after diagnosis and treatment. Their symptoms typically include fatigue, memory loss, sleep disturbance, and depression. However, the etiology of this syndrome remains controversial. It is generally thought that Lyme patients with abnormal cerebral spinal fluid (CSF) have a neurological basis to their illness. To further examine this question, we compared Lyme patients with evidence of abnormal CSF, intrathecal antibody to Borrelia burgdorferi, elevated protein, or a positive polymerase chain reaction for B. burgdorferi DNA (n = 14); Lyme patients with normal CSF (n = 18); and healthy controls (n = 15) on a battery of neuropsychological and personality tests. Although both Lyme groups reported memory problems, only the Lyme group with abnormal CSF had measurable memory deficits. Both Lyme groups had higher depression scores than the normal control group, although depression was not correlated with memory scores. It appears that Lyme patients with abnormal CSF may have a neurological basis to their illness, whereas affective symptoms, common to many chronic disorders, may predispose other Lyme patients to the perception of cognitive dysfunction.

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PMID: 10382565 [PubMed - indexed for MEDLINE]

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Absence of Borrelia burgdorferi-specific immune complexes in chronic fatigue syndrome.

Schutzer SE, Natelson BH.

Department of Medicine, University of Medicine and Dentistry, New Jersey Medical School, Newark 07103, USA. schutzer@umdnj.edu

Chronic fatigue syndrome (CFS) and Lyme disease often share clinical features, especially fatigue, contributing to concern that Borrelia burgdorferi (Bb), the cause of Lyme disease, may underlie CFS symptoms. We examined 39 CFS patients and 40 healthy controls with a Bb immune complex test. Patients and controls were nonreactive. Centers for Disease Control and Prevention-defined CFS patients lacking antecedent signs of Lyme disease--erythema migrans, Bell's palsy, or large joint arthritis--are not likely to have laboratory evidence of Bb infection.

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PMID: 10522896 [PubMed - indexed for MEDLINE]

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Comment on:
Neuropsychological deficits in neuroborreliosis.

Primavera A, Gazzola P, De Maria AF.

Publication Types:
PMID: 10489074 [PubMed - indexed for MEDLINE]

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[A case of Lyme disease with the triad of neurologic manifestations (meningitis, radiculoneuritis, facial nerve palsy) and dermatitis of the nail roots]

[Article in Japanese]

Murakami I, Hara H, Shigeto H, Yamada T, Isogai E, Kira J.

Department of Neurology, Graduate School of Medicine, Kyushu University.

A 23-year-old man experienced dysesthesia of the distal parts of four limbs and spilling of drinking water from the right corner of his mouth. He also experienced low grade fever, headache, and nausea. Neurological examination showed weakness of the right frontal, orbicularis oculi and orbicularis oris muscles, atrophy and weakness of the interosseous muscles in both upper limbs and dysesthesia in the distal parts of four limbs. Laségue's sign was also positive on the left side. Examination of CSF showed lymphocytic pleocytosis and an increase of total protein. Serum antibody against Borrelia garinii was positive as determined by ELISA. The patient was diagnosed as a case of Lyme disease. His symptoms were not alleviated by administration of ceftriaxone (2 g/day) for 15 days, and dermatitis of nail roots appeared. Following administration of penicillin G at a high dose (12 million units/day) for 20 days, both neurologic symptoms and dermatitis were alleviated. Since B. garinii was reported to move preferentially toward the sites of low temperature, dermatitis of nail roots may be one of the characteristic features of Lyme disease caused by B. garinii.

Publication Types:
PMID: 10424152 [PubMed - indexed for MEDLINE]

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Central nervous system infection caused by Borrelia burgdorferi. Clinico-pathological correlation of three post-mortem cases.

Bertrand E, Szpak GM, Pi?kowska E, Habib N, Lipczy?ska-Lojkowska W, Rudnicka A, Tylewska-Wierzbanowska S, Kulczycki J.

Department of Neuropathology, Institute of Psychiatry and Neurology, Warszawa.

The spirochete Borrelia burgdorferi (B. burgdorferi) may cause severe meningoencephalomyelitis as the sole manifestation of Lyme borreliosis. We would like to present three such cases, where definite neuroborreliosis was clinically diagnosed in two cases and possible neuroborreliosis was recognized in one case. Alive spirochetes were isolated and cultured from blood and cerebrospinal fluid (CSF) in both definite cases. B. burgdorferi as the causative agent of the infection was confirmed in CSF by polymerase chain reaction (PCR) in one definite case. In the possible case spirochetes were cultured from blood and CSF. Alive spirochetes were not isolated, however anti-B. burgdorferi antibody value in serum was significantly elevated. On necropsy gross examination brain edema without focal changes was detected in two cases. Cerebral atrophy was seen in Case 3. Microscopically, lymphocytic infiltrates, microglial diffuse and nodular activation, spongiform changes, diffuse demyelination of the cerebral and cerebellar white matter, and diffuse astrocytosis, were characteristic pathological features in all presented cases. Multifocal, perivascular degenerative changes in the cerebral and cerebellar white matter were observed in the first case. Inflammatory changes in the nuclei and roots of cranial nerves were present in the third case.

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PMID: 10337063 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder.

Hess A, Buchmann J, Zettl UK, Henschel S, Schlaefke D, Grau G, Benecke R.

Department of Neurology, University of Rostock, Germany.

BACKGROUND: We report on a 42-year-old female patient who presented with a schizophreniform disorder and complete relief of symptoms after specific therapy. METHODS: Cerebrospinal fluid and magnetic resonance imaging findings led to the diagnosis of Lyme disease. RESULTS: To our knowledge this is the first reported case with an exclusive psychiatric manifestation of Lyme disease. CONCLUSIONS: In case of first manifestation of psychotic disorder, although neurological symptoms are lacking, Lyme disease should be considered and be excluded by cerebrospinal fluid analysis.

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PMID: 10188012 [PubMed - indexed for MEDLINE]

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Pathogenesis of neuroborreliosis--lessons from a monkey model.

Pachner AR, Schaefer H, Amemiya K, Cadavid D, Zhang WF, Reddy K, O'Neill T.

Department of Neurology, Georgetown University Hospital, Washington, D.C., USA.

The diagnosis of human LNB can be difficult, because its major clinical manifestations--meningitis, facial palsy, radiculitis, and neuritis--are non-specific and the characteristic skin lesion is usually absent at the time of neurological involvement. Thus, CSF assays are often used in diagnosis. Culture of CSF is rarely performed because it has a low yield and requires special culture medium. PCR of the CSF identified spirochetal DNA in clinical specimens with greater sensitivity, but it suffers from a number of disadvantages. Measurement of specific antibody in the CSF also has its limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. The recent development of the nonhumane primate (NHP) model of LNB allows us to address this need in a faithful model of human LNB. We compared PCR and culture in their ability to detect spirochetal presence in the CSF and brain tissue of infected NHPs, and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Using these four assays (PCR, culture, MIT, and CSF Ab) at least one assay for spirochetal presence in CSFs from NHPs was positive in 87% of CSFs tested during early infection in the CNS. Detection of spirochetal presence by PCR, MIT, and culture in the CSF was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR in infected NHPs; antibody in the CSF was the most useful assay in immunocompetent NHPs. This is the first study demonstrating that a bioassay using inoculation of mice, the mouse infectivity test (MIT), has potential as a useful adjunct in the diagnosis of LNB. The MIT for LNB was modeled after the rabbit infectivity test or RIT, which is considered the "gold standard" for the diagnosis of the related CNS infection, neurosyphilis, and felt to be very sensitive and specific. The presence of specific anti-B. burgdorferi antibody in the CSF is the most widely used assay for Lyme neuroborreliosis. In the immunocompetent NHPs in our study it was a very successful assay for detection of CNS invasion. However, it is frequently false-negative, especially early in the course of the infection, or if there is transient immunosuppression. Transient suppression of the anti-B. burgdorferi immune response in the human could occur in instances of co-infection, i.e. simultaneous transmission via the tick of another pathogen other than B. burgdorferi. Thus, mild immunosuppression as accomplished in our NHPs with corticosteroids was designed to mimic conditions in the human host which allow B. burgdorferi in the natural state to gain a firm foothold in the central nervous system in the 10-15% of B. burgdorferi-infected patients who develop clinically symptomatic nervous system disease. This study is the first to compare utility of available diagnostic techniques in LNB in which necropsy proved presence of infection in the CNS. None of the assays was ideal for all conditions, and the utility of the assay was associated with the host immune status. The differences in the responses of immunocompromised and immunocompetent NHPs in this study were striking. In immunocompetent NHPs the window of opportunity for CNS invasion prior to the development of CSF antibody was brief, and the chance of detection of spirochete low by any of the three techniques used (i.e. culture, PCR, or MIT); in this group, measurement of CSF antibody was generally diagnostic. In immunocompromised NHPs, intrathecal antibody production was delayed, and this helpful diagnostic assay was false-negative; diagnosis required more labor-intensive assays such as PCR, culture, an

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PMID: 10048168 [PubMed - indexed for MEDLINE]

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Comment in:
Clinical and serologic follow-up in patients with neuroborreliosis.

Treib J, Fernandez A, Haass A, Grauer MT, Holzer G, Woessner R.

Department of Neurology, University of the Saarland, Homburg, Germany.

The authors performed a clinical and serologic follow-up study after 4.2 +/- 1.2 years in 44 patients with clinical signs of neuroborreliosis and specific intrathecal antibody production. All patients had been treated with ceftriaxone 2 g/day for 10 days. Although neurologic deficits decreased significantly, more than half the patients had unspecific complaints resembling a chronic fatigue syndrome and showed persisting positive immunoglobulin M serum titers for Borrelia in the Western blot analysis.

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PMID: 9818893 [PubMed - indexed for MEDLINE]

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Prevalence of antibodies to tick-borne encephalitis virus and Borrelia burgdorferi sensu lato in samples from patients with abnormalities in the cerebrospinal fluid.

Treib J, Woessner R, Grauer MT, Mueller-Reiland D, Haass A, Schimrigk K.

Department of Neurology, University of the Saarland, Homburg, Germany. nejtre@krzsun.med-rz.uni-sb.de

Within the last few years, an increase in cases of tick-borne encephalitis (TBE) as well as an expansion of TBE-endemic regions have been noted in southern Germany. In 1994, a patient was diagnosed for the first time with TBE that had been acquired in Saarland. Up to this point, the Saarland had been considered TBE-free. In a retrospective study, we tested serum samples from 904 patients with abnormalities in the cerebrospinal fluid (CSF) for TBE antibodies. The IgG ELISA used (Immunozym-FSME-IgG, Immuno GmbH, Heidelberg, Germany) yielded 47 positive and 134 borderline sera. The percentage of positive sera showed a significant increase during the time period studied (1989-1994): One IgG-positive serum sample was also IgM-positive. Of the CSF samples, 2 were IgG-positive and 7 were borderline for IgG. In three patients, a positive intrathecal antibody index (IAI) was found, indicating an incrathecal antibody production. An analysis of the vaccination history of the patients showed that only 19% of the patients with a positive TBE IgG titre and only 5.9% of the borderline patients had been vaccinated against TBE. We compared 98 patients that tested positive or borderline for TBE IgG with 98 sex-and-age-matched patients that tested negative. The parameters studied included the patient's complaints upon discharge, the average duration of stationary treatment and 16 different neurological symptoms. We did not observe any significant differences between the two groups. We also tested the sera of 704 of the 904 patients for antibodies to Borrelia burgdorferi (Borrelia burgdorferi ELISA, Genzyme Virotech GmbH, Rüsselsheim, Germany). 155 (22.0%) of the sera were IgG-positive, 136 (19.3%) were borderline, 32 patients (4.6%) had a positive intrathecal antibody index (IAI). The fact that no patient with a clinically manifest case of TBE had acquired the disease in the Saarland indicates that the actual risk of acquiring an acute TBE in the Saarland is very low, despite the high percentage of samples that tested positive for IgG in the ELISA. The increase in the number of serum samples that tested positive for TBE IgG during the last years could be explained by an expansion of TBE regions into the Saarland, increasing vaccination of the population or more travel to endemic regions. The proportion of patients with IgG antibodies to Borrelia was 22%. Because only part of the patients suffered from an acute, clinically manifest borreliosis, and since the serum IgG titre had remained positive for many years after contact with the microorganisms, we suspected that a large percentage of the population would show signs of a clinically silent infection in their sera. 4.6% of the patients had a positive IAI quotient, a clear indication of neuroborreliosis.

PMID: 9809406 [PubMed - indexed for MEDLINE]

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10 questions about Lyme neuroborreliosis.

Prasad A, Hanson R.

Department of Neurology, New York University Medical Center, New York 10016, USA.

The diagnosis of Lyme neuroborreliosis requires a high index of suspicion and chronological correlation of the clinical findings and laboratory data. The limitations of serologic tests must be understood. Cerebrospinal fluid anti-Borrelia burgdorferi antibody index is currently the best indicator of Lyme neuroborreliosis.

PMID: 9784947 [PubMed - indexed for MEDLINE]

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Comment in:
Mechanisms of clearance of Treponema pallidum from the CSF in a nonhuman primate model.

Marra CM, Castro CD, Kuller L, Dukes AC, Centurion-Lara A, Morton WR, Lukehart SA.

Department of Neurology, University of Washington Regional Primate Research Center, University of Washington, Seattle, USA.

OBJECTIVES: To establish a model of CNS invasion by Treponema pallidum and to use it to investigate the immune mechanisms responsible for clearance. METHODS: Four macaques were intrathecally inoculated with 0.6 to 2.1 x 10(8) T. pallidum and underwent clinical examinations and blood and CSF collections every 1 to 2 weeks for 12 to 13 weeks. The following were determined: serum Venereal Disease Research Laboratory (VDRL) and microhemagglutination-T. pallidum reactivities, CSF-VDRL, CSF white blood cell (WBC) count, and the presence of viable T. pallidum in CSF by the rabbit infectivity test (all animals), as well as the presence of T. pallidum in CSF by reverse transcriptase (RT)-PCR, WBC phenotype by fluorescence-activated cell sorter, WBC cytokine production by RT-PCR, and brain MRI at 10 weeks (two animals). RESULTS: All animals became systemically infected and developed CSF pleocytosis that resolved after 8 weeks. CSF T. pallidum was detected from 2 to 8 weeks. CSF T lymphocytes were predominantly CD4+. Interferon-gamma (IFN-gamma) mRNA was consistently detected in CSF WBCs, but interleukin (IL)-4 and IL-5 were not. All animals remained clinically well. MRIs were normal. CONCLUSIONS: In this model, T. pallidum is cleared from the CNS just as in most humans with early syphilis. Local production of IFN-gamma likely participates in this process. This model could be used to clarify the effect of retrovirus-induced immunodeficiency on clearance of T. pallidum from the CNS and on the local CNS immune response.

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PMID: 9781512 [PubMed - indexed for MEDLINE]

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Detection of active infection in nonhuman primates with Lyme neuroborreliosis: comparison of PCR, culture, and a bioassay.

Pachner AR, Zhang WF, Schaefer H, Schaefer S, O'Neill T.

Department of Neurology, Georgetown University School of Medicine, Washington, D.C., USA. apachn01Wgumedlib.georgetown.edu

Ideally a diagnosis of infection of the central nervous system (CNS) is made by culture of the etiologic pathogen, but Borrelia burgdorferi, the causative agent of Lyme neuroborreliosis (LNB), is rarely cultured from the cerebrospinal fluid (CSF). PCR and measurement of specific antibody in the CSF also have their limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. There is a need to assess the reliability of assays and to increase the ability to document active infection in the CNS. The recent development of the nonhuman primate (NHP) model of LNB allowed us to address this need in a faithful model of human LNB. In this study we compared the abilities of PCR and culture to detect the presence of spirochetes in the CSF and brain tissue of infected NHPs and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Fourteen of 16 CSFs from four NHPs were positive by at least one of these techniques. Detection of spirochetes in the CSF by PCR, the MIT, and culture was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR for infected NHPs; antibody in the CSF was the most useful assay for immunocompetent NHPs.

Publication Types:
PMID: 9774573 [PubMed - indexed for MEDLINE]

PMCID: PMC105309


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[Value of antibody titers for diagnosis of neuroborreliosis]

[Article in German]

Woessner R, Treib J, Haass A, Stoll M, Holzer G, Schimrigk K.

Neurologische Klinik, Universitätskliniken des Saarlandes, Homburg/Saar.

Neuroborreliosis is a very frequent subtype of infection with Borrelia burgdorferi. Because of the widely spread inapparent infections finding of diagnosis by analysis of serum antibodies is very difficult. In the years 1990-1994 the serum of 6.775 patients of the Department of Neurology in Homburg, Germany was analysed with regard to Borrelia burgdorferi specific IgG antibodies. 24% showed a positive serum titer and 20% a borderline result. 73 patients showed a specific intrathecal IgG antibody synthesis. In contrast to patients with antibodies in serum these patients showed a significant cumulation during summer. The high percentage of positive serum titers and the season independence support the assumption of widely spread inapparent infections. If a patient shows neurological symptoms the finding of serum antibodies against Borrelia burgdorferi is not sufficient for the diagnosis of Neuroborreliosis. A specific intrathecal synthesis of antibodies, is the most reliable serological indicator for Neuroborreliosis. Intrathecal synthesis usually starts three to four weeks after the first clinical symptoms.

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PMID: 9757421 [PubMed - indexed for MEDLINE]

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Pseudotumor cerebri in Lyme disease: a case report and literature review.

Kan L, Sood SK, Maytal J.

Division of Pediatric Neurology, Schneider Children's Hospital, Long Island Jewish Medical Center, Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.

Pseudotumor cerebri is an unusual presentation of Lyme disease. The case of an 8-year-old girl with pseudotumor cerebri secondary to acute neuroborreliosis is reported. She presented with acute onset of headache, papilledema, sixth nerve palsy, increased intracranial pressure, and cerebrospinal fluid pleocytosis. Serum and cerebrospinal fluid Lyme antibodies were positive. Twelve reported cases that mostly presented with systemic findings and signs of Lyme disease before development of pseudotumor cerebri were reviewed. We conclude that acute neuroborreliosis can present with pseudotumor cerebri as an initial manifestation. It is important to include Lyme disease in the differential diagnosis of pseudotumor cerebri in an area endemic for Lyme disease.

Publication Types:
PMID: 9650688 [PubMed - indexed for MEDLINE]

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Stages and syndromes of neuroborreliosis.

Oschmann P, Dorndorf W, Hornig C, Schäfer C, Wellensiek HJ, Pflughaupt KW.

Department of Neurology, Justus-Liebig-University, Giessen, Germany.

To ascertain the varieties of neuroborreliosis, 330 patients were identified at the Departments of Neurology in Würzburg and Giessen from 1979 to 1994. Patients who fullfilled at least one of three strict case definitions based on clinical and laboratory criteria were included in the study. Ninety-one per cent of the patients had second-stage neuroborreliosis (duration of symptoms < or = 6 months). The most common syndrome was a painful spinal meningoradiculitis, alone (37%) or in combination with a cranial radiculitis (29%). Meningoradiculitis cranialis (9%), isolated meningitis (4%) and erythema chronica migrans-associated mono/polyneuritis (3%) were further stage II features. Central nervous system involvement occurred either as an acute meningomyelitis or meningomyeloradiculitis (5%) and meningoencephalitis or meningenocephaloradiculitis (4%). Less than 9% of the patients ran a chronic course (stage III) with a disease duration between 6 months and 9 years, either as acrodermatitis chronica atrophicans associated mono- or polyneuritis (2%) or a chronic progressive encephalomyelitis (6%). Cerebrovascular neuroborreliosis (1%) occurred in both stages; however, the primary nature of the course was a chronic one. Involvement of other organs except the skin was rare (joints 3%, heart 1%) but elevated hepatic enzymes were frequent. Our study demonstrates that neuroborreliosis has to be considered in the differential diagnosis of a wide variety of neurological conditions. Cerebrospinal fluid analysis and the search for specific intrathecal antibody production are important diagnostic procedures.

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PMID: 9617706 [PubMed - indexed for MEDLINE]

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Nervous system Lyme disease.

Halperin JJ.

Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA. halperin@nshs.edu

Lyme disease is a multisystem infectious disease caused by tick-borne spirochetes of the Borrelia burgdorferi group. The disease occurs primarily in specific areas of North America, Europe and Asia, reflecting the distribution of the hard-shelled Ixodes ticks that are required for disease transmission. Diagnosis of this infection can be somewhat problematic, although in clinically appropriate settings, serologic testing can be highly useful, particularly if Western blots are used to confirm borderline or positive results. The organism has several specific organotropisms-involvement of the heart, joints and nervous system being particularly common. The nervous system can be involved in one or more ways. Early in infection, patients tend to get a lymphocytic meningitis, cranial neuritis (particularly the facial nerves) or a painful radiculitis. Rarely, an encephalomyelitis can occur. In patients with more protracted and indolent involvement, a more disseminated mononeuropathy multiplex may occur, or a mild, non-focal alteration of cognitive function and memory, i.e. an encephalopathy. In patients with central nervous system involvement, the most sensitive diagnostic test is the demonstration of intrathecal production of anti-Borrelia burgdorferi antibody. Culture, polymerase chain reaction and other techniques appear to be less specific. In most instances, the disease is quite responsive to antimicrobial therapy. Oral treatment with doxycycline has been shown to be effective in meningitis. In more serious cases two to four week courses of parenteral ceffriaxone or cefotaxime are effective in the vast majority of patients.

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PMID: 9511877 [PubMed - indexed for MEDLINE]

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Identification of a T cell subset capable of both IFN-gamma and IL-10 secretion in patients with chronic Borrelia burgdorferi infection.

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

Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.

A novel population of both IFN-gamma- and IL-10-secreting human T cells that differentiate in the presence of exogenous IL-12 in vitro has recently been described. Whether this T cell population exists in vivo is unknown. Borrelia burgdorferi, the etiologic agent of Lyme disease, can induce a chronic infection in the presence of a vigorous humoral immune response. We established T cell lines specific for B. burgdorferi and tetanus toxoid from subjects with chronic B. burgdorferi infection and healthy controls in limiting dilution experiments and assessed proliferation and cytokine secretion. As expected, higher frequencies of B. burgdorferi-specific precursor T cells were observed in Lyme patients compared with controls. In both groups of subjects, T cell lines specific for B. burgdorferi secreted high amounts of IFN-gamma. However, in patients with Lyme disease, 27% of T cell lines secreted not only IFN-gamma but also IL-10, which was only observed in 0.6% of B. burgdorferi-reactive T cell lines generated from controls and in none of the tetanus toxoid-reactive T cell lines generated from either Lyme patients and controls. Single cell PHA cloning confirmed that both cytokines were secreted from one clonally expanded precursor cell. Whole mononuclear cells from B. burgdorferi-infected individuals, but not from controls, secreted IL-12. Moreover, neutralizing anti-IL-12 mAbs inhibited the generation of the IFN-gamma/IL-10 population. These data demonstrate that this novel population of IL-12-induced IFN-gamma/IL-10-secreting T cells is generated in response to chronic B. burgdorferi infection.

Publication Types:
PMID: 9469440 [PubMed - indexed for MEDLINE]

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Neuroborreliosis during relapsing fever: review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals.

Cadavid D, Barbour AG.

Department of Neurology, Georgetown University School of Medicine, Washington, D.C. 20007, USA.

The spirochetal disease relapsing fever is caused by different Borrelia species. Relapsing fever is well recognized as an infection of the blood, but little is known about its predilection for the nervous system and the eyes. To investigate neurological and ocular involvement during relapsing fever, we reviewed the clinical manifestations, pathology, and treatment of relapsing fever of humans and experimental animals. The results indicate that Borrelia turicatae and Borrelia duttonii, the agents of tick-borne relapsing fever in southwestern North America and sub-Saharan Africa, respectively, cause neurological involvement as often as Borrelia burgdorferi in Lyme disease. Evidence of this is the frequent occurrence of lymphocytic meningitis and peripheral facial palsy in human disease; the identification of spirochetes in the brain and other nervous tissues of humans, animals, and arthropod vectors; and the persistence of brain infection after treatment with antibiotics that do not readily penetrate the blood-brain barrier.

Publication Types:
PMID: 9455525 [PubMed - indexed for MEDLINE]

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Comment in:
Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy.

Belman AL, Reynolds L, Preston T, Postels D, Grimson R, Coyle PK.

Department of Neurology, School of Medicine, State University of New York at Stony Brook, USA. abelman@neuro.som.sunysb.edu

OBJECTIVE: To determine the relative frequency of abnormal cerebrospinal fluid (CSF) findings in children with Lyme disease-associated facial nerve palsy. DESIGN: A clinical series. A prospective evaluation was undertaken of the condition of children seen between 1988 and 1996 at a single medical center in a Lyme disease endemic area. PATIENTS: Forty children (24 boys and 16 girls, aged 3-19 years) with new onset facial nerve palsy who met the Centers for Disease Control and Prevention case definition of Lyme disease. INTERVENTIONS: Neurologic examinations. Cerebrospinal fluid analysis. MAIN OUTCOME MEASURES: Rates of abnormal CSF findings: white blood cell count, protein level, and Borrelia burgdorferi-specific CSF assays. RESULTS: Cerebrospinal fluid white blood cell count, protein level, or both were abnormal in 27 (68%) of the children. Thirty-six (90%) of the 40 children had a CSF abnormality consistent with central nervous system infection or immune involvement by B burgdorferi. Of the 22 children with CSF pleocytosis, only 7 (32%) had headache and none had meningeal signs. CONCLUSIONS: Most children with Lyme disease-associated facial nerve palsy have CSF abnormalities. Our studies indicate that, in endemic areas, facial nerve palsy in children may be a marker of Lyme disease and occult meningitis. When Lyme disease is suspected, CSF should be examined; in some cases, it may be helpful to expand beyond routine CSF studies to look at a battery of B burgdorferi-specific assays.

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PMID: 9412598 [PubMed - indexed for MEDLINE]

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Compartmentalization of antigen specific cytokine responses to the central nervous system in CNS borreliosis: secretion of IFN-gamma predominates over IL-4 secretion in response to outer surface proteins of Lyme disease Borrelia spirochetes.

Ekerfelt C, Ernerudh J, Bunikis J, Vrethem M, Aagesen J, Roberg M, Bergström S, Forsberg P.

Department of Neurology, Faculty of Health Sciences, University Hospital, Linköping, Sweden.

The neurological manifestations of Lyme disease have been proposed to be partly due to cytokine-mediated immunopathological mechanisms. In this study, the number of Borrelia-specific cells secreting interferon-gamma and interleukin-4 was determined in blood and cerebrospinal fluid from patients with CNS borreliosis (n = 23), other neurological diseases (n = 20), and in blood from healthy controls (n = 10), utilizing an ELISPOT-assay. Elevated specific secretion of IFN-gamma was found in CNS borreliosis, most pronounced in cerebrospinal fluid, whereas secretion of IL-4 was strikingly low. This may indicate that symptoms are due to side effects of the immune response, since IFN-gamma secretion in the absence of corresponding levels of IL-4 may be associated with tissue destruction.

Publication Types:
PMID: 9394788 [PubMed - indexed for MEDLINE]

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Diagnostic value of cerebrospinal fluid examination in children with peripheral facial palsy and suspected Lyme borreliosis.

Albisetti M, Schaer G, Good M, Boltshauser E, Nadal D.

University Children's Hospital of Zurich, Switzerland.

Our objective was to determine the diagnostic value of CSF examinations in the diagnosis of neuroborreliosis in children with peripheral facial palsy (PFP). Paired serum and CSF samples from 21 children with PFP were investigated for antibody responses to Borrelia burgdorferi antigens using three different ELISA systems and one Western blot assay. Twenty of the children (95%) had detectable immunoglobin (Ig) M or IgG in the acute-phase serum, but discrepancies between serologic assays were noted in 33% for IgM and 22 to 50% for IgG. Intrathecal specific-antibody production was detected in five of the 20 seropositive children (25%). These five patients showed seroconversion in convalescent sera in at least one assay. Similar seroconversion suggesting recent infection with B. burgdorferi was observed in eight of the 10 children (80%) without intrathecal specific-antibody production, from whom convalescent serum samples could be obtained. All patients with intrathecal antibodies or seroconversion had shown lymphocytic pleocytosis in the acute phase of PFP. In the acute phase of PFP the detection of intrathecal production of antibodies to B. burgdorferi allows prompt diagnosis of neuroborreliosis. For patients with lymphocytic pleocytosis but no detectable intrathecal antibodies, analysis of convalescent serum may help to establish this diagnosis.

PMID: 9305347 [PubMed - indexed for MEDLINE]

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Interleukin-6 is expressed at high levels in the CNS in Lyme neuroborreliosis.

Pachner AR, Amemiya K, Delaney E, O'Neill T, Hughes CA, Zhang WF.

Department of Neurology, Georgetown University School of Medicine, Washington, DC 20007, USA.

In patients with Lyme neuroborreliosis, inflammation and symptoms of fatigue and malaise occur out of proportion to the relatively low number of spirochetes present. Previous studies have identified interleukin-6 (IL-6) as a candidate molecule for amplification of CNS inflammation in this disease. We pursued this possibility by measuring cytokine gene expression by reverse-transcriptase polymerase chain reaction (RT-PCR) in the brain of rhesus macaques actively infected with Borrelia burgdorferi. Samples of brain tissue were screened for IL-6 and interferon gamma using RT-PCR-ELISA, a technique that uses RT-PCR, subsequent hybridization of the PCR product with a biotinylated probe, and capture and ELISA readout of hybridization product. The number of copies in positive samples was then quantitated using qRT-PCR-ELISA, in which wild-type cytokine cDNA competes with recombinant competitor DNA in the PCR. Elevated levels of IL-6 cDNA and, to a lesser extent, interferon gamma were detected in three of three nonhuman primates with persistent infection with B burgdorferi, whereas the brains of three uninfected animals and undetectable levels of gene expression of these cytokines. These data support the hypothesis that cytokines such as IL-6 are important amplification molecules for CNS inflammation in Lyme neuroborreliosis.

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PMID: 9222183 [PubMed - indexed for MEDLINE]

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Peripheral neuropathy in acrodermatitis chronica atrophicans - a late Borrelia manifestation.

Kindstrand E, Nilsson BY, Hovmark A, Pirskanen R, Asbrink E.

Karolinska Institute, Department of Neurology, Stockholm Söder Hospital, Sweden.

Clinical and/or neurophysiological signs of peripheral neuropathy were found in 64% of 63 consecutive untreated patients with the late borrelial manifestation acrodermatitis chronica atrophicans (ACA). The neuropathy frequency was significantly higher in the patients than in 30 age- and sex-matched control persons of whom 27% had neuropathy findings. The most common neuropathy in ACA was a symmetric distal sensory polyneuropathy. In a subgroup of patients with localized or asymmetric neuropathy, the changes were found more often in extremities with than without visible ACA lesions. Neuropathy symptoms, most often pain and/or paresthesia, were present in 64% of the patients, compared to in 13% of the control persons. Thus, both symptoms and signs of neuropathy were significantly more frequent in patients with untreated ACA than in control subjects.

PMID: 9228267 [PubMed - indexed for MEDLINE]

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Mechanisms of injury in Lyme neuroborreliosis.

Garcia-Monco JC, Benach JL.

Department of Neurology, Hospital de Galdacano, Vizcaya, Spain.

Neurologic injury in infection with Borrelia burgdorferi can be due to the direct action of the spirochetes and spirochetal products on neural cells. There is in vitro evidence for the adherence of this organism to neurons, to glia, and to Schwann cells. Adhesion was found to be associated with galactocerebroside, a glycolipid component of myelin, and could act as a receptor for B. burgdorferi in oligodendroglia and in Schwann cells. Another pathway for neurologic injury could be through amplification of the inflammatory response by newly invading organisms (acute) and persisting (chronic) organisms. There is experimental evidence for production of IL-6, TNF-alpha, and nitric oxide by neural cells exposed to B. burgdorferi. Similar findings have been obtained from neuroborreliosis patients. Although less likely, there is the possibility that autoreactive mechanisms could have a role in the development of some manifestations of neuroborreliosis.

Publication Types:
PMID: 9166961 [PubMed - indexed for MEDLINE]

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Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease.

England JD, Bohm RP Jr, Roberts ED, Philipp MT.

Department of Neurology, Louisiana State University School of Medicine, New Orleans 70112, USA.

Peripheral neuropathy is a recognized but poorly understood manifestation of Lyme disease. We performed serial electrophysiological studies on 8 rhesus monkeys chronically infected with the JD1 strain of Borrelia burgdorferi and compared the results with those of similar studies on 10 uninfected control monkeys. Four infected and 2 uninfected animals underwent sural nerve biopsy. Five of the infected and 1 of the uninfected animals also had postmortem neuropathological examinations. Altogether, 5 of the infected monkeys demonstrated primarily axonal-loss-variety multifocal neuropathies. Only one nerve lesion exhibited findings compatible with demyelination. Pathologically, peripheral nerve specimens showed multifocal axonal degeneration and regeneration and occasional perivascular inflammatory cellular infiltrates without vessel wall necrosis. Free spirochetal structures were not seen, but several macrophages exhibited positive immunostaining with a highly specific anti-B. burgdorferi, 7.5-kd lipoprotein monoclonal antibody. In the infected animals, serial analysis of serum antibodies to B. burgdorferi showed increasing numbers of IgG specificities and new IgM specificities, suggesting persistent infection. Thus, peripheral neuropathy in the form of a mononeuropathy multiplex develops frequently in rhesus monkeys chronically infected with B. burgdorferi. The pathogenesis of these nerve lesions is not yet known, but our studies suggest an immune-mediated process perhaps driven by persistent infection with B. burgdorferi.

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PMID: 9066359 [PubMed - indexed for MEDLINE]

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Clinical value of specific intrathecal production of antibodies.

Treib J, Woessner R, Dobler G, Fernandez A, Holzer G, Schimrigk K.

Department of Neurology, University of the Saarland, Homburg, Germany.

The production of intrathecal antibodies is considered a highly specific marker for an infection of the central nervous system (CNS), e.g. borreliosis or tick-borne encephalitis (TBE). To investigate the validity of this assumption, we examined records of patients who had been hospitalized between 1989 and 1995, who were tested for borreliosis (n = 8003) and TBE (n = 904) and whose cerebrospinal fluid (CSF) had subsequently tested positive for intrathecal production of antibodies. The time period between the beginning of the symptoms and the time of the CSF examination ranged from one day to six weeks. Seventy-seven patients showed a production of intrathecal antibodies against Borrelia burgdorferi. Three of these patients were false positives with no history and no clinical signs of neuroborreliosis. In two cases, this was due to a non-specific cross-reaction caused by a preceding infection with syphilis. The third false positive was possibly caused by an earlier administration of immunoglobulins. Three patients showed a production of intrathecal antibodies against TBE virus. Two of these patients were false positives. In one case, we suspect that the production of intrathecal antibodies was caused by a non-specific immune reaction during an acute neuroborreliosis. One year earlier, the patient had contact with TBE virus through a vaccination against TBE. The cause of the second false positive is unclear, the clinical findings, acute encephalitis and the serological analysis suggest a cross-reaction with a virus similar to TBE. A specific intrathecal production of antibodies is not a proof for an infection of the CNS. In unclear cases, one should carry out a Western blot analysis or, if one suspects a case of TBE, a neutralization test.

Publication Types:
PMID: 9199711 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi infection: clinical diagnostic techniques.

Coyle PK.

Department of Neurology, School of Medicine, State University of New York at Stony Brook 11794, USA.

Borrelia burgdorferi is a tick-borne spirochete and the etiologic agent of Lyme disease. This pathogen now accounts for 91% of vector-borne infections in the United States, and from a public health viewpoint is one of our major emerging infectious disorders. Specific properties of B. burgdorferi have resulted in diagnostic problems, including the lack of a readily available laboratory assay to detect active infection. Most laboratory testing for Lyme disease relies on serologic documentation of prior exposure to the agent. However, such testing detects asymptomatic infections, and does not detect seronegative infections. In addition, antibody tests for Lyme disease are not standardized. Cases of Lyme disease are both underdiagnosed and overdiagnosed. This review will discuss the spirochetal properties which contribute to diagnostic difficulties, will discuss current laboratory diagnostic tests, including serology and detection of B. burgdorferi DNA, and will discuss diagnostic tests in development, including recombinant-based serologic assays and detection of B. burgdorferi antigens.

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PMID: 9037617 [PubMed - indexed for MEDLINE]

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[A case of neuroborreliosis with unilateral radiculoneuropathy and elevated serum antibodies for Borrelia garinii and Borrelia afzelii]

[Article in Japanese]

Miyazaki K, Iijima M, Takeuchi M, Uchiyama S, Iwata M.

Department of Neurology, Tokyo Women's Medical College.

A 24-year-old male patient was admitted to our hospital because of dysesthesia and weakness of the right leg. Six weeks before admission he traveled to southern China. A week later he noticed multiple papules with itching on his right leg that were suspected to be insect bites. Four days later numbness of the right leg developed. Then he began to limp because of the leg weakness. Two weeks before admission severe pain in the right leg developed. On admission neurological examination revealed hypesthesia, muscle weakness and atrophy, areflexia, radicular pain and Lasègue sign of the right leg, and patchy hypesthesia of the left leg. The cranial nerves were intact, and meningeal signs were negative. Complete blood counts and serum biochemistry were unremarkable except for eosinophilia and mild elevation of IgE. A test for antinuclear antibody was positive. Cerebrospinal fluid was normal. Nerve conduction study and sural nerve biopsy showed multifocal severe axonopathy. Although antibody for Borrelia burgdorferi sensu stricto was negative, antibodies for B. garinii and for B. afzelii were positive in serum immunoblotting. Neurological symptoms improved after administration of intravenous ceftriaxon following oral doxycycline. In Japan, this is the second case of neuroborreliosis not due to B. burgdorferi sensu stricto. To test antibodies for B.garinii and for B. afzelii is recommended in patients with suspected neuroborreliosis.

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PMID: 8997140 [PubMed - indexed for MEDLINE]

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Diagnosis of neurosyphilis in patients infected with human immunodeficiency virus type 1.

Marra CM, Gary DW, Kuypers J, Jacobson MA.

Department of Neurology, University of Washington, Seattle, USA.

Establishing the diagnosis of neurosyphilis may be particularly difficult in human immunodeficiency virus type 1 (HIV)-infected persons. Polymerase chain reaction (PCR) was used to detect Treponema pallidum DNA in cerebrospinal fluid (CSF) from 81 HIV-infected patients. On the basis of reactive serum and CSF-VDRL tests, 2 patients were diagnosed as having neurosyphilis. T. pallidum DNA was not consistently detected in any sample, even when the CSF-VDRL was reactive. CSF pleocytosis, elevated protein, or depressed glucose concentration was not significantly associated with a history of exposure to or infection with T. pallidum. On the basis of results of routine CSF measurements and T. pallidum PCR results, no evidence was found for undiagnosed neurosyphilis in HIV-infected patients. T. pallidum DNA PCR on CSF did not provide more information than conventional CSF analysis. Further study is needed to determine the utility of this test in the diagnosis and treatment of neurosyphilis.

Publication Types:
PMID: 8655999 [PubMed - indexed for MEDLINE]

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Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis. Influence of concomitant human immunodeficiency virus infection.

Marra CM, Longstreth WT Jr, Maxwell CL, Lukehart SA.

Division of Neurology, School of Medicine, University of Washington, Seattle, USA.

BACKGROUND AND OBJECTIVES: Little is known about resolution of serum and cerebrospinal fluid abnormalities after neurosyphilis treatment, especially in patients infected with human immunodeficiency virus (HIV). GOAL: To examine the time course of resolution of these abnormalities. STUDY DESIGN: Case series of 22 patients with neurosyphilis (13 infected with HIV) with reactive cerebrospinal fluid Venereal Disease Research Laboratory test who underwent at least one lumbar puncture after treatment. RESULTS: Resolution of all serum and cerebrospinal fluid measures was slower in patients infected with HIV. Serum and cerebrospinal fluid abnormalities resolved in most patients not infected with HIV by 30 weeks, and all met Centers for Disease Control and Prevention criteria for cure. One patient infected with HIV failed therapy by Centers for Disease Control and Prevention criteria, and three others had persistent pleocytosis. CONCLUSIONS: HIV-infected patients with neurosyphilis have slower resolution of serum and cerebrospinal fluid abnormalities after therapy. This observation may suggest impaired clearance of Treponema pallidum from the central nervous system.

Publication Types:
PMID: 8724507 [PubMed - indexed for MEDLINE]

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Lyme neuroborreliosis: evidence for persistent up-regulation of Borrelia burgdorferi-reactive cells secreting interferon-gamma.

Wang WZ, Fredrikson S, Sun JB, Link H.

Division of Neurology, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden.

The T-cell response to the aetiologic pathogen Borrelia (B.) burgdorferi in patients with Lyme neuroborreliosis (LN) and in control patients with other neurological diseases was examined by enumerating B. burgdorferi-reactive T cells secreting interferon-gamma (IFN-gamma) with an ELIspot assay. LN patients had elevated numbers of B. burgdorferi-reactive IFN-gamma secreting cells in blood and approximately 20-fold enriched in the cerebrospinal fluid (CSF). A positive correlation existed in CSF between B. burgdorferi-reactive IFN-gamma secreting cells and B cells secreting anti-B. burgdorferi IgG antibodies. The up-regulation of antigen-specific IFN-gamma secreting cells persisted in peripheral blood up to at least 9 months and in the CSF for at least 4 months after termination of treatment with antibiotics, when the patients were mostly free from clinical signs and symptoms due to LN. How IFN-gamma interplays with other cytokines and influences the pathogenesis of LN remains to be studied.

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PMID: 8552994 [PubMed - indexed for MEDLINE]

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Neurologic manifestations in children with Lyme disease.

Bingham PM, Galetta SL, Athreya B, Sladky J.

Division of Neurology, Children's Hospital of Philadelphia, PA 19104, USA.

OBJECTIVE. Lyme disease (LD) is a tick-borne spirochetal infection with a wide range of neurologic and non-neurologic manifestations. The clinical diversity of LD and limitations in serologic diagnosis often make it difficult to document the diagnosis of neuroborreliosis with certainty. METHODS. We reviewed clinical manifestations in 97 seropositive children with particular attention to neurologic manifestations. Diagnostic criteria used in other case surveys were applied to determine how often a definitive diagnosis of neuroborreliosis could be made in children. RESULTS. Of 69 children who met criteria for LD, 32% (22) had new neurologic signs, 73% (16) of which were accounted for by facial palsy and aseptic meningitis. Five of those with neurologic findings also had erythema migrans (EM), and one had both EM and arthritis. Among those with neurologic involvement, boys outnumbered girls two to one. Neurologic abnormalities resolved spontaneously in five children before their serologic results were known. CONCLUSION. In our series, only 27% of children with neurologic abnormalities due to LD had a history of EM or arthritis. Seropositivity commonly constituted the primary basis for diagnosis of LD. Despite its nonspecificity, seropositivity for LD in children with neurologic symptoms usually signifies active neuroborreliosis.

PMID: 7491220 [PubMed - indexed for MEDLINE]

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Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease.

Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ.

Department of Neurology, SUNY at Stony Brook, USA.

OBJECTIVE: To determine the potential of detection in CSF of specific Borrelia burgdorferi antigen, OspA, as a marker of infection in neurologic Lyme disease and compare this with the detection of antibody. DESIGN: CSF from 83 neurologic patients in an area highly endemic for Lyme disease was examined prospectively for (1) OspA by antigen capture ELISA and Western blot employing monoclonal antibodies, and for (2) B burgdorferi antibodies by ELISA. RESULTS: Of the 35 of 83 (42%) patients who were positive for OspA antigen in their CSF, 15 (43%) were antigen positive despite being antibody-negative in CSF. Seven of these 15 (47%) had otherwise normal routine CSF analyses. Six of these 15 (40%) patients met strict CDC surveillance criteria for Lyme disease; four (27%) patients had seroconversion coincident with new neurologic problems; and three (20%) with characteristic syndromes for Lyme disease were seronegative, but had complexed antibody to B burgdorferi. The final two patients (13%) were seropositive and had unexplained neurologic problems not characteristic of Lyme disease. CONCLUSIONS: B burgdorferi antigen can be detected in CSF that is otherwise normal by conventional methodology, and can be present without positive CSF antibody. Since CSF antigen implies intrathecal seeding of the infection, the diagnosis of neurologic infection by B burgdorferi should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.

Publication Types:
PMID: 7501150 [PubMed - indexed for MEDLINE]

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Comment in:
Neuroborreliosis in the nonhuman primate: Borrelia burgdorferi persists in the central nervous system.

Pachner AR, Delaney E, O'Neill T.

Department of Neurology, Georgetown University School of Medicine, Washington, DC 20007, USA.

Neurological involvement in Lyme disease is common, and is frequently difficult to diagnose and treat. Little is known about the fate of the causative spirochete Borrelia burgdorferi in the central nervous system (CNS). To determine the frequency of parenchymal infection and to determine localization of the organism, polymerase chain reaction/hybridization assays were performed in a newly described model of Lyme neuroborreliosis in nonhuman primates infected with B. burgdorferi. Polymerase chain reaction/hybridization of CNS tissues from 5 infected nonhuman primates was performed. Substantial amounts of B. burgdorferi DNA were detected in the CNS in all infected animals, with a predilection toward subtentorial structures. These data suggest that Lyme neuroborreliosis represents persistent infection with B. burgdorferi.

PMID: 7574465 [PubMed - indexed for MEDLINE]

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Experimental immunization with Borrelia burgdorferi induces development of antibodies to gangliosides.

Garcia-Monco JC, Seidman RJ, Benach JL.

Department of Neurology, Hospital de Galdacano, Vizcaya, Spain.

Patients with neuroborreliosis produce antibodies, mostly of the immunoglobulin M (IgM) class, to gangliosides, particularly to those with Gal(beta 1-3)GalNac terminal sequences. Lewis rats were immunized with a nonpathogenic strain of Borrelia burgdorferi and with a chloroform-methanol extract (nonprotein) of this organism (CM) to determine whether antibodies to B. burgdorferi also recognized gangliosides. Rats were also immunized with asialo-GM1 to determine whether the elicited antibodies recognized antigens in B. burgdorferi. Rats immunized with B. burgdorferi produced low levels of IgM antibodies that cross-reacted with asialo-GM1 and GM1. Rats immunized with CM had marked IgM reactivity to asialo-GM1 and GM1. Immunization with asialo-GM1 resulted in antibodies that cross-reacted with B. burgdorferi antigens. Although antibodies to B. burgdorferi were of both the IgM and IgG classes, those to CM and to asialo-GM1 and GM1 were predominantly in the IgM fraction. Reactivity of the IgM antibodies decreased after adsorption with the heterologous and the homologous antigens, indicating bidirectional cross-reactivity between CM, asialo-GM1, and GM1 and that immunization with one produces antibodies to the other. There was no in vivo deposition of Ig in peripheral nerves, nor was there nerve pathology as a result of immunizations, but IgM antibodies to asialo-GM1 and CM recognized homologous antigens in the nodes of Ranvier of peripheral nerves from nonimmunized rats. This immunization model suggests that antibodies to gangliosides in Lyme disease have a microbial origin and are potentially relevant in pathogenesis.

Publication Types:
PMID: 7558329 [PubMed - indexed for MEDLINE]

PMCID: PMC173580


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Relevance of cerebrospinal fluid variables for early diagnosis of neuroborreliosis.

Tumani H, Nölker G, Reiber H.

Laboratory of Neurochemistry, University of Göttingen, Germany.

We describe the specificity and sensitivity of measuring a combination of basic CSF variables and Borrelia burgdorferi (Bb)-specific IgG and IgM antibody index (AI) values for the diagnosis of early neuroborreliosis. Basic CSF variables included total cell count, quantitation of activated B cells (IgG, IgA, and IgM classes), CSF/serum quotient diagrams for IgG, IgA, and IgM (to quantitate brain-derived immunoglobulin fractions in CSF), and CSF/serum albumin ratio as a measure of blood-CSF barrier function. The Bb-specific component of immunoglobulins in CSF and serum was quantitated by ELISA. Results are based on data from CSF and serum of 24 patients with definite neuroborreliosis, 45 patients with other neurologic diseases, and 28 control individuals. Combined evidence of an elevated CSF cell count, IgM-class dominance in both the cellular and intrathecal humoral immune response, and blood-CSF barrier dysfunction yielded 70% diagnostic sensitivity and 98% diagnostic specificity for detection of neuroborreliosis. Intrathecal production of Bb-specific IgM, evaluated as Bb-specific IgM antibody index (Bb-IgM-AI; pathologic value > 1.4) showed 79% diagnostic sensitivity and 96% diagnostic specificity. Correspondingly, elevated Bb-specific IgG antibody index (Bb-IgG-AI; pathologic value > 1.4) displayed 63% diagnostic sensitivity and 89% diagnostic specificity. Combined analysis of Bb-specific AI values and basic CSF variables gave the highest sensitivity (80%) and specificity (98%). Analysis of CSF variables over a disease course showed that acute versus past disease could be discriminated by a combination of basic CSF variables and Bb-specific AI.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 7675224 [PubMed - indexed for MEDLINE]

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Lyme neuroborreliosis.

Garcia-Monco JC, Benach JL.

Department of Neurology, Hospital de Galdacano, Vizcaya, Spain.

Neuroborreliosis, an infection of the nervous system caused by spirochetes of the genus Borrelia, has achieved worldwide attention in the last decade as part of the clinical spectrum of Lyme disease. This disorder, caused by Borrelia burgdorferi, has increased in incidence to become the most frequent arthropod-borne infection in North America and Europe. As a result of this rapid rise in incidence and of its protean neurological manifestations, this disease has created an important challenge to modern neurology. The diverse manifestations of neuroborreliosis require that it be included in the differential diagnosis of many neurological disorders. This review takes a chronological approach to clinical neuroborreliosis to summarize its most important aspects. The limitations as well as the benefits of laboratory diagnosis are also considered, with the aim of providing assistance in this area. Recent advances in neuroimmunology regarding the pathogenesis of neuroborreliosis that may elucidate its protean clinical spectrum are summarized.

Publication Types:
PMID: 7778842 [PubMed - indexed for MEDLINE]

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Neuroborreliosis.

Halperin JJ.

Department of Neurology, North Shore University Hospital, Manhasset, New York 11030, USA.

Lyme disease is a multisystem infectious disease with frequent nervous system involvement. It affects peripheral nerves, the meningeal lining of the central nervous system (CNS), and the CNS parenchyma, but the underlying pathophysiology remains unclear. Considerable data suggest that dividing Lyme neuroborreliosis into early and late disease stages, as has been done with syphilis--the other well-known spirochetosis that affects the nervous system--lacks pathophysiologic validity. Early CNS seeding has been demonstrated, however, and lymphocytic meningitis and facial paralysis tend to occur relatively early in infection, although radiculoneuropathy and cranial neuropathies may also occur later. Less fulminant forms of peripheral nerve or CNS involvement may present later in the disease course. Encephalomyelitis may occur early or late but is rare; encephalopathy is far more common and tends to occur in patients with evidence of systemic (but not necessarily CNS) Lyme disease. Diagnosis of CNS infection has been difficult, and most studies have relied on indirect methods. Demonstration of intrathecal production of anti-Borrelia burgdorferi antibodies provides the strongest evidence, but correction for the amount of peripheral blood immunoreactivity to B. burgdorferi that crosses the blood-brain barrier is essential. Newer technologies have been applied in an effort to improve detection of B. burgdorferi itself--polymerase chain reaction may provide a sensitive tool for organism detection to complement immunologic techniques. The optimal treatment regimen for Lyme disease has not been defined, but a course of ceftriaxone (2 g/day) or cefotaxime (6 g/day) for 3-4 weeks is commonly prescribed. Intravenous penicillin and oral doxycycline (200 mg/day) for 2 weeks have been used successfully to treat Lyme meningitis, but these results require confirmation.

Publication Types:
PMID: 7726192 [PubMed - indexed for MEDLINE]

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Intrathecal immune response in neuroborreliosis: importance of cross-reactive antibodies.

Kaiser R.

Department of Neurology, University of Freiburg, Germany.

The intrathecal IgG response to Borrelia burgdorferi was evaluated in 35 patients with neuroborreliosis (NB). Samples were tested with and without preabsorption with Treponema phagedenis. Specific antibody concentrations in the CSF and serum were determined by ELISA. The antibody index (AIBb = QBb/QIgG) was calculated from the ratio between the CSF/serum quotients for specific antibodies (QBb) and total IgG (QIgG). Intrathecal synthesis of B. burgdorferi antibodies was demonstrated in 31 samples before and in 24 samples after preabsorption with T. phagedenis. The clonal distribution of intrathecally produced IgG antibodies was determined by isoelectric focusing combined with affinity blotting. B. burgdorferi-specific oligoclonal IgG bands occurring predominantly in the CSF were demonstrated in 32/35 patients. In 29/32 samples, the major proportion of these bands also reacted with T. phagedenis. Preabsorption of samples with T. phagedenis removed a considerable share of bands reacting with B. burgdorferi. In patients with neurosyphilis, intrathecal synthesis of antibodies with specificity for B. burgdorferi was demonstrated in 7/10 samples before, and in no sample, after preabsorption of cross-reactive antibodies. Due to the lower sensitivity in determining the AIBb (-20%), preabsorption of cross-reactive antibodies cannot be generally recommended. In all patients with suspected neuroborreliosis, but uncommon neurological symptoms and missing anamnestic data concerning a tick bite or erythema migrans, neurosyphilis should be excluded by a negative TPHA test.

Publication Types:
PMID: 7549163 [PubMed - indexed for MEDLINE]

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Phenotypic analysis of cerebrospinal fluid cells over the course of Lyme meningoradiculitis.

Sindern E, Malin JP.

Department of Neurology, Ruhr University, Kliniken Bergmannsheil, Bochum, Germany.

Cytologic cerebrospinal fluid abnormalities that most distinctly point to the diagnosis of Lyme meningoradiculitis are pronounced mononuclear pleocytosis composed mainly of T lymphocytes, large amounts of plasma cells and IgM-positive B cells. In this study, repeat examinations revealed decreasing cell numbers and almost normal cell counts 100-130 days after the onset. B cells persisted over the whole observation period in five of six patients and were not related to any clinical symptoms or signs indicative of persistent meningitis or central nervous system involvement. The CD4/CD8 ratio of the helper/inducer and suppressor/cytotoxic lymphocyte subsets declined in all the patients after antibiotic treatment. It might be useful as a marker of the disease activity.

PMID: 7847012 [PubMed - indexed for MEDLINE]

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Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease.

Pachner AR, Delaney E, O'Neill T, Major E.

Department of Neurology, Georgetown University Medical Center, Washington, DC.

We injected rhesus macaques with a highly infective strain of Borrelia burgdorferi to assess whether experimentally inoculated nonhuman primates (NHPs) could serve as models of human Lyme neuroborreliosis (LNB). The animals developed biopsy-confirmed erythema migrans in the area of the inoculations. ELISA testing of sera revealed strong antibody reactivity to B burgdorferi antigens, and Western blotting showed that 16-, 22-, 31-, 34-, and 41-kd proteins of the spirochete were major antigens recognized by antibody. Culture and polymerase chain reaction (PCR) testing of serial CSF specimens revealed that chronic infection of the CNS occurred in all NHPs injected. CSF pleocytosis occurred concurrently with CNS infection. Brain MRI revealed intense meningeal inflammation in one NHP as manifested by gadolinium uptake by the dura at the base of the temporal lobes. All animals had measurable antibody in the CSF after invasion. These studies are the first to demonstrate that experimental LNB in NHPs is a reliable model faithful to the human disease, with spirochetal invasion of the subarachnoid space. This also is the first report of CSF samples positive by culture in experimental LNB. Inflammation in the CNS as manifested by CSF pleocytosis and MRI findings was also correlated with the presence of spirochetal DNA detected by PCR. These data support the hypothesis that the pathogenesis of LNB is associated with direct spirochetal invasion, and provide evidence that CNS involvement is more common than heretofore thought.

PMID: 7824109 [PubMed - indexed for MEDLINE]

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Variable CSF findings in early and late Lyme neuroborreliosis: a follow-up study in 47 patients.

Kaiser R.

Department of Neurology, University of Freiburg, Germany.

The cerebrospinal fluid (CSF) of 37 patients with early Lyme neuroborreliosis (ELN) and of 10 patients with late Lyme neuroborreliosis (LLN, duration of symptoms > or = 7 months) was investigated for typical features differentiating between acute and chronic courses of disease. Individual patients were studied after 2 and 4 weeks, and 3, 6, and 12 months. Patients with ELN presented predominantly with symptoms of the peripheral nervous system, while patients with LLN generally suffered from symptoms of the central nervous system. At the first lumbar puncture, patients with ELN revealed a more intense pleocytosis in the CSF (P < 0.02) and a higher intrathecal synthesis of total IgM (P < 0.0003) and of Borrelia burgdorferi-specific IgM antibodies (P < 0.01). At the same time, in patients with LLN, the blood-CSF barrier was more severely impaired (P = 0.03), and local production of total IgG (P = 0.0001), of B. burgdorferi-specific IgG antibodies (P = 0.03) and of total IgA (P = 0.001) was more markedly increased. The quantity of intrathecally produced B. burgdorferi-specific IgA antibodies did not differ between the two study groups. Clinical recovery was usually accompanied by a considerable improvement of the blood-CSF barrier function and pleocytosis. After 6 months, the intrathecal synthesis of total IgG had significantly decreased in patients with ELN but not in those with LLN. At the same time, the CSF of most patients in both study groups still contained intrathecally produced B. burgdorferi-specific IgG antibodies. In the absence of clinical illness or symptoms of inflammation 6 and 12 months after treatment, B. burgdorferi-specific IgG antibodies in the CSF might simply indicate an anamnestic reaction to a previous infection of the central nervous system. Six months after antibiotic treatment, patients with ELN still revealed evidence of intrathecal synthesis of total IgM, whereas those with LLN did not. These antibodies, however, were not related to B. burgdorferi.

Publication Types:
PMID: 7897449 [PubMed - indexed for MEDLINE]

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A rabbit model of Lyme neuroborreliosis: characterization by PCR, serology, and sequencing of the OspA gene from the brain.

Pachner AR, Braswell ST, Delaney E, Amemiya K, Major E.

Department of Neurology, Georgetown University Medical Center, Washington, DC.

To test whether rabbits can serve as a model for Lyme neuroborreliosis (LNB), we injected New Zealand white rabbits with Borrelia burgdorferi. We obtained samples of blood and CSF for culture, polymerase chain reaction/hybridization (PCR/H), serology, and Western blot. We then sacrificed the rabbits 2 to 3 months after infection and removed organs for culture and PCR/H analysis. The rabbits developed an antibody response, characterized by ELISA and Western blot analysis, consistent with a systemic infection. PCR/H and blood cultures were negative, but PCR/H analysis of CSF in one rabbit was positive. Positive PCR/H analysis of organs from the rabbits was consistent with widespread dissemination of the organism. The most consistently infected organ was the CNS. To determine whether antigenic variation occurred at the genetic level, we compared the sequences of the OspA gene of both the infecting strain and the brain PCR product. The differences between the two were minimal, indicating that variation in the OspA gene did not occur during in vivo infection in the rabbit. Thus, rabbits, after intradermal inoculation with B burgdorferi, develop a chronic systemic infection in which the CNS is a consistent target. These data indicate that rabbits may be an excellent model of LNB.

Publication Types:
PMID: 7936251 [PubMed - indexed for MEDLINE]

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Comparison of intravenous penicillin G and oral doxycycline for treatment of Lyme neuroborreliosis.

Karlsson M, Hammers-Berggren S, Lindquist L, Stiernstedt G, Svenungsson B.

Karolinska Institute, Stockholm, Sweden.

To compare the efficacy of oral doxycycline and IV penicillin G for the treatment of neuroborreliosis, we randomized consecutive patients with Lyme neuroborreliosis to receive either IV penicillin G (3 g q 6 h) or oral deoxycycline (200 mg q 24 h) for 14 days. All patients had antibodies against Borrelia burgdorferi in serum, CSF, or both, or had a positive CSF culture. Twenty-three patients randomized to penicillin G and 31 patients to doxycycline were included in the study. All patients improved during treatment, and there were no significant differences between the two treatment groups in patient scoring, CSF analysis, or serologic and clinical follow-up during 1 year. There were no treatment failures, although one patient in each treatment group was re-treated because of residual symptoms. In conclusion, oral doxycycline is an adequate and cost-effective alternative to IV penicillin for the treatment of Lyme neuroborreliosis.

Publication Types:
PMID: 8035916 [PubMed - indexed for MEDLINE]

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Evaluation of central nervous system involvement in Lyme borreliosis patients with a solitary erythema migrans lesion.

Kuiper H, de Jongh BM, van Dam AP, Dodge DE, Ramselaar AC, Spanjaard L, Dankert J.

Department of Neurology, Academisch Medisch Centrum, University of Amsterdam, The Netherlands.

To determine whether early dissemination of Borrelia burgdorferi to the central nervous system occurs in stage I of Lyme borreliosis, neurological and cerebrospinal fluid examination was performed in 48 consecutive patients in whom the only sign of infection was a solitary erythema migrans lesion. Long-term follow-up after treatment with tetracycline was carried out by telephone interview. At presentation, neurological findings were normal in all 48 patients. Cerebrospinal fluid samples were obtained from 29 (60%) patients. Mild pleocytosis and mild impairment of the blood-brain barrier were present in four and one of these patients, respectively. No significant amount of tumor necrosis factor or interleukin 6 was found in the cerebrospinal fluid samples. Culture results of 13 cerebrospinal fluid samples were negative. Borrelia burgdorferi DNA was only detected by the polymerase chain reaction in one of two aliquots of the cerebrospinal fluid sample of one patient. None of 46 patients who were interviewed 12 to 51 (median 25) months after antibiotic treatment developed manifestations consistent with disseminated or chronic Lyme borreliosis. Thus, no compelling evidence was found for the presence of asymptomatic central nervous system involvement in patients with clinically localized Lyme borreliosis.

PMID: 8070450 [PubMed - indexed for MEDLINE]

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Solitary erythema migrans: a clinical, laboratory and epidemiological study of 77 Dutch patients.

Kuiper H, Cairo I, Van Dam A, De Jongh B, Ramselaar T, Spanjaard L, Dankert J.

Department of Neurology, Academisch Medisch Centrum, University of Amsterdam, The Netherlands.

Regional variations in the clinical spectrum of Lyme borreliosis have been described previously. These may be related to strain variations, or reflect selection bias. We compared the clinical and epidemiological profiles of Dutch patients presenting with solitary erythema migrans alone, with the profiles in other European studies, and studies from the U.S.A., and cultured Borrelia burgdorferi from erythema migrans to identify the genospecies. Seventy-seven consecutive patients with a final diagnosis of erythema migrans were admitted into the study. Various clinical and epidemiological data were obtained, and serum was evaluated for antibodies to Borrelia burgdorferi with an enzyme-linked immunosorbent assay. Skin biopsy specimens were taken from the border of the erythema migrans and cultured in modified Kelly's medium. The different genospecies of Borrelia burgdorferi were identified by reactivity with monoclonal antibodies H3TS, LA-26, LA-31 and D6, and by rRNA gene restriction patterns. Patients were treated with tetracycline or doxycycline, and were seen for follow-up 6 weeks after treatment. Long-term follow-up was by telephone interview. A tick bite had been noticed by 45% of the patients. The onset of erythema migrans occurred in 97% of these patients within 3 months of the tick bite. Erythema migrans was present for 1-319 days (median 2 months). No concomitant manifestations were spontaneously reported. Borrelia burgdorferi was cultured from 52 (84%) of 62 skin biopsy specimens. Fifty isolates (96%) were identified as Borrelia burgdorferi group VS461. No therapy failures occurred among patients treated with tetracycline (follow-up 1-4 years, median 27 months) or doxycycline (follow-up 6-31 months, median 19 months).(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 8186111 [PubMed - indexed for MEDLINE]

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Different methods of sample preparation influence sensitivity of Mycobacterium tuberculosis and Borrelia burgdorferi PCR.

Liedtke W, Opalka B, Zimmermann CW, Schmid E.

Department of Neurology, University of Essen, Germany.

PMID: 8038699 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi reactivity in patients with severe persistent fatigue who are from a region in which Lyme disease is endemic.

Coyle PK, Krupp LB, Doscher C, Amin K.

Department of Neurology, Health Sciences Center, SUNY, Stony Brook 11794.

Borrelia burgdorferi is the pathogen that causes Lyme disease. Patients frequently experience fatigue and malaise that can persist after antibiotic treatment. This study examined serological reactivity to B. burgdorferi in patients with chronic fatigue who were from a region in which Lyme disease is endemic. Blood and CSF were collected from patients without a history of infection due to B. burgdorferi (n = 12) and patients with persistent fatigue after antibiotic treatment of Lyme disease (n = 13). Serum and CSF were examined by ELISA for antibodies to B. burgdorferi, and routine studies of CSF were done. In the first group, one patient (8%) was seropositive; no patients had detectable antibodies in CSF. In the second group, nine patients (69%) were seropositive or borderline seropositive; seven (54%) had detectable antibodies in CSF. Unexplained abnormalities in CSF were noted in 42% and 31% of patients in each group, respectively. In this study positive serologies for Lyme disease were not found at a higher than expected rate for patients from a region of Lyme disease endemicity who had idiopathic chronic fatigue. Fatigued patients did show a surprisingly high rate of unexplained minor CSF abnormalities suggestive of CNS or meningeal dysfunction.

Publication Types:
PMID: 8148448 [PubMed - indexed for MEDLINE]

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Stroke due to Lyme disease.

Reik L Jr.

Department of Neurology, University of Connecticut Health Center, Farmington 06030-1845.

A 56-year-old Connecticut woman suffered multiple strokes 18 months after antibiotic treatment for early Lyme disease with facial palsy. Pleocytosis, intrathecal synthesis of anti-Borrelia burgdorferi antibody, and the response to antibiotic treatment substantiated the diagnosis of neuroborreliosis. This is the first report of stroke caused by Lyme disease acquired in North America.

Publication Types:
PMID: 8255484 [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 polymerase chain reaction in the diagnosis of Lyme neuroborreliosis.

Pachner AR, Delaney E.

Department of Neurology, Georgetown University School of Medicine, Washington, DC.

The polymerase chain reaction is sensitive and specific in the detection of defined DNA sequences and holds promise for diagnosing the presence of fastidious microorganisms in human infectious diseases. We developed a methodology for nested polymerase chain reaction and hybridization analysis of the cerebrospinal fluid using primers from a genomic Borrelia burgdorferi sequence and applied it to the cerebrospinal fluid (CSF) of patients suspected of having Lyme neuroborreliosis and other diseases. Polymerase chain reaction and hybridization demonstrated extremely high sensitivity for spirochetal DNA, and was highly specific, with a false-positivity rate of less than 3%. However, the results were negative or indeterminate in 54% of CSF samples from patients with definite or probable disease, indicating an absence, or extremely low level, of spirochetes or spirochetal DNA in a significant percentage of patients with Lyme neuroborreliosis. Polymerase chain reaction and hybridization of the CSF can thus be considered a useful adjunct in diagnosis, but its negativity does not rule out Lyme neuroborreliosis.

Publication Types:
PMID: 8215242 [PubMed - indexed for MEDLINE]

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Reactivity of locally produced CSF antibodies in patients with neurosyphilis against antigens of Treponema pallidum.

Bollensen E, Albrecht S, Beuche W, Mäder M, Prange HW.

Department of Neurology, University of Göttingen, Germany.

The reactivity and specificity of locally produced cerebrospinal fluid (CSF) antibodies against antigens of Treponema pallidum were assessed by Western blotting in patients with clinical signs of parenchymal or meningovascular neurosyphilis. All nine patients showed local production of treponeme-specific antibodies in the central nervous system (CNS). In most of the patients serum and CSF antibodies were bound to the same antigens: the common treponemal 48/45 kDa protein and the putative specific T. pallidum protein in the range of 12-14 kDa. In some patients the intensity of staining obtained by CSF antibodies was higher than that derived from serum, indicating locally produced antibodies. In contrast to other more acute inflammatory CNS diseases, no expanded or different antigen binding of the CSF antibodies compared with serum antibodies was found in neurosyphilic patients. The results presented are discussed with regard to the role of the blood-brain barrier in antibody concentrations of CSF and serum.

PMID: 8263552 [PubMed - indexed for MEDLINE]

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Myositis in Lyme borreliosis: an immunohistochemical study of seven patients.

Müller-Felber W, Reimers CD, de Koning J, Fischer P, Pilz A, Pongratz DE.

Friedrich-Baur-Institut, Department of Neurology and Internal Medicine, University of Munich, Germany.

Myositis is a rare complication of Lyme disease. In order to get information about the pathogenesis of this disorder, muscle specimens of 7 patients suffering from myositis as a manifestation of Lyme borreliosis were examined by immunohistology. Lyme spirochetes could be found in muscle biopsies of 6 patients. Infiltrates consisted mainly of macrophages and T helper/inducer cells. The T4/T8 ratio was 1.7 in the endomysium and 2.1 in the perimysium. Increased expression of MHC-I molecules by several muscle fibers was observed in 2 subjects only. No MHC-II molecules were expressed by muscle fibers. Lymphocytes expressing the interleukin-2 receptor were detected in 2 patients. Leu-15+ and Leu-11+ cells were found only to a slight extent in 2 patients. In conclusion the immunohistochemical findings in myositis due to Lyme borreliosis are different from other manifestations of this disease, and also from other forms of myositis.

Publication Types:
PMID: 8229071 [PubMed - indexed for MEDLINE]

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Peripheral neuropathies after arthropod stings not due to Lyme disease: a report of five cases and review of the literature.

Créange A, Saint-Val C, Guillevin L, Degos JD, Gherardi R.

Service de Neurologie, Hôpital Henri Mondor, Créteil, France.

Five patients developed neurologic symptoms a few hours to 2 months after being stung by a non-hooking arthropod with immediate cutaneous reaction. The patients had no clinical or serologic evidence for Lyme borreliosis and rickettsial disease. Clinical and electrophysiologic findings were consistent with a mixed axonal and demyelinating mononeuropathy, a monomelic multiple mononeuropathy, a mononeuropathy multiplex, a radiculoneuritis, and a distal symmetric polyneuropathy. Muscle and nerve biopsies showed lymphoplasmacytic small-vessel vasculitis in all patients, and wallerian degeneration in three. These patients, and 17 others from the literature, indicate a spectrum of peripheral neuropathies occurring after insect and spider stings.

Publication Types:
PMID: 8394519 [PubMed - indexed for MEDLINE]

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Intrathecal synthesis of specific antibodies in neuroborreliosis. Comparison of different ELISA techniques and calculation methods.

Kaiser R, Lücking CH.

Department of Neurology, University of Freiburg, Germany.

The sensitivity of six different ELISA techniques and calculation methods for the determination of intrathecal synthesis of IgG antibodies specific to Borrelia burgdorferi was investigated in paired CSF and serum specimens from 33 patients with neuroborreliosis. The diagnostic value of the Antibody Index (AI) was compared with the meaningfulness of serum antibodies to B. burgdorferi (Bb), established by immunofluorescence assay (IFA). The AI, as a standard for intrathecal antibody synthesis was determined from specific antibody ratios (QBb) in the CSF and serum and the CSF/serum ratio of IgG (QIgG) or albumin (QAlb). Using Western blotting with identical concentrations of IgG in the CSF and serum all patients displayed intrathecal synthesis of specific antibodies to at least two B. burgdorferi proteins. The different ELISA methods and calculation procedures were almost equivalent in demonstrating intrathecal synthesis of specific antibodies (32 and 33/33). Calculation of AI from IFA titers was somewhat less sensitive (30/33). In 5 patients titers of serum IgG- and IgM-antibodies to B. burgdorferi determined by IFA were within the normal range or borderline, while elevated AIBb values indicated an autochthonous immune response to B. burgdorferi in the CSF. In uncertain cases of neuroborreliosis calculation of AI from ELISA titers will be useful in clarifying the diagnosis.

Publication Types:
PMID: 8229052 [PubMed - indexed for MEDLINE]

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Painful lumbosacral plexitis with increased ESR and Borrelia burgdorferi infection.

García-Moncó JC, Gómez Beldarrain M, Estrade L.

Sección de Neurología, Hospital de Galdacano, Vizcaya, Spain.

Publication Types:
PMID: 8170584 [PubMed - indexed for MEDLINE]

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Detection of Borrelia burgdorferi antigens in cerebrospinal fluid.

Coyle PK, Deng Z, Schutzer SE, Belman AL, Benach J, Krupp LB, Luft B.

Department of Neurology, SUNY at Stony Brook 11794.

We examined CSF for Borrelia burgdorferi antigens using antigen-capture ELISA and Western (immuno) blot. Antigen-capture ELISA was positive in 38 of 77 (49%) CSF samples obtained from neurologic patients with presumed B burgdorferi infection, compared with one of 34 (3%) CSF samples obtained from other neurologic disease controls who came from a region endemic for Lyme disease. Western immunoblot was positive for B burgdorferi antigens in 12 of 22 (55%) CSF samples from the B burgdorferi infected groups, compared with none of 11 CSF samples from the control group. CSF antigen detection should prove helpful in evaluating patients for suspected neurologic Lyme disease.

Publication Types:
PMID: 8170548 [PubMed - indexed for MEDLINE]

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Preferential usage of T cell antigen receptor V region gene segment V beta 5.1 by Borrelia burgdorferi antigen-reactive T cell clones isolated from a patient with Lyme disease.

Lahesmaa R, Shanafelt MC, Allsup A, Soderberg C, Anzola J, Freitas V, Turck C, Steinman L, Peltz G.

Department of Neurology, Stanford University Medical Center, CA 94305.

Forty-three CD3+4+8- TCR alpha beta+ Borrelia burgdorferi-reactive T cell clones isolated from the peripheral blood of a single patient with clinically active chronic Lyme arthritis were characterized. The spirochetal Ag recognized by 16 of these T cell clones was determined by reactivity with a panel of recombinant spirochetal Ag, which included the OspA, OspB, flagellin, Hsp60 and Hsp70 proteins. All three T cell clones reactive with heat shock proteins recognized a non-cross-reactive epitope unique to the spirochetal Ag. Analysis of the TCR V regions revealed preferential usage of V beta 5.1; 5 of 15 T cell clones that recognized an unidentified spirochetal Ag utilized this V beta gene segment. Most of the T cell clones recognized a given spirochetal Ag exclusively within the context of one HLA class II allele. However, two T cell clones, which recognized an unidentified Ag in the spirochetal lysate within the context of different HLA class II alleles, were both TCR V beta 5.1+, although each displayed a distinct alpha-chain. Moreover, in vitro incubation of this patient's PBMC with B. burgdorferi Ag resulted in a specific increase in the percentage of T cells expressing TCR V beta 5.1. These results indicate that B. burgdorferi has a V beta-selective factor influencing the cellular immune response in a patient with clinically active Lyme disease.

Publication Types:
PMID: 7682589 [PubMed - indexed for MEDLINE]

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Intrathecal synthesis of anti-Borrelia burgdorferi antibodies in neuroborreliosis: a study with special emphasis on oligoclonal IgM antibody bands.

Wang ZY, Hansen K, Sidén A, Cruz M.

Department of Neurology, Karolinska Institute, Huddinge University Hospital, Sweden.

Pre- and post-treatment (up to 3-26 months after antibiotic therapy) humoral immune responses were investigated in five neuroborreliosis patients. Anti-Borrelia (B.) burgdorferi IgG and IgM antibodies in CSF and serum were quantitated by capture ELISA. Agarose gel isoelectric focusing (AIF) and protein blotting were used to detect oligoclonal IgG and IgM bands as well as oligoclonal anti-B. burgdorferi IgG and IgM antibodies. These latter components were visualized by transfer to antigen-coated membranes (immunoblot) and immunoenzymatic staining. By ELISA, intrathecal anti-B. burgdorferi IgG and IgM antibody synthesis was detected in all initial specimens and continued 3-26 months after antibiotic therapy in four and three cases, respectively. AIF with protein blotting showed oligoclonal bands of total IgG as well as total IgM in the initial CSF specimens of all patients and persistence of such components occurred in four and five cases, respectively. By AIF and immunoblot, oligoclonal anti-B. burgdorferi IgG and IgM antibody bands could be detected in the CSF of every patient. IgG antibody bands were present in all initial CSF samples. The first specimen of one patient was negative for IgM antibody bands but such components appeared 3 weeks later. Oligoclonal CSF anti-B. burgdorferi IgG antibody components persisted over the entire follow-up periods in all but one case where they disappeared 6 weeks after treatment. The oligoclonal IgM antibodies in CSF vanished in two cases (after being present up to 4 and 11 months after antibiotic therapy) while they persisted over the entire (3-6 months after antibiotic therapy) follow-up periods in three cases. The specificity of the IgM antibody immunoblot technique was corroborated by control experiments, including antibody absorption studies and use of 41 kDa flagellar antigen.

Publication Types:
PMID: 8441923 [PubMed - indexed for MEDLINE]

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Comparison of polymerase chain reaction with culture and serology for diagnosis of murine experimental Lyme borreliosis.

Pachner AR, Ricalton N, Delaney E.

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

After the intradermal inoculation of mice with Borrelia burgdorferi, the antibody response, culture, and histology of blood and target organs were assessed and compared with results of a nested polymerase chain reaction (PCR) assay. Of 247 specimens of heart, brain, bladder, and blood, the tested concordance between the PCR and culture was 72%. In the 69 instances of discordance, the PCR was positive in 51 and the culture was positive in 18; thus, the PCR was concordant or more sensitive in 93% of the tested organs. In mice infected with 10 spirochetes, serology confirmed by Western blotting (immunoblotting) was more sensitive than either culture or PCR of brain, bladder, or heart specimens. The organs most commonly culture or PCR positive were the heart and bladder; the brain was infected in only 26% of the animals. DNA hybridization was helpful in confirming the PCR product as being specific and, in some cases, in demonstrating a positive product in the face of negative agarose gels. PCR was less sensitive than culture in detecting the presence of spirochetes in blood specimens, possibly because of the presence of blood inhibitors. We thus found a nested PCR assay, using primers from a genomic sequence, to be a valuable adjunct to serology and culture in the study of murine Lyme borreliosis. The assay confirmed that, after small numbers of spirochetes are injected intradermally, the heart and bladder, and less frequently the brain, are sites of persistence of the spirochetes.

Publication Types:
PMID: 8432804 [PubMed - indexed for MEDLINE]

PMCID: PMC262737


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Lyme disease with neurological complications in Japan.

Takahashi A.

Department of Neurology, Nagoya University School of Medicine, Japan.

PMID: 8470508 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi-specific intrathecal antibody production in neuroborreliosis: a follow-up study.

Hammers-Berggren S, Hansen K, Lebech AM, Karlsson M.

Department of Infectious Diseases, Danderyd Hospital, Sweden.

We used a capture ELISA with biotinylated Borrelia burgdorferi flagella as antigen to analyze the kinetics of intrathecal antibody production against B burgdorferi in 27 patients with neuroborreliosis. All patients had lymphocytic pleocytosis, 13/27 had intrathecal specific IgM production, and 26/27 had intrathecal IgG synthesis against B burgdorferi before therapy. All patients improved after antibiotic treatment. At follow-up, 11 months to 8 years later (median, 1 1/2 years), 20 patients had had a complete clinical recovery, and seven suffered from sequelae. One patient without sequelae had persistent specific intrathecal IgM synthesis. Ten of 20 patients without sequelae and five of seven patients with sequelae had persistent intrathecal IgG production against B burgdorferi. None of the 16 patients with persistent specific intrathecal antibody synthesis had pleocytosis at follow-up. Therefore, intrathecal immunoglobulin production against B burgdorferi, especially IgG, may persist for years after treatment of neuroborreliosis without clinical signs of active disease.

Publication Types:
PMID: 8423881 [PubMed - indexed for MEDLINE]

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[Prevalence of Borrelia burgdorferi serum antibodies in 651 patients with predominantly neurologic diseases]

[Article in German]

Müller M, Retzl J, Plank E, Scholz H, Ziervogel H, Stanek G.

Hygiene-Institut, Universität Wien.

An analysis was undertaken to the records of 651 patients (median age 51 years, range 1-91; 334 male and 317 female patients), who were admitted for various reasons to the department of neurology and psychosomatics of the county hospital in Villach (Kärnten, Austria), over the period of one year. The clinical diagnoses were mostly neurological and psychiatric (n = 599), involving 25 different conditions. Other diagnoses (n = 52) comprised a group of 13 various conditions. Sera of all these patients were tested for antibodies to Borrelia burgdorferi. Overall seropositivity was 37.8%. Seropositivity increased significantly with age (p < 0.01). Seroprevalence exceeded 40% in patients with meningitis, paresis of the cranial nerves, cervical syndrome, pareses and sponylitis. The erythrocyte sedimentation rate (ESR) was raised in 37.9% of cases which was not related to seropositivity. ESR was significantly increased in patients with lumbago (p < 0.01) and with arthritis (p < 0.05). Antibiotics and dosages used were recorded in 164 cases. All these cases improved after therapy. Of 81 patients with a history of tick bite, 43 (53%) were seropositive. This is a significantly higher incidence than that of patients without tick bites (p < 0.01). The retrospective evaluation of patients' records showed that anamnestic and clinical findings alone do not suffice to establish the specific diagnosis of Lyme borreliosis and, hence, do not provide the indication of appropriate therapy. Furthermore, the mere demonstration of serum antibodies to Borrelia burgdorferi does not give information on the current state of infection. In case of a suspected Borrelia burgdorferi infection confirmatory tests are needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
PMID: 8273357 [PubMed - indexed for MEDLINE]

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Prevalence of antibodies to Borrelia burgdorferi in serum and cerebrospinal fluid samples from patients with neurological disorders in Berlin.

Kölmel HW, Neumann P, Schneider T, Barnick L, Lange R.

Department of Neurology, Klinikum Rudolf Virchow, Freie Universität, Berlin, Germany.

Paired serum and cerebrospinal fluid (CSF) samples from 800 patients of a neurological department were tested for antibodies to Borrelia burgdorferi. A flagellum enzyme-linked immunosorbent assay was used for antibody screening. All serum/CSF pairs with any elevated antibody response were also tested by Western blotting a method for confirmation. 65 patients (8.1%) had serum IgG antibodies in ELISA and 22 of these patients (2.8%) were confirmed by Western blot. 20 patients (2.5%) had elevated antibody titres in CSF by ELISA and 12 (1.5%) reacted in the Western blot. Clinical features of Bannwarth's syndrome were present in 12 patients (1.5%) and 4 patients (0.5%) showed other manifestations of Lyme borreliosis. All patients with Bannwarth's syndrome were seropositive by both methods and 10 had elevated antibody activity in the CSF proved by the two methods. The combination of a sensitive ELISA for screening and a sensitive and specific Western blot for confirmation reduced the number of false positive results but kept its standard in detecting antibodies in patients with active disease.

Publication Types:
PMID: 1303693 [PubMed - indexed for MEDLINE]

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MRI findings in children infected by Borrelia burgdorferi.

Belman AL, Coyle PK, Roque C, Cantos E.

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

Cranial magnetic resonance imaging abnormalities were observed in 8 children (5 boys, 3 girls; ages 4-14 years) with neurologic problems following infection by Borrelia burgdorferi, the etiologic agent of Lyme disease. Neurologic features included headache (6), behavioral changes (5), facial palsy (2), papilledema (2), papilledema with diplopia (1), disturbance of sleep pattern (2), and carpal tunnel syndrome (1). Two MRI studies demonstrated multiple focal areas of increased signal intensity in white matter on long TR (both proton-density and T2-weighted) images.

Publication Types:
PMID: 1476570 [PubMed - indexed for MEDLINE]

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Murine Lyme borreliosis: route of inoculation determines immune response and infectivity.

Pachner AR, Delaney E, Ricalton NS.

Georgetown University School of Medicine, Department of Neurology, Washington, DC 20007.

Outer surface protein A OspA is the major outer surface protein of B. burgdorferi, the causative agent of Lyme disease, and has been advocated as a vaccine candidate. It is recognized late or not at all in the course of human Lyme disease, but has been identified as a major antigenic epitope for the anti-spirochetal immune response in a number of experimental models of B. burgdorferi infection. We injected B.burgdorferi into mice and tested the appearance of immunoreactivity to OspA by Western blotting. Three routes of infection were studied; other variables investigated were inoculum size and isolate of spirochete and strain of mouse. OspA immunoreactivity, as determined by Western blotting, was readily elicited by injection of sonicates under almost any condition. Intraperitoneal or intravenous injection of infectious spirochetes, especially at infective inoculum sizes, or injection of the noninfectious B31 isolate by any route, resulted in OspA immunoreactivity. However, mice from the three strains tested infected intradermally did not develop significant OspA immunoreactivity, but instead developed strong responses to B.burgdorferi proteins of different molecular weights. These data suggest that during infection within the skin after intradermal inoculation, the OspA protein may be altered in some way to make it less immunogenic than when it is presented to the immune system under other circumstances.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
PMID: 1297405 [PubMed - indexed for MEDLINE]

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Comment on:
CNS Lyme disease.

Pachner AR.

Publication Types:
PMID: 1482459 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi and other related spirochetes bind to galactocerebroside.

Garcia Monco JC, Fernandez Villar B, Rogers RC, Szczepanski A, Wheeler CM, Benach JL.

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

Spirochetes are agents of neurologic disease that may utilize specific neural cell surface molecules for adhesion. Borrelia burgdorferi, the etiologic agent of Lyme disease, bound to galactocerebroside (GalCer) in numbers that were two- to threefold greater than to ceramide and glucocerebroside, and four- to fivefold greater than to sphingosine, psychosine, sulfatide, cholesterol, and three membrane phospholipids. The adherence was greater to GalCer and ceramide with a higher content of alpha-hydroxyl fatty acids. Treponema phagedenis Reiter and Borrelia hermsii also bound to GalCer. The binding of B burgdorferi to GalCer was inhibited in a concentration-dependent manner by rabbit polyclonal and murine monoclonal antibodies to this glycosphingolipid component of myelin. The monoclonal antibody to GalCer also inhibited adhesion of the organisms to Schwann cells. Neither free D or L monosaccharides nor the lectin peanut agglutinin inhibited binding. Since B burgdorferi and other spirochetes cause neurologic disease, these results suggest a role for GalCer as a binding site in both the central and peripheral nervous systems.

Publication Types:
PMID: 1620344 [PubMed - indexed for MEDLINE]

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Comment in:
Lyme borreliosis in Bell's palsy. Long Island Neuroborreliosis Collaborative Study Group.

Halperin JJ, Golightly M.

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

Lyme borreliosis (LB) causes a range of neurologic manifestations, the most common of which is facial nerve paralysis. To evaluate nervous system LB, we organized a neurologic collaborative study group in Suffolk County, NY, a region of high LB incidence. Between July and September 1989, LB serologies were performed on all patients with new-onset Bell's palsy. Seven of 32 had serologic evidence of LB at onset. One, initially seronegative, was highly seropositive 5 weeks later. In the five in whom we examined CSF, there was no evidence of intrathecal synthesis of specific antibody. In highly endemic areas, LB may be responsible for 1/4 of cases of Bell's palsy. Rarely, the palsy may occur prior to the development of a measurable antibody response, indicating a need for follow-up serologic testing.

Publication Types:
PMID: 1620330 [PubMed - indexed for MEDLINE]

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Antibodies to Borrelia burgdorferi in patients with carpal tunnel syndrome.

Kindstrand E.

Department of Neurology, Karolinska Institute Söder Hospital, Stockholm, Sweden.

In a study of 94 consecutive patients with neurophysiologically verified carpal tunnel syndrome (CTS) 7/94 had IgG and 0/94 IgM serum titers to Borrelia burgdorferi above the 98th percentile value of age and sex matched controls (n = 127). The difference in prevalence of positive IgG serum titers in patients, compared to controls, was not statistically significant. Even in patients, living in an area, highly endemic for Lyme borreliosis, routine serological screening for borrelia infection does not seem indicated in the investigation of CTS.

PMID: 1519478 [PubMed - indexed for MEDLINE]

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Immobilized pH gradient isoelectric focusing and immunoblotting for investigations of anti-Borrelia burgdorferi IgG antibodies.

Cruz M, Sidén A.

Department of Neurology, Karolinska Institute, Huddinge, Sweden.

Anti-Borrelia burgdorferi immunoglobulin G (IgG) responses in cerebrospinal fluid, serum, and joint fluid from Lyme disease patients were investigated by immobilized pH gradient (IPG) isoelectric focusing (IEF) in pH 4-10 and pH 4-7 gels. After focusing, the anti-B.-burgdorferi antibodies were blotted by affinity-driven transfer to antigen-coated polyvinylidene difluoride membranes (immunoblot) and the IgG antibodies were immunoenzymatically stained. IPG-IEF gels gave an excellent resolution of IgG and the immunoblot proved advantageous for the detection of anti-B. burgdorferi IgG antibodies. These antibodies, as judged from the electromigration characteristics, were found to contain oligoclonal as well as polyclonal subpopulations. This latter group included IgG antibodies that were inadequately resolved when separated by conventional carrier ampholyte IEF.

Publication Types:
PMID: 1378387 [PubMed - indexed for MEDLINE]

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Light chain distribution of anti-Borrelia burgdorferi IgG antibodies in Lyme arthritis.

Cruz M, Sidén A.

Department of Neurology, Karolinska Institute, Huddinge University Hospital, Sweden.

Joint fluid (JF) and serum IgG from eight Lyme arthritis patients was investigated by isoelectric focusing, blotting to membranes of uncoated nitrocellulose (NC) as well as Borrelia (B.) burgdorferi antigen-coated NC (immunoblot) and immunoezymatic staining for visualization of the IgG isotype and characterization of the kappa/lambda light chain distribution. Oligoclonal bands of total IgG occurred in JF as well as in serum (3 cases) or in JF only (1 case); IgG lambda components were present in all four subjects and IgG kappa in three. IgG (Fc frag) reactive but kappa/lambda light chain negative oligoclonal bands were present in JF of one further patient. Additional investigations supported the interpretation that these components were free gamma chains. Oligoclonal anti-B. burgdorferi IgG antibodies occurred in JF as well as in serum (6 cases) or in JF only (1 case). There were complete identities, as defined by isoelectric points and light chain types, between JF and serum antibodies in an individual patient while identities between oligoclonal bands of total IgG and anti-B. burgdorferi IgG were infrequent. Antibodies of IgG kappa identity were present in all seven patients and six of them also had IgG lambda antibodies. The antibody response was, therefore, by definition oligo- and not monoclonal in 6 out of 7 patients. Furthermore, the anti-B. burgdorferi antibodies of IgG kappa identity only that were present in one case did not exhibit any completely characteristic monoclonal microheterogeneity.

Publication Types:
PMID: 1535989 [PubMed - indexed for MEDLINE]

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Comment in:
PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients.

Keller TL, Halperin JJ, Whitman M.

Division of Cell and Molecular Biology, Dana Farber Cancer Institute, Boston, MA.

We used the polymerase chain reaction (PCR), a method useful in the detection of Borrelia burgdorferi in vitro, to evaluate CSF in patients thought to have neuroborreliosis. Nested pairs of oligonucleotide primers were designed to recognize the C-terminal region of B burgdorferi OspA. CSF samples were obtained from (1) patients with immunologic evidence of systemic B burgdorferi infection and clinical manifestations suggestive of CNS dysfunction, (2) seronegative patients with clinical disorders consistent with Lyme borreliosis, and (3) patient and contamination controls; all were analyzed in a blinded fashion. PCR detected B burgdorferi OspA DNA in CSF of (1) 10 of 11 patients with Lyme encephalopathy, (2) 28 of 37 patients with inflammatory CNS disease, (3) seven of seven seronegative patients with Lyme-compatible disorders, and (4) zero of 23 patient controls. Zero of 83 additional contamination controls were PCR-positive. In eight patients from whom we obtained CSF before and after parenteral antimicrobial therapy, PCR results invariably predicted clinical outcome accurately.

Publication Types:
PMID: 1734321 [PubMed - indexed for MEDLINE]

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An outer surface protein is a major T cell antigen in experimental Lyme disease in CB6F1 mice.

Pachner AR, Itano A, Ricalton N.

Department of Neurology, Georgetown University Hospital, Washington, DC 20007.

PMID: 1793226 [PubMed - indexed for MEDLINE]

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Neuroradiological findings of paretic neurosyphilis, a case report.

Saitoh H, Yazaki K, Yoshii F, Shinohara Y.

Department of Neurology, Tokai University School of Medicine, Kanagawa, Japan.

Neuroradiological findings of a patient with paretic neurosyphilis are described. A 50-year-old male patient showed personality changes, severe dementia and some neurological deficits. Serological analysis of serum and cerebrospinal fluid demonstrated the presence of antibodies to Treponema pallidum. Computed tomography showed diffuse cerebral cortical atrophy and ventricular dilatation, and magnetic resonance (MR) imaging revealed some small abnormal signals in the white matter. Single photon emission tomography using [123I] N-isopropyl-p-iodoamphetamine (IMP-SPECT) indicated decreased activities, most markedly in the right frontal and bitemporal cortices. Although the neuroradiological findings were nonspecific, the MR imaging and IMP-SPECT findings were interesting because they have not been described previously to our knowledge.

Publication Types:
PMID: 1820661 [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.

Publication Types:
PMID: 1922798 [PubMed - indexed for MEDLINE]

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Borrelia rhombencephalomyelopathy.

Kuntzer T, Bogousslavsky J, Miklossy J, Steck AJ, Janzer R, Regli F.

Department of Neurology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Three patients, in whom the diagnosis of Borrelia burgdorferi infection was unknown for several years, developed a biphasic involvement of the central nervous system: an acute brain-stem dysfunction was followed up, in two patients, by a progressive, disabling myelitis and, in one patient, by further relapsing-remitting episodes of severe multifocal rhombencephalitis. The most consistent cerebrospinal fluid abnormalities in the analysis of sequential specimens were elevated total IgM levels that normalized after penicillin therapy. The neuropathologic findings in one patient showed microgliosis and meningovascular involvement of the central nervous system, resulting in two ischemic infarcts in the myelencephalon. Few spirochetes were localized in the leptomeninges and around subependymal vessels of the fourth ventricle. The vascular element consisted of an obliterative inflammatory vasculopathy in the medullary parenchyma. This study (1) provides pathologic evidence that a vascular disease induced by B burgdorferi is a pathogenetic mechanism for cerebrovascular diseases, and (2) emphasizes the similarities between neuroborreliosis and neurosyphilis.

Publication Types:
PMID: 1898257 [PubMed - indexed for MEDLINE]

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Infective acute transverse myelopathy. Report of two cases.

Linssen WH, Gabreëls FJ, Wevers RA.

Institute of Neurology, University Hospital Nijmegen, The Netherlands.

Two children with acute transverse myelopathy following adenovirus and Borrelia Burgdorferi infections are presented. The diagnosis stems from the clinical presentation, the determination of specific antibodies in serum and the favorable response to penicillin treatment in the case of neuroborreliosis. Both children made a good recovery. The cerebrospinal fluid examination showed a highly increased myelin basic protein concentration, indicating demyelination.

Publication Types:
PMID: 1713310 [PubMed - indexed for MEDLINE]

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Comment on:
Lyme borreliosis: presentation and therapy.

Goldings AS.

Publication Types:
PMID: 2053959 [PubMed - indexed for MEDLINE]

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Anti-Borrelia burgdorferi antibody response over the course of Lyme neuroborreliosis.

Baig S, Olsson T, Hansen K, Link H.

Department of Neurology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.

Characteristic findings on examination of cerebrospinal fluid (CSF) in Lyme neuroborreliosis include mononuclear pleocytosis, oligoclonal immunoglobulin G (IgG) bands, and evidence for local production of specific antibodies. We utilized an immunospot assay to detect cells secreting anti-Borrelia burgdorferi antibodies of different isotypes over the course of disease. Such cells were detected in CSF from 13 consecutive patients with neuroborreliosis examined before treatment. IgG antibody-secreting cells were present in high numbers (mean, 32 cells per 10(4) CSF cells), whereas IgA and IgM antibody-secreting cells were found less frequently and at lower numbers (mean, 5 and 6 cells per 10(4) CSF cells, respectively). Clinical improvement after penicillin treatment was paralleled by a rapid decline of antibody-secreting cells in CSF, but they were still detected, although at lower numbers, in 5 of 10 patients examined more than 6 months after treatment. This specific B-cell response persisted despite clinical improvement. Whether it reflects persistence of antigen is unsettled.

PMID: 1997408 [PubMed - indexed for MEDLINE]

PMCID: PMC258366


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Brown-Séquard syndrome caused by Borrelia burgdorferi.

Berlit P, Pohlmann-Eden B, Henningsen H.

Department of Neurology, Klinikum Mannheim, University of Heidelberg, FRG.

We report the case of a patient with Brown-Séquard syndrome resulting from Borrelia burgdorferi infection. Antibiotic treatment led to complete recovery.

Publication Types:
PMID: 2015831 [PubMed - indexed for MEDLINE]

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Lyme arthritis: oligoclonal anti-Borrelia burgdorferi IgG antibodies occur in joint fluid and serum.

Cruz M, Hansen K, Ernerudh J, Steere AC, Link H.

Department of Neurology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.

The antibody response to Borrelia (B.) burgdorferi, and to measles virus as control antigen, was analysed by agarose isoelectric focusing (AIF) and immunoblot of joint fluid and serum from 10 patients with Lyme arthritis and 10 controls with rheumatoid arthritis. Among the Lyme arthritis patients, six had oligoclonal anti-B. burgdorferi IgG antibody bands in joint fluid and corresponding serum, one patient had oligoclonal antibody bands in joint fluid only and also an elevated B. burgdorferi-specific joint fluid to serum antibody ratio as evidence of intra-joint production of specific antibodies, and the remaining three patients were negative for oligoclonal-specific antibody bands. Absorption with B. burgdorferi antigen confirmed the specificity of the oligoclonal antibody bands. They comigrated only partially on AIF with oligoclonal bands of total IgG, and the specificity of most oligoclonal IgG in joint fluid and serum in Lyme arthritis remains undefined. Among the controls, no anti-B, burgdorferi IgG antibodies were detected by AIF and immunoblot. Instead, 9 of the 10 rheumatoid arthritis patients had oligoclonal anti-measles IgG antibody bands which were restricted to the joint fluid in three of them, indicating local production. We conclude that Lyme arthritis is often accompanied by an oligoclonal specific antibody response in joint fluid and serum simultaneously, and occasionally by intrasynovial synthesis of oligoclonal-specific antibodies.

Publication Types:
PMID: 1996408 [PubMed - indexed for MEDLINE]

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Cerebrospinal fluid immune complexes in patients exposed to Borrelia burgdorferi: detection of Borrelia-specific and -nonspecific complexes.

Coyle PK, Schutzer SE, Belman AL, Krupp LB, Golightly MG.

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

We analyzed cerebrospinal fluid (CSF) from 32 patients with neurological symptoms and evidence of Borrelia burgdorferi infection (29 were seropositive as determined by enzyme-linked immunosorbent assay, 2 were cell-mediated immune positive, and 1 had been seropositive as shown by enzyme-linked immunosorbent assay 9 months previously). CSF immune complexes were found in 22 (69%) of 32 patients; in 18, there was sufficient sample to isolate immune complexes. By enzyme-linked immunosorbent assay, isolated immune complexes from 10 of these 18 patients contained antibody specific for B. burgdorferi antigens. The isotypes were IgG (n = 8), IgM (n = 3), and IgA (n = 2). By immunoblot, these antibodies were directed against B. burgdorferi 41-kDa antigen and occasionally against the 33- and 17-kDa antigens. Anti-B. burgdorferi IgM was present in patients with acute neurological symptoms, was predominantly complexed rather than free, and decreased with clinical recovery in the one serial study. Three patients were nonreactive for free CSF antibodies, but had complexed antibodies to the organism. The preliminary finding of specific B. burgdorferi components in immune complexes in CSF suggests an active process triggered by the organism, even in the absence of other CSF abnormalities.

PMID: 2285261 [PubMed - indexed for MEDLINE]

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Immunological differentiation between neuroborreliosis and multiple sclerosis.

Heller J, Holzer G, Schimrigk K.

Department of Neurology, Universitätsnervenklinik, 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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Comment in:
Borrelia burgdorferi infection of the brain: characterization of the organism and response to antibiotics and immune sera in the mouse model.

Pachner AR, Itano A.

Department of Neurology, Georgetown University Hospital, Washington, DC 20007.

To learn more about the neurologic involvement in Lyme disease, we inoculated inbred mice with the causative agent of Lyme disease, Borrelia burgdorferi. We cultured brains and other organs, and measured anti-B burgdorferi antibody titers. We further studied a brain isolate for its plasmid DNA content and its response in vitro to immune sera and antibiotics. One strain of B burgdorferi, N40, was consistently infective for mice, and resulted in chronic infection of the bladder and spleen. SJL mice developed fewer culture-positive organs and had lower antibody titers than Balb/c and C57Bl/6 mice. Organism was cultured from the brain early in the course of infection, and this isolate, named N40Br, was further studied in vitro. The plasmid content of N40Br was different from that of the infecting strain, implying either a highly selective process during infection or DNA rearrangement in the organism in vivo. N40Br was very sensitive to antibiotics, but only after prolonged incubation. Immune sera from both mice and humans infected with B burgdorferi were unable to completely kill the organism by complement-mediated cytotoxicity. These data demonstrate that B burgdorferi infects the brain of experimental animals, and is resistant to immune sera in vitro but sensitive to prolonged treatment with antibiotics.

Publication Types:
PMID: 2215944 [PubMed - indexed for MEDLINE]

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[A case of cranial polyneuropathy presenting with prominent facial diplegia, elevated serum Borrelia burgdorferi antibody and lymphocytic pleocytosis]

[Article in Japanese]

Hasegawa Y, Ueno S, Takegami T, Okamoto S.

Department of Neurology, Nagoya National Hospital.

A 54 year-old male patient developed acute cranial polyneuropathy including prominent facial diplegia and radicular++-neuritis. He was proven to have lymphocytic pleocytosis, and elevated serum Borrelia burgdorferi antibody to X800 (normal; less than X200). A diagnosis of typical early neuro-borreliosis was made after these clinical and laboratory findings. This case is the first neuro-borreliosis showing the triad of neurological manifestations (meningitis, cranial neuritis, radicular++-neuritis) in Japan. It is concluded that neuro-borreliosis should be considered to be a cause of acute cranial polyneuropathy, particularly of facial diplegia, even if the patient has no apparent history of a tick bite.

Publication Types:
PMID: 2242636 [PubMed - indexed for MEDLINE]

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Immunologic reactivity against Borrelia burgdorferi in patients with motor neuron disease.

Halperin JJ, Kaplan GP, Brazinsky S, Tsai TF, Cheng T, Ironside A, Wu P, Delfiner J, Golightly M, Brown RH, et al.

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

Of 19 unselected patients with the diagnosis of amyotrophic lateral sclerosis (ALS) living in Suffolk County, New York (an area of high Lyme disease prevalence), 9 had serologic evidence of exposure to Borrelia burgdorferi; 4 of 38 matched controls were seropositive. Eight of 9 seropositive patients were male (8 of 12 male patients vs 2 of 24 controls). Rates of seropositivity were lower among patients with ALS from nonendemic areas. All patients had typical ALS; none had typical Lyme disease. Cerebrospinal fluid was examined in 24 ALS patients--3 (all with severe bulbar involvement) appeared to have intrathecal synthesis of anti-B burgdorferi antibody. Following therapy with antibiotics, 3 patients with predominantly lower motor neuron abnormalities appeared to improve, 3 with severe bulbar dysfunction deteriorated rapidly, and all others appeared unaffected. There appears to be a statistically significant association between ALS and immunoreactivity to B burgdorferi, at least among men living in hyperendemic areas.

Publication Types:
PMID: 2334308 [PubMed - indexed for MEDLINE]

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[Encephalomyelitis with elevated serum antibody against Borrelia burgdorferi]

[Article in Japanese]

Shimizu T, Hayashi H, Tanabe H, Iguchi K.

Department of Neurology, Tokyo Metropolitan Neurological Hospital.

A 60-year-old female was admitted because of intermittent fever, arthralgia, itching of whole body, pretibial edema, urinary incontinence, pain of both legs and gait disturbance, after an insect bite. On admission, she had fever of 38 degrees C, and nuchal pain and stiffness. Neurological examination revealed spasticity of lower legs and increased deep tendon reflexes of all extremities. Hyperesthesia and hyperalgesia were noted on C2-4 and L5-S5 areas. Leukocyte count was 10,100/mm3 and CRP was 2+. CSF showed no pleocytosis (3/mm3, lymphocyte), but total protein (50 mg/dl) and IgG (10.5 mg/dl) were increased. On T2-weighted images of brain MRI, multiple small high signal areas were shown. The symptom improved markedly by prednisolone, but 3 months later left lateral gaze palsy appeared abruptly. A demyelinating lesion of the pons to the medulla oblongata including the left paramedian pontine reticular formation was suspected, and a corticosteroid pulse therapy was very effective. Serum titer of anti-Borrelia burgdorferi-IgG antibody by indirect immunoperoxidase method was 400 x at first and 1600 x after 3 months. Neuroborreliosis was diagnosed, but high doses of intravenous penicillin were not effective, and an immune-mediated demyelinating mechanism was probably thought to play a role in the pathogenesis of neuroborreliosis.

Publication Types:
PMID: 2364635 [PubMed - indexed for MEDLINE]

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[A case of "neuralgic amyotrophy" with elevated serum antibody titer against Borrelia burgdorferi]

[Article in Japanese]

Nangaku M, Tamaoka A, Iguchi K, Inoue K, Mannen T.

Department of Neurology, Tokyo University School of Medicine.

A 39-year-old man experienced an abrupt onset of right back pain. The pain improved spontaneously, but weakness of the right upper extremity developed. The weakness deteriorated during the next month, and he was admitted to our hospital. Neurological examination disclosed impairment of superficial sensation in his right upper extremity. Blood examination showed no abnormal data. The cerebrospinal fluid was normal. Neuroradiological findings were also negative. Electrophysiological examinations were normal except for needle electromyographic findings of the right upper extremity, which showed neurogenic patterns of moderate degree. Those findings suggest neuralgic amyotrophy. However, examining the serum sample significantly elevated levels of antibody titers against Borrelia burgdorferi were observed, and we suspected that his illness was Lyme disease. He recalled, however, no arthropod bite. Neuralgic amyotrophy is a syndrome which takes a characteristic clinical course. It includes some heterogeneous disorders. On the other hand, Lyme disease, a tick-transmitted spirochetal illness, occurs in stages, with remissions and exacerbations and different clinical manifestations at each stage. The neurological abnormalities include aseptic meningitis, encephalitis, cranial neuritis, motor and sensory radiculitis, and myelitis in various combinations. They can be diagnosed serologically. However, it is possible that elevation levels of the antibody titers mean nonspecific damages of peripheral nerves. Further study is necessary to decide whether cases like ours suffer from so-called Lyme disease or not.

Publication Types:
PMID: 2331826 [PubMed - indexed for MEDLINE]

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Prevalence of Erythema migrans Borreliosis in blood donors.

Schmidt R, Gollmer E, Zunser R, Krüger J, Ackermann R.

Department of Neurology, University Hospital of Cologne, FRG.

European Erythema migrans Borreliosis and North American Lyme disease are closely related to syphilis. This implicates a potential risk of infection for blood recipients. Eighty-six of 3,157 blood donors tested showed IgG-antibodies against Borrelia Burgdorferi. From among 47 persons of this group who could be examined, clinical signs of diseased skin, joints or nervous system, not diagnosed before, were found or could be suspected in 13 cases. Since intrauterine transmission of Borrelia infection has been described, the inevitable question of whether this disease can also be transmitted as a result of blood transfusion becomes a major concern. As the pathogen can persist even in the presence of serum antibodies, it seems advisable to examine blood donors serologically, whenever Erythema migrans Borreliosis is suspected. Though further research is required to document a transfusion-transmitted Borrelia infection, infected persons should be treated to avoid serious or late manifestations.

PMID: 2625363 [PubMed - indexed for MEDLINE]

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Myositis during Borrelia burgdorferi infection (Lyme disease).

Schoenen J, Sianard-Gainko J, Carpentier M, Reznik M.

Department of Neurology, University of Liege, Belgium.

During the second stage of an illness caused by Borrelia burgdorferi, a young woman developed a myopathic syndrome characterised by severe muscular pains, incapacitating weakness of the proximal limb and the neck, as well as the bulbar muscles and elevated serum CK levels. Muscle biopsy revealed a non-inflammatory necrotising myopathy. B. burgdorferi infection was confirmed by a considerable rise of specific IgG antibodies. A course of high dose steroids alleviated the myalgias, but paresis began to improve only after treatment with antibiotics. Our observations confirm that B burgdorferi can cause, through an undertermined mechanism, a necrotising myopathy, in addition to the wide spectrum of already known neurological complications.

Publication Types:
PMID: 2795056 [PubMed - indexed for MEDLINE]

PMCID: PMC1031843


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Latent Lyme neuroborreliosis: presence of Borrelia burgdorferi in the cerebrospinal fluid without concurrent inflammatory signs.

Pfister HW, Preac-Mursic V, Wilske B, Einhäupl KM, Weinberger K.

Neurologische Klinik, Klinikum Grosshadern, University of Munich, Federal Republic of Germany.

Borrelia burgdorferi, the etiologic agent of Lyme borreliosis, was isolated from the CSF of a patient with elevated serum IgG antibody titers against B burgdorferi and a history of multiple tick bites. The absence of concurrent inflammatory signs of CSF as well as intrathecal antibody production indicates a phase of latent Lyme neuroborreliosis in which no tissue infection or reaction has yet occurred. Bilateral tinnitus was the only clinical symptom in this patient. The persistence of the bilateral tinnitus after antibiotic therapy did not support a causal relationship between this symptom and the borrelial infection.

Publication Types:
PMID: 2668788 [PubMed - indexed for MEDLINE]

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Predominance of Borrelia burgdorferi specific B cells in cerebrospinal fluid in neuroborreliosis.

Baig S, Olsson T, Link H.

Department of Neurology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.

A nitrocellulose immunospot assay that allows the counting of cells secreting IgG, IgA, or IgM antibodies to Borrelia burgdorferi was used to compare B cell response to B burgdorferi at the cellular level in cerebrospinal fluid (CSF) and blood from patients with neuroborreliosis with that in patients with aseptic meningoencephalitis (AM) or non-inflammatory neurological diseases. 13 of the 14 patients with untreated neuroborreliosis had CSF cells secreting IgG antibodies to B burgdorferi (mean 17 cells per 10(4) CSF cells), whereas 8 of 12 patients examined had cells secreting IgA antibodies (mean 6 cells) and 10 of 12 had cells secreting IgM antibodies (mean 6 cells) per 10(4) CSF cells. IgG antibody producing cells predominated except in 2 patients with mainly or only IgM secreting cells. Cells secreting antibodies to B burgdorferi were rarely found in the blood and then at very low numbers, which reflects preferential compartmentalisation of the specific B cell response to the CSF. The cells were not detectable in CSF or blood from the two control groups. Evaluation of humoral immunity at the cellular level is a novel approach to the detection and localisation of immune events in neuroinflammatory disorders.

Publication Types:
PMID: 2567872 [PubMed - indexed for MEDLINE]

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Locked-in state in Borrelia burgdorferi meningitis.

Merlo A, Weder B, Ketz E, Matter L.

Department of Neurology, Kantonsspital, St. Gallen, Switzerland.

The case is reported of a 28-year-old woman with persistent tetraplegia following acute meningitis due to Borrelia burgdorferi infection. The patient developed erythema chronicum migrans before radicular pain occurred in the upper extremities. The poor clinical outcome was suggestive of pontine infarction due to vasculitis of branches of the basilar artery.

Publication Types:
PMID: 2760649 [PubMed - indexed for MEDLINE]

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Central nervous system manifestations of Lyme disease.

Pachner AR, Duray P, Steere AC.

Department of Neurology, Georgetown University School of Medicine, Washington, DC.

We studied six patients with central nervous system manifestations of Lyme disease. Weeks to years after the initial infection, behavioral changes, ataxia, and/or weakness in bulbar or peripheral muscles developed. Four of the six patients had a lymphocytic pleocytosis in the cerebrospinal fluid, and two of them had magnetic resonance imaging scans suggestive of demyelination. In a patient with a subacute encephalitis, a brain biopsy specimen showed microgliosis without an inflammatory infiltrate and spirochetes morphologically compatible with Borrelia burgdorferi. All six patients had elevated antibody titers to B burgdorferi in serum, but none had selective concentration of specific antibody in the cerebrospinal fluid. All six patients were treated with high-dose intravenous penicillin; four had complete recoveries and two did not. Lyme disease may affect the central nervous system causing organic brain disease or syndromes suggestive of demyelination.

Publication Types:
PMID: 2742551 [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:
Clinical significance of cerebrospinal fluid tests for neurosyphilis.

Davis LE, Schmitt JW.

Neurology Service, Veterans Administration Medical Center, Albuquerque, NM 87108.

From 1978 to 1987, 1,665 cerebrospinal fluid (CSF) fluorescent treponemal antibody absorption (CSF-FTA-ABS) tests were performed as the screening procedure for neurosyphilis. The CSF samples from 48 patients were reactive, and the medical history and results of the CSF-Venereal Disease Research Laboratory test (CSF-VDRL) for syphilis for 38 of these patients were reviewed. Likely active neurosyphilis was diagnosed if the patient had a reactive CSF-FTA-ABS test, recent onset of neurological signs consistent with neurosyphilis, abnormal CSF, and no other recognized cause for the neurological illness. Fifteen patients were so classified. Four had a reactive CSF-VDRL test. The specificity of the CSF-VDRL in diagnosing likely active neurosyphilis was 100%, but the sensitivity was only 27%. The insensitivity of the CSF-VDRL test limits its usefulness as a screening test for neurosyphilis. The CSF-FTA-ABS test appears more sensitive for screening but is less specific than the CSF-VDRL test in distinguishing currently active neurosyphilis from past syphilis. These findings imply that clinical judgment is still essential in establishing the diagnosis of active neurosyphilis.

Publication Types:
PMID: 2643918 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi--specific and autoreactive T-cell lines from cerebrospinal fluid in Lyme radiculomyelitis.

Martin R, Ortlauf J, Sticht-Groh V, Bogdahn U, Goldmann SF, Mertens HG.

Department of Neurology, University of Würzburg, FRG.

In 3 patients with Lyme radiculomyelitis, cellular immune reactions of cerebrospinal fluid (CSF) lymphocytes were analyzed. Phenotypic analysis of CSF cells demonstrated that the majority were T cells (CD3+) of the helper/inducer subset (CD4+). These T cells were directly expanded from the CSF by limiting dilution. A total of 505 T-cell lines were tested for Borrelia burgdorferi (Bb)-specific proliferation and also partly tested for reactivity to a panel of central and peripheral nervous system antigens. Proliferative assays revealed 33 of them to be Bb specific, 16 to be specific for myelin basic protein, 16 to be specific for peripheral myelin, 1 to be specific for cardiolipin, and 2 to be specific for galactocerebrosides. The antigen-specific proliferation was restricted by autologous human leukocyte antigen (HLA) class II molecules. The majority of CSF-derived T-cell lines stained positively for CD3, CD4, and HLA class II antigens and negatively for CD8 (cytotoxic/suppressor subset). One T-cell line provided help for the production of specific IgG by autologous B cells and secreted gamma-interferon upon stimulation with Bb antigen in the presence of autologous antigen-presenting cells. These data show that in patients with severe neurological manifestations of late Lyme disease, not only Bb-specific T-cell lines but also T cells reactive to central or peripheral nervous system autoantigens can be found.

Publication Types:
PMID: 3266455 [PubMed - indexed for MEDLINE]

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Lyme disease patients' serum contains IgM antibodies to Borrelia burgdorferi that cross-react with neuronal antigens.

Sigal LH, Tatum AH.

Medical Service, VAMC-Syracuse.

Serum from patients with neurologic manifestations of Lyme disease had serum IgM antibodies that bound to normal human axons, whereas binding was absent or weak in patients without neurologic findings. Antiaxonal binding could be eliminated by absorption with Borrelia burgdorferi. A murine monoclonal antibody to the borrelial flagellin also bound to human axons.

PMID: 3412593 [PubMed - indexed for MEDLINE]

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Association of HLA-DR2 antigen with serum IgG antibodies against Borrelia burgdorferi in Bannwarth's syndrome.

Wokke JH, van Doorn PA, Brand A, Schreuder GM, Vermeulen M.

University Department of Neurology, Academic Hospital Utrecht, The Netherlands.

The frequency of the HLA-DR2 antigen in 33 patients with clinical symptoms and signs of Bannwarth's syndrome was 33%, which was not significantly different from the 29% occurrence in 505 control subjects. However, all 11 HLA-DR2-positive patients had elevated serum levels of IgG antibodies against Borrelia burgdorferi, and these were present in 45% of 22 HLA-DR2-negative patients (P = 0.004). In the 21 patients with anti-B. burgdorferi antibodies the frequency of HLA-DR2 was 52%, which is significantly higher than the frequency in the control group (P = 0.04). The diagnosis of Bannwarth's syndrome was serologically confirmed by a positive indirect immunofluorescence assay (IFA). A negative test result does not exclude the diagnosis, as has recently been demonstrated with more sensitive techniques. The association between HLA-DR2 and a positive IFA suggests that the IFA selects a subgroup of patients with Bannwarth's syndrome and a different immune response. We could not demonstrate differences in the clinical spectrum and outcome between the two groups.

PMID: 3265432 [PubMed - indexed for MEDLINE]

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CNS-borreliosis selectively affecting central motor neurons.

Fredrikson S, Link H.

Department of Neurology, Karolinska Institutet, Huddinge Hospital, Stockholm, Sweden.

A patient is described having Borrelia burgdorferi spirochetal infection clinically affecting central motor neurons selectively and without any sensory impairment. Diagnosis was based on elevated B. burgdorferi IgG antibody titers in cerebrospinal fluid (CSF) and titer normalization at clinical recovery. This occurred promptly and was complete after penicillin treatment despite 14 months of progressive central nervous system (CNS) dysfunction, favouring the hypothesis of the presence of the organism within the CNS. CSF findings characteristic of neuroborreliosis were registered, including parallel occurrence of mononuclear pleocytosis, severe blood-brain barrier damage and marked CSF IgM index elevation of prolonged duration. Some earlier reports of CNS manifestations related to B. burgdorferi are reviewed.

Publication Types:
PMID: 3227803 [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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Infections following tickbites. Tick-borne encephalitis and Lyme borreliosis--a prospective epidemiological study from Tyrol.

Schmutzhard E, Stanek G, Pletschette M, Hirschl AM, Pallua A, Schmitzberger R, Schlögl R.

Department of Neurology, University of Innsbruck.

We present here a prospective study on infections following tickbites in military recruits in the province of Tyrol (Austria). 84 recruits experienced tickbites and underwent clinical and serological examination twice at four-week intervals for signs of tick borne encephalitis (TBE)-virus or Borrelia burgdorferi infections. 56 and 50 recruits could be evaluated for TBE-virus and Borrelia infection, respectively. Whereas no recruit was found with clinical or laboratory evidence of TBE-virus infection, two (4%) recruits showed an erythema chronicum migrans as primary manifestation of a Borrelia burgdorferi infection and 11 (20%) recruits had a significant increase in the titer of anti-Borrelia burgdorferi antibodies. Our results support the predominance of a subclinical course of a tick-transmitted borrelia infection in the population under observation, and shed some light on the epidemiological situation of tick-transmitted diseases in Tyrol.

PMID: 3215687 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi in the nervous system: the new "great imitator".

Pachner AR.

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

There are many obvious similarities between Lyme disease and syphilis. The major ones are their spirochetal etiology, the ability of the spirochetes to stay alive in human tissue for years, occurrence of clinical manifestations in stages, early disease in the skin and later disease in the brain, and susceptibility to antibiotic treatment. Thus, one can assume that many of the same lessons learned from the centuries of experience with syphilis will apply to Lyme disease. One of these lessons that should be constantly borne in mind is that spirochetal disease of the brain can mimic many other neurological diseases. Thus, the "effective clinician" must take special care to consider Lyme disease primarily because of the excellent response to antibiotics early in its course in relationship to some of the diseases it mimics. Lyme meningitis, occurring in the "second stage" of the disease, usually is fairly easily recognized because it occurs in the summer or early fall, often is associated with ECM or a recent history of it, and has a characteristic clinical picture of lymphocytic meningoradiculoneuritis. Many patients with Lyme meningitis or ECM have very mild symptoms, and it is likely that a large percentage of patients go undiagnosed and untreated. The frequency of progression of these patients to third-stage disease is unknown but may be quite high. This can be inferred from a similar situation in the other major late manifestation of Lyme disease: Lyme arthritis. A large number of patients present with joint involvement as their only manifestation of Lyme disease. Similarly, patients may present with symptoms of third-stage Lyme disease affecting the CNS, but they may not be recognized because of the lack of earlier stages usually associated with the disease. Thus, serology has become a very important tool for identifying patients exposed to B. burgdorferi. At the present time, serologic tests are the key to diagnosis of Lyme disease in its later stages, since, as in neurosyphilis, cultures and tests for antigen have not proven useful. Lyme arthritis and acrodermatitis atrophicans (ACA) both are associated with quite high antibody titers to the organism, while the test is understandably unreliable for identification of patients with ECM. Antibody titers in Lyme meningoradiculoneuritis are generally positive but often are not as high as those in ACA or arthritis. The antibody response in serum in CNS Lyme disease seems to be related to the presence of other manifestations; patients who have had both arthritis and CNS disease have quite high titers, while those with only CNS disease sometimes do not.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID: 3190104 [PubMed - indexed for MEDLINE]

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Isolation and characterization of Borrelia burgdorferi-specific and autoreactive T-cell lines from the cerebrospinal fluid of patients with Lyme meningoradiculomyelitis.

Martin R, Ortlauf J, Sticht-Groh V, Mertens HG.

Department of Neurology, University of Würzburg, FRG.

Publication Types:
PMID: 2462820 [PubMed - indexed for MEDLINE]

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Chronic muscle weakness caused by Borrelia burgdorferi meningoradiculitis.

Wokke JH, de Koning J, Stanek G, Jennekens FG.

University Department of Neurology, Academic Hospital Utrecht, The Netherlands.

A 19-year-old man developed chronic weakness of the lower limbs as the predominant manifestation of Borrelia burgdorferi infection of the nervous system. Spirochetes were demonstrated in the cerebrospinal fluid. The condition resolved following intravenous penicillin treatment.

Publication Types:
PMID: 3674804 [PubMed - indexed for MEDLINE]

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Neurosyphilis in the antibiotic era.

Burke JM, Schaberg DR.

Among 30 patients with neurosyphilis diagnosed between 1970 and 1981, 43% had symptoms attributable to neurosyphilis, 43% had unrelated symptoms, and 14% were asymptomatic. Serum VDRL was positive in 86%, and the CSF VDRL was positive in 53%. Meningovascular and vascular syphilis were relatively more common than in the prepenicillin era; tabes dorsalis and general paresis were unchanged in relative frequency.

PMID: 3895036 [PubMed - indexed for MEDLINE]


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