Department of Neurology, University Hospital of Strasbourg, Louis Pasteur University, Strasbourg, France. firstname.lastname@example.org
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.
Division of Radiology, Department of Medicine and Care, Faculty of Health Sciences, Linkping University, Linkping, Sweden. email@example.com
BACKGROUND: Borrelia infections, especially chronic neuroborreliosis (NB), may cause considerable diagnostic problems. This diagnosis is based on symptoms and findings in the cerebrospinal fluid but is not always conclusive. PURPOSE: To evaluate brain magnetic resonance imaging (MRI) in chronic NB, to compare the findings with healthy controls, and to correlate MRI findings with disease duration. MATERIAL AND METHODS: Sixteen well-characterized patients with chronic NB and 16 matched controls were examined in a 1.5T scanner with a standard head coil. T1- (with and without gadolinium), T2-, and diffusion-weighted imaging plus fluid-attenuated inversion recovery (FLAIR) imaging were used. RESULTS: White matter lesions and lesions in the basal ganglia were seen in 12 patients and 10 controls (no significant difference). Subependymal lesions were detected in patients down to the age of 25 and in the controls down to the age of 43. The number of lesions was correlated to age both in patients (rho = 0.83, P<0.01) and in controls (rho = 0.61, P<0.05), but not to the duration of disease. Most lesions were detected with FLAIR, but many also with T2-weighted imaging. CONCLUSION: A number of MRI findings were detected in patients with chronic NB, although the findings were unspecific when compared with matched controls and did not correlate with disease duration. However, subependymal lesions may constitute a potential finding in chronic NB.
Katedry i Kliniki Neurologii, Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu. firstname.lastname@example.org
Lyme disease is a multisystem infectious disease with a wide variety of symptoms involving the skin as well as nervous, musculosceletal and cardiovascular systems. Lyme disease is caused by spirochaete Borrelia burgdorferi transmitted by Ixodes tics in endemic regions. The diverse manifestations of neuroborreliosis require it to be included in differential diagnosis of many neurological disorders. The paper reviews the spectrum of clinical symptoms of nervous system involvement in early and late Lyme disease.
Klinika Chorb Zakaznych Wieku Dzieciecego AM w Warszawie.
OBJECTIVE: Analysis of clinical picture in children hospitalized because of suspicion of neuroborreliosis and evaluation of usefulness of testing serum and cerebrospinal fluid (CSF) for specific antibodies. MATERIAL AND METHODS: 23 children (age: 13 months - 15.5 years) were hospitalized: 11 children with facial palsy, 2 children with radiculopathy and 10 children with headache. In 21 children lumbar puncture and CSF examination was done. Serum of all children and CSF of 21 children were tested by ELISA for specific antibodies (IDEIA DakoCytomation). RESULTS: Meningeal signs in physical examination were found in 4 children and inflammatory CSF changes in 8 children. Specific antibodies in sera of 19 children and in CSF of 7 children. Neuroborreliosis was diagnosed in 12 children: in 9 facial palsy (in 6 with inflammatory CSF changes), in 2 Bannwarth's syndrome and in 1 aseptic meningitis. Diagnosis was confirmed by detection of specific antibodies in sera of 10 children and in CSF of 6 children. CONCLUSIONS: Meningitis in the course of neuroborreliosis is not always accompanied by meningeal signs. Positive serology is not an unequivocal confirmation of neuroborreliosis especially if symptoms are nonspecific (e.g. headache).
Klinika Chorb Zakaznvch i Neuroinfekcii AM w Bialvmstoku.
Increased morbidity of viral tick borne encephalitis since the 90's indicates growing risk of Rother tick borne diseases, including neuroborreliosis. Analysis of demographical, epidemiological and clinical data of patients hospitalised in Departament on Infectious Diseases and Neuroinfections in years 2000-2005 revealed that among patients with Lyme disease 13% were with neuroborreliosis with broad spectrum of neurologic symptoms as cranial nerves paresis (mainly n.VII), as well concentration and memory disturbances, and general symptoms. Some of patiets did not recall tick bite and did not present earlier borreliosis symptoms. Imaging only supports recognitio.
Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland. email@example.com
Cerebrospinal fluid (CSF) and serum samples from 34 patients with proven neuroborreliosis (NB) and 22 patients with suspected neuroborreliosis (SNB) from Finland were analysed for antibodies to decorin-binding proteins A (DbpA) and B (DbpB). Antibodies to recombinant protein antigens originating from Borrelia burgdorferi sensu stricto, B. afzelii, or B. garinii species were studied by enzyme-linked immunosorbent assay (ELISA). Of the 34 patients with NB, 100% of the CSF and 88% of the serum samples had IgG antibodies to 1 to 3 variants of DbpA and 79% of the CSF and 70% of the serum samples were positive for 1 to 3 DbpB variants. Antibodies to DbpB seemed to be associated with lymphocytic pleocytosis in the CSF and short duration of the disease, whereas antibodies to DbpA in the CSF were observed irrespective of the duration of the disease and lymphocytic pleocytosis. Among the variant antigens, CSF reactivity was mainly with the DbpB from B. garinii, whereas positivity with the DbpA from B. afzelii or B. garinii predominated. The results suggest that CSF antibodies to DbpB might be useful as a marker of active infection whereas antibodies to DbpA seem to persist a long time after acute phases of NB.
Akademia Medyczna w Bialymstoku, Klinika Chorb Zakaznych i Neuroinfekcji. firstname.lastname@example.org
Pathogenesis of Lyme disease, including neuroborreliosis, remains unclear. However, pro-inflammatory cytokines seem to be involved and might be used to monitor the course of the disease. It has been also shown that B. burgdorferi protects itself from elimination by modulating function of the host's immune system. THE AIM OF THIS STUDY: The purpose of this study was to evaluate the serum and cerebrospinal fluid (CSF) concentrations of selected cytokines in patients with neuroborreliosis and their change during antibiotic treatment. MATERIAL AND METHODS: The group of 25 patients was examined, all undergoing antibiotic therapy due to meningitis caused by Borrelia burgdorferi infection. The group included 10 (40%) females and 15 (60%) males in the mean age x = 42,3 years. The control group for serum measurements consisted of 25 healthy individuals (mean age x =43, 1) while control group for CSF study included 10 patients (aged x = 53,5 years) from whom CSF with normal parameters was taken during diagnostic procedures neurosurgical. We examined serum and CSF before and after antibiotics for concentrations of interferon-gamma (INF-gamma), interleukin-6 (IL-6), interleukin-12 (IL-12) and interleukin-15 (IL-15). RESULTS: In the first examination the significant increase of IFN-gamma, IL-6, IL-2, IL-15 serum and CSF concentration was detected in comparison to control group. After 4-weeks antibiotic treatment the concentrations of studied cytokines decreased significantly in serum as well as in CSF but remained increased in comparison with controls. CONCLUSIONS: Although antibiotic treatment leads to withdrawal of clinical symptoms of neuroborreliosis and normalization of CSF general parameters, pro-inflammatory cytokines' concentrations in serum and CSF remain elevated. It may be explained by the persistence of inflammatory conditions, perhaps related to surviving of a fraction of Borrelia burgdorferi spirochetes within CNS tissue. This phenomenon might lead to development of chronic CNS lesions.
Department of Neurology, S¿rlandet Sykehus HF, Kristiansand, Norway. email@example.com
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.
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.
Microbiology Unit, Division of Laboratory Medicine, S¿rlandet Hospital HF, Service Box 416, 4604, Kristiansand, Norway. firstname.lastname@example.org
The purpose of this study was to evaluate the diagnostic sensitivity and specificity of a commercial C6 enzyme immuno assay, QuickC6, in acute Lyme neuroborreliosis (LNB) in endemic areas. Paired sera and cerebral spinal fluids (CSFs) from 60 patients with definite LNB, eight patients with possible LNB, 18 patients with conditions mimicking LNB and 42 persons with noninfectious neurological disease were examined. The case definition of LNB was based on strict criteria during a prospective 4-month follow-up. The sensitivity of QuickC6 was 98% both in sera and CSFs, and the diagnostic specificity was 61% in sera and 88% in CSFs. QuickC6 is a sensitive, simple and cost-effective screening test in serum and CSF in diagnosis of acute LNB. Specificity needs further evaluation.
Department of Medicine, Turku University Central Hospital, Kiinamyllynkatu 4-8, 20520, Turku, Finland. email@example.com
Despite rather strict recommendations for antibiotic treatment of disseminated Lyme borreliosis (LB), evidence-based studies on the duration of antibiotic treatment are scarce. The aim of this multicenter study was to determine whether initial treatment with intravenous ceftriaxone (CRO) for 3 weeks should be extended with a period of adjunct oral antibiotic therapy. A total of 152 consecutive patients with LB were randomized in a double-blind fashion to receive either amoxicillin (AMOX) 1 g or placebo (PBO) twice daily for 100 days. Both groups received an initial treatment of intravenous CRO 2 g daily for 3 weeks, followed by the randomized drug or PBO. The outcome was evaluated using the visual analogue scale at the follow-up visits. The final analysis included 145 patients, of whom 73 received AMOX and 72 PBO. Diagnoses of LB were categorized as either definite or possible, on the basis of symptoms, signs, and laboratory results. The diagnosis was definite in 52 of the 73 (71.2%) AMOX-treated patients and in 54 of the 72 (75%) PBO patients. Of the patients with definite diagnoses, 62 had neuroborreliosis, 45 arthritis or other musculoskeletal manifestations, and 4 other manifestations of LB. As judged by the visual analogue scale and patient records, the outcome after a 1-year follow-up period was excellent or good in 114 (78.6%) patients, controversial in 14 (9.7%) patients, and poor in 17 (11.7%) patients. In patients with definite LB, the outcome was excellent or good in 49 (92.5%) AMOX-treated patients and 47 (87.0%) PBO patients and poor in 3 (5.7%) AMOX-treated patients and 6 (11.1%) PBO patients (difference nonsignificant, p = 0.49). Twelve months after the end of intravenous antibiotic therapy, the levels of antibodies against Borrelia burgdorferi were markedly decreased in 50% of the patients with definite LB in both groups. The results indicate that oral adjunct antibiotics are not justified in the treatment of patients with disseminated LB who initially receive intravenous CRO for 3 weeks. The clinical outcome cannot be evaluated at the completion of intravenous antibiotic treatment but rather 6-12 months afterwards. In patients with chronic post-treatment symptoms, persistent positive levels of antibodies do not seem to provide any useful information for further care of the patient.
A 6-year-old boy presented with deterioration of general well-being during several weeks, headache and swelling of lymph nodes in the neck. In addition, the parents reported brief episodes resembling typical absence seizures. Serological tests and the examination of cerebrospinal fluid revealed neuroborreliosis. At the same time, electroencephalography showed characteristic patterns of absence epilepsy. The boy's condition improved rapidly during a 2-week course of intravenous ceftriaxone and after initiation of antiepileptic therapy. To our knowledge, absence epilepsy has not previously been reported in association with neuroborreliosis. We consider the two conditions to be coincidental.
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.
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).
Clinical Neuroimmunology Unit, Department of Neurology, University Hospital Zrich, Frauenklinikstrasse 26, CH-8091 Zrich, 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."
Laboratoire associ au CNR Borrelia, laboratoire de bactriologie, hpitaux universitaires de Strasbourg, 3, rue Koeberl, 67000 Strasbourg, France. firstname.lastname@example.org
The biological diagnosis of Borrelia burgdorferi sensu lato infection is usually made by antibody detection in patient sera. Thus, serological testing (Elisa, immunoblotting) is essential for a biological diagnosis. Specific antibody detection is usually done in serum and CSF of patients suspected of Lyme borreliosis. Laboratories must follow European recommendations to validate these assays in routine practice. Antibody detection lacks sensitivity in the early cutaneous phase of the infection. Therefore, serological testing is not recommended for the diagnosis of erythema migrans. The interpretation of serology must take into account the variability of Elisa sensitivity and specificity and the lack of standardization for Western-blotting in Europe. Besides these indirect diagnosis techniques, there is also direct detection of spirochetes by culture or by in vitro DNA amplification but these require adequate samples. These molecular tests must not be performed routinely, but only for specific clinical situations and in specialized laboratories only.
Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. email@example.com
Lyme neuroborreliosis (LNB), the neurological manifestation of systemic infection with the complex spirochaete Borrelia burgdorferi, can pose a challenge for practising neurologists. This Review is a summary of clinical presentation, diagnosis, and therapy, as well as of recent advances in our understanding of LNB. Many new insights have been gained through work in experimental models of the disease. An appreciation of the genetic heterogeneity of the causative pathogen has helped clinicians in their understanding of the diverse presentations of LNB.
Department of Medicine, Merkur University Hospital, Zagreb Medical School, Zagreb, Croatia. firstname.lastname@example.org
Leukemic involvement of the central nervous system (CNS) in previously undiagnosed chronic lymphocytic leukemia (CLL) is very rare. We report the case of a 62-year-old man with neuroborreliosis in which cytologic, immunocytochemical, and flow cytometry analyses revealed the presence of clonal B-lymphocytes in the cerebrospinal fluid (CSF). After the patient received antimicrobial therapy, his meningeal symptoms cleared up, and the number of cells in the CSF decreased. Monoclonal lymphocytes were still detectable at the same percentage, however, despite systemic chlorambucil therapy. The application of intrathecal dexamethasone therapy led to the disappearance of B-cell CLL (B-CLL) cells in the CSF. We presumed that the neuroborreliosis enabled the transmigration of leukocytes, including B-CLL cells, across the blood-brain barrier via activation of matrix metalloproteinase 9, an enzyme known to open the blood-brain barrier.
Department of Clinical Microbiology, Faculty Hospital Brno, Czechia. email@example.com
Selected cerebrospinal-fluid (CSF) parameters (intrathecal synthesis of Borrelia-specific antibodies, oligoclonal IgG bands, CSF-to-serum quotient of albumin as a marker of blood-CSF barrier function and cytology) and typical CSF profile in neuroborreliosis were evaluated with the aim of elucidating possible clinical and laboratory similarities of neuroborreliosis (NB) and other neurological diseases (OND). From the cohort of 58 patients (38 diagnosed for NB, 20 with OND) NB patients had positive Borrelia-specific IgG antibodies in 97 % and positive Borrelia-specific IgM antibodies in 55 %; oligoclonal IgG bands were detected in 55%. The blood-CSF barrier was impaired in 89%, positive cytology was detected in 97% of the NB patients. Evaluation of specific intrathecal synthesis improves CSF diagnosis of NB, therefore, a combined CSF analysis has to be considered along with the clinical picture and medical history when formulating the diagnosis of NB.
Dept. of Medicine III, University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany. Thomas.Harrer@med3.imed.uni-erlangen.de
We report on a patient who developed seronegative Lyme neuroborreliosis complicating chemotherapy for chronic lymphatic leukemia. After the fifth cycle of chemotherapy (FCR: fludarabine, cyclophosphamide, rituximab and prednisone) the 63-year-old patient developed night sweat, arthralgia in elbows, wrists, proximal interphalangeal joints (PIPs) and strong neuropathic pain in both legs, followed by paresthesia and hypesthesia in the feet, arms and face. Laboratory analysis revealed an elevated C-reactive protein (CRP), a slight elevation of liver enzymes and decreased IgG levels. Cerebrospinal fluid (CSF) analysis showed a lymphomononuclear pleocytosis and an elevation of protein. A broad diagnostic work-up was negative including a negative Borrelia IgG and IgM ELISA. The patient did not remember recent tick bites, but after specific questioning he recollected a transient erythema on his leg developing just before the start of the last cycle of chemotherapy. As the combination of neuropathic pain and arthralgia, the transient erythema and the lymphomononuclear pleocytosis raised the suspicion of Lyme neuroborreliosis, the patient was treated for 3 weeks with ceftriaxone. On therapy all symptoms resolved and CRP normalized. Retrospective PCR analysis of a CSF sample confirmed the clinical diagnosis by detecting Borrelia garinii DNA. This case demonstrates that in immunosuppressed patients borrelial serology may be negative and that additional diagnostic approaches (including tests for direct Borrelia detection) may be needed to demonstrate borrelial infection.
Service d'ophtalmologie, universit Paris-VI, CHU de la Piti-Salptrire, 47-83, boulevard de l'Hpital, 75651 Paris cedex 13, France. firstname.lastname@example.org
Despite the wide spectrum of clinical entities, eye involvement remains a rare event in patients with Lyme borreliosis. Most of ocular manifestations occur during the late phase of the disease. The infection needs to be considered along with more conventional causes of ocular inflammation, particularly in regions where Lyme disease is common. The pathogenesis of this condition remains controversial. Direct ocular infection and a delayed hypersensitivity mechanism may be involved at different disease stages. Uveitis and optic neuritis are the most common ocular complications. Serological testing lacks sensitivity and specificity. In atypical cases, ocular fluids sampling and analysis may be proposed. PCR seems to be an interesting diagnostic tool, allowing genotypic analysis. In the majority of cases, therapeutic strategy should be based on the association of antibiotics and corticosteroids. A new course of antibiotics may be prescribed to patients with chronic or relapsing inflammation due to bacterial persistence in ocular tissues.
Service de neurologie, centre hospitalier universitaire Henri-Mondor, APHP, universit Paris-XII, 94000 Crteil, France. email@example.com
Lyme disease is associated with various systemic and neurological manifestations. The neurological and psychiatric manifestations of Lyme disease are more frequently observed during its secondary phase (stage 2) than during its late tertiary phase (stage 3). In stage 2, cerebrospinal fluid and bacterial tests are consistent with the ongoing infection. Painful meningoradiculitis, encephalomyelitis and encephalitis, and symptoms of depression are the most characteristic at this stage. The diagnosis should be based on the association of clinical, epidemiological, and biological features. Adequate treatment usually leads to recovery. In stage 3 of the disease, the link between neurological manifestations and initial infection is uncertain. Distal axonal polyneuropathy and chronic encephalopathy are the most frequently reported presentations.
Service des maladies infectieuses et tropicales, hpitaux universitaires de Strasbourg, 1, place de l'Hpital, BP 426, 67091 Strasbourg cedex, France. firstname.lastname@example.org
The treatment of secondary and tertiary Lyme borreliosis is difficult because of antibiotic lack of efficacy. This fact may be explained by several factors: the specific pathophysiology, involving not only the presence of bacteria, but also immunological reactions. There is no specific method of diagnosis resulting in difficulties for good indication of treatment and to evaluate treatment efficacy. The literature review shows that ceftriaxone and doxycycline are the two most efficient antibiotics in this indication. Even if the methodology of the published studies is not always convincing, these two antibiotics proved their efficacy in articular as well as in neurological forms of the disease. In the late stage of borreliosis, antibiotics are less efficient. Various treatment modalities with different dosage or duration of treatment cannot let us conclude on a convincing regimen.
In a 29-y-old male with neuroborreliosis, partially responsive to ceftriaxone, myasthenia gravis with acetylcholine-receptor antibodies elevated almost 1000 times the upper reference limit was diagnosed. Pyridostigmine resolved all remaining neurological deficits. During a 1-y follow-up the patient remained symptom free, despite persistently high acetylcholine-receptor antibodies. They were attributed to epitope homology of the acetylcholine receptors and Borrelia surface antigens.
Department of Dermatovenerology, Rijeka University Hospital, Kresimirova 42, 51000 Rijeka, Croatia.
Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by chronic inflammation and demyelination. Studies suggested that the viral, especially Epstein-Barr virus infection, and bacterial infections, especially Borrelia burgdorferi infection, play a role in etiology of MS. MS prevalence parallels the distribution of the Lyme disease pathogen B. burgdorferi. Criteria used for diagnosis of MS can also be fulfilled in other conditions such as Lyme disease, a multisystem disorder resulting from infection by the tick-borne spirochete, B. burgdorferi. In the late period of Lyme disease demyelinating involvement of central nervous system can develop and MS can be erroneously diagnosed. A Lyme borreliosis can mimick central nervous system lymphoma. Also, B. burgdorferi has been implicated not only in etiology of MS, but also in etiology of lymphoma. Studies suggested that there is an increased risk of non-Hodgkin lymphoma in patients, who had a history of autoimmune diseases such as MS and that both non-Hodgkin's lymphomas and Hodgkin's disease were associated with Epstein-Barr virus infection. A small group of lymphomas called primary effusion lymphomas (PEL) is a recently individualized form of non-Hodgkin's lymphoma (WHO classification) that exhibit exclusive or dominant involvement of serous cavities, without a detectable solid tumor mass. These lymphomas have also been linked to Epstein-Barr virus and human herpes virus type 8 infections but virus negative cases have been described. Therefore, we propose that MS and neuroborreliosis are linked to central nervous system primary effusion lymphomas. As a first step in confirming or refuting our hypotheses, we suggest a thorough study of CSF in the patients suspected for the diagnosis of MS and Lyme borreliosis.
Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals.
Division of Clinical Immunology, Faculty of Health Sciences, University of Linkping, Sweden. email@example.com
Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rbeta2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rbeta2 and FoxP3 mRNA expression was analysed with real-time reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of IL-12Rbeta2 on CD3(+), CD4(+), CD8(+) and CD56(+) cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-gamma, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rbeta2 on CD8(+) cells and also a lower number of Borrelia-specific IFN-gamma-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.
Institute of Microbiology and Immunology, Medical Faculty Ljubljana, University of Ljubljana, Slovenia. firstname.lastname@example.org
Serological tests for detection of borrelial antibodies are frequently used in laboratory diagnostics of Lyme borreliosis. Unfortunately these tests are not standardized and the results obtained with different assays may not be concordant. The aim of the present study was to compare two different serological tests, IFA and LIAISON, for detection of Borrelia burgdorferi sensu lato IgM and IgG antibody. We analyzed the serological immune response in 383 patients with different clinical manifestations of Lyme borreliosis and in 49 healthy blood donors. LIAISON detected IgM and IgG antibodies more often than IFA in all groups of patients except those with chronic Lyme borreliosis. The differences were significant for IgM and IgG antibodies in patients with solitary erythema migrans and in those with early disseminated Lyme borreliosis. There was no significant difference in the specificity of the two tests.
Pediatric Infectious Diseases, Schneider Children's Hospital at North Shore, Albert Einstein College of Medicine, Manhasset, NY 11030, USA. email@example.com
Although pediatric Lyme borreliosis (LB) need not be a separate nosological entity, there are clinically important differences in presentation, antibiotic regimens and outcomes in children, which provide lessons that can be extrapolated to the disease as it affects adults. A large proportion of the worldwide data is obtained from children. The aim of this presentation is not to present an exhaustive review of the pediatric literature, but to review a selection of pediatric studies that have made a significant contribution to our body of knowledge in Lyme borreliosis.
Department of Infectious Diseases, Ryhov County Hospital, 551 85, Jnkping, and Division of Clinical Immunology, Department of Molecular and Clinical Medicine, Linkping University, Sweden. Anna.Henningsson.Jonsson@lj.se
A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.
Neuroimmunology Branch, Cellular Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Neurological manifestations of Lyme disease are usually accompanied by inflammatory changes in the cerebrospinal fluid (CSF) and the recruitment of activated T cells into the CSF compartment. In order to characterize the phenotype and identify target antigens of CSF-infiltrating T cells in early neuroborreliosis with central nervous system (CNS) involvement, we combined T-cell cloning, functional testing of T-cell responses with positional scanning synthetic combinatorial peptide libraries, and biometric data analysis. We demonstrate that CD4+ gamma interferon-producing T cells specifically responding to Borrelia burgdorferi lysate were present in the CSF of a patient with acute Lyme encephalitis. Some T-cell clones recognized previously uncharacterized B. burgdorferi epitopes which show a specific enrichment for lysine, such as the heat shock-induced chaperone HSP90. Degenerate T-cell recognition that included T-cell responses to borrelia-specific and CNS-specific autoantigens derived from the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) could be demonstrated for one representative clone. Our results show that spirochetal antigen-specific and Th1-polarized CD4+ lymphocytes infiltrate the CSF during monophasic CNS symptoms of Lyme disease and demonstrate that cross-recognition of CNS antigens by B. burgdorferi-specific T cells is not restricted to chronic and treatment-resistant manifestations.
Children's Hospital, and Institute of Hygiene and Microbiology, University of Wrzburg, D-97080 Wrzburg, Germany. Latsch_K@kinderklinik.uni-wuerzburg.de
In childhood, facial nerve palsy and headache are typical symptoms of second and third stage neuroborreliosis. While focal demyelination is occasionally observed on MRI scans, the appearance of a tumorous lesion is extremely rare. The case of a 10-year-old girl with neuroborreliosis mimicking a space-occupying lesion in the brainstem, without any previously recognized manifestations of borreliosis, is reported.
Department of Pathophysiology, Charles University in Prague, Faculty of Medicine in Hradec Krlov, Czech Republic. firstname.lastname@example.org
Neuroborreliosis is a form of borreliosis that affects the central and/or peripheral nervous system. Although it can mimic neurologic and ophthalmologic disorders such as multiple sclerosis and optic neuritis, visual evoked potential (VEP) examination is usually not used in neuroborreliosis diagnostics. Combined VEP testing (pattern-reversal VEPs and VEPs produced in response to linear and radial motion) was performed in 81 patients with neuroborreliosis verified by laboratory results (positive polymerase chain reaction or intrathecal antibodies production). Thirty-four patients reported diplopia or blurred vision related to borreliosis. In 33 (40%) patients the VEPs were delayed: motion-onset VEPs were pathologic in 22 (27%) patients, reversal VEPs in 5 (6%) patients, and both VEP types in 6 (7%) patients. The findings suggest that VEP testing (especially the motion-onset VEP testing) can confirm CNS involvement. Much higher sensitivity of motion-onset VEPs in comparison with reversal VEPs can result from rather selective (earlier) involvement of the magnocellular system or the dorsal stream of the visual pathway.
Dansk Selskab for Klinisk Mikrobiologi, Dansk Selskab for Infektionsmedicin. email@example.com
The laboratory diagnosis of Lyme disease in Denmark is reviewed with recommendations for serological testing. In Denmark the laboratory testing is performed with an ELISA technique. Most laboratories use an assay based on purified flagella antigen. The two-tier approach with Western Blot as confirmatory testing is not recommended since the contribution to the diagnostic specificity is only marginal. Predictive values of Lyme serology are presented, based on the estimated prevalence of the different stages of Lyme disease in Denmark.
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.
Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. firstname.lastname@example.org
BACKGROUND: The most common cause of Lyme neuroborreliosis in Europe is Borrelia garinii, followed by Borrelia afzelii. However, no series describing patients with culture-confirmed cases of Lyme neuroborreliosis have been published, and no comparison of findings for patients with B. garinii and B. afzelii isolated from cerebrospinal fluid (CSF) has been reported. METHODS: All adult patients identified at a single medical center during a 10-year period who had borreliae isolated from CSF and typed as B. garinii or B. afzelii (using large DNA fragment patterns obtained with the MluI restriction endonuclease and separated with pulsed-field gel electrophoresis) were included. RESULTS: A comparison of 23 patients who had B. garinii isolated from CSF with 10 patients who had B. afzelii isolated from CSF revealed that a reliable clinical diagnosis of Lyme neuroborreliosis (before obtaining a CSF culture and intrathecal borrelial antibody production result) was established more frequently in the B. garinii group than in the B. afzelii group (19 of 23 patients vs. 1 of 10 patients). Patients in the B. garinii group reported radicular pains and expressed meningeal signs more often, but reported dizziness less often (occurrences of several other symptoms and/or signs were comparable). Lymphocytic pleocytosis, as well as several other CSF abnormalities, were frequent among patients with B. garinii isolated from CSF but were rare among patients in the B. afzelii group. CONCLUSIONS: Patients with B. garinii isolated from their CSF have a distinct clinical presentation, compared with patients with B. afzelii. B. garinii causes what, in Europe, is appreciated as typical early Lyme neuroborreliosis (Bannwarth syndrome), whereas the clinical features associated with B. afzelii are much less specific and more difficult to diagnose.
Klinika Chorb Zakainych i Neuroinfekcji AM w Bialymstoku.
The aim of the study was the evaluation of the efficiency of Western blot (EcoLine) test detecting simoultanous presence of IgM and IgG antibodies against B. burgdorferi in diagnosis of early and late stage of Lyme borreliosis. The comparison of results achieved by performing test Western-blot, ELISA (based on recombinant antigens of three genospecies of Borrelia) and EIA (based on antigens of one B. burgdorferi genospecies). The tests Western blot: EcoLine (Virotech) with antygens "in vivo", ELISA Borrelia IgM, IgG recombinant (Biomedica), EIA: B. b. ss. IgG, EIA B. garinii IgG, EIA B. afzelii IgG (TestLine) were used. Results showed efficacy of detecting IgM, IgG antibodies against VlsE simultanously and IgG antibodies against "in vivo" antigens in diagnosis of early stages of Lyme disease when atypical picture skin lessions arise diagnostic doubts and in discerning early and late stage of disease. The EIA tests based on one B. burgdoreferi genospecies seem less effective in comparison to ELISA tests based on 3 genospecies antigens.
Klinika Chorb Zakaznych i Neuroinfekcji AM w Bialymstoku.
B. burgdorferi can evade the destructive effects of the immune system by binding host's complement regulators, which leads to inhibition of the complement activation cascade. Complement activity is blocked by CRASPs--complement regulator acquiring surface proteins. Complement resistance might therefore represent one major pathogenic factor favoring spirochete transmission to the vertebrate host, as well as determine host reservoirs of Borrelia burgdorferi genospecies. The cause of neuro-psychiatric disorders developing in some patients with Lyme borreliosis is still unknown. One of the hypotheses links them to neuro-hormonal disturbances induced by B. burgdorferi infection.
Oddzial Internistyczno-Kardiologiczny SP ZOZ w Soklce.
OBJECTIVE: The aim of this study was to evaluate the serum and CSF concentration of soluble intercellular adhesion molecules sICAM-1, sICAM-2, sICAM-3 and proinflammatory cytokine IFNgamma in patients with tick-borne encephalitis (TBE) and neuroborreliosis. METHODS: The study group consisted of 40: 20 with TBE meningitis and 20 with Lyme meningitis. The serum and CSF levels of adhesion molecules and IFNgamma were determined by ELISA assay twice: before and after treatment. RESULTS: Before treatment the concentrations of adhesion molecules and IFNgamma in serum as well as in CSF were significantly higher in both studied groups than in control group (with the exception of the serum level of sICAM-2 in TBE group). After the treatment, the serum parameters in TBE group decreased to the control level. CSF levels were also reduced, but still remained higher than in the control group. In patients with neuroborreliosis serum concentration of sICAM-1 and sICAM-2 did not change as compared with its level before treatment but other studied parameters in serum and CSF decreased significantly. CONCLUSIONS: The results of our study confirm the participation of intercellular adhesion molecules in the pathogenesis of viral (TBE) and bacterial (neuroborreliosis) neuroinfections.
Multiple sclerosis is the most frequent multifocal disease of the central nervous system, but in a diagnosis of atypical cases about 100 other diseases should be considered. Neuroborreliosis plays a particular role among them, especially in endemic regions. Difficulties result from similarities of clinical symptoms and lack of specific diagnostic investigations. Diagnostic procedures in neuroborreliosis are mostly based on laboratory analyses and serologic examinations of serum and cerebrospinal fluid, in connection with a clinical picture and an epidemiological state. Since the year 2001, multiple sclerosis neurological diagnostic is based on the diagnostic criteria established under the auspices of The US National Multiple Sclerosis Society and International Federation of Multiple Sclerosis Societies. Those recommendations regarding relapsing-remitting MS and primary progressing MS are discussed in this paper. Current knowledge of those diseases warrants cautiousness in the diagnostic of atypical cases.
Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
This study reports the development and evaluation of an internally controlled real-time PCR targeting the ospA gene for detection of Borrelia burgdorferi sensu stricto, Borrelia garinii, Borrelia afzelii and Borrelia valaisiana. DNA was extracted using QIAamp DNA Blood Mini kit columns. DNA from 33 B. burgdorferi sensu lato strains reacted in the assay, whereas no reactivity was observed with DNA from four relapsing fever Borrelia spp., 11 unrelated spirochaetes, and 31 unrelated microorganisms. The quantitative sensitivity of the assay was 1-10 fg of Borrelia DNA and one to five cultured Borrelia spirochaetes. Cerebrospinal fluid (CSF) specimens from 70 patients sent for routine testing for neuroborreliosis, and three CSF specimens containing B. garinii were also tested. Positive PCR results were obtained with all three culture-confirmed neuroborreliosis specimens, five of ten neuroborreliosis specimens with specific antibodies in CSF and pleocytosis, none of nine specimens from possible cases of early neuroborreliosis (antibodies in serum, CSF pleocytosis, no antibodies in CSF), one of 15 specimens from patients with active or past Lyme disease with neurological signs (antibodies in serum, no pleocytosis or antibodies in CSF), and none of 36 specimens from patients without Lyme borreliosis (no antibodies in serum or CSF). Overall, the real-time PCR assay enabled sensitive and specific detection of all B. burgdorferi sensu lato species tested. The PCR had a sensitivity of 50% in patients with neuroborreliosis. The main diagnostic role of the assay could be to confirm neuroborreliosis in patients for whom the diagnosis is doubtful.
Nationales Referenzzentrum fr Borrelien, Max v. Pettenkofer Institut, LMU Mnchen. email@example.com
Every manifestation of Lyme borreliosis needs to be treated with antibiotics. The type of antibiotic applied and duration of treatment will depend on the stage and severity of the disease. Erythema migrans, Borrelia lymphocytoma, Lyme arthritis and acrodermatitis chronica atrophicans are primarily treated orally. If neurological symptoms, severe Lyme carditis or eye manifestations are present, intravenous treatment is initially recommended. For oral therapy, doxycycline, amoxicillin, cefuroxime and, if intolerance is shown, azithromycin, are available. For intravenous treatment ceftriaxone, cefotaxime or penicillin G is employed. The overall prognosis for treated Lyme borreliosis is good. However, in particular when manifestations with substantial organic injury have persisted, incomplete healing must be expected. With the exception of erythema migrans, every manifestation should be subjected to a careful diagnostic work-up prior to the start of treatment, because premature antibiotic administration is not only associated with an elevated risk for the patient, but can also mask important diagnostic signs.
NYU School of Medicine, Great Neck, NY, USA. Halperin@LINeuro.com
Although Lyme disease affects the nervous system in many ways (collectively known as neuroborreliosis), only rarely does it present as a medical emergency. In extreme cases, it may cause (1) encephalitis, (2) a rapidly progressive peripheral neuropathy, or (3) a painful truncal radiculopathy that may be confused with a severe visceral process. Knowing when to consider this spirochetosis in the differential diagnosis requires an understanding of its true clinical spectrum, and of an appropriate diagnostic and therapeutic approach.
Department of Neurology, Ruprecht-Karl University, Heidelberg, Germany. firstname.lastname@example.org
We report the case history of a patient who suffered a subarachnoid hemorrhage (SAH) in association with early Lyme neuroborreliosis. After a tick bite, this patient developed erythema chronicum migrans and complained of stinging radicular pain in both legs. A computed tomography (CT) scan was performed because of acute headache and nuchal rigidity, which revealed an occipital SAH. Cerebrospinal fluid analysis provided further evidence of acute neuroborreliosis. Digital substraction angiography showed irregularities in the right posterior cerebral artery, which might be due to vasculitis, but no aneurysms.
Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy.
BACKGROUND AND PURPOSE: Neuroborreliosis is frequently indistinguishable from multiple sclerosis (MS) on both clinical and radiologic grounds. By using MR imaging, we assessed "occult" brain white matter (WM), brain gray matter (GM), and cervical cord damage in patients with neuroborreliosis in an attempt to achieve a more accurate picture of tissue damage in these patients, which might contribute to the diagnostic work-up. METHODS: We studied 20 patients with neuroborreliosis and 11 sex- and age-matched control subjects. In all subjects, we acquired dual echo, T1-weighted, diffusion tensor (DT) and magnetization transfer (MT) MR imaging scans of the brain and fast short-tau inversion recovery and MT MR imaging scans of the cervical cord. T2-visible lesion load was measured by using a local thresholding segmentation technique. Mean diffusivity and fractional anisotropy histograms of the brain and cervical cord MT ratio histograms were produced. Normalized brain volumes (NBV) were measured by using SIENAx. RESULTS: Brain T2-visible lesions were detected in 12 patients, whereas no occult damage in the normal-appearing WM and GM was disclosed by using MT and DT MR imaging. No macroscopic lesions were found in the cervical cord, which was also spared by occult pathology. NBV did not differ between patients with neuroborreliosis and control subjects. CONCLUSION: This study shows that, contrary to what happens in MS, occult brain tissue damage and cervical cord pathology are not frequent findings in patients with neuroborreliosis. These observations might be useful in the diagnostic work-up of patients with neuroborreliosis and T2 brain lesions undistinguishable from those of MS.
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.
Department of Neurology, University of Greifswald, Greifswald, Germany. email@example.com
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.
Department of Neurology, Ludwig-Maximilians-University, Klinikum Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany. firstname.lastname@example.org
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.
Klinika Chorb Zakanych i Neuroinfekcji, Akademia Medyczna w Bialymstoku, Bialystok. email@example.com
BACKGROUND AND PURPOSE: The interaction between CD40 and CD40L is essential in generating of an immunological response also intrathecally. The aim of the study was estimation of a concentration soluble form of CD40, CD40L (CD154) in the bacterial and viral inflammation of the central nervous system in two compartments - blood circulation and intrathecally, before and after the treatment. MATERIAL AND METHODS: sCD40 and sCD40L were tested twice before and after treatment in pairs serum and CSF of 40 patients treated in the Dept. of Infectious Diseases and Neuroinfections. Patients were divided in two groups: (n=20) patients with tick borne encephalitis (TBE) (group I, n=20) and patients with neuroborreliosis in the form of lymphocytic meningitis (group II, n=20). ELISA assays were performed. RESULTS: Significantly increased concentrations of sCD40, sCD40L in CSF (higher in neuroborreliosis) were measured. We found also an increased concentration of sCD40L in inflammatory CSF in both tested groups (in neuroboreliosis lasting also after 4 weeks of treatment), compared with the control group (below the detection limit in normal CSF). CONCLUSIONS: Results of estimation of the sCD40 and sCD40L concentrations indicate their role in the intrathecal inflammation process of bacterial and viral etiology. The increased serum concentration of sCD40L in TBE and CD40 in neuroborreliosis indicate that peripheral activation of the immunological system persists after cessation of treatment and after the clinical recovery. The defense mechanisms are more pronounced in neuroborreliosis than in tick borne encephalitis.
Department of Neurodegenerative Diseases, Institute of Agricultural Medicine, Jaczewskiego 2, 20-090 Lublin, Poland. firstname.lastname@example.org
The 53-year-old woman was initially diagnosed with multiple sclerosis, despite the fact that she did not really meet the clinical criteria. Her only symptoms were clumsiness and weakness of the right extremities. Being a veterinary research worker she had been exposed to infectious material. In 1995, she was diagnosed with ELISA as having toxoplasmosis and treated as such. In 2002, after the infectious, flu-like disease, she revealed arthritis and drowsiness, also with memory and language impairment. The patient continued to have symptoms consistent with previously examined clumsiness. She was diagnosed with Lyme via ELISA and PCR, and treated. She made a full recovery from acute symptoms. After a few months, neurological and neuropsychological examinations were performed. On the background of mild cognitive decline apraxia and difficulties of attention were noted as the main problems. A apraxia of the right hand complicated the patient's life and depreciated her quality of life. The patient underwent MRI examination. FSE, FAST and FLAIR sequences were made. The MRI demonstrated the appearance of several small hyperintense lesions in the white matter of the left and right frontal and left parietal lobe. These lesions were typical of the post-inflammatory leucoencephalopathy. Additionally, a ring-shaped, low-intensity lesion in the posterior part of the left parietal lobe was noticed. The lesion was 8 mm in diameter and described to be an old toxoplasmosis lesion. The patient had been treated and the symptoms consistent with Lyme disease resolved. Patient continues to have symptoms consistent with focal destruction of the parietal lobe. Over the past six months, she has not progressed and relapsed in a manner that is consistent with MS.
Department of Medical Microbiology, University Hospital, Gttingen, Germany.
AIM: Acute peripheral facial palsy due to neuroborreliosis is associated with a distal neuritis. In patients with Lyme disease the activity of antioxidant enzymes is decreased. With respect to the pathogenesis of neuroborreliosis, sera of children with acute peripheral facial palsy were investigated for autoantibodies against human manganese superoxide dismutase (MnSOD), which were suspected of raising the oxidative injury of infected tissues. METHODS: Sera of 20 children with acute peripheral palsy with neuroborreliosis, sera of 20 children with facial palsy without reference to Lyme disease and sera of 14 blood donors were tested for antibodies against human MnSOD using an ELISA. RESULTS: The concentrations of IgM autoantibodies to MnSOD of the children with neuroborreliosis were significantly increased, compared with the two control groups. CONCLUSIONS: We propose that the antibodies detected block the protective effects of MnSOD resulting in an increased oxidative inflammation.
Service d'Ophtalmologie, HIA Clermont Tonnerre, BP 41, 29240 Brest-Armes.
INTRODUCTION: The diagnosis of Lyme disease in the presence of an acute optical neuritis always raises a difficult diagnostic problem. We present a case of Lyme-associated Leber's hereditary optic neuropathy (LHON). OBSERVATION: A 17-year-old Eurasian young man presented with left-eye visual impairment for 1 month. This loss of vision acuity in the left eye is related to an optic neuropathy. Mitochondrial DNA testing showed a G to A substitution at position 11778 confirming a diagnosis of LHON. The family history disclosed a case of LHON in a maternal cousin. The mother's family is Asian. Besides, serum examination of anti-Borrelia antibodies was performed and was positive against Borrelia burgdorferi garinii. The patient history indicated that he had been possessing a dog and was living in an endemic area of Lyme disease. But he did not recall receiving a tick bite nor having any erythema chronicum migrans. Initial examination showed bilateral green-red axis colour vision defects which made us fear bilateralisation of the optic neuropathy, which occurred 2 months later (that is 3 months after the onset of symptoms on the left eye). An antibiotic treatment by ceftriaxone was administered for 4 weeks all in all; and a long term ubidecarenone therapy was established. At present, after a 1-year follow up, the eyes' conditions remains unchanged. CONCLUSION: To our knowledge, this would be the first case reporting such an association, in which we can discuss the fortuitous character or the role of the infectious factor in the developing of the mitochondrial pathology. This observation also raises the problem of the positive diagnosis of Lyme disease when tick bite and erythema are absent or underestimated.
Division of Infectious Diseases, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Steenhoff@email.chop.edu
We report a patient with an initial diagnosis of Lyme-associated pseudotumor cerebri who developed cerebrospinal fluid pleocytosis consistent with Lyme meningitis. The case illustrates the importance of considering neuroborreliosis in the differential diagnosis of pseudotumor cerebri and describes the evolution of cerebrospinal fluid findings in this condition.
Department of Neurosciences, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103, USA.
Intrathecal antibody (ITAb) production is a common feature of neurological diseases, yet very little is known about its mechanisms. Because ITAb is prominent in human Lyme neuroborreliosis (LNB), in the present study we established a mouse model of LNB to study ITAb production. We injected different strains of Borrelia burgdorferi into a variety of mouse strains by the intracerebral (i.c.) route to develop the model. Spirochetal infection and ITAb production were identified by complementary methods. This study demonstrates that the mouse model of LNB can be utilized to test hypotheses related to the mechanisms of ITAb production.
Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, Poland. email@example.com
PURPOSE: Chronic inflammation in Lyme borreliosis may be sustained by aberrant inflammatory response, characterized by Th1 lymphocyte predominance, which in turn may be determined by chemokines synthesized in inflammatory focus. The aim of the study was to evaluate synthesis of chemokines: interferon-induced T cell chemoattractant (I-TAC--chemoattractant for Th1 lymphocytes), and monocyte chemotactic protein (MCP-1) in Lyme borreliosis. MATERIAL AND METHODS: Study group consisted of 13 patients with erythema migrans, 10 with Lyme arthritis and 6 with neuroborreliosis. Serum, as well as cerebrospinal fluid (CSF) in neuroborreliosis, was obtained before (examination 1) and during (examination 2) antibiotic treatment. Control serum was obtained from 8 healthy volunteers and control csf from 8 patients in whom meningitis and neuroborreliosis was excluded after diagnostic lumbar puncture. The samples were assayed for MCP-1 and I-TAC by ELISA. RESULTS: Serum mean I-TAC concentration in examination 1 was 73.0 pg/ml in erythema migrans, 78.9 pg/ml in Lyme arthritis and 87.3 pg/ml in neuroborreliosis (29.9 pg/ml in controls, difference significant for neuroborreliosis) and did not change significantly in examination 2. MCP-1 serum concentration was significantly increased to 497.5 pg/ml in neuroborreliosis in examination 2. I-TAC concentration in csf remained low, while MCP-1 concentration in examination 1 was increased to 589.1 pg/ml, significantly higher than simultaneously in serum. CONCLUSIONS: I-TAC synthesis is increased in Lyme borreliosis and may be a factor favoring predominance of Th1 lymphocyte subset. MCP-1 creates chemotactic gradient towards central nervous system and may contribute to csf pleocytosis in neuroborreliosis.
Month to years after an early local or an early disseminated infection some patients develop late manifestations of lyme borreliosis. Most frequently involved organs are the skin (acrodermatitis chronica atrophicans), joints (Lyme arthritis) and the nervous system. A history of exposure and the clinical picture may suggest Lyme borreliosis, however, confirmation by serological and other tests is needed. Antibiotic treatment during early stages normally prevents development of late manifestations. Late stages persist if not treated. By adequate antimicrobial therapy they are treatable and usually show a good prognosis. Recovery may be delayed, some patients suffer from residual difficulties. Currently there is no accepted case definition for a "post lyme syndrome". The term "chronic Lyme disease" suggests (a never proven) persistent infection by viable bacteria. Repeated and prolonged antibiotic treatments are not indicated.
The Cardiac Center of The Children's Hospital of Philadelphia and Division of Pediatric Cardiology, Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, USA. firstname.lastname@example.org
Department of Community Medicine, Lund University, Malm, Sweden. email@example.com
AIMS: To describe environmental and personal tick-preventive measures and their predictors, taken by a population living in a highly tick-endemic area. METHODS: Owing to the recent confirmation of human tick-borne encephalitis cases, vaccination against tick-borne encephalitis was offered to the population living in the endemic area through the use of leaflets and media campaigns. At the time of the initial dose, information and enrollment to this cohort study was carried out. Participants' characteristics, frequency of tick-bites and preventive measures were included in questionnaires. Logistic analysis was used to determine behavioural differences in activities taken in order to prevent tick bites. CONCLUSION: In total, 70% of the permanent residents had themselves vaccinated before the next tick season. Of the studied participants 356/517 (69%) regularly took preventive measures in their environment and/or personally. Women in particular, and those previously treated for a tick-borne disease, took significantly more preventive measures. When analysing all variables together, spending less time in a tick-endemic area and being tick-bitten during the latest tick season significantly increased the probability of taking preventive measures. After being tick-bitten, men were more inclined to start taking preventive measures than women. Awareness of the risks caused by living in a high tick-endemic area influenced the participant's daily life through preventive activities. Public health action should be considered, thus encouraging out-of-door activities for the population without anxiety as to the risks of contracting tick-borne disease after being tick-bitten.
The definitive diagnosis of acute neuroborreliosis (NB) is based upon the presence of lymphomonocytic CSF pleocytosis and intrathecal Borrelia burgdorferi (B.b.)-specific antibody production (expressed by an antibody index of >2). However, the latter might be absent in early stages of the disease. Now a recently discovered additional CSF marker-the cytokine CXCL13-was found to be positive in every initial CSF sample from patients with NB and therefore could be a valuable tool for early diagnosis and initiation of antibiotic therapy. We report an unusual case of NB in a patient with a history of metastatic carcinoma of the prostate and unilateral polyradiculitis. While no intrathecal B.b.-specific antibody production could be demonstrated initially, the CSF CXCL13 level was high (>500 ng/g vs <1.7 ng/g in healthy controls). During the course of the disease, the antibody index turned positive (4.8) and the patient responded to antibiotic therapy, thus confirming the diagnosis. In this case, measuring CXCL13 in the CSF would have led to earlier diagnosis and treatment of NB.
Center for Tick-borne Diseases, Visegrdi 14, H-1132 Budapest, Hungary. firstname.lastname@example.org
The diagnosis of neuroborreliosis (NB)--a serious complication of Lyme disease--relies on demonstration of intrathecal borrelia antibody production. We hypothesized that if a qualitative difference between the cerebrospinal fluid and the serum immunoblot-banding patterns was observed, then the borrelia antibodies found in the CSF could not be the result of leakage of serum antibodies to the CSF due to blood-brain barrier damage, but rather had to be produced intrathecally. CSF/serum pairs from 69 NB patients and from 85 control patients with other neurological disorders were investigated. All samples were tested blindly by immunoblot and a commercial capture ELISA kit for NB. The concordance between the two methods was 85.7%. When using the other method as reference, the accuracy of the two assays in the two patient materials was similar: 80% for sensitivity and 95% for specificity. Four types of comparative immunoblot-banding patterns that reflected intrathecal borrelia antibody synthesis were distinguished. The study showed that a simple comparison between the immunoblot pattern of serum and CSF samples allows for a reliable diagnosis of NB by demonstration of intrathecal antibody production. This is the first study to show that a qualitative difference of the antibody response between the immune response of serum and CSF is a rule. The findings also imply that partly different B-cell populations are responsible for the antibody production in the blood and in the central nervous system. In addition, our observation provides possible implications for other infectious diseases with CNS involvement.
Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
We describe a patient with a history of allogeneic hematopoietic stem cell transplantation complicated by chronic graft-versus-host disease who developed painful meningoradiculitis and myositis due to Lyme borreliosis. To our knowledge, this is the first report of such an infection occurring after allogeneic hematopoietic stem cell transplantation in the United States.
Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA. email@example.com
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.
Klinika Chorb Zakanych i Neuroinfekcji Akademii Medycznej, Bialymstoku. firstname.lastname@example.org
OBJECTIVE: The aim was to evaluate the concentrations of the soluble forms of ICAM-1, ICAM-2, ICAM-3 in the serum and cerebrospinal fluid (CSF) of patients with neuroborreliosis and thick borne encephalitis before and after therapy in comparison with the control group. MATERIAL AND METHODS: We examined 30 patients, 10 in each group: neuroborreliosis-group I (NB), tick borne encephalitis--group II (TBE) and in the control group (group K). The diagnosis of neuroborreliosis and TBE based on the clinical features was confirmed by ELISA assays: FSME Virus/TBE Virus test (VIRION, Germany) for TBE and Borrelia IgM and IgG Recombinant (Biomedica Austria) for NB. The assays of sICAM-1, sICAM-2, sICAM-3 (ELISA, Bender Med System, USA) were performed twice in group I and II: before and after 3-4 weeks long treatment and once in control group. RESULTS AND CONCLUSIONS: Increased concentration of soluble forms of ICAM-1, ICAM-2, ICAM-3 in CSF suggest their important role in inflammatory process of viral and bacterial origin. In NB group, the serum concentrations of sICAM-1, sICAM-2 were significantly increased before and after treatment in comparison with control as well as with the analogous test results in TBE group. It may suggest NB as the part of systemic inflammation. The CSF concentration of sICAM-2 decreases after treatment in NB group in comparison with the analogous test results of TBE group. The increased CSF concentration of sICAM-2 in TBE group when compared to the CSF concentration in NB group suggest slow recovery and still persisting immunological activation in this group, even when the neurological symptoms disappeared. Increased concentrations in CSF in both diseases indicate intrameningeal activity of lymphocytes and may be a useful marker of inflammation.
Department of Neurology, Otto-von-Guericke-University Magdeburg, Germany.
OBJECTIVE: To elucidate the relation between release patterns and cerebrospinal fluid/serum concentrations of neurobiochemical markers of cerebral damage and their potential value as monitoring parameters in central nervous system infections. METHODS: We investigated protein S-100B and neuron-specific enolase (NSE) in 102 sequential cerebrospinal fluid (CSF)-serum-pairs in patients with bacterial (n = 11) or viral (n = 13) meningitis/meningoencephalitis and neuroborreliosis (n = 8) in comparison with controls (n = 13). RESULTS: Highest S-100B values in CSF and serum were found on admission and showed a significant decrease afterwards. Comparison between disease groups revealed significant differences between bacterial and viral meningitis and neuroborreliosis for S-100B and also when compared with controls. NSE was not significantly elevated. CONCLUSIONS: S-100B is altered in CNS infection but does not provide additional benefit in the differential diagnosis when compared with standard CSF parameters. Nevertheless, S-100B values might be used as an additional monitoring parameter especially when sequential lumbar punctures are contraindicated.
First Clinic for Infectious Diseases, Second Medical Faculty of Charles University, Faculty Hospital Bulovka, Czech Republic.
OBJECTIVES: DNA proof is the only widely available direct diagnostic tool in Lyme borreliosis. Sensitive PCR detecting of spirochetal DNA was prepared and a prospective study in neuroborreliosis was performed. MATERIALS AND METHODS: 57 hospitalised patients with active neuroborreliosis and proved CSF antibodies synthesis were examined. Nested-PCR (utilizing three targets) was used for the detection of specific DNA in plasma, CSF and urine. RESULTS: Before treatment 36 positive patients (63.1%) were found in all tested specimens in parallel, 28 patients (49.1%) were positive in urine, 20 in CSF (35.0%) and 16 in plasma 28.0%). Later only urine was tested and the following results were obtained: 17 positive patients (30.0%) immediately after treatment, 8 (14.0%) after 3 months and one patient persisted positivity after 6 months. CONCLUSIONS: The highest sensitivity of PCR was achieved in the acute period of neuroborreliosis - 63.1% in three body fluids comparing with CSF antibody synthesis.
Department of Bacteriology and Immunology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
The Lyme disease-pathogen Borrelia burgdorferi binds the complement inhibitor factor H (FH) to its outer surface protein E- (OspE) and BbA68-families of lipoproteins. In earlier studies, only serum-resistant strains of the genospecies B. burgdorferi sensu stricto or B. afzelii, but not serum-sensitive B. garinii strains, have been shown to bind FH. Since B. garinii often causes neuroborreliosis in man, we have readdressed the interactions of B. garinii with FH. B. garinii 50/97 strain did not express FH-binding proteins. By transforming the B. garinii 50/97 strain with an OspE-encoding gene from complement-resistant B. burgdorferi (ospE-297), its resistance to serum killing could be increased. OspE genes were detected and cloned from the B. garinii BITS, Pistoia and 40/97 strains by PCR and sequencing. The deduced amino acid sequences differed in an N-terminal lysine-rich FH-binding region from OspE sequences of resistant strains. Recombinant B. garinii BITS OspE protein was found to have a considerably lower FH-binding activity than the B. burgdorferi sensu stricto 297 OspE protein P21 (P21-297). Unlike bacteria that had been kept in culture for a long time, neurovirulent B. garinii strains from neuroborreliosis patients were found to express approximately 27-kDa FH-binding proteins. These were not recognized by polyclonal anti-OspE or anti-BbA68 antibodies. We conclude that B. garinii strains carry ospE genes but have a decreased expression of OspE proteins and a reduced ability to bind FH, especially when grown for prolonged periods in vitro. Recently isolated neuroinvasive B. garinii strains, however, can express FH-binding proteins, which may contribute to the virulence of neuroborreliosis-causing B. garinii strains.
University Department of Ophthalmology, Clinical Hospital, Systers of Mercy, Zagreb, Croatia. email@example.com
Lyme disease is a multi-system organ disorder caused by Borrelia burgdorferi. Although ocular manifestations have been reported, these remain a rare feature of the disease. This report shows a 49-years old patient that has been bitten by a tick and as consequence of which developed symptoms of the Lyme disease. In 1998 the patient was hospitalized in our Eye Clinic due to operating treatment of the paralytic strabismus (abductal nerve paralysis), as a rare feature of the Lyme disease. Postoperative squint angle was significantly reduced, but without any temporal movement. Diplopia was still present, though slightly reduced with the use of prism eyeglasses. The improvement of the quality of life was achieved, as well as the patient's satisfaction.
Division of Clinical Immunology, University of Linkping, Sweden. firstname.lastname@example.org
The clinical course and outcome of several infectious diseases are dependent on the type of immune response elicited against the pathogen. In adults with neuroborreliosis (NB), a type 1 response with high production of Borrelia-specific IFN-gamma, but no IL-4, has been reported. Since children have a more benign course of NB than adults, we wanted to investigate type 1 and type 2 responses in children with NB. Cerebrospinal fluid (CSF) and blood were collected from children during the acute stage of 'confirmed NB' (n = 34), 'possible NB' (n = 30) and 'non-NB' (n = 10). The number of Borrelia-specific IL-4- and IFN-gamma-secreting cells was measured by enzyme-linked immunospot assay. Borrelia-specific secretion of both IL-4 and IFN-gamma was increased in CSF in confirmed (P < 0.05) and possible (P < 0.01) NB, when compared with non-NB controls. Furthermore, children with NB had significantly higher Borrelia-specific IL-4 secretion in CSF than an adult reference material with NB (P < 0.05). There were no differences in cytokine secretion in relation to onset or recovery of neurological symptoms. Since IL-4 is known to down-regulate the pro-inflammatory and possibly harmful effects of prolonged IFN-gamma responses, the prominent IL-4 response observed in the central nervous system compartment might contribute to the more benign disease course seen in children with Lyme NB.
A 78-year-old man with metastasised prostate carcinoma presented with a painless paraparesis. His cerebrospinal fluid showed elevated protein and a mononuclear pleiocytosis, but cytology investigations of 5 separate samples revealed no malignant cells in the cerebrospinal fluid. Extensive viral and bacterial tests (including ELISA for Borrelia burgdorferi) of serum and cerebrospinal fluid were negative. On the day radiation therapy for presumed leptomeningeal metastases was due to start the IgG and IgM Western blot for Borrelia were found to be positive, indicating neuroborreliosis. Soon after the start of antibiotic therapy the paraparesis began to improve and after four weeks the patient had made a complete recovery. In patients with a progressive paraparesis, neuroborreliosis should be considered even in the absence of pain.
Chair and Department of Developmental Neurology Poznan University of Medical Sciences, Poland. email@example.com
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.
Hospital for Children and Adolescents, University of Helsinki, Finland.
OBJECTIVE: To evaluate serology with novel Borrelia-specific protein or peptide antigens in the laboratory diagnosis of neuroborreliosis (NB) in children. METHODS: The performance of enzyme-linked immunosorbent assays with several recombinant borrelial protein antigens and invariable region 6 synthetic peptide antigen and of a commercial enzyme-linked immunosorbent assay with the flagella antigen were evaluated in the serodiagnosis and follow-up of children with clinical suspicion of NB. Serum samples were obtained from 20 children with neurologic symptoms indicative of NB. The patients were retrospectively divided into 2 groups based on the laboratory tests at presentation indicating definite (n = 7) or probable (n = 13) NB. RESULTS: In addition to cerebrospinal fluid (CSF) lymphocytic pleocytosis and CSF antiflagella antibodies, all 7 patients with definite NB had serum IgG antibodies to at least 2 of the 3 novel antigens at presentation. The 13 patients with probable NB had variable laboratory findings: CSF pleocytosis (n = 7), CSF antiflagella IgM antibodies (n = 4), serum antiflagella IgM and/or IgG antibodies (n = 10). Of these 13 patients, 7 had serum IgG antibodies to 2 of the 3 novel antigens at presentation. During long term follow-up, serum anti-invariable region 6 antibodies disappeared. CONCLUSIONS: The present study suggests that assessment of serum antibodies to a panel of Borrelia-specific antigens could improve the laboratory diagnosis of NB at presentation.
Department of Pediatrics, Alfred I. duPont Hospital for Children and Nemours Children's Clinic Wilmington, DE 19899, USA.
BACKGROUND: Cerebrospinal fluid (CSF) laboratory tests are frequently collected to help differentiate Lyme meningitis from other causes of aseptic meningitis. Previous studies using Lyme CSF polymerase chain reaction (PCR) have yielded varied results (sensitivity between 10 and 90%). No studies have specifically examined the diagnostic utility of Lyme CSF-PCR in North American children with Lyme meningitis. METHODS: Retrospective chart review of children presenting to a children's hospital in a Lyme-endemic region between October 1999 and September 2004. Patients were included if they had both Lyme serology and Lyme CSF-PCR performed during the same hospital encounter and had documented meningitis. Patients were considered to have Lyme meningitis if they had meningitis and met CDC criteria for Lyme disease. The Lyme CSF-PCR assay amplified a Borrelia burgdorferi DNA flagellin gene sequence. RESULTS: Of 108 patients with meningitis who qualified for the study, 20 patients met criteria for Lyme meningitis and 88 were classified as aseptic meningitis. Positive Lyme CSF-PCR was found in 1 patient (1 of 20, 5%) with Lyme meningitis and one patient classified as aseptic meningitis (1 of 88, 1%). Lyme CSF-PCR had a sensitivity of 5% and a specificity of 99%. The only Lyme meningitis patient with positive Lyme CSF-PCR had the highest CSF white blood cell count and CSF protein values compared with the other Lyme meningitis patients. CONCLUSIONS: This is the first study to evaluate Lyme CSF-PCR exclusively in North American children. This commercially available laboratory test is not generally helpful for identifying Lyme meningitis because of its low sensitivity.
Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany.
BACKGROUND: Chronic neuropathic pain occurs in 10-15% of patients with neuroborreliosis and is difficult to treat. OBJECTIVE: We evaluated the effect of gabapentin monotherapy on residual pain in patients with neuroborreliosis after intravenous ceftriaxone treatment. METHODS: Ten patients with neuroborreliosis and a long-lasting history of neurologic symptoms were treated with gabapentin, starting with 300 mg/day. Doses were raised over a period of 4-12 weeks to the individually effective and tolerated maximum dose (500-1,200 mg). Treatment was maintained until pain disappeared and then gradually reduced in dose over weeks. If symptoms recurred, the doses were raised again. Therapy was maintained over an average of 1-2 years. RESULTS: Pain quality and pain quantity were evaluated using the McGill pain questionnaire and a visual analogue scale. There was an improvement of 'crawling' and 'burning' pain sensations, neck and radiating lumbar pain in 9/10 (90%) patients as well as a positive effect on mood, general feeling of health and quality of sleep in 5/10 (50%) patients. The average dose leading to a clear-cut pain reduction was 700 mg. CONCLUSIONS: In an open pilot study (10 patients), gabapentin monotherapy which has to our knowledge not been published as treatment of chronic neuropathic pain in patients with late Lyme borreliosis is efficacious in treating pain associated with neuroborreliosis and can thus improve quality of life in these patients. (c) 2005 S. Karger AG, Basel
Department of Neurology, Ludwig-Maximilians University, Munich, Germany.
Using protein expression profiling, the authors identified an upregulation of the chemokine B lymphocyte chemoattractant (BLC) in the CSF of patients with neuroborreliosis but not in patients with noninflammatory and various other inflammatory neurologic diseases. This upregulation was confirmed by ELISA, showing increased BLC levels in every neuroborreliosis patient while being undetectable in patients with noninflammatory neurologic diseases. These results point to BLC as a putative additional diagnostic marker for neuroborreliosis.
Outpatients Clinic of Dermatology at the Tropical Diseases Unity of the Institute of Hygiene and Tropical Medicine, University Nova de Lisboa, Lisboa, Portugal. firstname.lastname@example.org
BACKGROUND: Borrelia lusitaniae was isolated from an Ixodes ricinus tick in Portugal in 1993 for the first time. Further, this borrelia genospecies has been found in ixodid ticks collected around the coasts of southern Portugal and North Africa. Its reservoir has not been defined yet. B. lusitaniae was isolated once until now from a patient with a long standing and expanding skin disorder. PATIENT AND METHODS: A 46-year-old Portuguese woman presented with a skin lesion on the left thigh which had evolved slowly over ten years. The patient reported limb paraesthesias, cramps, chronic headaches, and cardiac rhythm disturbances. History of tick bites was negative nor had the patient ever noticed a skin lesion comparable with erythema chronicum migrans. Skin biopsies were taken for histological evaluation, culture and DNA detection. Antibodies to borrelia were searched by indirect immunofluorescence assay and Western-blot. RESULTS: A bilateral carpal tunnel syndrome and local synovitis was diagnosed. Dermato-histology was normal, serology was negative. Spirochaetal organisms were cultured from a skin biopsy and identified as B. lusitaniae. The patient improved after a 2-week course of intravenous ceftriaxone; the skin lesions did not expand further. CONCLUSIONS: This culture confirmed skin infection by B. lusitaniae in a patient from Portugal suggests an additional human pathogen out of the B. burgdorferi sensu lato complex in Europe, particularly in Portugal.
Departments of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden. email@example.com
OBJECTIVES: The objectives of this study were to examine children with previous manifest neuroborreliosis and concommitant facial palsy to see whether there were any persisting symptoms and/or signs of persistent residual facial palsy. STUDY DESIGN: Open, controlled prospective study. SETTING: Tertiary referral center (University Hospital). PATIENTS: The study was conducted on twenty-four patients with clinically manifest neuroborreliosis and facial palsy 3 to 5 years prior to the investigation. MAIN OUTCOME MEASURES: Results of the clinical examination using the House-Brackmann scale were compared to results from two neuro-physiological examinations (qEMG and ENoG). RESULTS: Approximately one-half of the patients with reported subjective symptoms of residual facial palsy had signs of slight dysfunction in the clinical examination using the House-Brackmann scale. There was no correlation between the subjective feeling of facial dysfunction and presence of clinical signs. Likewise, about one-half of the subjective facial dysfunction group, as well as the control group, were found to demonstrate pathological values in their neurophysiological examinations using qEMG and ENoG. CONCLUSIONS: This study shows that the assumption is not true that all children who had neuroborreliosis with facial palsy will heal 100%. A small proportion of the children claim that several years after the infection, they have subjective symptoms of slight facial weakness on the affected side. Our study shows that some of these children, as well as some children without subjective symptoms of facial palsy, demonstrate a slight facial weakness when examined clinically. Likewise, signs of slight-to-moderate facial motor dysfunction were revealed in about half of the children with the two neurophysiological methods utilized in this study. It is interesting to note that there was no clear correlation between the presence of subjective symptoms, objective signs, and neurophysiological results.
Department of Infectious Diseases, Sahlgrenska University Hospital, Gteborg, Sweden. firstname.lastname@example.org
This prospective, open-label, non-randomized trial at the University Departments of Infectious Diseases in Ljubljana, Slovenia, and Gteborg, Sweden, was conducted to compare the kinetics of the cerebrospinal fluid (CSF) mononuclear cell count after 10-14 d of ceftriaxone or doxycycline for treatment of Lyme neuroborreliosis. 29 patients were treated with intravenous ceftriaxone 2 g daily in Ljubljana and 36 patients with oral doxycycline 400 mg daily in Gteborg. The study protocol included lumbar puncture before and 6-8 weeks after treatment initiation. There was a marked decrease (1.2 log10 x 10(6)/l) of the median CSF mononuclear cell count following treatment. With the assumption of a linear regression of the logarithmic mononuclear cell counts between the 2 lumbar punctures, no significant difference between the 2 antibiotic treatments could be found. All patients were clinically much improved after treatment. At 6 months follow-up 23 (79%) of the ceftriaxone- and 26 (72%) of the doxycycline-treated patients were completely recovered. Intravenous ceftriaxone or oral doxycycline was found to be effective, safe, and convenient for treatment of Lyme neuroborreliosis.
Department of Clinical Microbiology, Faculty Hospital, Masaryk University, Brno, Czech Republic.
OBJECTIVES: The aims were to investigate the frequency of intrathecal synthesis of specific antibodies against measles (M), rubella (R) and varicella zoster (Z) viruses (MRZ reaction) as a diagnostic marker between multiple sclerosis (MS) and neuroborreliosis (NB) groups and to postulate the most typical cerebrospinal fluid (CSF) variables profile of these entities. METHODS: Three cohorts of patients were investigated: MS (n = 42), NB (n = 27) and other neurological diseases (OND) (n = 15). Measles, rubella, varicella zoster and borrelia-specific IgG antibodies were measured by ELISA, Q(alb) (CSF/serum albumin ratio) as a marker of blood-CSF barrier function and specific antibody indices (AI) were calculated according to relevant formulae. IgG oligoclonal bands (OB) were detected by isoelectric focusing and immunoenzymatic staining. RESULTS: Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive anti-borrelia AI. Eighty-nine percent of NB patients had positive anti-borrelia AI and two patients had individually anti-measles and rubella positive AI. MS-CSF variables profile included the presence of IgG OB in 81%, elevated Q(alb) in 31% and normal cell count in 66.7%. Of NB patients IgG OB were positive in 74%, elevated Q(alb) in 81.5% and normal cell count in 7.4%. CONCLUSION: MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB. Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.
Divisions of Infectious Diseases, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, University Hospital, Linkping, Sweden. Johanna.Sjowall@imk.liu.se
Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in DCs and IL-1beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-alpha-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease.
Department of Psychiatry, Friedrich-Schiller-University of Jena, Jena, Germany. email@example.com
Neuroborreliosis has become the most frequently recognized tick-borne infection of the nervous system in Europe and the United States. In addition to dermatological, cardiac, articular, and neurologic manifestations, psychiatric disorders such as depression, panic attacks, and schizophrenia-like psychosis can also arise. We report on a 61-year-old woman who developed a severe pain syndrome following several tick bites. She was diagnosed with neuroborreliosis; she received various courses of antibiotics over several years, but without any clinical improvement in her condition. Her eventual admission to a psychiatric ward due to mental symptoms and neuroleptic treatment led to a dramatic improvement of her pain symptoms. However, increasing delusions disclosed a psychotic episode, which ceased over time. We discuss therapeutic difficulties and psychiatric complications in the absence of a clear-cut diagnosis of neuroborreliosis. Although this patient might have suffered from late-onset schizophrenia with painful hallucinations right from the start of her disease, the case highlights psychiatric complications that might be associated with neuroborreliosis.
Divisions of Infectious Diseases, The Children's Hospital of Philadelphia, PA, USA.
BACKGROUND: Differentiating Lyme meningitis from enteroviral meningitis remains difficult because both occur mostly in the summer and early fall. This distinction is clinically important because pathogen-specific diagnostic test results are not available immediately and only patients with Lyme meningitis require parenteral antibiotic therapy. OBJECTIVES: The objective of this study was to identify clinical and laboratory features that might help clinicians distinguish patients with Lyme meningitis from those with enteroviral meningitis. METHODS: This cross-sectional study compared patients diagnosed with Lyme or enteroviral meningitis evaluated at a large children's hospital between January 1, 1999 and September 20, 2002. RESULTS: Twenty-four patients with Lyme meningitis and 151 patients with enteroviral meningitis had median ages of 10.5 and 5.5 years, respectively (P < 0.0001). There was an equal proportion of boys with Lyme (63%) and enteroviral meningitis (62%; P = 1.0). The duration of symptoms before evaluation was longer for patients with Lyme meningitis (12 days) than with enteroviral meningitis (1 day; P < 0.0001). Cranial neuropathy was a presenting feature in 71% of children with Lyme meningitis. Cranial neuropathy, erythema migrans rash or papilledema occurred in 88% of patients with Lyme meningitis; no patients with enteroviral meningitis exhibited any of these findings (P < 0.0001). Lyme meningitis was unlikely when cerebrospinal fluid neutrophils exceeded 10% (negative predictive value, 99%). CONCLUSIONS: We identified several clinical and laboratory features that may permit early differentiation of Lyme from enteroviral meningitis. These results may assist clinicians with decisions regarding additional testing and empiric antibiotic therapy.
University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
Lyme neuroborreliosis (LNB) is a chronic infection in which B-cell activation, plasma cell infiltration, and enhanced Ig production in infected tissue are prominent feature. However, little is known about how B cells and plasma cells invade and persist in target organs. To assess this issue, we developed real-time PCR measurements of IgG and CXCL13 production. We used these RNA assays and specific enzyme-linked immunosorbent assays for protein and demonstrated that human peripheral blood mononuclear cells (PBMCs), stimulated by Borrelia burgdorferi sonicate, produced CXCL13 and IgG. Magnetic separation of PBMC populations and flow cytometry showed that CXCL13 is produced by dendritic cells. We then measure the expression of CXCL13 and IgG in tissues and correlated the expression of these host genes with spirochetal load. We also measured expression of dbpA and BBK32, two spirochetal genes important in chronic infection. There was a strong correlation between host immune response gene expression (CXCL13 and IgG) and spirochetal load. Immunohistochemistry of infected nonhuman primates tissue confirmed that CXCL13 is expressed in the nervous system. We conclude that persistent production of CXCL13 and IgG within infected tissue, two characteristics of ectopic germinal centers, are definitive features of LNB.
Department of Radiology, Nuclear Medicine and Radiooncology, Campus Virchow-Klinikum, University Hospital Charit, Berlin, Germany. firstname.lastname@example.org
The authors report on a patient suffering from acute Lyme borreliosis who underwent two consecutive [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) studies demonstrating the course of the disease. The first FDG-PET study revealed markedly increased glucose metabolism in the brainstem, matching exactly the signal abnormalities exhibited on magnetic resonance images and indicating a brainstem tumor. A second PET scan demonstrated no abnormality in this region, thus reflecting clinical remission following antibiotic therapy. Data in the present case indicate that hypermetabolic findings on FDG-PET studies in the brainstem region should be regarded with caution and that neuroborreliosis must be considered as a possible differential diagnosis.
Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433, USA.
Lyme borreliosis, which is prevalent both in the US and in Europe, is an infectious disease that may cause local inflammation in numerous organs. We have hypothesized that, as with some neurodegenerative diseases, the pathogenesis of the neurocognitive deficiencies associated with Lyme neuroborreliosis of the central nervous system also has an inflammatory component. Dysregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage. Mitogen-activated protein kinases (MAPK) play a key role in the regulation of neuronal development, growth, and survival, as well as that of pro-inflammatory cytokine production. As a model, we explored the possibility that MAPK-mediated lipoprotein-induced apoptosis and gliosis of rhesus monkey astrocytes stimulated in vitro. Lipoproteins are the key inflammatory molecule type of Borrelia burgdorferi, the spirochete that causes Lyme disease, and we had previously shown that lipoprotein-induced TNF-alpha production in astrocytes caused astrocyte apoptosis, and IL-6 enhanced proliferation of these cells. Lipoproteins readily activated p38 and Erk1/2 MAPK, thus enlisting these pathways among the kinase pathways that spirochetes may address as they invade the central nervous system. We also investigated whether specific inhibition of p38 and Erk1/2 MAPK would inhibit TNF-alpha and IL-6 production and thus astrocyte apoptosis, and proliferation, respectively. Lipoprotein-stimulated IL-6 production was unaffected by the MAPK inhibitors. In contrast, inhibition of both p38 and Erk1/2 significantly diminished TNF-alpha production, and totally abrogated production of this cytokine when both MAPK pathways were inhibited simultaneously. MAPK inhibition thus may be considered as a strategy to control inflammation and apoptosis in Lyme neuroborreliosis.
University Hospital for Infectious Diseases, Dr. Fran Mihaljevi, Mirogojska 8, 10000 Zagreb, Croatia. Snjezana.Zidovec.Lepej@bfm.hr
The aim of this study was to evaluate the contribution of chemokine receptor CXCR3 and the corresponding ligands CXCL10 and CXCL11 to the recruitment of peripheral blood (PB) memory CD4+ T-cells into the cerebrospinal fluid (CSF) of patients with acute neuroborreliosis. Percentages of memory CD45RO+CD4+ T-cells expressing CXCR3 and CCR5 were significantly enriched in the CSF compared to the PB. Concentrations of CXCL10 and CXCL11 in the CSF of neuroborreliosis patients were significantly higher compared with the corresponding serum samples. Our results suggest that CXCL10 and CXCL11 create a chemokine gradient between the CSF and serum and recruite CXCR3-expressing memory CD4+ T-cells into the CSF of neuroborreliosis patients and that CCR5 also plays a role in this process.
Department of Neurology, Georgetown University Medical Center.
This is a report of 2 patients with Lyme disease who initially presented with severe constipation, which progressed to ascending muscular weakness resembling acute idiopathic polyneuritis, with neuropsychiatric symptoms, severe urinary retention, and hyponatremia. These symptoms resolved following proper antibiotic therapy.
Oddzial Internistyczno-Kardiologiczny Samodzielnego Szpitala Miejskiego im. PCK w Bialymstoku.
Although borreliosis was first described as a separate entity more than 20 years ago its pathogenesis still remains unknown. In recent years the role of pro- and antiinflammatory cytokines in the pathogenesis of borreliosis has been discussed. The purpose of the present study was to evaluate the role of IL-1beta, IL-18 and sIL-1RII in the development of early and late stages of borreliosis. The study group consisted of 60 patients divided into 3 groups: patients with erythema migrans, Lyme arthritis and neuroborreliosis. In all groups serum levels of IL-1beta, IL-18 and sIL-1RII were determined and in the patients with neuroborreliosis additionally in cerebrospinal fluid (CSF). The levels of cytokines and sIL-1RII were measured before the start of treatment and after its termination. Before the treatment the levels of IL-1beta, IL-18 and sIL-1RII in serum and CSF were significantly higher in all studied groups compared with the control. After the treatment, despite the regression of the clinical symptoms and significant reduction of initially high levels of the cytokines and sIL-1RII, only the levels of IL-1beta in all patients and the serum level of IL-18 in the patients with neuroborreliosis were comparable with the values in the control group. It could suggest that the inflammatory process was not inhibited completely and confirms the role of IL-1beta, IL-18 and sIL-1RII in the pathogenesis of borreliosis.
We investigated the role of the CXCR3 chemokine CXCL11 (I-TAC) for leukocyte recruitment to the CSF in neuroborreliosis (NB). CXCL11 levels in the CSF of 17 patients with acute NB were elevated compared with 20 non-inflammatory controls (100.1 vs. 54.1 pg/ml, p = 0.002). Using a modified Boyden chamber chemotaxis-assay, the CSF of patients with acute NB was more chemotactic than the control CSF-samples (p = 0.001). A strong correlation (p < 0.001) between CXCL11 levels, chemotactic activity and CSF-white cell count was detected. Though the chemotactic activity of CSF from NB patients was only partially reduced by a human recombinant CXCL11 antibody, these findings suggest that, among other chemotactic factors, CXCL11 may play a role in the chemotaxis of mononuclear cells in NB.
I Oddzial Internistyczno-Kardiologiczny, Samodzielny Szpital Miejski im. PCK w Bialymstoku, ul. H. Sienkiewicza 79, 15-002 Bialystok, Poland. email@example.com
BACKGROUND AND PURPOSE: The aim of the present study was to determine the role of interleukin-18 (IL-18), interleukin-1beta (IL-1beta) and its soluble receptor sIL-1RII in the pathogenesis of neuroborreliosis as well as the usefulness of C-reactive protein (CRP) determination in the diagnosis and monitoring of treatment of Lyme neuroborreliosis. MATERIAL AND METHODS: The study group consisted of 20 patients with Lyme meningitis (age range 16-72 years, mean age 42.6 years). For measurements of IL-18, IL-1beta and sIL-1RII levels in serum and cerebrospinal fluid (CSF) the control group consisted of 10 healthy volunteers and 10 patients with infection of the central nervous system ruled out, respectively. Cytokines and sIL-1RII levels in serum and CSF were measured twice, before and after the 30-day treatment period. Serum and CSF levels of IL-18, IL-1beta and sIL-1RII were measured using ELISA, and CRP serum levels were measured using the immunoturbidimetric method. RESULTS: Before the treatment the concentration of IL-18, IL-1beta and sIL-1RII in serum as well as in CSF was significantly higher as compared to the controls. After the treatment end the level of IL-18, IL-1beta and sIL-1RII was reduced but the serum level of sIL-1RII and CSF level of IL-18 and sIL-1RII remained significantly higher than in the control group. The serum level of CRP was increased only in 15% of patients and after the treatment CRP concentration returned to a basal level (except one patient in whom CRP was slightly higher than in the control group). No correlation between CRP and IL-18, IL-1beta and sIL-1RII was observed. CONCLUSIONS: Our results confirm the involvement of IL-18, IL-1beta and sIL-1RII in the pathogenesis of neuroborreliosis and uselessness of CRP determination in the diagnosis of Lyme meningitis.
Department of Neurology, Centre Hospitalier de Mont de Marsan, 40000 Mont de Marsan, France. firstname.lastname@example.org
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.
Department of Neurology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA. email@example.com.
The challenge for the neurologist in the treatment of Lyme neuroborreliosis is not in the treatment per se, but in the diagnosis. Neurological manifestations of Lyme disease can present in many forms, and diagnostic techniques which detect the spirochete directly; the culture or polymerase chain reaction of the spirochete in cerebrospinal fluid, are of disappointingly low yield. Therefore, the diagnosis is frequently not easy. After the diagnosis is made, antibiotic therapy is straightforward; Lyme neuroborreliosis should be treated with at least 2 weeks of antibiotics. In the United States, intravenous therapy with ceftriaxone or penicillin for 2 weeks is the standard, whereas in Europe oral doxycycline therapy is commonly administered. Either is effective, and my choice of therapy generally depends on the patient. Many patients have symptoms which continue after antibiotic therapy referable to persistent inflammation, and, for those patients, I will commonly prescribe nonsteroidal anti-inflammatory medications.
PMID: 15676120 [PubMed - as supplied by publisher]
University Institute of Pathology, Division of Neuropathology, University Medical School (CHUV), 1011, Lausanne, Switzerland. firstname.lastname@example.org
The cause, or causes, of the vast majority of Alzheimer's disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD.
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.
We present laboratory data from 22 patients suspected of having neurosyphilis. In two cases the suspicion could not be confirmed, and in 20 cases neurosyphilis was detected. The sera from 17 patients were also assayed for Borrelia-specific antibodies. Suspicious immunoglobulin G antibody indices were detected in nine cases and a suspicious immunoglobulin M antibody index in one. In six of these, stored CSF/serum pairs were available to specify the antibodies by immunoblotting. This allowed for the identification of one patient apparently infected by both Borrelia spp. and Treponema pallidum. In all cases of newly suspected neurosyphilis, we recommend considering neuroborreliosis at the same time.
Pain is one of the presenting symptoms in acute neuroborreliosis. Classically, acute neuroborreliosis--also known in Europe as Bannwarth's syndrome--is a combination of radicular pain, cranial neuritis and peripheral radiculitis and inflammatory changes of the CSF. The prognosis following antibiotic therapy is favorable. At least in its early stages, however, the diagnosis neuroborreliosis might be missed or mistaken. Thus, targeted assessment of typical signs is needed to expedite examination of the CSF which then permits definitive diagnosis.
Department of Bacteriology University of Gttingen, Germany.
AIM: Children with acute peripheral facial palsy have often suffered tick bites and/or erythema migrans in the head/neck region on the same side. With respect to the pathogenesis of neuroborreliosis this topographical association was investigated in an animal model. METHODS: A Borrelia garinii strain, isolated from the CSF of a child with acute facial palsy, was injected in 9 rats intracutaneously in the right subauricular region. Infected rats were examined for clinical symptoms of Lyme disease, the spread of the spirochetes was investigated by PCR of necropsies (facial nerves, trigeminus nerves, heart, brain, skin) up to 47 days after infection. The nerve tissues were investigated by histology, immunohistochemistry and electron microscopy. RESULTS: None of the rats developed a facial palsy or other symptoms of Lyme disease. Borrelia DNA was found in the heart after 5 days and in the brain after 7 days of infection up to the end of investigation (47 days), as well as in the ipsilateral peripheral nerves after 7 to 33 days. Borrelia was detected by electron microscopy near endoneural vessels of the facial nerve. Peri-, epi-, and endoneural infiltrations of macrophages, plasma cells and B cells characterized an inflammation of the facial and trigeminus nerves ipsilateral to the infection site. CONCLUSION: An infection with Borrelia garinii in the subauricular region induces an ipsilateral neuritis of peripheral nerves. The particular vulnerability of the human facial nerve may be a result of its long intraosseus course. Thus, an inflammatory edema may injure the nerve in the canalis facialis.
Klinika Chorb Zakanych i Neuroinfekcji, Akademia Medyczna w Bialymstoku. email@example.com
BACKGROUND AND PURPOSE: Neuroborreliosis is a tick transmitted disease which becomes an increasingly frequent diagnostic and therapeutic problem in physician practice. The purpose of this work was to evaluate the concentration of proinflammatory cytokines: IL-1beta, IL-6, TNF-alpha, IFN-gamma in serum and cerebrospinal fluid of patients with neuroborreliosis. MATERIAL AND METHODS: 20 persons with diagnosed neuroborreliosis and 10 persons as a control group were examined in this study. The examination of serum and cerebrospinal fluid was performed twice, before and after 4-week therapy with antibiotics. The concentration of cytokines was measured by the ELISA method using kits of Bender Medical System and Quantikine RD Systems. RESULTS: The concentration of measured cytokines IL-1beta, IL-6, TNF-alpha and IFN-gamma in serum and cerebrospinal fluid was significantly higher before therapy. After 4-week therapy with antibiotics the concentration of cytokines in cerebrospinal fluid decreased but was still higher than in the control group except for IL-1beta. CONCLUSIONS: The detection of proinflammatory cytokine concentration in serum and cerebrospinal fluid might be helpful as another parameter monitoring the inflammation course and therapy efficacy.
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. firstname.lastname@example.org
OBJECTIVE: Facial paralysis is a manifestation of early disseminated Lyme neuroborreliosis. In the current study, we compared the immunoglobulin G (IgG) VlsE (sixth invariant region) peptide enzyme-linked immunosorbent assay (ELISA) with the current two-tier approach of sonicate ELISA and Western blot in the serodiagnosis of Lyme facial paralysis. STUDY DESIGN: Retrospective. SETTING: Tertiary referral center. PATIENTS: Serum samples from 47 Lyme patients with facial paralysis and 86 control subjects were analyzed for IgG antibodies to VlsE peptide of Borrelia burgdorferi and for immunoglobulin M (IgM) and IgG antibodies to sonicate antigens of B. burgdorferi using the two-tier approach. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: Serum IgG antibody responses to VlsE (IR6) peptide. RESULTS: All 47 (100%) patients with facial paralysis and 4 (5%) of 86 controls had positive antibody responses to the VlsE peptide. In the two-tier test, 41 (87%) patients had positive IgM, 31 (66%) had positive IgG, and all 47 patients had positive IgM or IgG responses. Of the 86 control subjects, 2 (2%) had positive results with the two-tier test. Thus, the sensitivities of the VlsE and the two-tier tests were 100%; the specificity of the VlsE ELISA was 95% and the specificity of the two-tier test was 98%. CONCLUSIONS: The VlsE peptide ELISA showed a high sensitivity and specificity in the serological diagnosis of Lyme facial paralysis, similar to the two-tier test. The principal advantage of the VlsE peptide ELISA is that it requires only one test rather than four tests. However, the specificity of the VlsE test may not be as high as that of the two-tier test.
Eleven patients with neuro-borreliosis had been treated with 200 mg fluconazole daily for 25 days after an unsuccessful therapy with antibiotics. At the end of treatment eight patients had no borreliosis symptoms and remained free of relapse in a follow-up examination one year later. In the remaining four patients, symptoms were considerably improved. At the end of therapy immune reactivity (IgM+) disappeared in three patients. Since borrelia spp. are almost exclusively localised intracellular, they may depend on certain metabolites of their eucaryotic host cell. Inhibition of P450 and other cytochromes by fluconazole may incapacitate Borrelia upon longterm exposure.
Between 1990 and 2000, a total of 101 patients with acute (n=86) or chronic (n=15) neuroborreliosis (proven by clinical data, pleocytosis in the CSF, and elevated Borrelia burgdorferi-specific antibody indices) were treated with 2 g of ceftriaxone per day for either 2 or 3 weeks. The patients were reexamined clinically and serologically after 3, 6, and 12 months. Six (12) months after the antibiotic treatment, about 93% (95%) of the patients with acute neuroborreliosis and 20% (66%) of the patients with chronic neuroborreliosis were cured. One year after treatment, four patients with acute neuroborreliosis still suffered from facial palsy and five with chronic neuroborreliosis still had moderate spastic ataxic gait disturbance. The prognosis of facial palsy in neuroborreliosis is quite similar to that in idiopathic facial palsy, while that in chronic neuroborreliosis largely depends on the time elapsed before diagnosis.
Divisions of Clinical Immunology and Infectious Diseases, Department of Molecular and Clinical Medicine, Linkoping University, Linkoping, Sweden. email@example.com
The Borrelia-specific interferon (IFN)- gamma and interleukin (IL)-4 responses of 113 patients and control subjects were analyzed using the sensitive enzyme-linked immunospot method. Cerebrospinal fluid (CSF) and blood samples were obtained, during the course of disease, from patients with chronic or nonchronic neuroborreliosis (NB) and from control subjects without NB. Blood samples were obtained from patients with Lyme skin manifestations and from healthy blood donors. Early increased secretion of Borrelia-specific IFN- gamma (P<.05) and subsequent up-regulation of IL-4 (P<.05) were detected in the CSF cells of patients with nonchronic NB. In contrast, persistent Borrelia-specific IFN- gamma responses were observed in the CSF cells of patients with chronic NB (P<.05). In patients with erythema migrans, increased IFN- gamma (P<.001) was observed in blood samples obtained early during the course of disease, whereas increased IL-4 (P<.05) was observed after clearance. On the contrary, patients with acrodermatitis chronica atrophicans had Borrelia-specific IFN- gamma (P<.001), but not IL-4, detected in blood samples. The present data suggest that an initial IFN- gamma response, followed by up-regulation of IL-4, is associated with nonchronic manifestations, whereas a persistent IFN- gamma response may lead to chronic Lyme borreliosis.
Flevoziekenhuis, afd. Neurologie, Hospitaalweg 1, 1315 RA Almere. firstname.lastname@example.org
OBJECTIVE: To determine the clinical spectrum and incidence of neuroborreliosis in the Netherlands. DESIGN: Retrospective. METHOD: All neurological practices in 106 hospital locations in the Netherlands were asked to look for patients with the codes 'other neurological infections' or 'Borrelia burgdorferi' in their Diagnosis & Treatment Combinations registration or the Neurological Coding System, respectively, concerning the year 2001, then to identify the patients with neuroborreliosis and to send a copy of the correspondence with the family doctor and the laboratory data on these patients, after making them anonymous, for data extraction. Pleocytosis in the cerebrospinal fluid combined with a positive test for IgM or IgG antibodies of B. burgdorferi in the serum or cerebrospinal fluid was used as the criterion for the diagnosis neuroborreliosis. RESULTS: Forty-seven (44%) neurological practices did not respond and twenty-two (21%) either did not use any kind of diagnosis registration system or linkage between the registration and the patient file was impossible. Of the 37 (35%) neurological practices that provided information, 17 had diagnosed neuroborreliosis in 30 patients, 20 of whom met the specified criteria. Fifteen (75%) patients had a radiculopathy, 8 (40%) a peripheral facial palsy and 3 (15%) a myelopathy. CONCLUSION: The clinical spectrum of patients with neuroborreliosis was consistent with that described in Denmark. The incidence of neuroborreliosis found was 3.6 per million inhabitants. The real incidence was probably higher because the registration systems used allowed patients with neuroborreliosis to be booked under other (symptomatic) diagnostic codes, paediatricians were not involved in the study, and relatively few participating neurologists practiced in high-risk areas for tick bites and erythema migrans. The low incidence of neuroborreliosis in combination with a high background level of seropositivity in the population implies a low predictive value of positive Borrelia serology. It is therefore essential that when neuroborreliosis is suspected, the cerebrospinal fluid should always be investigated.
In all three stages, Lyme borreliosis offers a wide range of possible differential diagnoses: even the "typical" erythema chronicum migrans may present as erysipelas, erysipeloid, erythema annulare centrifugum or a drug-induced exanthema. In the advanced stages II and III, neuroborreliosis in particular may be mimicked by various other conditions of both infectious and noninfectious etiology. Major examples are CEE (Central European Encephalitis), ehrlichiosis, chlamydial infections and multiple sclerosis. Currently, the biggest diagnostic problem is the non-standardized laboratory diagnostic work-up. For this reason, even in the presence of a positive or borderline IgG antibody result, unclear symptoms should prompt a differential diagnostic investigation.
Division of Pediatric Infectious Diseases, Department of Pediatrics, Schneider Children's Hospital of the North Shore-Long Island Jewish Health System, New Hyde Park, NY, USA.
We describe a previously healthy 11-year-old girl with acute neuroborreliosis, who presented with left sixth cranial nerve palsy, elevated intracranial pressure, markedly elevated cerebrospinal fluid leukocyte count and protein concentration and severe hypoglycorrhachia. These laboratory findings are atypical for neuroborreliosis.
Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging, Via Conte Ruggero 73, I-94018 Troina (EN), Italy. email@example.com
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.
Department of Clinical Biochemistry, Hospital Homolka, 150 30 Prague, Czechia.
Levels of most of the examined proteins in cerebrospinal fluid (CSF) of 107 patients with neuroborreliosis were associated with cytological findings, the status of hematoencephalic barrier as evaluated by Qalb (cerebrospinal fluid to serum quotient) and the intrathecal synthesis of immunoglobulins. Cytological findings consisted of normal cytology, or both oligocytosis and pleocytosis of monocytes or lymphocytes. The lipophagic elements were present in 20% of samples. Concentrations of apolipoproteins A-I and A-II in the CSF were correlated with the concentration of albumin without regard to the CSF cytology. The levels of apolipoprotein B were increased only in samples with lymphocytic pleocytosis and Qalb > 7.4. The presence of lipophages in the CSF was significantly associated with the CSF concentration of apolipoprotein A-II.
PMID: 15058201 [PubMed - indexed for MEDLINE]
144: Eur Radiol. 2004 Nov;14(11):2072-5. Epub 2004 Mar 27.
Institute of Neuroradiology, University of Frankfurt, Schleusenweg 2-16, 60528 Frankfurt, Germany. firstname.lastname@example.org
The central nervous system is involved in 10-20% of cases in Lyme disease. The neurological symptoms, time course of the disease and imaging findings are multifaceted. We report two patients with cervical radiculitis. Magnetic resonance imaging revealed strong enhancement of the cervical nerve roots on contrast-enhanced T1-weighted images. These imaging patterns of borrelia-associated radiculitis have not been reported before. Knowledge of these imaging features may help to diagnose neuroborreliosis, which presents with non-specific symptoms.
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. email@example.com
Borrelia burgdorferi antibodies preferentially present in cerebrospinal fluid (CSF) were examined by differentially probing a B. burgdorferi expression library with CSF and sera from patients with neurologic Lyme disease. Several phage clones selectively reacted with CSF, and these genes were then expressed in recombinant form and used to detect specific antibody in an enzyme-linked immunosorbent assay. Decorin-binding protein B (BBA25) and BBA50 (hypothetical protein) elicited immunoglobulin G (IgG) or IgM detectable in CSF-but not sera-of patients, demonstrating preferential antibody production during neuroborreliosis.
Department of Neuroradiology, Racliffe Infirmary, Oxford, OX2 6HE, UK. firstname.lastname@example.org
Early diagnosis of cranial sepsis is mandatory if morbidity is to be avoided. In the case of structural integrity of the skull, haematogenous spread or extension from adjacent structures, especially the sinuses, are the most common sources of infection. Infections may be limited to compartments by the meninges or spread diffusely. Focal disease includes brain abscess as well as subdural and extradural empyaema. A history or signs of sinus disease should always be sought. Tuberculosis, lyme disease and listeriosis may present specific pathological findings. A series of cases is presented to illustrate the role of imaging in infective disease and to draw attention to diagnostic and management points of which radiologists should be aware.
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.
Klinika Chorb Zakanych Uniwersytetu Medycznego w üodzi.
OBJECTIVE: Epidemiologic, etiologic and clinical assessment of patients with aseptic encephalomeningitis (AE); evaluation of efficacy of diagnostic process. METHODS: From January 1996 to August 2002, in seventy seven patients AE was diagnosed on the basis of lymphocytic predominance in cerebrospinal fluid (CSF) and negative culture of CSF. Analysis comprised: etiology, course of the disease and spectrum of used diagnostic tests. RESULTS: In 48/77 patients (62.3%) etiology was not identified. In 8/77 patients (10.3%) herpes simplex encephalitis was diagnosed, in 7/77 (9.1%) neuroborreliosis, in 6/77 (7.8%) tuberculosis encephalitis, in 3/77 (3.9%) listerial meningitis, in 3/77 (3.9%) mumps meningitis, and in remaining 2/77 (2.6%) tick-borne encephalitis. The incidence of AE was higher in summer (42.9%) than in any other season. In 14/77 patients (18.2%) the episode of unconsciousness occurred in the course of the disease. In 6 of these 14 patient etiology was unknown, in 4 tuberculosis AE, in 2 herpes simplex encephalitis and in 2 neuroborreliosis was diagnosed. In 7 of 77 patients (9.0%) et least one episode of convulsions occurred. CONCLUSIONS: In 62.3% of patients etiology remained unknown due to clinical and economic reasons. Aseptic encephalomeningitis in adults not always mean the viral etiology and mild course of the disease.
Department of Radiology, Medical Academy, Bialystok, Poland. email@example.com
We report results of a magnetic resonance spectroscopy (MRS) study in 12 patients with neuroborreliosis. We used a PRESS sequence, placing an 8 cm3 voxel in normal-appearing white matter of the frontal lobe. Peaks indicating N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), lipids (Lip) and lactate (Lac) were identified and ratios of NAA/Cr, Cho/Cr, mI/Cr, Lip/Cr, Lac/Cr calculated. Significant increases in Cho/Cr and Lip/Cr were noted. No abnormality was found in mean NAA/Cr and Lac/Cr, but in four patients there was a decreased NAA peak; mI/Cr ratio was slightly increased. Although the spectroscopic profile in patients with neuroborreliosis seems to be nonspecific, MRS might be useful for assessing tissue damage of the central nervous system.
Division of Clinical Immunology, Department of Molecular and Clinical Medicine, University of Linkping, Linkping, Sweden. Christina.Ekerfelt@imk.liu.se
The immuno-pathogenetic mechanisms underlying chronic Lyme neuroborreliosis are mainly unknown. Human Borrelia burgdorferi (Bb) infection is associated with Bb-specific secretion of interferon-gamma (IFN-gamma), which may be important for the elimination of Bb, but this may also cause tissue injury. In order to increase the understanding of the pathogenic mechanisms in chronic neuroborreliosis, we investigated which cell types that secrete IFN-gamma. Blood mononuclear cells from 13 patients with neuroborreliosis and/or acrodermatitis chronicum atrophicans were stimulated with Bb antigen and the phenotypes of the induced IFN-gamma-secreting cells were analyzed with three different approaches. Cells expressing CD8 or TCRgammadelta, which both have cytolytic properties, were the main phenotypes of IFN-gamma-secreting cells, indicating that tissue injury in chronic neuroborreliosis may be mediated by cytotoxic cells.
Haartman Institute, Dept. of Bacteriology and Immunology, University of Helsinki, 21, 00014, Helsinki, Finland. firstname.lastname@example.org
Three recombinant antigens, decorin binding protein A (DbpA), BBK32, and outer surface protein C (OspC), and IR(6) peptide of borrelial VlsE protein, were evaluated for the diagnosis of neuroborreliosis (NB), using cerebrospinal fluid (CSF) and serum samples from 89 patients. Their performances in enzyme-linked immunosorbent assay (ELISA) were compared with that of commercial flagella antigen. IgG ELISAs were performed with three variants of each recombinant antigen originating from Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii, and with the IR(6) peptide. IgM antibodies were analysed against OspC and flagella. Of the patients whose CSF contained elevated anti-flagella IgG antibodies, 93% were positive for at least three of the new antigens. Of those with negative or borderline CSF anti-flagella antibodies, 51% were positive for three new antigens. Antibodies to BBK32 were detectable mainly in early disease. Antibodies to DbpA and IR(6) were observed in early and late NB. The use of the new antigens at presentation of the disease improved the laboratory diagnosis of NB. In IgG ELISAs, the diagnostic sensitivity of assays with the new antigens was between 75 and 88%, but was only 52% with the flagella antigen. The discriminatory power between patient and control samples appeared better in the CSF than in the serum. We suggest that assessment of CSF antibodies to at least two antigens, using either flagella and one of the new antigens or two of the new antigens, would improve the current diagnostic yield of NB.
Antibiotic treatment--usually stage-dependent in terms of the active agent, duration and form of application--is the central pillar in the management of Lyme disease. In the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment. In this phase, borreliosis-typical neuropathy and neuralgia, chronic fatigue and neuropsychological deficits predominate. Irrespective of whether renewed antibiotic treatment is indicated or not, symptomatic treatment must be continued.
Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, Dluski District Specialized Hospital, ul. Zurawia 14, 15-540 Bialystok, Poland. email@example.com
BACKGROUND: Apoptosis plays an important role in the control of the immune system, and its impairment may be associated with autoimmune responses. Different bacterial and viral pathogens interfere with the regulation of apoptosis. This may take place in Lyme borreliosis, in which pathological autoimmune reactions are likely to occur. MATERIAL/METHODS: A study group consisted of 15 patients with erythema migrans (group I), 15 with Lyme arthritis (group II) and 9 with neuroborreliosis (group III); the control group consisted of 10 healthy subjects. The concentrations of the factors involved in apoptosis regulation--transforming growth factor-beta1 (TGF-beta 1), soluble Fas (sFas), soluble Fas ligand (sFasL) and protein bcl-2--were measured in serum before (examination 1) and after (examination 2) four weeks of antibiotic treatment. RESULTS: The mean concentration of sFas was significantly higher in all study groups compared to controls in examination 1 and 2, and showed a tendency to increase during treatment. The concentration of sFasL was significantly increased in groups II and III in examination 1. The concentration of bcl-2 was elevated significantly in all groups in examination 1 and dropped during treatment, remaining significantly increased in group I. The concentration of TGF-beta 1 was not significantly elevated except for group II in examination 2. CONCLUSIONS: The concentrations of soluble factors involved in the regulation of apoptosis were increased in serum of patients with different forms of Lyme borreliosis. Further studies are necessary to confirm if inappropriate apoptosis of immune cells may contribute to the pathogenesis of Lyme disease.
Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Universittsklinikum Charit, Berlin.
AIM OF THE STUDY: Only little is known about the epidemiology of Lyme borreliosis in Germany. As an example, it is still unclear if there are regional differences in the incidence of Lyme disease in general or of certain clinical manifestations like Lyme arthritis. Moreover, standardization of diagnostic or therapeutic procedures does not exist. Therefore, a Germany-wide questionnaire-based survey was conducted in order to achieve more epidemiological data and to obtain more information about the diagnostic and therapeutic approaches of general practitioners and specialists. METHODS: A self-designed questionnaire was distributed along with two editions of the journal "Deutsches Arzteblatt" (which is delivered to every physician in Germany) and additionally by a pharmaceutical company. During the collection period from March 1, 1998 to February 28, 1999, patients with Lyme disease were reported and information was given about site of infection, diagnostic procedures, clinical symptoms, treatment, and outcome. RESULTS: Altogether 3935 patients were reported. Their mean age was 43.4 years with the peak incidences around the ages of 10 and 60 years. 37.3% of the questionnaires were sent in by general practitioners, 17.6% by dermatologists, 15.7% by pediatricians, 9.7% by internists, and 2.7% by neurologists. 83% of the patients did not have a special infecion risk. The most frequent clinical Lyme manifestation was erythema migrans (EM), which occurred in 50.9% of the patients. 21.3% suffered from general symptoms. Of special interest, 24.5% of the patients had Lyme arthritis (14.7% mon- or oligoarthritis, 9.8% polyarthritis). Therefore, arthritis was more frequently reported than neuroborreliosis (18.4%). Only 16% of the neuroborreliosis patients and 32% of the arthritis patients remembered having had an EM. 189 patients (4.8%) with lymphadenosis cutis benigna and 100 patients (2.5%) with acrodermatitis chronica atrophicans were reported. In 80.4% of the patients, positive Lyme serology was detected. In a few cases, the diagnosis was established by isolation of borreliae, PCR or histology. 3754 patients were treated by antibiotics. The most frequently used compounds were doxycycline (50.4%), followed by ceftriaxone (22.4%), amoxicillin (13.6%), penicillin (7%), and erythromycin (4.2%) with differences depending on clinical manifestations and specialization of the prescribing physician. In less than 10% of the cases, not evaluated or recommended therapeutic procedures were performed. DISCUSSION: Lyme disease is endemic throughuot Germany. The most frequent manifestations are EM, followed by Lyme arthritis and neuroborreliosis. Less than one third of patients suffering from disseminated or chronic Lyme disease remembered an EM. Most of the physicians taking part in this survey follow treatment recommendations concerning choice of antibiotics and treatment durations.
INTRODUCTION: Central nervous system manifestations represent 0.54 to 8% of neurological complication in Lyme disease. OBSERVATION: A 78-year-old woman presented a severe meningo-encephalitis with visual disorders (agnosia, alexia) progressing towards coma. Cranial magnetic resonance imaging revealed large areas of hypersignal T2 in the white matter of the lower, parieto-occipital lobes and left temporal lobe. The cerebrospinal fluid (CSF) contained 16 then 293 white corpuscles/mm3 of lympho-monocytes, increased protein level from 2.67 to 5.83 g/l and an increase in IgG index with oligoclonal distribution of IgG. Serological Elisa analysis for Lyme disease was slightly positive in blood (confirmed by western blot) but clearly in the CSF (IgG and IgM). Treatment with ceftriaxone followed by methylprednisolone provided clinical improvement 3 months later. DISCUSSION: Acute meningo-encephalitis is often benign, protein-like and of good prognosis: the gnosic visual disorders with posterior leukoencephalopathy are unusual. A blood level of specific antibodies slightly positive on Elisa at the early stage of the infection warrants confirmation by Western blot in the blood and by Elisa in the CSF. Additional corticosteroid therapy may be required in the severe forms that evoke acute disseminated encephalomyelitis.
Klinika Chorob Zakaznych Wieku Dzieciecego, Akademia Medyczna, ul. Wolska 37, Warszawa, Poland.
Lyme Disease (Borreliosis) is a multisystem inflammatory disease caused by the spirochete Borrelia burgdorferi, transmitted by the bite of ixodes infected ticks. We would like to present our experience with the treatment of borreliosis in collaboration with the Warsaw Medical Academy's Department of Infectious Disease. Fifty-nine children (aged between 14 months to 16 years) were hospitalized or ambulatory treated due to borreliosis during 5 years between 1997 and 2001. Erythema migrans was observed in 50 cases. The main localisations of erythema were: face, neck and chest. One patient showed erythema in several other localisations. Erythema migrans returned in two cases after therapy with Amoxicillin in one case at 6 months, in the other one 12 months later. The incubation period of erythema migrans in children varied from 4 to 30 days. Seven cases from the 59 occurred with central nervous system manifestations. These were children between 6 and 16 years of age. The most frequent (65.5%) clinical manifestations of the central nervous system were meningitis and facial nerve palsy, depression and headaches were observed in 6% of cases. In one case admission to hospital was the result of leucopaenia (2800/mm3), bradycardia, headache and fatigue. The positive serologic test results (Elisa assay) were confirmed in two independent laboratories. We had one patient (5 years old boy) with arthritic manifestations. The diagnosis of Lyme disease was based on clinical manifestations and positive serologic test results (Elisa assay). In the acute stage Elisa assay was positive in 33% only. The erythema migrans cases received treatment with Amoxicillin for two weeks, whilst patients with neuroborreliosis were treated for 4 weeks with Ceftriaxon.
HPL, Ltd., Microbiological Laboratory, Bratislava, Slovakia. firstname.lastname@example.org
BACKGROUND: Neuroborreliosis affects peripheral and central nervous system. OBJECTIVES: Point out on possibilities of laboratory diagnostics of neuroborreliosis. SUBJECTS AND METHODS: During 1997-2001 we tested 666 pair samples of CSF and serum from 661 patients with different neurological diagnosis by ELISA, Westernblot, PCR, completed by biochemical and cytological investigations. RESULTS: We confirmed intrathecal specific IgG antibodies production by AI in 14 cases (2.1%) of total 666 samples tested. From those in 7 cases there were present also IgM antibodies in CSF. We found borderline AI values in 3 cases (0.5%) and isolated intrathecal production, antibodies present only in CSF, in 1 case (0.15%). There were normal AI values found in 25 cases (3.8%). Specific antibody possitivity by WB method was detected only in one case. DNA positivity by PCR was detected in one CSF from 43 samples during 2 years period. CONCLUSIONS: The microbiological test results should not be used in isolation but used in correlation with the biochemical and cytologic tests and also with clinical symptoms and epidemiological data to produce an overall clinical diagnosis. (Tab. 7, Fig. 1, Ref. 21)
Department of Medicine, California Pacific Medical Center, 450 Sutter Street, Suite 1504, San Francisco, CA 94108, USA. email@example.com
Musical hallucinations are poorly understood auditory hallucinations that occur in patients with otologic or neurologic diseases. We report the first cases of musical hallucinations in two patients with neurologic Lyme disease. Both subjects were women with clinical and laboratory evidence of chronic Lyme disease, progressive neurologic dysfunction, and abnormal magnetic resonance imaging of the brain. There was no evidence of hearing loss in either case. Musical hallucinations had a sudden onset and took the form of patriotic or operatic music. The auditory hallucinations disappeared with intravenous (i.v.) antibiotic therapy in both patients, but the hallucinations recurred when i.v. antibiotic therapy was discontinued in one case. Response to therapy was accompanied by an increase in the CD57 lymphocyte subset in one patient, whereas recurrent hallucinations were associated with persistently low CD57 levels in the other case. We conclude that musical hallucinations may be associated with neurologic Lyme disease. These auditory hallucinations appear to respond to i.v. antibiotic therapy. Patients with musical hallucinations of unknown cause should be tested for infection with the Lyme disease spirochete.
Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA 70433, USA.
Brain invasion by Borrelia burgdorferi, the agent of Lyme disease, results in an inflammatory and neurodegenerative disorder called neuroborreliosis. In humans, neuroborreliosis has been correlated with enhanced concentration of glial fibrillary acidic protein in the cerebrospinal fluid, a sign of astrogliosis. Rhesus monkeys infected by us with B. burgdorferi showed evidence of astrogliosis, namely astrocyte proliferation and apoptosis. We formulated the hypothesis that astrogliosis could be caused by spirochetal lipoproteins. We established primary cultures of rhesus monkey astrocytes and stimulated the cells with recombinant lipidated outer surface protein A (L-OspA), a model B. burgdorferi lipoprotein, and tripalmitoyl-S-glyceryl-Cys-Ser-Lys(4)-OH (Pam(3)Cys), a synthetic lipopeptide that mimics the structure of the lipoprotein lipid moiety. L-OspA elicited not only astrocyte proliferation but also apoptosis, two features observed during astrogliosis. Astrocytes produced both IL-6 and TNF-alpha in response to L-OspA and Pam(3)Cys. Proliferation induced by L-OspA was diminished in the presence of an excess of anti-IL-6 antibody, and apoptosis induced by this lipoprotein was completely suppressed with anti-TNF-alpha antibody. Hence, IL-6 contributes to, and TNF-alpha determines, astrocyte proliferation and apoptosis, respectively, as elicited by lipoproteins. Our results provide proof of the principle that spirochetal lipoproteins could be key virulence factors in Lyme neuroborreliosis, and that astrogliosis might contribute to neuroborreliosis pathogenesis.
Patients with borreliosis caused by exodic tick infestation running with affection of the nervous system were exposed to scanning EHF-therapy (59-63 GHz) on biologically active zones of the upper third of the chest, right brachial joint, biologically active points GI4, E36. Also, they took radon baths. The treatment was planned with consideration of the principles of chronotherapy. This therapeutic approach produced stimulation of general adaptive reactions and reparative processes in the peripheral nervous system.
Zakladu Biologicznych Szkodliwoæci Zawodowych, Instytutu Medycyny Wsi w Lublinie. firstname.lastname@example.org
The objective of the study was to evaluate the incidence of tick-borne encephalitis virus and Borrelia burgdorferi infections in farmers of the Lublin province. The study involved sero-epidemiological examinations of 242 farmers (the study group) and 50 healthy urban blood donors (the control group). In both tick-transmitted diseases, the frequency of sero-positive reactions was significantly higher in farmers than in controls. Serological examinations for the detection of tick-borne encephalitis showed 17.3% of positive results among farmers, and only 6.0% (p < 0.05) in the control group. The presence of specific antibodies IgG against Borrelia burgdorferi was observed in 15.3% of the farmers versus 4.0% (p < 0.05) in controls. In the IgM class, 14.0% of farmers showed positive reactions to B. burgdorferi, while in the control group no sero-positive reactions were noted (p < 0.01). The results of the study indicate that farmers are at increased risk of infection with zoonotic tick-transmitted diseases.
Departments of Neurology and Neuroradiology, Mount Sinai School of Medicine, New York, New York, USA. email@example.com
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.
Stony Brook University, Department of Pediatrics, Stony Brook, NY 11794-8111, USA. Sharon.Nachman@stonybrook.edu
Lyme disease is a disease caused by the spirochete, Borrelia burgdorferi. It is transmitted to humans via a bite from an infected tick. It has several classic stages or categories of illness, including early localized disease, early disseminated disease, and late disease. The focus of this article is on the manifestations, diagnosis, and treatment of Lyme disease of the central nervous system. Copyright 2003 Elsevier Inc. All rights reserved.
Department of Neurology, North Shore University Hospital, 300 Community Drive, Manhasset, New York 11030, USA. firstname.lastname@example.org
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.
Department of Neurology, Stony Brook University Medical Center, Stony Brook, NY 11794-8121, USA. email@example.com
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.
University of Connecticut School of Medicine, Farmington, USA. firstname.lastname@example.org
BACKGROUND: It is controversial whether additional antibiotic treatment will improve cognitive function in patients with post-treatment chronic Lyme disease (PTCLD). OBJECTIVE: To determine whether antibiotic therapy improves cognitive function in two randomized double-blind placebo-controlled studies of patients with PTCLD. METHODS: A total of 129 patients with a physician-documented history of Lyme disease from three study sites in the northeast United States were studied. Seventy-eight were seropositive for IgG antibodies against Borrelia burgdorferi, and 51 were seronegative. Patients in each group were randomly assigned to receive IV ceftriaxone 2 g daily for 30 days followed by oral doxycycline 200 mg daily for 60 days or matching IV and oral placebos. Assessments were made at 90 and 180 days after treatment. Symptom severity was measured from the cognitive functioning, pain, and role functioning scales of the Medical Outcomes Study (MOS). Memory, attention, and executive functioning were assessed using objective tests. Mood was assessed using the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory. RESULTS: There were no significant baseline differences between seropositive and seronegative groups. Both groups reported a high frequency of MOS symptoms, depression, and somatic complaints but had normal baseline neuropsychological test scores. The combined groups showed significant decreases in MOS symptoms, higher objective test scores, and improved mood between baseline and 90 days. However, there were no significant differences between those receiving antibiotics and placebo. CONCLUSION: Patients with post-treatment chronic Lyme disease who have symptoms but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo.
Division of Pediatrics, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, University Hospital, SE-581 85, Linkping, Sweden. email@example.com
OBJECTIVE: Acute facial palsy in children is believed to be a rather benign neurological condition. Follow-up-studies are sparse, especially including a thorough otoneurological re-examination. The aim of this study was to examine children with a history of facial palsy in order to register the incidence of complete recovery and the severity and nature of sequelae. We also wanted to investigate whether there was a correlation between sequelae and Lyme Borreliosis, treatment or other health problems. METHODS: Twenty-seven children with a history of facial palsy were included. A re-examination was performed by an Ear-Nose-Throat (ENT) specialist 1-2.9 years (median 2) after the acute facial palsy. The otoneurological examination included grading the three branches of the facial nerve with the House-Brackman score, otomicroscopy and investigation with Frenzel glasses. A paediatrician interviewed the families. Medical files were analysed. RESULT: The incidence of complete recovery was 78% at the 2-year follow-up. In six out of 27 children (22%), the facial nerve function was mildly or moderately impaired. Four children reported problems with tear secretion and pronunciation. There was no correlation between sequelae after the facial palsy and gender, age, related symptoms, Lyme neuroborreliosis (NB), treatment, other health problems or performance. CONCLUSION: One fifth of children with an acute facial palsy get a permanent dysfunction of the facial nerve. Other neurological symptoms or health problems do not accompany the sequelae of the facial palsy. Lyme NB or treatment seems to have no correlation to clinical outcome. Factors of importance for complete recovery after an acute facial palsy are still not known.
Department of Infectious Diseases, Sahlgrenska University Hospital/Ostra, SE-416 85 Gteborg, Sweden. firstname.lastname@example.org
Neurogenic pain with radiculitis is often the starting symptom in adult patients with tick-borne Lyme neuroborreliosis and in some cases the only clinical manifestation. Cranial paresis and other neurologic signs usually occur after the onset of pain. The present paper describes four patients who had severe pain as the main presenting symptom of Lyme neuroborreliosis. Opioids had good short-term effect in two of the cases. Oral doxycycline treatment was used successfully to eliminate the infection.
Universittsklinikum Charit, Medizinische Klinik m.S. Rheumatologie und Klinische Immunologie, 10098 Berlin, Germany.
Of the ten different species of Borrelia (B.) burgdorferi sensu lato which have been characterized to date, only B. burgdorferi sensu stricto, B. garinii and B. afzelii have been identified as pathogenic in humans. It was suggested that different species possess different organotropisms and may preferentially cause distinct clinical manifestations of Lyme disease. Molecular analyses revealed a strong association of B. afzelii with the late cutaneous manifestation acrodermatitis chronica atrophicans, whereas B. garinii was predominantly identified in clinical samples from patients with neuroborreliosis. PCR-based analyses of samples from European patients with Lyme arthritis had given controversial results, but B. burgdorferi sensu stricto appears to be the major pathogen. The identity of the infecting species seems to be a major determinant in the pathogenesis of Lyme arthritis, although its complex immunopathological background and its clinical heterogeneity clearly indicate concomitant factors. Thus, characterization of the infecting organism at the species level on the one hand and linkage of clinical data with pathogenetically relevant immune parameters on the other, shall lead to a more precise understanding of the pathogenesis and the individual clinical course of Lyme borrelioses.
BACKGROUND: Lyme disease has been described as one possible cause of sudden sensorineural hearing loss and vestibular neuronitis. The necessity of serological diagnosis and its therapeutic consequences have been discussed controversially. PATIENTS AND METHODS: 344 patients with acute sensorineural hearing loss and 66 patients with vestibular neuronitis were examined in retrospect. By means of ELISA (Enzygnost Borreliosis, Dade Behring Marburg) the specific prevalences of IgG- and IgM-antibodies against borrelia in serum were evaluated. The frequency of seroprevalences for both diseases were compared to those given in the literature. Neurootological findings of the seropositive patients were compared with those of seronegative and analysed statistically. RESULTS: 15.7 % of the patients with sudden sensorineural hearing loss had positive levels of IgG-antibodies. IgM-titers were elevated in 4.7 % of the patients. The seroprevalences for IgM and IgG were above those described by other investigators for the healthy population. Patients with positive IgM-antibodies showed more often low frequency hearing loss than IgG-positive patients. 18.2 % of the patients with neuronitis vestibularis had IgG- and 1.5 % IgM-antibodies against Borrelia. Whereas IgG occurred more often than known for the healthy population, IgM was within the limit for the healthy population. The seropositive group did not show any remarkable neurootological signs compared with the seronegative group. CONCLUSIONS: Because of the elevated seroprevalences Borrelia infections may be one possible but very rare cause of sudden sensorineural hearing loss and vestibular neuronitis. Low frequency hearing loss may be a sign for an infection with Borrelia as an etiological factor especially in combination with seropositive titers. In case of the presence of IgM-antibodies, patients may be treated with oral antibiotics (Doxycyclin, Cefuroxim). In patients with neuronitis vestibularis a neuroborreliosis should be excluded by means of lumbar puncture.
Neuroimmunology Unit, Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Italy.
The recruitment of lymphocytes across the blood brain barrier (BBB) is mediated by adhesion molecules and chemokines. The expression of activation markers and of chemokine receptors on T cells homing to the nervous system (NS) may help define their functional state. In the cerebrospinal fluid (CSF) of subjects with inflammatory neurological diseases (IND), including multiple sclerosis, we observed an increased number of T cells coexpressing CXCR3 and CCR5 as well as T cells with a CD45RO+ CCR7+ CD27+ memory phenotype. A subset of CCR7+ T cells coexpressed CXCR3 and CCR5. We also detected an increased number of interferon-gamma-producing T cells in the CSF compared with peripheral blood, mostly but not exclusively in the CD45RO+ CCR7- CD27- compartment. T helper 1 (Th1) clones, established from the CSF of individuals with IND and from a healthy subject, similarly migrated to CXCL10, CXCL12, and CCL5. CXCL10, CXCL12, and CCL19 were increased in the CSF of individuals with neuroinflammation. These findings suggest that CSF is enriched in Th1-polarized memory T cells capable of differentiating into effector cells upon antigen encounter. These cells are recruited into the CSF by inducible chemokines. Thus, CSF represents a transitional station for T cells trafficking to and from the NS.
We report a case of Lyme disease presenting as an oculomotor nerve palsy and meningitis. T1-weighted postcontrast magnetic resonance images showed marked enhancement of the right third, fifth and sixth nerves. This case illustrates neuroradiological features of cranial nerves during neuroborreliosis.
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.
Department of Paediatrics, Cliniques Universitaires de Mont-Godinne, Universit Catholique de Louvain, Mont-Godinne, 5530 Yvoir, Belgium. email@example.com
The purpose of this study was to characterise Lyme meningitis (LM) in a Belgian paediatric population and to suggest findings that could allow early distinction from aseptic meningitis (AM). The medical records of patients hospitalised between 1993 and 2000 and with a discharge diagnosis of LM (n=14) or AM (n=16) were retrospectively reviewed. The Kruskal-Wallis test was used to compare data. Of the patients, 16 were identified with AM and 14 with LM, amongst which 7 presented with isolated LM and 7 with associated peripheral facial palsy (PFP). Patients with AM, when compared with LM, complained of more pronounced signs and symptoms of meningitis (fever, headaches, and neck stiffness); they statistically displayed a shorter period of symptoms before admission (1.6 vs 15 days), higher neutrophilic component (mean 56% vs 2.4%), and lower protein levels (mean 0.39 vs 1.12 g/l) on cerebrospinal fluid analysis. In the neuroborreliosis group, the duration of symptoms was shorter and the cerebrospinal protein level was lower in cases of LM associated with PFP compared to isolated LM (mean 1.3 vs 15 days; mean 0.55 g/l vs 1.12 g/l). Conclusions.Our results suggest that some clinical data and laboratory findings may help the physician to diagnose aseptic or Lyme meningitis before completion of serologic testing. LM should be suspected in cases of meningitis with very low CSF neutrophilic counts and high protein levels associated with prolonged duration of symptoms, low grade fever, and absence of pronounced signs of meningitis.
Significant improvement of the recombinant Borrelia-specific immunoglobulin G immunoblot test by addition of VlsE and a DbpA homologue derived from Borrelia garinii for diagnosis of early neuroborreliosis.
Max von Pettenkofer-Institut fr Medizinische Mikrobiologie und Hygiene der Ludwig-Maximilians-Universitt Mnchen, D-80336 Munich, Germany. Bettina.Wilske@mvp-bak.med.uni-muenchen.de
We investigated whether the recombinant Borrelia Western blot test previously described (B. Wilske, C. Habermann, V. Fingerle, B. Hillenbrand, S. Jauris-Heipke, G. Lehnert, I. Pradel, D. Rssler, and U. Schulte-Spechtel, Med. Microbiol. Immunol. 188:139-144, 1999) can be improved by the addition of VlsE and additional DbpA and OspC homologues. By using a panel of sera from 36 neuroborreliosis patients and 67 control patients, the diagnostic sensitivity of the recombinant immunoblot test was significantly increased (86.1% versus 52.7%) without loss of specificity and was higher (86.1% versus 63.8%) than that of the conventional whole-cell lysate immunoblot test (U. Hauser, G. Lehnert, R. Lobentanzer, and B. Wilske, J. Clin. Microbiol. 35:1433-1444, 1997). Improvement was mainly due to the presence of VlsE and DbpA.
Service des maladies du Systme Nerveux et du Muscle, Hpitaux Universitaires, Strasbourg.
Lyme disease is a multisystemic disease caused by a spirochete, Borrelia Burgdorferi that is transmitted by ticks. A clinical diagnosis is easy when a tick bite is followed 3 weeks later by erythema migrans, than by involvement of nervous system, joints or heart. In case of neuroborreliosis, serological tests, performed in blood and cerebro-spinal fluid, support the diagnosis and patients recover rapidly with antibacterial treatments. However an accurate diagnosis remains sometimes problematic, especially distinction between a coincidental positive serologic test and a nervous system Lyme borreliosis which require antibiotics. Furthermore, the role of autoimmunity in the pathophysiology of late Lyme disease, antibiotic choice in early disease, duration of treatment, and utility of vaccination are discussed.
Klinika Chorb Zakanych i Neuroinfekcji AM w Bialymstoku.
AIM: The purpose of the study was to evaluate parameters of oxidoreductive system in serum and cerebrospinal fluid (CSF) of patients with neuroborreliosis. MATERIAL AND METHODS: The cases were 25 patients aged 21 to 64 (x = 42.3) hospitalized with diagnosis of neuroborreliosis. Activity of superoxide dismutase (Cu, Zn-SOD), glutathione reductase (GSSG-R), glutathione peroxidase (GSH-Px) and concentration of sulphydryl groups (-SH) and malondialdehyde (MDA) in serum and CSF were tested. The control group consisted of 10 patients with diagnosis of discopathy. An examination was performed twice: before and after treatment. RESULTS: Results of the study showed lack of stability in an oxidoreductive system during neuroborreliosis both in serum and in CSF. In CSF activity of SOD was increased while activity of GSH-Px and GSSG-R were decreased. Also concentration of -SH and lipid peroxidation products measured as MDA were increased. The increase of SOD, GSH-Px, GSSG-R activity and concentration of -SH and MDA in serum were detected. CONCLUSIONS: Disorders of an oxidoreductive system in CSF and serum during neuroborreliosis were observed. These changes persisted despite treatment and normalization of inflammatory CSF markers.
Division of Neuroradiology, Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, Germany.
We report a 57-year-old woman with neuroborreliosis presenting with headache, shoulder muscle pain and double vision. MRI demonstrated enhancement of the right third and sixth cranial nerves. A 3D MP-RAGE sequence was used to perform multiplanar reformations to show this more graphically. The patient was free of symptoms 1 month after completion of therapy, when thickening and contrast enhancement of the nerves were less pronounced.
Department of Otorhinolaryngology, Hospital das Clnicas and Faculdade de Medicina da Universidade de So Paulo, So Paulo, Brazil.
OBJECTIVES/HYPOTHESIS: Otolaryngological manifestations are common in Lyme disease, affecting up to 75% of patients. One of these symptoms is sudden deafness. Hearing loss has been frequently described in Lyme disease; on the other hand, titers seropositive for, the causal agent of this disease, have been found in almost 20% of cases of sudden deafness. No consensual information exists on the outcome of Borrelia-seropositive patients or on the importance of determining Borrelia antibody titers. The present study aimed to determine the prevalence of seropositivity for Borrelia in sudden deafness, describing clinical characteristics and outcomes. STUDY DESIGN: This was a prospective observational study. METHODS: Forty-seven consecutive patients with sudden deafness were enrolled in the study. Demographic data, the presence of tinnitus and vertigo, and low- and high-frequency pure-tone averages were recorded. The percentage of hearing recovery was determined. Data obtained from Borrelia-seropositive patients were described and compared with those from the seronegative group. RESULTS: Titers positive for antibodies were present in 21.3% of the cases. Seropositive and seronegative groups of patients were homogeneous concerning age, sex distribution, the presence of tinnitus and vertigo, and high- and low-frequency hearing thresholds. Hearing outcome was not significantly different between the groups of patients. CONCLUSIONS: No distinctive clinical characteristic was found between seropositive and seronegative subjects. The hearing outcome of treated Borrelia-seropositive patients was similar to that of the seronegative group.
Day Clinic of Cognitive Neurology, University of Leipzig, Germany. firstname.lastname@example.org
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.
BACKGROUND: There have been few large reports of the treatment and outcome of neuroborreliosis in children. METHODS: All 203 children with symptoms, cerebrospinal fluid and serologic findings compatible with neuroborreliosis and treated at one of the four pediatric hospitals in Stockholm from 1994 through 1996 were included. Children were treated with intravenous beta-lactam antibiotics or oral doxycycline for 10 days and followed until the resolution of symptoms. RESULTS: At the end of treatment 58% and after 2 months 92% of the children had no symptoms. Cerebrospinal fluid findings had no statistically significant influence on the outcome. Facial paralysis persisted longer than other symptoms. CONCLUSIONS: The prognosis of neuroborreliosis in children 2 months after treatment seems to be excellent with 10-day treatment regimens.
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
In this report we describe pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 (MCP-1) overexpression (PREMO), a novel animal model that exhibits features of human encephalopathic complications of inflammatory disorders such as viral meningoencephalitis and Lyme neuroborreliosis as well as the mild toxic encephalopathy that commonly precedes relapses of multiple sclerosis (MS). Overexpression of the mouse MCP-1 gene product (classically termed JE) in astrocytes, the major physiological CNS cellular source of MCP-1, failed to induce neurological impairment. Unexpectedly, transgenic (tg) mice overexpressing MCP-1 at a high level (MCP-1(hi)) manifested transient, severe encephalopathy with high mortality after injections of pertussis toxin (PTx) plus complete Freund's adjuvant (CFA). Surviving mice showed markedly improved function and did not relapse during a prolonged period of observation. Tg mice that expressed lower levels of MCP-1 were affected minimally after CFA/PTx injections, and tg expression of other chemokines failed to elicit this disorder. The disorder was significantly milder in mice lacking T-cells, which therefore play a deleterious role in this encephalopathic process. Disruption of CC chemokine receptor 2 (CCR2) abolished both CNS inflammation and encephalopathy, identifying CCR2 as a relevant receptor for this disorder. Proinflammatory and type 1 cytokines including TNF-alpha, IL-1beta, IFN-gamma, IL-2, RANTES, and IP-10 were elevated in CNS tissues from mice with PREMO. These studies characterize a novel model of reversible inflammatory encephalopathy that is dependent on both genetic and environmental factors.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, MD 20892-1400, USA. email@example.com
T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.
Division of Clinical Immunology, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, University Hospital, Linkping, Sweden.
Lyme neuroborreliosis is a complex disease with different clinical outcomes and where immunopathological mechanisms are probably involved. In this study, sera and cerebrospinal fluid (CSF) from 21 neuroborreliosis patients and 26 control patients were analyzed for the Th1-inducing cytokines, interleukin (IL)-12 and IL-18, and the Th2 associated, soluble CD30 (sCD30) by ELISA. The results showed an increased number of neuroborreliosis patients expressing IL-12 (p<0.05) and IL-18 (p<0.05) in the CSF when compared with the controls, but no indication of increased levels in the sera. Nor were there any differences regarding levels of sCD30 in the sera or the CSF, indicating a local Th1-generating milieu in the target organ of neuroborreliosis.
The limited information on co-infection with Borrelia burgdorferi sensu lato and tick-borne encephalitis (TBE) virus was a stimulus for presentation of two patients with well-defined double infection of the central nervous system. TBE virus and B. burgdorferi sensu lato infections are searched for in all patients with lymphocytic meningitis and/or meningoencephalitis admitted to our department. During the last ten years we identified two patients who had ELISA IgM and IgG antibodies to TBE virus in serum and a positive PCR result for TBE virus in cerebrospinal fluid as well as B. burgdorferi sensu lato isolated from cerebrospinal fluid. Intrathecal production of borrelial antibodies was not proven in either of the two patients. These findings show that in patients with acute lymphocytic meningitis originating in regions endemic for Lyme borreliosis and TBE, the possibility of concomitant infection should be considered.
Department of Bacteriology, National Institute of Hygiene, Warsaw, Poland. firstname.lastname@example.org
The aim of the study was to evaluate a one-step procedure using an ELISA test of high specificity and a two-step procedure using immunoblot as a confirmation test, and to compare the results of serological testing with detection of bacterial DNA and living spirochetes. Sera, synovial (SF) and cerebro-spinal fluids (CSF) were obtained from 90 patients with clinical symptoms of Lyme borreliosis. Serum samples were tested with recombinant ELISA and Western blot assay. Citrated blood, cerebrospinal and synovial fluids samples were cultured in cell line and tested by PCR to detect spirochetes. No correlation was found between levels of specific B. burgdorferi antibodies detected with a recombinant antigen ELISA and the number of protein fractions developed with these antibodies by immunoblot. Moreover, Lyme borreliosis patients who have live spirochetes in body fluids have low or negative levels of borrelial antibodies in their sera. This indicates that an efficient diagnosis of Lyme borreliosis has to be based on a combination of various techniques such as serology, PCR and culture, not solely on serology.
Institute of Microbiology and Immunology, Medical Faculty, Ljubljana, Slovenia. email@example.com
The aim of the study was to assess genotypic and phenotypic diversity among a large number of clinical isolates of Borrelia burgdorferi sensu lato obtained from patients in Slovenia. Plasmid profiles and species identification were determined by PFGE, protein profiles by SDS-PAGE. Of 706 B. burgdorferi sensu lato human isolates 599 (85%) were found to be B. afzelii, 101 (14%) B. garinii and six (1%) B. burgdorferi sensu stricto. The vast majority of strains (605; 86%) were isolated from skin, 58 (8%) from blood, and 43 (6%) from CSF. When analysed by RFLP, B. afzelii strains were unique, while heterogeneity was found within B. garinii and B. burgdorferi sensu stricto species. An unusual plasmid content was found in 52/706 (7%) isolated strains, more often in B. garinii than in B. afzelii strains. A plasmid dimer was found in B. afzelii and B. garinii strains, whereas multiple copies of the large plasmid were associated nearly exclusively with B. garinii strains. Analysis of protein profiles revealed that OspA and OspB are expressed more often by B. afzelii strains, and OspC by B. garinii strains. Heterogeneity of Borrelia strains may play a significant role in the virulence and pathogenesis of the infection. Differences in antigenic components have an important impact on serological testing and vaccine development.
Department of Neurology, University Hospital, Innsbruck, Austria. firstname.lastname@example.org
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.
Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia. email@example.com
BACKGROUND: Patients with non-specific long-lasting symptoms such as headache, concentration disturbances, and vertigo and who have positive serum borrelial antibody titres are often assumed to have chronic Lyme borreliosis. Because of the possibility that they may have central nervous system involvement they are frequently treated with courses of i.v. ceftriaxone. We assessed central nervous system involvement by examining cerebrospinal fluid samples in a group of such patients. PATIENTS AND METHODS: Adult patients who qualified for the study had non-specific symptoms suggesting central nervous system involvement for longer than six months (but without overt clinical signs of such involvement) and positive serum borrelial antibody titres and/or erythema migrans prior to the onset of symptoms. Cerebrospinal fluid was examined in all patients. RESULTS: None of the 77 patients included in the study (median duration of symptoms 18 months) had pleocytosis and there was no isolation of Borrelia burgdorferi sensu lato from cerebrospinal fluid. Mildly elevated protein concentration and intrathecal borrelial IgG antibody synthesis were demonstrated in 16 (21%) and 7 (9.1%) patients, respectively. CONCLUSIONS: In patients with non-specific long-lasting symptoms attributed to Lyme borreliosis but with the absence of overt clinical signs suggesting central nervous system involvement, the findings of cerebrospinal fluid examination are usually in the normal range. Routine treatment of such patients with i.v. ceftriaxone is not to be encouraged.
Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia. firstname.lastname@example.org
BACKGROUND: Serum and cerebrospinal fluid (CSF) procalcitonin levels were assessed and compared for different groups of patients with Lyme borreliosis. PATIENTS AND METHODS: 50 adult patients with Lyme borreliosis, referred to our department from March to June 2001, were included in this prospective study. Patients were divided into three groups. The first group consisted of 20 consecutive patients with typical solitary erythema migrans, representing early localised Lyme borreliosis, the second group comprised 20 patients with early disseminated Lyme borreliosis (10 with multiple erythema migrans and 10 with neuroborreliosis), and 10 patients with acrodermatitis chronica athrophicans represented the group with chronic Lyme borreliosis. Blood specimens were taken from all patients included in the study, but CSF samples were restricted to those with disseminated and chronic Lyme borreliosis. The serum and CSF procalcitonin levels were determined utilizing the LUMI PCT (an immunoluminometric assay using two antigen-specific monoclonal antibodies). RESULTS: Serum and CSF procalcitonin levels were in normal range in the large majority of patients. The levels of serum procalcitonin did not differ in the three groups of patients with Lyme borreliosis (p = 0.5006). The corresponding values for patients with solitary erythema migrans (early localised Lyme borreliosis), early disseminated Lyme borreliosis, and chronic Lyme borreliosis were 0.26 (0.11-0.43), 0.22 (0.10-0.67), and 0.28 (0.13-0.66) microgram/ml, respectively. Moreover, procalcitonin levels in CSF were also low and comparable for patients with multiple erythema migrans (median 0.38, range 0.24-0.54 microgram/ml), neuroborreliosis (median 0.16, range 0.10-0.47 microgram/ml), and acrodermatitis chronica athrophicans (median 0.30, range 0.15-0.45 microgram/ml). The differences were not statistically significant (p = 0.7579). CONCLUSIONS: In the large majority of patients with Lyme borreliosis procalcitonin values are within normal range. Serum and CSF procalcitonin levels are of no value for differentiation between early localised, early disseminated and chronic Lyme borreliosis.
Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia. email@example.com
OBJECTIVE: To establish eventual signs and symptoms suggestive for central nervous system involvement in children with multiple erythema migrans. METHODS: Patients younger than 15 years with multiple erythema migrans, diagnosed at our department from 1996 to 2000, were included in this prospective study. Demographic, clinical and laboratory findings were obtained and compared for a group of patients with pleocytosis (interpreted as a sign of central nervous system involvement) and a group of children with normal cerebrospinal fluid findings. RESULTS: Cerebrospinal fluid pleocytosis (cell counts > or = 5 x 10(6)/l) was detected in 55/214 (25.7%) children; it was lymphocytic in 94.5% of patients and ranged from 5 to 320 (median, 10 x 10(6)/l). Compared with the group with normal cerebrospinal fluid findings, patients with pleocytosis more often reported having had Lyme borreliosis in the past (8/55 versus 3/159; p = 0.0011), had longer incubation periods (25.5 versus 14 days; p = 0.0269), larger diameter of the largest erythema migrans at the time of first examination (10 versus 5.5 cm; p = 0.0055), higher frequency of associated systemic symptoms (45.5% versus 21.4%; p = 0.0011), positive meningeal signs (10.9% versus 1.9%; p = 0.0100), borrelial IgG antibodies in cerebrospinal fluid (3/49 versus 0/150; p = 0.0142) and B. burgdorferi s.l. isolated from cerebrospinal fluid (7/52 versus 1/147; p = 0.0004), but less often had mild initial disease (67.3% versus 88.7%; p = 0.0006). CONCLUSIONS: Cerebrospinal fluid pleocytosis was detected in 25.7% of children with multiple erythema migrans. Although several clinical and laboratory abnormalities were present significantly more often in patients with elevated cell counts than with normal cerebrospinal fluid findings, discriminatory significance for the majority of these abnormalities was low, particularly because of low negative predictive values. In more than 2/3 of patients with pleocytosis the initial disease was mild, fewer than 1/2 reported systemic symptoms, and meningeal signs were expressed in only 11%.
Charles University, Prague, First Faculty of Medicine, 3rd Department of Infectious and Tropical Diseases, Czech Republic. firstname.lastname@example.org
OBJECTIVE: The aim of this study was to analyze lymphocyte subset numbers in cerebrospinal fluid (CSF) from patients with tick-borne encephalitis (TBE) and acute neuroborreliosis. METHODS: CSF lymphocyte subsets were enumerated in 42 TBE and nine neuroborreliosis patients using flow cytometry. RESULTS: The CSF numbers of CD4+, CD8+, HLA-DR+ and total-T lymphocytes, B lymphocytes, and NK cells were all greater in neuroborreliosis patients than in TBE patients. Neuroborreliosis patients showed positive correlation of CSF protein levels with the numbers of CD4+, HLA-DR+ and total-T lymphocytes. Also, the numbers of CSF B lymphocytes correlated positively with intrathecal Borrelia burgdorferi-specific IgG antibodies. Conversely, TBE patients demonstrated intrathecal protein levels that correlated positively with all investigated CSF lymphocyte subsets. CONCLUSION: These results suggest an intensive recruitment of lymphocyte subsets into the central nervous system (CNS) during acute neuroborreliosis, whereas TBE is characterized by a lower accumulation of lymphocyte subsets in the CSF.
Department of Paediatrics, University of Lbeck Medical School, Germany. email@example.com
Neuroborreliosis is an infection of the nervous system caused by the spirochete Borrelia burgdorferi, from which patients most commonly develop lymphocytic meningitis, radiculoneuritis, or cranial neuropathy. In this report a 9-year-old male with an unusual neurological complication of neuroborreliosis--benign intracranial hypertension (BIH)--is described. Clinical symptoms of BIH, which consist of increased CSF pressure in the absence of an intracranial mass or obstruction to the circulation of CSF, resolved completely after antibiotic therapy with ceftriaxone.
Department of Biology, 9201 University City Boulevard, University of North Carolina at Charlotte, 28223, Charlotte, NC, USA.
Lyme disease has been associated with damaging inflammation within the central nervous system. In the present study, we demonstrate that Borrelia burgdorferi is a significant stimulus for the production of IL-6, TNF-alpha, and PGE(2) by microglia. This effect is associated with induction of NF-kappaB, and increased expression of Toll-like receptor 2 and CD14, receptors known to underlie spirochete activation of other immune cell types. These studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B. burgdorferi. Such production may play an important role during the development of Lyme neuroborreliosis.
Division of Clinical Immunology, Faculty of Health Sciences, University of Linkping, Sweden. firstname.lastname@example.org
The clinical outcome of the tick born infection Lyme borreliosis seems to be influenced by the type of immune response mounted during the disease, as suggested by various animal models. Here we report the serum and cerebrospinal fluid levels of tumour necrosis factor-alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1) and interleukin-6 (IL-6) in samples drawn at different disease intervals during the course of non-chronic neuroborreliosis (n=10), chronic neuroborreliosis (n=15), erythema migrans (n=8, serum only) and controls (n=7). When comparing early neuroborreliosis cerebrospinal fluid samples, significantly higher levels of TNF-alpha were found in non-chronic patients than in chronic patients (P<0.05). Moreover, TGF-beta1 was increased in the early serum samples of non-chronic patients, as compared to chronic patients (P<0.01). Elevated serum levels of TGF-beta1 were also found in erythema migrans as compared to neuroborreliosis and controls (P<0.05). The high TNF-alpha levels noted in early cerebrospinal fluid samples of non-chronic patients only, possibly reflects an ongoing pro-inflammatory immune response in the central nervous system, which could be beneficial in eliminating disease. High serum levels of TGF-beta1 probably mirror an anti-inflammatory response, which might play a role in controlling the systemic immune response.
Division of Neurology, University Hospital, Linkping, Sweden, Division of Neurophysiology, University Hospital, Linkping, Sweden. email@example.com
OBJECTIVES: The existence of chronic neuroborreliosis is controversial. The aim of our study was to investigate the existence and kind of persistent symptoms in patients previously treated because of neurological symptoms as a result of neuroborreliosis. MATERIALS AND METHODS: A total of 106 patients with neuroborreliosis, according to established criteria, and a control group of 123 patients with Borrelia induced erythema migrans diagnosed in a general practitioner office were studied. A questionnaire was sent to patients and controls concerning their health situation. Time from onset of neurological symptoms to the questionnaire send out was 32 months (mean) for the patients with neuroborreliosis and 33 months (mean) for the controls. RESULTS: Fifty per cent of the individuals in the patient group compared with 16% of the individuals in the control group showed persistent complaints after their Borrelia infection (P < 0.0001). The most significant differences between the groups were the presence of neuropsychiatric symptoms such as headache, attention problems, memory difficulties and depression. Paresthesia, pain and persistent facial palsy was also significantly more common in patients treated because of neuroborreliosis. CONCLUSION: Our study shows that persisting neurological symptoms are common after a neuroborreliosis infection. The pathological mechanisms that lay behind the development of chronic symptoms, however, are still uncertain.
BACKGROUND: Lyme borreliosis is a chronic, multisystem disease, of prolong course with three consecutive stages, caused by a tick-transmitted spirochete Borrelia burgdorferi. Tick Borne Encephalitis (TBE) is neuroinfection caused by Tick Borne Encephalitis Virus (TBEV). OBJECTIVE: We evaluated the occurrence of psychiatric manifestations in the early phase of borreliosis-erythema migrans and neuroboreliosis as well as in its late phase--in arthritis and in the Tick-Born Encephalitis. The aim of the study was to single out the most frequent psychiatric symptoms and psychopathological syndroms and to determine their dynamics. METHODS: The study was carried out between 1999 and 2000 and comprised 174 patients of the Department of Psychiatry and Department of Infectious and Neuroinfectious Diseases of Medical Academy in Bialystok. Seventy seven patients diagnosed with arthritis, 20 with neuroborreliosis, 26 with skin manifestation-erythrema migrans and 51 with KZM participated. All subjects underwent psychiatric evaluation twice--during hospitalization and six month after discharge. Mental status examinations included general psychiatric examination and battery of scales and tests: Mini Mental State Examination, Beck Depression Inventory, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Reitan's Trail Making Test, Choynowsky Memory Scale, Symptoms Inventory and neuropsychological testing. RESULTS: Both in the course of TBE and Lyme borreliosis the majority of patients experienced psychiatric problems in the acute phase of disease as well as in the late phase--3, 6 months after the onset of the disease. The most common psychiatric manifestations were depressive disorders--episodes of depression or organic mood disorders, and cognitive deficits which manifest themselves as mild cognitive disorder or dementia. CONCLUSION: Psychiatric assessment is important in early stage of kzm and borreliosis but first of all after termination of acute symptomatology.
Department of Community Medicine, Lund University, Malm, Sweden. firstname.lastname@example.org
The objective of this follow-up study was to determine the long-term outcome of strictly classified cases of neuroborreliosis treated with antibiotics. A 1-y prospective population-based survey of Lyme borreliosis was conducted in southern Sweden between 1992 and 1993. A total of 349 identified cases with suspected neuroborreliosis were followed up 5 y later. Medical records were reviewed and all participants filled in a questionnaire. Of those patients classified with definite neuroborreliosis, 114/130 completed the follow-up, of whom 111 had completed the initial antibiotic treatment. Of the 114 patients followed up, 86 (75%) had recovered completely and 70 (61%) had recovered within 6 months. Residual neurological symptoms, such as facial palsy, concentration disorder, paresthesia and/or neuropathy, were reported by 28/114 patients. No significant differences between different antibiotic treatments were observed in terms of the occurrence of sequelae. To conclude, we found that 25% (95% confidence interval 17-33%) of the patients suffered from residual neurological symptoms 5 y post-treatment. However, the clinical outcome of treated neuroborreliosis is favorable as only 14/114 (12%) patients had sequelae that influenced their daily activities post-treatment. Early diagnosis and treatment would seem to be of great importance in order to avoid such sequelae.
A case of a male patient with chronic Lyme borreliosis running with marked neurological symptoms (Garin-Bujardoux-Bannwarth syndrome) is reported. Two years before the disease manifestation the patient was infected by the tick with both borrelia and Rickettsia sibirica. The latter infection provoked an acute fever in tick-borne rickettsiosis immediately after the tick's bite. This masked development of Lyme borreliosis which manifested only 5 months later as a neurological disease. It is thought necessary to propose a rational scheme of antibiotic treatment of patients with tick-transmissible diseases.
Neurologische Abteilung, St. Josefs-Krankenhaus Potsdam. H.Kursawe@Alexius.de
Neurological manifestations are characteristic of stage 2 and stage 3 borreliosis. In stage 2, some 15% of the patients have neurological symptoms expressed as a triad of aseptic meningitis, cranial neuritis and radiculitis. Stage 3--chronic neuroborreliosis affects some 5% of untreated patients. The condition has its onset at the earliest 6 months after the infection, and is characterized by encephalopathic symptoms, such as fatigue, sleep and memory disturbances, and depressive states. Further manifestations of this stage may be Lyme polyneuropathy, in rare cases also progressive borrelia encephalomyelitis and cerebrovascular neuroborreliosis. The treatment of choice is intravenous administration of cephalosporins over 2-4 weeks. The success of treatment should be assessed on the basis of the clinical course rather than on laboratory results. Patience is required in the treatment of the post-Lyme syndrome, characterized by residual symptoms, recurrences or a relapsing course.
Department of Medical Microbiology, Dermatology and Infectious Diseases, Lund University, Sweden. email@example.com
The Lyme Borrelia genospecies Borrelia afzelii and B. garinii have previously been isolated using a culture method in Swedish patients with Lyme borreliosis (LB). There are reports suggesting that the genospecies distribution in human tissue specimens as determined by molecular methods is different from that obtained by culture. In the present study, we developed a nested PCR for detection of Lyme Borrelia-specific DNA in cerebrospinal fluid from Swedish patients with LB. The genospecies were subsequently identified by sequence analysis in a total of 7 PCR-positive patients. Two sequences were identified as B. burgdorferi sensu stricto (s. s.), 1 as B. afzelii and 4 as B. garinii. These are the first reported cases in which B. burgdorferi s. s. has been shown to be the causative agent of human LB in Sweden. The results of our study confirm that the use of direct molecular analytical methods for Borrelia genospecies identification in clinical specimens can provide epidemiological information additional to that obtained by culture.
Department of Ophthalmology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
PURPOSE: To report retrobulbar neuritis caused by Borrelia afzelii culturally proved from cerebrospinal fluid (CSF). METHODS: A 23 year old female underwent ophthalmologic, laboratory and other auxilliary examinations. RESULTS: CSF cultures grew spirochetal microorganisms, serotyped by monoclonal antibodies as Borrelia afzelii. Following the serological and cultural results, treatment with doxycycline 200 mg daily was started and kept for three weeks. Gradual improvement of the visual acuity of the right eye was observed with full recovery to 20/20. CONCLUSIONS: Borrelia infection should be considered in the differential diagnosis of retrobulbar neuritis. CSF should be examined also culturally. (Ref. 5.)
Department of Clinical Biochemistry, Statens Seruminstitut, Copenhagen, Denmark.
Lyme borreliosis caused by the spirochete Borrelia burgdorferi is now the most common vectorborne disease in North America, Europe and Asia. It is a multisystemic infection which may cause skin, neurological, cardiac or rheumatologic disorders. The aims of the present thesis were: (i) to develop a PCR assay for direct detection of B. burgdorferi DNA and to evaluate the diagnostic utility of PCR in clinical specimens from patients with Lyme borreliosis and (ii) to study the taxonomic classification of B. burgdorferi isolates and its implications for epidemiology and clinical presentation. Laboratory diagnosis of Lyme borreliosis by direct demonstration of B. burgdorferi in clinical specimens would compared to current serology allow (i) optimal specificity, (ii) increased sensitivity during the first weeks of infection, when the antibody response is not yet detectable and (iii) discrimination between ongoing and past infection. Due to the extreme paucity of spirochetes in clinical specimens neither in vitro culture nor antigen detection had yielded a sufficient diagnostic sensitivity. Thus the recently introduced highly sensitive PCR methodology could be a solution and was thus studied. Assays for PCR amplification and subsequent identification of B. burgdorferi specific sequences were established and used. For all assays the analytical sensitivity was a few genome copies using purified DNA as template. The efficacy of PCR was initially evaluated using tissue samples from experimentally infected gerbils in order to start with biological samples a priori known to contain B. burgdorferi. B. burgdorferi DNA was detectable in 88% of the specimens. Thus the diagnostic sensitivity of PCR was comparable to and even higher than in vitro culture. PCR was significantly more sensitive than a histological B. burgdorferi specific immunophosphatase-staining method. The utility of the PCR was then tested for identification of B. burgdorferi DNA in skin biopsies from 31 patients with erythema migrans. The sensitivity of PCR was 71%, which was superior to culture and serology. Based on own and otherwise published results there is clear evidence for PCR being the most sensitive and specific test for detection of B. burgdorferi in skin biopsies from patients with both early and late dermatoborreliosis. However, since the clinical diagnosis of dermatoborreliosis in most instances is easy, an invasive procedure as a skin biopsy, will only be justified in patients with an atypical clinical presentation. The most frequent and serious manifestation of disseminated Lyme borreliosis is neuroborreliosis. PCR was applied to 190 patients with untreated and confirmed neuroborreliosis. B. burgdorferi DNA was detectable in 17-21% of CSF samples from patients with neuroborreliosis. In patients with very early neuroborreliosis (< 2 weeks), still being negative for specific intrathecal antibody synthesis, a positive PCR was more frequent than in patients with longer disease duration. PCR can be used as a diagnostic aid in these patients. However, in general the measurement of specific intrathecal antibody production in patients with neuroborreliosis was superior to PCR. In urine samples from patients with Lyme borreliosis the diagnostic sensitivity varied, generally showing a low reproducibility. Urine is thus not regarded as a suitable sample source for B. burgdorferi PCR. The reason may be the variable presence of Taq polymerase inhibitors. Based on a semi-quantitative detection system for amplicons, reflecting the input amount of specific DNA and thus the density of spirochetes in the clinical samples high amounts of DNA were found in skin biopsies whereas especially in urine the amount of DNA was low. When the present study was initiated there was no accepted classification of B. burgdorferi. A heterogeneity among B. burgdorferi strains might have important implications for understanding the epidemiology and different clinical presentations (dermatoborreliosis versus neuroborreliosis) and courses (self-limiting versus chronic disease). Furthermore, strain differences were of importance for selection of suitable antigens for diagnostic assays and for vaccine development. Since then, B. burgdorferi isolates have been studied by phenotypic and genotypic traits and have been shown to be highly heterogeneous. Our first approach was to genotype a panel of human B. burgdorferi isolates by restriction fragment length polymorphism (RFLP) of three genes. Thereafter, sequencing and dideoxy fingerprinting of ospA was applied. By RFLP the strains could be differentiated into two to five groups. The RFLP classification was compared with four different phenotypic and genotypic methods including the rRNA typing. Results obtained with the different methods correlated highly and confirmed the meanwhile accepted taxonomic classification by Baranton et al., According to this the term B. burgdorferi sensu lato comprises three different human pathogenic genospecies B. burgdorferi sensu stricto, B. garinii and B. afzelii. All three genospecies have been isolated among Danish patients with Lyme borreliosis and are thus prevalent in Denmark. Since isolation of B. burgdorferi from patients with Lyme borreliosis is laborious and often unsuccessful molecular typing methods based on PCR are recommended obviating the need for isolation by prior culture. Of special interest was to study a possible association of neuroborreliosis to certain B. burgdorferi genospecies, indicating species depended organotropism. By RFLP all six CSF isolates tested belonged to B. garinii and that 6 out of 7 isolates from patients with acrodermatitis chronica atrophicans belonged to B. afzelii. Due to the low culture yield of B. burgdorferi from CSF, the association of B. garinii and neuroborreliosis was further studied by sequence analysis and dideoxyfingerprinting analysis of ospA PCR amplicons obtained from CSF samples from patients with neuroborreliosis. Phylogenetic analysis showed that in 11 out of 13 patients B. garinii DNA was found in CSF. These data strongly supports the hypothesis that B. garinii is the principal agent of Lyme neuroborreliosis in Europe. Similarly it was shown that B. afzelii is associated with acrodermatitis chronica atrophicans and thus dermatoborreliosis. Due to a strain dependent different selection pressure in culture only PCR based methods can be used to answer whether mixed infection in patients specimens occur. Our data indicate that mixed infections in humans if ever are rare.
Department of Neurology, School of Medicine, State University of New York, Stony Brook, Stony Brook, New York, USA. firstname.lastname@example.org
Lyme disease has emerged as a major infection with frequent neurologic manifestations. These manifestations probably reflect several predominantly indirect pathogenetic mechanisms and involve host, vector, and organism factors. With early diagnosis and appropriate antibiotic treatment, patients do well. Because culture is not reliable, diagnosis has relied on positive serology to document exposure. Serology should improve as second-generation assays become available. Although there is a preventive vaccine based on the lipoprotein OspA, newer vaccines in development may prove more desirable. Lyme disease provides a valuable model to study how infectious pathogens cause neurologic disease.
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University.
We report a 33-year-old man with bilateral facial paralysis due to neuroborreliosis. About three weeks after rhinorrhea and fever lasting four days, he noticed fatigue in the legs and paresthesia in all four extremities. Another week later, he developed paresthesia in his tongue and bilateral facial muscle weakness, and was admitted to our hospital. On admission, neurological examination revealed moderate bilateral facial muscle weakness, mild paresthesia in the tongue and four extremities, and decreased Achilles tendon reflex bilaterally. Mild pleocytosis and increased protein were found in the cerebrospinal fluid (CSF). IgM antibodies that reacted with the antigens of Borrelia garinii and Borrelia afzelii were found in his serum. Clinically and serologically, he was thus diagnosed as having neuroborreliosis. Brain MRI revealed gadolinium-enhanced lesions of the bilateral facial nerves in the facial nerve canal portion. After three weeks of treatment with 100 mg/day doxycycline and 2 g/day ceftriaxone sodium, his symptoms and CSF abnormalities were rapidly improved. Although facial nerve paralysis is a major symptom of neuroborreliosis, the present report is the first to detect the inflammatory lesions of the facial nerves in the facial nerve canal portion by MRI.
Neuroradiology Section, Department of Radiology, Charit Campus Mitte, Humboldt University Berlin, Germany. Randolf.Klingebiel@charite.de
We report on a 12-year-old, previously healthy girl with an acute hemiparesis as the predominant clinical manifestation of Lyme neuroborreliosis (LNB). The diagnosis of LNB was based on cerebrospinal fluid (CSF) studies, laboratory findings and the clinical course whereas the patient's history and the lack of characteristic skin lesions obscured the diagnosis in the beginning. After four weeks of antibiotic and physiotherapeutic treatment, the hemiparetic symptoms had completely resolved. Although evidence of vasculitic and perivascular inflammation in LNB has been described in the literature, large cerebral vessel occlusive disease represents a rare finding. Appropriate treatment strategies can lead to good clinical rehabilitation, as shown in this case, making the timely diagnosis a crucial issue. We conclude that LNB should be considered in every stroke-like episode of unknown origin in children, even in the absence of a history of a tick bite or typical skin lesions.
Kliniki Chorb Zakanych i Neuroinfekcji, Bialymstoku. email@example.com
Platelet counts and their morphologic parameters in patients with Lyme borreliosis before and after antibiotic therapy (4 weeks of treatment) were estimated. 30 patients aged 17-60, x = 41 were evaluated: 7 with Erythema migrans, 3 patients with neuroborreliosis in the from Lymphocytic meningitis and 20 ones with Lyme arthritis. Control group consisted of 19 healthy persons aged 34-52, x = 43. Hematologic analyser Coulter MAXM was used for testing PLT, MPV, PCT and PDW. The results indicated that patients with Lyme boreliosis have decreasing platelet count with simultaneously increasing their volume in comparison with healthy control. It may result from the involement of platelets in defense mechanisms of infected host. The decrease of platelet count after the antibiotic treatment in comparison with the control group may be the reflection of influence of antibiotic treatment on thrombopoesis.
Klinika Chorb Zakanych Wieku Dzieciecego Instytutu Chorb Zakanych i Pasozytniczych Akademii Medycznej w Warszawie.
OBJECTIVE: The aim of our analysis of causes of borreliosis in children hospitalized or ambulatory treated in the Clinic of Infectious Disease in Childhood of Medical University in Warsaw. METHODS AND MAIN OBSERVATIONS: We observed 113 children from 6 month to 15 years old. Erythema migrans was diagnosed in 97 cases and in 3 cases was multiple erytheme migrans. RESULTS AND CONCLUSIONS: Neuroborreliosis was diagnosed in 11 children. In the treatment neuroboreliosis the ceftriaxon and cristalline penicillin was administrated.
Departments of Psychiatry and Internal Medicine, Division of Consultation-Liaison Psychiatry, Medical College of Virginia, Campus of Virginia Commonwealth University, Richmond, Virginia, USA. firstname.lastname@example.org
Infectious diseases can cause an array of symptoms, including psychiatric symptoms. Psychiatrists serving the medically ill need to be aware not only of classic infectious diseases (e.g., neurosyphilis and HIV), but also of less commonly discussed infectious diseases (e.g., NCC, PANDAS, and Lyme disease). These examples represent an internationally endemic disease (e.g., NCC), a probable immunogenetic disease (e.g., PANDAS), and a frequently overdiagnosed and overtreated disease (Lyme disease).
Fdration de Neurologie Mazarin, Groupe Hospitalier Piti-Salptrire, Paris.
Meningo-radiculitis is the most common peripheral nerve system involvement of Lyme disease. We report the observation of a 73 year-old woman presenting a subacute multiple mononeuropathy and a severe inflammatory syndrome. Diagnosis of Lyme disease was confirmed by a lymphocytic meningitis with positive serologic results in the cerebrospinal fluid. Nerve biopsy showed inflammatory cells spreading along the endoneurium. This case report emphasizes that Lyme disease may present as a multiple mononeuropathy mimicking a vasculitic neuropathy.
Nevrologisk avdeling, Fylkessjukehuset i Molde 6407 Molde. email@example.com
BACKGROUND: The broad variations in the clinical manifestation in Lyme borreliosis underline the importance of laboratory investigations in serum and cerebrospinal fluid. MATERIAL AND METHODS: We have studied patients with neurological signs compatible with Lyme neuroborreliosis, pleocytosis in cerebrospinal fluid and positive Borrelia serology in serum/cerebrospinal fluid analysed by ELISA. We have evaluated clinical characteristics, laboratory parameters, treatment effects, and incidence variations. RESULTS: We included 25 patients in the study. Isolated facial palsy was often seen, but clinical manifestations showed huge variation. Fourteen of 25 (56%) patients had positive Borrelia burgdorferi-IgM and IgG titres in cerebrospinal fluid despite negative tests in serum. The mean annual incidence rate in the county judged by notified cases to the Norwegian Surveillance System for Communicable Diseases (MSIS) was 4.4/100,000 in the period 1989-99 as compared to the national rate of 4.3/100,000 in the same period. In 1998, however, the annual incidence rate in the county was 8.8/100,000 as compared to the national rate of 4.1/100,000. INTERPRETATION: The diversity of symptoms and signs suggests a liberal attitude towards serological testing including CSF analyses. M¿re and Romsdal is a high incidence region for Lyme borreliosis in Norway. The annual variation in incidence might reflect a changing prevalence of the tick vector along the Norwegian coastline.
Hospital for Children and Adolescents, University of Helsinki, Finland. firstname.lastname@example.org
The antigenic potential of decorin binding protein A (DbpA) was evaluated in serodiagnosis of human Lyme borreliosis (LB). The dbpA was cloned and sequenced from the three pathogenic Borrelia species common in Europe. Sequence analysis revealed high interspecies heterogeneity. The identity of the predicted amino acid sequences was 43 to 62% among Borrelia burgdorferi sensu stricto, B. afzelii, and B. garinii. The respective recombinant DbpAs (rDbpAs) were produced and tested as antigens by Western blotting and enzyme-linked immunosorbent assay (ELISA). One hundred percent of patients with neuroborreliosis (NB) and 93% of patients with Lyme arthritis (LA) reacted positively. Sera from the majority of patients reacted with one rDbpA only and had no or low cross-reactivity to other two variant proteins. In patients with culture-positive erythema migrans (EM), the sensitivity of rDbpA immunoglobulin G (IgG) or IgM ELISA was low. The DbpA seems to be a sensitive and specific antigen for the serodiagnosis of LA or NB, but not of EM, provided that variants from all three pathogenic borrelial species are included in the combined set of antigens.
Servicio de Neurofisiologa Clnica; Hospital Universitario Marqus de Valdecilla, Santander, 39008, Espaa. email@example.com
INTRODUCTION: Lyme disease, caused by spirochete Borrelia burgdorferi, is a multisystemic infectious disorder with prominent neurologic involvement, affecting both the peripheral and the central nervous system. Meningitis, cranial neuritis and radiculoneuritis are the usual manifestations in the acute phase, and peripheral neuropathy in the chronic phase. Other less common manifestations have been also described. Here we report one case of Lyme disease confirmed by PCR, with a previously undescribed neurological manifestation, and the neurophysiological studies performed before and after treatment. CLINICAL CASE: Our patient showed a chronic and progressive clinical picture consisting of instability on walking and distal paresthesia of lower limbs, suggestive of posterior column disfunction. The neurophysiological exam performed prior to treatment with ceftriaxone revealed bilateral absence of lower limbs somatosensory evoked potentials (SEPs), without alterations in the distal nervous conduction or in upper limbs SEPs. The exam performed after treatment revealed a partial recovery of lower limb SEP with presence of an evoked response in SEP of left lower limb, coincident with a transitory clinical improvement of paresthesia in the same extremity. CONCLUSIONS: Our findings reveal that posterior column disfunction can be a neurological manifestation of Lyme disease. Furthermore the neurophysiological study shows that this manifestation is partially reversible following treatment. Our study emphasize the importance of the neurophysiological tests for the diagnosis and follow up of neurological manifestations of Lyme disease.
Neurosciences, UMDNJ - New Jersey Medical School, Newark, NJ, USA.
Similarity of pathology and disease progression make the non-human primate (NHP) model of Lyme neuroborreliosis appropriate and valuable. In the NHP model of Lyme neuroborreliosis, spirochetal density in the nervous system and other tissues has been measured by polymerase chain reaction and correlated to anti-Borrelia burgdorferi antibody in the serum and cerebrospinal fluid and to inflammation in tissues. Despite the demonstrable presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, only minor inflammation of the central nervous system occurs, though inflammation can be demonstrated in other tissues. Infected animals also develop anti-Borrelia burgdorferi antibody in the serum, although increased amplitude of antibody is not predictive of higher levels of infection. The NHP model continues to provide important insight into the disease process in humans.
Division of Neurology, Karolinska Institute, Huddinge University Hospital R54, SE-14186, Stockholm, Sweden. Mikhail.Pashenkov@neurotec.ki.se
Dendritic cells (DC) accumulate in the CNS during inflammation and may contribute to local immune responses. Two DC subsets present in human cerebrospinal fluid (CSF) are probably recruited from myeloid (CD11c(+)CD123(dim)) and plasmacytoid (CD11c(-)CD123(high)) blood DC. In bacterial meningitis and especially in Lyme meningoencephalitis, numbers of myeloid and plasmacytoid DC in CSF were increased, compared to non-inflammatory neurological diseases, and correlated with chemotactic activity of CSF for immature monocyte-derived DC (moDC). Multiple DC chemoattractants, including macrophage inflammatory protein (MIP)-1beta, monocyte chemotactic protein (MCP)-1, MCP-3, RANTES and stromal cell-derived factor (SDF)-1alpha were elevated in CSF in these two neuroinfections. Chemotaxis of immature moDC induced by these CSFs could be partially inhibited by mAbs against CXCR4, the receptor for SDF-1alpha, and CD88, the receptor for C5a. SDF-1alpha present in CSF also chemoattracted mature moDC, which in vivo could correspond to a diminished migration of antigen-bearing DC from the CSF to secondary lymphoid organs. Regulation of DC trafficking to and from the CSF may represent a mechanism of controlling the CNS inflammation.
Cliniques Universitaires UCL de Mont-Godinne, Universit Catholique de Louvain, Yvoir, Belgium.
The authors report three cases of thoracic radiculoneuropathy disclosing neuroborreliosis. All three patients had low back and abdominal pain and two had marked abdominal wall paresis. EMG confirmed a motor involvement of the lower thoracic roots and CSF analysis revealed a lymphocytic meningitis in all three cases. Antibodies against Borrelia burgdorferi were present in both the serum and the CSF. A favourable outcome was obtained in all three patients with appropriate antibiotherapy. The differential diagnosis of this misleading presentation is discussed.
Department of Neurology, Albert Ludwig University, Freiburg, Germany. firstname.lastname@example.org
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.
Columbia University Department of Psychiatry, Division of Behavioral Medicine, New York, New York 10032, USA. email@example.com
Although neurologic Lyme disease is known to cause cognitive dysfunction in adults, little is known about its long-term sequelae in children. Twenty children with a history of new-onset cognitive complaints after Lyme disease were compared with 20 matched healthy control subjects. Each child was assessed with measures of cognition and psychopathology. Children with Lyme disease had significantly more cognitive and psychiatric disturbances. Cognitive deficits were still found after controlling for anxiety, depression, and fatigue. Lyme disease in children may be accompanied by long-term neuropsychiatric disturbances, resulting in psychosocial and academic impairments. Areas for further study are discussed.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1400, USA.
OBJECTIVE: To determine patterns of abnormalities on cerebral MRI that may characterize subgroups of patients with post-treatment Lyme disease syndrome (PTLDS) and to help identify pathomechanisms of disease. METHODS: The authors analyzed the distribution of cerebral lesions in a cohort of 27 patients with PTLDS. A subgroup of eight patients with PTLDS was further studied using whole-brain magnetization transfer ratio measures to identify abnormalities not seen on T2-weighted images. RESULTS: Four patients had focal neurologic deficits, relapsing-remitting disease, and lesions in a distribution typical of MS. Twenty-three patients presented with nonfocal symptoms such as fatigue, subjective memory deficits, and mood disturbance. Twelve of these patients had normal MRI, including the more sensitive fluid-attenuated inversion recovery sequence, 10 had primarily punctate and subcortical lesions, and one patient had multiple periventricular lesions. CONCLUSIONS: In a portion of patients with post-treatment Lyme disease syndrome, white-matter hyperintensities tend to occur in subcortical arteriolar watershed areas and are not specific. Magnetization transfer ratio analysis did not provide evidence for structural abnormalities of the brain parenchyma in patients with nonfocal disease.
Department of Otorhinolaryngology, Sahlgrenska University Hospital, Mlndal, Sweden.
The serum and cerebrospinal fluid (CSF) pathology of patients with sudden sensorineural hearing loss (SHL), both seropositive and seronegative to Borrelia burgdorferi (Bb), was prospectively studied. Nineteen consecutive patients were included and trends between the degree of hearing recovery and serum/CSF pathology and given therapy were examined. The pilot study showed a high prevalence (68%) of pathology in serum and CSF in patients with SHL. In 54% of the patients, elevated levels of CSF proteins and/or pathological CSF cell counts were present without positive antibodies to Bb. Positive levels of antibodies against Bb or pathological proteins in CSF were associated with better hearing recovery (means of 47.2 and 51.7%, respectively). The audiometric configuration "high frequency sloping" hearing impairment was associated with the lowest degree of hearing recovery. Patients with SHL and positive serology to Bb who received antibiotic treatment (oral tetracycline), with or without steroids, had the best hearing recovery in this study (61.7 and 48.4%, respectively). In conclusion, we found a high prevalence of serum and CSF pathology in a consecutive group of patients with SHL. Early appropriate antibiotic treatment may prevent the development of major late complications of Lyme disease/borreliosis. We also find it justified to perform more general serological analyses, including CSF analysis, in patients with SHL. A more liberal approach to testing and development of test protocols for SHL patients will increase our knowledge in this field.
Universitt Leipzig, Veterinrmedizinische Fakultt, Institut fr Immunologie, An den Tierkliniken 11, 04103, Leipzig, Germany. firstname.lastname@example.org
In an effort to develop a safe and effective vaccine for the prevention of Lyme borreliosis that addresses concerns raised over currently available vaccines, dogs were vaccinated twice with a multiantigenic preparation of Borrelia burgdorferi, strain N40, on days 0 and 20 of the experiment. About 70 and 154 days after the first immunization, dogs were challenged by exposing them to field-collected Ixodes scapularis ticks harboring B. burgdorferi. Vaccinated dogs were completely protected from infection by all criteria utilized to assess infection, developed high-titer anti-B. burgdorferi serum antibodies and growth inhibitory activity which persisted for over 200 days, and did not demonstrate any untoward consequence of vaccination. Serum absorption experiments revealed that borreliacidal and most likely protective antibodies in dogs receiving the multiantigenic preparation were not only elicited against the OspA antigen, but were also produced against additional yet to be determined targets on B. burgdorferi organisms. These data demonstrate that a multiantigenic vaccine is effective in preventing Lyme disease transmitted via the natural vector.
OBJECTIVES: To investigate Bartonella henselae as a potential human tick-borne pathogen and to evaluate its role as a coinfecting agent of the central nervous system in the presence of neuroborreliosis. DESIGN: Case report study. SETTING: A primary health care center in Flemington, NJ, and the Department of Research and Development at Medical Diagnostic Laboratories LLC in Mt Laurel, NJ. SUBJECTS: Two male patients (aged 14 and 36 years) and 2 female patients (aged 15 and 30 years, respectively) with a history of tick bites and Lyme disease. MAIN OUTCOME MEASURES: Laboratory and diagnostic findings before and after antimicrobial therapy. RESULTS: Patients residing in a Lyme-endemic area of New Jersey with ongoing symptoms attributed to chronic Lyme disease were evaluated for possible coinfection with Bartonella species. Elevated levels of B henselae-specific antibodies were found in these patients using the immunofluorescent assay. Bartonella henselae-specific DNA was detected in their blood. None of these patients exhibited the clinical characteristics of cat-scratch disease. Findings of cerebrospinal fluid analysis revealed the presence of both B henselae- and Borrelia burgdorferi-specific DNA. Bartonella henselae-specific DNA was also detected in live deer ticks obtained from the households of 2 of these patients. CONCLUSIONS: Our data implicate B henselae as a potential human tick-borne pathogen. Patients with a history of neuroborreliosis who have incomplete resolution of symptoms should be evaluated for B henselae infection.
Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark 07103, USA. email@example.com
The relationship between chronic infection, antispirochetal immunity, and inflammation is unknown in Lyme neuroborreliosis. In the nonhuman primate model of Lyme neuroborreliosis, we measured spirochetal density in the nervous system and other tissues by polymerase chain reaction and correlated these values to anti-Borrelia burgdorferi antibody in the serum and cerebrospinal fluid, and to inflammation in tissues. Despite substantial presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, in the central nervous system, only minor inflammation was present there, though skeletal and cardiac muscle, which contained similar levels of spirochete, were highly inflamed. Anti-Borrelia burgdoferi antibody was present in the cerebrospinal fluid but was not selectively concentrated. All infected animals developed anti-Borrelia burgdorferi antibody in the serum, but increased amplitude of antibody was not predictive of higher levels of infection. These data demonstrate that Lyme neuroborreliosis is a persistent infection, that spirochetal presence is a necessary but not sufficient condition for inflammation, and that antibody measured in serum may not predict the severity of infection.
PURPOSE: Neuroborreliosis may cause various neuro-ophthalmological complications. We describe a case with a bilateral optic neuropathy. CASE REPORT: A 58-year-old female developed facial paresis six weeks after an insect bite. One week later she developed bilateral optic disc swelling with haemorrhages and nerve fibre bundle defects in the lower visual field of the left eye. In CSF and serum, raised IgM and IgG titres to Borrelia burgdorferi were found. Systemic antibiotic treatment led to improvement of the vision and facial paresis, but not all visual field defects resolved, probably due to ischemic lesions of the optic disc. DISCUSSION/CONCLUSIONS: In optic nerve lesions due to neuroborreliosis it is difficult to distinguish between inflammatory and ischemic lesions. This patient demonstrated features of an ischemic optic nerve lesion.
Outpatients Neurological Department, Institute of Agricultural Medicine, Jaczewskiego 2, P.O. Box 185, 20-950 Lublin, Poland. firstname.lastname@example.org
This report presents a case of dysarthria due to hypoglossal nerve mono-neuropathy as the only consequence of neuroborreliosis. The 65-year-old man with a seven-months history of articulation disturbances was examined. The speech of the patient was slow and laboured. A slight weakness of the muscles of the tongue (left-side) was observed. The patient suffered from meningitis due to Borrelia burgdorferi infection in 1999 and initially underwent a successful antibiotic treatment. Detailed radiological investigation and psychological tests were performed and co-existing neurological diseases were excluded. To describe profile of speech abnormalities the dysarthria scale was designed based on S. J. Robertson Dysarthria Profile. There were a few disturbances found in self-assessment of speech, intelligibility, articulation, and prosody but especially in the morphology of the articulation muscles, diadochokinesis, the reflexes (in the mouth, larynx and pharynx). Needle EMG examination confirmed the diagnosis of mono-neuropathy of left hypoglossal nerve. The study confirms the fact that neuroborreliosis may evoke chronic consequences.
Outpatients Neurological Department, Institute of Agricultural Medicine, Jaczewskiego 2, P.O. Box 185, 20-950 Lublin, Poland. email@example.com
The purpose of this study was to delineate distant neurological and neuropsychological effects of severe neuroborreliosis. A group of 33 patients (12 men and 21 women) were selected for the study. Every patient had suffered from severe meningitis, meningoencephalitis or meningopolyradiculoneuritis due to neuroborreliosis in the chronic form of the illness. Standardised medical interview, physical examination and a series of neuropsychological tests (WAIS-R, BDI, BENTON-BENDER, DUM) were performed. In the clinical history, 36.4% of the patients complained of headache, 27.3% of subjective memory distortions; 33.3% of the patients suffered from sleeplessness. The neurological examination showed that 36.4% of the patients experienced such cerebellum integrity disturbances as abnormalities in gait and coordination or even mild ataxia. 21.2% of the patients experienced dysfunction in the proprioceptive pathways, 9% asymmetry in deep tendon reflexes (DTR's), 27.3% disturbances in the sensory responses. The examination showed, however, no muscular strength abnormalities. Half of the patients had slight depression. Psychological tests indicated that 21.2% of the patients had problems in thinking process and experienced memory impairment. 36.4% of the patients had significant organic damage in the central nervous system. The results of this study suggest the existence of long-lasting consequences of acute neuroborreliosis, which can significantly influence the quality of life of patients.
Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany.
Chronic intrathecal immunoglobulin (Ig) production is a hallmark of multiple sclerosis characterized by the presence of oligoclonal IgGs and, in addition, polyspecific recognition of different pathogens such as measles, rubella and herpes zoster virus. While the antigen specificity of the oligoclonal IgGs in multiple sclerosis is largely unknown, the oligoclonal IgGs arising during CNS infectious diseases are reactive against the specific pathogen. Recently, a link between Chlamydia pneumoniae and multiple sclerosis has been claimed. To test the possible role of C. pneumoniae in multiple sclerosis, we analysed (i) whether there is intrathecal IgG production against C. pneumoniae in multiple sclerosis and (ii) if the oligoclonal IgGs in the CSF of multiple sclerosis patients recognize C. pneumoniae. By studying paired serum-CSF samples from 120 subjects (definite multiple sclerosis, 46; probable multiple sclerosis, 12; other inflammatory neurological diseases, 35; other neurological diseases, 27) by enzyme-linked immunosorbent assay, we found that 24% of all patients with definite multiple sclerosis, but only 5% of patients with other inflammatory or non-inflammatory diseases, produced IgGs specific for C. pneumoniae intrathecally (definite multiple sclerosis versus other inflammatory neurological diseases: P = 0.027). The presence of intrathecal IgGs to C. pneumoniae was independent of the duration of disease and relatively stable over time. The major CSF oligoclonal IgG bands from multiple sclerosis patients with an intrathecal Ig production to C. pneumoniae did not react towards purified elementary bodies and reticulate bodies of C. pneumoniae on affinity-mediated immunoblot following isoelectric focusing (IEF-western blots). In contrast, the IgGs in the CSF of control patients with neuroborreliosis strongly reacted with their specific pathogen, Borrelia burgdorferi, by IEF-western blot analysis. Concomitant analysis of the CSF of 23 patients with a nested polymerase chain reaction for C. pneumoniae was negative in all cases. Together, our findings strongly suggest that the immune response to C. pneumoniae is part of a polyspecific intrathecal Ig production, as is commonly observed with other pathogens. This argues against a specific role for C. pneumoniae in multiple sclerosis.
Three girls, aged 3, 7 and 13 years, developed acute peripheral facial palsy. The first patient was initially diagnosed as having Bell's palsy. The third patient had negative serology at first assessment, on the basis of which the diagnosis of Lyme disease was temporarily rejected. Ultimately, all three appeared to have neuroborreliosis. They were treated with intravenous ceftriaxone and recovered well. Facial palsy in childhood is frequently caused by Lyme borreliosis and infection with Borrelia burgdorferi should therefore be investigated, even if there are no signs of a tick bite or erythema migrans. Diagnosis is made by serology, followed by immunoblotting to confirm a positive result. In case of strong suspicion based on the patient's history or physical examination or a positive serology, lumbar puncture should be carried out. Antibiotic treatment facilitates recovery and prevents complications.
Department of Infectious Diseases, Karolinska Institutet, Huddinge, Sweden.
The clinical outcome for 69 patients treated with oral doxycycline for Lyme neuroborreliosis was studied retrospectively. The clinical follow-up time was 14 d to 2 y (median 7 months). All patients improved during and after treatment. A complete recovery was seen in 56 patients by 14 d to 9 months (median 6 weeks) after therapy, while 13 patients (19%) still had persistent sequelae 1 y after antibiotic treatment. Six patients were retreated because of new or persistent symptoms, but in no patient was a treatment failure proven. A questionnaire was sent to each patient, asking for time to recovery, sequelae and relapse of symptoms. No patient had experienced relapse of symptoms associated with Lyme neuroborreliosis when answering the questionnaire 2-9 y after treatment. Oral doxycycline seems to be an effective, convenient and inexpensive alternative for the treatment of Lyme neuroborreliosis.