ABSTRACT
Telemedicine is widely used in the field of stroke treatment. Following the pioneering and implementation phase, the quality of the whole stroke treatment process needs to be ensured in telemedically connected hospitals. This is particular important for telestroke hospitals without neurological expertise and can be achieved by integrating telemedicine into the stroke unit concept and stroke networks. The Stroke Network with Telemedicine in Northern Bavaria (STENO) provides an example of how quality management can be practically implemented. The implementation of STENO has established a network-wide quality management system which has been certified according to DIN EN ISO 9001:2008 since 2011.
Subject(s)
Community Networks/organization & administration , Emergency Medicine/organization & administration , Models, Organizational , Stroke Rehabilitation/methods , Telerehabilitation/organization & administration , Germany , Humans , Quality Assurance, Health Care/organization & administrationABSTRACT
OBJECTIVES: Transcranial magnetic stimulation is useful for the assessment of cortico-spinal tract integrity in multiple sclerosis (MS). An advanced approach is the triple stimulation technique (TST), utilizing a combination of central and peripheral stimuli, reducing individual response variability. Although TST measures have been implemented in longitudinal studies, basic methodological data on temporal properties of abnormal TST values in MS are sparse. METHODS: Normative TST data were obtained from 48 healthy participants. Longitudinal measures were derived from 17 MS-patients (relapsing-remitting: N=10; clinically isolated syndrome: N=7) prior to, three and twelve months following therapy initiation. Intraclass correlations were used to examine test-retest reliability. Complementary, patient ambulation and cognition were assessed. RESULTS: Patient TST parameters were abnormal, involving excellent test-retest reliability and stable mean values. Cognitive and motor performance improved. CONCLUSIONS: Results are the first to show that abnormal TST values in MS, reflecting diagnostic utility, are highly reliable in a long-term follow-up. Methodological properties are adequate for a longitudinal implementation of TST. Parameters were insensitive to alterations in cognitive/motor functioning. Sensitivity may be verified in subgroups with different treatment regimes. SIGNIFICANCE: Results provide new normative data, support diagnostic utility of TST measures in MS, and confirm their long-term robustness.
Subject(s)
Multiple Sclerosis/diagnosis , Multiple Sclerosis/physiopathology , Transcranial Magnetic Stimulation/methods , Transcranial Magnetic Stimulation/standards , Adult , Evoked Potentials, Motor/physiology , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Motor Cortex/physiopathology , Reproducibility of Results , Statistics as Topic/methods , Statistics as Topic/standardsABSTRACT
We investigated the expression of intercellular adhesion molecules ICAM-1 and ICAM-3 on peripheral blood mononuclear cells in a subgroup of 34 patients with relapsing-remitting multiple sclerosis who were treated orally with the chemokine receptor 1 antagonist BX 471 in a 16-week, randomised, double-blind, placebo-controlled phase II study. ICAM-1 and ICAM-3 expression was measured by flow cytometry at different time points during and after therapy and compared using multivariate analysis of variance and non-parametric Mann Whitney test. ICAM-3 expression on CD14( +) peripheral blood mononuclear cells was increased in the verum group under therapy, but did not differ significantly between the verum and placebo groups. Most likely, this trend represents a small epiphenomenon only mediated by receptor cross-talk and feedback mechanisms.
Subject(s)
Antigens, CD/blood , Cell Adhesion Molecules/blood , Immunologic Factors/administration & dosage , Leukocytes, Mononuclear/drug effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Phenylurea Compounds/administration & dosage , Piperidines/administration & dosage , Receptors, CCR1/antagonists & inhibitors , Administration, Oral , Double-Blind Method , Flow Cytometry , Germany , Humans , Intercellular Adhesion Molecule-1/blood , Italy , Leukocytes, Mononuclear/immunology , Lipopolysaccharide Receptors/blood , Multiple Sclerosis, Relapsing-Remitting/immunology , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Blood-brain barrier (BBB) breakdown is an early event in the pathogenesis of multiple sclerosis (MS). In a previous study we have found a direct stabilization of barrier characteristics after treatment of bovine brain capillary endothelial cells (BCECs) with human recombinant interferon-beta-1a (IFN-beta-1a) in an in vitro BBB model. In the present study we examined the effect of human recombinant IFN-beta-1a on the barrier properties of BCECs derived from four different species including humans to predict treatment efficacy of IFN-beta-1a in MS patients. METHODS: We used primary bovine and porcine BCECs, as well as human and murine BCEC cell lines. We investigated the influence of human recombinant IFN-beta-1a on the paracellular permeability for 3H-inulin and 14C-sucrose across monolayers of bovine, human, and murine BCECs. In addition, the transendothelial electrical resistance (TEER) was determined in in vitro systems applying porcine and murine BCECS. RESULTS: We found a stabilizing effect on the barrier characteristics of BCECs after pretreatment with IFN-beta-1a in all applied in vitro models: addition of IFN-beta-1a resulted in a significant decrease of the paracellular permeability across monolayers of human, bovine, and murine BCECs. Furthermore, the TEER was significantly increased after pretreatment of porcine and murine BCECs with IFN-beta-1a. CONCLUSION: Our data suggest that BBB stabilization by IFN-beta-1a may contribute to its beneficial effects in the treatment of MS. A human in vitro BBB model might be useful as bioassay for testing the treatment efficacy of drugs in MS.
Subject(s)
Adjuvants, Immunologic/pharmacology , Blood-Brain Barrier/drug effects , Endothelial Cells/drug effects , Interferon-beta/pharmacology , Animals , Astrocytes/cytology , Blood-Brain Barrier/immunology , Capillary Permeability/drug effects , Capillary Permeability/immunology , Cattle , Cells, Cultured , Coculture Techniques , Dose-Response Relationship, Drug , Drug Interactions , Endothelial Cells/cytology , Histamine/pharmacology , Histamine Agonists/pharmacology , Interferon beta-1a , Mice , Rats , Species Specificity , SwineABSTRACT
OBJECTIVES: In a pilot study we found a correlation of the clinical outcome with adhesion molecule (AM) concentrations in ventricular cerebrospinal fluid (CSF) but not in serum in patients with intracerebral haemorrhage. We now determined the time course of AM concentration in CSF and serum after basal ganglia haemorrhage (BGH) in order to further uncover pathogenetic mechanisms. MATERIALS AND METHODS: We included 11 patients with acute BGH and ventricular tamponade in which an extraventricular drainage had been applied to treat ventricular ballonade. Paired CSF and serum samples were obtained within 8 h after onset of BGH, as well as on the consecutive days 2, 4, 6, and 8, respectively. The concentrations of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) in CSF and serum were measured by enzyme-linked immunosorbent assay. Moreover, we determined blood volume and perifocal oedema by a semi-automated planimetry technique from initial cranial computed tomography scans. RESULTS: sICAM-1 and sVCAM-1 levels in CSF were highest within the first hours after onset of BGH, then decreased significantly (P < 0.005 and <0.05, respectively) on day 2 and slightly increased thereafter. Furthermore, BGH volume was significantly correlated with the concentrations of sICAM-1 (r = 0.63, P < 0.05) and sVCAM-1 (r = 0.66, P < 0.05) in ventricular CSF but not in serum. CONCLUSIONS: Our results might indicate that the local inflammatory reaction is pronounced early after onset of BGH and appears to be restricted to the central nervous system. Moreover, AM concentrations measured early after BGH onset correlated stronger with radiological and clinical data than follow-up measurements.
Subject(s)
Basal Ganglia Hemorrhage/metabolism , Brain Edema/etiology , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Aged , Aged, 80 and over , Basal Ganglia Hemorrhage/complications , Basal Ganglia Hemorrhage/physiopathology , Blood Volume/physiology , Cerebral Ventricles/metabolism , Cerebral Ventricles/physiopathology , Cerebrovascular Circulation/physiology , Female , Humans , Male , Middle Aged , Time FactorsABSTRACT
OBJECTIVES: Multiple sclerosis (MS) is believed to be an autoimmune disease of the human central nervous system mediated by autoreactive T cells. Interferon-beta1b (IFN-beta1b) has been shown to be effective in reducing disease activity defined by clinical and magnetic resonance imaging (MRI) criteria in relapsing-remitting MS (RRMS). Yet, the exact mechanisms by which these benefits are achieved remain unknown. CD45RA is a marker for naive T lymphocytes and intercellular adhesion molecule-3 (ICAM-3) is expressed on resting lymphocytes. MATERIAL AND METHODS: Forty-eight patients with RRMS, 24 of them treated with recombinant IFN-beta1b and 24 untreated, were enrolled in this prospective study over 18 months. We investigated the percentage of CD45RA+ ICAM-3+ cells within the total lymphocyte subset in the peripheral blood serially every 3 months and in CSF once at baseline. Detailed clinical examination including Expanded Disability Status Scale (EDSS) score was performed every 3 months and cranial MRI scans were assessed every 6 months. RESULTS: We found a temporary increase in the CD45RA+ ICAM-3+ lymphocyte ratio in peripheral blood of both untreated and IFN-beta1b-treated RRMS patients. Moreover, we determined a significant negative correlation (r = -0.5874; P < 0.01) between age as well as the EDSS score (r = -0.3629; P < 0.05) and the percentages of CD45RA+ ICAM-3+ lymphocytes in peripheral blood but a positive correlation between EDSS score and the CD45RA+ ICAM-3+ ratio (r = 0.3913; P < 0.05) in the CSF at baseline. CONCLUSION: CD45RA+ ICAM-3+ lymphocyte ratio in peripheral blood might indicate immunosenescence in MS. However, from our data it cannot be finally concluded whether it is also influenced by IFN-beta1b treatment.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Antigens, CD/immunology , Interferon-beta/immunology , Interferon-beta/therapeutic use , Leukocyte Common Antigens/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Adjuvants, Immunologic/pharmacology , Adult , Biomarkers/analysis , Cell Adhesion Molecules , Female , Humans , Injections, Subcutaneous , Interferon beta-1b , Interferon-beta/pharmacology , Lymphocyte Subsets , Magnetic Resonance Imaging , Male , Middle Aged , Recombinant Proteins , RecurrenceSubject(s)
Intercellular Adhesion Molecule-1/cerebrospinal fluid , Subarachnoid Hemorrhage/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Acute Disease , Enzyme-Linked Immunosorbent Assay , Glasgow Coma Scale , Prospective Studies , Subarachnoid Hemorrhage/mortality , Survival RateABSTRACT
OBJECTIVE: Chronic and acute dysregulation of the cytokine network has been described in multiple sclerosis (MS). Inflammatory lesions in the central nervous system of MS patients can be assessed by brain magnetic resonance imaging (MRI). This study has been performed to investigate whether changes of cytokines correlate with morphological changes as determined by MRI. MATERIALS AND METHODS: We included 46 patients with relapsing-remitting MS in the study. The serum concentrations of tumor necrosis factor-beta (TNF-beta), TNF receptor-1 (TNFR-1; 55 kDa) and TNFR-2 (75 kDa), interleukin-4 (IL-4), interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) were measured by enzyme linked immunosorbent assay in all patients. Each parameter was correlated with clinical findings and brain MRI parameters. We measured both the number (lesion load) and cumulated area (disease burden) of all lesions on brain MRI. In addition, the number and cumulated area of those lesions showing signs of activity [Gadolinium (Gd)-enhancement, perifocal edema] were determined. RESULTS: A non-significant trend (P < 0.05) was found only for the correlation of serum IFN-gamma levels and the number of active MRI lesions showing both Gd-enhancement and perifocal edema in the subgroup of patients (n=21) with active lesions. When corrected for multiple comparisons, this correlation was not significant anymore, as it was above the corrected P-value of 0.001. We could not observe any further correlation of cytokine levels and MRI parameters. However, TNF-beta serum levels were significantly (P < 0.05) elevated in the patient subgroups with higher number of lesions and disease burden, respectively. CONCLUSION: Our data show that the determination of serum levels of the investigated cytokines and cytokine receptors is not useful as a tool to determine subclinical disease activity and severity as assessed by brain MRI.
Subject(s)
Brain/pathology , Cytokines/blood , Magnetic Resonance Imaging , Multiple Sclerosis/diagnosis , Multiple Sclerosis/immunology , Adult , Antigens, CD/blood , Biomarkers/blood , Female , Humans , Interferon-gamma/blood , Interleukin-10/blood , Interleukin-4/blood , Lymphotoxin-alpha/blood , Male , Middle Aged , Receptors, Tumor Necrosis Factor/blood , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type IIABSTRACT
BACKGROUND: The expression of soluble cell adhesion molecules (AM) in cerebrospinal fluid (CSF) and blood and their significance as measures of disease activity has been extensively studied in patients with multiple sclerosis (MS). In previous studies, we found that cell surface bound AM on mononuclear cells (MNC) in CSF and blood might be useful markers of clinical disease activity in MS patients. OBJECTIVE: To analyze the correlation of cell surface bound and soluble AM in CSF and blood with magnetic resonance imaging (MRI) markers of subclinical disease severity and activity in patients with MS. METHODS: Expression levels of cell surface bound AM on peripheral blood and CSF MNC were determined by flow cytometry analysis in 77 (CSF: 33) MS patients. Concentration levels of the soluble forms of AM were measured by enzyme-linked immunosorbent assay (ELISA). In corresponding cerebral gadolinium (Gd)-enhanced MRI scans, we determined both measures of subclinical disease severity and subclinical disease activity. RESULTS: The expression levels of cell surface bound AM in peripheral blood correlated inversely with parameters for subclinical disease severity and activity on cerebral MRI scans as well as with the disease duration. Furthermore, we found significant correlations between serum levels of soluble AM and patient age but not with disease duration. CONCLUSIONS: Our results suggest that subclinical disease progression may be associated with a decrease of the expression of cell surface bound AM on peripheral blood MNC. This might be a result of activated MNC migration into the CNS.
Subject(s)
Antigens, CD , Antigens, Differentiation , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Multiple Sclerosis/pathology , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Antigens, Surface/blood , Antigens, Surface/cerebrospinal fluid , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/cerebrospinal fluid , Female , Flow Cytometry , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/cerebrospinal fluid , Predictive Value of Tests , Severity of Illness Index , SolubilityABSTRACT
The objective of this study was to investigate the effect of interferon (IFN) beta-1b on the serum levels of soluble tumor necrosis factor receptor 1 (sTNF-R1) and sTNF-R2 in patients with multiple sclerosis (MS) in correlation with clinical and magnetic resonance image (MRI) activity. Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN beta-1b every other day (treatment group) and from 21 patients without any immunomodulatory therapy (control group) over a 15-month observation period. The cytokine receptor levels were assessed by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease. In the treatment group, the MRI responders had significantly larger mean values for the area under the concentration-time curve of sTNF-R1 (p = 0.04) and sTNF-R2 (p = 0.01) when compared to the MRI nonresponders during the 15-month observation period. With regard to an increase in sTNF-R1 and -2 of more than 20% during the first 3 months of treatment, we observed a sensitivity of 33 and 58%, respectively, a specificity of 90 and 60%, respectively, and a positive predictive value of 80 and 64%, respectively, for MRI response during the 15-month observation period. A decrease in sTNF-R1 and -2 of more than 20% during the first 3 months of treatment had a sensitivity of 40 and 20%, respectively, a specificity of 100 and 100%, respectively, and a positive predictive value of 100 and 100%, respectively, for further MRI nonresponse (during the 15-month observation period). The present data suggest that assessment of sTNF-Rs may contribute to the identification of subgroups of patients who are likely to respond better than others to treatment with IFN beta-1b. This could help to establish a cost-effective prescription pattern for this expensive treatment, which is of importance for the future management of patients with MS.
Subject(s)
Antigens, CD/drug effects , Interferon-beta/therapeutic use , Multiple Sclerosis/drug therapy , Receptors, Tumor Necrosis Factor/drug effects , Adult , Antigens, CD/blood , Brain/drug effects , Brain/pathology , Disability Evaluation , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Interferon beta-1a , Interferon beta-1b , Interferon-beta/adverse effects , Magnetic Resonance Imaging , Male , Multiple Sclerosis/blood , Multiple Sclerosis/diagnosis , Prognosis , Prospective Studies , Receptors, Tumor Necrosis Factor/blood , Receptors, Tumor Necrosis Factor, Type IIABSTRACT
OBJECTIVES: To investigate the influence of interferon (IFN) beta-1b on the serum levels of sTNF-R1, sTNF-R2 and TNF-beta in patients with multiple sclerosis (MS) in correlation with clinical and MRI activity. MATERIALS AND METHODS: Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN beta-lb every other day (treatment group) and from 21 patients without any immunomodulatory therapy (control group) over a 15-month observation period. The cytokine levels were measured by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease of every patient. RESULTS: In the treatment group we found an obvious increase of sTNFR1 and sTNF-R2 (P < 0.001) and relatively stable serum levels of TNFbeta with no statistical significance (P = 0.56). In the control group, sTNF-R1 showed a significant decrease (P < 0.001) during the same observation period of 15 months. During the 15-month observation period, the MRI-responders group had significant larger mean AUC (area under the concentration-time curve) values of sTNF-R1 (P = 0.04) and sTNF-R2 (P = 0.01) when compared to the group of MRInonresponders. CONCLUSION: The present data suggest that IFN beta-1b induces the expression and shedding of TNF-R1 and TNF-R2. The magnitude of an increase of sTNF-Rs may be a marker for the effectiveness of treatment with IFN beta-1b.
Subject(s)
Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Antigens, CD/drug effects , Brain/pathology , Interferon-beta/pharmacology , Magnetic Resonance Imaging , Multiple Sclerosis/diagnosis , Receptors, Tumor Necrosis Factor/drug effects , Adult , Antigens, CD/blood , Enzyme-Linked Immunosorbent Assay , Follow-Up Studies , Humans , Interferon-beta/therapeutic use , Lymphotoxin-alpha/blood , Male , Multiple Sclerosis/drug therapy , Prospective Studies , Receptors, Tumor Necrosis Factor/blood , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II , Sensitivity and Specificity , Treatment OutcomeABSTRACT
OBJECTIVES: Autoreactive T cells targeted against antigens of the myelin sheath are suggested to play an important role in the pathogenesis of multiple sclerosis (MS). Naive (CD45RA+) T cells and intercellular adhesion molecule-3 (ICAM-3) are markers for un-activated lymphocytes. This study was performed to investigate, whether the expression levels of these antigens both on cerebrospinal fluid (CSF) and peripheral blood lymphocytes can be used as activity markers in MS. MATERIALS AND METHODS: Corresponding blood and CSF samples were obtained from 31 patients with relapsing-remitting MS. Of the 31 MS patients 23 were suffering from acute relapses at the time of examination and all of them were treated with high-dose methylprednisolone (MP). Blood was collected again on the 10th day of therapy and after 3 months. The control group consisted of 12 healthy persons. Two-color flow cytometry was performed to evaluate the percentage of both CD45RA+ and ICAM-3+ cells within the lymphocyte population. RESULTS: The percentage of CD45RA+ ICAM-3+ cells in the CSF of MS patients with relapses was significantly increased compared to patients in remission (P<0.05). In blood, a significantly lower percentage of CD45RA+ ICAM-3+ lymphocytes was found in both patient groups compared to healthy controls (Relapse: P<0.05, Remission: P<0.10). Additionally, we found a significant increase (P < 0.01) in the percentage of CD45RA+ ICAM-3+ lymphocytes in blood of MS patients suffering from acute relapse on the 10th day of high-dose MP treatment. CONCLUSION: Our data suggest that the percentage of CD45RA+ ICAM-3+ lymphocytes in CSF can be used as marker of disease activity in MS patients.
Subject(s)
Antigens, CD , Antigens, Differentiation , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/cerebrospinal fluid , Leukocyte Common Antigens/blood , Leukocyte Common Antigens/cerebrospinal fluid , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , Acute Disease , Adult , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Case-Control Studies , Female , Humans , Lymphocytes/immunology , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/immunology , Multiple Sclerosis, Relapsing-Remitting/physiopathology , RecurrenceABSTRACT
OBJECTIVE: The expression of intercellular adhesion molecule-3 (ICAM-3), a member of the Ig supergene family, is restricted to immune competent cells. Expression of soluble and cell surface ICAM-3 (s- and c-ICAM-3) is preferentially seen in the state of low activation of the immune system. We studied the relevance of the expression levels of s- and c-ICAM-3 in cerebrospinal fluid (CSF) and blood as markers for disease activity as well as the influence of high-dose methylprednisolone (MP) treatment upon the expression of s- and c-ICAM-3 in blood of patients with multiple sclerosis (MS). MATERIALS AND METHODS: A total of 33 patients (relapses n = 25, remission n = 8) with relapsing-remitting MS were included into the study. CSF and blood were acquired from all of them. Of the patients 24 were treated with high-dose MP. In those, blood was additionally collected at the 10th day of the therapy and after 3 months. Expression of c-ICAM-3 was determined by two colour FACS analysis, whereas the concentration levels of s-ICAM-3 were measured by ELISA. RESULTS: In CSF we detected a significant decrease of the expression levels of c-ICAM-3 on CD3+ T cells in 25 patients suffering from an acute relapse in contrast to 8 patients with remission (P= 0.04). In comparison to the levels before treatment and after 3 months, at the 10th day of MP treatment we obtained highly significant changes of the expression values of c-ICAM-3 both on CD3+ T cells (P = 0.0004; P= 0.005) and CD14+ monocytes/macrophages (P =0.0006; P=0.008) on the 10th day of high-dose MP treatment from 24 MS patients. CONCLUSION: The increase of ICAM-3 levels might indicate the anti-inflammatory effect of the MP treatment. It could be interesting to search for similar effects investigating the new immune modulatoring therapy forms of MS.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antigens, CD , Antigens, Differentiation , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/cerebrospinal fluid , Methylprednisolone/pharmacology , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid , Acute Disease , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Biomarkers , CD3 Complex , Cell Adhesion Molecules/chemistry , Cell Adhesion Molecules/drug effects , Disease Progression , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Lipopolysaccharide Receptors , Lymphocytes/drug effects , Methylprednisolone/therapeutic use , Middle Aged , Monocytes/drug effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/immunologyABSTRACT
OBJECTIVE: The intercellular adhesion molecule-1 (ICAM-1) is a member of the Ig supergene family. ICAM-1 is expressed on various cells like peripheral blood lymphocytes, endothelial cells or thymic cells and the cell surface form is supposed to be shed into a soluble form. The expression of ICAM-1 is induced by cytokines like Interleukin-1, TNF alpha or interferon gamma. The aim of the study was to investigate whether changes of cell surface and soluble ICAM-1 in the cerebrospinal fluid (CSF) and blood are indicative for disease activity in patients with multiple sclerosis (MS). MATERIAL AND METHODS: In all patients with relapsing-remitting MS (relapse: n=31, remission: n=11) and controls (n=13) the expression of cell surface ICAM-1 (c-ICAM-1) was determined by two colour flow cytometry. Soluble ICAM-1 (s-ICAM-1) was measured by ELISA. Follow-up examinations were done 3 months later. RESULTS: In 31 patients with a current relapse we found significantly decreased expression levels of c-ICAM-1 on leukocytes in CSF (P<0.001) and blood (P<0.10), when compared to those 11 individuals experiencing remission. In contrast we observed significantly (P<0.05) increased levels of s-ICAM-1 in CSF of patients with relapses. Comparing patients who had been in remission for more than 4 weeks (n=11) with remission lasting longer than 3 months (n=28) we detected stable c-ICAM-1 expression on CD3+ T cells in blood. CONCLUSION: Our results demonstrate for the first time that c-ICAM-1 on CD3+ T-cells in CSF and blood is an activity marker in MS.
Subject(s)
Intercellular Adhesion Molecule-1/metabolism , Multiple Sclerosis/immunology , Adolescent , Adult , Biomarkers/analysis , Female , Humans , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Male , Middle Aged , Multiple Sclerosis/classification , Recurrence , Time FactorsABSTRACT
To ascertain the varieties of neuroborreliosis, 330 patients were identified at the Departments of Neurology in Würzburg and Giessen from 1979 to 1994. Patients who fullfilled at least one of three strict case definitions based on clinical and laboratory criteria were included in the study. Ninety-one per cent of the patients had second-stage neuroborreliosis (duration of symptoms < or = 6 months). The most common syndrome was a painful spinal meningoradiculitis, alone (37%) or in combination with a cranial radiculitis (29%). Meningoradiculitis cranialis (9%), isolated meningitis (4%) and erythema chronica migrans-associated mono/polyneuritis (3%) were further stage II features. Central nervous system involvement occurred either as an acute meningomyelitis or meningomyeloradiculitis (5%) and meningoencephalitis or meningenocephaloradiculitis (4%). Less than 9% of the patients ran a chronic course (stage III) with a disease duration between 6 months and 9 years, either as acrodermatitis chronica atrophicans associated mono- or polyneuritis (2%) or a chronic progressive encephalomyelitis (6%). Cerebrovascular neuroborreliosis (1%) occurred in both stages; however, the primary nature of the course was a chronic one. Involvement of other organs except the skin was rare (joints 3%, heart 1%) but elevated hepatic enzymes were frequent. Our study demonstrates that neuroborreliosis has to be considered in the differential diagnosis of a wide variety of neurological conditions. Cerebrospinal fluid analysis and the search for specific intrathecal antibody production are important diagnostic procedures.
Subject(s)
Borrelia Infections/pathology , Borrelia burgdorferi Group , Nervous System Diseases/microbiology , Adolescent , Adult , Aged , Aged, 80 and over , Borrelia Infections/cerebrospinal fluid , Cerebrovascular Disorders/microbiology , Encephalomyelitis/microbiology , Female , Humans , Male , Meningitis, Bacterial/microbiology , Middle Aged , Nervous System Diseases/cerebrospinal fluid , Neuritis/microbiology , Polyradiculopathy/microbiology , Prospective Studies , Retrospective Studies , SyndromeABSTRACT
Two B. afzelii strains EB1 and FEM1, classified in normal human sera (NHS) as serum-resistant, and an intermediate serum-sensitive B. burgdorferi s.s. strain 297, were tested in regard of their serum sensitivity in immune sera (IS) of patients at all stages of Lyme borreliosis by a growth inhibition assay (GIA). Fifty-four per cent (13/24) of the tested IS were GIA positive, while the sera of patients in stage III disease inhibited the growth more frequently than did the patients with sera of stage II or stage I disease. Growth inhibition was predominantly directed against strain FEM1 (12/24), less against strain EB1 (4/24) and strain 297 (2/24). A growth inhibiting effect on two strains was only detectable for two IS and merely one stage III serum inhibited all three strains. Positive results in the GIA required fresh serum and resulted in the killing of the borreliae. The detection of the deposited complement components C3 and C9 on the surfaces of the inhibited strains by means of immunofluorescence assays confirmed the role of complement. In Westernblot analyses of strain FEM1, it was striking that GIA-positive IS reacted 3- to 5-fold more often with proteins of molecular masses of 48.9-, 38.6-, 27.5-, 25-, 23.1- (OspC), 21.7-, and 16-kDa, than did GIA-negative IS. Furthermore, two proteins of approximately 20- and 31.2-kDa reacted exclusively with GIA-positive IS. Antibodies reacting with these proteins could play a role in the growth inhibition of NHS-resistant borrelial strains, OspC.
Subject(s)
Blood Bactericidal Activity/physiology , Borrelia burgdorferi Group/growth & development , Borrelia burgdorferi Group/physiology , Immune Sera/pharmacology , Lyme Disease/microbiology , Antigens, Bacterial/metabolism , Borrelia burgdorferi Group/immunology , Complement C3/metabolism , Complement C9/metabolism , Humans , Lyme Disease/blood , Lyme Disease/immunologyABSTRACT
To investigate whether circulating immune complexes can be used as a disease marker for assessment of the activity of Lyme disease and for monitoring patients response to treatment, we tested 104 sera from patients with different stages of Lyme disease using the C1q enzyme-linked immunosorbent assay (ELISA) and a modified Raji cell test. Among 62 sera of patients with clinically active disease 27 sera (43.5%) reacted positively in the C1q-ELISA and 21 sera (33.9%) positively in the Raji cell test. In contrast, serum circulating immune complexes were found in less than 10% of 42 sera after antibiotic treatment. Similar results were obtained by both tests in 35 cerebrospinal fluid samples from patients with neuroborreliosis. Most importantly, dot blot analysis revealed the presence of both Borrelia burgdorferi-specific antigen(s) and host-derived components in the isolated immune complexes from serum samples of patients with active Lyme disease. These results indicate that detection of circulating immune complexes may be an useful parameter for judging the activity of Lyme disease. Moreover, preliminary characterization of spirochete-specific immune complexes implies new pathophysiological aspects of Lyme disease.
Subject(s)
Antigen-Antibody Complex/blood , Lyme Disease/immunology , Antibodies, Bacterial/blood , Antigen-Antibody Complex/isolation & purification , Antigens, Bacterial/blood , Biomarkers/blood , Borrelia burgdorferi Group/immunology , Complement System Proteins/isolation & purification , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin G/bloodABSTRACT
One hundred untreated neuroborreliosis patients were investigated by IgG/IgM immunoblot to find out if different stages and syndromes are characterized by different patterns of their Borrelia burgdorferi specific immune responses in CSF and serum. Stage III (n = 10) was characterized by a broad, highly specific intrathecal immune response (the mean number of IgM bands in CSF was 3.1 and of IgG bands 6.3). All patients recognized one or more of the following proteins (p35, p21, p18) or the 5 kd glycolipid. In contrast, the immune response in stage II (n = 90) was less restricted (28%) and heterogeneous (mean number of IgM bands 1.4 and of IgG bands 3.4). It was mainly directed against the highly crossreactive p41 antigen (91%). The different clinical features of stage II were comparable regarding the intrathecal immune response. However anti-glycolipid and anti-p35, -p21, -p18 IgG antibodies were detected in a small subset of patients, mainly corresponding to more severe courses of the disease. Our data are compatible with a direct agent-related pathomechanism in neuroborreliosis. Antibodies against certain proteins and the glycolipid of B. burgdorferi seem to have a prognostic value as to the development of more severe disease or transition to stage III.
Subject(s)
Antibodies, Bacterial/biosynthesis , Borrelia burgdorferi Group/immunology , Lyme Disease/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Immunoblotting , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Male , Middle AgedABSTRACT
Lyme Borreliosis is an infectious disorder caused directly by Borrelia burgdorferi. Secondary immunological mechanisms might play an additional pathogenetic role. The natural course of the disease in stage I and II is in most cases benign, therefore the influence of antibiotic therapy is difficult to assess. Double-blind, placebo-controlled randomized studies were performed rarely. However, by comparing untreated and treated patient groups it seems, that antibiotic therapy shortens the disease duration and prevents late complications. In stage III the course of the disease is usually chronic progressive (central nervous system, joint, skin), if no antibiotic therapy is applied. Currently performed clinical trials were up to now unable to determine the optimal antimicrobial agent, route of application, dosage and optimal duration of therapy for the different manifestations of the disease. Susceptibility testing, antimicrobial pharmacokinetic considerations (e. g. CSF penetration, half-life) and clinical experiences are therefore the basis of our recommendations. Stage I: Doxycyclin 2 x 100 mg p. o. or if contraindicated Cefuroxim 2 x 500 mg, at least 14 days. In case of systemic symptoms (e. g. fever) a intravenous therapy is indicated. Stage II and III: Ceftriaxon 1 x 2--2 x 2 g i. v. or Cefotaxim 3 x 2 g i. v., at least 14 days. Corticosteroids can be given in defined cases (pain syndrome!) additionally. Therapy failure was described regarding all used antibiotics, therefore clinical and laboratory follow up is mandatory. Residual symptoms can disappear over months and are usually not due to refractory disease.(ABSTRACT TRUNCATED AT 250 WORDS)